The Dementias: Diagnosis, Treatment, and Research, Third Edition

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The Dementias Diagnosis, Treatment, and Research Third Edition

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The Dementias Diagnosis, Treatment, and Research Third Edition

Edited by Myron F. Weiner, M.D. Professor of Psychiatry, Associate Professor of Neurology, Aradine S. Ard Chair in Brain Science, and Dorothy L. and John P. Harbin Chair in Alzheimer’s Disease Research, University of Texas Southwestern Medical Center at Dallas, Texas

Anne M. Lipton, M.D., Ph.D. Assistant Professor of Neurology and Psychiatry, University of Texas Southwestern Medical Center at Dallas, Texas

Washington, DC London, England

Note: The authors have worked to ensure that all information in this book is accurate at the time of publication and consistent with general psychiatric and medical standards, and that information concerning drug dosages, schedules, and routes of administration is accurate at the time of publication and consistent with standards set by the U.S. Food and Drug Administration and the general medical community. As medical research and practice continue to advance, however, therapeutic standards may change. Moreover, specific situations may require a specific therapeutic response not included in this book. For these reasons and because human and mechanical errors sometimes occur, we recommend that readers follow the advice of physicians directly involved in their care or the care of a member of their family. Books published by American Psychiatric Publishing, Inc., represent the views and opinions of the individual authors and do not necessarily represent the policies and opinions of APPI or the American Psychiatric Association. Diagnostic criteria included in this book are reprinted, with permission, from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Copyright 2000, American Psychiatric Association. Copyright © 2003 American Psychiatric Publishing, Inc. ALL RIGHTS RESERVED Manufactured in the United States of America on acid-free paper 07 06 05 04 03 5 4 3 2 1 Third Edition Typeset in Adobe’s Janson Text and ITC Highlander Book American Psychiatric Publishing, Inc. 1400 K Street, N.W. Washington, DC 20005 www.appi.org Library of Congress Cataloging-in-Publication Data The dementias : diagnosis, treatment, and research / edited by Myron F. Weiner, Anne M. Lipton. — 3rd ed. p. ; cm. Includes bibliographical references and index. ISBN 1-58562-043-2 (alk. paper) 1. Dementia. I. Weiner, Myron F., 1934– II. Lipton, Anne M., 1966– [DNLM: 1. Dementia—diagnosis. 2. Dementia—therapy. WM 220 D376391 2003] RC521 .D458 2003 616.8'3—dc21 2002074565

British Library Cataloguing in Publication Data A CIP record is available from the British Library.

To Jack Weiner, my father, who struggled valiantly against the ravages of Alzheimer’s disease, and in the hope that others may not have to endure the agony he suffered. M.F.W. For my mother, Anne G. Peternel. A.M.L.


Contents

Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .xi Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv Marcelle Morrison-Bogorad, Ph.D.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii Myron F. Weiner, M.D. Anne M. Lipton, M.D., Ph.D.

Chapter 1 Clinical Diagnosis of Cognitive Dysfunction and Dementing Illness . . . . 1 Myron F. Weiner, M.D.

Chapter 2 Dementing Illness as a Psychobiological Process. . . . . . . . . . . . . . . . . . 49 Myron F. Weiner, M.D.

Chapter 3 Medical Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 Myron F. Weiner, M.D. Anne M. Lipton, M.D., Ph.D. Ramón Diaz-Arrastia, M.D., Ph.D.

Chapter 4 Neuroimaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Gene E. Alexander, Ph.D. Eric M. Reiman, M.D.

Chapter 5 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Anne M. Lipton, M.D., Ph.D. Myron F. Weiner, M.D.

Chapter 6 Psychological and Behavioral Management . . . . . . . . . . . . . . . . . . . . 181 Myron F. Weiner, M.D. Linda Teri, Ph.D.

Chapter 7 Drugs for Behavioral, Psychological, and Cognitive Symptoms . . . . . . 219 Myron F. Weiner, M.D. Lon S. Schneider, M.D.

Chapter 8 Evaluation of Cognitive Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 C. Munro Cullum, Ph.D. Ronald G. Paulman, Ph.D. Elisabeth Koss, Ph.D. Sandra Bond Chapman, Ph.D. Laura Lacritz, Ph.D.

Chapter 9 Supporting Family Caregivers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 Kristin Martin-Cook, M.S. Doris Svetlik, B.S.N., R.N., M.S. Myron F. Weiner, M.D.

Chapter 10 Legal and Ethical Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341 John Z. Sadler, M.D. Barton E. Bernstein, J.D., L.M.S.W. Daniel C. Marson, J.D., Ph.D.

Chapter 11 Mobilizing Community Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . 371 Doris Svetlik, B.S.N., R.N., M.S. Jan W. Weaver, Ph.D., R.N.

Chapter 12 Nursing Care for Persons With Cognitive Impairment . . . . . . . . . . . . 381 Elaine Souder, Ph.D., R.N. Cornelia Beck, R.N., Ph.D.

Chapter 13 Structuring Environments for Persons With Cognitive Impairment . . . 405 Paul K. Chafetz, Ph.D. Kevan H. Namazi, Ph.D.

Chapter 14 Advances in the Molecular and Genetic Basis of Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 Roger N. Rosenberg, M.D.

Chapter 15 Advances in the Treatment of Alzheimer’s Disease . . . . . . . . . . . . . . . 453 Steven C. Samuels, M.D. Kenneth L. Davis, M.D.

Appendix A Dementia Questionnaire . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483 Appendix B Mental Status Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487 Appendix C Neurological Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495 Appendix D Blessed Dementia Rating Scale. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499 Appendix E Washington University Clinical Dementia Rating Scale . . . . . . . . . . . 501 Appendix F Alzheimer’s Disease Assessment Scale . . . . . . . . . . . . . . . . . . . . . . . . . 503 Appendix G Neuropsychiatric Inventory: Community Dwelling Version . . . . . . . . 513 Appendix H Agitated Behavior in Dementia Scale. . . . . . . . . . . . . . . . . . . . . . . . . 525

Appendix I Quality of Life in Alzheimer’s Disease Scale . . . . . . . . . . . . . . . . . . . . 529 Appendix J Quality of Life in Late-Stage Dementia (QUALID) Scale . . . . . . . . . . 535 Appendix K Abnormal Involuntary Movement Scale (AIMS) . . . . . . . . . . . . . . . . . 539 Appendix L Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547

Contributors

Gene E. Alexander, Ph.D. Associate Professor, Department of Psychology and Center for Alzheimer’s Disease Research, Arizona State University, Tempe, Arizona Cornelia Beck, R.N., Ph.D. Professor, Department of Geriatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas Barton E. Bernstein, J.D., L.M.S.W. Adjunct Professor of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Texas Paul K. Chafetz, Ph.D. Adjunct Associate Professor of Rehabilitation Counseling Psychology, University of Texas Southwestern Medical Center at Dallas, Texas Sandra Bond Chapman, Ph.D. Research Scientist, University of Texas at Dallas, Texas C. Munro Cullum, Ph.D. Professor of Psychiatry and Neurology, University of Texas Southwestern Medical Center at Dallas, Texas Kenneth L. Davis, M.D. Professor of Psychiatry and Pharmacology and Chairman, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York Ramón Diaz-Arrastia, M.D., Ph.D. Associate Professor of Neurology, University of Texas Southwestern Medical Center at Dallas, Texas Elisabeth Koss, Ph.D. Assistant Director, Alzheimer’s Disease Centers Program, National Institute on Aging, Bethesda, Maryland

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THE DEMENTIAS, THIRD EDITION

Laura Lacritz, Ph.D. Assistant Professor of Psychiatry and Neurology, University of Texas Southwestern Medical Center at Dallas, Texas Anne M. Lipton, M.D., Ph.D. Assistant Professor of Neurology and Psychiatry, University of Texas Southwestern Medical Center at Dallas, Texas Daniel C. Marson, J.D., Ph.D. Associate Professor of Neurology, University of Alabama at Birmingham, Alabama Kristin Martin-Cook, M.S. Family Services Coordinator, Clinic for Alzheimer’s and Related Diseases, Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Texas Marcelle Morrison-Bogorad, Ph.D. Associate Director, Neuroscience and Neuropsychology of Aging Program, National Institute on Aging, National Institutes of Health, Bethesda, Maryland Kevan H. Namazi, Ph.D. Associate Professor and Chair, Department of Gerontology and Geriatric Services, University of Texas Southwestern Medical Center at Dallas, Texas Ronald G. Paulman, Ph.D. Clinical Professor of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Texas Eric M. Reiman, M.D. Professor and Associate Head of Psychiatry, University of Arizona, Phoenix, Arizona Roger N. Rosenberg, M.D. Abe (Brunky) Morris and William Zale Distinguished Chair in Neurology; Professor of Neurology and Physiology, University of Texas Southwestern Medical Center at Dallas, Texas John Z. Sadler, M.D Professor of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Texas

Contributors

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Steven C. Samuels, M.D. Assistant Professor of Psychiatry, Mount Sinai School of Medicine, New York, New York Lon S. Schneider, M.D. Professor of Psychiatry, Neurology, and Gerontology, University of Southern California Keck School of Medicine, Los Angeles, California Elaine Souder, Ph.D., R.N. Professor, College of Nursing, University of Arkansas for Medical Sciences, Little Rock, Arkansas Doris Svetlik, B.S.N., R.N., M.S. Administrative Director, Clinic for Alzheimer’s and Related Diseases, Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Texas Linda Teri, Ph.D. Professor, Department of Psychosocial/Community Health, School of Nursing, University of Washington, Seattle, Washington Jan W. Weaver, Ph.D., R.N. Director of Health and Wellness, Hearthstone Assisted Living, Inc., Houston, Texas Myron F. Weiner, M.D. Professor of Psychiatry, Associate Professor of Neurology, Aradine S. Ard Chair in Brain Science, and Dorothy L. and John P. Harbin Chair in Alzheimer’s Disease Research, University of Texas Southwestern Medical Center at Dallas, Texas


Foreword

This is the third edition of The Dementias: Diagnosis, Treatment, and Research. Primarily aimed at clinicians and other health care professionals who work with dementia patients, this book summarizes state-of-the-art, practical approaches to the diagnosis and treatment of dementing illnesses. Current exciting advances in understanding the etiology, diagnosis, and treatment of these illnesses are reviewed, including a new chapter on advances in diagnosis using neuroimaging. Alzheimer’s disease is a major public health issue for the United States. It is by far the most common form of dementing illness, with estimates of its prevalence in the United States as high as 4 million. If treatments to delay onset are not identified, the demographic trend toward increased numbers of elderly persons in populations worldwide means that this number will continue to climb. The age category most affected by Alzheimer’s disease, those over age 85, is projected to grow from 4.4 million in 2001 to 19.3 million in 2050. The yearly cost of Alzheimer’s disease, now estimated at around $100 billion, is only part of the societal cost. The suffering and stress to individuals and families as their family member gradually becomes more and more impaired is incalculable. Since the first edition of this book was published in 1991, advances in the understanding, diagnosis, and treatment of dementing illnesses like Alzheimer’s disease have been accelerating. This edition summarizes the latest strategies for differential diagnosis of the dementing illnesses and evaluation of cognitive functions. One important new focus both in the clinic and in the laboratory is on understanding early, preclinical stages of dementing illness and how they differ from normal aging. With imaging, neuropsychological, and clinical tools, scientists are determining the best ways to identify persons who are at the highest risk for developing Alzheimer’s disease. This helps us to better understand the very beginnings of the disease process and identifies persons for whom treatment will be most effective as new drugs and therapies become available. Genetic, epidemiological, and molecular clues to the disease are also rapidly being discovered. Perhaps most exciting, a number of treatments have been shown to decrease the number of brain plaques in transgenic mouse models of Alzheimer’s disease, including vaccination against plaque amyloid itself. Several of these potential interventions are already at various stages of testing in xv

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clinical trials to delay progression in persons with Alzheimer’s disease or to delay onset in cognitively normal persons or individuals with only mild cognitive impairment. Clues to the origin of other dementing illnesses have also been uncovered, and both commonalities and differences are being found. These aid in differential diagnosis and also with identifying underlying disease mechanisms. One common theme emerging from the study of various neurodegenerative diseases is the accumulation of aggregated proteins in particular brain cells and brain regions; avenues for preventing or reversing this aggregation are being explored. Studies identifying causal or risk-factor genes give us powerful clues to the nature of the brain processes that first go awry in particular diseases. There is more reason than ever to believe that advances in understanding Alzheimer’s disease and other dementing illnesses will someday soon pay off in terms of delaying disease onset or preventing Alzheimer’s disease or dementia entirely. Today, however, families and society continue to be faced with the challenge of caring for persons with dementia, and it is vital that (as is done in this volume) materials for clinicians include review of the latest information on disease management and long-term care. Much of the challenge of dealing with dementia patients, for example, comes not from the cognitive loss but from behavioral symptoms such as wandering and agitation. The chapters on psychological and behavioral management and drug management are excellent summaries of practical approaches to maintaining the best possible level of function for individual patients at different stages of illness. They are full of helpful, concrete examples. So, too, is the chapter on family support and that on mobilizing community resources. Nursing care of cognitively impaired individuals is an area in which much research still needs to be done. The chapter on this subject nicely summarizes practical research on coping with a variety of problems faced by nursing staffs. Again emphasizing the human element, the chapter on legal and ethical issues addresses the rights of demented patients, including research on assessment of decisional capacity. In this as in every chapter, the reader is afforded insight, where appropriate, into the physiological, psychological, and social underpinnings of diagnosis and treatments. Marcelle Morrison-Bogorad, Ph.D.

Introduction

My husband is most often kind, considerate and understanding. I love him! But he does not understand my circumstances— He wants me to drive a strange car—little does he understand the danger involved. The synapses in my brain are not up to making quick decisions, such as a speeding car trying to cut around me—or a need to push some crucial button on the dashboard—which takes a minute or two to find. In that minute the oncoming car has hit me (a synapse is the [point] where neurons in the brain touch and nerve impulses are transmitted from one to another). I am certainly sorry that you can’t always handle the way I am. I will try to stay out of your way and be as little trouble to you as possible. Let me know if you want something! I love you!

The woman who wrote the preceding words was trying to say that she should not drive a strange car and to tell why she should not. She handed the note to a man she did not recognize as her husband when she wrote the note. She did not know that the strange car was the new family car. After all, it was strange to her. She pointed out that she reacts slowly and would have difficulty locating a “crucial button” and might thereby be a danger to herself and others. She could spell the word “synapse” and knew what it meant, but at first she misspelled the simple word “point.” She felt sorry for her husband having to put up with her. She would try not to be a bother. Then, finally recognizing him, she writes that she loves him. We can see in this woman’s words the confusion and fear that she experiences, her attempts to come to grips with her illness, her difficulty in expressing herself, and her wish to maintain her loving relationship with her husband. This is the human experience of Alzheimer’s disease, and it is at the heart of the third edition of The Dementias: Diagnosis, Treatment, and Research. This book is designed to meet the needs of clinicians dealing with persons with dementing illness, to serve as an introduction to the neurobiology of dementing illnesses, and to serve as a resource for clinical investigators. The present edition has been revised, updated, and expanded to cover xvii

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changes in the classification, management, treatment, and research in dementing illness. We have changed the book’s subtitle to indicate that we can now offer disease-modifying treatments for many dementing illnesses, including Alzheimer’s disease. Because of these advances, attempts are being made to identify those at risk for the development of these disorders and to develop prophylactic treatments. In the case of vascular dementia, aggressive treatment of hypertension and hyperlipidemia has reduced the incidence of stroke. Studies are under way to determine if treating persons at high risk for developing Alzheimer’s disease will reduce their risk. The change in emphasis to early detection is reflected in the change of title for Chapter 1 from “Diagnosis of Dementia” to “Clinical Diagnosis of Cognitive Dysfunction and Dementing Illness.” Since the publication of the last edition, formal criteria have been proposed for the diagnosis of mild cognitive impairment, vascular dementia, dementia with Lewy bodies, and frontotemporal dementia. Progress has been made in developing behavioral interventions for behavioral and psychological symptoms of dementia. Many changes have come about in the pharmacological management of psychiatric symptoms, such as the virtual replacement of the use in elders of tricyclic antidepressants by the use of selective serotonin reuptake inhibitors and the wide use of anticonvulsant and antimanic drugs for control of behavioral symptoms. Several drugs that augment cholinergic function modestly improve cognition, slow clinical deterioration, and reduce behavioral symptoms in Alzheimer’s disease patients. High-dosage vitamin E has been shown to slow the progression of Alzheimer’s disease. Trials of estrogen and prednisolone in persons with Alzheimer’s disease have unfortunately been unsuccessful thus far. Mutations of the presenilin genes on chromosomes 1 and 14 have been found that account for many of the early-onset familial cases of Alzheimer’s disease, and the EA4 allele of apolipoprotein E4 has been found to be an important risk factor for late-onset Alzheimer’s disease. Nonsteroidal antiinflammatory drugs and statin drugs may have prophylactic effects in Alzheimer’s disease, with statins also having prophylactic effects in vascular dementia. Further strides have been made in elucidating the pathophysiology of Alzheimer’s disease. Accumulation of toxic >-amyloid protein in brain through overproduction or abnormal processing of amyloid precursor protein may result in amyloid plaques. Interest in the tau protein, the main constituent of neurofibrillary tangles, has undergone a resurgence since the discovery of familial and sporadic tauopathies. This book embodies a broadly based approach to the diagnosis and management of the dementias and conveys the spirit of optimism in contemporary dementia research. This volume is coedited by a geriatric psychiatrist (M.F.W.) and a behavioral neurologist (A.M.L.), reflecting the close

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alliance between psychiatry and neurology in the diagnosis and treatment of dementing illness. There have also been changes in the authorship of several chapters. The section on neuroimaging has been expanded into an entire chapter because of the rapid accumulation of imaging information. Full-blown dementia, the result of many types of brain insult, is a diagnostic term referring to global impairment of higher cortical function sufficient to compromise social or work adaptation. Dementing illness is accompanied by emotional, behavioral, ideational, perceptual, and vegetative disturbances in addition to impaired cognitive function. Although these cognitive, emotional, behavioral, ideational, perceptual, and vegetative disturbances result from many different dementing illnesses, certain general principles guide management and treatment. Unlike many other illnesses, dementing illness attacks the personhood of its victims, robbing them of their ability to understand, communicate, fend for themselves, or tend to the needs of others. This loss of personhood is well described in patients’ own words in Cohen and Eisdorfer’s The Loss of Self: A Family Resource for the Care of Alzheimer’s Disease and Related Disorders (New York, WW Norton, 2001) and in many other recent volumes. Persons with dementia have described it as a painful dismemberment, a drifting away, a sense of being lost, or a feeling of being enveloped by a hazy curtain. Ultimately, it is an alienation from self and others. Many individuals are unaware of their progressive loss of function and do not appear to struggle against it. Those who struggle against dementing illness—trying to remember what was once familiar, or trying to grasp new situations—experience enormous emotional pain. Yet, such pain may be overlooked by clinicians who focus primarily on the cognitive aspects of these diseases and can be aggravated by the clinicians addressing family members as though the person with dementia were not present. The perception of many who work with these patients is that the remnants of a person can often be detected through the distorting effects of perceptual and cognitive impairment. Such persons can often be reached, if not through spoken language, through tone of voice or physical contact. It is a unique experience to momentarily touch another—who is drifting out of contact with his or her world—and to be experienced as an anchor to reality. This experience, at once painful and gratifying, is the essence of the therapeutic relationship, maintaining both hope and human contact. Patients and their families are grateful to health care professionals and others who allow themselves to be “in touch” in this way, and they bond strongly to those who are willing to do so. Although patients want to be cured, they and their families also value health care providers as compassionate companions who provide comfort and support. It is our aim to help clinicians comfort, support, and treat individuals with dementing illnesses.

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Working effectively with these patients, their families, and other caregivers requires knowledge derived from medicine; pharmacology; cognitive, behavioral, and linguistic assessment; psychodynamics; family interaction; and systems management to address the interaction between biological, psychological, and social aspects of dementing illness. Effective diagnosis and management call for collaboration between primary care physicians; psychiatrists; neurologists; psychologists; nurses; social workers; physical, occupational, and speech therapists; lawyers; nursing home administrators; and other persons concerned with various aspects of family life, rehabilitation, and extended care. The diagnostic process is ongoing. Many individuals present with problems of memory or other aspects of cognitive function, but without overall significant impairment. We know that many of these individuals will soon develop clinical Alzheimer’s disease, but at present, diagnosis can be made in these cases only by longitudinal follow-up. Also, an apparent progression of dementia may not be due to the illness originally diagnosed. Various systemic illnesses mimic the symptoms of dementing illness. Treating illnesses such as urinary tract infection, pneumonia, and congestive heart failure can help alleviate these aggravating factors. The treatment strategy for dementing illness depends on various factors: whether or not the illness is reversible, the individual’s life situation, and the availability of family and community resources. Complicated emotional, legal, and ethical decisions must often be faced at different points in the evolution of a dementing illness. Early on, important role changes occur between child and parent or spouse and spouse; later, a decision may be needed regarding nursing home placement. Legal issues include power of attorney and guardianship. Ethical issues may involve decisions on the inclusion of a loved one in antemortem and postmortem scientific research or feeding by nasogastric tube or gastrostomy. Health care professionals help to maintain patients’ and families’ hope while at the same time encouraging a realistic approach to each patient’s illness. Humane, effective care of persons with dementing illness is one of the important challenges facing the next few generations of health care providers. We hope this book conveys the positive attitude of those of us who deal day to day with dementing illness. The appreciation of families who care for loved ones with dementing illness is gratifying; their courage, strength, and ingenuity are inspiring.

Acknowledgments We are heavily indebted to the local and national Alzheimer’s Associations for providing information, support, and advocacy for our patients and their

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families and to the National Institute on Aging for funding and guiding the University of Texas Southwestern Medical Center’s Alzheimer’s Disease Center (ADC) and its satellite clinics. We thank our present and former colleagues at the University of Texas Southwestern Medical Center ADC, including Roger Rosenberg, Kyle Womack, Ron Tintner, Jim Hom, Charles White III, Eileen Bigio, Perrie Adams, Munro Cullum, Barbara Foster, Laura Lacritz, Alan Frol, Kathleen Saine, Samuel Speciale, Joan Reisch, Linda Hynan, Margaret Higgins, Ramón Diaz-Arrastia, Sandra Chapman,and Lawrence Honig. We also extend our gratitude to the staff of our ADC Clinical Core, led by Doris Svetlik, and including Jackie Rabb, Robbin Peck, Shelly Daniels, Kristin Martin-Cook, Kathleen Koch, Carol Moore, Mary Riojas, Loretta Pedyfoot, Dianne Phillips, Alice Cox, Barbara Remakel, Taylor Ninman, Kim Booker, and Kim Moser. The generous support of Marsha Ard and John Harbin has allowed Dr. Weiner time to become immersed in dementia research and teaching. Dr. Lipton was supported during a year of fellowship by funding from the State of Texas and the Department of Neurology at the University of Texas Southwestern Medical Center. We also appreciate the help of Dr. Richard Barohn, former professor and interim chair of Neurology at the University of Texas Southwestern Medical Center. Thanks also to Carol Laabs for organizing the correspondence, keeping track of chapters, and organizing the text for submission, and to American Psychiatric Publishing for their willingness to undertake a third edition. Jeanette Weiner and Lee Lipton continue to be patient and understanding. Myron F. Weiner, M.D. Anne M. Lipton, M.D., Ph.D.


CHAPTER

1

Clinical Diagnosis of Cognitive Dysfunction and Dementing Illness Myron F. Weiner, M.D.

Cognitive dysfunction and dementing illnesses are most common in elderly persons. Mild levels of cognitive impairment appear to be part of the normal aging process. More severe impairment in cognitive spheres such as memory or language may herald the onset of dementing illnesses. The overall incidence and prevalence of these illnesses are not known, because estimates concerning diseases such as Alzheimer’s disease are based on persons who meet criteria for dementia and thus miss the large number of patients with mild symptoms. A survey of memory function was performed among community-dwelling elderly persons in the United States as part of the 2000 census. Individuals were rated as having moderate to severe memory problems if they recalled 4 or fewer words from a list of 20 words on combined immediate and delayed recall. On the basis of this criterion, 4% of individuals between ages 65 and 69 years and 36% of those ages 85 years or older had moderate to severe memory problems (Federal Interagency Forum 2000). A study was performed in England using the Mini-Mental State Exam (MMSE) (Folstein et al. 1975) followed by the Cambridge Examination for Mental Disorders of the Elderly (Roth et al. 1988). In this study, incidence rates for dementia were 2.3% for persons ages 75–79 years, 4.6% for persons ages 80–84 years, and 8.5% for persons ages 85–89 years—the incidence approximately doubles for every 5 years of age (Paykel et al. 1994). Based on a study using age-specific incidence rates summarized from several epidemiologic studies, United States mortality rates, and U.S. Census Bureau projections, the prevalence of Alzheimer’s disease in the United States was 2.32 million in 1997 (Brookmeyer et al. 1998). This prevalence is expected to quadruple by 2050. If Alzheimer’s disease and mixed dementia (Alzheimer’s disease plus vascular dementia) account for approximately 56% of dementia cases (Folstein et al. 1991), the total number of elderly persons with dementia in 1

2


1997 was more than 4 million. These figures are much less than those given in a federal government publication estimating that in the year 2000, there were approximately 35 million Americans ages 65 years or older with dementia (Federal Interagency Forum 2000). Whatever the figure, Alzheimer’s disease and dementing illness in general are clearly of considerable importance to public heath. A Canadian study suggests that dementing illness in old age has a very malignant course, with individuals having Alzheimer’s disease or vascular dementia surviving only an average of 3.3 years, but the study had important design flaws. It was a retrospective study; in many cases it employed as the starting point the date of the first medical visit for memory problems; and its participants had an average age at enrollment of nearly 85 years (Wolfson et al. 2001). On the other hand, it is clear that Alzheimer’s disease is now on a par with stroke as the third leading cause of death in the United States, accounting for 7.1% of all United States deaths in 1995 (Ewbank 1999). Of course, cognitive dysfunction and dementing disorders are not confined to old age. Cognitive dysfunction is a common consequence of head injury in youth and early adulthood, of alcoholism in middle age, and of acquired immunodeficiency syndrome (AIDS) at all ages. Dementing illness may also manifest at younger ages, for example, in hereditary illnesses such as Huntington’s disease or in the frontotemporal dementias. As research in dementing illnesses has progressed, three major developments have occurred for clinicians. There has been a shift from defining these diseases in terms of their full-blown, late manifestations toward earlier diagnosis, classification of subtypes, and identification of the underlying pathophysiological processes. The goal of diagnosis has become early recognition of dementing illnesses or their prodromes in the hope of treating them before they result in dementia. Thus, clinicians now speak of Alzheimer’s disease instead of the DSM-IV-TR category dementia of the Alzheimer’s type (American Psychiatric Association 2000). The second major shift has been the realization that diseases and conditions producing cognitive deficits that are not primarily memory-related can disrupt social or occupational function (Royall 2000). This applies especially to the group of disorders produced by frontotemporal disease processes (called frontotemporal dementias in the neurological literature) in which the first deficits may be in language or in executive function as manifested by impaired initiative or social judgment. The third shift has been the understanding that behavioral and emotional symptoms are part of the intrinsic manifestations of dementing illnesses, not just by-products of or reactions to cognitive impairment (Finkel et al. 1996). In this chapter I review and critique the relevant DSM-IV-TR diagnoses and set the stage for Chapter 3, which deals with detecting the illnesses underlying the DSM-IV-TR syndromes described in this chapter.

Cognitive Dysfunction and Dementing Illness

3

DSM-IV-TR diagnoses describe symptom clusters that meet a threshold of “clinically significant distress or impairment in social, occupational, or other important areas of functioning” (American Psychiatric Association 2000, p. 8). The diagnosis therefore indicates the minimal level of personal discomfort or dysfunction that is present. On the other hand, a person may have a dementing illness but does not meet DSM-IV-TR criteria for dementia. The advantage of threshold diagnoses over disease diagnoses is that they are less likely to yield false-positive diagnoses. On the other hand, threshold diagnoses lack the sensitivity to detect early disease and thus have the potential for delaying possible disease-modifying treatments. Despite these shortcomings, it is important to make diagnoses by criteria that are stable, are reproducible, and reflect the impact of diseases on the persons affected by them.

DSM-IV-TR Mental Disorders DSM-I through DSM-III contained the category of organic mental disorders—constellations of cognitive, behavioral, and emotional symptoms resulting from demonstrable changes in brain anatomy or physiology. Organic disorders were differentiated from functional disorders, in which no alteration in brain anatomy or physiology had been demonstrated or was thought to occur. It is now clear that any mental disorder, whether classified as organic or functional, results from altered brain activity, making distinctions between organic and functional perhaps superfluous and misleading. For these reasons, the American Psychiatric Association deleted the diagnostic category of organic mental disorders from DSM-IV and the most recent DSM-IV-TR (American Psychiatric Association 2000). In its place are the categories shown in Table 1–1. They are 1) delirium, dementia, and amnestic and other cognitive disorders; 2) mental disorders due to a general medical condition; and 3) substancerelated disorders. Although these disorders are diagnosed as separate entities, they are overlapping symptom complexes that often involve the same disease. For example, a disease beginning in the frontal lobes might be diagnosed initially as a personality change due to a general medical condition. As executive function and information processing become affected with disease progression, it would become diagnosable as a dementia. Nevertheless, diagnosis of DSM-IV-TR mental disorder subtype is important because of the differences in treatment and prognosis. In some cases, proper diagnosis is a life-or-death issue, such as differentiating barbiturate withdrawal or acute Wernicke’s syndrome from alcoholic dementia. There are many


4

TABLE 1–1.

DSM-IV-TR classification (partial listing)

Delirium, Dementia, and Amnestic and Other Cognitive Disorders DELIRIUM 293.0 Delirium Due to . . . [Indicate the General Medical Condition] —–.–

Substance Intoxication Delirium (refer to Substance-Related Disorders for substance-specific codes) —–.– Substance Withdrawal Delirium (refer to Substance-Related Disorders for substance-specific codes) —–.– Delirium Due to Multiple Etiologies (code each of the specific etiologies) 780.09 Delirium NOS DEMENTIA 294.xx Dementia of the Alzheimer’s Type, With Early Onset (also code 331.0 Alzheimer’s disease on Axis III) .10 Without Behavioral Disturbance .11 With Behavioral Disturbance 294.xx Dementia of the Alzheimer’s Type, With Late Onset (also code 331.0 Alzheimer’s disease on Axis III) .10 Without Behavioral Disturbance .11 With Behavioral Disturbance 290.xx Vascular Dementia .40 Uncomplicated .41 With Delirium .42 With Delusions .43 With Depressed Mood Specify if: With Behavioral Disturbance

Code presence or absence of a behavioral disturbance in the fifth digit for Dementia Due to a General Medical Condition: 0 = Without Behavioral Disturbance 1 = With Behavioral Disturbance

294.1x Dementia Due to HIV Disease (also code 042 HIV on Axis III) 294.1x Dementia Due to Head Trauma (also code 854.00 head injury on Axis III) 294.1x Dementia Due to Parkinson’s Disease (also code 332.0 Parkinson’s disease on Axis III) 294.1x Dementia Due to Huntington's Disease (also code 333.4 Huntington's disease on Axis III) 294.1x Dementia Due to Pick's Disease (also code 331.1 Pick's disease on Axis III) 294.1x Dementia Due to Creutzfeldt-Jakob Disease (also code 046.1 CreutzfeldtJakob disease on Axis III) 294.1x Dementia Due to . . . [Indicate the General Medical Condition not listed above] (also code the general medical condition on Axis III) —–.–– Substance-Induced Persisting Dementia (refer to Substance-Related Disorders for substance-specific codes) —–.–– Dementia Due to Multiple Etiologies (code each of the specific etiologies) 294.8 Dementia NOS


TABLE 1–1.

5

DSM-IV-TR classification (partial listing) (continued)

AMNESTIC DISORDERS 294.0 Amnestic Disorder Due to . . . [Indicate the General Medical Condition] Specify if: Transient/Chronic

—–.– 294.8

Substance-Induced Persisting Amnestic Disorder (refer to SubstanceRelated Disorders for substance-specific codes) Amnestic Disorder NOS

OTHER COGNITIVE DISORDERS 294.9 Cognitive Disorder NOS Mental Disorders Due to a General Medical Condition Not Elsewhere Classified 293.89 Catatonic Disorder Due to . . . [Indicate the General Medical Condition] 310.1

Personality Change Due to . . . [Indicate the General Medical Condition] Specify type: Labile Type/Disinhibited Type/Aggressive Type/Apathetic Type/ Paranoid Type/Other Type/Combined Type/Unspecified Type

293.9

Mental Disorder NOS Due to . . . [Indicate the General Medical Condition]

Substance-Related Disorders The following specifiers apply to Substance Dependence as noted: a

With Physiological Dependence/Without Physiological Dependence b Early Full Remission/Early Partial Remission/ Sustained Full Remission/Sustained Partial Remission c In a Controlled Environment d On Agonist Therapy The following specifiers apply to Substance-Induced Disorders as noted: I

With Onset During Intoxication/WWith Onset During Withdrawal

ALCOHOL-RELATED DISORDERS Alcohol Use Disorders 303.90 Alcohol Dependencea,b,c 305.00 Alcohol Abuse Alcohol-Induced Disorders 303.00 Alcohol Intoxication 291.81 Alcohol Withdrawal Specify if: With Perceptual Disturbances

291.0 291.0 291.2 291.1

Alcohol Intoxication Delirium Alcohol Withdrawal Delirium Alcohol-Induced Persisting Dementia Alcohol-Induced Persisting Amnestic Disorder


6

TABLE 1–1. 291.x .5 .3 291.89 291.89 291.89 291.89 291.9


Alcohol-Induced Psychotic Disorder With DelusionsI,W With HallucinationsI,W Alcohol-Induced Mood DisorderI,W Alcohol-Induced Anxiety DisorderI,W Alcohol-Induced Sexual DysfunctionI Alcohol-Induced Sleep DisorderI,W Alcohol-Related Disorder NOS

AMPHETAMINE (OR AMPHETAMINE-LIKE)–RELATED DISORDERS Amphetamine Use Disorders 304.40 Amphetamine Dependencea,b,c 305.70 Amphetamine Abuse Amphetamine-Induced Disorders 292.89 Amphetamine Intoxication Specify if: With Perceptual Disturbances

292.0 292.81 292.xx .11 .12 292.84 292.89 292.89 292.89 292.9

Amphetamine Withdrawal Amphetamine Intoxication Delirium Amphetamine-Induced Psychotic Disorder With DelusionsI With HallucinationsI Amphetamine-Induced Mood DisorderI,W Amphetamine-Induced Anxiety DisorderI Amphetamine-Induced Sexual DysfunctionI Amphetamine-Induced Sleep DisorderI,W Amphetamine-Related Disorder NOS

CAFFEINE-RELATED DISORDERS Caffeine-Induced Disorders 305.90 Caffeine Intoxication 292.89 Caffeine-Induced Anxiety DisorderI 292.89 Caffeine-Induced Sleep DisorderI 292.9 Caffeine-Related Disorder NOS CANNABIS-RELATED DISORDERS Cannabis Use Disorders 304.30 Cannabis Dependencea,b,c 305.20 Cannabis Abuse Cannabis-Induced Disorders 292.89 Cannabis Intoxication Specify if: With Perceptual Disturbances

292.81 Cannabis Intoxication Delirium


TABLE 1–1.


292.xx Cannabis-Induced Psychotic Disorder .11 With DelusionsI .12 With HallucinationsI 292.89 Cannabis-Induced Anxiety DisorderI 292.9 Cannabis-Related Disorder NOS COCAINE-RELATED DISORDERS Cocaine Use Disorders 304.20 Cocaine Dependencea,b,c 305.60 Cocaine Abuse Cocaine-Induced Disorders 292.89 Cocaine Intoxication Specify if: With Perceptual Disturbances

292.0 292.81 292.xx .11 .12 292.84 292.89 292.89 292.89 292.9

Cocaine Withdrawal Cocaine Intoxication Delirium Cocaine-Induced Psychotic Disorder With DelusionsI With HallucinationsI Cocaine-Induced Mood DisorderI,W Cocaine-Induced Anxiety DisorderI,W Cocaine-Induced Sexual DysfunctionI Cocaine-Induced Sleep DisorderI,W Cocaine-Related Disorder NOS

HALLUCINOGEN-RELATED DISORDERS Hallucinogen Use Disorders 304.50 Hallucinogen Dependenceb,c 305.30 Hallucinogen Abuse Hallucinogen-Induced Disorders 292.89 Hallucinogen Intoxication 292.89 Hallucinogen Persisting Perception Disorder (Flashbacks) 292.81 Hallucinogen Intoxication Delirium 292.xx Hallucinogen-Induced Psychotic Disorder .11 With DelusionsI .12 With HallucinationsI 292.84 Hallucinogen-Induced Mood DisorderI 292.89 Hallucinogen-Induced Anxiety DisorderI 292.9 Hallucinogen-Related Disorder NOS INHALANT-RELATED DISORDERS Inhalant Use Disorders 304.60 Inhalant Dependenceb,c 305.90 Inhalant Abuse

7


8

TABLE 1–1.


Inhalant-Induced Disorders 292.89 Inhalant Intoxication 292.81 Inhalant Intoxication Delirium 292.82 Inhalant-Induced Persisting Dementia 292.xx Inhalant-Induced Psychotic Disorder .11 With DelusionsI .12 With HallucinationsI 292.84 Inhalant-Induced Mood DisorderI 292.89 Inhalant-Induced Anxiety DisorderI 292.9 Inhalant-Related Disorder NOS NICOTINE-RELATED DISORDERS Nicotine Use Disorder 305.1 Nicotine Dependencea,b Nicotine-Induced Disorder 292.0 Nicotine Withdrawal 292.9 Nicotine-Related Disorder NOS OPIOID-RELATED DISORDERS Opioid Use Disorders 304.00 Opioid Dependencea,b,c,d 305.50 Opioid Abuse Opioid-Induced Disorders 292.89 Opioid Intoxication Specify if: With Perceptual Disturbances

292.0 292.81 292.xx .11 .12 292.84 292.89 292.89 292.9

Opioid Withdrawal Opioid Intoxication Delirium Opioid-Induced Psychotic Disorder With DelusionsI With HallucinationsI Opioid-Induced Mood DisorderI Opioid-Induced Sexual DysfunctionI Opioid-Induced Sleep DisorderI,W Opioid-Related Disorder NOS

PHENCYCLIDINE (OR PHENCYCLIDINE-LIKE)–RELATED DISORDERS Phencyclidine Use Disorders 304.60 Phencyclidine Dependenceb,c 305.90 Phencyclidine Abuse


TABLE 1–1.


Phencyclidine-Induced Disorders 292.89 Phencyclidine Intoxication Specify if: With Perceptual Disturbances

292.81 292.xx .11 .12 292.84 292.89 292.9

Phencyclidine Intoxication Delirium Phencyclidine-Induced Psychotic Disorder With DelusionsI With HallucinationsI Phencyclidine-Induced Mood DisorderI Phencyclidine-Induced Anxiety DisorderI Phencyclidine-Related Disorder NOS

SEDATIVE-, HYPNOTIC-, OR ANXIOLYTIC-RELATED DISORDERS Sedative, Hypnotic, or Anxiolytic Use Disorders 304.10 Sedative, Hypnotic, or Anxiolytic Dependencea,b,c 305.40 Sedative, Hypnotic, or Anxiolytic Abuse Sedative-, Hypnotic-, or Anxiolytic-Induced Disorders 292.89 Sedative, Hypnotic, or Anxiolytic Intoxication 292.0 Sedative, Hypnotic, or Anxiolytic Withdrawal Specify if: With Perceptual Disturbances

292.81 292.81 292.82 292.83 292.xx .11 .12 292.84 292.89 292.89 292.89 292.9

Sedative, Hypnotic, or Anxiolytic Intoxication Delirium Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium Sedative-, Hypnotic-, or Anxiolytic-Induced Persisting Sedative-, Hypnotic-, or Anxiolytic-Induced Persisting Amnestic Disorder Sedative-, Hypnotic-, or Anxiolytic-Induced Psychotic Disorder With DelusionsI,W With HallucinationsI,W Sedative-, Hypnotic-, or Anxiolytic-Induced Mood DisorderI,W Sedative-, Hypnotic-, or Anxiolytic-Induced Anxiety DisorderW Sedative-, Hypnotic-, or Anxiolytic-Induced Sexual DysfunctionI Sedative-, Hypnotic-, or Anxiolytic-Induced Sleep DisorderI,W Sedative-, Hypnotic-, or Anxiolytic-Related Disorder NOS

POLYSUBSTANCE-RELATED DISORDER 304.80 Polysubstance Dependencea,b,c,d OTHER (OR UNKNOWN) SUBSTANCE–RELATED DISORDERS Other (or Unknown) Substance Use Disorders 304.90 Other (or Unknown) Substance Dependencea,b,c,d 305.90 Other (or Unknown) Substance Abuse

9


10

TABLE 1–1.


Other (or Unknown) Substance–Induced Disorders 292.89 Other (or Unknown) Substance Intoxication Specify if: With Perceptual Disturbances

292.0

Other (or Unknown) Substance Withdrawal Specify if: With Perceptual Disturbances

292.81 292.82 292.83 292.xx .11 .12 292.84 292.89 292.89 292.89 292.9

Other (or Unknown) Substance–Induced Delirium Other (or Unknown) Substance–Induced Persisting Dementia Other (or Unknown) Substance–Induced Persisting Amnestic Disorder Other (or Unknown) Substance–Induced Psychotic Disorder With DelusionsI,W With HallucinationsI,W Other (or Unknown) Substance–Induced Mood DisorderI,W Other (or Unknown) Substance–Induced Anxiety DisorderI,W Other (or Unknown) Substance–Induced Sexual DysfunctionI Other (or Unknown) Substance–Induced Sleep DisorderI,W Other (or Unknown) Substance–Related Disorder NOS

instances in which several disorders affecting mental function coexist. Persons with cognitive impairment often become delirious. Major depression may coexist with dementia (Weiner et al. 1991, 1993). Persons with Down syndrome often develop Alzheimer’s disease (Crapper et al. 1975). Also, a dementing illness may be engrafted on a preexisting psychiatric disorder such as schizophrenia or bipolar disorder. A crucial diagnostic differentiation is between early pathological cognitive decline and normal aging. This is the question raised by many persons who detect changes in their cognitive functioning and is of paramount significance in early clinical intervention.

Normal Aging The cognitive changes of aging vary between individuals, but in general, young and old adults perform differently on problem-solving tasks. On concept-identification tasks, old persons use less efficient strategies, are less successful at finding solutions, make more errors, and are less likely to change their strategy when their responses are incorrect. Older adults also use less sophisticated strategies on classification and categorization tasks (Reese and Rodeheaver 1985). Older adults recall as well as younger adults the gist of material with which they are presented, but recall details less well (Ulatowska et al. 1998). Because they rely on their general world knowledge to supplement their memory, older adults are also more prone to errors in recall.


11

Older adults often complain of memory difficulties: 83% report forgetting names frequently; 60% report losing objects such as keys; and 57% report forgetting telephone numbers that were just checked (Bolla et al. 1991). Studies of memory function assessed by digit span show little change in immediate or primary memory with age (Drachman and Leavitt 1972). Encoding and retrieval from recent (secondary) memory appear to decline with normal aging, especially when the information cannot be placed in context and seems irrelevant or nonsensical (Schludermann et al. 1983), but vocabulary, general information, and recall of past historical or personal events (tertiary memory) remain relatively intact (Poon 1985). A cross-sectional study of cognitively normal individuals ranging from 62 to 100 years of age showed that learning ability decreased with advancing age (unrelated to education), but recall, adjusted for the amount of material initially learned, did not (Petersen et al. 1992). Thus, healthy elders’ memory is generally preserved for relevant, well-learned material, but the ability to process novel information declines. Slowing the presentation of new information helps normal elders; cueing helps them retrieve more effectively from recent memory (Derouesne and Lacomblez 2000). Neither memory aid is greatly helpful when a disease such as Alzheimer’s disease reaches the level of dementia. Thus, when asking for recall of three words—for example, apple, table, and penny—after a 5-minute period of distraction, mentioning fruit, furniture, and coins are associative memory aids that can help distinguish between normal aging changes and disease-related cognitive impairment.

Age-Associated Memory Impairment and Mild Cognitive Impairment Memory impairment is so troublesome for many persons over age 50 years that a specific syndrome of age-associated memory impairment (AAMI) has been proposed (Blackford and LaRue 1989; Crook et al. 1986), but it has not achieved wide acceptance. Criteria for AAMI begin with complaints of gradual memory loss in persons older than age 50. They include objective evidence of impairment on a standardized memory test (compared with the mean established for young adults), evidence of adequate intellectual function, and absence of dementia or any medical condition that could produce cognitive deterioration. AAMI is reported to have variable prevalence at different ages in elderly persons. A Finnish study showed a prevalence of approximately 40% in persons ages 60–70 years, with highest prevalence in the younger persons sampled (Koivisto et al. 1995). AAMI and subjective memory complaints in elders are seen by some as a stable condition (Hel-

12


kala et al. 1997; Wang et al. 2000). Others find increased risk for the development of dementing illness (Ritchie et al. 2000) and also report that such complaints are frequently associated with physical illness and depression. By contrast, objective evidence of impaired free recall and response to cueing has been found to be associated with higher risk of the development of a dementing illness (Grober et al. 2000). As treatments for Alzheimer’s disease have been developed, there has been an effort to identify as potential subjects for intervention trials individuals who are at high risk for developing Alzheimer’s disease or individuals who are affected but do not yet meet criteria for dementia. This has led to the development of the diagnostic entity of mild cognitive impairment (MCI) (Petersen et al. 1997). Individuals with MCI have complaints of abnormal memory; have normal activities of daily living and normal general cognitive function; have abnormal memory function for age; and do not meet criteria for dementia. They differ from persons with AAMI in that their memory impairment is more severe (Bowen et al. 1997). When observed for up to 5 years, 10%–15% of individuals with MCI developed Alzheimer’s disease each year—far more than the expected 1%–2% per year expected in the general population. A comparison of 76 MCI patients with 234 healthy control subjects and 106 persons with mild Alzheimer’s disease showed that MCI patients differed cognitively from control subjects only in memory. They were similar in memory function to early Alzheimer’s disease patients but differed from them in that only one area of cognition (memory) was affected (Petersen et al. 1999). Therefore, it appears that these individuals are probably in the earliest stage of clinically detectable Alzheimer’s disease. This group of individuals is discussed further in Chapters 5 and 8. In my experience, the most sensitive tests for incipient Alzheimer’s disease include impaired concentration and impaired recent and remote memory. Assessment of remote memory is confounded by educational level when using general knowledge questions such as names of past presidents of the United States or historical events. Remote memory is more effectively tested by gathering information from knowledgeable informants that is relevant to the persons being examined, such as family events or the number, names, and ages of grandchildren. Another sensitive indicator is loss of the abstract attitude—detected by the similarities and proverbs part of the mental status examination. Proverb interpretation is highly culture bound and may yield false-positive results in persons from other cultures. Performance on the similarities subtest, although not culture bound, is related strongly to education and premorbid intelligence. Early in the course of the illness, Alzheimer’s disease patients may also demonstrate difficulty with verbal fluency (e.g., name all the animals you can think of in the next


13

minute), object naming (dysnomia) and drawing geometrical figures (constructional dyspraxia). There are no clinical criteria for the prodromal stages of non-Alzheimer’s disease dementing illnesses.

Dementia The term dementia has a long history. It is derived from the Latin de (out of)+mens (mind)+ia (state of); its literal meaning is a state of being out of or deprived of one’s mind. The poet Juvenal, in the first or second century, is alleged to have used dementia in reference to the mental decrepitude of old age (Lipowski 1980). The term was used through the nineteenth century to designate mental impairment of many kinds (Thomas 1889). Pinel (1806/1962) used the term to designate one of the five classes of mental derangement. Although it is described as the derangement that abolishes the thinking faculty, dementia appeared to refer to schizophrenia and other psychotic disorders (Pinel 1806/1962, p. 165). Esquirol (1845/1965) used dementia to describe mental disorders that were manifested by weakened sensibility, understanding, and will, with impaired recent memory, attention, reasoning, and abstracting ability. Prichard (1837) suggested that dementia might be primary or secondary to other disorders and described a four-stage natural history of dementia: 1) loss of recent memory with preservation of remote memory; 2) loss of reason, 3) loss of comprehension, and 4) loss of ability to care for vegetative functions. Kraepelin (1913) distinguished the so-called functional psychoses from the consequences of obvious brain damage, calling the former the insanities and the latter varieties of imbecility. The two categories of imbecility were acquired imbecility (dementia) and congenital (ordinary) imbecility. The dementia category included apoplectic dementia due to vascular disease, old age (or senility), and epilepsy. Dementia is a diagnosis of impaired mental function. Thus, the clinical history and the mental status examination are the most important tools in making the diagnosis. Dementia cannot be diagnosed on the basis of radiological, biochemical, genetic, or psychological tests alone. Such tests serve to confirm the presence of altered brain function and to help determine the cause of the dementia syndrome. As indicated previously, individuals with dementing illnesses may not meet formal criteria for dementia early on. Dementia is defined as a reduction or impairment of multiple cognitive abilities, including memory, sufficient to interfere with self-maintenance, work, or social relationships. This intellectual impairment occurs without clouding of consciousness and may or may not be permanent. The diagnosis is based on the history (usually supplied by informants other than the

14


patient) and clinical examination. At times, the history and clinical examination will suggest the nature of the dementing illness, as in the case of a person who has experienced multiple strokes and whose cognitive decline was related in time to the strokes. At other times, extensive interdisciplinary evaluation and laboratory procedures are required to determine the cause of dementia. On rare occasions, brain biopsy is needed for a definitive diagnosis. The diagnosis of dementia is complicated by the enormous variation between individuals. For example, many persons who have declined cognitively may still function at a level comparable to an average person their own age. Therefore, the clinician must compare a person’s present abilities with his or her own past abilities. However, this can usually be accomplished only by the retrospective accounts furnished by patients and their families—accounts that are subject to strong bias. For example, family members often minimize deficits by stating that a loved one who appears impaired on clinical examination was never interested in reading or in current events. Individual family members’ biases are minimized through the use of multiple informants. However, with the use of multiple informants and standardized instruments such as the Dementia Questionnaire (see Appendix A) and the Blessed Dementia Rating Scale (BDRS) (see Appendix D), accurate data can be obtained. The fundamental DSM-IV-TR criteria for dementia are presented in Table 1–2 and include the clinical means to elicit the diagnostic signs and symptoms. Table 1–3 indicates the criteria for diagnosing specific dementias. In DSM-IV-TR, the dementia syndrome is not regarded as either progressive or irreversible. There have been optimistic reports on the frequency of reversible conditions producing the dementia syndrome (Garcia et al. 1981; Marsden and Harrison 1972). Mild cognitive impairment, especially due to medications or metabolic disorders, is frequently reversible, but a full-blown dementia syndrome is rarely reversible. In a review of 32 studies of 2,889 cognitively impaired patients with a mean age of 72 years, Clairfield (1988) found clinical diagnoses of Alzheimer’s disease in 56.8%, vascular dementia in 13.3%, depression in 4.5%, alcohol-induced dementia in 4.2%, and drug use in 1.5% of the patients evaluated. Potentially reversible causes of dementia accounted for 13.2% of the cases, but not all cases of potentially reversible dementia were followed to see whether reversal actually occurred. In the 11 studies that provided follow-up, 8% of the dementias resolved partially, and only 3% resolved fully. Reversible causes of dementia included drug use (28%), depression (26%), and toxic-metabolic problems (15.5%). Katzman (1992) suggested that treatable dementia-producing conditions account for about 10.5% of cases and include neurosyphilis, fungal


TABLE 1–2.

15

General diagnostic criteria for dementia based on DSM-IV-TR criteria

A. The development of multiple cognitive deficits manifested by both (1) memory impairment (impaired ability to learn new information and to recall previously learned information) (a) Primary memory can be assessed by digit span forward and in reverse, with a discrepancy of three digits or more suggesting impairment. Secondary memory can be tested by asking the examinee to recall three words presented by the examiner after an interval of 5 minutes. Secondary memory can also be tested by presenting three objects without naming them, covering them up, and asking the examinee to name them 5 minutes later. Another test of short-term memory is to read a short paragraph aloud to the examinee and then ask the examinee to tell what he or she recalls. (b) Long-term or tertiary memory is tested by asking for personal information that can be validated by the accompanying person (date of birth, graduation from high school, marriage, etc.) and by asking facts of common knowledge compatible with the examinee's education and cultural background, including questions such as the name of the president of the United States, the immediate past presidents, the state capital, or the location of the U.S. Capitol. (2) one (or more) of the following cognitive disturbances: (a) aphasia (language disturbance) including, in addition to the classic aphasias, difficulty with word finding and confrontational naming. Word finding difficulty is evidenced in advanced dementia by empty speech devoid of nouns and verbs, with relative preservation of socially overlearned speech, such as “How are you?” Earlier, it can be demonstrated by asking the evaluee to name as many animals as possible in 1 minute. Dementia patients will typically name fewer than 10 animals and will often repeat names. They also have difficulty naming the parts of a watch (watchband, stem, back, crystal), making paraphasic errors (such as strap for band or lens for crystal), or describing functions (e.g., “it's how you set it” for watch stem) instead. (b) apraxia (inability to carry out motor activities despite intact motor function; e.g., strength and coordination), i.e., to draw the face of a clock and set the hands at 10 minutes after 11 (Sunderland et al. 1989). (c) agnosia (failure to recognize or identify objects despite intact sensory function) (d) disturbance in executive functioning (i.e., planning, organizing, sequencing, abstracting).


16

TABLE 1–2.

General diagnostic criteria for dementia based on DSM-IV-TR criteria (continued)

1. Impaired planning, organizing, and sequencing are indicated by an ability to deal with interpersonal, family, and employmentrelated issues and to describe logically how they might be dealt with. Changes in long-standing habits and personal hygiene may reflect executive dysfunction. The history is the best source of information about executive functioning, but it may also be evaluated by posing problems that individuals might encounter in daily life, such as an overdrawn bank account or a medical emergency. Executive functioning can be additionally assessed by asking examinees to perform serial tasks, such as going through the steps of mailing a letter (i.e., folding the paper, inserting it into an envelope, addressing the envelope, placing a stamp on it, and sealing it). 2. Impaired abstracting ability is evidenced by inability to abstractly categorize the similarity between objects such as a chair and a table, or a knife and a fork, or for highly educated persons, between a poem and a statue or praise and punishment. Impaired abstracting ability is also evidenced by inability to interpret abstractly common proverbs such as “don’t cry over spilled milk” or “the grass always looks greener on the other side of the street.” (See Appendix B for detailed mental status examination.) B. The cognitive deficits in Criteria A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning. C. The deficits do not occur exclusively during the course of delirium.

infections, tumor, alcohol abuse, subdural hematoma, normal-pressure hydrocephalus, and epilepsy. On the other hand, according to Katzman, reversible dementias, including drug toxicity, metabolic disorders, hyponatremia, vitamin B12 deficiency, hypothyroidism, and hypoglycemia account for only 4.7% of cases.

Delirium Delirium is a state of altered consciousness and cognition, usually of acute onset (hours or days) and of brief duration (days or weeks). Delirium is very common in general hospital patients, with estimates of prevalence ranging from 30% to 50% in patients age 70 years or older (Lipowski 1987). In a prospective study of 225 nonconfused individuals age 65 years or older who were undergoing repair of hip fracture or elective hip replacement surgery, DSM-IV-TR delirium was diagnosed in 20%. The incidence was 24% in the group with hip fractures and only 12% in those undergoing elective hip


TABLE 1–3.

17

DSM-IV-TR diagnostic criteria for specific dementia syndromes

Dementia of the Alzheimer’s Type A. The development of multiple cognitive deficits manifested by both (1) memory impairment (impaired ability to learn new information and to recall previously learned information) (2) one (or more) of the following cognitive disturbances: (a) aphasia (language disturbance) (b) apraxia (impaired ability to carry out motor activities despite intact motor function) (c) agnosia (failure to recognize or identify objects despite intact sensory function) (d) disturbance in executive functioning (i.e., planning, organizing, sequencing, abstracting) B. The cognitive deficits in Criteria A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning. C. The course is characterized by gradual onset and continuing cognitive decline. D. The cognitive deficits in Criteria A1 and A2 are not due to any of the following: (1) central nervous system conditions that cause progressive deficits in memory and cognition (e.g., cerebrovascular disease, Parkinson’s disease, Huntington’s disease, subdural hematoma, normal-pressure hydrocephalus, brain tumor) (2) systemic conditions that are known to cause dementia (e.g., hypothyroidism, vitamin B12 or folic acid deficiency, niacin deficiency, hypercalcemia, neurosyphilis, HIV infection) (3) substance-induced conditions E. The deficits do not occur exclusively during the course of a delirium. F. The disturbance is not better accounted for by another Axis I disorder (e.g., major depressive disorder, schizophrenia). Vascular Dementia A.–B. See A and B under Dementia of the Alzheimer’s Type. C. Focal neurological signs and symptoms (e.g., exaggeration of deep tendon reflexes, extensor plantar response, pseudobulbar palsy, gait abnormalities, weakness of an extremity) or laboratory evidence indicative of cerebral vascular disease (e.g., multiple infarctions involving cortex and underlying white matter) that are judged to be etiologically related to the disturbance. D. The deficits do not occur exclusively during the course of a delirium. Dementia Due to Other General Medical Conditions A.–B. See A and B under Dementia of the Alzheimer’s Type.

18

TABLE 1–3.


DSM-IV-TR diagnostic criteria for specific dementia syndromes (continued)

C. There is evidence from the history, physical examination, or laboratory findings that the disturbance is the direct physiological consequence of a general medical condition other than Alzheimer’s disease or cerebrovascular disease (e.g., HIV infection, traumatic brain injury, Parkinson’s disease, Huntington’s disease, Pick’s disease, Creutzfeldt-Jakob disease, normalpressure hydrocephalus, hypothyroidism, brain tumor, or vitamin B12 deficiency). Substance-Induced Persisting Dementia A.–B. See A and B under Dementia of the Alzheimer’s Type. C. The deficits do not occur exclusively during the course of a delirium and persist beyond the usual duration of substance intoxication or withdrawal. D. There is evidence from the history, physical examination, or laboratory findings that the deficits are etiologically related to the persisting effects of substance use (e.g., a drug of abuse, a medication). Dementia Due to Multiple Etiologies A.–B. See A and B under Dementia of the Alzheimer’s Type. C. There is evidence from the history, physical examination, or laboratory findings that the disturbance has more than one etiology (e.g., head trauma plus chronic alcohol use, dementia of the Alzheimer’s type with the subsequent development of vascular dementia). D. The deficits do not occur exclusively during the course of a delirium. Dementia Not Otherwise Specified This category should be used to diagnose a dementia that does not meet criteria for any of the specific types described in this section. An example is a clinical presentation of dementia for which there is insufficient evidence to establish a specific etiology.

replacement; the former group probably had greater baseline cognitive impairment (Duppils and Wikblad 2000). The onset of delirium was postoperative in 96% of patients and generally resolved within 48 hours. Predisposing factors were older age, cognitive impairment, and preexisting brain disease. Impaired attention is the sine qua non of delirium, which is usually accompanied by fluctuating consciousness. Sleep-wake disturbances are common, and there is often reduced or increased psychomotor activity. In a series of 227 patients with DSM-IV-TR delirium, 27% experienced visual hallucinations, 12.4% auditory hallucinations, and 2.7% tactile hallucinations (Webster and Holroyd 2000). Delirium is usually characterized by generalized slow waves in the electroencephalogram (EEG); the course of delirium can be followed with serial EEGs (Engel and Romano 1959). The DSM-IV-TR criteria for delirium are presented in Table 1–4.


TABLE 1–4.

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DSM-IV-TR criteria for delirium

Delirium Due to … [Indicate the General Medical Condition] A. Disturbance of consciousness (i.e., reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention. B. Change in cognition (such as memory deficit, disorientation, language disturbance) or the development of a perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia. C. The disturbance develops over a short period of time (usually hours to days) and tends to fluctuate during the course of the day. D. There is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by the direct physiological consequences of a general medical condition. Substance Intoxication Delirium A.–C. See A–C under Delirium Due to … [Indicate the General Medical Condition] D. There is evidence from the history, physical examination, or laboratory findings of either (1) or (2): (1) the symptoms in Criteria A and B developed during substance intoxication (2) medication use is etiologically related to the disturbance Substance Withdrawal Delirium A.–C. See A–C under Delirium Due to … [Indicate the General Medical Condition] D. There is evidence from the history, physical examination, or laboratory findings that the symptoms in Criteria A and B developed during, or shortly after, a withdrawal syndrome. Delirium Due to Multiple Etiologies A.–C. See A–C under Delirium Due to … [Indicate the General Medical Condition] D. There is evidence from the history, physical examination, or laboratory findings that the delirium has more than one etiology (e.g., more than one etiological general medical condition, a general medical condition plus substance intoxication or medication side effect). Delirium Not Otherwise Specified Examples include 1. A clinical presentation of delirium that is suspected to be due to a general medical condition or substance use but for which there is insufficient evidence to establish specific etiology 2. Delirium due to causes not listed above (e.g., sensory deprivation)

Dementia and delirium frequently coexist, with dementia serving as a predisposing factor (Gustafson et al. 1988). In many individuals, the first sign of a dementing illness is postoperative delirium. Delirium differs from dementia in that delirium has a rapid onset and has a greater degree of personality disorganization and clouding of consciousness. Fluctuating cognitive ability occurs in dementia but not to the extent that it occurs in delirium. Dementia patients usually give their best cognitive performance

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early in the day when they are not fatigued, under circumstances in which they do not feel challenged or anxious. Toward the end of the day, many cognitively impaired persons become transiently delirious, a phenomenon often referred to as sundowning. Although sundowning is often attributed to the waning of sensory cues, Volicer et al. (2001) have suggested that in Alzheimer’s disease, the mechanism of sundowning may be a disturbance of circadian rhythm related to a phase delay in body temperature. The diagnosis of dementia cannot be made in the presence of delirium; the patient must be clear of the acute disturbance.

Amnestic Disorder The primary manifestation of amnestic disorder is memory impairment. The DSM-IV-TR diagnostic criteria for this uncommon disorder are presented in Table 1–5. The most common cause is thiamine deficiency associated with long-term alcohol abuse. Persons with Korsakoff’s syndrome (in DSM-IV-TR called substance-induced persisting amnestic disorder due to alcohol) differ from those with Alzheimer’s disease. The former may recall rules and principles for organizing information and have access to previously acquired knowledge with impairment of recent memory, whereas the latter may have little access to previously acquired information and may therefore have difficulty encoding ongoing events (Weingartner et al. 1983). Patients with amnestic disorder often meet criteria for dementia, with the exception of patients with brief amnestic episodes that occur with the short-acting benzodiazepines lorazepam and triazolam. Bilateral lesions of the hippocampus appear to impair recent memory without impairing remote memory (Scoville and Milner 1957; Zola-Morgan et al. 1986). The importance of considering amnestic disorders in differential diagnosis is that they are reversible in the case of minor tranquilizers and are partly reversible in thiamine deficiency–based Wernicke’s encephalopathy seen in alcoholic patients or in nutritionally deprived persons.

Psychotic Disorder Due to a General Medical Condition The DSM-IV-TR diagnostic criteria for psychotic disorder due to a general medical condition are presented in Table 1–6. Hallucinations and delusions are the most common symptoms of this disorder. The following case, which is probably a combination of Alzheimer’s disease with other medical problems, is typical.


TABLE 1–5.

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DSM-IV-TR criteria for amnestic disorder

Amnestic Disorder Due to... [Indicate the General Medical Condition] A. The development of memory impairment as manifested by impairment in the ability to learn new information or the inability to recall previously learned information. B. The memory disturbance causes significant impairment in social or occupational functioning and represents a significant decline from a previous level of functioning. C. The memory disturbance does not occur exclusively during the course of a delirium or a dementia. D. There is evidence from the history, physical examination, or laboratory findings that the disturbance is the direct physiological consequence of a general medical condition (including physical trauma). Substance-Induced Persisting Amnestic Disorder A.–B. See A and B under Amnestic Disorder Due to … [Indicate the General Medical Condition] C. The memory disturbance does not occur exclusively during the course of a delirium or a dementia and persists beyond the usual duration of substance intoxication or withdrawal. D. There is evidence from the history, physical examination, or laboratory findings that the memory disturbance is etiologically related to the persisting effects of substance use (e.g., a drug of abuse, a medication). Amnestic Disorder Not Otherwise Specified An example is a clinical presentation of amnesia for which there is insufficient evidence to establish a specific etiology (i.e., dissociative, substance induced, or due to a general medical condition).

Mrs. M. was an 84-year-old woman who had been delusional for 3 years. Her delusions seemingly began when her memory started to fail. She insisted that her husband was consorting with prostitutes and that he was trying to drive her crazy so that he could get rid of her. Mrs. M. had been jealous of her husband for nearly all of their 58-year marriage, beginning a year after the birth of their daughter, when he confessed a marital infidelity. He continued to be unfaithful, and she continued to accuse him of having affairs. In the 3 years prior to her evaluation, she developed increasing difficulty with her memory. Her emotions became increasingly labile, and at times she threatened her husband with physical harm. She was eating poorly and had reversed her sleep-wake cycle. She was hospitalized for evaluation, and physical examination revealed a cachectic woman with marked hearing impairment and marked visual impairment due to cataracts. Laboratory testing showed macrocytic anemia, a vitamin B12 level of 79 pg/mL, a folic acid level of 1.3 ng/mL, and low serum iron concentration. Mental status examination showed impaired concentration, impaired recent and remote memory, and a markedly reduced fund of information. Her MMSE score was 14. She became more tractable in a structured environment where she received an adequate diet, multiple

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TABLE 1–6.


DSM-IV-TR criteria for mental disorders due to a general medical condition

Psychotic Disorder Due to...[Indicate the General Medical Condition] A. Prominent hallucinations or delusions. B. There is evidence from the history, physical examination, or laboratory findings that the disturbance is the direct physiological consequence of a general medical condition. C. The disturbance is not better accounted for by another mental disorder. D. The disturbance does not occur exclusively during the course of a delirium. Mood Disorder Due to...[Indicate the General Medical Condition] A. A prominent and persistent disturbance in mood predominates in the clinical picture and is characterized by either (or both) of the following: (1) depressed mood or markedly diminished interest or pleasure in all, or almost all, activities (2) elevated, expansive, or irritable mood B. There is evidence from the history, physical examination, or laboratory findings that the disturbance is the direct physiological consequence of a general medical condition. C. The disturbance is not better accounted for by another mental disorder (e.g., adjustment disorder with depressed mood in response to the stress of having a general medical condition). D. The disturbance does not occur exclusively during the course of a delirium. E. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. Anxiety Disorder Due to...[Indicate the General Medical Condition] A. Prominent anxiety, panic attacks, or obsessions or compulsions predominate in the clinical picture. B. There is evidence from the history, physical examination, or laboratory findings that the disturbance is the direct physiological consequence of a general medical condition. C. The disturbance is not better accounted for by another mental disorder (e.g., adjustment disorder with anxiety in which the stressor is a serious general medical condition). D.–E. See Criteria D and E under Mood Disorder Due to … [Indicate the General Medical Condition]. Catatonic Disorder Due to...[Indicate the General Medical Condition] A. The presence of catatonia as manifested by motoric immobility, excessive motor activity (that is apparently purposeless and not influenced by external stimuli), extreme negativism or mutism, peculiarities of voluntary movement, or echolalia or echopraxia. B. B. There is evidence from the history, physical examination, or laboratory findings that the disturbance is the direct physiological consequence of a general medical condition.


TABLE 1–6.

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DSM-IV-TR criteria for mental disorders due to a general medical condition (continued)

C. The disturbance is not better accounted for by another mental disorder (e.g., a manic episode). D. The disturbance does not occur exclusively during the course of a delirium. Personality Change Due to...[Indicate the General Medical Condition] A. A persistent personality disturbance that represents a change from the individual’s previous characteristic personality pattern. (In children, the disturbance involves a marked deviation from normal development or a significant change in the child’s usual behavior patterns lasting at least 1 year). B. There is evidence from the history, physical examination, or laboratory findings that the disturbance is the direct physiological consequence of a general medical condition. C. The disturbance is not better accounted for by another mental disorder (including other mental disorders due to a general medical condition). D. The disturbance does not occur exclusively during the course of a delirium. E. The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. Mental Disorder Not Otherwise Specified Due to a General Medical Condition This residual category should be used for situations in which it has been established that the disturbance is caused by the direct physiological effects of a general medical condition, but the criteria are not met for a specific mental disorder due to a general medical condition (e.g., dissociative symptoms due to complex partial seizures).

vitamins with iron, and parenteral vitamin B12, but she was transferred to a nursing home because it was believed that her husband could not manage her care adequately from a physical standpoint.

Mood Disorder Due to a General Medical Condition Mood disorder due to a general medical condition and substance-induced mood disorder can be confused with dementia because of the many overlapping signs of both dementia and depression. The essential feature of this disorder is prominent and persistent mood alteration associated with a general medical condition. Carcinoma of the pancreas, viral illness, and stroke can cause depression. Hyperthyroidism and hypothyroidism and hyperadrenocorticism and hypoadrenocorticism can cause depression or mania. The DSM-IV-TR criteria for mood disorder due to a general medical condition are listed in Table 1–6. This disorder usually remits when the underlying cause is treated.

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Substance-Induced Mood Disorder Substance-induced mood disorder is characterized by prominent and persistent mood alteration associated with substance use. Depressive symptoms may be caused by drugs, including reserpine, methyldopa, >-blockers, and some hallucinogens. Exogenous steroids can cause depression or mania. This condition usually remits when the causative agent is withdrawn. The DSM-IV-TR criteria for substance-induced mood disorder are listed in Table 1–7. TABLE 1–7.

DSM-IV-TR criteria for substance-induced mood disorder

A. A prominent and persistent disturbance in mood predominates in the clinical picture and is characterized by either (or both) of the following: (1) depressed mood or markedly diminished interest or pleasure in all, or almost all, activities (2) elevated, expansive, or irritable mood B. There is evidence from the history, physical examination, or laboratory findings of either (1) or (2): (1) the symptoms in Criterion A developed during, or within a month of, Substance Intoxication or Withdrawal (2) medication use is etiologically related to the disturbance C. The disturbance is not better accounted for by a Mood Disorder that is not substance induced. Evidence that the symptoms are better accounted for by a Mood Disorder that is not substance induced might include the following: the symptoms precede the onset of the substance use (or medication use); the symptoms persist for a substantial period of time (e.g., about a month) after the cessation of acute withdrawal or severe intoxication or are substantially in excess of what would be expected given the type or amount of the substance used or the duration of use; or there is other evidence that suggests the existence of an independent non-substance-induced Mood Disorder (e.g., a history of recurrent Major Depressive Episodes). D. The disturbance does not occur exclusively during the course of a delirium. E. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

Anxiety Disorder Due to a General Medical Condition Generalized anxiety or recurrent panic attacks are the chief characteristics of anxiety disorders due to a general medical condition, which characteristically impair concentration. Endocrine disorders such as hyperthyroidism and hypothyroidism, pheochromocytoma, hypercortisolism, and fasting


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hypoglycemia are potential causative factors, along with a host of others. DSM-IV-TR criteria for anxiety disorder due to a general medical condition are listed in Table 1–6. Many persons with dementia become distressed or anxious when their cognitive and adaptive abilities are challenged. Often, the distress or anxiety is expressed through reiteration of physical complaints when the individual is intellectually challenged or emotionally stressed. Overt dysphoria is most common early in the course of a dementing illness. As dementing illnesses progress, anxiety often appears to diminish. This may occur because the ability to anticipate real or symbolic danger becomes impaired or because patients’ ability to communicate anxiety diminishes.

Personality Change Due to a General Medical Condition The greatest impact of a general medical condition may be exaggeration of preexisting personality traits or a change in personality instead of obvious intellectual impairment. There are many patterns, but emotional instability, recurrent outbursts of aggression or rage, impaired social judgment, apathy, suspiciousness, and paranoid ideation are frequent. Brain tumors, head trauma, multiple sclerosis, frontotemporal degenerative diseases, and strokes are common causes of personality changes. These symptoms may also occur as interictal phenomena in temporal lobe epilepsy. The DSMIV-TR criteria for personality change due to a general medical condition are presented in Table 1–6. Although many such cases do not meet criteria for dementia, their functional deficits may be as severe as those of persons diagnosed with dementia, as illustrated in the following case: Mr. M., a 69-year-old man, was referred for evaluation by his wife and son. They complained that he talked to himself, did “silly things,” failed to maintain his personal hygiene, and did not pay his bills on time. Mr. M. was a college graduate who had worked at a military installation until he contracted viral encephalitis at age 44 years. He was comatose for a week and experienced residual weakness and slowness of motion. His personality changed. He became highly emotional and negativistic. At age 66 years, he suffered a right-hemisphere stroke that mildly weakened the left side of his body and impaired his speech for a short time. On examination, Mr. M. was poorly groomed. His speech and language were normal, but he tended to engage in long diatribes. He laughed at inappropriate times during the interview. Difficulty with concentration was detected with serial subtraction. Recent and remote memory appeared intact. His construction ability was good. He was able to abstractly categorize the similarity between an egg and a seed but was unable to interpret simple

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proverbs. He had good knowledge of current events but had difficulty when asked to think of an appropriate course of action for dealing with a medical emergency. Neuropsychological testing revealed a verbal IQ of 117, a performance IQ of 94, and a full-scale score of 108—a performance surpassing 70% of his age peers. There was great scatter in his verbal intellectual abilities from below average to superior. He had difficulty with tasks requiring attention to verbally presented material. His perceptual motor abilities were much poorer, ranging from mentally defective to average. He had difficulty with sequencing social stimuli and with understanding part-whole relationships. He performed poorly on complex verbal problem solving and had mild to moderate difficulty with short- and long-term verbal memory. Language, communication, and constructional abilities were intact.

Other Cognitive Disorders Cognitive disorder not otherwise specified (NOS) is a diagnosis for cognitive dysfunction presumed to be due to the direct physiological effect of a general medical condition that does not meet criteria for delirium, dementia, or amnestic disorder. Examples include impairment in cognitive functioning as evidenced by neuropsychological testing or quantified clinical assessment, accompanied by objective evidence of a systemic illness or central nervous system dysfunction; postconcussion disorder; and impairment in memory or attention with associated symptoms after a head trauma. Many cases of postoperative cognitive dysfunction (POCD) fall into this category. Older adults often complain of deficits in cognitive function following major noncardiac surgery. In one prospective study employing measures of memory and attention, including cognitive speed and speed of general information processing, deficits were present at 1 week but largely gone at 3 months after surgery. However, after 6 months, 29% continued to complain of cognitive deficits (Dijkstra et al. 1999). A prospective study of POCD in 1,218 persons age 60 or older undergoing major noncardiac surgery under general anesthesia showed cognitive dysfunction in 26% at 1 week after surgery and in 10% at 3 months compared with control rates of 3.4% and 2.8%, respectively (Biedler et al. 1999). Risk factors for early POCD were increasing age and duration of anesthesia, little education, a second operation, postoperative infection, and respiratory complications. Only age was a risk factor for long-term POCD.

Mental Retardation Mental retardation must be considered in the evaluation for dementing illness. Except when there are obvious stigmata of a syndrome ordinarily


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associated with mental retardation (such as in Down syndrome), it is often impossible to distinguish clinically between mental retardation and dementing illness. The examiner must rely instead on the patient’s history by an outside informant. That history usually includes academic failure with early dropout from school, or graduation from a special education program. Job history usually indicates limited skills and limited comprehension. In many instances, educational history can be deceptive. Graduation from an ungraded school, for example, while requiring 10–12 years, may be the equivalent of only a third- or fourth-grade education. A study of an educationally and socially deprived group showed a correlation of intelligence with educational level (Weiner and Lovitt 1984). However, half the studied individuals with more than 12 years of education had full-scale IQs of less than 85; half of the individuals with fewer than 12 years of education had IQs less than 75. A low level of schooling or limited intelligence markedly impairs performance in the fund of information, abstract reasoning, and judgment aspects of the mental status examination. Two important distinguishing features between developmental disorders and dementing illness are vocabulary and fund of information, which tend to be less impaired than other aspects of the mental status examination in dementing illnesses that do not primarily affect language function. A significant problem for those dealing with mentally retarded persons is the issue of cognitive decline in Down syndrome patients. Virtually all Down syndrome patients who live past age 35 years demonstrate the microscopic pathology of Alzheimer’s disease (reviewed by Mann 1988; Wisniewski et al. 1978). In 57 Down syndrome patients over age 30 years, 5year follow-up showed severe cognitive deterioration in 28% (Oliver et al. 1998). The rate of cognitive impairment increased with age and degree of preexisting cognitive impairment. It is important in this population, as in all others, to seek remediable causes of functional decline such as metabolic abnormalities and psychiatric disorders and not to assume that all functional worsening in these patients is due to Alzheimer’s disease.

Depression Depression is the most important psychiatric disorder to be considered in the diagnostic evaluation of a person with cognitive impairment, either as a primary diagnosis or as a complication of an underlying disease. The prevalence of depression in Alzheimer’s disease is highly controversial, largely due to the substantial overlap of depressive symptoms with the symptoms of Alzheimer’s disease. Most of the nine DSM-IV-TR criteria for major depression are seen in Alzheimer’s disease, including decreased

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interest in activities, weight loss, insomnia or hypersomnia, loss of energy, and diminished ability to think or concentrate. The most important difficulty is that criteria for major depression do not require depressed mood. Thus, Lyketsos and Olin (2002) report 50% prevalence of depressive disorders in Alzheimer’s disease. It seems reasonable that distinct criteria be established for the diagnosis of major depression in Alzheimer’s disease. Weiner and Sairam (2000) have proposed that five or more of the following nine criteria be present for at least 1 week and nearly every day: sadness most of the day, no apparent enjoyment when engaged by others in ordinarily pleasurable activities (or active refusal), little interest in food when presented by others and helped to engage in eating, increased irritability, psychomotor agitation or retardation, low energy, feelings of worthlessness or crying, function below expectation for the level of cognitive impairment, and expressions of a positive wish to die and suicide plans or attempts. In my experience in a dementia clinic, depressive syndromes are a common cause of cognitive impairment in persons without demonstrable brain pathology, but major depression is a rare complication of Alzheimer’s disease. Of 317 consecutive patients in our dementia clinic, 19 (6%) had little or no evidence of brain disease or damage. In that group, 8 (42%) were thought to have depression-related cognitive impairment. In the 192 patients diagnosed as having probable or possible Alzheimer’s disease, only 4 (2%) were thought to be depressed; of those, only 2 (1%) met DSM-III-R criteria for major depression (Weiner et al. 1991). The low prevalence of major depression seen in dementia clinics was later reconfirmed by Weiner and Doody (2002). By contrast, there is a 20%–25% prevalence of major depression in the first 2 years after stroke (Robinson and Forrester 1987), and depression is also frequent in Parkinson’s disease (Mayeux et al. 1981). Many depressed persons have cognitive impairment, although the severity of their impairment does not always correspond with the severity of their depressive symptoms. Much attention has been paid to the phenomenon of pseudodementia (now described as the dementia of depression), a term attributed by Bleuler (1924) to Wernicke in the 1880s and later resurrected by Kiloh (1961). Cognitive processes susceptible to depression are attention, perception, speed of cognitive response, problem solving, memory, and learning. Depressed persons appear to use weak or incomplete strategies to encode events to be remembered. If depressed patients are provided organization and structure, memory deficits disappear (Weingartner et al. 1981). The cognitive and motor tasks most impaired are those requiring sustained effort (Cohen et al. 1982). Depressed persons tend to show impaired recent memory without impaired long-term memory. Short-term memory deficits are correctable by successful treatment with


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antidepressants (Sternberg and Jarvik 1976). MMSE scores improved in depressed elders after successful treatment with antidepressants or electroconvulsive therapy (Greenwald et al. 1989). In a 12-week trial comparing two antidepressant drugs, Butters et al. (2000) found depressed elders as a group showed minimal improvement on the Mattis Dementia Rating Scale (Mattis 1988). Those who had cognitive impairment at baseline had improvement in the domains of conceptualization and initiation relative to those of depressed patients with normal cognition, but they still remained mildly impaired. The response of both depressive and cognitive symptoms to antidepressant treatment does not firmly establish elderly patients’ sole diagnosis as depression. Of 23 patients who had amelioration of cognitive symptoms with treatment of their depression, nearly half went on to develop a dementing illness (Alexopoulos et al. 1993). Although depression is widely presumed to be an important source of comorbidity in Alzheimer’s disease, one small series of depressed Alzheimer’s disease patients showed no difference in free recall, recognition of slowly and rapidly presented words, and digit span (Fahlander et al. 1999). DSM-IV-TR criteria for a major depressive episode are presented in Table 1–8. The differentiation between the cognitive impairment of depression and that due to degenerative or metabolic brain disorder is based on the following: 1. Onset of depressive symptoms preceding cognitive impairment 2. Sudden, fairly recent (weeks or months), and often identifiable onset of cognitive impairment, in terms of both time and emotionally important life events (loss of job or spouse) 3. Patients’ emphasizing inability to think, concentrate, and remember 4. Signs and symptoms of depression 5. Objective cognitive testing showing patients’ deficits to be less severe than their complaints, with performance improved by encouragement, cueing, and structure 6. Depressed patients more commonly giving “I don’t know” answers in contrast to making near misses, confabulating, or repeating (perseverating) answers 7. Normal EEG 8. Absence of any condition known to affect brain function Radiological evidence of mild generalized brain atrophy is not helpful in differentiating depression from dementing illness in elderly persons; nor is the dexamethasone suppression test. The dexamethasone suppression test is positive in 40%–70% of patients with melancholic depression (Rubin and Poland 1984), but it is also frequently positive in patients with

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TABLE 1–8.


DSM-IV-TR criteria for major depressive episode

A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Note: Do not include symptoms that are clearly due to a general medical condition, or mood-incongruent delusions or hallucinations. (1) depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). Note: In children and adolescents, can be irritable mood. (2) markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others) (3) significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. Note: In children, consider failure to make expected weight gains. (4) insomnia or hypersomnia nearly every day (5) psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) (6) fatigue or loss of energy nearly every day (7) feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick) (8) diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others) (9) recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide B. The symptoms do not meet criteria for a Mixed Episode C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism). E. The symptoms are not better accounted for by Bereavement, i.e., after the loss of a loved one, the symptoms persist for longer than 2 months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.


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Alzheimer’s disease and vascular dementia (Balldin et al. 1983; Greenwald et al. 1986; Jenike and Albert 1984). As indicated in Chapter 8, neuropsychological testing can help distinguish depression from degenerative or metabolic brain disorder and can also identify depression in cognitively impaired patients.

Other Psychiatric Disorders Ganser syndrome is subsumed in DSM-IV-TR under the heading of Dissociative Disorder NOS. In this syndrome, ludicrous approximate answers or responses are made to simple questions or commands, indicating that the questions are clearly understood and that deliberately incorrect responses are being given (Goldin and MacDonald 1955). When asked to add 2 and 2, the answer may be 5. The sum of 3 and 3 may be stated as 7. When asked to point upward, the patient may point down and then point up when asked to point down. The Ganser syndrome is frequently accompanied by complaints of auditory and visual hallucinations, circumscribed amnesia, and disorientation. Neuropsychological testing yields highly inconsistent performance consistent with malingering (Heron et al. 1991). These symptoms develop rapidly and usually occur in response to a severe environmental stress, such as facing trial or imprisonment. This syndrome is short lived and requires essentially no active treatment. Impaired cognition may also be malingered for various types of gain. The effects of trivial head injuries may be magnified to escape hard labor or to gain monetary compensation. Mental status examination and neuropsychological testing of the individual who is malingering impaired cognition show inconsistent deficits, with better performance on many items that call for high-level integration than on some items calling for lesser levels of cognitive function. For example, simple similarities will not be understood, whereas more complicated similarities will call forth an abstract response; or digit span, a simple test of attention, will be limited to three digits, whereas the patient can follow complicated directions to the restroom. Attempts have been made to develop a formal set of criteria for the detection of malingered cognitive malfunction (Slick et al. 1999). Schizophrenia and bipolar disorder are discussed in Chapter 5.

Language Disorders Language disorders due to brain damage (aphasias) are easily confused with dementia. The categorization of aphasias is based on which language functions (e.g., fluency, comprehension, repetition, and naming) are impaired.

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Global aphasia impairs all language functions and occurs with large lefthemisphere strokes. Anomic aphasia, by contrast, primarily affects word finding, may be related to lesions of the left angular or left posterior middle temporal gyrus, and is common in Alzheimer’s disease. Broca’s (anterior, nonfluent) aphasia impairs verbal fluency, repetition, and naming and results from lesions of the posterior inferior portion of the left (or dominant) frontal lobe (Benson 1985). In Broca’s aphasia, speech requires great effort, and the speaker omits word modifiers such as articles, prepositions, and conjunctions. For example, a person who wants to go to the bathroom might say, “Want...go...bath...room,” with great effort and great relief after having expressed himself or herself. These patients generally understand what is said to them and can obey commands but have difficulty with repetition, reading aloud, and writing. Although they have difficulty with naming, they are helped by prompting. Patients with Wernicke’s (posterior, fluent) aphasia have fluent paraphasic, neologistic speech with poor comprehension, repetition, and naming. The naming difficulty is not usually aided by prompting. Reading and writing are also impaired. The sentence “I want to go to the bathroom” might be rendered by a posterior aphasic patient as “I wish to go to the you-know bath place now soon,” with no awareness of the peculiarity of his or her speech. The brain damage in this syndrome is to the posterior superior portion of the first temporal gyrus of the dominant hemisphere. Other aphasia syndromes are transcortical motor (impaired fluency and naming with preserved repetition), transcortical sensory (impaired comprehension and naming with preserved repetition), conduction (impaired repetition and naming), and mixed transcortical aphasia—a combination of transcortical sensory and transcortical motor aphasia that leaves patients able only to echo speech (Cummings 1985). The history of aphasia patients will usually reveal an obvious brain insult, most often stroke or head trauma. Examination often demonstrates focal neurological deficits such as hemiparesis (especially in the Broca type), unilateral hyperreflexia, and visual field deficits. On the other hand, frontotemporal dementia may present with progressive aphasias such as primary progressive aphasia and semantic dementia (Kertesz and Munoz 1997; Mesulam 1982) that are at times familial (Morris et al. 1994). (For more detailed discussions of primary progressive aphasia, see Chapters 3 and 8.)

Clinical Techniques and Tools for Diagnosing Cognitive Dysfunction The clinical evaluation includes history taking and direct examination of patients. History and mental status examination establish the presence of


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cognitive dysfunction; the neurological examination helps to determine its etiology. History taking involves the patient, a knowledgeable informant, and all pertinent medical information. Direct access to medical records is important because most lay informants do not know actual blood pressure values or the outcomes of various laboratory tests. In the case of very old nursing home residents, there may be little information available other than from the nursing home staff and records. In addition to eliciting information concerning patients’ cognitive abilities, evidence is sought of emotional or interpersonal contributions to the presenting symptoms. Patients’ emotional responses to their mental difficulties are evaluated, and an attempt is made to determine family strengths and weaknesses. Patients’ personality patterns are also considered. This information helps shape the plan of management, even if treatment of the underlying brain disorder is not possible.

History Taking Under ideal circumstances, medical records are gathered and reviewed in advance of examining the patient. My policy is to have a clinic staff member obtain a history from an outside informant over the telephone before the first visit. I also ask what medications are being taken. This information helps to focus the mental status examination. Trained interviewers may employ a dementia questionnaire such as the one modified from Breitner and Folstein (1984), shown in Appendix A. Personal and medical history are also elicited directly from the patient and accompanying friends or family members, if any, when I see them in person. I first interview the patient in the presence of the accompanying person so that more accurate information can be obtained. I allow time to interview patients alone. I also allow time to interview the patients’ accompanying friends or relatives alone because they often withhold information in the patients’ presence out of concern that they may humiliate or anger them. Typical information withheld concerns patients’ paranoid thinking, hallucinations, or incontinence. Having a friend or relative present during the psychiatric interview is a comfort to most cognitively impaired persons. Thus, history taking tends to be a three-way conversation rather than a formal interview. If patients object to an outside informant being in the room at the time of the examination, I honor their request but still interview the outside informant if one is available. In the flow of the conversation, many clues emerge concerning the relationship between patients and significant others, the impact of patients on their families, and the impact of others on the patients. Husbands often resent their wives’ diminished ability to maintain their household. Wives may

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resent having to be responsible for their formerly dominant husbands. In many cases, there is tension between spouses because one does not believe that the other truly cannot learn, remember, or understand. For example, a man who knew his wife had Alzheimer’s disease chided her for reading romance novels instead of the more substantial reading she had done earlier in her life. Examining one spouse in the presence of the other can be helpful in breaching the intact spouse’s denial and in demonstrating how to deal with defects in the other’s ability to remember, plan, and cooperate.

Mental Status Examination The mental status examination can demonstrate the probable presence or absence of a mental disorder and may also suggest the nature of the underlying brain or systemic disease. (For a highly detailed mental status examination, see Strub and Black 2000.) The mental status examination contained in Appendix B is employed at my clinic. It can ordinarily be accomplished in the course of a 60-minute visit if historical and medical information have been gathered and reviewed in advance. Patients and their families are asked to bring all of the medications in the family medicine chest. After the patient history has been taken, a formal mental status examination is performed (with the patient’s consent) in the presence of any accompanying persons. During this time, tentative hypotheses are made as to how far patients can be pushed to perform and how to best support their coping and defense mechanisms while simultaneously obtaining the needed information. Hearing and vision should be assessed: hearing by whispering or using a tuning fork, and vision by having patients read a standardized vision chart or identify small objects. Mental status examination is performed with consideration for patients’ frustration tolerance and is also tailored to their level of cognitive performance. For example, when it becomes obvious that the patient is not oriented to year and month, I do not usually inquire about orientation to day and date. A patient who cannot perform well on the serial subtraction of 3s is not asked to do serial subtraction of 7s. When the patient is irritable or easily frustrated, I abbreviate each category of inquiry. All responses are treated as equally valid, whether correct or not, and the patient is praised for effort by saying “good” or “that’s fine” after a series of responses. Exceptions to this general approach are in formal testing of cognition for various studies, when completeness is important, or when I suspect that the patient is not making an effort to perform the task, and I therefore withhold praise until the patient has made adequate effort. Primary memory (attention) is tested by using digit span, forward and in reverse. Secondary memory (recent memory, new learning, encoding) is


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tested by asking patients to recall three words in 5 minutes. This test can be performed with objects presented verbally (verbal memory) or objects shown to the patient without naming them (visual memory). Response to cueing is also important, because it helps to distinguish retrieval deficits from failure to encode. As indicated previously testing remote memory is more difficult. Patients with little formal education can be asked about current events that fall within their range of interest; this is done most effectively when an outside informant is asked about recent events in the patient’s life. A detailed examination of language function includes assessment of articulation, fluency, comprehension, repetition, naming, reading, and the ability to write sentences. Assessing language fluency includes delayed word finding, paraphasias, and neologisms. Word fluency (the ability to generate a list of words), a very sensitive indicator of cognitive impairment, can be tested by asking patients to name all the animals they can think of in 1 minute. The average score is 18±6 (Goodglass and Kaplan 1972). Persons with Alzheimer’s disease tend to name few animals and to repeat names they have already mentioned. Comprehension tests begin with graded tasks, asking patients to point to one, two, and three objects in the room, followed by asking simple logic questions, as indicated in Appendix B. Naming tests should include the parts of objects, such as the parts of a watch (stem, watchband, back or case, face, crystal or glass) or the parts of a shirt. Reading ability should be considered in the context of patients’ education. Writing ability is assessed by asking patients to write a dictated sentence and by then asking them to compose a sentence of their own. Calculating ability is tested with simple problems in addition, subtraction, multiplication, and division. Praxis is evaluated by asking patients to imitate an action performed by the examiner, to perform simple motor acts in response to the examiner’s request and to copy a set of simple geometric figures. For the figures, we employ intersecting rectangles, a Greek cross, and a cube (see Appendix B). Drawing the cube is used to detect constructional dyspraxia in mildly impaired, well-educated persons. It is our experience that cognitively intact persons of age 80 years or older cannot draw the cube well. Fund of information is assessed by using a standard set of questions ranging from simple to difficult and by evaluating the responses in relation to patients’ level of education and job performance. The patient’s ability to think abstractly can be assessed by using similarities and proverbs, but assessment of abstract reasoning by the use of proverbs and similarities requires consideration of patients’ education, cultural background, and native language. Judgment can be estimated by asking

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patients questions on how they would manage certain life situations, such as “What would you do if you were in a church or theater and noticed a fire that nobody else saw?” or “What would you do if the electric company called and told you that the last check you wrote them was returned because of insufficient funds?” However, judgment is probably best assessed from a history by an informant other than the patient. Other tests of executive function than those included in Appendix B (ideomotor and constructional praxis, abstract reasoning, and judgment) are contained in the neurological examination (Appendix C) and include the Luria hand sequence, go–no go tasks, and tests for impersistence.

Characterizing Dementing Illnesses Dementing illnesses can be characterized as cortical or subcortical (see also Chapter 8), based on the association of their characteristics with cortical or subcortical pathology. Cortical dementias present as one of two overlapping groups: frontotemporal or temporoparietal. Frontal dementia can be due to Pick’s disease or anterior cerebral artery stroke. It occurs less frequently in Alzheimer’s disease. Frontal lobe degeneration presents in a number of ways. A common presentation is progressive personality change and breakdown in social conduct (Kumar and Gottlieb 1993). Other features are defective judgment, difficulty in focusing attention, apathy, disinhibition, silliness, echoing words, mirroring others’ behavior, unawareness of deficit, difficulty in following instructions (often manifested as motor dyspraxia), and often a slightly prancing gait. As an example of defective judgment, Neary (1990), for example, reported on a patient who insisted on repeatedly changing into fresh clothes but refused to bathe. Personality changes often antedate cognitive symptoms in frontal dementia; Miller et al. (1991) found social withdrawal and behavioral disinhibition to be the earliest symptoms. In primary progressive aphasia, initial symptoms include difficulty with verbal expression. Normal pressure hydrocephalus often presents with frontal signs, such as complete indifference to urinary incontinence. Temporoparietal dementia, the most common presentation of Alzheimer’s disease, is accompanied by naming difficulties and constructional dyspraxia with relative preservation of personality. Persons with cortical dementias may be aware or unaware of their deficits. Subcortical dementias, with primary pathology in the thalami, basal ganglia, rostral brainstem, and their frontal projections, overlap in symptomatology with frontal dementias but also usually involve speech and motor abnormalities. The most prominent symptoms include overall slowing of movement and cognitive processing and deficits in social judgment and


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mood change. Causes of subcortical dementia include cerebrovascular disease, Parkinson’s disease, Huntington’s disease, Wilson’s disease, and progressive supranuclear palsy (Cummings 1990). The following case histories provide examples of each of these syndromes:

Frontotemporal Dementia This patient was a 77-year-old married man with 6 years of education, whose problems began at age 73. In addition to difficulty with memory, attention, and problem solving and word finding, he experienced personality changes. He made inappropriate advances toward women, asking them if he could feel their breasts. He tended to eat excessively and shoveled food into his mouth. He became incontinent of urine, reporting auditory hallucinations telling him that he did not need to use the toilet. When seen during his third year of illness, he had been experiencing gait difficulty for about 2 months and was largely wheelchair bound. Mental status examination revealed mild disorientation in time, impaired attention, concentration, mildly impaired verbal fluency, and memory deficits that responded to cueing. His constructional praxis was intact, except for tremor, and he had impaired abstract reasoning. Neurological examination revealed an unsteady, shuffling gait and both resting and intention tremor. He had atrophy of his interosseus muscles, generalized weakness and reduced deep tendon reflexes. He had no frontal release signs. Neuropsychological testing showed borderline to average intelligence. He had an MMSE score of 21, showed marked perseveration, and had difficulty with placing the numbers on a clock. His immediate recall of structured verbal material was average. Although he forgot 50% of the material he initially learned after a brief delay, he benefited from semantic cueing. Delayed recall of simple geometrical figures was mildly to moderately impaired. His difficulties were primarily in the areas of memory and executive function. A magnetic resonance imaging scan of the brain showed mild cerebral atrophy, more severe frontally. Over the next year he became unable to walk and was admitted to a nursing home. He developed a deep venous thrombosis and had surgical intervention with insertion of an inferior vena cava filter. Subsequently, he developed sepsis. He died approximately 5 years after the onset of his illness. At postmortem examination, this patient’s brain weighed 1,240 grams. There was moderate hydrocephalus ex vacuo, severe atrophy of the frontal lobes, and mild atrophy of the temporal and parietal lobes. There were small numbers of plaques and neurofibrillary tangles but not sufficient for a diagnosis of Alzheimer’s disease. There was also depopulation of the substantia nigra without Lewy bodies. The presence of vacuolation in the upper layers of the cortex, intraneuronal inclusions staining positive for ubiquitin, and swollen axons in frontal lobe neurons led to a diagnosis of frontal lobe dementia with ubiquitinated inclusions (also called motor neuron inclusion dementia).

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Temporoparietal Dementia A 60-year-old woman with 12 years of education had a history of slowly progressive impairment of memory over 3 years. She was having difficulty balancing her checkbook, was forgetting to keep appointments, and could not remember information communicated to her a few moments earlier. She had stopped sewing and cooking, but she was still driving and continued to do gardening. She had experienced depression since the onset of her memory symptoms and had some remission of her depressive symptoms with antidepressant medication. When the patient was evaluated during her third year of illness, the physical neurological examination was entirely within normal limits. Psychiatric examination revealed no significant depression. Neuropsychological testing showed a verbal IQ of 91, performance IQ of 92, and a full-scale IQ of 91. She had very poor abstract reasoning and mild impairment of verbal fluency. On complex verbal list learning tasks she had severe impairment. On tests of contextual verbal memory, her immediate recall score was in the first percentile. She remembered none of the information presented after a 30-minute delay. An EEG and a magnetic resonance imaging scan of the brain showed no abnormality. A regional cerebral blood flow examination showed a mild reduction of blood flow in the posterior superior parietal areas and mild frontal flow reduction. Seven years after the onset of symptoms, she had become completely disoriented and was unable to discriminate between relatives and strangers. She had developed anxiety, sadness, restlessness, and fearfulness, and she spent most of her waking hours pacing about the house and wandering outside if allowed to. She also became irritable and uncooperative. Her spontaneous speech steadily decreased. She often talked or mumbled to herself. She became incontinent of urine and feces and needed to be assisted with all activities of daily living. Various antipsychotic and antianxiety agents were prescribed with little effect. In her seventh year of illness, she stopped eating and drinking, regressed to a fetal position and died a few months later. At postmortem study, this patient’s brain weighed 935 grams. There was moderate hydrocephalus ex vacuo and mild frontal temporal and parietal atrophy as well as pallor of the locus coeruleus. She had numerous neuritic plaques and intraneuronal neurofibrillary tangles in the neocortex and hippocampus. Her final diagnosis was Alzheimer’s disease.

Subcortical Dementia The patient was a 60-year-old married woman with 13 years of education. During the first year of her illness, her husband noted that she could no longer balance the books for their family-owned business. During that year, her husband and daughter noticed a marked personality change; she had become quieter and did not want to socialize as much. She had difficulty maintaining her train of thought. The patient complained of weakness and nervousness. Her weakness affected her lower extremities to the point that she had difficulty arising out of a chair.


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Over the next 2 years she had progressively greater difficulty with balance, judging distance, and falling. The patient’s daughter was afraid to let her mother care for her children because she was afraid her mother would fall and drop a child. The patient had difficulty judging distances and had on several occasions scraped the sides of her car in the garage. Her husband noted that she tended to leave doors open, and he reported minimal change in her ability to put on makeup and dress herself appropriately. She had also been stopped for speeding while driving, which was totally out of character for her. When seen for comprehensive evaluation 3 years after the onset of her symptoms, she had difficulty dressing, feeding herself, and controlling her bowel and bladder functions. She tended to flop rather than to sit down, and she was unable to raise the volume of her voice. She had slightly decreased upward gaze. Her handwriting was noticeably micrographic. Her deep tendon reflexes were generally increased and she had reflex spread in the lower extremities. She had difficulty with rapidly alternating movement and had unsteady gait and severe impairment of postural reflexes. On mental status examination she was alert and oriented to year, month, date, and season. Her MMSE score was 25. Neuropsychological testing revealed a verbal IQ of 81, performance IQ of 91, and full-scale IQ of 85. She had difficulty with attention, concentration, and flexibility of thought. She had moderate to severe impairment of both short- and long-term verbal memory and figural memory. However, she demonstrated no language or communication dysfunction. A magnetic resonance imaging scan of the brain showed moderate cortical atrophy. A regional cerebral blood flow study showed reduced flow in the left frontal region and an area of superficially reduced flow in the right frontal region. Six years after the onset of her symptoms, the patient was bed bound and needed to have pills crushed for her to swallow. She died in a nursing facility 10 years after the onset of her illness. At postmortem examination, the patient’s brain weighed 1,050 grams. There was mild hydrocephalus and pallor of the substantia nigra and locus coeruleus. There was atrophy of the brainstem nuclei, deep cerebellar nuclei, and subthalamic nuclei. Microscopic examination of the brain revealed neuron loss, atrophy, gliosis, and intraneuronal neurofibrillary tangles in subthalamic nucleus, globus pallidus, substantia nigra, periaqueductal gray matter, tectum, medullary olivary nuclei, and cerebellar dentate nucleus. The final diagnosis was progressive supranuclear palsy.

Quantifying Aspects of Dementing Illness Clinicians generally rely on impressionistic data to make diagnoses and to follow the course of an illness and its treatment. They also employ objective measures, such as pulse, temperature, blood pressure, hematocrit, and blood urea nitrogen concentration. Growing awareness of the potential reversibility of some dementias and the potential for treatment of dementing

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illness and dementia-related symptoms has led to the development of instruments to quantify the phenomena associated with dementing illness, including overall functional ability; cognition; and behavioral, emotional, perceptual, and ideational symptoms. Described below are some commonly employed scales. In addition, I have included recently developed research scales for quantifying behavioral and emotional symptoms and quality of life.

Measures of Global Function The BDRS (Blessed et al. 1968) (see Appendix D) is a 17-point activities of daily living scale that includes a wide range of behaviors. It is administered to a knowledgeable informant—usually a person who spends 20 or more hours per week with the patient. This scale takes approximately 10 minutes to administer and is a useful complement to testing patients directly, a process that often does not expose many of the behavioral concomitants of dementia, such as lack of sphincter control or difficulty in eating or dressing. Its high degree of subjectivity and the use of an untrained observer make it less reliable than the MMSE and the Alzheimer’s Disease Assessment Scale (ADAS), but it encompasses a broader range of function and correlates well with MMSE and ADAS scores in Alzheimer’s disease patients. The Washington University Clinical Dementia Rating (CDR) Scale (Hughes et al. 1982) (see Appendix E) was designed for the assessment of Alzheimer’s disease outpatients. It grades on a scale ranging from 0 (normal) to 3 (severe) and is based on a structured interview that takes 30–40 minutes and involves interviewing an informant as well as the patient. Two additional stages have been added to the CDR Scale (Morris 1993): stages 4 (profound) and 5 (terminal). In stage 4, speech is usually unintelligible or irrelevant, and patients are unable to follow simple instructions or understand commands. Patients occasionally recognize the spouse or caregiver, use fingers more than utensils, and require much assistance. They are able to walk a few steps with help (but usually are chair bound), often make purposeless movements, and are frequently incontinent. In stage 5, patients are unresponsive and neither comprehend communication nor recognize others. Patients are bedridden and unable to sit or stand. They need to be fed, often by nasogastric tube, and may have difficulty swallowing.

Measures of Cognitive Function The MMSE (Folstein et al. 1975), administered directly to the patient, is probably the most widely used brief cognitive assessment tool. It requires 10–15 minutes to administer and samples orientation, attention, concentra-


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tion, recent memory, naming, repetition, comprehension, ideomotor praxis, constructional praxis, and the ability to construct a sentence. A perfect score is 30 points. The MMSE is confounded by premorbid intelligence—higher intelligence making for better performance and lower intelligence for worse. The originators indicate that a score of 23 or below by someone with a high school education is suggestive of dementia. A cutoff score of 18 or below is suggested for those with an eighth grade education or less. A population-based study showed an inverse relationship between test score and education. The median score was 29 for unscreened individuals with at least 9 years of schooling, 26 for those with 5–8 years of schooling, and 22 for those with 0–4 years of education. The same study also showed an inverse relationship between age and test score, with a median of 29 for those ages 18–24 years and a median of 25 for those ages 80 years and older (Crum et al. 1993). Although the MMSE is not a sensitive test, its brevity and the minimal training required in its administration make it especially useful as a screening test for cognitive impairment and for following the course of delirium in medical and surgical patients. This instrument is protected by copyright and must be ordered from Psychological Assessment Resources, Inc., P.O. Box 998, Odessa, FL 33556 (1-800-331-8378). The ADAS (Rosen et al. 1984) (see Appendix F) is a research scale designed to be sensitive to small changes in Alzheimer’s disease patients. Used to assess the effectiveness of cognition-enhancing drugs, the scale is based on the symptoms most commonly seen in 31 Alzheimer’s disease cases confirmed by brain biopsy (Mohs et al. 1983). The scale consists of 21 items, half of which are cognitive and half of which are noncognitive. Items are rated on a 6-point scale ranging from 0 (no impairment) to 5 (severe impairment). This test requires approximately 45 minutes and an outside informant, and needs to be administered by a person trained specifically in its use. The cognitive subtest items correlate well with other measures of clinical progression in Alzheimer’s disease. The noncognitive items such as depression, appetite, and pacing do not correlate well with dementia progression, but they do assess the major behavioral symptoms seen in Alzheimer’s disease. The cognitive portion of the ADAS has been used extensively in trials of cognitive enhancers for Alzheimer’s disease. The ADAS administration kit has not been standardized, and the test is too cumbersome for routine clinical use. It was not designed to be used as a diagnostic instrument.

Measures of Behavioral and Emotional Symptoms The Neuropsychiatric Inventory (NPI) (Cummings et al. 1994) (see Appendix G) was designed to assess the entire range of psychopathology in cognitively impaired individuals. The newest version has 10 probe ques-

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tions concerning dysphoria, euphoria, anxiety, agitation, aberrant motor behavior, apathy, irritability, disinhibition, delusions, hallucinations, nighttime behavior disturbances, and appetite and eating abnormalities (Cummings 1997). It also includes a measure of caregiver distress (Kaufer et al. 1998). If the response to the probe question is positive, further questions are asked. If the response is negative, the examiner proceeds to the next domain. A nursing home version has been also been created, but the authors caution that it is best administered by trained research personnel (Wood et al. 2000). Because of its design, the instrument can be administered in 5–10 minutes by an experienced technician or clinician. It is a good general screening tool and can also be used to follow the course of treatment. The instrument is available from Jeffrey Cummings, M.D., 710 Westwood Plaza, Suite 2238, Los Angeles, CA 90095-1769. The Agitated Behavior in Dementia (ABID) Scale (Logsdon et al. 1999b) (see Appendix H) is a 16-item instrument administered to caregivers. It has a 2-week window of observation. The scale evaluates the frequency of and caregiver reaction to common agitated behaviors in community-dwelling persons with Alzheimer’s disease. Derived from clinical experience and items from several other scales, it evaluates the behaviors rated as most problematic in persons with mild to moderate dementia that can be observed and described objectively. Administration time is about 15 minutes. This instrument is also useful for tracking response to treatment.

Measures of Quality of Life The impact of treatments on patients’ quality of life is as important as the impact of treatment on patients’ symptoms or the diseases that produce these symptoms. Because quality of life is subjective, it can be measured directly only in persons with relatively mild cognitive impairment. Persons with severe cognitive impairment are often unable to perceive or report on quality-of-life issues. The scales described below, although still in development, appear to have the most promise for clinical trials. The Quality of Life in Alzheimer’s Disease (QOL-AD) Scale (Logsdon et al. 1999a) (see Appendix I) is a 13-item instrument that can be administered directly to persons with Alzheimer’s disease or other forms of cognitive impairment. When administered directly, it is reliable for persons with MMSE scores between 10 and 28. The scale can also be given as a selfcompleted questionnaire to a caregiver surrogate. Each item is rated on a 4-point scale from poor to excellent. The patient and caregiver scales may be scored independently or may be combined by multiplying the patient score by 2, adding the caregiver score, and dividing by 3, thus giving more


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weight to the patient report. The scale has a 1-week window of observation. Administration time is about 15 minutes. Its sensitivity to interventions is not yet known. The Quality of Life in Dementia (QUALID) Scale (Weiner et al. 2000) (see Appendix J) is an 11-item scale with a 1-week window of observation designed to rate quality of life in persons with advanced dementing illness. Items consist of observable behaviors such as smiling, crying, and apparent enjoyment of interaction with others. It is administered to family or professional caregivers. Administration time is about 5 minutes. Pilot data suggest that the scale is sensitive to change and can be used in treatment studies.

Summary Cognitive impairment is detected from history and mental status examination. As a result of increasing precision in diagnosis, clinicians are able to better determine the underlying brain or systemic pathology in persons with cognitive impairment. Along with greater precision in diagnosis has come greater awareness of the diversity of symptoms associated with these illnesses, including behavioral, emotional, vegetative, ideational, and perceptual disturbances. Many instruments have been developed to quantify the cognitive, behavioral, and psychological aspects of dementing illness. These instruments can provide valid and reliable measures of the effects of interventions with patients and can thereby aid in developing effective treatments.

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Katzman R: Diagnosis and management of dementia, in Principles of Geriatric Neurology. Edited by Katzman R, Rowe JW. Philadelphia, PA, FA Davis, 1992, pp 167–206 Kaufer DI, Cummings JL, Christine D, et al: Assessing the impact of neuropsychiatric symptoms in Alzheimer’s disease: the Neuropsychiatric Inventory Caregiver Distress Scale. J Am Geriatr Soc 46:210–215, 1998 Kertesz A, Munoz DG: Primary progressive aphasia. Clin Neurosci 4:95–102, 1997 Kiloh LG: Pseudo-dementia. Acta Psychiatr Scand 37:336–351, 1961 Koivisto K, Reinikainen KJ, Hanninen T, et al: Prevalence of age-associated memory impairment in a randomly selected population from eastern Finland. Neurology 45:741–747, 1995 Kraepelin E: Lectures on Clinical Psychiatry, 2nd Edition. Translated by Johnstone T. New York, William Wood, 1913 Kumar A, Gottlieb G: Frontotemporal dementias: a new clinical syndrome? American Journal of Geriatric Psychiatry 1:95–108, 1993 Lipowski ZJ: Organic mental disorders: introduction and review of syndromes, in Comprehensive Textbook of Psychiatry/III, 3rd Edition, Vol 2. Edited by Kaplan HI, Freedman AM, Sadock BJ. Baltimore, MD, Williams & Wilkins, 1980, pp 1359–1391 Lipowski ZJ: Delirium (acute confusional states). JAMA 258:1789–1792, 1987 Logsdon RG, Gibbons LE, McCurry SM, et al: Quality of life in Alzheimer’s disease: patient and caregiver reports. J Ment Health Aging 5:21–32, 1999a Logsdon RG, Teri L, Weiner MF, et al: Assessment of agitation in Alzheimer’s disease: the Agitated Behavior in Dementia Scale. J Am Geriatr Soc 47:1354– 1358, 1999b Lyketsos C, Olin J: Depression in Alzheimer’s disease: overview and treatment. Biol Psychiatry 52:243–252, 2002 Mann DM: The pathological association between Down syndrome and Alzheimer disease. Mech Ageing Dev 31:213–255, 1988 Marsden CD, Harrison MJG: Outcome of investigation of patients with presenile dementia. Br Med J 2:229–252, 1972 Mattis S: Dementia Rating Scale. Odessa, FL, Psychological Assessment Resources, 1988 Mayeux R, Stern Y, Rosen J, et al: Depression, intellectual impairment and Parkinson’s disease. Neurology 31:645–650, 1981 Mesulam M-M: Slowly progressive aphasia without generalized dementia. Ann Neurol 11:592–598, 1982 Miller BL, Cummings JL, Villanueva-Meyer J, et al: Frontal lobe degeneration: clinical, neuropsychological, and SPECT characteristics. Neurology 41:1374–1382, 1991 Mohs RC, Rosen WG, Greenwald BS, et al: Neuropathologically validated scales for Alzheimer’s disease, in Assessment in Geriatric Psychopharmacology. Edited by Crook T, Ferris S, Bartus R. New Canaan, CT, Mark Powley, 1983 Morris JC: The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 43:2412–2414, 1993 Morris JC, Cole M, Banker BQ, et al: Hereditary dysphasic dementia and the PickAlzheimer spectrum. Ann Neurol 16:455–466, 1994


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Neary D: Dementia of frontal lobe type. J Am Geriatr Soc 38:71–72, 1990 Oliver C, Crayton L, Holland A, et al: A four-year prospective study of age-related cognitive change in adults with Down’s syndrome. Psychol Med 28:1365– 1377, 1998 Paykel ES, Brayne C, Huppert FA, et al: Incidence of dementia in a population older than 75 years in the United Kingdom. Arch Gen Psychiatry 51:325–332, 1994 Petersen RC, Smith G, Kokmen E, et al: Memory function in normal aging. Neurology 42:396–401, 1992 Petersen RC, Smith GE, Waring SC, et al: Aging, memory, and mild cognitive impairment. Int Psychogeriatr 9 (suppl 1):65–69, 1997 Petersen RC, Smith GE, Waring SC, et al: Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 56:303–308, 1999 Pinel P: A Treatise on Insanity (1806). New York, Hafner, 1962 Poon LW: Differences in human memory with aging: nature, causes and clinical implications, in Handbook of the Psychology of Aging, 2nd Edition. Edited by Birren JE, Schaie KW. New York, Van Nostrand Reinhold, 1985, pp 427–462 Prichard JAC: A Treatise on Insanity. Philadelphia, PA, Haswell, Barrington, & Haswell, 1837 Reese HW, Rodeheaver D: Problem solving and complex decision making, in Handbook of the Psychology of Aging, 2nd Edition. Edited by Birren JE, Schaie KW. New York, Van Nostrand Reinhold, 1985, pp 474–499 Ritchie K, Ledesrt B, Touchon J: Subclinical cognitive impairment: epidemiology and clinical characteristics. Compr Psychiatry 41 (2 suppl 1):61–65, 2000 Robinson RG, Forrester AW: Neuropsychiatric aspects of cerebrovascular disease, in The American Psychiatric Press Textbook of Neuropsychiatry. Edited by Hales RE, Yudofsky SC. Washington, DC, American Psychiatric Press, 1987, pp 191–208 Rosen WG, Mohs RC, Davis KL: A new rating scale for Alzheimer’s disease. Am J Psychiatry 14:1356–1364, 1984 Roth M, Huppert FA, Tym E, et al. CAMDEX. The Cambridge Examination for Mental Disorders of the Elderly. New York, Cambridge University Press, 1988 Royall DR: Executive cognitive impairment: a novel perspective on dementia. Neuroepidemiology 19:293–299, 2000 Rubin RT, Poland RE: Variability in cortisol level assay methods. Arch Gen Psychiatry 41:724–725, 1984 Schludermann EH, Schludermann SM, Merryman PW, et al: Halstead’s studies in the neuropsychology of aging. Arch Gerontol Geriatr 2:49–172, 1983 Scoville WB, Milner B: Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry 20:11–21, 1957 Slick DJ, Sherman EM, Iverson GL: Diagnostic criteria for malingered neurocognitive dysfunction: proposed standards for clinical practice and research. Clin Neuropsychol 13:545–561, 1999 Sternberg DE, Jarvik ME: Memory functions in depression: improvement with antidepressant medication. Arch Gen Psychiatry 33:219–224, 1976

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Strub RL, Black FW: The Mental Status Examination in Neurology, 4th Edition. Philadelphia, PA, FA Davis, 2000 Thomas J: A Complete Pronouncing Medical Dictionary. Philadelphia, PA, JB Lippincott, 1889 Ulatowska HK, Chapman SB, Highley AP, et al: Discourse in healthy old-elderly adults: a longitudinal study. Aphasiology 12:619–633, 1998 Volicer L, Harper DG, Manning BC, et al: Sundowning and circadian rhythms in Alzheimer’s disease. Am J Psychiatry 158:704–711, 2001 Wang PN, Wang SJ, Fuh JL, et al: Subjective memory complaint in relation to cognitive performance and depression: a longitudinal study of a rural Chinese population. J Am Geriatr Soc 48:295–299, 2000 Webster R, Holroyd S: Prevalence of psychotic symptoms in delirium. Psychosomatics 41:519–522, 2000 Weiner MF, Lovitt R: An examination of patients’ understanding of information from health care providers. Hosp Community Psychiatry 35:619–620, 1984 Weiner MF, Sairam R: The relationship of major depressive disorder to Alzheimer’s disease, in Physical Illness and Depression in Older Adults: A Handbook of Theory, Research, and Practice. Edited by Williamson GM, Shaffer DR, Parmelee PA. New York, Kluwer Academic/PlenumPublishers, 2000, pp 257– 276 Weiner MF, Bruhn M, Svetlik DS, et al: Experiences with depression in a dementia clinic. J Clin Psychiatry 52:234–238, 1991 Weiner MF, Edland SD, Luszczynska H: Prevalence and incidence of major depression in Alzheimer’s disease. Am J Psychiatry 151:1006–1009, 1993 Weiner MF, Martin-Cook K, Svetlik DA, et al: The Quality of Life in Late-Stage Dementia (QUALID) Scale. Journal of the American Medical Directory Association 1:114–116, 2000 Weiner MF, Doody RS, Sairam R, et al: Prevalence and incidence of major depressive disorder in Alzheimer's disease: findings from two databases. Dement Geriatr Cogn Disord 13:8–12, 2002 Weingartner H, Cohen RM, Murphy DL, et al: Cognitive processes in depression. Arch Gen Psychiatry 38:42–47, 1981 Weingartner H, Grafman J, Boutelle W, et al: Forms of memory failure. Science 221:380–382, 1983 Wisniewski K, Howe J, Williams DG: Precocious aging and dementia in patients with Down’s syndrome. Biol Psychiatry 13:619–627, 1978 Wolfson C, Wolfson DB, Asgharian M, et al: A reevaluation of the duration of survival after the onset of dementia. N Engl J Med 344:1111–1116, 2001 Wood S, Cummings JL, Hsu MA, et al: The use of The Neuropsychiatric Inventory in nursing home residents. Characterization and measurement. Am J Geriatr Psychiatry 8:75–83, 2000 Zola-Morgan S, Squire LR, Amaral DG: Human amnesia and the medical temporal region: enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus. J Neurosci 6:2950–2967, 1986

CHAPTER

2

Dementing Illness as a Psychobiological Process Myron F. Weiner, M.D.

Although certain symptoms by definition constitute the core of the dementia syndrome, the clinical presentation of any dementing illness differs among individuals because these symptoms result from interacting social, psychological, physical, and biochemical forces. These symptoms fluctuate from hour to hour and from day to day, depending on patients’ emotional makeup, their interpersonal and physical environment, and changes in their general health and in the nature and progression of their underlying brain disease. As illustrated in Figure 2–1, the development of the full-blown dementia syndrome results when the threshold for adequate cognitive function—a threshold that varies from individual to individual and from time to time within any given individual— has been exceeded. Progression from normal functioning to mild cognitive impairment to dementia may be subtle and gradual, as in the case of Alzheimer’s disease, or progression to dementia may occur catastrophically, as in stroke, brain trauma, or fulminant Creutzfeldt-Jakob disease. A dementing illness may also manifest suddenly after a trivial brain insult, such as a mild episode of hypotension during spinal anesthesia for prostate surgery. In the latter case, we hypothesize that the minor brain insult reduces the brain’s overall integrative capacity to the point that the formerly subthreshold process manifests. The same phenomenon may result from psychological factors in persons whose brain function is already compromised. When experiencing high levels of anxiety or depression, such persons become more confused because they are unable to deal simultaneously with intense emotion and multiple environmental stimuli. Another frequent occurrence is the increased confusion of persons whose compromised brain function is not apparent until they attempt adapting to a new living situation, such as moving from one house to another. Still another is the unmasking of the cognitive impairment of one spouse on the death of the other. 49

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FIGURE 2–1. A model of cognitive functioning. If the symptoms that develop in the course of dementing illness are viewed outside the constraints of dementia as defined in DSM-IV-TR (American Psychiatric Association 2000), it can be seen, using the same analogy as in Figure 2–1, that the threshold model can be applied to other aspects of dementing illness than information processing. The threshold model applies, for example, to behavioral disinhibition with resultant verbal and physical aggression toward others. Although this symptom is related in part to memory and other information-processing deficits, cognitively impaired persons with relatively mild memory deficits frequently lose their ability to refrain from grasping or striking out at others verbally or physically when frustrated or distressed. This is especially a problem when caregivers see them as psychologically clinging, illtempered, or vindictive and begin to react to cognitively impaired persons as manipulative or deliberately cruel. Consultation was requested for a 69-year-old man who had been admitted to a special care unit for disturbed dementia patients. The examiner greeted

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the patient, who was seated at a dining room table, and had a pleasant interaction concerning the patient’s former business and the types of merchandise he had sold. The patient acknowledged that he had difficulty with memory that was annoying, and also that he had difficulty with word finding. The examiner noted that the patient was seated in a wheelchair and asked the patient if he had difficulty walking. The patient said that he had mild difficulty walking due to his Parkinson’s disease. A few minutes later, the patient began attempting to stand and was told by an attendant to seat himself. This angered him. He pulled away from the table and wheeled himself away. When another attendant offered to tie his shoelaces, he began an angry, accusatory outburst, saying that he would decide if his laces needed to be tied and that if they did he would do it himself. The angry interaction between him and the staff members escalated as he again began to stand and they attempted to reseat him. He finally stood up and was able to walk by pushing the wheelchair. When the patient was reapproached by the examiner another angry outburst ensued, and the patient said he would never speak to the examiner again. The staff had a particularly difficult time with this man because his memory was far less impaired than that of others on the unit; they had difficulty understanding that his impairment was largely in the realm of judgment and emotional control.

Personality Function in Dementia Although it is not independent of the brain, the mind can be thought of as having a dynamic structure of its own. There are many dynamic schemas to explain the functioning of the mind. I use the Freudian schema, which conceives of mental functioning as a balance of the mind’s adaptive, coping, and defensive functions (the ego), the pressure of the sexual and aggressive drives (the id), and internal standards of behavior (conscience or superego). In brain-damaged persons, adaptive or coping ability is reduced, which may result in the development of emotional symptoms, perceptual or ideational disturbances, or problem behaviors. The nature of the symptoms and behaviors is partly determined by a preexisting personality structure and the new relationship between individuals and their sense of what they ought to be (their ego ideal). For some persons, their ego ideal may be the ability to nurture others or to competently maintain a household; for others, it may be the ability to function at a paying job. Thus, in early dementing illness, loss of ability to function in ways that are significant to the individual causes greater distress than does a person’s global loss of function. For example, a man with early Alzheimer’s disease who prided himself on his organizational ability became enormously distressed when he was unable to gather income tax information for his accountant and literally spent days and nights repeatedly making lists of his assets that he was unable to organize.

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Coping Ability The concept of adaptive or coping ability is important for understanding much of the phenomenology of dementing illness. To cope adequately with the demands of everyday living, a person must have sufficient ability to appropriately suppress, repress, or sublimate the demands of drives and conscience or to find adequate substitutes for meeting those demands. When a person lacks the ability to repress, suppress, sublimate, or substitute, the classic psychological defense mechanisms delineated by Anna Freud (1946) come into play. Coping ability is related only in part to cognitive integrity. It is also related to the biological integrity of the person as a whole and to that person’s ability to make positive relationships with others, to control impulses, test reality, take psychological or physical action, and assume responsibility for actions taken. Biological integrity refers to the ability to receive and interpret stimuli, to initiate and perform motor behavior necessary for self-maintenance, and to have sufficient psychological and physical energy to attend to matters outside of maintaining the integrity of one’s physical being. Thus, a person who has just experienced a myocardial infarction and is having intense chest pain has little ability to deal effectively with other matters. The same is true of a person whose emphysema is so severe that breathing requires active concentration and deliberate effort. By contrast, a trivial distraction makes it impossible for a cognitively impaired person to function at a task requiring concentration.

Personality Structure Personality refers to an individual’s predominant patterns of coping mechanisms and defenses. Common patterns of personality structure are found in DSM-IV-TR in their most exaggerated form—as personality disorders. Personality disorders differ from the traits that constitute more normal personality structure in the personality-disordered individuals’ tendency to employ stereotyped patterns of dealing with the world. Thus, many persons enjoy self-display and being the center of attention, as do persons with a histrionic personality disorder. The person with a histrionic trait is still able to function when not the center of attention. The person with a histrionic personality disorder often seeks attention through physical symptoms or outrageous behavior when he or she is unable to secure it through ordinary self-display. Personality styles include obsessive-compulsive, paranoid, avoidant, antisocial, and schizoid. Premorbid personality has much to do with the ability to concentrate, to establish positive relationships with others, to test reality, and to assume


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responsibility. Dementing illness uncovers aspects of the personality that were partially suppressed when the individual was biologically intact. Individuals who were formerly able to suppress their irritability may begin to lash out. Persons with pronounced dependent needs may become even less willing to do for themselves. Those who relish their autonomy may strive in unrealistic ways to maintain that autonomy and refuse appropriate help. This is often seen in the case of widowed elders, independent for many years, who refuse the help of neighbors and the public health nurse in meeting their needs as their sight, hearing, cognitive function, and physical health fail. Through historical information provided by the patient and others, it is possible to determine which behaviors are temporary reactions and which are aspects of the individual’s personality and are largely unalterable (Weiner 1984). This information also gives cues for managing patients. Knowing, for example, that a particular patient has had a lifelong inability to share, it would not be expected that this patient could comfortably tolerate a nursing home setting that involved sharing a room. A person who has been dominant in relationships throughout life will find it difficult to be under the control of others.

Dementing Illness as a Psychological Process A dynamic psychological view of dementing illness makes it easy to understand the fluctuating cognitive and behavioral symptoms of persons with intact and impaired brain function. Emotionally healthy persons are kept alert and are challenged by small increments of anxiety. Intense anxiety, on the other hand, impairs concentration, learning, and behavioral control. The greater number of brain systems that are affected, the greater the detrimental effect of anxiety. Thus, small changes in a person’s level of emotional tension during the course of a day can produce large fluctuations in coping ability and behavioral control. The same is true of sensory input. Adequate sensory input helps to maintain orientation in time and space; overwhelming input in the form of too novel or too many stimuli also increases confusion and impairs self-control. Persons with dementing illness are frequently accused by family members and professional caregivers of exaggerating their degree of cognitive impairment because these individuals appear to remember emotionally charged events but seem to rapidly forget neutral information, such as the location of items in the kitchen. This, however, is not unique to persons with dementing illness. The same phenomenon occurs in cognitively intact persons (Heuer and Reisberg 1990); it appears to be mediated by the >-adrenergic system and can be blocked by the >-adrenergic receptor antagonist propranolol (Cahill et al. 1994)


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The psychology of dementing illness involves all of the coping mechanisms and defense mechanisms outlined in Tables 2–1 and 2–2. Table 2–1 indicates positive adaptive or coping mechanisms. TABLE 2–1.

Coping mechanisms

Decision making Mobilization of will Assumption of responsibility Stimulus seeking Mastery Attribution of meaning Trust of oneself and important others Hope

TABLE 2–2.

Defense mechanisms

Neurotic

Immature

Psychotic

Repression Intellectualization Isolation Displacement Reaction formation Dissociation

Projection Fantasy Hypochondriasis Passive-aggressive behavior Acting out

Denial of external reality Distortion Delusional projection

Source.

Adapted from Vaillant 1977.

The capacity for positive adaptation involves the ability to make decisions and to follow through with appropriate activity. Making decisions and taking action both involve the assumption of responsibility: acknowledging one’s own actions as a product of one’s own wishes or fears. Psychologically healthy persons tend to seek out novel stimuli and attempt to master and attribute meaning to their environment. They learn when they can trust their own judgment and the judgment of others, and they maintain hope that they can positively influence the world about them and derive a sense of satisfaction from their activities. Five other coping mechanisms have been described by Vaillant (1977) based on a long-term study of healthy men. They are 1) sublimation, 2) suppression, 3) altruism, 4) anticipation, and 5) humor. Sublimation is converting physical and psychological drives into socially acceptable thoughts and actions. Suppression is waiting for the best moment to express a thought or to act. Altruism is doing for others without expectation of personal gain. Anticipation is planning constructive action. It differs from


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worry or rumination, which lead primarily to greater worry rather than constructive action. Humor is the ability to enjoy surprise and uncertainty and to surprise others in a pleasant way. Coping mechanisms begin to fail in cognitively impaired persons. Because decision making and follow-through become difficult, such persons often blame others instead of recognizing that they have lost decisionmaking ability and initiative. Instead of acknowledging an inability to remember, these persons blame others when they do not meet their responsibilities. They rationalize inappropriate behaviors; they avoid new stimuli. They find that comprehension and mastery of the environment become more difficult, leading to feelings of hopelessness and helplessness. Instead of sublimating, raw drives emerge, sometimes in the form of inappropriate aggression or inappropriate genital display. Lack of ability to suppress leads to impatience. Self-centeredness replaces altruism as impaired coping ability reduces the capacity for empathy. Anticipation gives way to impulsiveness or inertia. Laughter in reaction to novel stimuli is replaced by startle and upset. A positive strategy for dealing with reduced coping ability is acknowledging the deficit and consciously developing compensatory mechanisms such as making lists, avoiding unfamiliar places, asking questions, and depending on others to solve problems. Often, however, there is damage to the brain regions that enable self-awareness. Patients with Alzheimer’s disease, for example, are frequently unaware of their memory deficits (Sevush and Leve 1993). Persons with frontal lobe damage are unaware of their impaired judgment. Persons with Wernicke’s aphasia frequently do not grasp their inability to understand what others are trying to communicate to them. Without self-awareness, conscious compensatory mechanisms are less likely to be developed. Persons with dementing illness whose coping mechanisms and self-awareness are intact may experience normal mourning for the loss of their former self (Bahro et al. 1995). Many persons with mild cognitive impairment become self-critical and experience lowering of self-esteem resulting from an imbalance between their ego ideal, their performance standards, and their impaired coping ability. The person can no longer live up to an ego ideal that includes productive work. In addition, self-criticisms that would ordinarily be dismissed overwhelm the personality and flood it with guilt and self-recrimination. The defenses shown in Table 2–2 represent failures of positive coping ability. They are mechanisms used to deal with its inadequate capacity to perceive, integrate, and act effectively on stimuli that impinge on the organism from within and without. As originally formulated (Freud 1946), these mechanisms referred to defenses against awareness of unconscious wishes or conflict, but they can also defend against awareness of unpleasant

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or frightening aspects of reality. The defense mechanisms listed in Table 2–2 are classified by Vaillant (1977) into three groups: neurotic, immature, and psychotic, based on the frequency with which they are associated with various mental disorders and stages of development. Many types of defense are adopted by persons with dementing illness, depending on their premorbid personality, their environment, and the rate at which their illness progresses. Rapidly progressive brain disorders may provoke more primitive defense mechanisms, such as denial, distortion, and delusional projection. Denial is found frequently in all forms of dementing illness. It is not the same as neglect, such as the syndrome of contralateral neglect that often accompanies lesions of the right (nondominant) hemisphere (Denny-Brown et al. 1954). The apparent denial by many cognitively impaired patients of their defects in memory and judgment is often due to losing the neuronal substrate for self-observation. In a study of individuals with Alzheimer’s disease, Derouesne et al. (1999) showed that persons with mild Alzheimer’s disease were aware of the existence of their deficits, but not the severity of deficit or their degree of incapacity. Decreased awareness correlated positively with apathy and frontal perfusion deficits detected with single photon emission computed tomography, whereas, as would be expected from the psychological standpoint, persons with greater awareness of deficit were more anxious. Defenses from Vaillant’s category of neurotic mechanisms are not prominent in dementing disorders. Some persons appear to accept their impairment, but then demonstrate by their behavior that they simultaneously do not recognize any impairment. Displacement is occasionally employed, as indicated in the following case of Alzheimer’s disease: A 67-year-old widow was being evaluated for symptoms of dementia that had progressed over a 4-year period. When asked if she had any difficulties, she replied that she had a painful ankle and showed her leather-braced ankle to the examiner. She said that since she had started wearing the brace, the arthritis in her ankle was considerably less troublesome. Later, the examiner began a formal inquiry into her cognitive state, asking questions to test her memory, concentration, and fund of information. When at a loss for an answer to a question, she would reply that her ankle was hurting and interfering with her concentration.

Other persons develop reaction formations against their impairment, putting in longer hours at work to compensate for their slowed thinking and impaired comprehension. On one occasion, it was necessary to hospitalize a man with early dementia who had become delirious from working long hours and losing sleep in an effort to keep up with his work. The catastrophic reactions (Goldstein 1942) that occasionally occur when cognitively impaired persons are faced with an intense emotional


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stimulus or unmanageable cognitive input may take the form of a confused state. The person suddenly becomes unable to recognize a familiar environment or undergoes a sudden emotional regression and begins calling for long-dead parents or other relatives as though they were still alive. This is illustrated in the following example: A 70-year-old man with Alzheimer’s disease became frightened when he was unable to recognize his wife and began calling out for his mother. He remained in this excited state until he was calmed by his son, whom he was able to recognize.

Catastrophic reactions are usually self-limited and are best contained by distraction or by removing or making understandable the aggravating environmental stimuli. Immature defense mechanisms are often employed by dementia patients. Projection in the form of blaming (as opposed to delusional projection) often occurs early in the course of a dementing illness. A wife will exclaim with irritation that her husband did not tell her the children were coming to visit. An impaired husband will rage at his wife for hiding the car keys that he misplaced. The potential use of fantasy as a defense mechanism is impaired because of attention and memory deficits, but somatic preoccupation is often encountered, with a host of physical complaints being offered to distract from the potential awareness of decreased cognitive ability. Rather than passive opposition (which involves the ability to inhibit an impulse), cognitively impaired persons often express direct aggression in the form of blaming. Acting out is also common, precisely because these individuals lack the ability to inhibit their behavior. Thus, inappropriate aggression or sexual display may sometimes occur. For example, a nursing home roommate is screamed at for intruding instead of being politely asked to leave, or open masturbation may occur in response to genital stimulation from tight clothes. Psychotic defense mechanisms are seen frequently in dementia patients. The denial of impairment is common, as was previously noted. Distortion is illustrated by a dementia patient thinking that he or she is in a prison rather than a nursing home. Delusional projection may occur when a dementia patient who is unaware of having a defective memory attributes an inability to keep up with house keys to others deliberately removing them. Persons with dementing illness occasionally develop a transient delusional system to support such contentions, as seen in the following example: A woman with severe cognitive impairment who was unable to comprehend her environment, dealt with the problem by refusing to leave her house to

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venture into an unfamiliar environment. She responded to all visitors as intruders, calling them whores and attempting to drive them off in an effort to keep her environment simple and comprehensible.

Delusion formation also occurs without the element of projection, especially in persons who develop prosopagnosia, the inability to identify faces. A man with prosopagnosia became very concerned when he failed to recognize his wife while on a trip. He became agitated and exclaimed that he was being kidnapped. Such delusions are usually transient and tend to occur when the environment becomes too demanding. Regression, another prominent mechanism employed by cognitively impaired persons, is reverting to adaptive mechanisms appropriate to an earlier era of life, usually early childhood. Regression can take many forms. It may manifest as infantile clinging to loved ones, avoidance of strangers, tantrums, inappropriate or unnecessary dependence, or attempts to obtain special attention from others. When regression takes the form of physical clinging to other persons, dolls or stuffed animals can often be substituted for the constant presence of another person. This parallels the use of socalled transitional objects to serve the emotional needs of young children who also lack object constancy—the ability to recognize that an object no longer in reach or in view can continue to exist (Piaget 1954). Whether such cognitive regression occurs in dementing illness has not been formally tested, but clinical experience suggests that it probably does occur. And, as with a young child, reassurances that one will return are often insufficient. A young child becomes upset recalling the unpleasurable experience of loss; a cognitively impaired person becomes upset in some measure because of inability to remember the promise to return. The psychological mechanism of splitting, which is frequently evident in dementing illness, may be part of the regressive process. This mechanism, theorized by Klein (1957) to be characteristic of an early stage of personality development, involves the active separation of good from bad experiences, perceptions, and emotions linked to other persons. Thus, the frustrating aspects of an emotionally important person are split off from his or her caring aspects to form an entirely separate person: one is all good and the other is all bad, as seen in the following example: A woman with Alzheimer’s disease, was having increasing difficulty identifying her husband. One night, frustrated with her seemingly endless repetitiveness, her husband spoke to her with a harsh tone of voice. The woman reacted with alarm. She perceived him as having become two persons, both of whom were claiming to be her husband. Frightened and unable to determine who was her real husband, she fled the house to the home of a neighbor and had the neighbor call the police. The following day, she was still not certain which of the two men was her husband. She could not fathom


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how her real husband could be so unkind to her and resolved her psychological problem by splitting him in two.

The splitting process described in the preceding case may contribute to the development of Capgras’ syndrome.

Psychological, Behavioral, Ideational, and Perceptual Concomitants of Dementing Illness Certain frequent psychological and behavioral concomitants of dementing illness warrant individual discussion from a psychological viewpoint. They are 1) depression, 2) delirium, 3) anxiety, 4) behavioral dyscontrol, 5) sleep-wake disturbances, 6) suspiciousness and delusion formation, 7) hallucinations, and 8) apathy and withdrawal. The catastrophic response has already been discussed.

Depression Major depression occurs in some series in 10%–20% of Alzheimer’s disease patients (Wragg and Jeste 1988). In our own dementia clinic, major depression was present in only 1% of Alzheimer’s disease patients at initial evaluation (Weiner et al. 1991), and there were no new cases of major depression in 153 patients followed up for an average of 3 years (Weiner et al. 1994). However, our experience may not reflect the true prevalence of major depression in Alzheimer’s disease because ours is a tertiary care clinic. Presumably, most cases of major depression would have been diagnosed and treated elsewhere. On the other hand, symptoms usually associated with depression are frequent in Alzheimer’s disease (Cummings et al. 1995), with agitation, motor restlessness, sleep disturbance, and tearful episodes occurring in 25%–50% of patients in one series (Reisberg et al. 1987). Chen et al. (1999), who prospectively studied a large series of elders, found that a “depression cluster” of five or more DSM-III-R depression symptoms (including depressed mood) followed the onset of dementia (15.4%) and Alzheimer’s disease (17.6%) compared with nondemented subjects (3.2%). Among other dementia-associated disorders, depression occurs in Parkinson’s disease (Cummings 1992), Huntington’s disease, multiple sclerosis, epilepsy, brain trauma, and stroke (Starkstein and Robinson 1993). The prevalence of depression is high during the first 2 years after a stroke (Robinson and Price 1982). The relationship between depression and the size, location, or cognitive impairment of stroke is controversial (Robinson et al. 1983; Schwartz et al. 1993), but depression does appear to magnify the cognitive effects of the stroke.

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There is evidence that depression occurring in old age may herald the onset of a dementing illness, whether the depressive episode is one of many lifelong depressive or manic-depressive episodes or whether it arises de novo in old age. In one study, 57% of depressed nondemented elderly patients developed frank dementia within 3 years (Reding et al. 1985). In a study of 14 patients still alive at 15- to 47-month follow-up, 43% had developed dementia (Bulbena and Berrios 1986). Dhingra and Rabins (1991) found that of 25 bipolar patients age 60 years or older followed up for 5–7 years, 32% had developed significant cognitive impairment. It has been suggested that episodes of mood disorder may do damage to the brain, possibly caused by the accompanying hypersecretion of cortisol (Altshuler 1993). More recent large prospective studies have not added strong confirmation to earlier studies. Speck et al. (1995), using a case-control design, compared 294 probable Alzheimer’s disease patients with 300 age- and sexmatched control subjects. Depression was defined in this study as depression for which medical/psychological consultation, medication, or hospitalization occurred, and excluded treatment for grief reactions. The odds ratio for Alzheimer’s disease was 1.8 (95% confidence interval = 0.9–3.5) after adjusting for age, gender, education, and type of informant. When stratified by year of onset, the association between depression and Alzheimer’s disease was present only in the group with depressive symptoms preceding cognitive impairment by 10 or more years (odds ratio of 2.0, 95% confidence interval = 0.9–4.6). In another prospective community-based study, 954 nondemented persons 65 years or older were followed every 2 years over 8 years (Chen et al. 1999). In this group, there was an association between Alzheimer’s disease and depression defined by the presence of five or more depressive symptoms, including depressed mood (odds ratio = 6.5, 95% confidence interval = 2.2–19.1), but depression did not confer significantly greater risk for the development of dementia or Alzheimer’s disease. Major depression appears to be a psychosomatic-somatopsychic disorder involving the interaction of genetically determined and environmentally induced vulnerabilities with intercurrent psychological and physiological factors. In a study of poststroke depression, for example, 20% of the depressed patients had a prestroke history of depression (Schwartz et al. 1993). Two studies (Pearlson et al. 1990; Strauss and Ogrocki 1996) found that depressed Alzheimer’s disease patients with no previous history of depression had significantly more first-degree relatives with depression than did nondepressed Alzheimer’s disease patients. In a prospective study, Heim et al. (2000) studied four groups of women: control subjects with no history of childhood abuse or psychiatric disorder, women with childhood abuse and no major depression, women with childhood abuse and depres-


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sion, and women with depression and no childhood abuse. Women with childhood abuse had increased adrenocorticotropic hormone and heart rate response to stress; this increased response was even greater in women with childhood abuse and depression or anxiety. Abnormalities of the norepinephrine and serotonin systems appear to be important in the development of depressive illness, but their dysfunction is likely due to their role in modulating and being modulated by other neurobiological systems (Ressler and Nemeroff 2000). There is considerable evidence for dysfunction of the hypothalamic-pituitary-adrenal axis in major depression, including increased basal cortisol levels, dexamethasone-mediated negative feedback resistance, increased cerebrospinal fluid levels of corticotropinreleasing factor, and blunted adrenocorticotropic hormone response to challenge with exogenous corticotropin-releasing factor (Plotsky et al. 1998). However, these seem to be state rather than trait markers. Depression may be triggered by physiologic or psychological factors or by both. At first, an amotivational state appears. This state may result from catecholamine dysregulation, neuroendocrine factors, or an exaggerated phylogenetically determined reaction to a situation experienced as an overwhelming threat to psychological or physical survival. This state was described as conservation withdrawal by Engel and Schmale (1972) and was later suggested by Weiner and Lovitt (1979) as a possible physiologic substrate of depression. The physiologic reaction, once established, becomes partially autonomous and unresponsive to changes in the precipitating psychological factors. Even so, it is useful to conceptualize depression psychodynamically. The utility of the psychodynamic conceptualization of depression is that it suggests a means for patients’ psychological management. Injury to or death of neurons depletes the capacity of the ego to deal effectively with the demands of the id, superego, ego ideal, and external reality. Subclinical brain damage also interferes with the ability to live up to one’s ego ideal and results in guilt and lowering of self-esteem. There is an increased danger of id impulses erupting or irrational superego demands increasing at the same time that the ego is having greater difficulty interpreting environmental stimuli. Given a biological vulnerability to depression, overt depression may manifest when triggered by stressors such as illness, brain damage, or aging. The most common of these stresses is loss, including loss of a loved one, loss of health, loss of meaningful occupation, and so on (Engel 1962). These losses may be real, but symbolic or threatened losses may be equally powerful precipitants of depression. Thus, the illness of a spouse (or other loved one) or a spouse’s threat to leave can be as potent a trigger as the death of a spouse, as illustrated in the following example:

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An 82-year-old retired ironworker became increasingly withdrawn and apathetic after his daughter’s divorce and the near loss of a favorite grandson in a motorcycle accident. His sleep pattern was disturbed with initial, middle, and terminal insomnia. He reacted to his slowing of bowel function by refusing to eat, for fear that food would block his intestinal tract. The patient had no history of emotional disorder before experiencing a stroke some 10 years previously. This was his third episode of severe depression since that time. At the time of his first depressive episode, he developed the delusion that federal agents were pursuing him for tax evasion. He had previously responded well to electroconvulsive therapy; therefore, he was given five such treatments, because his depression was refractory to treatment with antidepressants and because of the immediate danger of inanition. His mood responded well to that treatment.

Depression may not be accompanied by guilt (Harrow and Amdur 1971); in my experience, depression in the elderly is less often accompanied by guilt and self-derogation than is depression in younger adults. It more commonly appears as apathy and listlessness out of proportion to that person’s physical state. When pathological ideation is present, it may involve delusions of persecution for misdeeds, as indicated in the previous example. In the case of a 92-year-old nursing home patient with cognitive impairment, delusions centered on her being possessed by the devil and the nursing home staff planning to get rid of her because she was too demanding.

Suicidal Behavior and Suicide Suicidal behavior and completed suicide in persons with dementing illness may result from depression or from a combination of factors including depression (Rubio et al. 2001). Such factors may include other physical illness, social isolation, diminishing financial reserves, diminishing quality of life, and concern over burdening others. Depression-related suicidal ideation usually diminishes when the depression is treated successfully. There is not a great danger of suicide in cognitively impaired patients who are unaware of their deficits and who deny or do not comprehend their prognosis. On the other hand, persons with progressive dementing illnesses who are painfully aware of their cognitive deficits, their growing dependence on others, and the potential outcome of their disease may choose to end their own lives. They may make successful suicide attempts without being significantly depressed (Rohde et al. 1995). There is a strong association between Huntington’s disease and suicide. In a review of 831 Huntington’s disease patients from the National Huntington’s Disease Research Roster, 5.7% of deaths among affected persons resulted from suicide; 27.6% of patients had attempted suicide at least once (Farrer 1986). A review of death certificates for 395 Danish subjects with


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Huntington’s disease and 282 unaffected siblings showed that suicide accounted for 5.6% of deaths among those affected with Huntington’s disease compared with 2.7% in the general Danish population (Sorensen and Fenger 1992). Risk factors were identified in 9 persons affected with Huntington’s disease. Of these, 8 were male; 6 were single or divorced. Duration of illness was 1 to 14 years. The largest risk factor in the Huntington’s disease patients was having no children. Other factors were living alone, other suicides in the family, contact with other Huntington’s disease patients, and depression (Lipe et al. 1993). The availability of genetic testing for Huntington’s disease raises the issue of risk for those certain to develop the disease but who are not yet affected. Ethical aspects of such testing is discussed in Chapter 10. A survey of Huntington’s disease predictive centers worldwide showed that a total of 44 persons (0.97%) in a cohort of 4,527 test participants had catastrophic events: 5 suicides, 21 suicide attempts, and 18 psychiatric hospitalizations (Almqvist et al. 1999). All persons who committed suicide were symptomatic, whereas only half of the persons attempting suicide and 44% of those with psychiatric hospitalization were symptomatic. Increased risk in this series was associated with unemployment and history of psychiatric illness within 5 years of testing. Lawson et al. (1996) suggest that all persons entering into predictive testing with some evidence of depression warrant special vigilance and that counseling and support should be available for all participants in such testing.

Delirium From the psychological standpoint, delirium is the result of rapidly developing impairment of coping or adaptive abilities, manifesting when the individual becomes acutely unable to understand the environment and experiences overload from internal or external stimuli. The cardinal features of delirium include reduced clarity of awareness of the environment; reduced ability to focus, sustain, and shift attention; and cognitive deficits, including memory disturbance and disorientation (see also Table 1–4). These symptoms develop acutely and often fluctuate in severity during the day, becoming most pronounced at night. There is often a prodromal stage of disturbed sleep, bad dreams, and increasing anxiety (Lipowski 1987). Delirium can occur in a person whose nervous system is intact if the systemic illness is severe and has a rapid onset. An example is the sudden onset of pneumococcal pneumonia accompanied by high fever. More often, there is an antecedent vulnerability of the central nervous system, whether due to central nervous system immaturity or damage. Delirium that occurs in response to trivial insults is virtually pathognomonic of an underlying impairment of brain function. In the medical setting, the development of delirium

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in elders is frequent; it often predicts poor functional outcome. For example, among 54 consecutive elderly patients treated surgically for femoral neck fracture, the incidence of postoperative delirium was 27.8% (Edlund et al. 1999). Dementia and prolonged waiting time for surgery were the two principal risk factors. A significantly greater percentage of persons who became delirious were unable to return to their previous dwelling or were either dead, wheelchair bound, or bedridden 6 months after surgery. From the Freudian perspective, persons who experience a sudden increase in brain damage become unable to adequately repress the contents of the unconscious part of the mind and to interpret environmental stimuli. Fragmented, repressed memories may come pouring forth, and persons in the environment become confused with important personages from the past. Therefore, it is easy to understand how a person can appear intact when admitted to a hospital in the company of a familiar loved one but can become delirious in the recovery room with no familiar person, no orienting cues, and sensorium clouded by anesthetic and analgesic medication. Despite the ease of a psychological explanation, each case of delirium warrants medical investigation for conditions such as an undetected stroke (Dunne et al. 1986). The following case is an illustration of delirium: A 67-year-old man, had sought help for memory problems of 1–2 years’ duration. He was treated for presumed normal-pressure hydrocephalus with a ventriculoperitoneal shunt. To his disappointment (and that of his family), no change occurred in his cognitive state. In addition, he was very disturbed by a flare-up of his daughter’s chronic illness. As a result, he became increasingly depressed. He was seen by a psychiatrist who elicited a history of weight loss, appetite loss, decreased energy, terminal insomnia, and crying spells. His mood was depressed, he had psychomotor retardation, and he cried during the interview. His concentration, attention, and recall were all markedly impaired. He saw himself as only a shadow of his former self. The psychiatrist prescribed 40 mg of imipramine per day in divided doses in addition to the 50 mg of diphenhydramine and 15 mg of flurazepam that he was already taking at bedtime to help him sleep. Because there was only slight amelioration of symptoms after 2 weeks, the imipramine dose was increased to 50 mg daily. Two weeks later, the psychiatrist received a call from the patient’s internist, who said that the patient had become psychotic. When interviewed at the hospital to which he had been admitted by the internist, the patient was disoriented to time and space. He thought that his wife was trying to poison him. He insisted that he was in a brothel and that the nurses were trying to solicit him.

In this case, the patient was experiencing a delirium brought on by the three medications he was taking, two of which had strong anticholinergic effects. When his medications were discontinued, his delirium cleared, his mood normalized, and there was no further need for the antidepressant medication.


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Anxiety Anxiety is often experienced in early dementing illness. Many individuals report a fear of losing their mental capacities and a sense of helplessness to understand and deal with their environment. If the personality is totally overwhelmed by new or complex environmental demands, a catastrophic response or a delirium may occur. As individuals become more compromised cognitively, the conscious experience of anxiety may no longer be communicated because of impaired language. Patients may also lose insight into their dementing illness. Agitation and restlessness supervene as alarm responses and as preparation for fighting against or flight from an incomprehensible environment. Teri et al. (1999) found a 70% prevalence of anxiety symptoms in community-dwelling Alzheimer’s disease patients. Chemerinski et al. (1998) found that 5% of 398 persons with probable Alzheimer’s disease met criteria for generalized anxiety disorder during the 4 weeks before undergoing a standardized psychiatric examination. An examination of 92 persons with vascular dementia showed that 72% had two or more anxiety symptoms, with higher prevalence (94%) in persons with severe dementia (Ballard et al. 2000).

Behavioral Dyscontrol Behavioral self-control is related to intactness of executive function: the ability to think abstractly and plan, initiate, sequence, monitor, and stop complex behavior. Although it is not localized to any portion of the brain, executive function is frequently related to the frontal lobes. Impairment of executive function reduces ability to learn from experience, to understand the impact of one’s behavior on others, or to regulate that behavior. Executive dysfunction can manifest as loss of initiative, impulsivity, emotional indifference, or labile mood. Impairment of self-observation manifests in poor personal hygiene and inappropriate interpersonal conduct. Persons with impaired executive function may indulge in inappropriate sexual activity or display; they may develop abnormal eating patterns such as hyperphagia or may readily eat from the plates of others in restaurants or institutions. One form of behavioral dyscontrol has been termed agitation.

Agitation The term agitation has been accepted into the informal nosology of dementia-related behavior disturbances. Agitation is an atheoretical descriptive term that includes behaviors originally observed in a cohort of

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demented and nondemented nursing home residents (Cohen-Mansfield and Billig 1986). The definition given by these authors was “inappropriate verbal, vocal, or motor activity that is not explained by needs or confusion per se” (Cohen-Mansfield and Billig 1986, p. 712). In other words, the term did not apply to persons crying out because they were hungry, because their incontinence pads needed changing, or because they were ignored or abused. Behaviors included under this designation of agitation form the basis of the Cohen-Mansfield Agitation Inventory (CMAI) (CohenMansfield 1986) and include such diverse behaviors as hitting, kicking, pacing, complaining, and screaming. Thus, the term agitation applies to vocal or physical behaviors whose origins or meanings are not understood. Because these behaviors are so heterogeneous, it seems unlikely that they constitute a syndrome, that they have a common etiology, or that they will respond as a group to specific behavioral, environmental, or psychopharmacologic interventions.

Sleep-Wake Disturbances Sleep-wake disturbances are common among persons with dementing illness and are an important factor in caregivers’ decisions to institutionalize them (Pollack and Perlick 1991). The most common sleep-wake disturbances are hypersomnia, insomnia, and reversal of the sleep-wake cycle. A study of demented and nondemented nursing home patients showed highly fragmented sleep, with patients averaging only 40 minutes of sleep per hour during the night (Ancoli-Israel et al. 1989). Comparing Alzheimer’s disease patients with age-matched control subjects, Bliwise et al. (1989) found no difference in the total amount of sleep. However, Alzheimer’s disease patients had poorer quality of sleep, as evidenced by lower mean sleep efficiency, lower percentages of stage 3 and 4 sleep, and a higher percentage of stage 1 sleep. Moe et al. (1995) found in Alzheimer’s disease patients that wakefulness during the night and greater rapid eye movement latency were associated with greater cognitive and functional impairment, suggesting that the neural substrate underlying these processes degenerate at comparable rates. Cognitively impaired persons who are not active frequently doze during the day because of boredom and are awake and restless at night because they have already obtained their required sleep during their naps. Elders’ sleep is often disturbed by pain, by the need to urinate, or by the need to take medications. Stimulants such as coffee, tea, or bronchodilators may contribute to the problem. Obstructive sleep apnea may occur, resulting in frequent sleep interruption, poor quality of sleep, and daytime hypersomnolence (Guilleminault et al. 1973).


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Hypersomnia Medications to control agitation or treat insomnia are highly sedative. Anticonvulsants and antihistamines are as well. Metabolic disturbances stemming from chronic lung disease, renal failure, or liver failure also cause somnolence. From the environmental standpoint, the chief cause of daytime sleepiness is a lack of engaging activities. Sleeping excessively is a way to deal with boredom and to evade the challenge of trying to understand the environment or to initiate behavior. Sometimes caregivers promote daytime sleeping to ease their burden. Unfortunately, this may promote nighttime wakefulness. A sleeping person is easier to manage than a person who is restless and demanding and does not understand how or why certain things must be done, such as urinating or defecating in the toilet.

Insomnia The inability of person with dementing illness to sleep the night through is a common complaint of caregivers. Family caregivers look forward to and need relief at night; nursing homes and other institutions are staffed lightly at night. Thus, both family and institutional caregivers bear an extra burden when their charges cannot sleep. Sleep is interrupted by anxiety, but the most common psychiatric syndrome leading to sleep loss is depression. Severely depressed persons have difficulty falling asleep and staying asleep, often waking 3–4 hours before their usual time and dreading the day ahead. Excessive stimulant intake in the form of caffeine in coffee, tea, or soft drinks or theophylline for bronchopulmonary disease adds to sleep difficulty. In addition, if there is little daytime physical activity, there is little physiological demand for rest.

Reversal of the Sleep-Wake Cycle Daytime napping and nighttime awakening may lead to reversal of the sleep-wake cycle. For elderly persons, getting to sleep and staying asleep are made difficult by painful arthritis and the need to urinate during the night, the latter being aggravated by diuretics to control blood pressure or to ameliorate heart failure. Sleep apnea, with its frequent interruptions of sleep, is also more common in elderly persons. More often than not, sleep difficulty is produced or aggravated by environmental factors, such as scheduling bedtime too early. When examined objectively, many individuals are found to be sleeping 6–8 hours, but their sleep time begins at 8 P.M. and ends at 2–4 A.M.—with attempts at getting up and beginning the day. In many cases, individuals get sufficient sleep from napping during the day.

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In a preliminary study (Satlin et al. 1991), exposure of 10 late-stage Alzheimer’s disease patients to 2,000 lux of light from 7–9 P.M. for 1 week increased evening wakefulness and reduced nighttime activity, with return to former levels 1 week after discontinuance of exposure to bright light.

Suspiciousness and Delusion Formation Many persons attempt to compensate for their impairment with hyperalertness. In a hyperalert state, one becomes aware of many environmental stimuli that are not readily understood, so that the coping mechanism of hyperalertness leads to increasing confusion. Suspiciousness is a variant of the hyperalert or hypervigilant state in which stimuli are interpreted as dangerous. In a situation in which it is not possible to distinguish what is safe from what is dangerous, it makes sense to first view everything as dangerous. It is also frustrating and aggravating to find so much that cannot be understood in a world that one could formerly grasp. What better explanation than the explanation that attempts are being made to deceive? In this way, defective perception and integration can be denied, and it is no longer necessary to explain every event individually or to try to understand each confusing stimulus. The answer is that one is being deliberately deceived. For example, a man with dementia does not perceive himself as being unable to identify his wife. Instead, he regards the woman who says she is married to him as an impostor. A final important aspect of delusional thinking is that it enables action. Perceiving danger as external enables one to avoid it or to attack it, thus reducing the unpleasant feeling of helplessness that comes from being confused. Anxiety is dealt with in the same way. No longer able to recognize that anxiety results from inner tension, the person with dementia experiences fear and attributes it to the external environment. Common delusional beliefs include believing that others are in the house (phantom boarders), that one is not in one’s own home, that one’s spouse is an impostor (Capgras’ syndrome), and that deceased loved ones are still alive. The delusional beliefs of persons with dementing illness can often be temporarily reduced by gentle confrontation with reality, in contrast to such beliefs of persons with mental illnesses such as schizophrenia.

Confabulation and Related Phenomena When individuals with severe memory impairment, such as those with amnestic syndromes, are asked questions, they often supply elaborate, incorrect answers. When questioned about their place of residence, for example, individuals living at home with a spouse may indicate that they live in a


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hotel and may provide details about the hotel that are often based on earlier experiences in life. Confabulations do not have the emotional force of delusions, nor do confabulators cling to their stories. Other cognitively impaired persons speak of long-deceased persons as though they were still present without giving evidence that they have experienced hallucinations. Or they will look for children who long ago grew up and moved away. Common questions by these individuals are, “Where has mother gone?” or “Where are the children? It’s time for them to go to school.”

Delusional Syndromes A number of delusional syndromes have been reported in cognitively impaired persons. They include Capgras’ syndrome (Burns and Philpot 1987) and Cotard’s syndrome. In the former, there is the fixed belief that there are doubles of others, and there may be the belief that there are doubles of one’s self. Merriam et al. (1988) found Capgras-like symptoms to occur in 17% of Alzheimer’s disease patients. In Cotard’s syndrome, individuals believe that parts of their bodies are missing, that they do not exist, or that the world about them does not exist. In dealing with Cotard’s syndrome, the clinician must suspect major depression in addition to dementing illness. Alzheimer’s disease patients also often express the notion that an unseen person is living in the house; the so-called phantom boarder syndrome (Rubin et al. 1988). Patients who are unable to recognize themselves in a mirror may develop the delusion that another person is present. One of our patients became fearful of entering an automobile because he always saw the face of the same person in the window glass on entering a car.

Illusions Illusions occur commonly in cognitively impaired persons. An illusion is a mistaken perception: mistaking one thing for something else because of a real or imagined resemblance. For example, a man with dementia mistakes his wife for his mother. She resembles his mother in that she is roughly his mother’s age when she was last alive, and the notion of “mother” is nurturing and comforting. An illusion that becomes a fixed belief is a delusion.

Hallucinations Hallucinations are false perceptions; that is, they are reports of sensory impressions that cannot be consensually validated. Hallucinations are frequent in delirium and dementia. Delirious persons frequently envision animals crawling up the walls or feel ants crawling on their skin. Dementia

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patients often report children or small adults running in and out of their homes or airplanes flying overhead. They frequently watch in fascination but often become excited and upset. Hallucinations can be explained psychologically in the same way as delusions. They are means to organize an otherwise incomprehensible environment and are often determined by personal needs or wishes, as exemplified by the frequent hallucination of loved ones who are no longer living. Hallucinations may also have a physiological component; that is, they may be stimulated by abnormal electrical discharges of the brain, as in partial complex seizures, which often have an olfactory aura of an unpleasant smell such as burning feathers or burning rubber. Just as it does with incomprehensible environmental stimuli, the mind can organize incomprehensible sensory stimuli from within the brain into perceptions that can be understood and reacted to (Weiner 1961).

The Charles Bonnet Syndrome Patients with Alzheimer’s disease frequently experience a type of visual hallucinatory state or hallucinosis that may or may not be disturbing to them. Often described as the Charles Bonnet syndrome, and often attributed to visual impairment, the state consists of seeing formed, complex, often stereotyped visual hallucinations. Patients often have the sense that they are not real. There are no accompanying delusions, and hallucinations are not present in other sensory modalities (Gold and Rabins 1989). One of our patients with Alzheimer’s disease saw people in his house with Xs for eyes. They were never the same people from day to day, and none was recognizable as anyone he knew. He was mildly puzzled by the presence of these people, would talk to them (they did not reply), and was able to tolerate their presence very well. Another Alzheimer’s disease patient saw individuals with peculiarly colored hair. They seemed to appear in groups. They did not speak. Some of them had only half-bodies that they propelled with their hands. This type of hallucinatory experience has been reported to occur commonly in the Lewy body variant of Alzheimer’s disease and in diffuse Lewy body disease.

Apathy and Withdrawal Apathy has become the subject of a large body of recent literature. The term is derived from the Greek a (without) + pathos (feeling or passion) (Thomas 1889). The term has been expanded to include the absence or lack of feeling, emotion, interest, concern, or motivation (Robinson and Starkstein 2000), but the motor aspect of apathy is properly termed abulia, from the Greek a (without) + boulon (will) (Thomas 1889). The latter term was


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reintroduced by Adams and Fisher (Fisher 1984) to describe the slowness and loss of spontaneity in cerebral disease ranging from its mild form, apathy, to the extreme form, akinetic mutism. Apathy may be a direct result of or a psychological reaction to brain injury. Apathy, as manifested by social withdrawal, is one of the earliest signs of Alzheimer’s disease, antedating the clinical diagnosis by 2 years or more (Jost and Grossberg 1996). Apathy is often associated with injury to frontal convexity and is a frequent concomitant of frontotemporal degenerative disorders; it also occurs after closed head injury (Kant et al. 1998) and in individuals who are seropositive for human immunodeficiency virus (Castellon et al. 1998). In a series of persons with traumatic brain injury, stroke, and hypoxic brain injury, apathy was associated with subcortical and right hemisphere damage (Andersson et al. 1999). Although apathy is frequently associated with depression, for example, in left hemisphere stroke (Marin et al. 1994), many depressed persons do not display apathy. Marin et al. (1991) showed that apathy as detected by the Apathy Evaluation Scale was distinguishable from anxiety and depression. Levy et al. (1998) used the Neuropsychiatric Inventory (Cummings et al. 1994) to evaluate the relationship between depression and apathy in patients with Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease, Huntington’s disease, and progressive supranuclear palsy. Apathy did not correlate with depression in the combined sample. Although apathy was related to decreased cognitive function, depression was not. Apathy can also be a psychological reaction to an environment perceived as hostile, unrewarding, or incomprehensible. As a result of feeling overwhelmed, cognitively impaired patients first withdraw into an environment that they can comprehend. When that fails, they may become apathetic and withdraw emotionally as well as physically.

Summary Viewing the symptoms of dementing illness as the product of a dynamic interaction between biological and psychological forces enables clinicians to recognize that fluctuations in cognitive and behavioral/emotional symptoms in persons with dementing illnesses are the norm. However, when confronted with increased disorientation in a cognitively impaired person, clinicians must consider whether the increased confusion or behavioral/emotional symptoms result from progression of the underlying brain disease, metabolic factors, the onset of depression, change in the relationship between the patient and others, or change in the physical environment.

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The clinician’s intervention will depend on which variable or group of variables predominates. Having made an adequate diagnosis of the disease underlying the presenting symptoms, clinicians perform appropriate examinations, order appropriate tests, and assay the effects of interpersonal and environmental changes when the clinical course appears out of line with what is known of the general progress of the illness. In some cases, cognitive function or behavioral dyscontrol will improve when cardiac function is improved, when a urinary tract infection is treated, when the patient is better hydrated, when the environment is simplified by maintaining the same routine every day, or when the person is kept in a familiar environment. In other cases, there will be no change or the patient’s status may actually worsen. The clinician will again investigate to determine whether there are adverse effects from medications or unexpected reactions to interpersonal or environmental changes. In all cases, the patient’s level of functioning is the result of a delicate balance between factors that become increasingly difficult to evaluate as dementing illnesses progress.

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Cahill L, Prins B, Weber M, et al: >-Adrenergic activation and memory for emotional events. Nature 371:702–704, 1994 Castellon SA, Hinkin CH, Wood S, et al: Apathy, depression, and cognitive performance in HIV-1 infection. J Neuropsychiatry Clin Neurosci 10:320–329, 1998 Chemerinski E, Petracca G, Manes F, et al: Prevalence and correlates of anxiety in Alzheimer’s disease. Depress Anxiety 7:166–170, 1998 Chen P, Ganguli M, Mulsant BH, et al: The temporal relationship between depressive symptoms and dementia: a community-based prospective study. Arch Gen Psychiatry 56:261–266, 1999 Cohen-Mansfield J: Agitated behaviors in the elderly, II: preliminary results in the cognitively deteriorated. J Am Geriatr Soc 34:722–727, 1986 Cohen-Mansfield J, Billig N: Agitated behaviors in the elderly, I: a conceptual review. J Am Geriatr Soc 34:711–721, 1986 Cummings JL: Depression and Parkinson’s disease: a review. Am J Psychiatry 149:443–454, 1992 Cummings JL, Mega M, Gray KF, et al: The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 44:2308– 2314, 1994 Cummings JL, Ross W, Absher J, et al: Depressive symptoms in Alzheimer’s disease: assessment and determinants. Alzheimer Dis Assoc Disord 9:87–93 1995 Denny-Brown D, Meyer JS, Horenstein S: Amorphosynthesis from left parietal lesion. Arch Neurol 71:302–313, 1954 Derouesne C, Thibault S, Lagha-Pierucci S, et al: Decreased awareness of cognitive deficits in patients with mild dementia of the Alzheimer type. Int J Geriatr Psychiatry 14:1019–1030, 1999 Dhingra U, Rabins PV: Mania in the elderly: a 5–7 year follow-up. J Am Geriatr Soc 39:581–583, 1991 Dunne JW, Leedman PJ, Edis RH: Inobvious stroke: a cause of delirium and dementia. Aust N Z J Med 16:771–778, 1986 Edlund A, Lundstrom M, Lundstrom G, et al: Clinical profile of delirium in patients treated for femoral neck fractures. Dement Geriatr Cogn Disord 10:325–329, 1999 Engel GE: Psychological Development in Health and Disease. Philadelphia, PA, WB Saunders, 1962 Engel GE, Schmale AH: Conservation withdrawal: a primary regulatory process of organismic homeostasis, in Physiology, Emotion and Psychosomatic Illness: CIBA Foundation Symposium No 8. Amsterdam, Elsevier–Excerpta Medica, 1972, pp 57–85 Farrer LA: Suicide and attempted suicide in Huntington disease: implications for preclinical testing of persons at risk. Am J Med Genet 24:305–311, 1986 Fisher CM: Abulia minor vs agitated behavior. Clin Neurosurg 31:9–31, 1984 Freud A: The Ego and the Mechanisms of Defense. New York, International Universities Press, 1946

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Gold K, Rabins PV: Isolated visual hallucinations and the Charles Bonnet syndrome: a review of the literature and presentation of six cases. Compr Psychiatry 30:90–98, 1989 Goldstein K: After Effects of Brain Injuries in War. New York, Grune & Stratton, 1942 Guilleminault C, Eldridge FL, Dement WC: Insomnia with sleep apnea: a new syndrome. Science 181:856–858, 1973 Harrow M, Amdur MJ: Guilt and depressive disorders. Arch Gen Psychiatry 25: 240–246, 1971 Heim C, Newport DJ, Heit S, et al: Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA 284:592– 597, 2000 Heuer F, Reisberg D. Vivid memories of emotional events: the accuracy of remembered minutiae. Mem Cognit 18:496–506, 1990 Jost BC, Grossberg GT: The evolution of psychiatric symptoms in Alzheimer’s disease: a naturalistic study. J Am Geriatr Soc 44:1078–1085, 1996 Kant R, Duffy JD, Pivovarnik A: Prevalence of apathy following head injury. Brain Inj 12:87–92, 1998 Klein M: Envy and Gratitude. London, Tavistock, 1957 Lawson K, Wiggins S, Green T, et al: Adverse psychological events occurring in the first year after predictive testing for Huntington’s disease. The Canadian Collaborative Study of Predictive Testing. J Med Genet 33:856–862, 1996 Levy ML, Cummings JL, Fairbanks LA, et al: Apathy is not depression. J Neuropsychiatry Clin Neurosci 10:314–319, 1998 Lipe H, Schultz A, Bird TB: Risk factors for suicide in Huntington’s disease: a retrospective case controlled study. Am J Med Genet 48:231–233, 1993 Lipowski ZJ: Delirium (acute confusional states). JAMA 258:1789–1792, 1987 Marin RS, Biedrzycki RC, Firinciogullari S: Reliability and validity of the Apathy Evaluation Scale. Psychiatry Res 38:143–162, 1991 Marin RS, Biedrzycki RC, Firinciogullari S: Group differences in the relationship between apathy and depression. J Nerv Ment Dis 182:235–239, 1994 Merriam AE, Aronson MK, Gaston P, et al: The psychiatric symptoms of Alzheimer’s disease. J Am Geriatr Soc 36:7–12, 1988 Moe KE, Vitiello MV, Larsen LH, et al: Symposium: cognitive processes and sleep disturbances: sleep/wake patterns in Alzheimer’s disease: relationships with cognition and function. J Sleep Res 4:15–20, 1995 Pearlson GD, Ross CA, Lohr WD, et al: Association between family history of affective disorder and the depressive syndrome of Alzheimer’s disease. Am J Psychiatry 147:452–456, 1990 Piaget J: The Construction of Reality in the Child. New York, Basic Books, 1954 Plotsky PM, Owens MJ, Nemeroff CB: Psychoneuroendocrinology of depression. Hypothalamic-pituitary-adrenal axis. Psychiatr Clin North Am 21:293–307, 1998 Pollack CP, Perlick D: Sleep problems and institutionalization of the elderly. J Geriatr Psychiatry Neurol 4:204–210, 1991


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Reding M, Haycox J, Blass J: Depression in patients referred to a dementia clinic. Arch Neurol 42:894–896, 1985 Reisberg B, Borenstein J, Salob S, et al: Behavioral symptoms in Alzheimer’s disease: phenomenology and treatment. J Clin Psychiatry 48:9–15, 1987 Ressler KJ, Nemeroff CB: Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety 12 (suppl 1):2–19, 2000 Robinson RG, Price TR: Post-stroke depressive disorders: a follow-up study of 103 stroke outpatients. Stroke 13:635–641, 1982 Robinson RG, Starkstein SE: Neuropsychiatric aspects of cerebrovascular disorders, in Comprehensive Textbook of Psychiatry/VII, Seventh Edition. Edited by Sadock BJ, Sadock VA. Philadelphia, PA, Lippincott Williams & Wilkins, 2000, pp 242–253 Robinson RG, Starr LB, Kubos KL, et al: Mood changes in stroke patients: relationship to lesion location. Compr Psychiatry 24:555–566, 1983 Rohde K, Peskind ER, Raskind MA: Suicide in two patients with Alzheimer’s disease. J Am Geriatr Soc 43:187–189, 1995 Rubin EH, Drevets WC, Burke WJ: The nature of psychotic symptoms in senile dementia of the Alzheimer type. J Geriatr Psychiatry Neurol 1:16–20, 1988 Rubio A, Vertner AL, Stewart JM, et al: Suicide and Alzheimer’s pathology in the elderly: a case-control study. Biol Psychiatry 49:137–145, 2001 Satlin A, Teicher MH, Liberman HR, et al: Circadian locomotor activity rhythms in Alzheimer’s disease. Neuropsychopharmacology 5:115–126, 1991 Schwartz JA, Speed NM, Brunberg JA, et al: Depression in stroke rehabilitation. Biol Psychiatry 33:694–699, 1993 Sevush S, Leve N: Denial of memory deficit in Alzheimer’s disease. Am J Psychiatry 150:748–751, 1993 Sorensen SA, Fenger K: Causes of death in patients with Huntington’s disease and in unaffected first degree relatives. J Med Genet 29:911–914, 1992 Speck CE, Kukull WA, Brenner DE, et al: History of depression as a risk factor for Alzheimer’s disease. Epidemiology 6:366–369, 1995 Starkstein SE, Robinson RG (eds): Depression in Neurologic Disease. Baltimore, MD, Johns Hopkins University Press, 1993 Strauss ME, Ogrocki PK: Confirmation of an association between family history of affective disorder and the depressive syndrome in Alzheimer’s disease. Am J Psychiatry 153:1340–1342, 1996 Teri L, Ferretti LE, Gibbons LE, et al: Anxiety of Alzheimer’s disease: prevalence and comorbidity. J Gerontol 54:M348–M352, 1999 Thomas J: A Complete Pronouncing Medical Dictionary. Philadelphia, PA, JB Lippincott, 1889 Vaillant GE: Adaptation to Life. Boston, MA, Little, Brown, 1977 Weiner MF: Hallucinations in children. Arch Gen Psychiatry 5:54–63, 1961 Weiner MF: Coping styles and behaviors of medical/surgical patients, in Manual of Psychiatric Consultation and Emergency Care. Edited by Guggenheim FG, Weiner MF. New York, Jason Aronson, 1984, pp 124–134

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Weiner MF, Lovitt R: Conservation-withdrawal versus depression. Gen Hosp Psychiatry 1:347–349, 1979 Weiner MF, Bruhn M, Svetlik DS, et al: Experiences with depression in a dementia clinic. J Clin Psychiatry 52:234–238, 1991 Weiner MF, Edland SD, Luszczynska H: Prevalence and incidence of major depression in Alzheimer’s disease. Am J Psychiatry 151:1006–1009, 1994 Wragg RE, Jeste DV: Neuroleptics and alternative treatments: management of behavioral symptoms and psychosis in Alzheimer’s disease and related conditions. Psychiatr Clin North Am 11:195–213, 1988

CHAPTER

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Medical Evaluation Myron F. Weiner, M.D. Anne M. Lipton, M.D., Ph.D. Ramó n Diaz-Arrastia, M.D., Ph.D.

Subjective complaints of cognitive impairment, the objective development of cognitive impairment, or the sudden worsening of cognitive impairment or behavior in a person diagnosed with dementia all indicate the need for clinical evaluation. The elements of the evaluation are summarized in Table 3–1. Additional studies used for selected patients are listed in Table 3–2. The extent of the evaluation depends on the physician’s assessment of the problem, the facilities available to undertake a diagnostic evaluation, and the cost-benefit ratios of the various diagnostic procedures available. The most important reason for undertaking a medical evaluation is the possibility of finding a reversible cause of cognitive impairment. Fully reversible dementia syndromes are rare, but an important goal of clinical assessment is to identify causes of cognitive dysfunction that are at least partially reversible. Reversible cognitive impairment is most often due to depression, medications, or hypothyroidism. A medical evaluation can also search for factors leading to excessive disability (Barry and Moskowitz 1988), in which functional impairment is exacerbated by infection, cardiac decompensation, or even environmental changes. Depression may worsen the cognitive impairment resulting from such conditions as head injury, acquired immunodeficiency syndrome (AIDS), and stroke. Barry and Moskowitz (1988) suggest that, in general, evaluation of cognitive impairment should be undertaken with the goal of improving patient well-being rather than simply identifying disease. On the other hand, the number of untreatable diseases is shrinking, and precise diagnosis is important in deciding which medications to prescribe or avoid. For example, anticholinergic drugs may aggravate cognitive impairment in patients with Alzheimer’s disease by increasing the preexisting cholinergic deficit. We find three main groups who present for cognitive status evaluation. A few (usually self-referred) individuals seek evaluation because of a family 77

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TABLE 3–1.


Medical evaluation of cognitive dysfunction

History and physical examination Neurological examination Mental status examination Attention and concentration, recent and remote memory, language, executive functioning, visuospatial skills Mini-Mental State Exam or comparable objective screening measure Assessment of mood Blood tests Complete blood count and differential Erythrocyte sedimentation rate Blood chemistries (electrolytes, urea nitrogen, creatinine, glucose, calcium, magnesium, liver function tests, hemoglobin A1c, lipid profile) Thyroid stimulating hormone Vitamin B12 level Serologic tests for syphilis (RPR and treponemal test) Computed tomographic or magnetic resonance imaging of the brain

history of Alzheimer’s disease or concern about the cognitive changes that normally begin in middle or advanced age. The second and largest group is persons brought in by concerned friends or family members. Virtually all of these individuals have dementing illnesses. The third group is composed of individuals with cognitive impairment whose cognition is worsening. The families of these individuals have often been told that the cognitive change they noted in their loved ones was due to advanced age or that they may have Alzheimer’s disease. These families seek second opinions for various reasons, including the wish to explore every possibility of uncovering a treatable cause for cognitive impairment or to find treatment for a dementing illness that had previously been described as untreatable. Welldiagnosed nursing home residents whose cognitive state changes suddenly are also within this group. Different medical evaluations may be indicated for a subjective complaint of cognitive impairment, for the initial evaluation of a person whose friends and family have noted signs of cognitive impairment, and for the follow-up evaluation of sudden cognitive deterioration in an adequately diagnosed dementia patient. A subjective complaint of cognitive impairment that is unsubstantiated by an outside informant nevertheless requires a medical and psychiatric history, a formal mental status examination, and a general physical examination, including neurological examination and routine screening laboratory tests. If the history and mental status examinations do not confirm cognitive impairment and there is no sign of brain

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TABLE 3–2.

Medical evaluation of cognitive dysfunction—additional measures

Neuropsychological testing Blood tests Antinuclear antibodies Ceruloplasmin DNA studies (prensenilin 1, CAG repeats, ataxia profile) Human immunodeficiency virus Homocysteine Methylmalonic acid Paraneoplastic antibodies (anti-Hu, anti-MaTa, anti-Ri, anti-Yo) Porphyrins Vasculitis workup (protein C and S activity, activated protein C resistance, anti-thrombin III, factor V Leiden, lupus anticoagulant, prothrombin 20201 A) Lumbar puncture Routine studies (cell count and differential, total protein, glucose, VDRL, Gram stain, and bacterial culture) Additional studies: A-> and tau protein concentrations Acid-fast bacillus stain and culture Cryptococcal antigen Cytology Fungal culture Immunoglobulin G index/synthesis rate Lyme titer or polymerase chain reaction (PCR) Oligoclonal bands Viral tests: titers and PCR (cytomegalovirus, herpes simplex, varicella zoster) 14-3-3 protein Whipple antibody by PCR Urine tests Urinalysis 24-hour urine copper 24-hour urine heavy metals 24-hour urine porphyrins Toxicology screen Electroencephalogram Cisternogram Arteriography (invasive or noninvasive) Single photon emission computed tomography Positron emission tomography

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damage, psychiatric evaluation and neuropsychological testing may be indicated. The complaint of cognitive impairment, like any other medical complaint, may be a means to deal with emotional issues and concerns (Weiner 1969). This is illustrated in the following case: A 60-year-old woman complained of impaired memory and concentration. Her medical history indicated that she had been worked up for several physical complaints with no definite findings. Her husband reported that he had not observed difficulty with her cognitive functioning. A complete battery of blood tests and a urinalysis were performed and were negative or within normal limits. A complete neurological evaluation, including computed tomography of the head and an electroencephalogram, was negative. Neuropsychological testing showed no clinically meaningful impairment, but personality testing using the Minnesota Multiphasic Personality Inventory showed her to be highly anxious and highly preoccupied with physical symptoms. To the psychiatric examiner, she confided that her greatest problem was her husband’s physical abuse, which she related to their chronic marital conflict. This patient was assured that she did not have a brain disorder and was helped to draw her husband into brief marital counseling.

In addition, the syndrome of mild cognitive impairment is characterized by subjective memory decline in the absence of functional decline. Persons with mild cognitive impairment often have no detectable cognitive deficits on mental status testing by a physician, but testing of memory based on immediate and delayed recall of a paragraph-long narrative can reveal their deficit (Petersen et al. 1999).

Setting The medical evaluation of cognitively impaired persons is generally performed in an outpatient setting. Hospitalization is required only when behavioral symptoms make outpatient evaluation impossible or when it is suspected that an emergency medical or surgical procedure might be needed—such as the emergency treatment of lupus cerebritis with bolus intravenous steroids or evacuation of a rapidly expanding subdural hematoma. Otherwise, hospitalization may actually have transient deleterious effects, because some individuals become more confused in a hospital environment (Etienne et al. 1981). A comprehensive multidisciplinary evaluation requires 1–3 days, depending on the efficiency of scheduling, the patient’s tolerance, and the extensiveness of medical and neuropsychological testing. In this chapter, discussion is limited to the medical aspects of the evaluation. Neuroimaging is discussed in Chapter 4. Neuropsychological and language testing are discussed in Chapter 8.

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History The diagnostic process begins with history taking. An adequate evaluation also involves obtaining information from collateral sources. The evaluation process begins with gathering medical and psychological information. It is useful to obtain prior medical and psychological records in advance to avoid duplication of tests and loss of information due to informants’ lack of awareness or understanding of the diagnostic procedures that have already been employed or the medications that have been prescribed. In all instances, we try to include a person with close knowledge of the patient in the diagnostic process. We also request that patients or family members bring in all prescribed or unprescribed medications to which the patient has access. The history of the present illness should be gathered with regard to the patient’s and family’s chief current concern, the first cognitive and/or behavioral problem(s) noted, the course of the problem(s), and other problems that may have developed. In addition to the patient’s age and handedness, the level of education and current or prior occupation should be determined. A few patients report inability to learn or to recall the names of people and objects. Many do not report cognitive impairment but are brought for evaluation because others have noted lapses in memory or judgment and are concerned. Does the history specifically indicate difficulties characteristic of cognitive impairment? Have there been problems in cognitive domains of memory, language, visuospatial skills, and/or executive dysfunction? Have there been any changes in personality or behavior such as apathy, depression, agitation/irritability, or psychosis? A number of key questions are useful in delineating the history of the cognitive and/or behavioral problems: 1. Were the symptoms acute, subacute, or gradual in onset? An acute onset (within minutes or hours) suggests delirium rather than dementia and a large differential diagnosis that includes infectious, toxic/metabolic, vascular, traumatic, psychiatric, or multifactorial causes. When vascular, the symptoms may be due to ischemic stroke (secondary to embolization or atherosclerotic thromboembolic disease), hemorrhage (traumatic, hypertensive hemorrhage, aneurysmal, amyloid angiopathy, and within a tumor), or vasculitis (including systemic lupus, temporal arteritis, and central nervous system vasculitis). Intermittence of symptoms occurs with all disorders of brain function. Waxing and waning of symptoms over hours is typical of delirium. Dementing illnesses are also characterized by fluctuating symptoms, but the fluctuations are less dramatic and are often more prolonged. There is often

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diurnal confusion that may or may not be associated with fatigue. Symptoms of all illnesses producing cognitive impairment tend to worsen in unfamiliar environments or when emotional and cognitive demands increase. In young adults developing schizophrenia, a catatonic episode may come on within hours. Malingered cognitive impairment and fugue states also develop suddenly (Lamb and Prigatano 2000), both usually occurring in the context of extreme environmental or interpersonal stress. Subacute onset (days to weeks) suggests infectious, toxic/metabolic, or neoplastic origin, whereas a gradual progressive decline over months to years is more typical of degenerative disorders. It is often difficult to date the onset of cognitive difficulties, however. A family may be unaware of any significant changes until their loved one is hospitalized for one reason or another. The combination of an unfamiliar environment and a medical illness or a surgical procedure often unmasks preexisting dementia and may also precipitate delirium in a person with cognitive impairment. Therefore, it is important to reevaluate the person for cognitive impairment once any delirium has resolved. Several questions can help determine the onset and progression of any symptoms of cognitive impairment. How is the person’s job performance? If he or she is retired, was retirement due in part to impaired performance? Has there been any change in the performance of usual activities (e.g., conversation and social interaction, housekeeping, meal preparation, operating appliances, making routine purchases, making change, writing checks, driving, dressing, grooming, and performance in hobbies and social activities). When was the first change or loss of interest in these activities? Did symptoms precede or follow any significant medical illness or surgery? 2. Are the symptoms progressive, diminishing, or stabilized? Lack of progression suggests a single insult, such as a vascular accident, trauma, or depression. Progression may be associated with infectious diseases (AIDS, Creutzfeldt-Jakob disease [CJD], neurosyphilis), trauma (subdural hematoma), metabolic (diabetes), and degenerative disorders. Degenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Pick’s disease, and multisystem atrophy have a relatively smooth downward course. Vascular dementia generally has a stepwise progression. In the case of stepwise progression, sensory and motor changes accompany the cognitive change in vascular dementia and multiple sclerosis. Symptomatic improvement is associated with trauma, acute vascular disorders, and acute toxic and metabolic disorders. Fluctuations in cognitive dysfunction may occur in many types of dementing illness, including the degenerative disorders, but they do not include a return to baseline. This is frequently the case in dementia with Lewy bodies (McKeith et al.

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1996). In most dementing illnesses, cognitive impairment fluctuates, depending on the complexity of the environment, emotional strain, fatigue, general physical health, and time of day. Symptoms are frequently worse in the evenings due to fatigue and loss of orienting sensory cues. Such nighttime worsening is referred to as sundowning. Paroxysmal deterioration with relatively full interepisode recovery occurs in alcoholic persons with encephalopathy due to liver disease. Transient global amnesia is a syndrome of intermittent confusion of diverse etiology, probably due in many cases to ischemia of the medial temporal lobes. Partial complex seizures can cause intermittent behavioral disruption with cumulative chronic deterioration, but the history also reveals motor stereotypy and postictal sleepiness. 3. Has the person experienced the same or similar symptoms in the past? Past experience of short confusional episodes may suggest epilepsy or transient ischemic attacks. Periods of cognitive dysfunction lasting days or weeks may be related to emotional disorders, metabolic disorders such as porphyria, or diseases associated with Lewy bodies. Individuals who are malingering or in fugue states will often report similar previous episodes. Depressed persons may report similar episodes of cognitive impairment with past episodes of depression. 4. Is there a history of psychiatric disorder or severe environmental stress? An episode of depression, whether mild or severe, can markedly impair cognitive functioning (Boone et al. 1995). Persons with long-standing schizophrenia frequently develop severe cognitive impairment (Purohit et al. 1998). Cognitive impairment due to malingering occurs in individuals facing imprisonment (Allen et al. 2000), and fugue states may develop in individuals seeking to escape the consequences of acts such as bigamy. In Ganser syndrome, patients’ answers are one-off or near misses (nearly correct). 5. Are there behavioral or psychiatric symptoms? Frequently, the first symptoms noted in a dementing illness are loss of initiative and loss of interest in activities that were formerly pleasurable. Individuals with impaired frontal lobe function may show apathy and/or disinhibition. Suspiciousness and irritability may accompany early dementing illness, as may depression or elation and grandiosity. Depressive, psychotic, and obsessive-compulsive symptoms may herald the onset of Huntington’s disease (De Marchi and Mennella 2000). Visual hallucinations unaccompanied by explanatory delusions are frequent in Alzheimer’s disease and dementia with Lewy bodies. Tactile hallucinations and illusions are common in delirium. Complex delusional systems are unusual in dementing illness.

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Auditory hallucinations in dementia tend to be of familiar others, whereas accusatory or threatening voices that speak through the radio or television are more characteristic of schizophrenia. 6. Are there associated neurological symptoms? Neurological symptoms often suggest specific dementia diagnoses. Such symptoms may include loss of consciousness, seizures, dyscoordination, gait and balance problems, movement disorders, weakness (generalized or localized), impairment of vision or hearing, and other cranial nerve dysfunction. Loss of consciousness may accompany severe head trauma, lupus cerebritis, and toxic-metabolic disorders. Seizures may point to a primary seizure disorder or to other conditions such as neoplasm, in which seizures are secondary. Gait apraxia and early urinary incontinence are associated with normalpressure hydrocephalus. Dysarthria and paralysis of gaze suggests progressive supranuclear palsy. Unilateral limb apraxia suggests corticobasal ganglionic degeneration (Schneider et al. 1996) or frontal dementia (Kertesz et al. 2001). Bradykinesia may indicate depression, early Parkinson’s disease, or another subcortical process. Dyscoordination and sensory and cranial nerve symptoms may indicate multiple sclerosis or progressive supranuclear palsy. Choreiform movements accompany Wilson’s and Huntington’s disease; myoclonic jerks accompany CJD and mid- to late-stage Alzheimer’s disease (Chen et al. 1991). Lateralized abnormalities of strength, tone, reflexes, or sensation suggest a possible vascular origin. Visual field deficits point to possible vascular or neoplastic disease, and unilateral hearing loss points to neoplasm. 7. Is there a personal or family history of a disease or disorder associated with cognitive decline? The presence of diabetes, hypertension, strokes, hypercholesterolemia, and signs of generalized atherosclerosis point to possible vascular dementia. Severe renal or hepatic disease may produce metabolic encephalopathy. Human immunodeficiency virus (HIV-1) seropositivity raises the possibility of direct effects of the virus on the brain (HIV-1–associated minor cognitive motor disorder or HIV-1– associated dementia [American Academy of Neurology 1991]) or an opportunistic brain infection. Huntington’s and Wilson’s diseases exemplify familial diseases associated with dementia. Alzheimer’s disease very rarely occurs as an autosomal dominant familial disease. Nearly half of frontal dementias may be hereditary (Chow et al. 1999; Knopman et al. 1990; Neary et al. 1988; Stevens et al. 1998). A variety of mutations (over 20) in the gene encoding tau, a microtubule-associated protein, have been associated with inherited frontotemporal dementia (see Genetic Markers section in this chapter).

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8. Does the person take any prescribed or unprescribed medications? Many medications have the ability to impair cognitive function, including benzodiazepine hypnotics and tranquilizers, barbiturates, anticonvulsants, propranolol, and cardiac glycosides. Episodes of confusion in persons with porphyria may be induced by various medications, including barbiturates and chlordiazepoxide (Sack 1990). In addition, patients and families should be specifically asked what sleep medications, over-the-counter medications (e.g., aspirin), vitamins, and other supplements (calcium, herbal—Gingko biloba, St. John’s Wort, etc.) the patient is taking, as this information is often not proffered. Patients and their families should be asked in advance of the patient’s appointment to bring in either the patient’s medication bottles or a detailed list including the name of each medication, its dose, and the number of times per day it is taken. 9. Is there a history of abuse or heavy intake of alcohol or other substances? History of alcohol abuse may point to the origin of an amnestic disorder or dementia. Prolonged heavy alcohol use without evidence of intoxication may rarely cause significant cognitive impairment, but we have not seen this in our clinic. On the other hand, repeated episodes of delirium tremens are significant. In teenagers and young adults, evidence of glue or paint sniffing is important. 10. Has there been exposure to environmental toxins? Arsenic, mercury, lead, organic solvents, and organophosphate insecticides can produce encephalopathies, usually accompanied by severe systemic symptoms. 11. Has there been exposure to HIV infection? Intravenous drug abuse and unprotected sexual contact are risk factors for infection with HIV in adults. Increased screening of blood and blood transfusions has virtually eliminated this form of HIV transmission. Highly active antiretroviral therapy (HAART) has postponed the occurrence of AIDS caused by HIV as well as associated symptoms, such as AIDS dementia. Even when the history suggests that a patient has a depressive disorder, is functioning normally, or is overreacting to the normal cognitive changes accompanying aging, a formal mental status examination should always be performed. When possible, information should be obtained separately from a knowledgeable informant. It is wise to obtain a baseline measure of cognitive performance such as the Mini-Mental State Exam (Folstein et al. 1975) or the more sensitive Mattis Dementia Rating Scale (Mattis 1988). Follow-up should also be arranged, with a revisit scheduled after a period of 1 year or sooner, depending on the findings of the initial evaluation and progression of any problems.

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Physical Examination A general physical examination is an important part of the medical evaluation. Diseases of many organ systems can lead to transient or progressive impairment of brain function or can contribute to excessive morbidity in dementing illness. Funduscopic examination may reveal optic atrophy in the case of multiple sclerosis or papilledema in the case of increased intracranial pressure such as tumor. Cardiovascular examination may demonstrate an irregular rhythm consistent with atrial fibrillation and increased risk for stroke. Carotid bruits may be an indicator of stenosis. Abdominal examination may reveal the presence of hepatomegaly. Examination of the skin and extremities may reveal signs of vasculitis such as petechiae.

Neurological Examination A detailed neurological examination is performed on every patient (see Appendix C).

Cranial Nerves Cranial nerve examination may include olfaction, but the relationship of olfactory deficits to dementing illness remains controversial. There is wide consensus that olfactory deficits occur in Alzheimer’s disease and Parkinson’s disease (Mesholam et al. 1998), but such deficits also occur in normal elders. Bacon et al. (1998) found changes in olfactory threshold in the year preceding change in diagnosis from nondemented to Alzheimer’s disease. On the other hand, a neuropathologically confirmed study showed no difference in olfactory discrimination between patients with Alzheimer’s disease and control subjects, but a significant difference between control subjects and subjects with cortical Lewy bodies (McShane et al. 2001). Anosmia of sudden onset may point to a significant head injury. It is important to test visual and auditory acuity, because sensory impairment may influence mental status testing. Pupillary abnormalities occur with neurosyphilis but may also result from cataract surgery. The typical Argyll Robertson pupil seen with neurosyphilis is small, irregular, and reactive to accommodation but not to light. Retinal examination may reveal damage from long-standing hypertension or diabetes. Impairment of gaze in progressive supranuclear palsy usually affects downward gaze first, then upward gaze, and, finally, horizontal gaze. Asymmetry of the facial muscles in the lower part of the face occurs with an upper motor neuron lesion such as a stroke or tumor. Weakness of

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muscles supplied by other cranial nerves (such as the tongue, sternocleidomastoids, and trapezia) and/or altered facial sensation may also suggest a stroke.

Motor System Patients are assessed for muscle bulk, tone, and strength as well as for any apraxia or abnormal involuntary movements, such as tremor, dyskinesia, or chorea. Increased resistance to passive movement (rigidity) is common as Alzheimer’s disease progresses. The occurrence of rigidity early in the course of a dementing illness may indicate a parkinsonian syndrome, especially when accompanied by tremor or other parkinsonian symptoms. Clonus may be demonstrable in patients with upper motor neuron damage due to a stroke or spinal damage. Myoclonus is a lightning-like jerk of a limb, limbs, or the entire body, that may be induced by testing reflexes (reflex myoclonus) or if the patient is suddenly startled (startle reflex), such as by a loud noise. Myoclonus in the setting of rapidly progressive dementia should raise the possibility of CJD, but myoclonus may occur later in the course of other dementias, such as Alzheimer’s disease and Lewy body disease.

Parkinsonism We prefer this term to the more nonspecific term extrapyramidal symptoms. Bradykinesia, resting tremor, rigidity, and postural instability are the cardinal signs of idiopathic Parkinson’s disease. The presence of two or more, but not all, of these signs is suggestive of secondary parkinsonism, such as medication-induced Parkinson’s-plus syndromes or Lewy body disease. Other parkinsonian features that may be seen in Parkinson’s disease and these related syndromes include restriction of extraocular movements, masklike facies, hypophonia, dysarthria, dysphagia, collapsing movements, micrographia, difficulty arising from a sitting position, stooped posture, slow gait, turning en bloc, festinating gait, and decreased arm swing with walking.

Sensation Vibration sense in the lower extremities is frequently reduced in the elderly, but position sense is not. Sensory neuropathies, characterized by loss of vibratory and pinprick sensation in the periphery, and greatest distally, occur in individuals with hypothyroidism, significant alcohol use, diabetes, syphilis, and vitamin B12 deficiency. In the case of the tabes dorsalis syn-

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drome of neurosyphilis, the dorsal columns are involved, and both vibratory and position sense are frequently impaired due to involvement of the dorsal columns.

Reflexes Deep tendon reflexes are generally reduced in sensory neuropathy. Increased deep tendon reflexes may accompany the sensory neuropathy of vitamin B12 deficiency. Asymmetric reflexes and the presence of a plantar extensor response (Babinski reflex) suggest upper motor neuron pathology. Frontal release signs, also called frontal reflexes or primitive reflexes (grasp, palmomental, rooting, snout, suck), may be seen even in healthy elderly persons. These signs are therefore relatively nonspecific, except when seen in younger adult patients and in the context of other frontal abnormalities on neurological or mental status examination.

Gait and Posture Gait tends to slow with aging, and tandem walking may be difficult for elders. Gait apraxia or “magnetic” gait, in which a patient has difficulty initiating steps, raises the possibility of normal-pressure hydrocephalus. Data from the neurological examination, mental status examination, and history enable the clinician to classify dementing illnesses into one of the types described in Chapter 1: frontotemporal, temporoparietal, or subcortical. The neurological examination facilitates the differentiation of dementing illness into these categories and the categories of cortical, subcortical, and mixed dementing illness. Frontotemporal disorders are often accompanied by cortical release signs such as the palmomental, suck, and snout reflexes; by difficulty with simple programmed motor activities such as the Luria hand sequence; language impairment; and disinhibition. Temporoparietal disorders, in addition to severe difficulty with recent memory, are often accompanied by difficulty with word finding and spatial orientation. Subcortical dementias may be accompanied by apathy, disinhibition, emotional lability, and depression. These illnesses also tend to have motor signs that may be pyramidal or extrapyramidal. The anatomic loci for cortical dementias are the neocortical association areas and hippocampus; the loci for subcortical dementias are the thalamus, basal ganglia, and rostral brainstem (Albert et al. 1974). Based on the foregoing criteria, the prototypical cortical dementias are Alzheimer’s disease and frontotemporal dementia/Pick’s disease, but mild extrapyramidal signs, such as rigidity and bradykinesia, can occur in conjunction with Alzheimer’s disease. Typical subcortical dementias are Huntington’s disease,

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Wilson’s disease, AIDS dementia, and progressive supranuclear palsy. Vascular dementia, CJD, and trauma typically produce mixed cortical and subcortical signs.

Laboratory Studies Blood The Quality Standards Subcommittee of the American Academy of Neurology (1994) recommended routine blood tests, including serum electrolytes; glucose, blood urea nitrogen/creatinine, folate, and vitamin B12 concentrations; thyroid function; and syphilis serology. The only change in these recommendations in the most recent guidelines (Knopman et al. 2001) is that testing for syphilis be performed only if there is clinical suspicion of neurosyphilis. No changes were made in the other recommended tests because no further studies of their utility have been performed. In our clinic, we perform the following laboratory studies: complete blood count and differential, erythrocyte sedimentation rate, electrolytes, urea nitrogen, creatinine, blood glucose, hemoglobin A1c, calcium, magnesium, liver function tests, thyroid-stimulating hormone (TSH), vitamin B12 level, lipid profile, and serologic tests for syphilis (the rapid plasmin reagin [RPR] test and the microhemagglutinin assay for antibodies to Treponema pallidum [MHA-TP]). We have discontinued determining folic acid levels in blood because of the lack of evidence of its utility. We have not seen folate deficiency in more than 2,500 evaluations for dementia. We have not encountered a case of pernicious anemia, but we have treated all persons with serum vitamin B12 level below 200 pg/mL and have had no positive cognitive response. Others, however, have reported improvement in neuropsychiatric symptoms in patients with low serum cobalamin levels in the absence of anemia (Lindenbaum et al. 1988). Eastley et al. (2000) reported on 1,432 persons seen in a dementia clinic, of whom 125 had low vitamin B12 concentrations. Of these, 65 were demented, and 22 had lesser degrees of cognitive impairment. After treatment of vitamin B12 deficiency, there was improved verbal fluency in the nondemented cognitively impaired group but no change in the demented group. Therefore, we feel justified in treating patients with serum vitamin B12 levels below 200 pg/mL. When levels of vitamin B12 are low normal (below 400 pg/mL), we also determine methylmalonic acid and homocysteine levels, because these tests may be evidence of functional vitamin B12 deficiency when vitamin B12 levels are still within the normal range. Patients with homocysteine levels above 15 mmol/L or with methyl-

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malonic acid levels above 950 nmol/L are treated with cobalamin supplements. Vitamin B12 deficiency should be treated first weekly, then monthly, with parenteral B12 supplementation. Abnormalities in homocysteine metabolism may partly explain the association between folate and vitamin B12 levels and neurodegenerative diseases (Diaz-Arrastia 2000). Hyperhomocysteinemia has been associated with cerebrovascular disease, and high homocysteine levels have been retrospectively correlated with increased risk for developing vascular dementia and Alzheimer’s disease (Clarke et al. 1998; McCaddon et al. 1998). A recent analysis of prospectively collected data in Framingham, Massachusetts, indicates that persons with increased homocysteine levels have approximately a 2.5-fold increased risk of developing Alzheimer’s disease within 3–11 years (Seshadri et al. 2002). Further research on the role of homocysteine in dementia is ongoing, particularly on whether homocysteinelowering therapy can decrease the incidence of dementia or slow its rate of progression. We obtain a lipid profile because hypercholesterolemia is an independent and treatable risk factor for cerebrovascular disease. Moreover, so-called statins, hypolipidemic agents that act by inhibiting hepatic hydroxymethylglutaryl coenzyme A reductase, have been retrospectively associated with increased risk of dementia and Alzheimer’s disease (Jick et al. 2000; Wolozin et al. 2000). We continue to perform serologic test for syphilis because we are a tertiary care center and neurosyphilis is a treatable cause of dementia. Because tests for antibodies specific for treponemal antigens, such as the MHA-TP or the fluorescent treponemal antibody absorption (FTA-ABS) test, are highly specific for the diagnosis of syphilis, we do these in conjunction with the RPR test. We use TSH levels as our measure of thyroid function. We also perform routine liver function tests and use erythrocyte sedimentation rate as a screening test for systemic inflammatory disorders. Serum ceruloplasmin and 24-hour urinary copper are determined in possible cases of Wilson’s disease, as in a young person (age less than 40 years) presenting with cognitive impairment. It is also necessary to measure 24-hour urine copper output because serum ceruloplasmin may be low or normal in a person with Wilson’s disease. Unless specific evidence is present on clinical examination, we do not routinely perform tests to determine if toxic substances have been ingested. If, on the other hand, there is a suspicion of covert or unreported drug use or of exposure to toxins such as lead or mercury, appropriate toxicologic testing is performed. When patients are taking digitalis, anticonvulsants, antidepressants, lithium, or other drugs that produce confusion when the

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therapeutic blood level is exceeded, we determine the serum concentrations of these drugs.

Urine In the case of frail elders, a urinalysis is indicated routinely. In many instances, a urinary tract infection will cause confusion (usually delirium), but in others it may present only as a worsening of cognitive state. Urine studies (Table 3–2) may be indicated in individuals with suspected exposure to heavy metals, substance abuse, Wilson’s disease (see previously in this chapter), or porphyria.

Spinal Fluid Lumbar puncture is a relatively benign procedure that has produced virtually no complications in our hands, but in only one instance in more than 400 cases did our findings help in the differential diagnosis of patients evaluated for long-standing progressive cognitive impairment. Our experience is similar to that of Hammerstrom and Zimmer (1985), who reviewed the value of lumbar punctures in evaluating 80 dementia patients age 50 years or older. No diagnosis was made on the basis of the information derived from lumbar puncture in the 42 patients who underwent lumbar puncture. The only abnormalities found were 11 cases of nonspecific protein elevation and 1 case of increased cell count not due to bacterial infection. These researchers reviewed an additional series of 422 cases from other series and found 4 patients whose diagnoses could have been made by lumbar puncture. One patient had neurosyphilis, and the other 3 had postencephalitic parkinsonism. Nevertheless, lumbar puncture is often justified, especially in the evaluation of young and middle-aged patients. It is indicated specifically in rapidly progressive dementia, positive syphilis serology, and suspected central nervous system infection. It is also indicated in all cases of dementia occurring in persons with diagnosed or suspected AIDS and in persons who have had a blood transfusion. The detection of the 14–3–3 protein in cerebrospinal fluid is useful in confirming the diagnosis of CJD (Zerr et al. 1998), but a negative result does not exclude CJD. In the diagnosis of Alzheimer’s disease, measurements of b-amyloid1-42, tau, or AD7C-NTP levels in cerebrospinal fluid have not been shown to increase diagnostic specificity and specificity over that of the clinical diagnosis and are not recommended for routine diagnosis (Knopman et al. 2001).

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Special Diagnostic Procedures Genetic Markers There are no genetic markers recommended for routine diagnostic purposes (Knopman et al. 2001) or for asymptomatic persons concerned about the future development of dementing illness (Small et al. 1997). Genetic testing may be appropriate for some asymptomatic persons in selected cases of hereditary dementing illnesses such as Huntington’s disease, in which genetic testing can confirm a diagnosis of or detect presymptomatic disease (International Huntington Association 1994). A variety of mutations in the tau gene on chromosome 17 have been associated with familial frontotemporal dementias (Hutton et al. 1998; Pickering-Brown et al. 2002; Poorkaj et al. 1998; Spillantini et al. 1998), but a number of these illnesses have genetic mutations that have yet to be determined. Mutations in the amyloid precursor protein gene and the presenilin 1 and 2 genes can be detected in some cases of familial early-onset Alzheimer’s disease (Rosenberg and Iannaccone 1995). Inheritance of the e4 allele of the cholesteroltransporting protein apolipoprotein E is associated with late-onset familial and sporadic Alzheimer’s disease, but it cannot be used as a diagnostic test or to predict the onset of Alzheimer’s disease. It is therefore not recommended for asymptomatic persons. However, in persons who meet clinical criteria for Alzheimer’s disease, the presence of an e4 allele increases the specificity of the diagnosis from 55% to 84% (Mayeux et al. 1998).

Neuroimaging Neuroimaging is discussed extensively in Chapter 4. Structural neuroimaging, brain magnetic resonance imaging (MRI), or computed tomography (CT) of the head, is done as part of our routine initial evaluation and is a guideline recommendation by the American Academy of Neurology (Knopman et al. 2001). Brain MRI is our structural neuroimaging test of choice. We generally perform brain MRI without contrast medium, but gadolinium is used in some patients, particularly if the history or examination raises a concern for neoplasm or infection. Functional neuroimaging, such as single photon emission computed tomography (SPECT), is employed in diagnostic dilemmas and to confirm frontotemporal dementias. Cisternography is employed for suspected normal-pressure hydrocephalus.

Cisternogram Radionuclide cisternography is used to differentiate between communicating and noncommunicating hydrocephalus and helps establish the diagno-

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sis of normal-pressure hydrocephalus by demonstrating reflux into the ventricles and delayed pericerebral diffusion.

Other Diagnostic Procedures Angiography Intracerebral angiography should be performed for specific indications, such as diagnosis of aneurysms; vascular malformations; occluded arteries and veins; and mass lesions, such as hemorrhages, abscesses, and neoplasms. A radiopaque contrast medium injected percutaneously into a carotid, brachial, or femoral artery allows visualization of the entire circulation of the neck and brain. With this technique, there is a risk of embolization, and high concentrations of contrast medium may cause spasm and occlusion. MR and CT angiography, which produce computer-generated images of the major cervical and intracranial arteries, are much more benign and less expensive techniques, but they are somewhat less precise. These techniques involve the intravenous injection of a small amount of contrast material.

Brain Biopsy Brain biopsy is reserved for situations in which a treatable illness is suspected. We have reserved this procedure for suspected autoimmune cerebral vascular disease and infectious brain diseases not diagnosable by spinal fluid studies. We have requested brain biopsy four times in 14 years. All instances were cases of rapidly progressive dementia. In one case, the biopsy report was normal brain tissue; in the other three, it was Alzheimer’s disease. Brain biopsy is of limited use in that only small amounts of tissue can be sampled, and the brain areas most affected by diseases such as Alzheimer’s disease are not readily accessible. Brain biopsy is generally not advisable in cases of suspected CJD because of the high risk to the surgical team, the possibility of iatrogenic transmission to others, and the untreatable nature of this illness, unless the biopsy has some likelihood of revealing a treatable cause. (Even postmortem examination of potential CJD necessitates advance notice to the pathologists, as additional protective gear and special tissue preparation techniques are required to avoid inadvertent transmission.)

Carotid and Transcranial Sonography Evidence of generalized arteriosclerosis, carotid bruits, transient ischemic attacks, or stroke warrants sonographic investigation of the carotid and in-

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tracranial vasculature. Patients with evidence of stroke on history, examination, or neuroimaging are referred for echocardiography to be evaluated for any cardiac source of emboli. Patients with evidence of large-vessel cerebrovascular disease are referred for cerebral angiography. Transcranial Doppler imaging may be performed to image the intracranial vasculature, including the circle of Willis (Sadik et al. 2001). In our experience, vascular stenosis does not often contribute to the development of dementia, but we tend to see few cases of vascular dementia. We have had one anecdotal report of progressive dementia with pronounced bilateral carotid narrowing that improved dramatically after bilateral endarterectomy (R. Rosenberg, personal communication, October 3, 1989).

Electroencephalography The electroencephalogram (EEG) is of limited utility in the evaluation of cognitive impairment. It has been argued that electroencephalographic evidence of an objective abnormality of cerebral function is useful in distinguishing between a degenerative disease and a psychiatric disorder, such as depression with cognitive impairment (depressive pseudodementia) (Brenner 1999). In practice, however, the sensitivity and specificity of electroencephalography is low. Electroencephalographic findings in Alzheimer’s disease include slowing of the posterior dominant rhythm, an increase in diffuse slow (theta or delta) activity, and generalized bursts of slow activity, but none of these findings are specific or sensitive for Alzheimer’s disease. Most persons with severe to moderate Alzheimer’s disease have such electroencephalographic abnormalities, reflecting the degree of impairment of cortical function. However, with mild impairment early in the illness, the EEG is often normal (Markand 1990). The majority of persons with Pick’s disease have normal EEGs (Stigsby 1988). However, these studies were based on very small numbers of patients, and one of us (A.M.L.) has seen a 39-year-old man with frontotemporal dementia with a low-voltage EEG. Huntington’s disease patients typically show low voltage (Robinson et al. 1994). This pattern is neither sensitive nor specific, and the utility of electroencephalography in making the diagnosis is limited, particularly in the early stages (Pedley and Miller 1983). The presence of triphasic waves is frequently an indication of delirium-producing toxic and metabolic disorders (Engel and Romano 1959). Focal slow waves may suggest destructive lesions such as strokes and tumors. Electroencephalography is far less sensitive and specific in diagnosing these conditions than is neuroimaging or other studies. Electroencephalography is useful in the diagnosis of patients with rapidly progressive cognitive deterioration in whom CJD is considered in

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the differential. In persons with CJD, the electroencephalographic pattern is distinctive. In the initial phase of the illness, electroencephalographic changes consist of a progressive disorganization of background rhythms and increased amounts of generalized slow (theta-delta) activity. As the disease progresses, the EEG is characterized by periodic, bilaterally synchronous, sharply contoured biphasic and triphasic waves, which appear at irregular intervals of one or two per second (Brenner 1999). These findings have a sensitivity of 67% and a specificity of 86% compared with neuropathologic findings when prospectively studied in a group of patients in whom CJD was clinically suspected (Steinhoff et al. 1996). Similar electroencephalographic findings have been reported in rare cases of lithium intoxication, baclofen encephalopathy, myoencephalopathy ragged red-fiber disease, and HIV encephalopathy (Brenner 1999). Electroencephalographic studies are most widely performed in the evaluation of cognitively impaired persons who may have epileptic seizures. The incidence of epilepsy increases significantly after age 65 (Hauser 1992), and several studies indicate that epilepsy complicates 5%–25% of cases of Alzheimer’s disease (Risse et al. 1990). The diagnosis of Alzheimer’s disease or other dementia increases the risk of unprovoked seizures approximately sixfold (Hesdorffer et al. 1996), and it is estimated that by 10 years after diagnosis, 15% of Alzheimer’s disease patients will have experienced epileptic seizures (Hauser 1997). However, persons with dementing illness are also at high risk for other paroxysmal neurologic events that mimic, but are distinct from, epileptic seizures. These include transient ischemic attacks, syncopal episodes, and acute behavioral disturbances. Electroencephalography is often the best way to establish the diagnosis, because the presence of paroxysmal generalized or focal spikes, sharp waves, or sharp and slow wave complexes (interictal epileptiform discharges, or IEDs) are highly predictive of epileptic seizures. Although the specificity of IEDs for epileptic seizures is high (>95%), the sensitivity in elderly patients is poor (25%–35% for patients age 65 and older, compared with 50%–70% for younger persons (Drury and Beydoun 1998). A significant proportion of elderly persons admitted to epilepsy monitoring units for evaluation of presumptive seizures are found to have nonepileptic phenomena (Drury et al. 1999). Quantitative electroencephalography and long-latency cortical evoked potentials such as the P300 do not seem to add to clinical diagnostic specificity in the dementing illnesses, although they remain a subject for clinical research. Neither technique is mentioned in recently published practice parameters for the diagnosis of dementia (Knopman et al. 2001).

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How Much Workup Is Enough? Opinions differ regarding what constitutes an adequate laboratory workup for dementing illness. The Canadian guidelines (Mohr et al. 1995) suggest that measurement of blood urea nitrogen, vitamin B12, and folic acid concentrations; serologic testing for syphilis; urinalysis; and erythrocyte sedimentation rate should be performed only if they are indicated by history or physical examination. These guidelines also suggest neuroimaging if patients are less than age 60 years, if there is use of anticoagulants or a history of bleeding disorder, recent head trauma, cancers that metastasize to brain, unexplained neurological symptoms, rapid progression of disease, dementia duration of less than 2 years, or urinary incontinence and gait disorder suggestive of normal-pressure hydrocephalus. As noted previously, the Quality Standards Subcommittee of the American Academy of Neurology (Knopman et al. 2001) recommends routine blood tests, including serum electrolytes; glucose, blood urea nitrogen/creatinine, folate, and vitamin B12 concentrations; and thyroid function. Syphilis serology is recommended only if there is clinical suspicion of neurosyphilis. Structural neuroimaging with CT or MRI is now a guideline recommendation. In our clinic, the minimum medical evaluation includes patient history; physical and neurological examinations; mental status examination; brain MRI (preferably) or CT; and laboratory studies, including complete blood count and differential; erythrocyte sedimentation rate; electrolytes, urea nitrogen, creatinine, blood glucose, hemoglobin A1c, calcium, magnesium, TSH, and vitamin B12 concentrations; liver function tests; lipid profile; and serologic tests for syphilis (RPR and MHA-TP). Lumbar puncture is performed if an infectious, inflammatory, or autoimmune disorder is suspected. We use electroencephalography if epilepsy or CJD is suspected. We have typically used SPECT for atypical dementias, to confirm frontal dementias, and to differentiate dysphasic dementia (primary progressive aphasia) from aphasia due to cerebrovascular disease. Jobst et al. (1994) combined temporal lobe CT with SPECT in Alzheimer’s disease and reported a sensitivity of 90% and a specificity of 97%.

How Often Are Evaluations Indicated? Brief reevaluations should be done at least yearly, including an interim clinical history, a neurological examination, and mental status testing. Monitoring progression of the illness through history and examination and by noting the response to any treatment may help to confirm the original diagnosis or raise doubt if the typical clinical course and findings are not

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observed. An unusually fast progression may raise suspicion for an illness such as CJD. Marked improvement may suggest a reversible disease, even depression, responding to treatment or remission. New focal signs may point to a vascular or neoplastic component. More comprehensive evaluations are indicated when such new findings arise, particularly when a reversible component of cognitive impairment is suspected, as in the following example: A 74-year-old widow with a 4-year history of progressive dementia was diagnosed as having Alzheimer’s disease after a comprehensive evaluation including a head CT scan. Six months later, a positron emission tomographic scan showed findings typical of Alzheimer’s disease. Six months after that, she returned with severe gait problems, marked urinary incontinence, and increasing ventricular size accompanied by diffuse white matter changes on brain MRI. A diagnosis of normal-pressure hydrocephalus was made, and a ventriculoperitoneal shunt was inserted. Over the next 2 years, the woman showed marked improvement in her cognitive status (Friedland 1989).

When Is Reevaluation Longer Needed? Additional comprehensive evaluations are not indicated when an adequately diagnosed disease process is following its predicted course. Continued reevaluation of minor degrees of cognitive dysfunction is probably not indicated after 5 years of stability. On the other hand, it has been our experience that departures from the normal trajectory of a patient’s diagnosed dementing illness are often worthy of investigation, particularly in frail elders. A minimum evaluation in these cases includes medication check, physical examination, chest X ray, electrocardiogram, blood chemistries, and urinalysis. EEG, head CT, or serum drug levels may also be useful in some cases.

Summary Although the specific procedures that are used to determine etiology differ according to the type of cognitive impairment or dementing illness, the medical evaluation of cognitive impairment requires accurate history taking, mental status examination, physical and neurological evaluation, a relatively small number of blood tests, and neuroimaging. Illnesses that progress rapidly or that have an atypical course warrant more comprehensive investigation at a tertiary care center, where investigators have experience with a variety of dementing illnesses. As techniques and treatments evolve, methods such as functional neuroimaging may be used more frequently as a means for early detection and for monitoring the course of treatment.

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CHAPTER

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Neuroimaging Gene E. Alexander, Ph.D. Eric M. Reiman, M.D.

During the past three decades, advances in radiological and nuclear medicine technologies have led to the development of high-resolution structural and functional neuroimaging methods that allow for the evaluation of regional brain anatomy and neural activity in the living human brain. With these advances it has become possible to study with increasing sensitivity and specificity the effects of neurodegenerative diseases on the brain. Clinically, these techniques have been used in the differential diagnosis of dementing illness to exclude potentially treatable, spaceoccupying abnormalities (e.g., tumors or subdural hematomas), and they have begun to have a role in the diagnosis of Alzheimer’s disease and other progressive neurodegenerative disorders. Scientifically, these neuroimaging techniques have investigated the structural, physiological, and chemical effects of dementing illnesses. Neuroimaging research in Alzheimer’s disease has increased the understanding of the brain changes associated with the progressive cognitive and behavioral dysfunction characteristic of this debilitating illness. Furthermore, studies have illustrated the clinical potential for such neuroimaging methods by aiding the detection of Alzheimer’s disease before the onset of clinical symptoms. This provides a way to test the potential of prevention therapies to slow neurological disease progression without having to wait many years to determine whether or when treated individuals develop symptoms. Sensitive and specific markers that identify individuals early in the course of dementing illness offer the opportunity to implement treatments in the very early stages of disease when intervention may be most beneficial. Thus, the use and further development of such neuroimaging techniques hold great promise in aiding the clinical evaluation and treatment of dementing illnesses. In this chapter we review the major structural and functional neuroimaging methods that are currently used to aid the evaluation of dementing illnesses. These include computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon 103

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emission computed tomography (SPECT). In addition, we discuss two neuroimaging techniques with potential clinical applications: functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS). These techniques have already provided important information on physiological and chemical processes in the brain.

Structural Neuroimaging Structural neuroimaging techniques are indicated in the diagnostic evaluation of cognitive impairment to help rule out the presence of potentially treatable conditions, including space-occupying lesions, such as brain tumors, stroke, subdural hematomas, abscesses, infections, and normalpressure hydrocephalus. In addition, structural brain imaging can provide supportive evidence for several forms of dementing illness, including vascular dementia, frontotemporal dementia, asymmetrical cortical degeneration syndromes, and evidence of prior traumatic brain injury. A recent review and consensus report by Knopman et al. (2001), as part of the Quality Standards Subcommittee of the American Academy of Neurology, has provided support for the use of either a non-contrast CT or an MRI scan as part of a routine initial diagnostic evaluation for dementia. Interestingly, the report also noted that one recent study showed that 5% of patients had a significant finding on structural imaging without having clinical features discovered on examination or by history that would have suggested the presence of such imaging abnormalities (Chui and Zhang 1997). In addition, a major area of research with structural neuroimaging has focused on applications for aiding early diagnosis and tracking progression in Alzheimer’s disease. Recent studies have emphasized the development and evaluation of rating scales and semi- and fully quantitative methods to analyze structural brain images to evaluate the potential of these techniques for use in making early diagnosis of Alzheimer’s disease, in identifying individuals at increased risk for developing Alzheimer’s disease, and in tracking disease progression. In this section we review the two major structural imaging techniques that are commonly used in the evaluation of dementia.

Computed Tomography CT provides a valuable method for the visualization of anatomic abnormalities of the skull and brain with high resolution, producing images that reflect tissue density differences with X-ray refraction. This technique relies on the use of a rotating radiation source that transmits a fan beam of X rays through the head. An array of scintillation detectors measure the attenua-

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tion of the X rays as they pass through tissues of different densities, producing differential trajectories. A computer algorithm transforms the attenuation information into sections that reflect the density of the tissues. Generally, tissues with high radiation attenuation, such as bone, appear white, whereas cerebrospinal fluid (CSF), which has low attenuation, appears black. The brain has intermediate levels of attenuation and appears gray. With this technique, visualization of the cerebral gray and white matter and ventricles can permit identification of a wide range of cerebral abnormalities, including the presence of space-occupying lesions and shifts in midline brain structures, cerebral infarction and bleeding, and demyelinization of white matter. Generalized and focal areas of cortical and subcortical atrophy can be observed, and the main divisions between structures such as the basal ganglia and thalamus can be seen. Iodinated and nonionic contrast agents can also be administered intravenously with CT to enhance differences in tissue density, which can help reveal lesions associated with vascular abnormalities and the breakdown of the blood-brain barrier, such as with tumors, infections, and other inflammatory processes. CT has the advantage of being a relatively inexpensive and widely available technology that can produce images of the brain quickly. This can be especially important in detecting lesions that require acute surgical intervention, such as subarachnoid hemorrhages, and for restless patients who have difficulty maintaining their head position during the MRI scanning procedure. Another potentially important advantage of CT over MRI is the absence of adverse reactions to being in a closed space and the need for sedation in the 10% of individuals who may experience this problem. CT also has an advantage in detecting bone abnormalities and calcified tumors, as well as providing a safe structural procedure for patients with pacemakers and other ferromagnetic materials present. A major limitation of CT is the presence of beam-hardening artifacts that make it difficult to visualize brain tissue that is in proximity to bone, such as the posterior fossa. Other limitations of CT include its relatively poor contrast between gray and white matter, its relatively lower sensitivity for detecting white matter lesions, and the potential for allergic reactions to iodinated contrast agents. In a clinical evaluation, CT can provide evidence supportive of several forms of dementing illness. Lobar frontal and anterior temporal cortical atrophy can often be observed in the variants of frontotemporal dementia. Loss of tissue in the caudate nucleus may be visualized in Huntington’s disease. Generalized cortical atrophy and enlarged ventricles can be seen in Alzheimer’s disease, especially as the illness progresses, but the appearance of normal, age-related atrophy is also not unusual in Alzheimer’s disease. Enlarged ventricles can be observed in both obstructive and normalpressure hydrocephalus.

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Research efforts to test the potential of CT for aiding the early clinical diagnosis of Alzheimer’s disease have focused on studying its ability to provide sensitive and specific measures of brain atrophy in groups of Alzheimer’s disease patients. In addition to evaluating cortical atrophy and ventricular size (DeCarli et al. 1990), a major focus in structural imaging research in dementia has been the development and testing of methods to rate or measure atrophy in structures of the medial temporal lobes, such as the hippocampus, a structure that is affected early in Alzheimer’s disease (Braak and Braak 1996). By acquiring CT images oriented along the long axis of the medial temporal lobe, axial images of the medial temporal lobes and its structures (such as the hippocampus) can be qualitatively rated or quantitatively assessed with linear measurements of width. Some studies using such hippocampal atrophy measures have shown very good sensitivity and specificity for groups of Alzheimer’s disease patients with clinical diagnoses of dementia compared with healthy elderly persons (George et al. 1990). However, in a study using neuropathological diagnosis as the diagnostic standard, medial temporal lobe width measurements provided high sensitivity (95%) but low specificity (40%) for Alzheimer’s disease (Nagy et al. 1999). Given the wide variability in the range of sensitivity and specificity values reported across studies for such quantitative medial temporal lobe measures in CT (and MRI), their use for assisting clinical diagnosis in routine evaluations is not currently supported (Knopman et al. 2001).

Magnetic Resonance Imaging MRI is a high-resolution structural imaging technique that allows for the visualization of brain anatomy with a high degree of contrast between brain tissue types. The anatomical information provided by this imaging method is fundamentally based on the response of hydrogen protons in water to the perturbations created by an externally applied magnetic field. For clinical use, MRI applies strong magnetic fields created by powerful magnets that range from 0.5 to 3.0 T. In the presence of the magnetic field, the hydrogen protons in water precess in the same frequency along the axis of the magnetic field. Brief radiofrequency pulses are delivered that temporarily reorient these protons away from the axis induced by the magnet. After this radiofrequency pulse, the time that it takes for protons to relax back to their original energy state, in realignment with the axis of the magnetic field, is accompanied by the emission of radio waves characteristic of the particular tissue containing the protons. Radiofrequency receivers detect these radio waves, and three parameters are measured: two tissue-specific relaxation constants, known as T1 and T2, and the proton density. T1 relaxation reflects the rate at which the protons in water return to the axis of the mag-

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netic field. T2 relaxation is a measure of the rate at which the protons decline to precess at the same frequency because of the inherent nonuniformities in the surrounding protons. MRI images that are T1 weighted are commonly used to visualize brain anatomy, with gray matter tissue appearing gray, white matter appearing white, and CSF appearing black. T2-weighted images are commonly used to detect the presence of brain pathology, because both CSF and brain lesions, which are often associated with increased water content, appear white. Proton density scans have intermediate image density. In addition, MRI can be performed after the administration of a paramagnetic contrast agent, which (like in CT) can enhance the ability to discern vascular abnormalities and the breakdown in the blood-brain barrier that is associated with the presence of tumor, infection, and other inflammatory conditions. MRI has a number of advantages over CT, including excellent contrast between gray matter, white matter, and CSF; a high level of sensitivity for white matter lesions with T2-weighted images; the ability to obtain volumetric images in any sectional orientation with high spatial resolution of contiguous slices; the availability of paramagnetic contrast agents that are nonallergenic; and the absence of ionizing radiation. Because bone is not visualized with MRI, brain tissue that is in close proximity to the skull can be studied equally well. Because gray matter, white matter, and CSF can be distinguished with MRI, cortical gyri and sulci can be seen in great detail, and even relatively small brain structures—including structures in the basal ganglia, thalamus, and limbic brain regions such as the hippocampus and amygdala—can be visualized quite well. In contrast to CT, MRI is a relatively expensive procedure. It cannot reveal skull abnormalities and calcified tumors, and it generally requires a longer scanning duration, making it prone to motion artifacts. It is potentially less useful when acute surgical intervention is required and with restless patients who have difficulty maintaining their head position for the duration of the imaging procedure. The MRI scanner can produce claustrophobic anxiety in some patients (although sedation may be helpful, and open MRI scanners are available for such patients). Another important contraindication to MRI is the presence of a pacemaker or certain ferromagnetic materials. With a few exceptions, MRI is generally considered the structural imaging method of choice for clinical and research studies of brain anatomy in the evaluation of dementing illness. In MRI, it is common to obtain either a T1-weighted or proton density image together with a T2-weighted image to enhance the ability to screen for brain abnormalities. T1-weighted images can be particularly helpful in detecting generalized and focal cortical atrophy. Narrowing of the cerebral cortex in Alzheimer’s disease can be observed as the illness progresses and

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specific regional patterns of cortical atrophy can be discerned that may correlate with clinical findings. For example, persons with frontotemporal dementia can show prominent cortical atrophy in the prefrontal and anterior temporal brain regions (Miller and Gerhart 1999). In focal dementias, such as primary progressive aphasia, atrophy can appear unilaterally in frontal and temporal regions (Abe et al. 1997). Patients with normal-pressure hydrocephalus may have ventricles that appear disproportionately enlarged compared with cortical atrophy. The abnormalities underlying dementing illnesses that are associated with movement disorders can be revealed by MRI. Atrophy in the caudate nucleus can be observed in Huntington’s disease. Structural changes that are observed in multiple system atrophy, including cerebellar atrophy, may be helpful in distinguishing this disorder from other parkinsonian syndromes. T2-weighted images are especially helpful in detecting the presence of brain infarcts and other lesions due to cerebrovascular abnormalities and demyelinization. In the elderly, T2-weighted images can show areas of increased signal intensity in the white matter around the ventricles or in the deep white matter. This finding can be observed in healthy elders, but it has also been associated with the presence of cardiovascular risk factors such as hypertension, and it appears to occur to a greater extent in Alzheimer’s disease (DeCarli et al. 1996). Although the clinical and pathological significance of white matter hyperintensities are not fully understood, they can be associated with subtle cognitive impairment and are suspected to reflect cerebrovascular pathology in some patients, especially when the hyperintensities are extensive (DeCarli et al. 1995). Current interest in the application of research methods, such as diffusion-weighted tensor MRI, may help to discern the potential role that white matter hyperintensities and other white matter abnormalities can have in the development and progression of dementia. As with CT, MRI can identify space-occupying lesions and midline shifts in brain structures with brain tumors and can help to identify and track the effects of infection and other inflammatory conditions. The use of MRI with a paramagnetic (e.g., gadolinium-based) contrast agent increases the sensitivity for detecting neoplastic and inflammatory lesions. The gadolinium-based contrast agents cross damaged regions of the bloodbrain barrier like iodinated CT contrast media. In multiple sclerosis, gadolinium-based MRI can help distinguish areas of active inflammation within acute demyelinating plaques from the more chronic lesions and may assist in monitoring disease progression over time. Gadolinium-enhanced MRI can also assist in the detection of meningitis, encephalitis, and myelitis and can help distinguish the many types of lesions that can occur in acquired immune deficiency syndrome. Figure 4–1 shows a T1-weighted

O Neuroimaging FIGURE 4–1. Case example of a 53-year-old woman with a suprasellar craniopharyngioma compressing the hypothalamus and midbrain. The patient presented with severe headaches and memory loss, both of which improved after tumor resection. Gadolinium enhanced T1weighted magnetic resonance imaging (MRI) scan shown in the sagittal, transverse, and coronal views (left to right). Source.

Figure courtesy of R.J. Caselli, M.D.

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magnetic resonance image with gadolinium contrast of a suprasellar craniopharyngioma affecting the hypothalamus and midbrain in a patient who was experiencing headaches and memory loss, both of which improved after the tumor was resected. This case example illustrates how structural brain imaging can help to identify potentially treatable causes of memory impairment. Research in the use of MRI to characterize the early and progressive effects of Alzheimer’s disease on the brain have focused on the development of methods to quantify the changes in the size and shape of brain structures that appear particularly vulnerable to Alzheimer’s disease neuropathology very early in the clinical course. In these studies, T1-weighted volumetric images are most often used to distinguish brain anatomy with high spatial resolution. One major approach has used manually traced structures in the medial temporal lobes—including the hippocampus, entorhinal cortex, and amygdala—to compute the volumes of these brain structures defined by strict anatomical landmarks and decision rules to establish high interrater and intrarater reliabilities. Although this method is relatively labor intensive, requires neuroanatomical expertise, and requires ongoing qualitycontrol procedures to ensure rater reliability, differences between groups of Alzheimer’s disease patients and healthy elderly have been demonstrated using such volumetric measures, with the hippocampus being the brain structure most consistently studied (de Leon et al. 1989; Jack et al. 1992; Krasuski et al. 1998). It has been also shown that these volumetric measures decline with the clinical progression of dementia (Jack et al. 2000). Furthermore, nondemented individuals with increased risk for Alzheimer’s disease have also shown reduced medial temporal lobe volumes compared with healthy control subjects (Jack et al. 1999; Killiany et al. 2000; Krasuski et al. 2002), supporting the potential for using these methods in aiding early detection and tracking the progression of Alzheimer’s disease before the onset of symptoms. Shown in Figure 4–2 is an example of a T1-weighted MRI scan in an Alzheimer’s disease patient with observable atrophy of the medial temporal lobe compared with a scan of a healthy elderly individual. Another brain structure that has been studied with MRI in Alzheimer’s disease is the corpus callosum. Using manually traced area measurements from a midsagittal MRI section, researchers have shown that such measures are reduced in Alzheimer’s disease and that specific subregions of the corpus callosum (i.e., the rostrum and splenium) may be preferentially affected. They are correlated with reductions in cerebral metabolism with PET and neuropsychological performance, and they continue to decline with disease progression (Teipel et al. 1999, 2002). Although it is thought that medial temporal lobe structures such as the hippocampus and entorhi-

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FIGURE 4–2. Examples of T1-weighted MRI scan slices acquired perpendicular to the sylvian fissure for a healthy comparison subject (HC) and an Alzheimer’s disease patient (AD) with mild dementia. The arrow highlights a portion of the left medial temporal lobe with observable atrophy in the vicinity of the hippocampus and amygdala in the Alzheimer’s disease patient. nal cortex are among the earliest affected in Alzheimer’s disease, atrophy of the corpus callosum may have a role in the progressive loss of corticocortical connections that occur as Alzheimer’s disease progresses (Hampel et al. 1998). In addition to investigating areas and volumes of specific brain structures, structural MRI images have been used to quantitate reductions of whole brain volume in sequentially acquired scans. The best-established method for characterizing whole brain atrophy involves the semiautomated computerized digital subtraction of sequential MRI scans to compute annual rates of decline (Fox et al. 1996). This method is highly reliable and effective in detecting differences between groups of Alzheimer’s disease patients and healthy elderly persons. Furthermore, annual decline rates of whole brain volume have distinguished individuals with increased risk for Alzheimer’s disease from healthy elders. These findings suggest that whole-brain MRI digital subtraction may be helpful in evaluating the effects of Alzheimer’s disease throughout the course of illness and may hold promise as an outcome measure in clinical trials (Fox et al. 2000). Promising methodological developments in the analysis of structural MRI data include the use of probabilistic brain maps to compute regional alterations in gray matter, white matter, CSF, and whole brain. This developing technique, known as voxel-based morphometry, uses fully automated linear and nonlinear warping computer algorithms to place brain scans into a common template space with stereotactic coordinates; to segment the image into gray matter, white matter, and CSF; and to compute differences in tissue concentration or degree of deformation to test group differences that

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can reflect alterations in shape and size of specific brain structures, whole brain, or cortical atrophy (Fox et al. 2001; Good et al. 2001; Thompson et al. 2001). Although these methods are only beginning to be applied in Alzheimer’s disease and other neurodegenerative diseases, they hold great promise for enhancing the ability to detect the earliest effects of these diseases, to track their progression, and to evaluate treatments to diminish or delay the progression of neurodegenerative diseases (Reiman et al. 2001a).

Functional Neuroimaging Interest in the use of functional brain imaging in the evaluation of dementing illness has grown in recent years with the increasing availability of these imaging techniques and growing research suggesting that functional imaging methods may have a helpful role in aiding diagnosis. These methods may be especially helpful when patients present with unusual or confusing clinical symptoms. Functional neuroimaging techniques can potentially provide supportive evidence for several forms of dementia, including Alzheimer’s disease, vascular dementia, frontotemporal dementia, and asymmetrical or focal cortical degeneration syndromes. Research in the clinical application of these functional neuroimaging methods has ranged from using simple rating scales with visual inspection to applying complex computerized algorithms that provide probabilistic brain maps of cerebral activity to test the ability of these neuroimaging methods in aiding early diagnosis, in tracking progression in Alzheimer’s disease, and evaluating individuals at risk for developing Alzheimer’s disease. In this section, we review the two most commonly used functional imaging methods in the evaluation of cognitive dysfunction, PET and SPECT. We also discuss the potential for developing clinical applications from two neuroimaging research methods that assess physiological and chemical processes in the brain, fMRI and MRS.

Positron Emission Tomography PET is a functional imaging technique that can provide information on physiological and chemical processes that occur in brain tissue and that may be useful in the evaluation of dementia. In PET, positron-emitting radiotracers are used to construct images of functional brain activity. These unstable radiotracer compounds have an excess of protons in their nuclei. Positrons with the same mass as an electron but with a positive charge are emitted and have the kinetic energy to travel a few millimeters within tissue. When it is nearly at rest, the positron interacts with an unbound electron, causing an annihilation event to occur. This results in two gamma ray photons of 511 KeV energy being emitted at 180 degrees from each other

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(Horwitz 1990). In a PET scanner, the gamma photons are detected by rings of detectors surrounding the head. Pairs of these detectors face each other and are connected by an electronic coincidence circuit that detects the photons emitted at the moment when the positron meets an electron. The multiple pairs of coincidence circuits in the scanner measure the number of photon pairs originating from all angles. Through a computer algorithm, it is possible to determine both the amount and the regional location of activity throughout the brain. Because energy for brain function is produced through the oxidation of glucose and because neurons require energy in the form of adenosine triphosphate (ATP), measurements of the cerebral metabolic rates for glucose with PET provide an index of neural activity (Sokoloff 1982). Under most conditions, cerebral blood flow is closely associated with cerebral metabolism (Sokoloff 1981), allowing measures of blood flow to also act as an index of functional brain activity. Kety and Schmidt (1945) were the first to use a nitrous oxide technique to measure average brain blood flow as a quantitative, in vivo index of human brain function. Interest in evaluating brain function on a regional basis led to the development and use of radioactive tracers to measure blood flow with the use of external scintillation detectors placed around the head to quantify the regional clearance of freely diffusible radioactive gases, such as xenon-133 (Obrist et al. 1967). Although this method represented an advance over the Kety-Schmidt technique, this planar imaging technique was limited to assessing regional brain function over the cortical surface. The inability to measure regional activity from deeper, subcortical structures led to the further development of the tomographic imaging techniques of PET and SPECT. Advances in scanner design and the development of radiolabeled compounds to study various aspects of brain function allow us to measure regional cerebral blood flow (rCBF) and the regional cerebral metabolic rates for glucose (rCMRglc) and oxygen (rCMRO2) throughout the human brain with relatively high spatial resolution (Jagust et al. 1993). The development of additional radiolabeled compounds allow for the in vivo assessment of other neurophysiologic processes, including uptake of precursors for neurotransmitter synthesis, neuroreceptor density and binding (Busatto and Pilowsky 1995), and (more recently) cellular signal transduction (Rapoport 2001). Furthermore, the ability to repeat scans over relatively short intervals due to the relatively shorter radioactive half-life of the cerebral blood flow tracer, H215O, has made it possible to assess regional brain activity in the same individual during the performance of different cognitive tasks or behavioral conditions and before and after pharmacological treatment or challenge.

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Because PET requires the use of a cyclotron to manufacture positronemitting tracers for local use, its availability has typically been limited to research medical centers. Availability of PET for use in clinical hospital settings has been increasing in recent years because 1) long-lived radioisotopes such as fluorodeoxyglucose can be distributed to other institutions or cities and 2) the number of scans has dramatically increased to accommodate reimbursable indications in the field of oncology. The cost of PET is on the order of about $2,000 per scan, higher than that of SPECT or MRI. Other limitations of this technology include its use of ionizing radiation and its relatively lower spatial and relatively poor temporal resolution compared with that of fMRI. The use of PET to aid clinical diagnosis of dementing illness is based on the distinctive patterns of cerebral metabolism and blood flow that are typically observed in different neurodegenerative diseases. Alzheimer’s disease is most frequently characterized by reductions of cerebral metabolism and blood flow in parietotemporal brain regions early in the disease course, as well as reductions in other association brain regions such as frontal and occipital association cortices as the disease progresses. Figure 4–3 shows a typical pattern of cerebral hypometabolism in a patient with Alzheimer’s disease compared with that of a healthy elderly individual. Although several disorders can be accompanied by cerebral dysfunction in these association brain regions at different stages of dementia severity, PET can provide valuable input to aid clinical diagnosis by confirming Alzheimer’s disease when a parietotemporal deficit is observed (Small and Leiter 1998). PET can also help characterize and follow the progression of Alzheimer’s disease during different stages of dementia severity. Examples of cerebral hypometabolism in Alzheimer’s disease are shown in Figure 4–4 for patients with mild, moderate, and severe dementia compared with those of a healthy elderly individual. In addition, PET can assist in characterizing the pattern of cerebral dysfunction in unusual or atypical cases of dementia. For example, patients with the visual variant of Alzheimer’s disease typically present with visual disturbances as their earliest clinical symptoms. It has been reported that such patients show preferentially greater cerebral metabolic reductions in occipital cortical brain regions compared with those of typical Alzheimer’s disease patients (Pietrini et al. 1996). Figure 4–3 shows an example of a PET scan in a patient with the visual variant of Alzheimer’s disease whose diagnosis was subsequently confirmed at autopsy. Patients with frontotemporal dementia, including Pick’s disease, typically demonstrate reductions in prefrontal and anterior temporal lobe cerebral metabolism and blood flow early in the clinical course (Ishii et al. 1998). Shown in Figure 4–3 is an example of the cerebral metabolic reductions seen with PET in a patient with a clinical diagnosis of frontotemporal dementia. In focal dementias, such as primary progressive aphasia, PET

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FIGURE 4–3. Examples of positron emission tomographic scans measuring glucose metabolism in a healthy comparison subject (HC), a patient with typical Alzheimer’s disease (AD), a patient with the visual variant of Alzheimer’s disease (AD+VS), a patient with frontotemporal dementia (FTD), and a patient with primary progressive aphasia (PA). Higher values of the regional cerebral metabolic rate for glucose (CMRglc) in milligrams per 100 g per minute are indicated by the orange end of the colorimetric scale. Relative to the healthy comparison subject, the Alzheimer’s disease patient without visual symptoms shows the typical pattern of reductions in glucose metabolism in parietal, temporal, and frontal association areas, with preservation in primary sensory regions. The AD+VS patient shows prominent glucose hypometabolism in parietal and occipital areas, including primary visual cortex, along with preservation of metabolism in frontal and temporal regions. The FTD patient shows marked reductions in CMRglc in frontal and anterior temporal regions, and the PA patient shows hypometabolism in the left frontal and temporal cortex.

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FIGURE 4–4. Transverse images at three different levels of brain positron emission tomographic scans in a healthy comparison (HC) subject and in Alzheimer’s disease (AD) patients with mild, moderate, and severe dementia (from top to bottom). Regional cerebral metabolic rate for glucose (CMRglc) values reported on the colorimetric scale are in milligrams per 100 g per minute. Reductions in CMRglc are present mostly in the association areas and become more severe as Alzheimer’s disease progresses. Primary neocortical areas are relatively spared, even in the late stages of the disease. Source.

Adapted from Grady and Rapoport 1992.

can reveal unilateral reductions in metabolism in frontal and temporal brain regions. Figure 4–3 illustrates cerebral metabolic findings with PET in a patient with progressive aphasia. Reductions in frontal blood flow and metabolism have been reported in other neurological diseases that can lead to dementia, such as progressive supranuclear palsy (Blin et al. 1990), as well as in disorders such as depression (Baxter et al. 1989). Symptomatic patients with Huntington’s disease show observable decrements in metabolism in the caudate nucleus (Kuhl et al. 1984). Vascular dementia can be characterized by widely distributed and varied patterns of cerebral dysfunction that can be observed in the cerebral cortex, cerebellum, and subcortical nuclei (Mielke and Heiss 1998; Yao et al. 1990). In Parkinson’s disease with dementia, cortical hypometabolism can be observed that may be most

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pronounced in parietotemporal cortex and can appear similar to the pattern observed in Alzheimer’s disease (Kuhl et al. 1984; Schapiro et al. 1993). It has been reported that patients with Lewy body dementia show relatively greater cerebral metabolic reductions in occipital cortex (Minoshima et al. 2001). Global hypometabolism together with relatively greater regional decrements in lateral temporal, inferior parietal, and frontal opercular cortex has been reported in corticobasal ganglionic degeneration (Eidelberg et al. 1991). In multiple-system atrophy syndromes, PET can show pontocerebellar hypometabolism (Rosenthal et al. 1988). In a consensus statement, Knopman et al. (2001) cited a recent study with 22 patients that reported 93% sensitivity and 63% specificity for PET using autopsy-confirmed diagnoses (Hoffman et al. 2000). Furthermore, it was indicated that PET may be superior to SPECT in differentiating Alzheimer’s disease from vascular dementia regardless of patient differences in dementia severity (Mielke and Heiss 1998). On the basis of the reviewed studies, the statement indicated that PET shows promise as an adjunct test in the clinical evaluation of dementing illness, but that it is not currently recommended for routine use in the clinical evaluation of dementing illness. In a recent multicenter study by Silverman et al. (2001) to evaluate the ability of PET rCMRglc to detect dementing illness, 284 patients were followed up with longitudinal clinical evaluation of 2 years or more (n=146) or to autopsy (n=138). Using a simple rating scale and visual inspection of the PET scans, the pattern of cerebral metabolism with PET was 93% sensitive and 76% specific in detecting any progressive dementing illness and 93% sensitive and 73% specific for Alzheimer’s disease in persons undergoing evaluation for dementing illness. In addition, it was shown that an individual having a normal PET scan was unlikely to experience progressive cognitive impairment in the subsequent average of 3 years of clinical follow-up. Figure 4–5 shows the typical PET patterns forming six commonly occurring categories for the 284 patients in this study. This is the largest study to date with clinical follow-up and neuropathological confirmation showing the promise of PET in aiding the clinical diagnosis of dementing illness. Efforts to provide additional diagnostic utility for PET have included the development and application of analytical methods that produce computerized probabilistic brain maps (Friston 1995) of brain activity that can be compared to normative samples or characteristic patterns in disease groups (Minoshima et al. 1995; Signorini et al. 1999). With the use of a brainmapping program to compare a group of 14 Alzheimer’s disease patients with mild to moderate dementia to 34 healthy age-matched subjects, the characteristic pattern of reductions involving parietotemporal hypometabolism with additional reductions extending into occipital and frontal association brain regions was observed (Alexander et al. 2002). Figure 4–6 shows the sta-

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FIGURE 4–5. Positron emission tomography (PET) patterns and occurrence of progressive disease in 284 patients undergoing evaluation for dementing illness. PET scans typical of each of six categories of cerebral metabolic patterns (designated N1, N2, N3, P1, P2, and P3) are shown. Images displaying N1, P1, and P3 patterns were acquired with a Siemens ECAT EXACT HR+ scanner; those displaying N2, N3, and P2 patterns were acquired with a Siemens ECAT 931 scanner. Image set in black background was acquired using a GE Signa 1.5 T MRI scanner, TR=2,100, TE=80. L indicates outcome established by longitudinal monitoring; H indicates diagnosis established by histopathologic examination. *Includes 3 cases of Alzheimer’s disease, 1 case of Alzheimer’s disease plus progressive supranuclear palsy, and 3 cases of Creutzfeldt-Jakob disease. **Includes 86 cases of Alzheimer’s disease; 4 cases of Alzheimer’s disease plus Lewy bodies; 1 case of Alzheimer’s disease plus Parkinson’s disease; 1 case of Alzheimer’s disease plus cerebrovascular disease; 1 case of Alzheimer’s disease plus Lewy bodies and cerebrovascular disease; 7 cases of frontotemporal dementia; 6 cases of Lewy body disease; 3 cases of subcortical gliosis; 2 cases of Creutzfeldt-Jakob disease; 1 case of progressive supranuclear palsy; and 1 case of Kuf’s lipofuscinosis. Source. Reprinted from Silverman DHS, Small GW, Chang CY, et al.: “Neuroimaging in Evaluation of Dementia: Regional Brain Metabolism and Long-Term Outcome.” Journal of the American Medical Association 286:2120–2127, 2001. Used with permission. Copyright © American Medical Association.

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FIGURE 4–6. Reductions in regional cerebral metabolism (in milligrams per 100 g per minute) in Alzheimer’s disease patients (n=14) compared with healthy comparison subjects (n=34). Significant (P-Blockers =-Methyldopa Analgesics Narcotic analgesics Propoxyphene Anticonvulsants Diphenylhydantoin Topiramate

the most important in elders (Wilcox et al. 1994). In young adults, drug ingestion leads to delirium or acute psychosis rather than a dementia syndrome. In elders, dementia syndromes arise from the use of long-acting benzodiazepines, barbiturates, meprobamate (Equanil), and a host of others depending on their dose and the length of time they have been used. Drugs such as flurazepam (Dalmane), with a half-life of more than 120 hours, accumulate rapidly. Others accumulate more slowly or require relatively high doses for toxicity to develop.

Alcohol Victor (1994) maintains that there are only four distinct brain diseases associated with chronic alcoholism: Wernicke-Korsakoff syndrome, Marchiafava-Bignami syndrome, pellagrinous encephalopathy, and acquired hepatocerebral degeneration. Victor holds that the role of alcohol in each is secondary. Nevertheless, there is evidence of alcohol toxicity in animal developmental models and in neuronal cell culture (Luo et al. 1999). Fur-

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thermore, Brun and Andersson (2001) found loss of synapses in the superior laminae of Brodmann’s area 10 in frontal cortex of 18 heavy drinkers who were compared with a control group with regard to liver disease and preexisting mental disorder. They suggested that this type of change might be responsible for the personality deterioration of persons with alcoholism. We have observed seven elderly persons referred to our clinic for evaluation of memory impairment who had a history of long-standing alcoholism or alcohol intake equivalent to four or more ounces of alcohol per day. All had good nutrition. Their cognitive impairment was mild but definite and primarily affected short-term memory and abstract reasoning. Followup of these patients over several years revealed progression to Alzheimer’s disease in all but one case.

Chemical Poisoning Chemical poisons that impair CNS function usually have their primary effects on other systems: gastrointestinal, renal, hepatic, hemapoietic, and peripheral nervous systems.

Organic Compounds, Solvents, and Inhalants The list of potential toxins is long and includes carbon disulfide, halogenated hydrocarbons such as carbon tetrachloride, naphthalene, benzene and its derivatives, and many others. Neural and cognitive symptoms tend to occur preterminally. Toluene (methylbenzene), one of the toxins in glue and paint sniffing, causes extensive white matter damage (Filley et al. 1990) and profound cognitive impairment in addition to tremor, ataxia, and loss of vision and hearing (Fornazzari et al. 1983). Commonly used inhalants, in addition to those listed above, include Freon, butane lighter fluid, and nitrous oxide (McGarvey et al. 1999)

Metabolic Disorders Azotemia Uremic encephalopathy may develop slowly or acutely. If it develops slowly, it usually produces apathy, impaired concentration, and irritability. The mechanism of uremic encephalopathy is presumed to be multiple metabolic derangements, including the accumulation of toxic metabolites (Moe and Sprague 1994). If uremia is acute, there is altered sensorium. Prerenal azotemia may be caused by diuretics, dehydration, and hypokalemia; postrenal azotemia may be caused by urinary tract obstruction.

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Hyponatremia Hyponatremia may cause cognitive impairment (Pentimone and Del Corso 1992). Serum sodium levels below 120 mEq/L are accompanied by impaired attention, drowsiness, and stupor. Hyponatremia may be due to diuretics, inappropriate antidiuretic hormone (ADH) secretion, salt-wasting renal disease, and water intoxication. Diuretic abuse is common in young women preoccupied with losing weight, and hyponatremia occurs frequently in elders treated with diuretics for hypertension (Vieweg et al. 1994). Polyuria due to decreased renal reabsorption of water is common with lithium treatment (Siegel et al. 1998). Inappropriate ADH secretion may occur with various brain lesions, lung tumors, and use of chlorpromazine and carbamazepine (Vishwanath et al. 1991); it is commonly reported with use of serotonin reuptake inhibitors (Kirby and Ames 2001). Saltwasting nephropathy may lead to hyponatremia. Water intoxication has been reported in subjects diagnosed with schizophrenia, mental retardation, depression, and alcoholism (Jose et al. 1979).

Volume Depletion Volume depletion may occur as a result of diuretic administration, diarrhea, vomiting, bleeding, or inadequate fluid intake. Electrolyte abnormalities may accompany the use of diuretics or may be associated with vomiting and diarrhea.

Hypoglycemia and Hyperglycemia Hypoglycemia primarily appears as delirium (Fishbain and Rotundo 1988) but may manifest as sudden worsening of cognitive impairment, especially in elders. Oral hypoglycemic agents are the most common cause of hypoglycemia in patients over age 60 years (Seltzer 1972). The oral hypoglycemic agent chlorpropamide is contraindicated in elders because of its 35-hour half-life. Other drugs may potentiate the action of sulfonylureas, including aspirin, dicumarol, lithium, and monoamine oxidase inhibitors. Other conditions leading to hypoglycemia in elders include alcoholism, sepsis, malnutrition, and myxedema. With rapid decrease in blood glucose, symptoms may appear at blood sugar levels greater than 45 mg/dL. Hyperglycemia may cause impaired mentation in uncontrolled diabetic patients.

Hepatic Encephalopathy Hepatic encephalopathy may occur in both acute and chronic liver failure. About 30% of persons with cirrhosis die in hepatic coma (Abou-Assi and Vlancevic 2001). Liver failure is usually accompanied by obvious clouding

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of sensorium, but intermittent mental dulling may be the primary symptom. Subclinical hepatic encephalopathy (e.g., significant impairment on neuropsychological testing) is present in as many as 60% of individuals with cirrhosis, and these individuals are prone to develop full-blown hepatic encephalopathy (Das et al. 2001). Diagnosis of hepatic encephalopathy is by demonstration of arterial ammonia concentration greater than 100 mg/dL (A.J.L. Cooper and Plum 1987). Borderline low serum albumin and increased prothrombin time and asterixis should raise suspicion of liver failure and hepatic encephalopathy. Recommendations for the treatment of both acute and chronic hepatic encephalopathy have been published by the American College of Gastroenterology (Blei and Cordoba 2001).

Thyroid Disease Although hypothyroidism is associated with lethargy, slowed thinking, slowed speech, and impaired recent memory (Haupt and Kurz 1993), there is no strong evidence that hypothyroidism produces a dementia syndrome or that the neurocognitive deficits associated with hypothyroidism remit fully with treatment (Dugbartey 1998). We have seen individuals with chemical hypothyroidism, but we have not seen a single case of hypothyroid dementia among more than 3,000 persons evaluated for cognitive symptoms over the past 14 years. Indeed, the few reports in the literature suggest a stronger relationship between hypothyroidism and symptoms of depression than with dementia. Hyperthyroidism is associated with impaired attention and concentration and diminished short-term memory. The usual symptoms of tachycardia, increased sweating, and fine tremor may not be apparent in elders (Meneilly et al. 1988), who may present with apathy.

Hyperparathyroidism and Hypercalcemia Hyperparathyroidism is most often due to parathyroid adenoma. Demineralization of bone and the presence of kidney stones are the most common clinical indicators. Blood calcium is increased, as is parathyroid hormone level. The predominant mental symptoms are depression and lassitude, but both delirium and dementia syndromes may occur (Alarcon and Franceschini 1984; Molaschi et al. 1994). Hypercalcemia itself can cause mental dulling. In one case, a woman with multiple myeloma had been given calcium supplementation to minimize pathological fractures that were occurring in the course of her illness. Over a period of months, she became increasingly dull and lethargic. When she was found to have an elevated serum calcium concentration, her calcium supplementation was discontinued, and her mentation improved considerably.

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Although hypoparathyroidism with its accompanying neuromuscular irritability and paresthesias has been suggested as a cause of dementia (Sier et al. 1984), there is little to support this contention.

Hypercortisolemia/Cushing’s Syndrome Chronic elevation of cortisol concentration is associated with hippocampal atrophy and subsequent deficits in declarative, episodic, spatial, and contextual memory performance (McEwen 1997). Cushing’s syndrome is caused by a chronic excess of circulating cortisol, whether endogenous or exogenous. Its clinical features include facial and truncal obesity, flushed facies, purplish abdominal striae, hypertension, diabetes, and osteoporosis. Depression and delirium are the most common associated mental states; neuropsychological testing shows impairment in nonverbal, visual ideational, visual memory, and spatial-constructional abilities more frequently than impairment in language or verbal reasoning (Whelan et al. 1980).

Wilson’s Disease This recessively inherited disorder of copper metabolism has symptomatic onset in the second or third decade of life; its first manifestations are usually related to impaired liver function, including jaundice and hepatosplenomegaly. Neurological symptoms begin with head or limb tremor, slowed movement, dysarthria, dysphagia, and choreic movements or dystonia (Dening 1991). As many as 20% of Wilson’s disease patients develop prominent emotional symptoms before the diagnosis is made, but cognitive impairment is not a prominent feature early in the disease (Dening and Berrios 1989). As the disease progresses, patients drool and become dysphagic; have rigid, slow-moving limbs; develop a fixed, vacuous smile; and develop a wing-beating tremor when their limbs are outstretched. The disease is diagnosed by the findings of low serum ceruloplasmin (80 mg/day; 2.8 for >120 mg/day) (Knopman et al. 1996). This finding is difficult to interpret because of the bias introduced by attrition (Knopman et al. 1998). Donepezil is a piperidine-based reversible acetylcholinesterase inhibitor. Peak plasma concentrations occur 2–4 hours after an oral dose. It is 100% bioavailable, and food has no effect on its absorption. The drug is more than 90% protein bound. Plasma concentrations increase linearly with dosage increase. The half-life of the drug is approximately 70 hours. At 5 mg/day, donepezil produces 64% red blood cell cholinesterase inhibition (Crismon 1998). A relationship has been shown between the cognitive effect of donepezil and the degree of plasma acetylcholinesterase inhibition; however, a plateau of acetylcholinesterase inhibition was reached at plasma concentrations greater than 50 ng/mL (Rogers and Friedhoff 1996). In a 24-week study, roughly 80% of patients receiving donepezil 5 or 10 mg showed no cognitive worsening on the ADAS-Cog compared with 42% of the placebo group (Rogers et al. 1998). On a measure of global function, approximately 25% of the donepezil-treated group (5 or 10 mg) improved compared with 11% of the placebo group. Thus, the overall effect of the drug was to maintain patients at their baseline level of function for approximately 24 weeks, whereas those receiving placebo decline below baseline.

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In a report on donepezil administered for as long as 144 weeks it was found that, on average, cognitive scores for individuals who had received 10 mg/day remained above baseline for 51 weeks (Doody et al. 2001). However, this finding is of limited value because it only included patients who were benefiting from the medication. Side effects of donepezil include muscarinic cholinomimetic effects such as decreased pulse, increased gastrointestinal motility, urinary urgency, and sweating. Common side effects reported by patients are nausea, vomiting, diarrhea, muscle cramps (due to nicotinic effects), mild stimulation, and vivid dreams that are sometimes frightening. The gastrointestinal side effects are usually transient and respond to short-term abstinence from the drug or lowering of the dose. The medication is available in 5- and 10-mg tablets. Although there is slightly greater efficacy at 10 mg/day, there are significantly greater side effects at that dose. Titration from 5 to 10 mg is recommended after 4–6 weeks; earlier increases in dosage are associated with more frequent side effects. Donepezil has low affinity in vitro for CYP 2D6 and 3A4, making drug-drug interactions unlikely. Although the manufacturer recommends dosing the medication at bedtime, the stimulating effects of the drug (including vivid dreams) may be better tolerated if it is administered in the morning. The carbamate rivastigmine is a reversible inhibitor of both acetylcholinesterase and butyrylcholinesterase. It is rapidly absorbed orally, has a bioavailability of 0.36, and is only 40% protein bound. Elimination halflife is approximately 2 hours. It is converted to an inactive metabolite at the site of action and is not metabolized by the liver (Jann 2000). Its effects are dose dependent. In a double, blind, placebo-controlled study, rivastigmine in dosages of 1–4 mg/day and 6–12 mg/day were compared with placebo over a 26-week period (Corey-Bloom et al. 1998). Dosage was titrated upward on a weekly basis until the maximum tolerable dosage was reached. In the placebo and low-dosage groups, the dropout rate was 15%, whereas in the high-dosage group the dropout rate was 35%. Only 55% of the persons in the high-dosage group achieved the maximum rivastigmine dosage of 12 mg/day. At 26 weeks, the high-dosage rivastigmine group differed from the placebo group by nearly 5 points on the ADASCog, remaining 1 point above baseline. At 26 weeks, the high-dosage rivastigmine group had improved 0.3 point over baseline on the Mini-Mental State Exam (Folstein et al. 1975), whereas the placebo-treated group had declined by 0.79 points. On an activities of daily living scale, 25% of highdosage rivastigmine-treated patients showed clinically meaningful improvement (10%) compared with 15% of persons in the placebo group. There was no difference in outcome between low-dosage rivastigmine and placebo. Rösler et al. (1999) performed a parallel study showing a similar

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dropout rate for high-dosage rivastigmine. Using an intent-to-treat analysis, the proportion of high-dosage treated subjects who achieved a meaningful improvement (4 points on the ADAS-Cog) was higher than in the placebo group (24% versus 16%). (Among those who completed the 26 weeks of study, the proportion was 29% versus 19%.) The incidence of treatment-related side effects increased with rivastigmine dosage and decreased with dosage reduction in both studies. The most common side effects were cholinergic, including nausea, vomiting, diarrhea, and anorexia. Nausea and vomiting occurred most commonly in the dosage titration phase. Rivastigmine is available in tablets of 1.5, 3, 4.5, and 6 mg. The drug is administered twice a day with food. The initial recommendation of the manufacturer was titration of the drug at a minimum 2-week interval to 6 mg twice a day. However, clinical experience indicates that fewer side effects will be encountered with dose titration at 4-week intervals, and it is now suggested that the medication be taken after a full meal. Galantamine is an alkaloid derived from the bulbs of the daffodil. It reversibly and competitively inhibits acetylcholinesterase (Bores et al. 1996). It also allosterically modulates the response of nicotinic receptors to acetylcholine. The enhancement of cholinergic nicotinic neurotransmission may increase the release of acetylcholine (Albuquerque et al. 1997). This is of potential importance for the therapy of Alzheimer’s disease, in which there is a significant loss of cortical nicotinic acetylcholine receptors (Court et al. 2001). However, there is no evidence that this is related to the observed therapeutic actions of galantamine. Galantamine is well absorbed and has absolute bioavailability of about 90%. It has a terminal elimination half-life of 7 hours and has linear pharmacokinetics in dosages from 8 to 32 mg/day. It is 18% protein bound. The drug is metabolized by the hepatic P450 isoenzymes and by glucuronidation, and it is also excreted unchanged in the urine. A 6-month randomized, placebo-controlled trial was undertaken in 636 persons with mild to moderate Alzheimer’s disease by Raskind et al. (2000). Patients were randomized to placebo or to escalating dosages of galantamine up to 24 or 32 mg/day. (Eligible subjects also entered a 6-month open-label study of the 24-mg/day dosage.) Patients receiving either dosage of drug had significantly better ADAS-Cog scores than did those receiving placebo (patients receiving 24 mg/day scored 3.9 points higher on average than the placebo group; patients receiving 32 mg/day scored 3.6 points higher), and both groups showed significantly better scores than the placebo group on the Clinician’s Interview-Based Impression of Change plus Caregiver Input) (Schneider et al. 1997). At 12 months on the 24-mg/ day dosage, ADAS-Cog scores and daily function showed no deterioration

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from baseline. The dosage of galantamine was increased weekly in this study; dropout rates for adverse events were 7.5% for placebo, 23% for 24 mg/day, and 32% for 32 mg/day. Wilcock et al. (2000) reported on a double-blind, placebo-controlled study of 653 persons with mild to moderate Alzheimer’s disease whose daily dose of galantamine was escalated weekly over 3–4 weeks to 24 or 32 mg/ day. The dropout rates for adverse events were 13.5% for the placebo group, 20% for the 24-mg group, and 22% for the 32-mg group. ADASCog scores differed significantly from placebo at 6 months (2.9 points difference for 24 mg; 3.1 points difference for 32 mg) based on an intent-totreat analysis. Apolipoprotein E genotype had no effect on outcome. Titration at monthly intervals in a third study (Tariot et al. 2000) reduced the dropout rate for adverse events to 7% for 16 mg/day and 10% for 32 mg/ day. In this study, there were significant differences in scores on a global measure (the Clinician’s Interview-Based Impression of Change plus Caregiver Input), on activities of daily living, and on behavioral symptoms, using the Neuropsychiatric Inventory as the measure. Adverse events in all studies were primarily gastrointestinal symptoms. On the basis of these studies, the manufacturer recommends titration to 16 or 24 mg/day (8 or 12 mg twice a day) at 1-month intervals. It is available in 4-, 8-, and 12-mg tablets and is administered twice a day. The cholinesterase inhibitors are used with caution in persons with complete heart block or sinus bradycardia and in the presence of active peptic ulcer disease or asthma. Drug-drug interactions are uncommon. Patients and their families need to be counseled about the concomitant use of highly anticholinergic drugs such as diphenhydramine and oxybutynin. In our practice, we offer cholinesterase inhibitors to persons whom we believe to be in the prodromal stage of Alzheimer’s disease and have not reached the stage of full-blown dementia. We generally attempt to reach the maximum dosage suggested by the manufacturer, because the effects of these drugs are dose related. Our hope is to maintain the patient’s level of function. In dealing with families, we emphasize that temporary stabilization is the optimal result with the cholinesterase inhibitors. It is difficult to know how long treatment should be continued, because with many patients discontinuance of these drugs is associated with worsening of cognitive symptoms. In general, we do not recommend initiation of treatment with cholinesterase inhibitors in persons who require institutional care (as opposed to assisted living). When the decision is made to discontinue a cholinesterase inhibitor, gradual downward dosage titration seems appropriate; our experience is that rapid withdrawal is often followed by an exacerbation of cognitive and behavioral symptoms. If symptoms worsen with slow withdrawal, we continue the medication.


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Anticholinesterases for Behavioral and Psychological Symptoms On the hypothesis that the delusions of Alzheimer’s disease might be due to cholinergic deficit in the limbic system, Cummings et al. (1993) administered oral physostigmine to two Alzheimer’s disease patients. The researchers found delusions to be markedly diminished, dosing the drug at 1 mg approximately every 2 hours (due to the short half-life of physostigmine). Later, Cummings and Kaufer (1996) and Cummings and Back (1998) postulated that a variety of neuropsychiatric symptoms in Alzheimer’s disease might be related to cholinergic deficit and might respond to cholinergic treatment. Cummings (2000) suggested that acetylcholinesterase inhibitors should be considered psychotropic drugs as well as cognitive enhancers, because his literature review suggested that anticholinesterases have an effect on apathy and visual hallucinations. He speculated that the connection of behavioral and psychological symptoms to the cholinergic system might be loss of input from cholinergic neurons in the basal forebrain to the limbic and paralimbic regions and to the cerebral cortex. Raskind et al. (1997) reviewed the data from a 30-week tacrine trial using last observation carried forward. They compared outcomes for persons receiving placebo (n=181) and those receiving tacrine (n=234) in dosages ranging from 40 to 160 mg/day. They found that on 3 of the 10 ADAS noncognitive items (cooperation, delusions, and pacing), there were significant improvements with tacrine over placebo. In an open-label study of tacrine in outpatients with Alzheimer’s disease, there was significant reduction in total Neuropsychiatric Inventory scores, with the group classified by MiniMental State Exam score as moderately impaired showing greater improvement than the mildly or severely impaired groups (Kaufer et al. 1998). Mega et al. (1999) studied 86 community-dwelling persons with Alzheimer’s disease who were treated with donepezil 5 mg/day for 4 weeks, followed by treatment with 10 mg/day for 4 weeks. Using global Neuropsychiatric Inventory scores as the criterion, behavioral improvement was seen in 41% and behavioral worsening in 28%. Persons who showed behavioral responses had worse initial scores on the following Neuropsychiatric Inventory subscales: Delusions, Agitation, Depression, Anxiety, Apathy, Disinhibition, and Irritability. Cummings et al. (2000) reported on 84 persons with Alzheimer’s disease treated with donepezil for 6 months and contrasted them with a group of Alzheimer’s disease patients (n=248) who were not taking the drug. Patients taking donepezil were significantly less likely to be threatening, destroy property, or talk loudly, and fewer were receiving sedatives. Weiner et al. (2000) performed a prospective

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12-month study of donepezil in 25 Alzheimer’s disease patients using a reference group for comparison. The reference group was of communitydwelling persons with Alzheimer’s disease who were not receiving anticholinesterase treatment (n = 153) and were enrolled in a 1-year study of assessment instruments for Alzheimer’s disease patients (Patterson et al. 1997). Using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Behavioral Rating Scale for Dementia (CBRSD) (Tariot et al. 1995), Weiner et al. (2000) found that the donepezil-treated group showed improvement in CBRSD total scores at 3 months and in Depression and Behavioral Dysregulation scores at 4 months. In this group, CBRSD total, Depression, and Behavioral Dysregulation scores returned to baseline at 12 months, in contrast with the reference group, whose CBRSD scores worsened minimally over the 12 months. In an open-label study of rivastigmine in 11 persons diagnosed clinically with dementia with Lewy bodies, Neuropsychiatric Inventory scores fell after 12 weeks of treatment by 73% for delusions, 63% for apathy, 45% for agitation, and 27% for hallucinations. Of the 11 persons treated, 5 had not responded to prior treatment including low-dose neuroleptics. Furthermore, parkinsonian symptoms tended to improve. The mean dosage of rivastigmine was 9.6 mg/day (range, 3–12 mg/day) (McKeith et al. 2000a). A larger (n=120) double-blind, placebo-controlled study was conducted over 20 weeks in patients with dementia with Lewy bodies. Of the 120 participants, 18 taking rivastigmine and 10 taking placebo dropped out. The mean dosage of rivastigmine of 9.4 mg/day at the end of the 8-week titration period declined slightly afterward. The maximum daily dosage of 12 mg was achieved by only 56% of the 48 completers; most (92%) were able to tolerate at least 6 mg/day. There was no change in extrapyramidal symptoms when patients were taking rivastigmine. Despite the lack of significant differences at 20 weeks between rivastigmine and placebo in MiniMental State Exam and Clinical Global Change scores, patients receiving rivastigmine were significantly less anxious and apathetic and had fewer delusions and hallucinations than control subjects, based on observed cases (McKeith et al. 2000b). A later report from this same study indicated that therapeutic benefits were lost when the drug was discontinued after 20 weeks (Wesnes et al. 2002), underscoring the need to maintain treatment with cholinesterase inhibitors. Although there appears to be much reporting of salutary behavioral effects from cholinesterase inhibitors, these are generally uncontrolled case series. These patients often had little behavioral disturbance at baseline, and the significance of any apparent differences is not clear. The responsiveness of the persons with greater symptoms may be a function of having scores high enough on behavioral instruments to be detected.


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Antioxidants Evidence of possible central nervous system damage due to lipid peroxidation and oxidative injury (Lethem and Orrell 1997; Sano et al. 1996) led to a trial of vitamin E (a-tocopherol) and the MAOI selegiline in 341 persons with Alzheimer’s disease (Sano et al. 1997). The trial, conducted over 2 years, compared a-tocopherol (2,000 IU/day), selegiline (10 mg/day), and a-tocopherol plus selegiline with placebo. The primary outcome measure (end point) was time to death, institutionalization, loss of ability to perform basic activities of daily living, or severe dementia (Clinical Dementia Rating Scale score of 3). When adjusted for severity of illness at the beginning of the study, selegiline was associated with a delay of 655 days to end point; a-tocopherol, with 670 days; and selegiline and a-tocopherol combined, 585 days. There was no difference between groups in cognitive measures or in overall side effects. The most important contraindication to high-dose vitamin E is the use of warfarin (Coumadin) as an anticoagulant.

Drugs for Prevention and Treatment of Cerebrovascular Disease In theory, vasodilators such as papaverine might be useful in cases of cerebrovascular insufficiency. However, studies using the vasodilator acetazolamide (Diamox) have shown that blood flow actually diminishes in ischemic areas after drug administration, because it reduces perfusion pressure throughout the brain and results in a “steal” of blood from areas of high resistance (Bonte et al. 1986).

Blood Viscosity Reducers and Antiplatelet Drugs The blood viscosity reducers and antiplatelet drugs seem to be a logical means to slow or arrest the progress of dementia due to cerebrovascular disease. Prevention of sludging and platelet aggregation should prevent the formation of clots on arterial atherosclerotic plaques and possibly help maintain arteriolar patency. Aspirin is the most widely used drug of this class. In low doses, aspirin inhibits the enzyme cyclooxygenase, which is responsible for the synthesis by platelets of thromboxane, a substance that promotes platelet aggregation. The effectiveness of aspirin in preventing transient ischemic attacks and reducing thrombotic strokes and myocardial infarction is well known (Fields et al. 1978; Swedish Cooperative Study Group 1987). Its principal adverse effects are gastric irritation and gastrointestinal bleeding. Rarely, aspirin will cause thrombocytopenia. Reducing the dose from the conven-

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tional 325 mg and employing an 81-mg dose that is enterically coated reduces the gastrointestinal complications. Ticlopidine hydrochloride (Ticlid) is a platelet antiaggregant that inhibits the adenosine diphosphate pathway of platelet aggregation. It does not inhibit the cyclooxygenase pathway or block the production of thromboxane by platelets or the production of prostacyclin by endothelial cells (Hass et al. 1989). When compared with placebo in 1,072 subjects with completed strokes, ticlopidine (250 mg twice a day) reduced the rate of stroke or stroke death by 33.5% over 3 years (Gent et al. 1989). Compared with aspirin at a dose of 325 mg four times a day, ticlopidine at 250 mg twice a day reduced the rate of strokes in more than 3,000 persons with prior cerebrovascular symptoms (transient ischemic attacks, amaurosis fugax, mild stroke) 21% more frequently than did aspirin. It was equally effective in men and women (Hass et al. 1989). The chief side effects of ticlopidine are diarrhea and skin rash. An uncommon but important side effect is severe reversible neutropenia, which occurs within the first 3 months of treatment. Clopidogrel (Plavix), an adenosine diphosphate receptor antagonist, was slightly more effective than aspirin in reducing the combined risk of ischemic stroke, myocardial infarction, or vascular death in 19,185 patients treated an average of 1.9 years with clopidogrel 75 mg once a day versus aspirin 325 mg/day (Jarvis and Simpson 2000). For aspirin, the overall annual rate was 5.83%; for clopidogrel, it was 5.33%. Drug interactions are rare with this medication (Easton 1999), but like aspirin, it may cause severe thrombocytopenia. Gastrointestinal hemorrhage was slightly less frequent with this drug than with aspirin. It shares with ticlopidine the occasional development of diarrhea or skin rash, but it is less likely to cause neutropenia. The dosage is 75 mg once a day. Dipyridamole (Persantine) is a platelet adhesion inhibitor whose mechanism of action is unknown but may be related to red cell update of adenosine. In a large randomized clinical trial, persons who had survived a stroke or transient ischemic attack were randomized to placebo, aspirin 50 mg/ day, sustained-release dipyridamole (400 mg/day), or a combination of aspirin and dipyridamole (Forbes 1998). Dipyridamole and aspirin were equally effective in reducing the recurrence of stroke (16% for dipyridamole versus 18% for aspirin) compared with placebo; when they were combined, there was a 37% reduction in stroke recurrence compared with placebo. Aspirin was associated with enhanced bleeding and gastrointestinal side effects; dipyridamole was associated with headache. Dipyridamole is administered in doses ranging from 25 to 100 mg four times a day. The use of warfarin (Coumadin) to prevent stroke in persons with atrial fibrillation is well documented (Lodwick 1999) but is beyond the scope of this review.


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Hypolipidemic Agents Based on evidence accumulated in the 1990s, it is evident that 3-hydroxy3-methylglutaryl coenzyme A reductase inhibitors (so-called statin drugs) significantly reduce cardiovascular events, including stroke (Amarenco 2001). The literature is vast and is beyond the scope of this discussion. Of note, it has been recommended that persons with established atherosclerosis be treated with a statin to achieve a low-density lipoprotein cholesterol level less than 100 mg/dL (Ansell 2000).

Drugs to Reduce Hyperhomocysteinemia Epidemiologic studies have shown hyperhomocysteinemia (serum concentration greater than 12 mM/L) to be associated with increased risk for atherosclerotic cardiovascular disease (W. Herrmann 2001). Research is now under way to determine the impact of reducing homocysteine levels in blood by use of high-dose folic acid and B vitamins.

Summary Many drugs have been employed to treat emotional, behavioral, and cognitive symptoms in cognitively impaired persons. Most of these drugs have very modest efficacy. Their dosage depends in part on patients’ general physical state and in part on the specific dementing illness. Almost all of the potent drugs that are available have important side effects and toxicity. NMS, paradoxical hypertension from MAOIs, withdrawal from minor tranquilizers, and bradycardia from anticholinergics can be life threatening. Parkinsonian symptoms and tardive dyskinesia from neuroleptics can be disabling. Patients often fall when sedated. Therefore, although drugs do much to enhance the quality of life of some patients, they may also do harm if prescribed inappropriately or not monitored adequately. In progressive dementing disease, different medication regimens may be required at different stages of the illness. Early on, an antidepressant may be indicated to treat mood disturbance or irritability; later, an antipsychotic or anticonvulsant may be needed to deal with agitated behaviors with and without psychotic symptoms; and ultimately, stimulants may be used to combat apathy and withdrawal. Drugs are available that produce transient improvement of global function and that appear to slow progression and improve behavioral symptoms in Alzheimer’s disease, but they do not yet address the underlying disease process. On the other hand, the use of statins addresses an important aspect of the pathophysiology of vascular dementia, and they, along with anticoagulants, are reducing the occurrence of stroke.

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CHAPTER

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Evaluation of Cognitive Functions C. Munro Cullum, Ph.D. Ronald G. Paulman, Ph.D. Elisabeth Koss, Ph.D. Sandra Bond Chapman, Ph.D. Laura Lacritz, Ph.D.

The clinical neuropsychological evaluation plays important roles in detecting and diagnosing dementing illness and in characterizing patients’ cognitive strengths and weaknesses. The information obtained in the evaluation is used in making the differential diagnosis, in planning patient management and disposition, and in providing education and support to patients’ families. Neuropsychological data provide an objective, quantitative means to establish levels of cognitive functioning and produce profiles that can be used to assist in differential diagnosis and in understanding individuals’ functional impairments (Naugle et al. 1998; Zakzanis et al. 1999). Neuropsychological evaluation techniques are recognized and accepted neurodiagnostic procedures (American Academy of Neurology Task Force 1996) and are the most sensitive existing means of evaluating human brain function and cognitive abilities. Because the oldest age groups are the most rapidly growing segment of society and because of the association between age and dementing illness, the use of neuropsychological testing in persons with known or suspected dementing illness is one of the most important roles for modern clinical neuropsychology. The inclusion of cognitive screening instruments and neuropsychological test batteries is considered routine to establish cognitive criteria for Alzheimer’s disease (McKhann et al. 1984) and was recently included as a recommended practice guideline for the early detection of dementing illness (Petersen et al. 2001). In fact, detailed neuropsychometric testing has shown high sensitivity and specificity in detecting dementing illness (Becker et al. 1994). 285

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Goals of Neuropsychological Assessment Characterization of Cognitive Functioning The neuropsychological evaluation provides objective information that relates to a variety of everyday functional tasks and can help address important practical questions such as the patient’s ability to understand procedures, make independent decisions, manage finances, function on a job, and drive a car. Neuropsychological testing places individuals in a structured situation requiring effortful processing of both new and previously acquired information. By examining performance on standardized tasks, clinicians may use neuropsychological data to help assess how individuals may be expected to perform in occupational or psychosocial settings. For example, this can help to determine if a business executive continues to possess the higher-order organizational abilities required to manage a department with multiple simultaneous needs. At the other end of the spectrum, it may also help predict whether a widowed elderly woman will be able to meet her needs in an independent living situation, or whether she needs assistance or requires a more structured placement. Thus, the neuropsychological evaluation provides a quantified, comprehensive characterization of neurobehavioral abilities that may confirm and extend observations and impressions derived from physicians, family, and other caregivers.

Role of Cognitive Assessment: Neurodiagnosis An understanding of the cognitive patterns and changes associated with normal aging is an important prerequisite to identifying dementing illnesses in older adults. Although improved norms for many neuropsychological tests have been published over the past two decades, additional knowledge regarding what constitutes “normal” cognition among the oldest old is needed. Cognitive decline generally does not become apparent until after age 70, and this decline is not uniform across cognitive abilities. Decreases in activities requiring executive function, visuospatial processing, mental speed, and psychomotor speed are most notable, whereas relative stability is observed for language-related skills (Albert 1988). Memory decline associated with aging has been described as “benign senescent forgetfulness” (Kral 1978) and “age-associated memory impairment” (Crook et al. 1986). However, criteria for applying these terms are not uniform, are too all-encompassing, and do not adequately consider the high degree of individual variability in memory functions among elderly individuals (see Larrabee and McEntee 1995). Whereas the ability to acquire and retain certain types of new information (e.g., visual

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memory) declines with aging, other aspects of memory (e.g., paragraph retention) shows little change (e.g., Cullum et al. 1990; see Verhaeghen et al. 1993 for a review). Cognitive changes observed as part of normal aging are trivial compared with those observed in persons with dementing illness (Koss et al. 1991). Memory loss is by definition in DSM-IV-TR (American Psychiatric Association 2000) the common abnormality in all the dementing illnesses. Also present are varying degrees of disturbances in awareness, orientation, insight, general behavior, ability to efficiently access stored information, language function, praxis, visuospatial function, topographical orientation, problem-solving ability, judgment, calculation, and emotion. These nonspecific dysfunctions cover all cognitive domains. It should be noted that changes in some of these areas can be associated with normal aging as well. The intensity, qualitative differences, unique symptom constellation, and progressive nature seen in dementing illness serve to distinguish them from normal aging. As noted in Chapter 1, DSM-IV-TR diagnostic criteria for dementia include impairment in short- and long-term memory and at least one of the following: aphasia, apraxia, agnosia, and impairment in executive functioning. These deficits must also represent a decline from premorbid status and be associated with impairments in everyday activities. As such, an evaluation of several cognitive domains is a necessary part of the assessment of dementing illness. Multilevel assessment of cognitive changes in an individual offers the best opportunity for discriminating between age-related and diseaserelated changes in cognitive status (Albert 1988). A person’s performance on neuropsychological tests is combined with historical, developmental, educational, and medical information (including neurological, psychiatric, and neuroimaging) to assist in the diagnosis of dementing illness. Both the age and education of patients must be taken into account. For example, low performance by an individual of limited premorbid intelligence, education, or occupational attainment may not suggest a dementing condition. Conversely, average performance on cognitive tasks by a university professor may signal the onset of a dementing illness. Thus, the diagnostic process necessitates integration of all information relevant to a patient’s past and present functioning. Furthermore, the pattern of cognitive test performance, including specific pathognomonic signs and error types, may be illuminating in terms of differential diagnosis.

Recommendations for Interventions In addition to describing cognitive function and assisting in diagnosis, neuropsychological evaluation may lead to specific recommendations con-

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cerning further evaluation and treatment. These might include considering neuroimaging studies (if they have not yet been performed); giving behavioral prescriptions to help compensate for specific cognitive deficits such as memory, language, or visuospatial impairments; or designing strategies for management of problem behaviors in the living environment. Results of a neuropsychological evaluation may also be useful to family members in terms of guidance in setting appropriate expectations for their loved one and restructuring their environment to help capitalize on the patient’s cognitive strengths.

Comprehensive Neuropsychological Evaluation A comprehensive neuropsychological evaluation provides an assessment of multiple cognitive domains and abilities. This requires an integration of multiple sources of information, including 1) the patient’s developmental, medical, social, and educational history; 2) collateral information from others familiar with the patient’s recent and past functional status; 3) quantitative and qualitative testing of a range of neurocognitive skills; and 4) assessment of the patient’s emotional status. Elements of these examinations are described in more detail in the following sections.

History The past and present context of a person’s life influences the interpretation of neurocognitive evaluation results. Although an objective score on a particular test may be the same for two individuals, the implications of that score may be different based on individual differences such as cultural background and educational or professional achievement. Neuropsychological assessment therefore begins with a systematic inquiry into early medical and developmental history; language acquisition; school performance, including any special needs; military record (if relevant); occupational experience; and acquired insults to the central nervous system such as head trauma, toxin exposures, or other neurological conditions. Current medical history is also important in that conditions such as diabetes, hypertension, vitamin deficiencies, hormonal imbalance, cardiac problems, kidney or liver disease, infections, and chronic obstructive pulmonary disease can influence neuropsychological function (see Chapter 5). Past psychiatric history and treatment are also important, in addition to current medication regimen. Functions such as attention and memory are particularly susceptible to disruption in the elderly by medications such as anxiolytics or antidepressants with anticholinergic side effects (Weiner and Davis 1986). Finally, family history of dementing


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illness should be queried, because some dementing illnesses have a genetic component.

Interviewing Clinical interviewing is covered in Chapters 1 and 2. The availability of external sources of information is important in corroborating information gathered during a patient interview. Observational data from physical appearance, motor function, level of awareness, sensory impairments, and speech are easily obtained in interview. By contrast, a person’s selfreport can be unreliable. Persons presenting for cognitive evaluation may provide erroneous or confabulated answers to questions or may have difficulty finding words or remembering what was asked of them. As a result, it is advisable to have a close relative or caregiver available when conducting an initial mental status examination or clinical interview. Although patients should be questioned directly, it is often advantageous to also interview caregivers separately so that they may feel free to disclose information about the patient that might be upsetting to him or her. It is important to note that caregiver appraisals concerning memory deficits in persons with Alzheimer’s disease frequently correlate well with objective test measures (Koss et al. 1993). However, the interviewer must be aware that families or caregivers present information from their perspective, and therefore may exaggerate the problems or may minimize or deny them.

Neurocognitive Testing Many tests and measures of cognitive functioning have been developed, and many of the more popular tools in clinical use are summarized in texts such as those by Lezak (1995), Snyder and Nussbaum (1998), and Spreen and Strauss (1998). Although several standard batteries of tests have been developed, the important factor in the comprehensive cognitive evaluation of dementia is the inclusion of tests that tap specific cognitive domains. Particular attention must be paid to the areas that are most susceptible to the effects of different types of dementing illness. This generally means an emphasis on memory assessment, in addition to other ability areas commonly involved in different dementing illnesses. As noted, interpretation of the level as well as the pattern of performance, is important, as qualitative features of different tests can be useful in diagnosis (see Cahn et al. 1997; Rosenstein 1998). A list of some common measures used in the comprehensive neuropsychological evaluation of cognitive dysfunction is presented in Table 8–1.

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TABLE 8–1.


Typical neuropsychological test battery for dementia with tests listed by cognitive domaina

Global cognitive functioning Mini-Mental State Exam Dementia Rating Scale Intellectual ability Wechsler Adult Intelligence Scale, 3rd Edition (WAIS-III) or Revised (WAIS-R)b Premorbid intellectual level National Adult Reading Test–Revised (NART-R) or Wide Range Achievement Test, 3rd Edition (WRAT-3) Reading test Executive function Wisconsin Card Sorting Test Trail Making Test—Part B Attention Trail Making Test—Part A Digit Span (WAIS-III/R) Language Boston Naming Test Verbal fluency (letter and category fluency) Vocabulary (WAIS-III/R) Visuospatial skills Block Design (WAIS-III/R) Clock drawing test Cross, cube drawings Rey-Osterreith Complex Figure Learning and memory California Verbal Learning Test (or other list learning tests such as the Hopkins Verbal Learning Test, Rey Auditory Verbal Learning Test, Buschke Selective Reminding Test) Wechsler Memory Scale, 3rd Edition (WMS-III) or Revised (WMS-R) Logical Memory, Visual Reproduction subtests Psychomotor abilities Finger tapping test Hand dynamometer Grooved pegboard a

References for tests can be found in Lezak (1995), Snyder and Nussbaum (1998), and Spreen and Strauss (1998). b Selected subtests are often used to provide an estimate of current intellectual status (e.g., Vocabulary, Information, Block Design, Digit Symbol/Coding)


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Cognitive Domains Typically Assessed in the Neuropsychological Evaluation Intellectual Ability and Global Cognitive Status Intellectual assessment is a frequent component of the comprehensive cognitive workup for several reasons. A determination of global cognitive or intellectual status can be used to estimate the extent to which current intellectual functioning likely reflects a decline from presumed premorbid abilities. Furthermore, having an estimate of overall intellectual ability is useful in interpreting the results from other neurocognitive measures. For example, are memory test results lower than expected given an individual’s overall mental ability level? In addition, because clinical measures of intellectual function are composed of multiple subtests, the pattern of subtest scores can be useful to infer cognitive decline in addition to providing information relevant to specific cognitive strengths and weaknesses. For example, the ability to define words tends to maintain its integrity relatively well into the course of Alzheimer’s disease, in contrast to early compromise in the ability to interpret proverbs or assemble three-dimensional blocks to replicate patterns. The Wechsler scales—including the Wechsler Adult Intelligence Scale, 3rd Edition (WAIS-III), and the earlier revised version (WAIS-R)— are the most popular means of assessing intellectual capacity in adults and may be useful for detecting cognitive deficits. These measures evaluate academically acquired knowledge in addition to many global verbal and visuomotor problem-solving skills important in daily life. As such, these measures are well-standardized indices of overall cognitive function, comparing an individual’s responses with those of same-age peers. Verbal and nonverbal intellectual abilities are assessed, and composite scores can be derived that provide general descriptors of overall intellectual capacity. The WAIS-III includes a Verbal Comprehension Index and a Perceptual Motor Index, which reflect verbal and nonverbal cognitive skills. Results of intellectual assessment may suggest a decline in intelligence but are not sufficient to make a diagnosis of dementing illness, because many other areas of cognitive functioning are not evaluated by these measures. In fact, intellectual testing is often much less sensitive to acquired cognitive impairment secondary to dementing illness than are many other neurocognitive measures. The estimation of premorbid cognitive functioning is also useful in interpreting current neurocognitive test scores and inferring the presence and extent of cognitive decline. There are a number of ways to obtain such estimates (Kareken 1997), including 1) clinical judgment (given the patient’s education, age, social and occupational background, was he or she

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likely average, above average, or below average premorbidly?); 2) regression-based approaches using demographic data (e.g., Barona et al. 1984); 3) examination of patterns of neuropsychological performance on tests that are generally less sensitive to cognitive decline (vocabulary or word definitions, general fund of information) in comparison with other measures; and 4) use of tests that hold up better in the presence of dementing illness and correlate well with premorbid intelligence. These include sight-word reading tests such as the National Adult Reading Test–Revised (NART-R) (Blair and Spreen 1989) and its variants and the Reading subtest from the Wide Range Achievement Test, 3rd Edition (WRAT-3) (G.S. Wilkinson 1993). The NART-R, for example, has shown reasonably good stability relative to the WAIS-R in Alzheimer’s disease, even as the disease progresses (Maddrey et al. 1996; Paolo et al. 1997). The use of such procedures (often in combination) can provide a reasonable estimate of premorbid cognitive ability, although predictive limitations at the upper and lower ends of the intellectual spectrum restrict the accuracy of these approaches in individual cases. Global cognitive status is typically assessed by using cognitive screening tools, which provide a cursory examination of several cognitive domains yet yield a global score that is useful in the overall characterization of cognitive impairment. Among the assessment instruments commonly used in persons with dementia are the Dementia Rating Scale (Mattis 1988) and the Mini-Mental State Exam (MMSE) (Folstein et al. 1975). Such instruments are often included in drug treatment studies to examine the effects of medications on overall cognitive status and in clinical and research settings to provide a quick, quantitative index of the level of cognitive impairment. Despite the utility of some of these brief screening instruments in distinguishing between demented and nondemented groups (van Gorp et al. 1999), the limitations of such tools are numerous as a result of their brief nature, insensitivity to some forms of dementing illness, and poor sensitivity at both ends of the cognitive continuum (subtle or mild cognitive impairment and severe dementia). In the Alzheimer’s Disease Center at the University of Texas Southwestern Medical Center, for example, 14% of 673 consecutive patients with a clinical diagnosis of possible or probable Alzheimer’s disease obtained scores in the normal range (higher than 23) on the MMSE (Cullum and Rosenberg 1998). As with more detailed neurocognitive measures, these measures are influenced by demographic factors such as age, education, and ethnicity; as a result, careful interpretation and use of appropriate norms are important when evaluating findings. Despite their limitations, cognitive screening tools can provide quantitative scores that aid not only in diagnosis, but in tracking the progression of dementing illness in a standardized fashion. They are often included in


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neuropsychological test batteries for the reasons just mentioned; furthermore, they may be particularly useful as dementing illness progresses and as patients become less amenable to more detailed cognitive testing. As an intermediate approach to cognitive screening, a brief battery of tests was assembled by the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). This group identified a basic neuropsychological battery (Morris et al. 1989) evaluating memory, language functions, and constructional praxis, with level of difficulty allowing for the evaluation of persons with mild to relatively severe cognitive impairment. The CERAD battery evaluates global cognitive function (MMSE), acquisition of new information (a 10-word list learning task), memory (delayed recall and recognition of the word list plus recall of drawings), language functions (category fluency plus a 15-item version of the Boston Naming Test), and constructional praxis (copying simple geometric figures). The CERAD battery typically requires 30–45 minutes to complete, has available norms to age 90 (Welsh et al. 1994a), and has shown positive correlations with regional cerebral function in Alzheimer’s disease (Welsh et al. 1994b). With progression of dementing illness, scores on many standard tests quickly decline, and this may result in a floor effect. Patients eventually may become untestable using traditional cognitive assessment techniques, and eventually it becomes necessary to rely on clinical observation and informant ratings to obtain information about disease progression. Nevertheless, several tests have been developed to provide quantitative neurobehavioral data in cases of more profound cognitive impairment. For example, the Severe Impairment Battery (Saxton et al. 1990) was developed to evaluate cognitive functioning in persons who may not be amenable to standard neuropsychological assessment. It includes a variety of subtests to evaluate various basic areas and has shown evidence of convergent validity in relation to other formal measures and behavioral observations. Similarly, the Texas Functional Living Scale (TFLS) (Cullum et al. 2001) was designed to provide a brief index of daily functional abilities in persons with dementing illness, with an emphasis on cognitive tasks (e.g., making change, looking up and dialing a telephone number, remembering simple instructions). In preliminary studies, the TFLS has shown good convergent and discriminant validity, with promise as a cognitively oriented measure of independent activities of daily living in persons at various stages of dementing illness.

Attention and Concentration Attention and concentration abilities underlie all higher cognitive processes. Although it is often characterized as a specific ability, attention is a

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highly complex set of functions involving many brain regions, including reticular, thalamic, and frontal systems. In dementing conditions, the finetuned balance between awareness of novel stimuli and the focus on those with greatest relevance is frequently disrupted. Therefore, impaired selective attention in cognitively impaired persons leads them to be either highly distractible or excessively focused, thereby missing important environmental cues. Accompanying problems in sustaining or dividing attention are also usually present (Butters et al. 1987; Lines et al. 1991), even though simple attention may remain grossly intact. Simple attention is often assessed by having patients repeat strings of single-digit numbers (e.g., WAIS-III digit span forward), in addition to observing the degree to which they are able to follow instructions, track conversation, and respond to questions. Such basic attentional skills are often intact in the early stages of dementing illness, and it is not uncommon for patients with Alzheimer’s disease or Korsakoff’s syndrome to demonstrate normal performance on digit span forward tasks, despite the presence of amnesia. Selective attention may be assessed in numerous ways. The ability to track digit sequences backward and perform mental arithmetic problems on the WAIS-III, for example, requires more working memory and selective attention. Selective attention is also required in the discrimination of visual stimuli in the presence of a competing cognitive set, as in the Stroop Color Word Test. Sustained attention may be evaluated by requiring patients to be vigilant for recurrent target stimuli in a long auditory or visual sequence (e.g., Digit Vigilance Test; Lewis and Rennick 1979). The Verbal Series Attention Test (VSAT; Mahurin and Cooke 1997) assesses simple and selective attention using a variety of brief, repeatable tasks, as does the Mental Control subtest of the Wechsler Memory Scale, 3rd Edition (WMS-III; Wechsler 1997) and its precursors. Divided attention tasks may require the patient to perform two tasks simultaneously (Paulman and Kennelly 1984) or to respond alternately on a number-letter sequencing test. Because the construct of attention represents a hierarchical set of abilities, persons with mild dementing illness may demonstrate little or no impairment in simple or selective attention, although they may be unable to divide or alternate their attentional focus. Conversely, persons with moderate to severe levels of cognitive impairment have difficulty with all levels of attentional processing.

Executive Functions Loss of executive processing abilities, such as organizing, planning, and monitoring one’s problem-solving behaviors, is common in dementing ill-


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ness. Executive functions are thought to be primarily mediated by anterior brain systems, although damage to other brain systems may produce deficits on the complex tests used to assess this construct. As this set of abilities represents the highest level of cognitive control and planning, executive functions rely heavily on a variety of supportive cognitive skills. Similarly, executive functions may mediate other ability areas such as memory (Troyer et al. 1994). Difficulties with planning, reasoning, and inhibition may be manifested in many ways, and standardized assessment of this complex set of skills has proved challenging. Most commonly, however, these abilities are examined by tests that rely heavily on novel problem-solving skills. Commonly used measures include the Wisconsin Card Sorting Test (Heaton 1981), the Category Test (Reitan and Wolfson 1985), and the recently published Delis-Kaplan Executive Function Test (2001) and its component tests. Most of these instruments require patients to generate and test hypotheses while using success-failure feedback to flexibly alter responses with changing task demands. Other tasks that rely on some degree of flexible generation (e.g., word fluency) or inhibition and the switching of mental sets (e.g., Trail Making Test Part B [Reitan and Wolfson 1985], Stroop Test [Trenerry et al. 1989], go–no-go tasks) are also commonly used to evaluate persons with known or suspected dementing illness. Tests of verbal reasoning and judgment can also be used to assess aspects of executive function, but as with other tasks, these tests may show impairment resulting from a variety of reasons besides impairment of executive function.

Memory Memory impairment is a sine qua non of dementia in DSM-IV-TR, and it is typically the earliest and most severe symptom in Alzheimer’s disease. However, memory complaints are also frequently reported by depressed individuals and healthy elderly adults. The clinician has the task of determining whether a patient’s memory problem is due to a neuropathological process, a psychiatric disturbance, or a normal variation. Memory is a higher-order set of abilities that includes the acquisition, storage, and retrieval of information. As such, memory is another complex construct that requires the integration of many functional systems of the brain. Some inconsistency exists in the terminology used to describe memory tasks and abilities, and a number of functional dichotomies have been posited (see Squire 1986 and Schacter and Tulving 1994 for reviews). Another important distinction related to clinical memory assessment is the concept of recall versus recognition. Free recall of information is required on an essay type of examination, wherein subjects are asked to

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remember information presented earlier. In contrast, recognition memory is evaluated in a multiple-choice type of test, wherein subjects must choose the correct response from an array of stimuli. Problems in recognition memory are often related to faulty retrieval rather than encoding: information may be learned, but problems may occur with the active retrieval of the stored material. This distinction can be useful in differentiating between cortical and subcortical disorders, between cognitive impairment associated with depression and dementia, or between Alzheimer’s disease and frontotemporal dementia (FTD). Persons with a cortical dementia such as Alzheimer’s disease often exhibit difficulties in encoding, free recall, and recognition memory, whereas depressed persons and those with subcortical disorders more frequently show only deficits in free recall and show significant improvement on recognition testing. One important factor in clinical memory assessment pertains to the nature and complexity of the test. For example, although very brief tasks such as three-word recall (as included in the MMSE) may distinguish large groups of demented subjects from nondemented subjects, the results of such tests may vary widely within the normal population and in individual cases (Cullum et al. 1993). Other related factors that may influence results include the instructional set provided at the time of stimulus presentation (explicit versus implicit recall), the nature of the stimuli (simple versus complex words or ideas), the provision of cues during recall, and the number of pieces of information to be recalled. For example, longer memory tests may be needed to better elicit some of the characteristic errors during recall that typify some dementing illnesses (Kaltreider et al. 2000). No single test of memory is capable of tapping all of the dimensions of memory. Most assess episodic memory, the ability to recall information within a temporal context, such as remembering recently presented information. Along these lines, formal memory tests, particularly those assessing delayed verbal recall, are the most efficient means of discriminating dementing illnesses from normal aging (Welsh et al. 1991). Some of the verbal memory measures used in cognitive assessment are the California Verbal Learning Test (CVLT), the Rey Auditory Verbal Learning Test (RAVLT), the Hopkins Verbal Learning Test (HVLT), and the Buschke Selective Reminding Test. Such instruments have the advantage of multiple learning trials (versus one-time exposure to stimuli), adequate length to require secondary (long-term) memory, a delayed recall condition, and a recognition trial. The CVLT, for example, provides a quantitative assessment of multiple qualitative aspects of verbal learning and memory, including learning style, errors during recall, ability to benefit from cueing during recall, and errors made during recall and recognition trials. Figure 8–1 shows typical learning scores by trial in normal elders.


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FIGURE 8–1. California Verbal Learning Test learning scores by trial (T1–T5) in normal subjects ages 50–89 (N=174). This wealth of information has proved useful in the differential diagnosis of various amnestic and dementing disorders (Bondi et al. 1994; Delis et al. 1991), particularly in the early stages (Cullum et al. 1995) (Figure 8–2). In addition to the word list–learning tasks listed above, the Logical Memory subtest of the WMS-III (Wechsler 1997), assesses recall for paragraph-length information (stories). Two paragraph-long stories are read to the patient, one at a time. After each presentation, patients are asked to recall as much information from the story as possible. Delayed recall is also assessed after 30 minutes to examine how much of the initially learned information is retained. The inclusion of delayed-recall trials in such tests is critical, because some amnestic persons are able to perform relatively well on immediate recall trials, showing the severe decay of memory only after a period of time has passed. Visual memory is commonly evaluated by measures such as the Visual Reproduction subtest of the WMS-III and by the Rey-Osterreith Complex Figure Test (Visser 1985). In these tasks, subjects are presented with printed geometric designs of varying complexity. After the figures are removed from view, patients are asked to reproduce the designs from memory. Typically, recall after a 15–30 minute delay is also assessed. Although such tasks are susceptible to the confound of visuoconstructional and motor impairments, comparison of patients’ direct copies of the test stimuli versus recalled reproductions can yield useful information in terms of visual memory ability.

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FIGURE 8–2. California Verbal Learning Test performance scores in subjects with mild Alzheimer’s disease (AD) and advanced normal aging. Note. %Retent = percent retention (delayed free recall/last learning trial ´ 100); Recency% = percentage of words recalled from recency region of the word list; Intrus%= percentage of total words recalled that were intrusions; Discrim%=recognition hits adjusted for false-positive errors. Source. Adapted from Cullum et al. 1995.

Visuospatial Functioning Visuospatial processes are complex and involve a variety of functional systems in the brain, particularly in the right hemisphere. Visuoconstructional functioning is frequently evaluated through use of various standard figure drawings and the Block Design subtest from the WAIS-III and WAIS-R. Some of the more common drawing tasks include clocks (to command and copy, with hands set at a specified time), crosses, cubes, and intersecting lines and pentagons. Various scoring methods have been developed for such tasks, most notably the clock drawing test (see Freedman et al. 1994; Kozora and Cullum 1994). Having patients render drawings of common but visually complex objects such as houses and bicycles can also be useful, even within the context of cognitive screening examinations. Another standard visuospatial drawing test is the copy of the Rey-Osterreith Complex Figure, which can also be used later as a visual memory task. Drawings by patients with Alzheimer’s disease often exhibit oversimplification, poor angulation, and impaired perspective (Kirk and Kertesz


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1991). They may also display poor planning in their layout, organization, and presentation. Perseverative features may also be observed, particularly in drawings by patients whose disease includes greater involvement of anterior brain systems. In addition to central brain mechanisms, primary visual impairments and motor deficits may complicate the interpretation of constructional dyspraxia in the elderly. As a result, the use of multiple measures of visuospatial functioning may be in order to preclude the rendering of conclusions on the basis of too little information. Figure 8–3 presents an example of perseveration on the copy of the alternating ramparts from the Dementia Rating Scale.

FIGURE 8–3. Perseveration in frontotemporal dementia as depicted by the copying task from the Dementia Rating Scale.

Language Receptive and expressive language abilities can be disrupted by many forms of dementing illness. Receptive language involves the comprehension of oral and written communication. An individual may lose the ability to attach semantic meaning to words or to understand their syntactical meaning within a sentence, such as “lost woman’s purse” versus “woman’s lost purse.” Visual comprehension of written material is based on auditory mastery and is also often disturbed when an individual has auditory comprehension deficits. In dementing illness, the appreciation of nonverbal components of language, such as prosody or body movements, may also be disrupted. Expressive language disturbances (disorders of production) can take numerous forms. These include disturbances of articulation and word finding and the loss of grammar, syntax, repetition, verbal fluency, and writing. To speak a word, it is necessary to locate it in the extensive repository or

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semantic lexicon of words previously learned. As noted, knowledge of word definitions—and particularly the ability to read single words—tends to remain relatively better preserved in cognitively impaired persons without frank aphasia. Accordingly, performance on the Vocabulary subtest of the WAIS-III can often be used as a gross index of overall intellectual functioning, and in early to middle-stage Alzheimer’s disease, sight-word reading may correlate well with premorbid IQ (Maddrey et al. 1996). A number of standard tests of comprehension exist (e.g., the Token Test; Van Dongen and van Harskamp 1972), although a great deal of information along these lines can be obtained during the clinical interview and by examining patients’ responses to instructions. Cognitively impaired persons can often describe the use of an object but cannot retrieve the name of it (dysnomia). Although bedside testing of confrontation naming (e.g., having the patient name a pen, watch, door, etc.) may elicit the deficit, standard psychometric instruments such as the Boston Naming Test and its derivations (Lansing et al. 1999; Morris et al. 1989), which include line drawings of objects, are more sensitive to dysnomia. Verbal fluency, the ability to produce words and sentences in uninterrupted strings, is affected by numerous factors, including dysnomia associated with frontal and temporal lobe lesions. Common fluency tasks include the rapid generation of words within a minute that begin with a specified letter (letter or phonemic fluency [e.g., “F, A, S” or “C, F, L”]) or that belong to a specific category (category or semantic fluency, e.g., “animals” or “fruits and vegetables”). Whereas some age-related changes on such tests are seen (Abwender et al. 2001; Kozora and Cullum 1995), individuals with Alzheimer’s disease commonly show deficits on the verbal fluency tasks. Some studies have suggested that individuals with dementing illness have greater difficulty with category fluency than with phonemic fluency (Monsch et al. 1994), although this finding is not universally seen in Alzheimer’s disease (Epker et al. 1999; Sherman and Massman 1999). Salmon and Chan (1994) present a detailed discussion of the hypothesized breakdown in semantic knowledge that leads to verbal fluency deficits. Phonemic fluency has been linked with frontal lobe function, whereas category or semantic fluency has been associated more with temporal lobe activation (Moscovitch 1994). Therefore, performance patterns on these tasks in the context of a comprehensive neuropsychological profile may be useful in identifying cerebral regions having greatest dysfunction, which may have implications for diagnosis (e.g., Alzheimer’s disease versus FTD). In addition to the traditional neuropsychological evaluation of basic language abilities, neurolinguistic analysis of discourse can be useful in assessing the communication abilities of cognitively impaired persons


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(Joanette and Brownell 1990). Discourse refers to the linguistic expression of ideas, knowledge, and opinions, typically conveyed as a sequence of sentences that has coherent organization and meaning. The capacity to produce coherent discourse entails a complex interplay of basic linguistic skills, cognitive processes, and information-handling abilities. Discourse abilities are assessed using a variety of procedures, including descriptive, conversational, narrative, procedural, and expository procedures. Early discourse disturbances in Alzheimer’s disease may include reduced elaboration or embedding of ideas (Snowdon et al. 1996), impaired gist-level processing (Chapman et al. 1998), impaired coherence of ideas (Chapman et al. 1995), and interrupted flow of information during verbal expression (Bayles et al. 1989; Ripich and Terrell 1998). A disrupted flow of information often occurs in the Alzheimer’s disease process as the speaker has difficulty fluently translating his or her thoughts into language, resulting in fragmentation of ideas. Discourse gist (e.g., the ability to abstract the overall theme of a story) is also vulnerable in the early stages of Alzheimer’s disease, and deficits are found in persons with mild cognitive impairment (Chapman et al. 1998). In contrast, cognitively healthy adults typically demonstrate a remarkable capacity to derive the gist (central or synthesized meaning) well into the tenth decade of life (Radvansky 1999; Ulatowska et al. 1998). Procedural discourse, a genre that requires an individual to provide the props and sequence of actions to complete an activity, reveals differential breakdowns in component skills involved in generating procedures. Persons with FTD show reduced verbal fluency and also show a noticeable reduction in the specificity of verbs used to describe actions or steps in a task sequence compared with cognitively healthy control subjects and persons with Alzheimer’s disease.

Motor Abilities Motor abilities range from strength and fine motor speed to more complex skilled movements (praxis). Basic motor deficits occur commonly in vascular and subcortical dementias. Simple motor strength is often assessed through use of a hand dynamometer, whereas manual speed may be tested through procedures requiring finger tapping or fine motor dexterity. Decreases in motor strength and/or fine motor speed beyond the effects of normal aging deserve further follow-up (examining for vascular or other focal lesions), particularly when lateralized. If such lateralized findings occur within the context of other lateralized cognitive results (e.g., decreased tapping and dexterity on the right hand in conjunction with impaired verbal versus nonverbal memory and dysnomia), the case for predominant involvement of the left hemisphere can be made.

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Disorders of complex skilled movements that do not arise from basic motor difficulties are known as apraxias. Persons may be unable to carry out a motor response to command that is easily performed spontaneously (ideomotor apraxia). Alternatively, they may be unable to sequence known motor acts toward a specific goal (ideational apraxia). These impairments in the production and organization of skilled behaviors are common in the later stages of Alzheimer’s disease. Evaluation of praxis involves instructing the patient to pantomime a series of common activities (e.g., waving goodbye, brushing teeth, preparing a cup of coffee) through both verbal command and imitation.

Sensory-Perceptual Abilities The interaction between performance on cognitive tests and perceptual deficits must be evaluated carefully. A substantial number of cognitively impaired persons complain of visual problems. Although these complaints are often dismissed by clinicians and family members, several studies have reported visual distortions in persons with dementing illnesses in one or more of the following domains: color vision, depth perception, detection of motion, eye movements, low-contrast sensitivity, and higher-order visual perception (Cronin-Colomb et al. 1991; Mendez et al. 1990). Such complications, which can occur at any stage of the disease process, may affect reading and performance on tasks that rely on visual input. It is essential that primary visual dysfunction be ruled out before interpretation of visuospatial processing deficits are posited. Individuals may be asked to read sample text or identify small objects to help ensure adequate basic visual acuity, and this can often be incorporated as a routine examination procedure. Similarly, because most neurocognitive tasks require verbal instruction, decreased hearing thresholds must be considered as a potential confound to the interpretation of cognitive test results. Clinical assessment of hearing level during interview may suffice along these lines, in addition to direct inquiry of the patient and family about hearing problems. Also, olfactory dysfunction may occur early in the course of Alzheimer’s disease (Koss et al. 1988). Formal assessment of sensory-perceptual functions may be undertaken to provide information concerning lateralized somatosensory dysfunction, potentially useful in the identification of focal neuropathological conditions. Several standardized sensorimotor assessment tasks include measures of basic sensory-perceptual skills. The Sensory Perceptual Examination (Reitan and Wolfson 1993) includes measures of simple touch, response to double simultaneous stimulation, finger graphesthesia, gnosis,


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and stereognosis in a standardized and quantifiable fashion. A word of caution is necessary when interpreting sensory-perceptual testing results in cognitively impaired persons, however. Impairments in attention, memory, or confusion about instructions may, for example, predispose cognitively impaired persons to make errors in responding to sensory-perceptual testing. Thus, overinterpretation of sensory-perceptual deficits, particularly on tasks that require more complex responses, may occur in such cases. Consideration of the person’s entire neuropsychological profile is therefore of critical importance.

Personality and Emotional Assessment Clinical interviewing of individuals is sometimes difficult because of their memory impairment, lack of insight into internal mood states, or limited ability to cooperate. Instruments such as the Beck Depression Inventory (Beck et al. 1961) and the Geriatric Depression Scale (Yesavage et al. 1983) provide brief, reliable indices about depression and mood symptoms. When a more detailed assessment of mood and personality is desirable and feasible, the Minnesota Multiphasic Personality Inventory–2 (MMPI-2; Hathaway and McKinley 1989) may be considered. However, the length of this measure and its requirement of a higher level of cognitive integrity (e.g., sustained concentration, reading comprehension at or above the eighth grade level) must be considered. Nevertheless, the findings from such self-report mood and psychological measures can provide important information that may not be immediately available from either the patient or other informants (see Rush et al. 2000 for a listing of many popular psychiatric measures). In any case, some assessment of psychological functioning is an integral part of the neuropsychological evaluation, particularly because psychiatric disorders can influence performance on tests of cognitive ability.

Reporting Cognitive Evaluation Results Results of a comprehensive neurocognitive evaluation are presented in several ways. A verbal report is frequently provided to the referral source on completion of the assessment, followed by a written report containing the patient’s relevant history, clinical interview data, and neuropsychological test results. Conclusions are made concerning the presence, severity, and likely type of dementia, if possible. A description of adaptive functioning in a variety of areas is also commonly made, and prognostic statements are offered concerning relationships with personal, occupational, and psychosocial functioning. Specific recommendations can also be made for further

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neurodiagnostic testing, treatment, disposition, or future reevaluation. Finally, a reporting session may be held with the patient and/or primary caregiver. At this session, findings are presented in everyday language with frequent use of real-life examples to illustrate an individual’s neurobehavioral strengths and deficits. Family members or other caregivers are also given help in devising strategies for patient management in the home, along with support and recommendations for their well-being, in addition to information regarding community resources and referrals as indicated.

Cognitive Patterns of Various Types of Dementia Alzheimer’s Disease Alzheimer’s disease is the most common form of dementing illness. Although the heterogeneity in the behavioral manifestations and the slow progression of Alzheimer’s disease sometimes complicate its early clinical identification, neurocognitive test results and profiles tend to show common characteristics. For example, whereas early or mild Alzheimer’s disease is associated with memory impairment, detailed psychometric assessment often reveals prototypical neuropsychological findings, including limited acquisition and impoverished association abilities, rapid forgetting of newly learned information, and faulty retrieval. Persons with Alzheimer’s disease also tend to make intrusion errors (i.e., injecting incorrect but often related material into information they are trying to remember) during learning and recall attempts on some, but not all, memory tasks. Similarly, when their recognition for previously presented material is assessed, as in a yes-no identification of stimuli, they sometimes make a proportionally large number of false-positive or false alarm errors on tasks such as the CVLT. Such characteristics of episodic memory breakdown often distinguish cortical dementias such as Alzheimer’s disease from subcortical dementias (discussed below). In addition to amnesia (see Bondi et al. 1994), symptoms that characteristically develop in Alzheimer’s disease include degradations in confrontation naming and word-finding, abstract reasoning, linguistic discourse processing (discussed earlier), and visual-constructional skills. Early in the disease course, general intellectual skills may remain relatively intact, and individuals with higher premorbid cognitive abilities may produce normal results on cognitive screening tests, with their impairments only manifesting on detailed psychometric analysis of their memory skills. It is also important to note that although the overall pattern of impairments in Alzheimer’s disease usually suggests greatest involvement of temporal, and to a lesser extent, frontal systems (Chen et al. 2001), heterogeneity of the


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overall neurocognitive profile is common, with some individuals showing greater deficits in certain areas (e.g., primary verbal versus visuospatial). This may relate to long-standing cognitive patterns as well as different neurobehavioral phenotypes of the illness (Johnson et al. 1999; Mayeux et al. 1985; Naugle et al. 1985). Figure 8–4 depicts common patterns as seen in Alzheimer’s disease.

FIGURE 8–4. Typical neuropsychological performance pattern in Alzheimer’s disease (AD). Note. Attn = attention; ExFx = executive function; Verbal = verbal/language skills; Visuo=visuospatial skills; Learn=learning; Mem=memory. Source. Adapted from the meta-analysis by Zakzanis et al. 1999.

Vascular Dementia Vascular dementia accounts for approximately 10% of all cases of dementing illness, although some vascular pathology was present in 30%–40% of autopsied dementia patients in recent population-based studies (Holmes et al. 1999). Vascular dementia often includes both cortical and subcortical manifestations, frequently including the presence of neurological signs (e.g., focal weakness, sensory changes, or gait disturbance). Several series of standard diagnostic criteria for vascular dementia have been developed (see Román et al. 1993), although it remains a challenging clinical diagnosis (see Knopman et al. 2001). Neuropsychologically, there is considerable overlap between the cognitive impairments of Alzheimer’s disease and those of vascular dementia, and the fact that the disorders may coexist further complicates the situation.

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Nevertheless, neuropsychological evaluation may assist the diagnosis of vascular dementia through the identification of focal cerebral dysfunction or asymmetries in sensorimotor performance, which are more common in vascular dementia. Some studies have suggested that specific aspects of the neuropsychological profile can be used to distinguish vascular dementia and Alzheimer’s disease. For example, better performance on verbal recognition memory testing, yet worse performance on phonemic fluency was recently reported in patients with vascular dementia compared with patients with Alzheimer’s disease (Tierney et al. 2001). Finally, serial neuropsychological testing can help to characterize the pattern and severity of decline over time, and the extent to which an individual patient varies from the typical progression and/or pattern associated with Alzheimer’s disease can be particularly useful diagnostically.

Dementia With Lewy Bodies Dementia with Lewy bodies (DLB), including the Lewy body variant of Alzheimer’s disease, is now recognized as one of the more common forms of dementing illness, probably second only to Alzheimer’s disease. It may account for 15%–20% of late-onset dementia cases (Campbell et al. 2001). Whereas early studies of DLB suggested a greater frequency of visual hallucinations, heightened sensitivity to antipsychotic medications, fluctuations in alertness, and gait disturbance (McKeith et al. 1996), other reports have indicated a great deal more overlap between DLB and Alzheimer’s disease (Weiner et al. 1996). Increasingly, evidence is suggesting that it may not be possible to reliably distinguish between DLB and Alzheimer’s disease using existing clinical means (Knopman et al. 2001). There have been reports that, unlike the presentation of Alzheimer’s disease, DLB tends to be associated with more prominent attention deficits, marked fluctuations in attention, impairments in visuoconstructional skills, and less involvement of memory (Heyman et al. 1999). However, other investigations suggest that DLB and Alzheimer’s disease are not reliably distinguishable using neurobehavioral or neuropsychological techniques (Ballard et al. 1999). For reviews of DLB, the reader is referred to Perry et al. (1996) and Cercy and Bylsma (1997).

Frontotemporal Dementias FTD includes a variety of disorders such as Pick’s disease (with or without Pick bodies), corticobasal ganglionic degeneration, nonspecific frontal gliosis, semantic dementia, and various tauopathies. Characteristic symptoms include deficits in executive function and self-awareness and changes


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in personality and behavior. These may include decreased emotion and insight, selfishness, neglect of self-care and grooming, increased preference for sweets, wanting, motor and verbal stereotypes, echolalia, and mutism (reviewed in Hodges 2001). Behavioral disturbance and personality change are often early signs, with disinhibition and inappropriate behaviors being common features. Clinical criteria for the diagnosis of FTD have been put forth, emphasizing these points (McKhann et al. 2001; Miller et al. 1997; Neary et al. 1998). Neuropsychological evaluation of these patients early in the disease course typically reveals prominent deficits in executive function (Filley and Cullum 1993). Lateralized patterns of deficits are also seen with some frequency (Boone et al. 1999; Razani et al. 2001) and have shown relationships to underlying neuropathology (Lipton et al. 2001). Perseverative behaviors are common in frontal lobe dementias and are often documented on a variety of neurocognitive tasks (see Figure 8–3). Impaired performance on executive function tasks is often a prominent feature of the neuropsychological record, outstripping deficits in other functional domains (including memory) in many cases, which can assist in differential diagnosis (Duke and Kaszniak 2000). Striking impairments on measures such as phonemic fluency (Controlled Word Association Test [FAS]; Borkowski et al. 1987), the Wisconsin Card Sorting Test (Heaton 1981), and the Trail Making Test Part B (relative to Trail Making Part A) are commonplace, in addition to the aforementioned perseverative features, which may be manifested on a variety of tasks (e.g., tests of visuoconstructional skills, memory, and word definitions). A typical cognitive profile seen in cases of FTD is presented in Figure 8–5.

Subcortical Dementias Subcortical dementias are caused by disorders that primarily involve subcortical structures and systems and have associated cognitive impairments (Cummings and Benson 1984). These include Huntington’s disease, Parkinson’s disease, and progressive supranuclear palsy. Other disorders that fall under the heading of subcortical or white matter dementias include progressive multifocal leukoencephalopathy, Binswanger’s disease, multiple sclerosis, acquired immunodeficiency syndrome–related dementia, and normal-pressure hydrocephalus (see Filley 1995). Similar to subcortical disorders such as Parkinson’s disease without dementia, mild cognitive difficulties have also recently been reported in patients with benign essential tremor (Lacritz et al. 2002). Whereas neuropsychological findings in subcortical dementias overlap considerably with those seen in the cortical dementias, several common distinctions are worth noting, with qualitative

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FIGURE 8–5. Neuropsychological performance pattern in frontotemporal dementia (FTD). Note. Attn = attention; ExFx = executive function; Verbal = verbal/language skills; Visuo=visuospatial skills; Learn=learning; Mem=memory. Source. Adapted from the meta-analysis by Zakzanis et al. 1999.

performance features often serving to distinguish these groups (Butters et al. 1987, 1998; Troster et al. 1993). Subcortical dementias frequently involve a pronounced slowing in general information processing in addition to problems with attentional, executive, and visuospatial functions. Marked aphasia and amnesia are characteristically absent in earlier stages. The pattern of deficits can mimic frontal lobe dysfunction in some cases and may be manifested as impairment in the organization of problem-solving behavior (Brandt and Bylsma 1993; Mahurin et al. 1993). Depression is also a common feature of subcortical dementias (Cummings 1990; Rosenstein 1998).

Alcohol-Related Dementia Chronic abuse of alcohol is associated with documented changes in brain morphology, blood flow, electrophysiology, and neuropsychological function (Parsons et al. 1987). Although the amnestic Wernicke-Korsakoff syndrome is relatively well understood, there is still debate surrounding the concept of alcohol-related dementia. Some have suggested that many years (typically several decades) of chronic, heavy alcohol abuse can result in a generalized cognitive deterioration characterized as alcoholic dementia (see Salmon et al. 1993; Saxton et al. 2000), whereas others believe that dementia in individuals with long-term alcoholism is attributable to a


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coexisting dementing illness such as Alzheimer’s disease. Nevertheless, the presence of a long, heavy history of alcohol abuse should raise suspicion that this may be a contributing factor, if not the sole factor, in causing cognitive impairment. Neuropsychologically, marked visuospatial deficits (relative to more intact verbal skills) are commonly seen in alcohol-related dementia, in addition to impairments in executive function and memory. In fact, it often presents with cortical as well as subcortical features (Munro et al. 2001). Although cognitive deterioration may slow with a cessation of drinking in some alcoholic persons (D.A. Wilkinson 1987), irreversible brain changes occur in both alcoholic dementia and Wernicke-Korsakoff syndrome (Butters 1985; Salmon et al. 1993).

Mild Cognitive Impairment The term mild cognitive impairment (MCI) has been used in recent years to describe patients with impaired memory who are otherwise functioning reasonably well and do not meet criteria for dementia (Petersen et al. 2001). Memory impairment is typically defined as performance on a standard neuropsychological test of memory that falls more than one standard deviation below average for a given age. General clinical criteria for MCI are presented in Table 8–2; see Honig and Mayeux (2001) for a review. MCI is often viewed as a transitional or prodromal stage of Alzheimer’s disease, as a high percentage of individuals who meet criteria for MCI eventually develop dementia, with conversion rates ranging from 6% to 25% per year (Petersen et al. 2001). Furthermore, a great deal of overlap between the qualitative features of memory and cognitive performances in MCI and Alzheimer’s disease has been noted. TABLE 8–2.

Criteria for mild cognitive impairment

1. Presence of memory complaint, preferably corroborated by informant 2. Evidence of objective (i.e., neuropsychological) memory impairment 3. Other cognitive abilities generally within normal limits for age and background 4. Unimpaired activities of daily living 5. Clinically nondemented (i.e., does not meet DSM-IV-TR criteria for dementia) Source.

Adapted from Petersen et al. 2001.

Figure 8–6 presents data from groups of patients with a clinical diagnosis of Alzheimer’s disease who are in the early stages of illness (having a score above 115 on the Dementia Rating Scale) and patients with a diagno-

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FIGURE 8–6. Neuropsychological performance in patients with MCI versus mild Alzheimer’s disease (AD). Note. ExFx = executive function; Attn = attention; Lang = language skills; Visuo = visuospatial skills; Vmem=visual memory; NVMem=nonvisual memory.

sis of MCI. As depicted in the figure, both curves show very similar cognitive patterns. In addition to the qualitative commonalities shared between these groups on memory measures, such data suggest that MCI likely represents a very early stage of Alzheimer’s disease in many (if not most) cases, as has been indicated by recent neuropathological findings (Morris et al. 2001).

Depression Depression can result in symptoms and behaviors that mimic dementia (Kaszniak and Christenson 1994). Disengagement from previous activities, decreased motivation, psychomotor slowing, slowed response times, decreased attention, and apparent forgetfulness may all be symptoms of depression. When such clinical features are accompanied by the depressed patient’s cognitive complaints and tendency to overreport symptoms, this can contribute to the appearance of dementing illness. The fact that persons with dementing illness may experience depressive symptoms can complicate attempts to distinguish the cognitive impairment of depression from structural brain diseases (Gilley 1993). Furthermore, because neuropsychological tests depend on adequate effort on the part of the patient, suboptimal or variable effort must be carefully considered lest it be interpreted as neurologically based cognitive impairment. It has been noted that individuals with the cognitive impairment of depression sometimes resemble persons with subcortical dysfunction in their slowed information processing and failure to spontaneously employ active


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learning and memory strategies (King and Caine 1990). When cognitive deficits on formal neuropsychological testing occur in these patients, several characteristic features or trends have been observed (Cummings 1990; Naugle et al. 1998, p. 263). Most commonly, the cognitive difficulties, when present, are very mild (Zakzanis et al. 1999) and often resemble subcortical dysfunction (e.g., see Massman et al. 1992) with evidence of frontal system disturbance (Veiel 1997). Attention and concentration may be reduced or variable across tasks. In terms of memory, depressed persons often show intact storage ability even though learning may be slow and retrieval problems may occur. This may be demonstrated on memory tasks that include cueing or recognition testing procedures, wherein the additional prompts often facilitate considerable improvement in the depressed patient’s performance. Along these lines, comparing recognition to free recall can be particularly illuminating, because more information is encoded than can be easily retrieved by some depressed patients. Greater difficulty with the recall of nonverbal information can also be seen; thus, verbal memory tasks may be more useful in differentiating depression from dementing illness. Whereas the results of cognitive testing in persons with depression are often normal, the performance of these persons may be characterized by variability within and across tests. For example, depressed persons may sporadically miss easier items and get more difficult ones correct. In addition, some tests may show depressed persons to have intact function, whereas other measures that tap similar abilities indicate impairment. Moreover, rapid onset of cognitive symptoms and the presence of patient complaints beyond those expressed by family members are also more common in depressed patients. Test results that do not fit any known neuropsychological profiles or reflect functioning that is widely discrepant from patient complaints should also be suspect. Nevertheless, persistence of deficits after recovery from depression may signal a concurrent dementing illness (Nussbaum et al. 1995). Neuropsychological patterns of performance can often be used to differentiate between Alzheimer’s disease and cognitive difficulties secondary to depression. However, the disorders may coexist, and differential diagnosis may be challenging in a small proportion of cases. Accordingly, serial neuropsychological evaluations may be very useful in monitoring patients over time, because the cognitive problems in persons with uncomplicated depression would not be expected to progress (although as noted, variability in performance can be seen). In contrast, persons with Alzheimer’s disease typically produce rather characteristic patterns of learning, forgetting, and making errors during recall and recognition that help distinguish them from persons with depression alone.

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Summary The value of the neuropsychological examination is several-fold: 1. 2. 3. 4. 5. 6.

To detect subtle cognitive impairment To quantitatively document level of impairment To outline cognitive strengths as well as weaknesses To aid in differential diagnosis To monitor changes over time (including responses to treatment) To assist in designing intervention strategies to help optimize patient functioning

Neuropsychological evaluation can contribute important diagnostic information in the following conditions: 1) when there is a discrepancy between the patient’s self-report of difficulties and the family’s assessment; 2) when the physician desires additional confirmation of a tentative diagnosis before recommending other neurodiagnostic procedures; 3) when emotional factors such as depression or anxiety may contribute to the symptoms; and 4) when a more thorough evaluation of cognitive functions is necessary. Several examples illustrate these points. Family members sometimes become concerned about an elderly parent’s behavior. However, in a short office visit, elderly persons may deny or minimize difficulties; if they possess intact vocabulary, conversational skills, and social comportment, cognitive deficits may be underappreciated. A neuropsychological evaluation provides valuable diagnostic information as well as useful practical recommendations to the physician and family regarding specific cognitive limitations and degree of independence. Initial neuropsychological presentation may also have implications for predicting future course of illness (Becker et al. 1988; Rasmusson et al. 1996). Or the physician may suspect that a patient is declining cognitively but also appears to be withdrawn and slightly depressed. The neuropsychological evaluation can often help to identify the various factors contributing to the apparent decline and quantify them for future reference. For example, distinguishing depression from dementing illness can often be accomplished using neuropsychological techniques and profile analysis. A brief neuropsychological screening examination can also be useful in the office or inpatient setting to help identify persons who may warrant further evaluation for dementing illness or other emotional disorders in a quick and cost-effective fashion. The neuropsychological evaluation can also help to assess the cognitive effects of various medical treatments. These evaluations can be employed in a pre-post design to assess the effects of treatments such as cognition-


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enhancing medications, electroconvulsive therapy, shunts for normalpressure hydrocephalus, antidepressant or antianxiety medications, and endarterectomy. Results may yield valuable objective data concerning patients’ cognitive response, allowing the physician to make decisions about whether to continue, change, or discontinue a particular form of therapy. Finally, the detailed analysis of a patient’s cognitive abilities may be used to plan interventions that focus on patients’ strengths and weaknesses. This can be done in conjunction with or following termination of medical therapy and includes attempts to minimize the effects of cognitive deficits on everyday functional abilities and overall quality of life. This often involves continuing education and support of the family to maximize the use of the available support network to help maintain safe, independent functioning for as long as possible. Such interventions can be particularly useful in progressive illnesses, in which planning and structuring an individual’s environment and working with the family to enhance the quality of life of all parties involved is the most useful intervention.

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Supporting Family Caregivers Kristin Martin-Cook, M.S. Doris Svetlik, B.S.N., R.N., M.S. Myron F. Weiner, M.D.

In the long-term management of dementing illness, especially in progressive illnesses such as Alzheimer’s disease, the clinician’s primary relationship is with the patient’s family. Families bear the burden of understanding and managing the patient’s person and property. Therefore, after making a diagnosis and instituting appropriate medical treatment, the most important issues to address are the education and physical and emotional support of family caregivers. Education About the Illness Caregivers often need (and want) to learn about the cognitive and behavioral effects of dementing illness, its anticipated course, and the various social and financial consequences of the illness. However, more is not always better. Different caregivers require different information. Some caregivers will cope best by seeking as much information as they can obtain; other caregivers become overwhelmed by thinking about the future. It is not a universal recommendation in our clinic to read caregiver-oriented or dementia-oriented books. Rather, we offer handouts or other literature providing an overview of issues and then explain that more information can be obtained as issues arise or whenever the caregiver feels it is needed. For those who are information seekers, many lay-directed guides are available for families of dementia patients, especially those with Alzheimer’s disease. The best resource is the third edition of The 36-Hour Day (Mace et al. 1999). Other recent guides are Alzheimer’s Disease: A Handbook for Caregivers (Hamdy et al. 1998) and Alzheimer’s Early Stages: First Steps in Caring and Treatment (Kuhn and Bennett 1999). See also Appendix K for additional sources of information. 321

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Family members need to understand that their loved ones have a reduced capacity to encode, process, integrate, communicate, and act on information that in turn impairs the ability to act appropriately in response to certain situations or information. The use of medical jargon should be avoided, and when it is used, it needs to be explained. For example, the term dementia requires explanation. Dementing illnesses cause invisible disability, which often leaves family members puzzled about patients’ abilities and inabilities and, very often, about the diagnosis. It is sometimes useful to show families brain images (magnetic resonance imaging, single photon emission computed tomography, or even textbook pictures), because this helps caregivers to view troubling behaviors in the context of a brain disease. Also, concrete examples of how cognitive symptoms may affect daily functioning are important, such as the following examples: Your husband becomes lost when trying to find his way to the bathroom at night. This is a frequent symptom of dementing illness. Because his memory is impaired, he has to rely on his eyesight to help him make up for that loss. When he can’t see well, his memory is no longer good enough to guide him. Your mother probably burns food on the stove because she is having difficulty with her concentration and her memory. Her attention wanders easily, and she forgets what she is doing. She gives the appearance of becoming careless when she is actually performing as well as she can at the moment.

Sometimes the cognitive impairment is best conveyed by analogizing the patient’s inability to reason and understand to that of a small child—including a child’s need for simple directions and for direction by example. You told me how you dealt with your own children when they were young—showing them instead of telling them. Instead of telling your mother to stir the soup for you so that it won’t burn, show her how you want the soup stirred, help her to do it for a few moments, and then let her do it on her own. When she gets confused on the way to the bathroom, guide her to it. If you tell her where the bathroom is, she won’t remember. She’ll be less irritable if she’s helped to do what you want her to do or what she wants to do instead of being told what not to do or that what she’s doing is wrong.

Because disturbing behaviors, even more than cognitive dysfunction, lead families to seek diagnosis and treatment, it is crucial to address these behavioral symptoms and to explain the link between these symptoms and the dementing illness. Irritability, for example, requires an explanation just like disorientation. Your observation that your father is more irritable goes along with his illness. His irritability is due in part to the fact that he is no longer able to sup-

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press minor irritation as you and I do when we get upset over something that we know is trivial. It is also partly due to his irritation with himself because he is unable to concentrate and remember.

The phenomenon of disinhibition also needs to be explained, for example, so that a cognitively impaired person who accidentally exposes his genitals is not believed to be manifesting potentially dangerous hypersexuality. Depression, too, is often a concern of families. The apathy inherent in most dementing illnesses is frequently misinterpreted as depression. In fact, many families and primary care physicians postpone diagnosis and treatment for dementing illness, believing that the patient is “just depressed.” It is important to help families understand that what is seen as withdrawal often represents positive disengagement from activities that are too challenging for the patient’s current cognitive functioning. The specific cognitive and behavioral problems in each case can be brought to light by including caregivers in the mental status examination of the patient and by reviewing that examination with them afterward. Performing the digit span test shows that defects in concentration make it difficult to remember and that information must be presented in small increments. Testing remote memory and immediate recall can demonstrate that recall is the type of memory that is most seriously affected—that what was encoded long ago may be partially intact. Understanding that there are different types of memory deficit helps caregivers deal with the logical inconsistency that a person can easily remember something from long ago but not something that happened only a few minutes ago. Failures in simple mathematical operations also point to difficulty in concentration. Impairment of abstract reasoning can be demonstrated through the use of similarities and proverbs, and impaired judgment can be demonstrated by asking simple questions involving social judgment. Observing the clinician’s management of the patient’s irritability or inappropriate social behavior can be translated by caregivers into useful management strategies. Caregivers learn how to avoid increasing patients’ irritability by observing the examiner. Families often want to know what element of cognitive functioning or behavior will be affected next and whether there is a predictable pattern of loss. In the case of progressive dementing illnesses, families can be told that there will be progressive impairment of the ability to learn new skills and ideas, so that patients will have to rely increasingly on what they already know how to do. They can also be told to expect impairment of abstract thinking and reasoning ability, as indicated in the following example: If you were to tell your wife that it is raining cats and dogs, she might be puzzled and say that she doesn’t see any cats or dogs. She also wouldn’t understand what you meant if you said that a place was only a hop, skip, and

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a jump away. She’d think you were talking about hopping, skipping, and jumping. Her impaired judgment is likely to show up in driving. She will probably stop at a red traffic light and go when the light turns green but may not take into account that somebody may still be crossing the street.

Families of Alzheimer’s disease patients in particular are becoming more sophisticated and educated. Many want to discuss the pathophysiology of the illness to find out what areas of the brain and what neurotransmitters are involved. They become able to understand why anticholinergic drugs are prone to cause delirium in Alzheimer’s disease and to guard their patients from the antihistamines and other medications with significant anticholinergic properties. Educating families about the potentially toxic side effects of medications is also helpful. They need not be given a list of delirium-producing medications. Instead, they can be encouraged to always consider the possibility that a new medication or an increase in dosage of a long-standing medication may be responsible for a change in mental status. Families also need to be cautioned about the potential paradoxical excitatory effects of minor tranquilizers in all forms of dementing illness. Families can be taught that difficulty with new learning makes it unwise to introduce their loved one into new situations and that it is wiser to involve that person in familiar activities in familiar places. They can be taught not to remind patients of their deficits and to serve as memory and a social buffer for their patients.

Prognosis Prognosis is a very important issue for families, from both practical and emotional points of view. Families want and need to know the anticipated course of the illness. Most families can tolerate being told that a disease is expected to progress but that the exact course cannot be predicted. They can be told that there may be long periods of no apparent decline. They generally appreciate being told the worst as well as the best possible outcome. Generally speaking, it seems unwise to suggest that the course of the illness may at any time involve agitation or violence. Such a suggestion makes families wary of their loved ones and may cause them to overreact to trivial events. Families of patients with acquired immunodeficiency syndrome (AIDS) can be told that there may be significant remission of cognitive symptoms with treatment of the underlying disease. In cases of patients with vascular dementia, the family may be offered the hope that progression may be slowed by the use of aspirin or antiplatelet drugs, but they should also be told that there still remains a good likelihood that the dementia will progress and that plans should be made accordingly. In cases


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of Alzheimer’s disease, families can be told that the disease will progress, that its rate of progression is uncertain, but that medications are available to slow progression. When families ask about the ultimate outcome of Alzheimer’s disease, they can be told that if the patient lives long enough, this disease may result in complete inability to communicate or to care for himself or herself. But it is also useful to state that other illnesses usually supervene long before the dementing illness has run its course. Our general policy is to suggest to families that they live one day at a time rather than live in anticipation of symptoms or behaviors that may never arise. When we are asked when nursing home care will be needed, we indicate that need for such care depends on several family factors, but that the ability of families to deal with and to tolerate behaviors such as wandering and incontinence is often the impetus, and that families generally know when their tolerance has been exceeded.

Family Risk Some dementing illnesses involve risk to family members. In the case of Huntington’s disease and Alzheimer’s disease, the risks are genetic. Because the former expresses in midlife, the pattern of dominant inheritance poses a serious threat to siblings and offspring; great sensitivity is needed in dealing with the issue of heritability. The situation in Alzheimer’s disease is similar for dominantly inherited early-onset Alzheimer’s disease, but not for late-onset disease. We respond to concern about the heritability of Alzheimer’s disease by stating that not enough is currently known to enable sound counseling but that the risk increases for siblings and children of affected persons, although we are unable to predict the exact risk for individuals. In the instances of familial Alzheimer’s disease with onset as early as the fifth decade, families can be reasonably counseled that the risk approaches 50% for offspring of an afflicted person should they live to the age of usual disease onset in the family. When presenting data concerning the heritability of illness, clinicians need to be alert to the impact of this information on family members. An open-ended discussion following the communication of this information usually brings to light fears, misgivings, and potential negative effects. When counseling about infectious disorders such as Creutzfeldt-Jakob disease or AIDS, the clinician indicates that these diseases can be communicated only from body fluid to body fluid, suggesting that appropriate precautions be taken. In the case of Creutzfeldt-Jakob disease, blood-to-blood transmission would only be likely in the event that a caregiver punctured himself or herself with a needle contaminated with the patient’s blood. In the latter case, contact with blood and seminal fluid is to be avoided.

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Other Major Issues It is important to deal with certain concrete issues. One issue is who will be the primary caregiver and conduit of information to and from the patient and family. The designated primary caregiver, in consultation with the clinician, the patient, and the rest of the family, needs to consider what supervision is necessary and how supervision is to be arranged. If the person is living independently, is independent living feasible or desirable? If so, how independent? Can the patient be allowed to continue driving? Buy groceries? Cook? Must eating and personal hygiene be supervised? In many instances, cognitively impaired persons can continue to live in their own accustomed residence, with once- or twice-a-day supervision by friends, relatives, and neighbors. If independent living is not feasible from the standpoint of safety or convenience, where can the person be served and accommodated best? Could the person live with a friend or relative? Would a day-care program ease the burden? Would assisted living be appropriate? Is a special care facility needed? Chapter 13 includes a full discussion of assisted living and special care units. Families attempt to balance these quality-of-life and safety issues. Because the awareness and insight of many patients is impaired, their families are often left to make decisions regarding the level of independence the patient will maintain—a situation that many patients resent and resist. Mandates to the family by the physician to stop patients from driving or to move patients into supervised living are rarely productive. It is usually more useful to discuss the options, barriers, and resources and a plan of action for dealing with the problem and minimizing risks in very practical and concrete terms. For patients with more advanced disease, the issue of nursing home care arises. With near-terminal patients in nursing homes, the issue is whether to institute tube feeding. Financial and legal issues must be raised (see Chapter 10). Has a will been made? If not, is the patient able to indicate his or her true wishes? Is the patient able to transact business or enter contracts, such as for the sale of property? Does another family member have the type of power of attorney that can be used when the patient is no longer able to grant power of attorney? Is guardianship necessary to ensure impartial supervision of the patient’s assets? If guardianship is needed, should it be full or partial? In anticipation of the need for Medicaid coverage of possible prolonged nursing home placement, is it best that the patient’s property be transferred to other family members? Although we typically refer to financial consultants specializing in the elderly for specific issues, it is important to provide some general information regarding financial issues. Many people mistakenly believe that Medicare will provide for the health


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care needs of patients. It is important to explain that custodial care of persons with dementing illnesses is not covered by Medicare, so that families can make plans accordingly.

Imparting a Psychological Point of View It is also useful to impart a psychological point of view to caregivers. Family members are often confused by daily fluctuations in cognitive ability and behavior and tend to see cognitively impaired persons as arbitrarily deciding to forget and consciously manipulating others. Both may be true to a certain extent. However, it is more often true that what appear willful and arbitrary behaviors are attempts to avoid becoming overwhelmed, based on each person’s own style of coping with or adapting to stress. Caregivers often see cognitively impaired persons as unreasonably irritable, failing to recognize how frustrating it is to be unable to reason, to remember, and to perform simple activities of daily living. When caregivers’ attempts at orienting cognitively impaired persons are met with apparent indifference, the caregivers must be reminded that this appearance of indifference is both a product of the disease and a psychological protection against overwhelming anxiety, not indifference to the caring of others. Family members, out of their own needs and inability to conceive of the impact of the brain changes that are taking place, often prefer to see cognitively impaired loved ones as intact persons who are concealed behind a confused exterior. They can be told that although fragments of their loved one may exist intact, changes in cognition necessitate adjusting and readjusting to a new person with different needs, interests, perceptions, and abilities throughout the course of the dementing illness. Nevertheless, cognitively impaired persons should be shown the same respect as human beings as cognitively intact persons. Attention must also be given to certain prominent mechanisms of defense in dementia.

Dealing With Denial and Projection Two of the most important mechanisms of defense in dementing illness, as pointed out in Chapter 2, are denial and projection. They need to be explained to caregivers as normal means of dealing with the emotionally overwhelming situation of literally losing one’s mind and control over one’s behavior. Caregivers need to be told how frightening it is to be unable to maintain a sense of self, how all persons use denial to avoid dealing with their own mortality, and how blaming others helps each person avoid full awareness of his or her deficits or limitations.

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It is often necessary for caregivers to respect patients’ need for denial while addressing their realistic inability to cope with certain aspects of the environment. For example, it may be better to say that the car is being repaired or has been borrowed by another family member than to tell a cognitively impaired person that he or she may no longer drive. One woman dealt with her concern about her husband’s driving by telling him that she wanted him to supervise her driving. Projection is more difficult for caregivers to tolerate than denial because they are usually the object of the projection. When a wallet or purse, house keys, or items of clothing cannot be found, caregivers are the ones usually blamed. We tell caregivers that it is not useful to argue that one has not borrowed or stolen a particular object. It is more useful to institute a search for what is missing, accompanied by the patient if he or she is willing. It is also useful to note where commonly used objects or possessions are kept and to see that they are kept in those places if at all possible (see also Chapter 6). Delusional projection is even more difficult for caregivers because it frequently ties in with their own wishes and concerns. Thus, a cognitively impaired person may express concern that caregivers are trying to steal his money. That may be true, in the sense that the family is attempting to control spending so that the person will not lose all of his or her financial resources, but it may also be true that the beneficiaries are trying to protect their inheritance. Their own emotional entanglement may lead caregivers into vigorous denials that further heighten mutual suspicion. Caregivers find it easier to cope when, instead of being blamed themselves, they are told that strange-looking little people are entering the house and stealing money. When something specific is missing, caregivers need only institute a matter-of-fact search and produce what is missing, if they can. Many times, missing items have been concealed by the patient, who can no longer remember where they are. For that reason, it may be useful to periodically search the environment as a matter of routine to find such hiding places. When accusations are made by the patient that cannot be controverted, such as “I know you are stealing my money,” it is best to give a brief assurance to the contrary and to then engage the patient in some distracting activity. A reasonable reply to the foregoing accusation would be, “No, I’m not stealing your money. Breakfast is ready. Let’s eat.” If delusional projection does not abate and results in great perturbation for the patient or family, the use of antipsychotic medication may be temporarily indicated. At times, the clinician may suspect that the patient’s suspicions of family members or other caregivers are well founded. If the family is suspected of


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financial or other abuse, Adult Protective Services can be contacted to investigate the situation. The family or proper agencies can be notified if abuse by professional caregivers is suspected.

Maintaining Self-Esteem Individuals in the early stages of a dementing illness have difficulty maintaining their self-esteem because they can no longer live up to their own notion of who they ought to be and at what level they ought to function. They also recognize that they cannot do for themselves what they have been able to do since childhood: perform simple calculations, follow directions, maintain orientation in time and space, button garments, tie shoelaces. As cognitive impairment progresses, the capacity for self-awareness and communication diminishes, and maintenance of self-esteem becomes less of a problem, both in terms of patients’ self-assurance and their ability to communicate concern about themselves. Many persons define who they are by what they do. Loss of capacity to work or to carry out one’s usual activities leads to a sense of uselessness. It is therefore useful for families to help persons with milder cognitive impairment to find activities at which they can feel competent. These may include activities as simple as dusting the furniture or helping to fold the laundry. Persons who enjoy and are kept occupied by housekeeping chores can be encouraged to do those chores daily—it makes little difference whether the house needs cleaning again or whether the laundry really needs to be folded again. Playing simple games such as bingo can be pleasurable. Each person is unique in the activities that are meaningful to him or her. Helping to discover those activities can be a positive experience for both caregiver and patient. It is often necessary for caregivers to redefine their notion of an activity and to reevaluate their view of their loved ones’ abilities. Caregivers frequently come to the clinic saying that their care recipient “can’t do anything anymore” simply because he can no longer engage in his previous activities. It is useful to provide examples of everyday activities that may be enjoyable and esteem maintaining, and how to initiate these activities. For example, less impaired persons might organize a drawer in the kitchen or roll coins, while more impaired persons can sort items in a drawer, sharpen pencils, test pens, or sort coins. Whatever the activity, it is important to help caregivers view an activity as a series of smaller, more doable tasks and to focus on the process of doing the activity rather than on the end product. The Pleasant Events Schedule (Teri and Logsdon 1991) mentioned in Chapter 6 is useful for discovering more activities.

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Impact of Dementia on the Family The development of a dementing illness affects different families and family members in many different ways. It affects spouses, companions, children, grandchildren, and (as in the case of AIDS) parents. Family members experience denial, bargaining, anger, depression, and acceptance—the stages of adjustment to disability and grief—many times throughout the course of the illness. These emotional reactions are especially prominent at diagnosis, placement in long-term care, and death, but also when patients have major declines in functioning or changes in personality. This process of adjustment and readjustment is complicated by the progression of the disease, and it requires practical lifestyle changes and medical management. Generally, there seems to be a theme or focus for caregiving in different stages of dementing illness and a task that must be negotiated for each stage. Like staging dementing illness, however, staging caregiving is imprecise, and the challenges that are prominent at one stage also may exist in some way in another stage. During the stage at which patients are experiencing mild cognitive impairment, the challenge for caregivers is awareness. Once caregivers become aware that things are not right, the task is obtaining a diagnosis (identifying the problem). This is not an easy task. It often requires that the caregiver deal with conflicting views of the patient’s functioning from the patient, other family members, and sometimes the patient’s primary care physician. Caregivers often are ambivalent about receiving a diagnosis. They are validated by the acknowledgment that something is wrong; yet are terrified to face the diagnosis. Mild declines are frequently unnoticed or glossed over by spouses of elderly persons. In many elderly couples, there is an automatic compensation by one for the other’s deficits. A husband will begin cooking as the wife becomes less competent in the kitchen, or the wife will take over household repairs from the husband. In our experience, it is not unusual for one member of a spousal pair to be physically handicapped but cognitively intact, whereas the other spouse is cognitively impaired and physically intact. In this situation, the physically disabled member guides the cognitively disabled person in doing the daily chores. Often, the first person to comment on the cognitive deficit of an elderly person with dementia is a son or daughter who lives at a distance and visits infrequently. Many times, it is difficult for the adult children to convince the intact parent that the cognitively impaired parent needs a medical evaluation. The challenge or focus of caregivers in early dementing illness is grieving, which is necessary for planning to begin. This involves grieving for the loss of the person, the relationship with that person, life as it was (nor-


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malcy), and dreams of the future. When the cognitive impairment of one spouse begins to markedly reduce a couple’s quality of life, the unaffected spouse or partner feels frustration, anger, sadness and, sometimes, frank depression. A common reaction in elders is a sense of having been robbed of one’s golden years. Many elders postponed pleasures earlier in life for the sake of their careers or their children, in the expectation that retirement would bring comfortable leisure. They become frustrated at their inability to enjoy a time when they are no longer burdened by work or family responsibilities, angry at having lost the opportunity, and sad for their spouse’s loss of quality of life. They become depressed as they look forward to their situation deteriorating further and eventually losing their spouse as a person. As cognitive function continues to deteriorate, the challenge or focus is role adjustment. Adjusting one’s role to fit the caregiving task at hand (financial manager, social coordinator, housekeeper) is crucial. Because this is a time when more fluctuation in behavior, functioning, and cognitive abilities occurs, the task is often simply life management or crisis management as it frequently seems for families. The personal challenge of the late stages of dementing illnesses is disengagement from the role of spouse or adult child and assumption of the role of physical caregiver. The work involved in this stage is feeding, maintaining hygiene, and helping with way finding and ambulating. Caregivers at this stage often make comments like “this person is not my wife,” or “my mom is already gone.” Spousal caregivers experience difficulties in many areas. Although many persons are indifferent to their loss of cognitive function, others strive to maintain their premorbid level of functioning and autonomy. A key area of conflict for many couples is driving. A wife will note that her husband’s judgment is becoming impaired. He not only becomes lost while driving but also changes lanes without looking or makes left turns from the right lane. Although she does not want her husband to feel less of a person, she fears for his and others’ safety. Furthermore, she does not wish to engage in the endless arguments that arise from intensely emotional issues such as relinquishing driving. In situations in which a spouse has difficulty saying no, we often suggest that the blame be assigned to the physician by saying, “The doctor doesn’t want you to drive right now.” Our female patients frequently insist that they can still cook, despite their forgetting how to follow simple recipes and ignoring food burning on a stovetop. Strategies employed here include turning off the gas supply or electricity to the stove unless there is someone who can directly supervise the cooking process. Another key area of difficulty for spouses is in coping with suspiciousness or outright delusional blaming. Being constantly accused of stealing

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and lying is demoralizing at best. Although spouses can be educated to not challenge suspicions and delusions, it is difficult for them not to feel unappreciated. In our experience, two situations most often precipitate nursing home admission. They are the advent of total incontinence in the dementia patient and the caregiver’s inability to get adequate sleep. Spouses seem able to tolerate occasional urinary incontinence. They are often able to manage toileting their spouse frequently and restricting fluid intake after supper to prevent “accidents” or using incontinence pads. Prolonged fecal incontinence is not well tolerated. The emotional transition from spouse to nurse often cannot be accomplished. When persistent incontinence appears to be a result of the dementing illness and not a result of factors such as urinary tract infection, bladder prolapse, fecal impaction, or improper diet, we begin raising the question of institutionalization with the now-exhausted spouse. The same is true when the dementia patient’s nighttime agitation or wandering make it impossible for the caregiver to sleep. Dementing illness affects both adult children and grandchildren. The adult children who are particularly compromised are those who are still actively raising their own children. They are sandwiched between caring for the generation ahead of and behind them. Our experience and that of others is that daughters and daughters-in-law are affected more than sons or sons-in-law. Brody (1989) suggests that this is so because women have more nurturing expectations of themselves than men do, but it may also have to do with the fact that men are more often employed full-time outside the home. However, this may change as more women enter the work force. It is often painful for children when their parents become less than fully competent. For many adult children, having an active, decisive parent is so important that they want to continue following that parent’s judgment and have difficulty substituting their own judgment for that of their parents. A surprisingly large number of adults continue to be emotionally and financially dependent on their parents and experience the onset of a dementing illness in their parent as a threat to their own integrity. There are also children who want to protect parents from the consequences of dementia but whose parents’ suspiciousness or need for autonomy is so great that they reject help offered regarding adequate nutrition or proper clothing. Many of our patients are widows who have lived and managed on their own for many years and are fiercely independent. In this situation, we try to help the children achieve a reasonable balance between safeguarding their parents and interfering with their parents’ much-needed sense of autonomy. Adult children are understandably upset that meals-


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on-wheels delivered to the home are uneaten, that ice cream and cookies are preferred to a balanced diet, that clothing goes unwashed, or that the house is not kept clean. Our general stance is that, as long as fiercely independent persons can maintain their nutrition and personal hygiene fairly well, they will have a better quality of life living on their own than in an institution, and it may be worth risking that they can continue to care for themselves. Tensions also develop between the adult children of cognitively impaired parents. Ordinarily, one adult child assumes the majority of the burden of care. This primary nonspousal caregiver is usually self-selected and is most often the child who has maintained the strongest attachment to the parents over the years. At times, the role of primary caregiver falls to the child who is geographically closest or who is not employed outside the home. The primary caregiver’s closeness to the parent is often envied by other siblings, who often deal with their envy by criticizing the primary caregiver’s quality of care. He or she is seen as too domineering, too harsh, or too easy on the affected parent. Despite their willingness to criticize, envious siblings who act out their rivalry by criticism are often difficult to engage as helpers. Grandchildren are generally not strongly affected unless the grandmother or grandfather comes to live with them. At times, there is a comfortable relationship, with the grandparent enjoying the interaction with grandchildren and grandchildren tolerating their grandparent’s deficit well. Often, however, grandparents with dementia regress significantly and feel competitive with grandchildren for their parents’ attention. Children, in turn, may have difficulty with their grandparents’ incapacity and may claim that the elders are faking. Children who feel deprived of nurturing by the presence of a grandparent in the house may also act against the older persons and attempt to discredit them or drive them out of the house. Dementing illness in an adult child also poses problems for parents. Many parents appreciate the opportunity to do what they can for a child of any age. Others feel that their freedom from child rearing has been hard won and are resentful of intrusion on their middle-age or late-life style of living. They feel a wish to care for their children, as well as guilt because they would now like to conserve some of their energy for themselves. In the case of patients with AIDS, many parents of homosexual persons or intravenous drug abusers are resentful of the child’s lifestyle, believe their child has caused his or her disease, and feel still further alienated. Having reached adulthood, many children are resentful of parents reentering their lives in a decision-making capacity. This is especially true for immature adults or adults for whom autonomy from parents has been a significant and poorly resolved struggle.

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Caregiver Stress It is clear that living with or coping with cognitively impaired persons can be extremely stressful. In fact, there is now a large body of literature on caregiver stress in Alzheimer’s disease (Light and Lebowitz 1989). Interventions designed to reduce caregiver burden and stress are frequently ineffective (Bourgeois et al. 1996). Although many supportive community resources exist—including support groups, respite care, elder companions, and adult day care—few caregivers use these services. It often seems that caregivers experience a type of survival guilt, in which they too “suffer” with the disease and cannot allow themselves more quality of life than their impaired loved one. Many authors suggest that caring for mentally impaired elders is more stressful than caring for the physically disabled (Brody 1989). Also, institutionalization does not totally relieve caregiver strain. George (1984) found that stress symptoms were as prevalent in caregivers whose loved ones with dementia resided in nursing homes as they were in caregivers who maintained their loved ones at home. Families maintain their supportive activities even when loved ones are institutionalized (Martin-Cook et al. 2001). They visit nursing homes frequently, interact with nursing personnel, help with feeding, feel sad about their loved one’s condition, and feel guilty because they were not able to maintain their loved one at home. They often feel helpless to complain about suboptimal care for fear that staff will retaliate against their loved ones. Cognitive impairment progresses in Alzheimer’s disease, most persons appear to lose awareness of their deficits. To the family, the deficits become increasingly apparent as they result in a heavier work and emotional load (Pratt et al. 1985; Zarit et al. 1985). Despite the heavy emotional burden and frequent signs of emotional and physical overload, several questionnaire studies show no strong relationship between duration or severity of illness and indices of caregiver burden (George and Gwyther 1986; Zarit et al. 1980). Patient and caregiver factors such as health status and problem solving seem to have greater impact on burden (Zarit and Teri 1992). Dysphoria is extremely common. In a survey of primary caregivers, Rabins et al. (1982) found that 87% reported chronic depression, fatigue, and/or anger when asked about their emotional state. Coppell et al. (1985) found that 40% of 68 Alzheimer’s disease caregivers were experiencing depressive symptoms. Only 1 caregiver, however, met criteria for major depression. Before recommending means to partially relieve the physical and emotional distress of caregivers, the particular stressors need to be identified. This requires spending time with the family. In the setting of our dementia clinic, this is done during the initial interview with the physician, in which


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the family is seen apart from the patient by both the physician and the clinic nurse. Caregiver stress is also assessed at the reporting interview, to which all concerned family members are invited. Aside from diagnosis and direct treatment recommendations, our clinic team tries to help families arrive at a management plan that is optimal for them and the patient. We state that our aim is to maintain the highest quality of life for all members of the family and that planning for a person’s care involves balancing that person’s needs against the needs of the rest of the family. On occasions, we recommend supportive counseling or active psychiatric treatment for a family member. So far, we have not suggested family therapy, but we would not hesitate to recommend it for the cognitively intact family members if we believed it was indicated. We also support professional caregivers doing home care, usually by telephone. They are liable to intense buffeting between family members with divergent points of view and often stand between an irritable, nonunderstanding spouse and the patient. Frequently, elderly spouses are only slightly less cognitively impaired than the primary patient and therefore cannot fathom why the husband or wife cannot understand. We offer continued advice and support by telephone and through regular revisits, and we suggest active involvement with the educational programs and support groups of the local Alzheimer’s Association and other sources of community support as indicated in Chapter 11.

Sexuality An area that is rarely addressed with regard to cognitively impaired persons and their spouses is the effect of dementing illness on their sexual feelings and behaviors. The need for affection and intimacy persist well into dementing illness for many persons (Davies et al. 1992). In some instances, especially with frontotemporal dementing illnesses (Joseph 1999), individuals become hypersexual. For spouses, sexual involvement with a partner who no longer provides an intimate relationship becomes uncomfortable or aversive. In our clinical experience, these statements hold true for many couples. In most couples in which the onset of dementia is after age 70, sexual involvement has already diminished and does not present a problem; but for younger couples with active sex lives, problems do occur. Spouses report that, as they assume a caregiver role in relation to their spouse and become more of a parent than a partner in the relationship, their sexual desire decreases. Some even report feelings of revulsion because it feels as though they are committing incest with their “child.” These feelings cause great conflict, guilt, and frustration for spouses who try to deal with them alone, and they are often not comfortable bringing these issues up with

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professionals. Therefore, the responsibility lies with the professional to address this aspect of the disease and its impact on the relationship Volicer et al. (1988) suggest that caregivers be taught how to distract or gently dissuade sexually persistent spouses. In our experience, some spouses cannot be dissuaded behaviorally nor is their sexual drive reduced through use of tranquilizers or antipsychotics. We have found medroxyprogesterone to be useful in reducing inappropriate sexual aggression in cognitively impaired men (see Chapter 7), but we have not found an effective treatment for our female patients. Although there are some anecdotal reports that selective serotonin reuptake inhibitors (SSRIs) have been effective in reducing sexual disinhibition, it is too early to conclude that SSRIs should be considered the treatment of choice in the elderly (Hashmi et al. 2000).

Long-Term-Care Placement Decisions regarding placement in long-term-care facilities are usually made by the family and are implemented when the primary caregiver becomes physically and emotionally overwhelmed. Chenoweth and Spencer (1986) found that 72% of caregivers indicated that being overwhelmed by 24-hour-a-day care was the most important precipitant of nursing home placement. Less frequently cited reasons were the caregiver becoming ill (21%), behavioral problems (18%), and incontinence (18%); many reported more than one reason. In our experience, long-term-care placement is the result of a process in which the needs of caregivers and care recipients are considered. It concludes with the decision that placement is best for each. The process includes caregivers dealing with their guilt over “abandoning” their loved one (usually a spouse whom they have promised never to institutionalize). It also includes acceptance by caregivers of their physical, emotional, and financial limitations, because hiring 24-hour help is more expensive than institutional care. An important obstacle to nursing home placement of persons with frontotemporal dementias is their unawareness of their impaired judgment and behavioral dyscontrol. Families are usually counseled to follow the path that offers the greatest quality of life to those able to appreciate that quality. Here again, an analogy to early childhood may be useful. Thus, one can say that a patient with severe dementia is very similar to an infant: not able to recognize the source of caregiving but in need of being cared for. The source of the caregiving is far less important than that caregiving be provided. Family scapegoating may become a difficulty in deciding about longterm-care placement. Family members living at a distance often tell the


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family member managing the patient how unfair it is to institutionalize the patient. The physician can help to undercut this process by adding the weight of medical opinion to the decision. Families also need to be counseled that, once a nursing home placement is made, the length and frequency of visits should be such that the patient comes to accept the long-term-care facility as a permanent place of residence. Thus, families are urged not to visit daily or to visit for hours at a time. Instead, they are encouraged to visit a few times a week and for brief periods. Once the transition to the facility is accepted, brief outings can be arranged. In our experience, the transition to full-time long-term-care placement is facilitated by enrolling patients in day care at the facility, later using the facility for respite care, and finally using it for full-time care.

Ethical Issues for Caregivers The primary ethical issues that arise in dealing with cognitively impaired persons are related to following that person’s wishes with regard to independence and maintenance of life. Many persons who eventually develop dementing illnesses express the desire to be cared for at home in the event of a debilitating illness. Their loved ones agree. However, the time comes when the patient becomes an impossible burden for the primary caregiver, often because the caregiver has become physically incapacitated. At that point, the family weighs practical necessity against the earlier expressed wishes of the patient and decides whether that person’s experienced quality of life is more important than state of health or length of life or whether the needs of other family members take precedence. The family may decide that the patient’s quality of life would not be measurably diminished by nursing home placement, whereas the quality of life of the now-disabled caregiver might be immeasurably improved. Many cognitively impaired persons who live alone do not want to leave their homes despite their inability to adequately maintain themselves. In some cases these individuals are a danger to themselves. In other cases, they are a danger to both themselves and others. If failure to institutionalize would lead to the person’s near-term death by starvation, it is unlikely that society at large would condone such inaction, and the family might find itself opposed by legally constituted authorities such as Adult Protective Services. In the eventuality that a severely impaired person living alone refuses needed institutionalization, Adult Protective Services can assist in arranging involuntary longterm-care placement. In the case of a person living alone in an apartment who has inadvertently started several fires and has flooded the building on

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several occasions by stuffing inappropriate objects in the toilet, long-term care may be required based on danger to self and others if adequate supervision cannot be provided. The conflict between maintaining life and quality of life also arises when dementia progresses to the point that the person is no longer capable of self-feeding and does not swallow spoon-fed food. Some individuals will have previously expressed their preference verbally or in writing to be or not to be sustained by artificial means. If they have expressed a preference not to be so sustained, and the family agrees, it is permissible to offer food and water at appropriate intervals and to let nature take its course. This position is supported by the Supreme Court of New Jersey, which held that every person has a common-law right to determine what medical interventions can be performed on him or her. That right continues after the person is no longer competent, as long as the person’s previous competently expressed wishes can be ascertained (In re Conroy 1985). The Conroy court also held that, where there has been no expression of preference on the part of the dementia patient, the family and physician have the right to decide, based on their knowledge of that individual’s interests and preferences, what he or she would have wanted. A decision to discontinue life-extending treatment was based by another court on the spouse’s testimony concerning his wife’s independent nature and dislike of physicians (In re Colyer 1983). When there has been no clear statement of the patient’s wishes concerning artificial maintenance of life support and when that person’s probable wishes cannot be clearly inferred, decisions can be made based on what appears to be in the best interest of the patient. To continue life support using the best interests of the patient as a guide, the generally accepted formula is that the benefits the patient derives from life should outweigh the burden of the treatment (Cantor 1987). The actual weighing of these factors is highly subjective and should involve discussion between physician and family, in consultation with a legal advisor familiar with the law in that particular jurisdiction. As indicated in Chapter 10, the U.S. Supreme Court has ruled that individuals have the right to terminate life-sustaining treatment or may designate a person to represent their wishes (Cruzan v. Director, Missouri Dept. of Health 1990).

Summary With no cure currently available for most dementing illnesses, an important role for health care professionals is family support. Educating families about the disease process helps reduce stress and anxiety, as does introducing families to a dynamic view of their loved one’s behavior. Making refer-


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rals to other agencies encourages interaction of the families with others and helps to avoid feelings of isolation. Providing concrete management suggestions for specific behaviors and help with decisions about placement is also necessary as part of family support. Addressing family issues can also be important. Being available to listen to complaints and validate emotions when there is no specific intervention or solution to a problem is also important for caregivers. Through discussion and addressing specific questions, the health care team can assess, enhance, and support family members’ knowledge, emotional comfort, and decisions.

References Bourgeois MS, Schulz R, Burgio L, et al: Interventions for caregivers of patients with Alzheimer's disease: a review and analysis of content, process, and outcomes. Int J Aging Hum Dev 43:35-92, 1996 Brody B: The family at risk, in Alzheimer’s Disease Treatment and Family Stress: Directions for Research. Edited by Light E, Lebowitz B. Rockville, MD, U.S. Department of Health and Human Services, 1989, pp 2–49 Cantor NL: Legal Frontiers of Death and Dying. Bloomington, IN, Indiana University Press, 1987 Chenoweth B, Spencer B: Dementia: the experience of family caregivers. Gerontologist 26:267–272, 1986 Coppell DB, Burton D, Becker J, et al: Relationship of cognitions associated with coping reactions to depression in spousal caregivers of Alzheimer’s disease patients. Cognitive Therapy Research 9:253–266, 1985 Cruzan v Director, Missouri Department of Health et al, 110 SCt 2841, 1990 In re Colyer, 660 P2d 738, 748, 1983 In re Conroy, 486 A2d 1209 (NJ 1985) Davies HD, Zeiss A, Tinklenberg JR: ’Til death do us part: intimacy and sexuality in the marriages of Alzheimer’s patients. J Psychosoc Nurs Ment Health Serv 30:5–10, 1992 George LK: Dynamics of Caregiver Burden. Durham, NC: Center for the Study of Aging and Human Development, 1984 George LK, Gwyther LP: Caregiver well-being: a multidimensional examination of family caregivers of demented adults. Gerontologist 26:253–259, 1986 Hamdy RC, Turnball JM, Edwards J (eds): Alzheimer’s Disease: A Handbook for Caregivers. St. Louis, MO, Mosby, 1998 Hashmi FH, Krady AI, Qayum F, et al: Sexually disinhibited behavior in the cognitively impaired elderly. Clinical Geriatrics 8:61–68, 2000 Joseph R: Frontal lobe psychopathology: mania, depression, confabulation, catatonia, perseveration, obsessive compulsions, and schizophrenia. Psychiatry 62:138–172, 1999 Kuhn D, Bennett DA: Alzheimer’s Early Stages: First Steps in Caring and Treatment. Alameda, CA, Hunter House, 1999

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Light E, Lebowitz B: Alzheimer’s Disease Treatment and Family Stress: Directions for Research. Washington, DC: Department of Health and Human Services, 1989 Mace N, Rabins P, McHugh PR: The 36-Hour Day: A Family Guide to Coping for Persons With Alzheimer’s Disease, Related Dementing Illnesses, and Memory Loss in Later Life, 3rd Edition. Baltimore, MD, Johns Hopkins University Press, 1999 Martin-Cook K, Hynan L, Chaftez P, et al: Impact of family visits on agitation in residents with dementia. Am J Alzheimers Dis Other Demen 16:1–4, 2001 Pratt C, Schmall V, Wright S, et al: Burden and coping strategies of caregivers to Alzheimer’s patients. Fam Relat 34:27–33, 1985 Rabins PV, Mece NL, Lucas MJ: The impact of dementia on the family. JAMA 248: 333–335, 1982 Teri L, Logsdon R: Identifying pleasant activities for individuals with Alzheimer’s disease: the Pleasant Events Schedule–AD. Gerontologist 31:124–127, 1991 Volicer L, Fabiszewski K, Rheaume Y, et al: Clinical Management of Alzheimer’s Disease. Rockville, MD, Aspen, 1988 Zarit SH, Teri L: Interventions and services for family caregivers, in Annual Review of Gerontology and Geriatrics. Edited by Schaie K, Lawton MP. New York, Springer, 1992, pp 287–310 Zarit SH, Reever K, Bach-Peterson J: Relatives of the impaired elderly: correlates of feelings of burden. Gerontologist 20:649–655, 1980 Zarit SH, Orr NK, Zarit JM: The Hidden Victims of Alzheimer’s Disease: Families Under Stress. New York, University Press, 1985

CHAPTER

10

Legal and Ethical Issues John Z. Sadler, M.D. Barton E. Bernstein, J.D., L.M.S.W. Daniel C. Marson, J.D., Ph.D.

In dealing with persons with dementing illness, clinicians and researchers are faced with an array of ethical and legal ambiguities, requirements, and duties. This chapter deals with the legal and ethical elements involved in caring for cognitively impaired persons and for engaging them as research subjects. In the first section, we discuss the legal issues associated with dementing illness, describing key legal terms and how they are implicated in care. In the second section we consider the ethical issues associated with dementing illness, from both the clinical and the research perspective. Legal Issues Deteriorated mentality in legal terms has to do with the capacity to function within specific legal contexts. Early in the course of a dementing illness, the functions of competency and testamentary capacity may be relatively intact. Individuals with slight cognitive impairment retain the capacity to sign a contract, to marry, to stand trial for committing a criminal offense, to remain in the public domain, and to not be committed to a mental hospital. They are sufficiently competent to be responsible for committing a crime and to be denied the plea of not guilty by reason of insanity. These individuals can continue to manage their own affairs; consent to medical treatment; and keep, be responsible for, maintain, and control all their property, as well as their civil rights and duties. Late in the course of a dementing illness it is likely that competency and testamentary capacity will be impaired. Therefore, it is important for clinicians, early in the process of treating persons with dementing illness, to call these gradually evolving issues to the attention of patients and their families. Legal issues need to be addressed, if possible, while patients have the capacity to function competently. Legal competency is situational, and cer341

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tain legal obligations are binding only when and while the individual has the mental capacity to perform that particular function. To relate dementing illness to competency, it is necessary to understand the interrelationship of the medical and legal definitions. Illustrative case examples follow:

Case 1 Mrs. S is a wealthy widow, married for the third time. She has children by her first and second husbands, and her current husband is encouraging her to update her will, offering him some protection in the event she dies. At this time she is forgetful, often fails to take her medicines, trails off sentences instead of finishing them, sometimes gets her grandchildren mixed up, and occasionally drifts away in the neighborhood. Her physician has considered that she may be in the very early stage of a dementing illness. Everyone in the neighborhood knows her, including the police officers and the mail carrier, and they periodically escort her home. Her new husband takes her to his lawyer. The lawyer drafts a new will, omitting her children and bequeathing all her assets to him, except for a few token items of little financial value that she bestows to her children. But does Mrs. S have the legal capacity to execute a will?

Case 2 Mr. P, a slightly deaf elderly man, was hearing voices, resisting medications, and feeling suspicious and had become convinced the CIA was going to “get” him. He wore old army uniforms, had numerous firearms around the house, and never went to the door without a loaded weapon. He gradually developed a fear of men in uniform. One day, the postman called to deliver a package. Thinking the postman was a CIA agent, Mr. P went to the door, and when the postman abruptly pulled out the package, Mr. P killed him. He was indicted for murder, and his lawyer raised the insanity defense.

Case 3 Mr. Q was a very successful businessman. He had accumulated a large financial estate. When his wife died, he was despondent, feeling that his world had collapsed. When he met a younger woman at a church party and she lavished him with attention and then affection, he was thrilled and couldn’t do enough for her personally and financially. His children were appalled when he bought her an expensive car and then a condominium apartment. They thought the woman was greedy, and they saw their potential inheritance or expectancy disappearing. The more he lavished gifts on “her” (always said through grinding teeth), the more she lavished affection on their dad, who never failed to show enthusiastic appreciation. One day, his children took Mr. Q to a physician, who brought up the subject of a “hint” of dementia. They were shocked and surprised. Their dad had been a forceful, independent, powerful captain of industry; always in complete control of his finances, which he had managed in a cool, care-

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ful, and competent manner. Now he was investing “peculiarly” and tossing money around. This was conduct completely inconsistent with his whole life history. Is this the time for his children to consider a guardianship (of the person?) (of the estate?)?

The Process In each of the examples above, the issue is one of competence in a specific circumstance. The measure of competence to draft, execute, and implement an enforceable will is different from competence when challenged by a lawyer proposing the insanity defense. And should a guardianship of the person or estate be desired, the yardstick is still different. The mental health of the individual is still a concern, but the legal requirements differ; when cognitive impairment is part of the equation, the question becomes, “What is the degree of cognitive impairment?” The legal question is, “Has the dementing illness progressed to the extent that legal competence is impaired and in question?” At that point the diagnosis takes on a different form, coordinating the current diagnosis, or the diagnosis at the time of the act, with the legal requirements needed to determine competence to perform the act in the particular situation.

Some Standards The question here is, “Has the dementing illness progressed to the time that a determination is needed to make the stage of dementia relevant and perhaps controlling in each specific situation?” Although standards may differ from state to state and from jurisdiction to jurisdiction, there are many general principles and rules of law that apply to clinicians when determining competence in specific situations. To relate cognitive impairment to competency, the professional must consider the following traditional standards: • Testamentary capacity. Capacity to make and execute an enforceable will means a person must have knowledge, at the time he or she signs or executes the will, of the extent of his or her property, of his or her kin, and the general nature of his or her bounty and must have sufficient memory to make a reasonable judgment concerning these elements and their relation to each other (Campbell v. Groves 1989). In other words, does the person know what he or she has and who “ought” to inherit it? • Insanity defense. If the defendant raises the insanity defense, he or she must prove by a preponderance of the evidence (the least rigorous legal standard) that he or she has a mental disease or defect and that at the

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time of the act, he or she lacked the capacity to appreciate the criminality of his or her conduct or to conform his or her conduct to the requirements of the law he or she allegedly violated (see Slovenko 1999). Does the defendant know the difference between right and wrong and that what was done was wrong? Could the impulses have been controlled? • Guardianship. When considering guardianship, the court will inquire into the ability of any allegedly incapacitated adult to feed, clothe, and provide shelter for himself or herself, to care for the person’s own physical health, and to manage the person’s property or financial affairs. The issues in the three cases presented previously will be determined by two somewhat unrelated factors. Did the individual have a mental defect, and did that mental defect result in a particular situation or circumstance in which the person is not responsible for present (guardianship), past (murder or drafting a will), or future actions (danger to self or others) (commitment and also guardianship)?

Other Standards There are numerous other legal standards that control capacity and competence (see Bernstein and Weiner 1980). These include the following: • Involuntary hospitalization or commitment. To meet this standard, persons must have a mental illness and must present an immediate threat to self and/or others. • Voidable marriage. A voidable marriage can occur if one of the marriage partners did not have the competence to consent to marriage or to understand the nature of the marriage ceremony. The competence to consent to marriage includes an understanding of the obligations and responsibilities of marriage. • Capacity to contract. The capacity to contract is determined by whether or not the individual did or did not understand the nature of the transaction and its implications.

Legal Needs Following the Diagnosis of Dementing Illness If the patient or the family contemplates making a will, organizing an estate, executing any of the various powers of attorney, petitioning for a guardianship, or making or executing any contracts, or if the individual is considering marriage or divorce, the potential progression of a dementing illness must be taken into consideration. There is usually no need to prepare for an insanity defense.


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Because each family and each patient is different, the suggestions below are options to be considered and either implemented or discarded. The final decision is up to the family and patient, but this list of choices should at least be considered. Options and tools include the following: • Creating an inventory of all assets and liabilities, including noting the whereabouts of all important papers such as deeds, insurance policies, bank and brokerage accounts, and all papers that indicate the ownership of any property and the right to property. All important papers indicates all papers of any value or containing critical information. • Drafting and executing a will and estate plan with the help of a competent attorney, financial planner, trust officer, accountant, insurance agent, and any other person with the specialized knowledge needed to put an estate (even a small one) in order. • Durable powers of attorney and medical powers of attorney address management of the patient’s affairs in particular domains. Durable powers of attorney address the management of property in general or specific properties in particular. Armed with a durable power of attorney, family members, or at least one in particular, can manage the patients’ property should the dementing illness progress and should the patient gradually lose competence to manage his or her estate. The property could then be preserved and managed by a loving and capable family member. Medical powers of attorney permit one or more family members to make medical decisions on behalf of a temporarily incompetent (e.g., delirious) or permanently incompetent (e.g., advanced irreversibly demented) patient. The legal definitions and boundaries of powers of attorney vary from jurisdiction to jurisdiction, and so the clinician should be familiar with the state or local statutes and local uses of powers of attorney. • Guardianship. When and whether a guardianship over person or property is appropriate is always a delicate issue. A guardian of the person can consent to medical treatment without the independent consent of the patient, and a guardian of the estate can control financial matters independently without consent of the ward (the patient). The powers of a guardian are far reaching. The process is judicial and must be considered carefully, beginning with the initial diagnosis and continuing throughout the treatment process. Often, cognitively impaired persons resent, resist, and respond angrily to any of the above. Clearly, each of the above procedures represents the patient’s loss of control. For this reason, a coordinated effort must be made wherein all interested parties, including the patient, must be consulted. With this in mind, the capacity to consent in an informed and ethical manner is paramount.

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Ethical Issues Bioethics or medical ethics is often cast in the framework of dilemma-based or conflict-based ethics, in which two or more goods are in conflict, and the problem is deciding the proper course of action in the face of such competing goods. A paradigmatic case in the situation of dementing illness is posed by the good of respecting a patient’s freedom versus the good of restraining freedom to protect the patient from self-harm, exploitation, or neglect. Often these goals can be in conflict, as in the case of a demented person driving an automobile or refusing potentially life-saving health care. A second model for ethical problems in medicine is the virtue ethics or agent-based ethics approach. Rather than focusing on particular moral problems at the times they arise, virtue or agent ethics focus on the everyday conduct of the moral person (the moral agent). Under this viewpoint, moral agents should cultivate virtues (fidelity, truth telling, respect for persons, etc.) in themselves and others. In the setting of dementing illness, a paradigmatic example of the value of virtue ethics is illustrated by a clinician’s careful planning for long-term care, where the patient’s day-in, dayout environment and social contacts are aimed toward maximizing the patient’s “good life.” We provide examples of how dilemma-based and virtue-based ethics are complementary as we consider the unfolding of a dementing illness over a long or a short period of time. In the circumstances of early diagnosis and management, dementing illnesses are often developmental in the sense that the disease process unfolds over time. An evolving or progressive disease process suggests a consideration of the dementing illness from such a pathodevelopmental perspective, at least for the purposes of clinical management. At the earliest period of the pathodevelopmental time line, dementing illness can be seen as a collection of risk factors involving such considerations as genetic testing for at-risk family members of dementia patients, early diagnosis, and planning for the possibility of incapacity and infirmity later in life. In the setting of a first-time medical evaluation for cognitively impaired persons, issues of informed consent for diagnosis, treatment, or research arise, usually followed by (and occasionally preceded by) considerations of long-term care, assuming the condition is not reversible. If a patient has irreversible and progressive disease, ethical concerns around deciding on the patient’s behalf arise as the patient’s ability to manage his or her activities of daily living are lost. In the case of dementing illness when undesirable or destructive behaviors arise, matters arise concerning behavior control and the appropriate use of restraint and psychopharmacological interventions. Finally, persons with dementia pose special consideration of ethical issues at the end of life


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and terminal care. Each of these general issues is considered in turn in the following sections.

At Risk for Dementing Illness Consider the following example: A middle-aged businesswoman, Ms. R, recently lost her father to complications of Alzheimer’s disease. Having labored though extended efforts to rectify her father’s lack of medicolegal preparations for his dementing illness, Ms. R has wondered if a diagnosis of Alzheimer’s disease is her fate. She has also noticed some word-finding difficulties in herself as well as occasional losing of household items. She wonders if she should pursue a medical evaluation.

Being at risk for a dementing illness can mean a number of things. As in the case of Ms. R, being at risk can mean having a particular probability of having a specific dementing disorder. To be at risk can also mean the patient or potential patient is engaging in behaviors, or has another medical condition, that may be associated with dementing illness, as, for example, inhalant abuse in the former case, and having cerebrovascular disease in the latter case. On the other hand, for a person who is sensitized to the insidious onset of dementing illness, being at risk may be signaled by forgetting a name or a face. Ethical considerations for at-risk situations can be broken down into three general situations: prospective planning for disability and death, early diagnosis before or at the onset of any set of suggestive symptoms, and the relation of a dementing illness at any stage of development to other family members.

Prospective Planning The legal aspects of dementing illness described earlier point to an obvious lesson in prospective planning for any medical impairment later in life: the sooner adults put their affairs in order the more likely their wishes are to be respected, and indeed, the easier matters become later. As will be noted below, advance genetic or other diagnostic testing is not required to make evident the wisdom of planning for disability. All families should discuss the possibilities of medical impairment later in life, so that each person’s viewpoints are well known about such important matters as end-of-life care, inheritance of fortune and property, preferred stewards of medical care and financial matters, and the like. Early discussions of each person’s wishes, values, and preferences permit a deliberate and detailed understanding of viewpoints that may be needed later, in application to complex

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clinical situations. Often such discussions result in the execution of wills, powers of attorney, and various sorts of advance directives for health care, but what makes the latter two legal documents particularly useful is that they convey a full understanding of the individual’s view about the good life and the good death.

Early Diagnosis Ms. R in the example above may represent the worried well, a person who may be vulnerable to exploitation because of her fears of Alzheimer’s disease or other serious dementing illness. Such exploitation may manifest itself through the selling of unnecessary screening tests and evaluations. Clinical features suggesting a need for a more thorough medical evaluation are discussed in Chapter 3. Diagnostic issues. Two issues often arise related to diagnostic procedures; one is the matter of consenting to diagnostic workups and the other, the issue of revealing the diagnosis. The issue of diagnostic workups can be considered under a risk-benefit rubric. For instance, in the case of a patient with human immunodeficiency virus disease, the possibility of a dementing process being arrested or even improved through a thorough workup and treatment is much more warranted than an extensive workup for suspected Alzheimer’s disease, for which treatment effects are not great. The issue of telling patients their diagnosis can be considered similarly. Does the patient want to know her diagnosis? People differ considerably on this matter, and requests not to be told the diagnosis do occur. What is to be gained by telling the patient? Often, there is much to be gained, such as the possibility of prospective planning for disability; disclosure of the patients’ preferences about treatment, research participation, and the like; as well as the provision of considerable support from the health care team, family, and support organizations like the Alzheimer’s Association. In sharing a diagnosis with patients, style counts as much as substance, and providing a supportive setting with adequate time to answer questions and process the patient’s emotional reaction is important. Such discussions should include considerations of treatment, course of illness, the nature of the dementing process, and the availability of various forms of support for the patient and family. Genetic testing. More recent ethics attention has been given to the issue of genetic testing for dementing illness, particularly early-onset Alzheimer’s disease and Huntington’s disease. The evolving organizational consensus over the issue of genetic testing for Alzheimer’s disease clusters around the idea that such testing is unwarranted and even harmful for asymptomatic


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individuals (Butler 1994; Farrer et al. 1995; Kahn 1997; Medical and Scientific Advisory Committee of Alzheimer’s Disease International 1995; Post and Whitehouse 1998b; Post et al. 1997; Relkin et al. 1996). For earlyonset, autosomal-dominant Alzheimer’s disease, the question about the value of genetic testing as a diagnostic adjunct is still open (Post 2000; Post et al. 1997). Ethical matters concerning genetic testing for conditions like Alzheimer’s disease are more complicated than this firm consensus suggests. One ambiguity that can be diminished with time and more research is the empirical value of adjunctive genetic testing. A second ambiguity is raised by the probabilistic nature of genetic testing even where a clear-cut probability of developing disease is known. What will it mean for a person, for instance, to have an 85% chance of developing a specific disease at some point in the future? What about a 50% chance? What are, or will be, the psychological ramifications and can or will they require treatment? The attractiveness of predictive testing in the public’s perception is unclear. One recent survey of relatives of Alzheimer’s disease patients found a majority of respondents positively disposed to predictive testing under five of six hypothetical case scenarios (J.S. Roberts 2000). The prevailing reasons for seeking testing revolved around the idea that testing would aid in planning for the future. This is in marked contrast with the experience of predictive testing for Huntington’s disease, where fewer than 20% of a sample of relatives of Huntington’s disease patients desired predictive testing (Babul et al. 1993). One wonders if the respondents in the Roberts study fully appreciated the need for advance preparation for medical disability regardless of the risk of developing Alzheimer’s disease. Roberts wondered also if the assenting respondents were overestimating the availability of effective treatment for Alzheimer’s disease. Unrealistic expectations on the part of the public regarding the benefits of genetic testing and genetics-driven therapy has been noted elsewhere (Nelkin and Lindee 1995; Post 2000), and are subject to exploitation by commercial interests. There is also the potential for creating needless anxiety and even worse psychological sequelae as a result of testing in the face of no or deficient therapies (Butler 1994; Post 2000).

Diagnosis and Other Family Members The questions of genetic testing spread to the issue of the impact of genetic diagnosis (for e.g., familial Alzheimer’s disease) on the patient’s relatives. In this scenario, the relatives have a vivid interest in the outcome of the testing; some may very much want such information, whereas others may not wish to know. Here the considerations of consent, risk, benefit, and

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respect for persons all come into play. Are there true benefits to be had from testing, and does it offset the risks to patients and other family members who have a stake in the testing outcome? What will be the implications for matters like insurability and employability? Clinicians should prompt families to discuss the pros and cons of genetic testing under such conditions.

Informed Consent The matter of informed consent with persons diagnosed with (or to be diagnosed with) dementing illnesses is complicated for a number of reasons. Most obvious is that the disease process itself ultimately reduces the affected individual’s ability to make decisions. The patient’s capacity to solicit, apprehend, and weigh medical information is compromised in varying degrees, and such variable deficits may also impede the patient’s ability to definitively choose a course of action. On the other hand, such variable impairment makes for no simple relation between diagnosis and incapacity to consent. Thus, with dementing illnesses, patients may be limited in both aspects: the informed aspect as well as the consent aspect. In addition, persons with dementing illnesses fluctuate over time in their decision-making capacity; for instance, a rested person in the morning may be sharper than a fatigued person in the evening. The clinical, ethical, and legal issues surrounding informed consent with cognitively impaired persons differ somewhat in clinical and research settings. Furthermore, medical standards for assessing capacity for decision making are still emerging; what guidelines have been developed are too often not commonly used, and even when they are, clinical conclusions about decision-making capacity may differ between physicians (Marson et al. 1997). Because of the foregoing ambiguities, significant amounts of variation in regional standards of care and legislative guidelines occur across the nation; clinicians are well advised to be familiar with pertinent local and state laws as well as the medical community standards for informed consent with cognitively impaired persons. Nevertheless, some further attention to clinical versus research consent and assessments for decision-making capacity may shed light on the entire matter of informed consent.

Informed Consent in Clinical Care Informed consent—the procedure of disclosing relevant information so that individuals may choose freely—applies as much to persons with dementing illnesses as to persons with other diseases. A diagnosis of a dementing illness is not in itself an indication that a person lacks decisionmaking capacity. Lo (1990) offers three general conditions indicating rela-


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tively intact decision-making capacity: 1) a recognition that the person has a choice; 2) an understanding of the medical situation and prognosis and an understanding of the recommended and alternative treatments with attendant risks and benefits and implications of no or limited treatment; and 3) a relative stability of the person’s decision-making capacity over time (e.g., a relative lack of vacillation or morbid indecisiveness). For example: A 90-year-old woman with impaired peripheral circulation was brought to a hospital for evaluation of a gangrenous big toe. Her surgeon found dry gangrene with no evidence of infection and recommended that her toe be amputated. When she refused, psychiatric consultation was obtained to determine her competence to consent or refuse treatment. The psychiatrist found her to be mildly to moderately demented but not depressed or suicidal. She was not oriented in time but knew that she was in a hospital and that her surgeon wanted to amputate her toe. She knew there was danger of an infection developing and spreading if the toe was not surgically amputated, and she knew that the toe would probably eventually fall off on its own. On that basis, the psychiatrist indicated to the surgeon that she was mentally capable of refusing surgery.

In the case of a person who cannot meet these general standards for informed consent, the physician or the family may want to seek a proxy decision maker as described earlier. It should be noted, however, that for some clinicians and commentators (e.g., Appelbaum and Grisso 1988), formal legal declarations of incompetence are often unnecessary; using the remaining decision-making capacities of the patient along with an appreciation of his or her earlier-stated values and preferences often suffices.

Informed Consent for Human-Subject Research Public and professional desires for basic and clinical research in dementing diseases have resulted in an increased awareness of the potential for discriminatory exclusion of mentally ill persons from research as well as an increased recognition of the potential for abuse of research subjects with varying levels of decision-making capacity (National Bioethics Advisory Commission 1999; Oldham et al. 1999; Osborn 1999). The Code of Federal Regulations (CFR) establishes eight general rules for informed consent procedures for research (45 CFR46.116): 1. A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject’s participation, a description of the procedures followed, and identification of any procedures that are experimental 2. A description of any reasonably foreseeable risks or discomforts to the subject

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THE DEMENTIAS, THIRD EDITION 3. A description of any benefits to the subject or to others that may reasonably be expected from the research 4. A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject 5. A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained 6. For research involving more than minimal risk, an explanation as to whether any compensation and medical treatments are available if injury occurs and, if so, what they consist of or where further information may be obtained 7. An explanation of whom to contact for answers to pertinent questions about the research and research subjects’ rights and whom to contact in the event of a research-related injury to the subject 8. A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

These guidelines are the model for human-subjects research in the United States and are explicitly used by institutional review boards in structuring informed consent documents for clinical research. However, they do not address impaired decision-making capacity; the guidelines pertain more to disclosure of information than to the competent authorization of research participation. More recent debate over the 1998 report by the National Bioethics Advisory Commission (NBAC), Research Involving Persons With Mental Disorders That May Affect Decision-Making Capacity, sharpens the particular complexities involved with obtaining informed consent for research with subjects who exhibit impaired decision-making capacity. The NBAC wanted to preserve the clinical research enterprise and the good it confers to persons with diseases that impair decision-making capacity. At the same time the NBAC wanted to prevent exploitation of research subjects with impaired decision-making capacity (IDMC) (L.W. Roberts and Roberts 1999). The NBAC report suggested that 1) research should not be carried out on subjects with IDMC if the research can be done on other subjects; 2) research should be well designed and minimize risk; 3) risks and benefits should be weighed carefully; 4) informed consent should be required; 5) mechanisms should be provided to include subjects with IDMC in medically beneficial research; 6) communication with the caregivers of patients with IDMC should be maintained; 7) educational materials about IDMC and clinical research should be developed; and 8) governmental-privateacademic coalitions should be fostered to address this issue. Controversy emerged around NBAC recommendations concerning a classification of research protocols by three kinds of risk: “minimal risk,”


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“greater than minimal risk with the prospect of direct medical benefit to subjects,” and “greater than minimal risk that does not offer the prospect of direct medical benefit to subjects.” Also controversial was the recommendation for development of legally authorized representation for subjects with IDMC who are recruited to participate in protocols with greater than minimal risk. Regarding the levels of risk, the research community favored a more graded assessment of risk other than the NBAC’s “minimal risk” and “greater than minimal risk.” For instance, Oldham et al. (1999) suggested adoption of the Belmont Report (1978) guidelines for risk, which included categories of “minimal risk,” “minor increase over minimal risk” and “more than a minor increase over minimal risk.” There was fear that the NBAC’s recommendation would unduly stigmatize and exclude patients with mental disorders or IDMC and that the heavier burden on researchers to obtain valid consent would result in less research on such needy but vulnerable subjects. The use of a legally authorized representative was opposed for a similar reason—that of unduly denying and encumbering the research endeavor. The Ethics and Humanities Subcommittee of the American Academy of Neurology (1998) called on the research community to present “reasons why other (less vulnerable) subjects cannot be studied and identify what additional safeguards will be implemented to protect subjects’ rights and safeguard their welfare.” The American Geriatrics Society (1998) advocated for “advance consent” for subjects with IDMC and, in cases where this is unavailable or impractical, the use of family or other surrogate decision makers who can represent the subject’s wishes or value system. True moral or legal consensus about the proper manner to safeguard human subjects with IDMC and to allow research has yet to be reached, and no legislation embracing the NBAC guidelines has been enacted. A few general principles seem clear: 1. Human subjects, including those with IDMC, require more safeguards than have been previously recommended. 2. Planning for persons with dementing illnesses should include not only financial, medical, and other personal considerations, but the possibility of participating in research protocols for that condition, particularly if the person otherwise has a favorable view of human-subjects research. Such discussions should include consideration of an advance consent for research (Dresser 2001; Sachs 1994) for jurisdictions that permit or support such documents. 3. Researchers as well as institutional review boards should carefully weigh risks and benefits for protocols involving subjects with IDMC

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and should be willing to make modifications of protocols for further protection of subjects with IDMC. 4. Involvement of family members or other caring surrogates in the consent process and even in the study proper (study partners) should be used if at all possible.

Empirical Assessment of Decision-Making Capacity in Dementia One of the most important clinical and ethical challenges in the management of dementing illness is the assessment of decisional capacity (Marson and Harrell 1996). As discussed earlier, the determination of whether an Alzheimer’s disease patient does or does not have decisional capacity has critical importance in consenting to treatment, consenting to research participation, and managing financial affairs (Marson et al. 1994, 1995). Clinical assessment of decisional capacity, however, has been impeded by a lack of objective instruments and a lack of conceptual knowledge and training among health care professionals (Karlawish and Schmitt 2000; Marson et al. 1997, 2000a). Recently there has been interest in the development of standardized instruments to assist clinicians and researchers in making capacity decisions (Grisso and Appelbaum 1991; Grisso et al. 1995; High 1992; Janofsky et al. 1992; Marson et al. 1994, 1995). A significant portion of this work has focused on assessment of the capacity to consent to treatment (Dymek et al. 2001; Janofsky 1992; Marson et al. 1995) and the capacity to manage financial affairs (Marson 2001; Marson et al. 2000b) in dementia patients. Marson and colleagues have developed an instrument for empirically assessing the capacity of patients with dementia and other cognitive impairments to consent to medical treatment under different legal standards, the Capacity to Consent to Treatment Instrument (CCTI) (Marson et al. 1995). Specifically, they have developed two specialized clinical vignettes (vignette A, neoplasm, and vignette B, cardiac) designed to test competency under five distinct standards of consent capacity. Each vignette presents a hypothetical medical problem and symptoms, and two treatment alternatives with associated risks and benefits. The vignettes are presented orally and in writing to subjects. The administration format for each vignette approximates an informed consent dialogue and requires the subject to consider two different treatment options with associated risks and benefits. The two CCTI vignettes together take about 20–25 minutes to administer to subjects. After simultaneously reading and listening to oral presentation of a vignette, subjects answer questions designed to test consent capacity under


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different legal thresholds or standards (LSs). These standards or thresholds have been drawn from case law and the psychiatric literature (Appelbaum and Grisso 1988; Roth et al. 1977). They are set forth below in order of increasing difficulty for dementia patients (Marson et al. 1994): • • • •

LS1: capacity simply to “evidence” a treatment choice LS3: capacity to “appreciate” the consequences of a treatment choice LS4: capacity to provide “rational reasons” for a treatment choice LS5: capacity to “understand” the treatment situation and treatment choices • LS2: capacity to make the “reasonable” treatment choice (when the alternative choice is unreasonable) (vignette A only) LS2 is currently not generally accepted as an appropriate standard for testing consent capacity, because of concerns about arbitrariness in determining what is a “reasonable” choice (Tepper and Elwork 1984). However, LS2 is still used in some studies in order to better understand the treatment preferences of cognitively impaired persons. The CCTI has a scoring system for each legal standard of each vignette, with high interrater reliability for standards with both interval scales (r>0.83; P-amyloid surrounded by degenerating neurites and inflammatory cells. Stimulated at least in part by >-amyloid (Lewis et al. 2001), neurofibrillary tangles composed of hyperphosphorylated tau protein develop, and loss of synapses and neurons occurs in the affected parts of the brain. The direct neuronal toxicity of >-amyloid in this pathological cascade causes activation of microglial cells (Meda et al. 1995) and induces the proinflammatory cytokines tumor necrosis factor = and interleukin 1> (IL-1>) in these cells (Dickson et al. 1993; Griffin et al. 1998), with subsequent formation of membrane-damaging free radicals (Markesbery 1999). TABLE 14–1. Genetic aspects of Alzheimer’s disease Chromosome 1 (autosomal dominant) early onset 14 (autosomal dominant) early onset 19 (risk factor) late onset 21 (Down syndrome)

Gene effects

Functional effects

Missense mutations of presenilin 2 gene

Increased synthesis and secretion of A>40, A>42

Missense mutations of presenilin 1 gene

Increased synthesis and secretion of A>40, A>42

Inheritance of ApoE A4 Increased >-amyloid allele aggregation destabilizes microtubules Reduplication of APP Overloads APP gene processing; plaques and tangles by age 40

Note. APP=amyloid precursor protein; A>40 =40–amino acid length >-amyloid protein; A>42 =42–amino acid length >-amyloid protein; ApoE=apolipoprotein E.

Amyloid Processing in Alzheimer’s Disease Alzheimer’s disease may be considered as a form of amyloidosis resulting from the abnormal processing of APP, a transmembrane protein whose function is unknown. There is evidence, however, that when released from the rest of the molecule, the intracellular portion of APP can activate or suppress gene expression in the nucleus (Cao and Südhof 2001). APP catab-

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olism is thought to involve three enzymes: =, >, and C secretase. As shown in Figure 14–1, APP is first cut enzymatically by = or > secretase. The products of these first cleavages are cut again by C secretase, yielding a soluble fragment from the portion of the molecule produced by =-C cleavage, and a self-aggregating insoluble fragment (>-amyloid 40–42) from the portion of the molecule produced by >-C cleavage. The C secretase apparently does not operate alone; recently a glycoprotein cofactor (nicastrin) was found (Yu et al. 2000). Additional peptides are needed for full activity, including aph-1=, aph-1>, and pan-2, in addition to presenilin 1 and nicastrin. Mutations in APP and in PS1 and PS2 lead to increased synthesis of >-amyloid from APP in the early-onset forms of Alzheimer’s disease (Tanzi et al. 1996). >-Amyloid peptides are produced by recycling endosomes after internalization of APP molecules from the cell surface (Yamazaki et al. 1996). >-Amyloid 40 is the most common form of >-amyloid in human cerebrospinal fluid (CSF) and plasma. >-Amyloid 42 aggregates into amyloid fibrils more rapidly and completely than does >-amyloid 40 and is contained in both early diffuse plaques and fully formed neuritic plaques (Selkoe 1998).

FIGURE 14–1.

Metabolic pathways for amyloid precursor protein.

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Deposition of >-amyloid precedes clinical symptoms of Alzheimer’s disease, and the brains of persons with Alzheimer’s disease contain increased numbers of >-amyloid plaques over time. The total concentration of >-amyloid in cortex is elevated early in the course of Alzheimer’s disease, correlates with cognitive decline, and appears before tangle formation occurs (Näslund et al. 2000). The latter observation suggests that abnormal processing of APP to >-amyloid or abnormal degradation and clearance of >-amyloid may be the initiating biochemical event in Alzheimer’s disease. Persons with Down syndrome have an extra copy of the APP gene on chromosome 21 (Masters et al. 1985), leading to overproduction of >-amyloid and the extensive development of plaques and tangles by age 40. Fibrillar >-amyloid is neurotoxic in vitro and in vivo (Geula at al. 1998). Accumulation of amyloidogenic peptides >-amyloid 40–42 may be due to increased activity of the proteases > and C secretase in familial cases due to APP and PS1 and PS2 gene mutations. Environmental or other nongenetic factors may also activate > and C secretase in sporadic Alzheimer’s disease. For example, PC12 neural cells in culture expressing amyloidogenic peptides can be differentiated further with phorbol esters, which increases nonamyloidogenic peptide synthesis (Baskin et al. 1992). There also may be decreased turnover of >-amyloid peptides. Neprilysin, a >-amyloid– degrading peptidase, is reported to be reduced in the brain in Alzheimer’s disease in regions enriched for amyloid plaques. Decreased degradation and clearance of >-amyloid in Alzheimer’s disease may be the result, partly due to reduced neprilysin activity (Iwata 2001; Yasojima et al. 2001). Another possible mechanism is downregulation of the protease = secretase, which cuts APP within the >-amyloid region (see Figure 14–1) and makes it soluble. The insulin-like degrading enzyme is also important for >-amyloid degradation and clearance.

Amyloid Precursor Protein Gene Mutations Missense mutations in the APP gene located on chromosome 21 cause some cases of early-onset inherited Alzheimer’s disease (Goate et al. 1991; Mullan et al. 1992; St. George-Hyslop et al. 1987). A mutation in this gene also causes hereditary cerebral hemorrhage with amyloidosis of the Dutch type (Haan et al. 1991; Levy et al. 1990). In this disease, there are plaques containing >-amyloid and deposits of >-amyloid in cerebral blood vessels that cause repeated cerebral hemorrhages. This mutation, near the proteolytic cleavage site inside the >-amyloid region, may decrease >-amyloid degradation. APP mutations in codon 717 cause early-onset autosomal dominant Alzheimer’s disease (Goate et al. 1991). A mutation at codon 692


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in exon 17 has been found in a family with both >-amyloid plaques and cerebral hemorrhages (Hendriks et al. 1992). At least seven different APP mutations in more than 20 families with early-onset dominantly inherited Alzheimer’s disease have been described; all missense mutations in the APP gene causing Alzheimer’s disease are situated at or near =, >, or C secretase sites and alter APP proteolysis (Rosenberg 2000).

The Presenilin Genes Although they are highly conserved throughout evolution, the function of the presenilin proteins is unknown. There is a high degree of homology of the human presenilin genes with sel-12, part of the Notch pathway in Caenorhabditis elegans for intercellular signaling during embryogenesis (Levitan et al. 1996). The PS1 gene on chromosome 14 encodes an integral membrane protein of 467 amino acids with eight transmembrane domains. PS1 was initially found to contain five different missense mutations that cosegregated with early-onset familial Alzheimer’s disease (Sherrington et al. 1995) and has since been associated with at least 90 different mutations in more than 80 families causing onset of Alzheimer’s disease between ages 35 and 65 years. All but two presenilin mutations are missense mutations, and most reside in regions that are conserved between PS1 and PS2 genes. Mutations in the PS1 gene account for about 25% of autosomal dominant cases of Alzheimer’s disease; the age at onset of Alzheimer’s disease in different PS1 families relates to the position and the type of amino acid substitution (Rosenberg 2000). The PS2 gene on chromosome 1 encodes a transmembrane protein of 448 amino acids with 67% overall homology with the PS1 protein amino acid sequence (Sherrington et al. 1995). A missense mutation in this gene causing Alzheimer’s disease has been found in descendants of a single German family that emigrated to Russia and later to the United States (Bird et al. 1998; Rogaeva et al. 1995). Two additional missense mutations have been found in an Italian and a Dutch family with early-onset Alzheimer’s disease (Rogaeva et al. 1995). The finding that missense mutations in the presenilin genes increase synthesis of >-amyloid and its own metabolic breakdown products by 50% (Lee et al. 1997) suggests that the presenilin genes are important for the regulation of APP processing. This is confirmed by the observation that PS1 transgenic mice and fibroblast cell cultures with PS1 mutations increase their synthesis of >-amyloid 42. The presenilins may either influence C secretase activity or may actually be C secretase. The presenilins may direct APP to specific intracellular endosomes containing C secretase, pro-

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ducing >-amyloid 42 preferentially (Beyreuther and Masters 1997; Cruts and Van Broeckhoven 1998). PS1 mutations increase the activity of caspase (cysteine-dependent aspartate-specific proteases), induce apoptosis, and downregulate the important signaling pathway of the unfolded protein response in the endoplasmic reticulum (Katayama et al. 1999). The increased levels of >-amyloid in PS1 mutant cells might therefore result from retention of the unfolded APP in the endoplasmic reticulum due to the impaired protein-folding system.

Apolipoprotein E There are three alleles (A2, A3, and A4) of the gene located on chromosome 19 that encodes the cholesterol transport protein apolipoprotein E (ApoE). Inheritance of the A4 allele of this lipoprotein is a risk factor for late-onset Alzheimer’s disease, whereas ApoE A2 is associated with delayed onset of Alzheimer’s disease (Corder et al. 1993). ApoE A4 heterozygotes have a threefold increase in risk and homozygotes an eightfold increase in risk for developing Alzheimer’s disease by age 75 compared with ApoE A3 heterozygous individuals (Saunders et al. 1993). However, Alzheimer’s disease may occur in the presence or absence of ApoE A4. The question of whether inheritance of the ApoE A4 allele affects the clinical course of Alzheimer’s disease is controversial. In reviewing our own cases at the University of Texas Southwestern Medical Center, we were unable to find evidence of an association between the ApoE A4 allele and either the onset or rate of progression of Alzheimer’s disease (M.F. Weiner et al. 1999). The ApoE A4 allele has been associated with an earlier age at onset in families having APP mutations, with the exception of the 692 mutation, but no similar effect has been found in early-onset families having PS1 and PS2 gene mutations (Rosenberg 2000). The increased risk for Alzheimer’s disease associated with ApoE A4 may be related to its effect on cholesterol metabolism. Notkola et al. (1998) studied elderly men in a population-based investigation and found high plasma cholesterol to be an independent risk factor for Alzheimer’s disease (odds ratio, 3.1; 95% confidence interval [CI], 1.2–8.5) after controlling for age and the presence of the ApoE A4 allele. Simons et al. (1998) showed that reducing the cholesterol level of hippocampal neurons in vitro by 70% with lovastatin and methyl->-cyclodextrin completely inhibited >-amyloid production while not affecting the generation of APP. The inhibition of >-amyloid formation was reversed by readding cholesterol to previously depleted cells. The requirement of cholesterol for >-amyloid formation suggests a possible link between cholesterol, >-amyloid, and Alzheimer’s


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disease. Depleting neuronal cholesterol may inhibit >-amyloid production by removing APP from cholesterol and sphingolipid-rich membrane microdomains and may reduce the ability of >-amyloid to self-aggregate (Simons et al. 2001). It is possible that the activity of > and C secretase is affected by cholesterol depletion. There is evidence that specific cholesterol-reducing agents may help prevent Alzheimer’s disease by lowering cholesterol, but also by lowering ApoE concentration, for example, by drugs inhibiting the action of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (Nishikawa et al. 1999; Nordoy et al. 1998). Evidence for a protective effect of HMG CoA inhibitors has been provided by Wolozin et al. (2000), who compared the prevalence of the diagnosis of Alzheimer’s disease in three groups of individuals from Veterans Administration hospital records. They found that the cohort of individuals receiving HMG CoA–inhibiting drugs had a prevalence 60%–73% lower than that of either the total patient population or compared with patients taking other medications typically used to treat hypertension or cardiovascular disease. In another retrospective study, persons age 50 or older who were prescribed HMG CoA inhibitors had substantially lower risk of developing dementia, independent of the presence or absence of untreated hyperlipidemia or exposure to non– HMG CoA lipid-lowering agents. The adjusted risk ratio for those receiving HMG CoA inhibitors was 0.29 (CI, 0.13–0.63; P=0.002) (Jick et al. 2000).

Transgenic Models of Alzheimer’s Disease Several human APP genes have been transfected into mouse lines. The human mutant V717F APP gene transfected into a mouse line causes these mice to express high levels of human APP 770, which selectively increases the generation of >-amyloid 42 (Games et al. 1995). These transgenic mice progressively develop many of the pathological features of Alzheimer’s disease, including numerous extracellular >-amyloid deposits, neuritic plaques, synapse loss, astrocytosis, and microgliosis. The development of amyloid plaques in the V717F transgenic mouse depends on the expression of ApoE. Knock-out mice lacking an ApoE gene developed only small amounts of cortical and hippocampal amyloid plaques; they were diffuse plaques and did not display the thioflavine-S fluorescence of mature neuritic plaques (Bales et al. 1997). Holtzman et al. (1999, 2000) found that human ApoE A3 and ApoE A4 suppressed >-amyloid deposition at 9 months of age in the APP V717F+/– transgenic mouse compared with mice lacking ApoE. By 15 months of age, expression of human ApoE A3 and A4 in this mouse model expressing APP V717F+/– and mouse ApoE–/– resulted in sig-

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nificant fibrillar >-amyloid deposits. There were at least 10 times more fibrillar deposits in mice expressing human ApoE A4, suggesting that a critical concentration of ApoE and >-amyloid is required for mature fibrillar >-amyloid to be deposited as plaque material. There also appears to be a relationship between hypercholesterolemia and >-amyloid deposition in the transgenic mouse, with high levels of cholesterol being related to increased deposition of plaque (Refolo et al. 2000). This would support the possibility that HMG CoA reductase inhibitors (statins) might influence the development of Alzheimer’s disease by reducing cholesterol synthesis in brain

Lipoprotein Receptor–Related Protein The lipoprotein receptor–related protein (LRP) is one of the low-density lipoprotein receptors. Reduced LRP expression correlates with increased Alzheimer’s disease susceptibility and younger age at disease onset (Kang et al. 1997). The LRP is a receptor that mediates the internalization and degradation of substances involved in the metabolic pathways of lipoproteins. Furthermore, eight ligands potentially involved in Alzheimer’s disease interact with the LRP. They include cholesterol, APP, =2-macroglobulin, ApoE, the cytosolic adaptor protein FE65, Mena, Dab1, and Reelin (Cooper and Howell 1999; Hyman et al. 2000). APP-ApoE complexes binding to LRP may be an early event in the intracellular routing of APP and may affect the ratio of nonamyloidogenic APP processing by = secretase to amyloidogenic APP processing by the > and C secretases. The =2-macroglobulin molecule binds both to >-amyloid and the LRP (Blacker et al. 1998). FE65 binds both to the LRP and APP. The LRP contains the NPxY motif found in the cytoplasmic tails of many cell surface receptors. NpxY is required for the clustering of the receptor in the coated pits and subsequent receptor endocytosis. Thus, the LRP receptor interacting with cholesterol, APP, >-amyloid, =2-macroglobulin, and ApoE may be involved in their internalization and subsequent trafficking of molecules to specific subcellular compartments (Trommsdorff et al. 1998). FE65, the peptide promoting APP and LRP binding, in turn binds the protein Mena. An additional protein, Dab1, binds both to APP and to the LRP. As a result, there is a complex of proteins involved in cell transduction that may determine the nature of APP processing and >-amyloid synthesis. Kang et al. (2000) have demonstrated that both the soluble >-amyloid 40 and the pathogenic >-amyloid 42 are transported from plasma by the LRP pathway and postulate that the reduction of LRP activity that normally accompanies aging may predispose to Alzheimer’s disease. They also note that the risk


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for or protection from Alzheimer’s disease associated with the LRP is greatest among persons without the ApoE A4 allele, which suggests that the LRP pathway cannot overcome the pathogenic effects of ApoE A4. Beffert et al. (1999) found the LRP C allele to be more frequent in autopsy-confirmed Alzheimer’s disease subjects (86.7%) than in control subjects (82.8%) (odds ratio, 1.34; 95% CI, 1.16–1.54; P-amyloid deposition and NFT formation. Lewis et al. (2001) crossed transgenic mice expressing a mutant tau protein (which develop NFTs) with mice expressing mutant APP and found increased NFT formation in the limbic system and olfactory cortex. By injecting >-amyloid 42 into the brains of mutant tau transgenic mice, Götz et al. (2001) were able to increase fivefold the number of NFTs in cell bodies within the amygdala from where neurons projected into the injection sites. A possible trigger for formation of paired helical filaments is a shift between neuronal protein kinases and phosphatases that control the phosphorylation state of tau. Protein phosphatase 2A (PP2A), located on microtubules, has been shown to regulate tau phosphorylation in vivo (Sontag et al. 1996), and a decrease in PP2A activity has been observed in the brains of individuals with Alzheimer’s disease (Gong et al. 1995). In addition, alterations in the microtubule binding site of tau due to mutation or posttranslational modification might compromise the ability of PP2A to bind to and thereby dephosphorylate tau (Sontag et al. 1999). Wilhelmsen et al. (1994) found that mutations in the tau gene on chromosome 17 cause a frontotemporal dementia with Parkinsonism (FTDP-17), but none of the many tau mutations found in families with autosomal dominant FTDP-17 (see Chapter 3 of this book) have been found in persons with Alzheimer’s disease. Hiesberger et al. (1999) have studied double-knock-out mice lacking low-density lipoprotein (LDL) receptor proteins, VLDLR and ApoE-R2.

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In this strain, there is an increase of hyperphosphorylated tau, linking VLDLR and ApoE-R2 expression to phosphorylated tau. Thus, tau hyperphosphorylation may be regulated directly by the ApoE-R2–VLDLR signaling pathway, contributing to the disruption of microtubules. A subtle alteration of cellular signals initiated by members of the LDL receptor gene family might affect the stability of the neuronal cytoskeleton and promote neuronal cell death. Hiesberger et al. (1999) have also shown that both VLDLR and ApoE-R2 can bind Reelin on their extracellular domains. Inside the cell, the Reelin signal is received by the cytosolic adapter protein Dab1, which contains a protein interaction domain that binds to the cytoplasmic tail of the VLDLR. Reelin stimulates tyrosine phosphorylation of Dab1 and thereby decreases Dab1. The action of Reelin on VLDLR and ApoE-R2 receptors modulates levels of cytoplasmic Dab1 tyrosine phosphorylation and tau phosphorylation. This has been demonstrated in the mouse mutants lacking Reelin, which have increased tau phosphorylation (Hiesberger et al. 1999). It therefore seems likely that tau hyperphosphorylation is regulated by the Reelin–VLDLR–ApoE-R2– Dab1 signaling pathway. When altered, this pathway may induce tau hyperphosphorylation and neurofibrillary tangle formation. The activity of cyclin-dependent kinase 5 (Cdk5) is also increased in the brain in Alzheimer’s disease (Patrick et al. 1999). This enzyme is partly responsible for the hyperphosphorylation of tau, reducing the ability of tau to associate with microtubules. Cdk5 activation requires that it associate with its plasma membrane regulatory subunit, p35. A truncated form of p35, p25, also accumulates in neurons in Alzheimer’s disease brain in direct proportion to the increased Cdk5 kinase activity. This p25-Cdk5 complex hyperphosphorylates tau. The plasma membrane location of p35 also suggests a possible linkage of altered tau phosphorylation with Reelin.

Amyloid Biomarkers Possible biomarkers for Alzheimer’s disease include elevated plasma levels of >-amyloid 42 in individuals over age 65 (Mayeux et al. 1999). Elevated plasma >-amyloid 42 levels fall as individuals develop Alzheimer’s disease; CSF levels of >-amyloid 42 fall with disease progression as well. The fall in CSF >-amyloid 42 levels is associated with a rise in tau in CSF, possibly related to increased neurofibrillary turnover and clearance in the CSF. The mean ratio of the 120- to 130-kD APP isoform to the 110-kD APP isoform in blood platelets in patients with Alzheimer’s disease has been shown to be significantly lower than that of control subjects (Rosenberg at al. 1997). APP processing by platelets differs in persons with Alzheimer’s disease


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from control subjects. This ratio decreases as the disease progresses, suggesting that the APP isoform ratio might be a severity marker for Alzheimer’s disease progression (Baskin et al. 2000). Unpublished data from our group indicate partial normalization of the mean ratio of the 120- to 130-kD APP isoform to the 110-kD isoform in Alzheimer’s disease patients treated for 6 weeks with a statin drug, suggesting possible use of this biomarker for monitoring drug effect.

Protective Genes Just as the ApoE A2 allele appears to delay the onset of Alzheimer’s disease, there may be other genetically determined factors that protect against Alzheimer’s disease. Hendrie et al. (1993) reported that Alzheimer’s disease is rare in the Cree Indian tribe of Canada compared with an urban white population. Henderson et al. (2002) found lower frequency of the ApoE A4 allele in Chocktaw Indians. We found among Cherokee Indians that as the genetic degree of Cherokee Indian ancestry increased, the representation of Alzheimer’s disease decreased (Rosenberg et al. 1996). The low incidence of Alzheimer’s disease in high genetic Cherokee Indians was not affected by the ApoE A4 allele. These data suggest that complex protective and disease-causal genetic factors may be involved in a variable manner in Alzheimer’s disease. If Native American tribes are descended from southeastern Asian peoples, a lower prevalence rate for Alzheimer’s disease in the Chinese of Hong Kong compared with white populations might be noteworthy (Mak et al. 1996). Also, Pericak-Vance et al. (1996) have reported a low prevalence of Alzheimer’s disease in another outbred population, the Amish of Indiana, and concluded that this finding is only partially explained by the decreased frequency of the ApoE A4 allele in this population.

Molecular Linkages APP processing produces >-amyloid 40 and >-amyloid 42 molecules that polymerize to form plaques. As noted earlier, there is a direct relationship between >-amyloid burden and cognitive impairment in Alzheimer’s disease. The microtubule-stabilizing protein tau is hyperphosphorylated to form neurofibrillary tangles. ApoE A4 promotes increased plaque and tangle formation in the Alzheimer’s disease brain, and in sporadic Alzheimer’s disease, degradation and clearance of >-amyloid 42 is impaired. How these various molecular events interrelate is uncertain. As mentioned earlier, ApoE knock-out mice having the human APP717 codon mutation produced minimal amyloid plaque compared with wild type mice.

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If almost no amyloid is produced when there is no ApoE, then dysregulated cell surface ApoE-R2 receptors might alter amyloidogenesis, resulting in excessive amyloid plaque formation. ApoE A4 binding to ApoE-R2 may facilitate the altered membrane signal transduction. Altered signaling via this pathway may direct transported >-amyloid internalized by way of the LRP or released from the endoplasmic reticulum into the incorrect subset of endosomes. >-Amyloid that is directed into the wrong endosomal circuit might be secreted by cells and subsequently form plaques. Thus, this cell surface membrane receptor model of Alzheimer’s disease provides a potential linkage of plaque and tangle formation through alteration of signal transduction from cell surface ApoE-R2, VLDL, and LRP receptors to cytosolic targets, including Dab1, which activates nonreceptor tyrosine kinases and their substrates. The downstream targets of this hypothetical kinase cascade initiated by Dab1 are unknown but may be concerned with >-amyloid trafficking. Tomiyama et al. (1999) have found evidence for endocytosis of ApoE– >-amyloid complexes. These lysosomal ApoE–>-amyloid aggregates may accumulate, alter APP metabolism, and produce neuronal degeneration. With neuronal breakdown and death, intracellular >-amyloid could contribute to extracellular deposits of amyloid. All proteins genetically associated with Alzheimer’s disease are linked through a single pathway to the LRP. Thus, the LRP may be central to Alzheimer’s disease pathogenesis (Hyman et al. 2000). Transgenic mice overexpressing PS1 or PS2 mutations show decreased levels of LRP expression in neurons in which PS1 and the LRP are colocalized or coexpressed. Thus, downregulation of the LRP would decrease internalization of =2-macroglobulin–>-amyloid complexes and increase serum >-amyloid levels, as occurs in PS1 transgenic mice and in humans with PS1 mutations (Van Uden et al. 1999). Linkages between cell membrane receptors (LRP, ApoE, and VLDLR, among others) suggest that amyloidogenesis and tau hyperphosphorylation may be tied together. Common polymorphisms found at many points in the genome may be risk factors for Alzheimer’s disease, including the LRP, =2-macroglobulin, ApoE, and FE65, among others (Tanzi 1999, 2000). These potential additive risk factors combined with environmental risk factors could trigger the chain of events that result in Alzheimer’s disease.

Molecular Therapy Targets for molecular therapy include increased >-amyloid production and aggregation, decreased degradation and clearance of >-amyloid, and block-


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age of >-amyloid–induced toxicity. One possible approach is the use of a vaccine. However, the amyloid in plaques has long been regarded as insoluble in vivo, being resistant to harsh detergents and requiring formic acid treatment to dissolve in vitro. For this reason, the notion of creating an anti-antibody to amyloid to reduce amyloid burden did not seem a reasonable approach. How would macrophages formerly unable to digest amyloid become able to do so? It was found that an antibody raised against the N-terminal region of >-amyloid led in cell cultures to disaggregation of amyloid fibrils and partial restoration or solubility (Solomon et al. 1997). More recently, monthly immunization for 11 months with injections of >-amyloid 42 was found to prevent the development of >-amyloid plaque formation, neuritic dystrophy, and astrogliosis in mice transfected with the V717F mutant human APP gene (Schenk et al. 1999). Partial regression and clearance of plaques was seen in animals that had already developed them; substantial reduction of reactive gliosis also occurred. Similar results have been reported in V717F transgenic mice by chronic intranasal administration of synthetic >-amyloid, which was applied weekly for 7 months (H.L. Weiner et al. 2000). There is evidence in these transgenic mice of both age-related progressive spatial learning deficit that correlates with plaque burden and ageindependent learning deficit (the latter in spatial learning but not object recognition). The age-independent learning deficit may be due to glucose hypometabolism or smaller hippocampal size in these animals (Chen et al. 2000). In another transgenic mouse model, 8 months of immunization therapy prevented learning and age-related deficits and reduced amyloid burden in animals that had already undergone plaque formation (Morgan et al. 2000). Whether the cognitive deficits that occur in mice are analogous to the cognitive deficits that occur in Alzheimer’s disease is unknown. Safety and efficacy trials of the injectable vaccine were initiated in humans but have been stopped because of CNS inflammatory complications (see also Chapter 15 of this book). Another issue is that these transgenic mouse models do not show neurofibrillary tangles. It may be sufficient to prevent or reduce >-amyloid plaque formation in these mice, but this may not be adequate to reverse tau pathology in humans. In another mouse model of Alzheimer’s disease (Tg2576) that overexpresses the 695–amino acid form of APP that contains a double APP mutation found in familial Alzheimer’s disease, administration of the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen reduced >-amyloid deposition, dystrophic neurites, and microglial infiltration of plaques (Lim et al. 2000). The investigators proposed that this effect, consistent with epidemiological findings suggesting neuroprotection by NSAIDs (Stewart et al. 1997), may be due to attenuated production of inflammatory cyto-

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kines such as IL-1> and products of reactive glia such as ApoE, which is associated with increased >-amyloid deposition. Ibuprofen and other NSAIDs inhibit the formation of cyclooxygenase 2, a prostaglandin precursor, which has been found to increase in the hippocampal formation as a function of the clinical progression of Alzheimer’s disease (Ho et al. 2001). Increased production of >-amyloid can be related to overexpression of both > and C secretase. The > secretase molecule has been identified and cloned. It is a pepsin-insensitive transmembrane aspartyl protease (BACE, Asp2) (Vassar et al. 1999). Identification of this >-site APP-cleaving enzyme enables the development of agents to inhibit the expression of this gene or the protease it encodes. Inhibition of C secretase has been achieved in vitro and in vivo with N-[N-(3,5-difluorophenaceytl)-L-alanyl]-Sphenylglycine t-butyl ester. Treatment with this substance reduces brain >-amyloid in a dose-dependent manner (Dovey et al. 2001). PS1 may be a cofactor for C secretase or may be C secretase (Wolfe et al. 1999), and both PS1 and PS2 have C secretase activities (Wolfe et al. 1999). Both > secretase and C secretase inhibitors will prevent >-amyloid synthesis and plaque formation. There is a threefold increase of soluble >-amyloid in the brain in Alzheimer’s disease, with a higher proportion of >-amyloid 42 in the soluble fractions, possibly representing a more neurotoxic intracellular pool (McLean et al. 1999). Reduction of soluble >-amyloid might block disease progression as well. Therapies may also be directed at the aggregation of amyloid into toxic fibrils. A small peptide that inhibits >-amyloid fibrillogenesis, disassembles preformed fibrils in vitro, and prevents neuronal death induced by fibrils in cell culture has been described by Soto et al. (1998). This peptide reduced >-amyloid deposition in vivo and blocked the formation of amyloid fibrils in a rat model. >-Amyloid induces apoptosis in part through inducing caspase 12 (Nakagawa et al. 2000). Caspase 12 is thus another potential target for protease inhibitor therapy. Polymorphisms in IL-1= IL-1> genes are strongly associated with early-onset Alzheimer’s disease (Nicoll et al. 2000). These Alzheimer’s disease–associated polymorphisms are common population polymorphisms that may be susceptibility factors (Tanzi 2000). Transforming growth factor >1, a key regulator of brain responses to injury and inflammation, promotes microglial >-amyloid clearance and reduces plaque formation in transgenic mice (Wyss-Coray et al. 2001). There also may be differences in sporadic and genetically determined Alzheimer’s disease that will involve different treatment. Because there is not a differential expression of APP mRNA isoforms in Alzheimer’s disease, posttranslational events in APP metabolism appear to be the most important in amyloidogenesis in Alzheimer’s disease (Panegyres et al. 2000).


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Thus, research in therapies that promote >-amyloid degradation and clearance from brain may be more important in treating sporadic Alzheimer’s disease than those related to differential gene expression. An understanding of risk factors including ApoE and the LRP may provide insight into sporadic Alzheimer’s disease. The relationship of the =2-macroglobulin (A2M) gene on chromosome 12 to Alzheimer’s disease is supported by some studies and not others (Dodel et al. 2000; Gibson et al. 2000). However, many of the genetic polymorphisms associated with Alzheimer’s disease, including A2M, are related to the LRP or LRP ligands. It is possible that >-amyloid is cleared by forming A2M complexes via an LRP-dependent mechanism and alteration of this process due to A2M polymorphisms might lead to reduced >-amyloid turnover. The finding that >-amyloid burden correlates more strongly with dementia severity than do the number of plaques adds to the rationale for inhibiting APP processing with >-C secretase inhibitors early in the disease. Statins may help prevent Alzheimer’s disease by reducing brain cholesterol or its precursors. Low cholesterol content in turn activates = secretase and thus reduces >-amyloid synthesis. Thus, lowered cholesterol content in neural cells promotes the nonamyloidogenic pathway (Kojro et al. 2001). Statins are clinically available, are reliable, and have minimal side effects. Their role in Alzheimer’s disease prevention may become increasingly important.

Conclusions Explorations in the molecular biology and genetics of Alzheimer’s disease have led to a number of potential therapeutic approaches, including immunization, secretase inhibitors, caspase inhibitors, statins, and compounds to disaggregate >-amyloid. Immunization therapy is under investigation; the secretase inhibitors have advanced to animal models of Alzheimer’s disease. Based on epidemiological and immunological evidence, treatment directed at the inflammatory cascade may be useful for both prevention and treatment. As the interaction between cholesterol metabolism and Alzheimer’s disease unfolds, there is evidence that substances reducing cholesterol and ApoE levels may have an impact on plaque formation in Alzheimer’s disease. Testing patients with Alzheimer’s disease for high-risk IL-1 polymorphisms may also be a means to develop genotype-specific guided treatments.

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Advances in the Treatment of Alzheimer’s Disease Steven C. Samuels, M.D. Kenneth L. Davis, M.D.

Progressive cognitive deterioration, the clinical hallmark of Alzheimer’s disease, is the main target of current therapeutic efforts. As with other diseases characterized by progressive deterioration, therapeutic goals can include alleviating symptoms, slowing or arresting the deterioration, or reversing the damage. The neurotransmitter-based approaches described in this chapter offer modest palliation by augmenting deficient neurotransmission. There is preliminary evidence that some of the cholinesterase inhibitors may also alter disease course. Many other empirically derived approaches have been assessed for potential palliative or deterioration-retarding properties in Alzheimer’s disease. Recent advances in understanding Alzheimer’s disease may permit the development of new strategies for retarding or halting the progression of the illness. These strategies, derived from various pathophysiological models of the illness, attempt to alter putative neurotoxic mechanisms such as the excitotoxic effects of glutamate, free radical–mediated neuronal damage, chronic brain inflammation, amyloid production, metal accumulation, and others. A vaccine against >-amyloid had intriguing initial results in animals but proved toxic in humans. Cholinergic Hypothesis of Alzheimer’s Disease and Cholinergic Enhancement Strategies Several lines of evidence support the hypothesis that enhancing cholinergic neurotransmission ameliorates cognitive dysfunction in persons with Alzheimer’s disease (see also Chapter 7). It has been repeatedly demonstrated that learning and memory impairment due to chemical, surgical, and phar453

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macological lesions of the cerebral cholinergic system are reversed in laboratory animals by cholinomimetic agents (Bartus 1982; Olton and Wenk 1987). Human trials with cholinesterase inhibitors also support the cholinergic hypothesis (Davis and Mohs 1982; Raskind et al. 2000; S.L. Rogers et al. 1998a, 1998b; Rosler et al. 1999; Tariot et al. 2000). The cholinergic cell loss in the septal nuclei and the nucleus basalis of Meynert in patients with Alzheimer’s disease is accompanied by a decrease in the cholinergic markers choline acetyltransferase and acetylcholinesterase, but this drop in cholinergic activity does not occur until the middle stage of the disease (Davis et al. 1999a). Therapeutic trials in Alzheimer’s disease aimed at augmenting cerebral cholinergic neurotransmission have employed acetylcholinesterase inhibitors, cholinergic agonists, acetylcholine precursors, acetylcholine-releasing agents, and drugs with less well-defined mechanisms. Despite the large number of known centrally active cholinomimetic agents, few are usable. Most such agents have a short biological half-life, poor blood-brain barrier penetration, instability in plasma, unpredictable absorption, frequent side effects, or a dangerously narrow therapeutic range. Acetylcholinesterase inhibitors have been the most extensively studied drugs and have had the best clinical results. There are four such drugs currently approved by the FDA: donepezil, rivastigmine, galantamine, and tacrine.

Acetylcholinesterase Inhibitor Donepezil Donepezil hydrochloride is a noncompetitive, reversible inhibitor of acetylcholinesterase with very little effect on butyrylcholinesterase. The drug is 95% protein bound and is metabolized through the 2D6 and 3A4 isoenzymes of the P450 system. The half-life of donepezil may exceed 100 hours, longer than any of the other FDA-approved cholinesterase inhibitors. This allows for once-daily dosing, but it may also explain the potential for this agent to disturb sleep in Alzheimer’s disease patients. Superiority of the 10-mg/day dosage to the 5-mg/day dosage was supported by one study (Burns et al. 1999) but not by others (S.L. Rogers et al. 1998a, 1998b). Higher dosages increase the risk of central and peripheral cholinergic effects.

Acetylcholinesterase Inhibitor Rivastigmine Rivastigmine is a nonselective cholinesterase inhibitor with activity against acetylcholinesterase and butyrylcholinesterase. The inhibition of acetylcholinesterase is considered pseudoirreversible, because the rivastigmineacetylcholinesterase combination is not hepatically metabolized but

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requires hydrolysis at the covalent esteratic site by other cholinesterases. The plasma half-life is 1.5 hours, but the effective half-life is 9 hours because of the pseudoirreversible inhibition described above (Jann 2000). The drug is not extensively protein bound and has minimal potential interaction with other agents. Clinical trial data revealed that this agent had efficacy for cognition, function, and behavior but was associated with adverse gastrointestinal side effects that appeared to be related to absolute dosage and rate of titration. There is a warning in the package insert about gastrointestinal side effects, anorexia, and weight loss. A “Dear Doctor” letter from the manufacturer reported a death from vomiting and esophageal rupture when the medication was restarted after a hiatus at a dosage higher than the suggested initiating dosage. As indicated in Chapter 7, rivastigmine requires titration to achieve an effective dosage.

Acetylcholinesterase Inhibitor Galantamine Galantamine hydrobromide is an alkaloid derived from the daffodil (snowdrop plant) that competitively and reversibly inhibits acetylcholinesterase. Galantamine is 10% protein bound and has a half-life of 7 hours. Metabolism occurs hepatically through the P450 2D6 isoenzyme. Galantamine differs from the other cholinesterase inhibitors in its competitive inhibition of acetylcholinesterase and its effect on nicotinic receptors. The competitive inhibition of acetylcholinesterase may translate to fewer side effects because the drug could have greater activity in brain areas with relative acetylcholine deficiencies. The mechanism of action of galantamine involves allosteric modulation of the presynaptic and postsynaptic nicotinic receptors, potentiating the release of acetylcholine (Maelicke 2000). In addition, galantamine may alter the transcriptional properties and stabilization of the nicotinic receptors (Samochocki et al. 2000).

Acetylcholinesterase Inhibitor Tetrahydroacridinamine (Tacrine) The synthetic aminoacridine 1,2,3,4,-tetrahydro-9-acridinamine, known as tacrine, was synthesized more than 40 years ago. The U.S. Food and Drug Administration (FDA) approved tacrine (Cognex) in 1993 for treatment of cognitive impairment in persons with mild to moderate Alzheimer’s disease. Despite a number of trials showing superiority to placebo (Conway 1998), tacrine has very limited clinical use because of four-timesa-day dosing, the potential for hepatotoxicity, gastrointestinal side effects, and the availability of alternative FDA-approved cholinesterase inhibitors that have an improved side-effect profile and preferred dosing schedule.

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Other Cholinesterase Inhibitors Huperzine A Huperzine A is a natural alkaloid from the plant Huperzia serrata. It is a reversible acetylcholinesterase inhibitor that is more selective and more potent than physostigmine (Wang et al. 1986). In a double-blind, placebocontrolled study in patients with multi-infarct dementia and Alzheimer’s disease, huperzine A was administered either 0.05 mg intramuscularly twice a day or 0.03 mg intramuscularly three times a day and was shown to have positive effects (S.L. Zhang et al. 1986). In a cell culture of rat pheochromocytoma cells that were exposed to >-amyloid, preincubation with huperzine A increased cell survival (Xiao et al. 2000). In addition, huperzine A appears to have some activity as an antagonist of N-methyl-Daspartic acid (NMDA), although the clinical relevance of this activity on dissociated rat hippocampal neurons remains unclear (J.M. Zhang and Hu 2001). Huperzine A has very low bioavailability, a factor that may limit its clinical utility.

Comparison of Cholinesterase Inhibitors Although the cholinesterase inhibitors have not been directly compared in clinical trials, they may have different mechanisms of action.

Butyrylcholinesterase Rivastigmine and tacrine nonselectively inhibit butyrylcholinesterase and acetylcholinesterase. The lytic effect of butyrylcholinesterase on acetylcholine is one-tenth that of acetylcholinesterase, and it depends on substrate concentration. Butyrylcholinesterase activity is found in glial cells and plaques and appears to be more pronounced in advanced Alzheimer’s disease. However, the presence of butyrylcholinesterase does not necessarily explain the class effect benefit of cholinesterase inhibitors in more advanced Alzheimer’s disease. In fact, for butyrylcholinesterase to have clinical activity in patients with more advanced Alzheimer’s disease, a selective acetylcholinesterase inhibitor must increase synaptic acetylcholine concentrations to the micromolar range and the acetylcholine has to diffuse the glial cell protoplasm near the synapse and ultimately be degraded. (Giacobini 2000b, p. 186). Butyrylcholinesterase inhibition also results in increased levels of acetylcholinesterase in cerebrospinal fluid (CSF) (Kennedy et al. 1999). The additional acetylcholinesterase activity may be therapeutically countertherapeutic and lead to pathological changes as well (Inestrosa et al. 1998;


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Munoz and Inestrosa 1999). In addition, there is an abundance of evidence against an association between the butyrylcholinesterase K-variant and Alzheimer’s disease (Ki et al. 1999; Kim et al. 2001; Lee et al. 2000). Thus, the clinical meaningfulness of butyrylcholinesterase inhibition on Alzheimer’s disease remains unclear.

Competitive or Noncompetitive Inhibition Cholinesterase inhibitors also may be distinguished based on their cholinesterase inhibition profile. The competitive inhibitors of acetylcholinesterase depend on acetylcholine concentration. At the acetylcholinesterase binding site, competitive inhibitors compete with acetylcholine, whereas noncompetitive inhibitors bind to the receptor site independent of acetylcholine concentration. In brain areas high in acetylcholine, competitive inhibitors are less likely to bind to the enzymatic site. In brain areas low in acetylcholine, competitive cholinesterase inhibitors will have a higher likelihood of binding to acetylcholinesterase compared with acetylcholine. This profile of the competitive inhibitors of acetylcholinesterase may offer an advantage for Alzheimer’s disease patients. Competitive inhibitors are more likely to act in brain areas with low acetylcholine levels and less likely to act in areas with higher acetylcholine levels. Alzheimer’s disease patients with low acetylcholine levels will more likely benefit from competitive inhibition. In contrast, a noncompetitive inhibitor binding to acetylcholinesterase where there are high levels of acetylcholine may have an increased propensity to produce adverse central cholinergic effects.

Nicotinic Mechanisms Nicotine has a theoretical benefit in Alzheimer’s disease (Davis 2001). Alzheimer’s disease patients have losses of nicotinic acetylcholine receptors that are distinct from aging alone (Court et al. 2001). Transdermal nicotine administration to Alzheimer’s disease patients results in short-term cognitive benefit (White and Levin 1999). The neurotoxicity of >-amyloid is blocked by nicotine in vivo and in vitro (Zeng et al. 2001). Enhancement of nicotinic transmission may benefit memory and learning, possibly by means of neuroprotective and neurotrophic effects (Coyle and Kershaw 2001). Stimulation of the presynaptic nicotinic acetylcholine receptor may augment acetylcholine, glutamate, and serotonin, which are attenuated in Alzheimer’s disease (Maelicke et al. 2001). In addition, when nicotine is administered directly to rat hippocampus, an increase of nerve growth factor results (Rattray 2001). Galantamine is unique among the cholinesterase inhibitors in that it has a modulating effect on the nicotinic acetylcholine receptor at a distinct allosteric binding site from acetylcholine (Schratten-

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holz et al. 1996). Taken together, this evidence supports the potential for upregulation or stimulation of nicotinic acetylcholine receptor as a therapeutic modality in Alzheimer’s disease.

Alteration of Course Clinical trial data suggest that cholinesterase inhibitors are both palliative and disease altering. All of the FDA-approved cholinesterase inhibitors demonstrated an initial increase from baseline in scores on the cognitive portion of the Alzheimer’s Disease Assessment Scale (ADAS-Cog) (Rosen et al. 1984). On average, Alzheimer’s disease patients worsen by 4 points over 6 months on the ADAS-Cog, although there is great individual variation. Patients receiving cholinesterase inhibitors remain at or above their baseline ADAS-Cog scores for as long as 24 months (Giacobini 2000a). However, in one clinical trial, half of the subjects were treated with a cholinesterase inhibitor for 6 months while a comparison group received placebo treatment. At the end of 6 months, the placebo group was started on active drug. These individuals responded to treatment but never achieved the same scores as those who had been receiving active treatment from baseline (Raskind et al. 2000). The fact that the group whose treatment was delayed 6 months did not achieve the same scores as those with ongoing treatment suggests that cholinesterase inhibitors have disease-modifying effects.

Limitations to the Approach Other means of stimulating the cholinergic system in Alzheimer’s disease have been tried and have failed; they include cholinergic agonists (Adamus et al. 1995; Thal et al. 2000), acetylcholine-enhancing agents (Huff et al. 1996; Rockwood et al. 1997), and acetylcholine precursors (Amenta 2001). Adverse effects of acetylcholinesterase inhibitors are primarily due to the enhancement of peripheral cholinergic tone. Cholinergic toxicity is often manifested by gastrointestinal symptoms (nausea, vomiting, abdominal cramping, and diarrhea), diaphoresis, lightheadedness, and occasionally cardiovascular symptoms such as bradycardia and hypotension. Depression and agitation have also been encountered. Individual susceptibility to such side effects varies widely, but clinical trial data support a relationship between dosage titration rate and gastrointestinal symptoms. There are limitations to the postsynaptic agonist strategy as well. Postsynaptic muscarinic agonists provide a nonphysiological tonic stimulation, whereas phasic processes characterize the physiological state. Also, it appears that the central nervous system contains spare cholinergic


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receptor sites that have lost functional innervation during development and maturation. The stimulation of such spare receptors and the resulting untoward effects might present one of the more significant impediments to the agonist approach. Augmenting both muscarinic and nicotinic cholinergic transmission at hypothesized specific nicotinic receptor subtypes could possibly further enhance the therapeutic efficacy of cholinergic agonists. This possibility is supported by the finding that single photon emission computed tomography performed after administration of scopolamine in young volunteers reveals a brain scan pattern of predominantly frontal flow reduction (Honer et al. 1988), unlike the pattern found in Alzheimer’s disease patients, which is characterized by temporoparietal flow reduction. The difference in these two patterns could be explained by the fact that scopolamine primarily induces a central cholinergic muscarinic blockade, whereas the Alzheimer’s disease pattern might be produced by additional deficits such as cholinergic nicotinic or other noncholinergic deficits. The pharmacology of the cholinergic system is far from fully understood. Research may reveal variables that have not yet been recognized, and the clinical implications of the various parameters need more accurate assessment.

Noncholinergic Neurotransmitter Replacement Strategies Alzheimer’s disease is characterized by marked noradrenergic and serotoninergic deficits (reviewed in Stern and Davis 1996). In addition, deficits in neuropeptidergic neurotransmission have been found (somatostatin in particular) (Davis et al. 1999b; Gabriel et al. 1996). On the basis of these findings and on encouraging experimental results, investigators have attempted to manipulate these neurotransmitter systems.

Monoaminergic Drugs Selegiline, or deprenyl (Eldepryl), is a monoamine oxidase B inhibitor with good brain permeability that is used in the treatment of Parkinson’s disease (Olanow and Koller 1998). Selegiline has been evaluated in several studies with Alzheimer’s disease patients. In the most recent of these, a large multicenter study involving patients with moderate to severe Alzheimer’s disease, selegiline was compared with =-tocopherol, the combination of selegiline and =-tocopherol, and placebo (Sano et al 1997). Both agents were superior to placebo in delaying progression to one of three end points:

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death, institutionalization, or loss of an activity of daily living. Of interest, there was no benefit of the combination therapy on the end points of the study. The centrally active adrenoreceptor agonists clonidine and guanfacine have been assessed for their therapeutic potential in Alzheimer’s disease but they produced no significant improvement (Crook et al. 1992; Mohr et al. 1989). These negative results do not mean that adrenergic enhancement is ineffective in Alzheimer’s disease or that it might not be a critical complement to a cholinergic therapy. It is possible that agonists have a significant activity at presynaptic receptors and inhibit transmitter release to an extent that yields a net diminution in noradrenergic activity. Therefore, an alternative strategy could employ an adrenoreceptor antagonist, selectively active at the presynaptic receptor, which would interrupt the feedback inhibition path and could lead to increased norepinephrine release. Both agonists and antagonists require further investigation.

Cholinergic-Monoaminergic Combinations Animal experiments have demonstrated that noradrenergic brain lesions block cholinomimetic enhancement of memory and that the efficacy of cholinomimetic treatment can be restored by administration of clonidine (Haroutunian et al. 1990). Combination strategies using cholinesterase inhibitors and presynaptic =-adrenergic antagonists are supported in animal studies (Camacho et al. 1996; Santucci et al. 1991). Clinical trials in humans using this strategy are under way (Friedman et al. 1999).

Miscellaneous Neuropeptides Corticotropin-releasing hormone has shown benefit in protecting neurons in cell culture from death caused by >-amyloid, lipid peroxidation, and glutamate (Pedersen et al. 2001). The benefit was associated with stabilization of calcium homeostasis. Neuropathological studies in Alzheimer’s disease patients have suggested that low levels of corticotropin-releasing hormone immunoreactivity may be an early marker for Alzheimer’s disease (Davis et al. 1999b). Animal studies are needed as a next step with corticotropin-releasing hormone, a compound whose receptor also has the potential as a drug target for depression (Holsboer 2001). Cerebrolysin (FPF-1070) is a mammalian tissue extract with neurotrophic activity but unclear mechanism of action. The agent has promoted neuron survival in vivo and in vitro (Deigner et al. 2000) A randomized, placebo-controlled trial supports the cognitive benefit of cerebrolysin at 28


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weeks, 3 months after drug withdrawal (Ruether et al. 2001). Long-term studies with cerebrolysin examining measures of cognition and function are needed.

Glutamatergic Drugs Excitatory amino acid (EAA)–mediated toxicity may produce lesions similar to the neurofibrillary tangles of Alzheimer’s disease. Furthermore, the glutamatergic system has been implicated in learning and memory. Blockade of NMDA receptors disrupts spatial learning and prevents long-term potentiation, which is thought to be the physiological basis of memory (Squire 1992). Several glutamate receptor subtypes exist. NMDA receptor antagonists may benefit Alzheimer’s disease patients because of the role of NMDA receptor stimulation in apoptosis. The relative role of caspasemediated apoptosis or necrosis in Alzheimer’s disease pathophysiology remains unclear (Behl 2000). NMDA receptor blockers have been shown to provide significant protection against ischemic and EAA-mediated cortical insults (Greenamyre and Young 1989). Glycine, an NMDA receptor modulator, is thought to enhance the effects of glutamate at the NMDA receptor site and thus to augment longterm potentiation processes and memory. It appears that the blockade of certain glutamate receptor subtypes may protect against EAA excitotoxicity, whereas activation of other subtypes may enhance cognitive functions in Alzheimer’s disease. Memantine, an NMDA receptor antagonist, demonstrated benefit in moderate to severely demented patients at 12 weeks as measured by a rating of caregiver time spent and a global impression of change (Winblad and Poritis 1999). An earlier trial had failed to demonstrate benefit (Fleischhacker et al. 1986), and an in vitro study demonstrated no attenuation of cholinesterase-inhibiting effects by the coadministration of memantine (Wenk et al. 2000). Muscarinic agonists may also have theoretical benefit for Alzheimer’s disease and are being developed for clinical trials (Cain et al. 2000). Animal models have demonstrated benefit with ampakines, allosteric modulators of the AMPA (=-amino-3-hydroxy-5-methylisoxazole-4-propionate) receptor (Yamada 2000), and AMPA potentiators are currently in drug development (Lynch et al. 1997). Cycloserine, a partial glycine agonist, enhances learning in rodents. In human volunteers, D-cycloserine was shown to ameliorate scopolamineinduced cognitive impairment (Jones et al. 1991), and there is evidence that at dosages of 50 or 100 mg/day, cognitive benefit can be achieved with this agent in Alzheimer’s disease patients (Tsai et al. 1999).

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Glutamatergic-modulating agents require further studies. The pharmacology of the EAA is a rapidly developing field. New NMDA receptor blockers, as well as possible EAA receptor subtype–specific partial agonists may open new avenues in the treatment of Alzheimer’s disease.

Antioxidants For more than 40 years, it has been proposed that free radicals produced during aerobic respiration cause cumulative oxidative damage that results in aging, disease, and death (Harman 1993; Harman et al. 1966). Aging and Alzheimer’s disease may be associated with increased production of free radicals (Harman et al. 1966). Increased superoxide dismutase–derived hydrogen peroxide fluxes, metal ions, and damaged mitochondria can contribute to cell damage mediated by free radicals (Multhaup et al. 1997). Free radical production in Alzheimer’s disease may also be caused by >-amyloid and glutamate (Behl et al. 1994). For example, >-amyloid may alter glucose metabolism in hippocampal neuronal cell lines via lipid peroxidation, an alteration that leads to cell membrane damage (Mark et al. 1997). In addition, fibrillar >-amyloid is associated with oxidative stress markers in transgenic mice models for Alzheimer’s disease (Matsuoka et al. 2001). Alteration in the oxidative metabolism may also increase the production of the soluble, aggregating form of >-amyloid (Gabuzda et al. 1994; Gasparini et al. 1997) Therefore, it has been hypothesized that antioxidant agents could have beneficial effects in Alzheimer’s disease by reducing free radical production and preventing subsequent cell injury. Selegiline is thought to be neuroprotective by quenching free radicals. Vitamin E and idebenone are also potential antioxidant treatments for Alzheimer’s disease because they prevent cell death caused by glutamate and >-amyloid protein (Oka et al. 1993). Idebenone is no longer in development in the United States, although clinical trial data were suggestive of its potential efficacy and relative safety in phase 3 trials (Gutzmann and Hadler 1998; Weyer et al. 1997).

Vitamins Epidemiological studies and some clinical trials suggest that vitamins may reduce the risk of developing cognitive impairment, and perhaps dementing illness (Chandra 2001). Dietary intake of vitamins C and E was associated with reduced risk of developing Alzheimer’s disease in a cohort from East Boston (Morris et al. 1998). Another large epidemiological trial of elderly men found that vitamin E and C supplements were associated with decreased risk of developing vascular dementia but no reduction in the risk of develop-


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ing Alzheimer’s disease (Masaki et al. 2000). Moreover, lower plasma levels of =-tocopherol were associated with lower cognition on a dementia rating scale (Schmidt et al. 1998). In a cohort study of elderly retirement-community residents in Australia, intake of vitamin C was associated with a lower prevalence of cognitive impairment (Paleologos et al. 1998). In a large epidemiological study, low dietary intake of >-carotene was associated with impaired cognitive function in Alzheimer’s disease patients (Jama et al. 1996). Thiamine has demonstrated no benefit in Alzheimer’s disease (Rodriguez-Martin et al. 2000). Pyritinol (Encephabol), a pyridoxine (vitamin B6) derivative, was administered orally in dosages of 600 mg/day to 100 Alzheimer’s disease patients in a 12-week double-blind, placebo-controlled, parallel study (Fischhof et al. 1992). Although pyritinol appeared to be superior to placebo, the differences between placebo and the active agent were not significant. Mecobalamin (vitamin B12) (0.5 mg intravenously every other day) was given to 10 Alzheimer’s disease patients for 8 weeks. Cognitive functions and communication abilities improved, and the improvements correlated with high levels of vitamin B12 in CSF (Ikeda et al. 1992). In another study, decreased vitamin B12 levels were associated with increased behavioral disturbance in Alzheimer’s disease (Meins et al. 2000).

Gingko Gingko, an extract of the Gingko biloba tree, is a popular preparation of unknown chemical constitution that may have scavenging effects on free radicals. It has been studied in double-blind, placebo-controlled trials. One study in a cohort of persons with Alzheimer’s disease, vascular dementia, or age-associated memory impairment did not demonstrate an effect on neuropsychological and behavioral measures (van Dongen et al. 2000). In another study, modest differences were found between gingko (120 mg/ day) and placebo groups on measures of cognition and function. (Le Bars et al. 1997). The utility of gingko for Alzheimer’s disease requires further investigation before it is recommended to patients.

Chelating Agents An association between aluminum and Alzheimer’s disease has been suspected for several decades. Aluminum is toxic to the cholinergic system (Clayton et al. 1992) and leads to >-amyloid conformational change and increase in aggregation in vitro (Kawahara et al. 2001). In a 2-year doubleblind, controlled trial, patients who received intramuscular desferrioxamine treatment showed less decline in daily living skills than did the placebo

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group (Crapper McLachlan et al. 1991). The therapeutic effects observed with this agent may not be due to its chelating action, because it has been shown to inhibit free radical formation and inflammation as well (Crapper McLachlan et al. 1991). The required intramuscular administration and toxic side effects of this compound might limit its clinical utility. Replication studies are necessary to confirm the efficacy of this approach. In addition, since desferrioxamine chelates iron very strongly, the possibility that iron overload may have a role in the pathogenesis of Alzheimer’s disease needs continued consideration (Savory et al. 1996). Agents that bind to copper and zinc may also be potential therapeutic agents for Alzheimer’s disease (Bush et al. 1994; Gouras and Beal 2001). Transgenic mice models had reduction in amyloid burden when treated with clioquinol, an antibiotic and a copper-zinc chelator (Cherny et al. 2001). Caution is needed in extrapolating from animal models for Alzheimer’s disease. Human trials are still required to validate the effectiveness of compounds that have demonstrated benefit in transgenic mice.

New Outlooks Nerve Growth Factor Another potential therapeutic approach for Alzheimer’s disease is the administration of neurotrophic factors. Nerve growth factor (NGF) is a 118– amino acid polypeptide that does not cross the blood-brain barrier. Other substances with neurotrophic activity—such as epidermal growth factor, brain-derived neurotrophic factor, and gangliosides—might have therapeutic potential as well. Intraventricular administration of NGF partially reverses lesion-induced deficits in the activity of cortical acetylcholinesterase and choline acetyltransferase (Haroutunian et al. 1985) and promotes survival of septal cholinergic neurons after fimbrial transection in adult rats (Hefti 1986). Animals with reduced levels of NGF demonstrate impairment in spatial learning (K.S. Chen et al. 1997). Human NGF has been produced by recombinant techniques, and in the near future sufficient amounts of pure human NGF may be available for experimental assessment and therapeutic trials in Alzheimer’s disease. There are promising pharmacological strategies—such as gene transfer, cell grafting, synthesis of liposomes, drug lipidization, and development of lipid-soluble prodrugs and chimeric nutrients or peptides—that might provide ways for improved noninvasive drug delivery to the central nervous system (reviewed in Martinez-Serrano and Bjorklund 1998). Other routes of administration could also be considered. Genetically modified NGF-secreting fibroblast grafts have been shown to prevent


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degeneration of cholinergic neurons after surgical lesions of the fimbriafornix in rats (Rosenberg et al. 1988). This opens the possibility of grafting genetically engineered cells to secrete in situ the required factor or neurotransmitter. For example, a fibroblast cell line was genetically modified to express choline acetyltransferase. The altered cells produced and released acetylcholine in vitro and in vivo after grafting into rat hippocampus. Thus, specially designed fibroblasts could provide a vehicle for delivering various substances to the brain. It is conceivable that in the future neuronal stem cells or neurotransmitter-secreting cell implants will become available for clinical trials in the treatment of Alzheimer’s disease. NGF conjugated to an antibody to the transferring receptor was shown to cross the blood-brain barrier and to increase the survival of cholinergic and noncholinergic neurons after peripheral injection in rats (Frieden et al. 1993). Pharmacological modulation of NGF within the central nervous system may be a future method to deal with the limitations of intracerebral administration of NGF (reviewed in Rattray 2001).

Estrogen Support for use of estrogen in Alzheimer’s disease comes from laboratory and epidemiological findings. Cholinergic and estrogen receptors are colocalized (Burton-Jones et al. 1999). Estrogen activates the cholinergic system, blocks anticholinergic effects, encourages neuron arborization, and attenuates the toxicity of >-amyloid in cell culture (Gibbs 1999; Luine et al. 1980; Segarra and McEwen 1991). In addition, estrogen has antioxidant properties and neurotrophic effects and promotes neuronal survival (Inestrosa et al. 1998; Nathan and Chaudhuri 1998). The women in the tacrine clinical trial who were receiving estrogen responded better to tacrine than the women who were not taking estrogen (Schneider and Farlow 1997). One explanation for this finding may be the effect of estrogen on increasing 1-hydroxy tacrine, an active metabolite of tacrine (Laine et al. 1999). In addition, the trial was not designed to ascertain the effect of estrogen on cholinesterase inhibitors, and the variable dosage of estrogen and the lack of randomization limit the conclusions that can be drawn from the report. Epidemiological support is consistent for the use of estrogen as a preventive for Alzheimer’s disease in postmenopausal women (Baldereschi et al. 1998; Kawas et al. 1997; LeBlanc et al. 2001; Paganini-Hill and Henderson 1996; Tang et al. 1996). The optimal duration of use and the preferred estrogen preparation and dosage could not be deduced from these epidemiological studies. The utility of estrogen as a therapeutic agent for Alzheimer’s disease is uncertain (Asthana et al. 1999, 2001; Henderson et al. 2000). In a large

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1-year randomized trial with estrogen, there was no benefit for Alzheimer’s disease in measures of cognition or function. The estrogen-treated group actually worsened in cognitive measures compared with the placebo group over the duration of the study (Mulnard et al. 2000). Longer-term trials are under way to clarify the effect of estrogen on the development and progression of dementia (Shumaker et al. 1998).

Anti-Inflammatory Agents Epidemiological, neuropathological, preclinical, and clinical data support involvement of the immune system and of inflammation in the pathophysiology of Alzheimer’s disease (Anthony et al. 2000; McGeer and McGeer 1995; McGeer et al. 1996). Activation of microglia and inflammatory markers are found in neurons and axons near amyloid plaques and neurofibrillary tangles. Acute-phase reactants are present in CSF, along with elevated levels of various cytokines, including tumor necrosis factor in serum and interleukins 1 and 6 in brain. Cellular immune responses include T4 and T8 lymphocytes and microglia and the production of complement. Several studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin may have protective effects against Alzheimer’s disease (Breitner et al. 1994). Interestingly, the benefit of NSAIDs in reducing risk of Alzheimer’s disease may require at least 2 years of exposure to the agents (Beard et al. 1998; in’t Veld et al. 1998, 2001; Stewart et al. 1997). The dosage of NSAIDs needed to achieve the risk reduction is not yet clear (Broe et al. 2000; McGeer et al. 1996). In a 6-month double-blind, placebo-controlled study of Alzheimer’s disease, oral indomethacin 100–150 mg/day was found to improve cognitive function and to delay further deterioration. These results are promising, but the toxicity of indomethacin limits its use (J. Rogers et al. 1993). Finally, NSAIDS are not alike in their effects on amyloid precursor protein (APP) processing. Some, such as ibuprofen and indomethacin, decrease >-amyloid 42 and increase the less toxic and less aggregating >-amyloid 38 fragment by alteration of C-secretase activity (De Strooper and Konig 2001; Weggen et al. 2001). Use of corticosteroids is another possible strategy for anti-inflammatory agents in Alzheimer’s disease. These agents are widely used for the treatment of central nervous system inflammatory diseases, including lupus cerebritis and multiple sclerosis. Unfortunately, the systemic toxicity of steroids limits the dosage and length of treatment that are possible with these agents. Treatment with prednisone 10 mg/day orally for 1 year was not effective in Alzheimer’s disease and was associated with adverse behavioral effects and worsening cognition compared with placebo (Aisen et al. 2000). Colchicine is another possible candidate among anti-inflammatory


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agents for the treatment of Alzheimer’s disease. This drug effectively treats familial Mediterranean fever, a condition in which recurrent inflammation and amyloidosis occur. Although the amyloid constituents in familial Mediterranean fever and Alzheimer’s disease differ, both illnesses involve chronic inflammation, elevated levels of acute-phase proteins, and abnormal processing of a precursor protein leading to deposition of insoluble amyloid fragments. Hydroxychloroquine, an antimalarial agent and an effective second-line drug for the treatment of rheumatoid arthritis and lupus erythematosus, is thought to affect the immune response by interacting with lysosomal functioning. This agent suppresses cytokine and acutephase reactant levels. The drug is relatively safe when administered chronically for the treatment of rheumatoid arthritis but was not found to slow the rate of decline in patients with mild Alzheimer’s disease over 18 months (Van Gool et al. 2001). Mouse studies suggest that these agents may vary in their ability to alter APP processing independent of cyclooxygenase activity (Weggen et al. 2001). Multicenter clinical trials with cyclooxygenase-2 inhibitors and other NSAIDs are currently in progress (Breitner and Zandi 2001; McGeer 2000). When these findings are available, the interpretation of the results should consider that differential effects of anti-inflammatory agents may reflect the specific agent used, dosage and duration of exposure, severity of cognitive impairment when exposed to the agent, and medical comorbidities. A study of celecoxib has been abandoned by the manufacturer, and both rofecoxib and naprosyn have been found ineffective over a 1-year course of treatment.

APP Metabolism There is abundant evidence that accumulation and aggregation of >-amyloid may be involved in the pathogenesis of Alzheimer’s disease (Selkoe 2000). The APP may or may not be cleaved to form the neurotoxic >-amyloid 42–43. Therapeutic targets for drug discovery include the secretase enzymes responsible for the alternative cleavage pathways. >-Secretase and C-secretase must both cleave APP to produce toxic >-amyloid (Vassar et al. 1999). =-Secretase cleaves within the >-amyloid domain and results in a nonneurotoxic fragment. Therefore, minimizing production of toxic >-amyloid could be accomplished by inhibition of >- or C-secretase or potentiation of =-secretase (see Selkoe 2001). Several manufacturers have C-secretase inhibitors under development. There is the possibility that C-secretase is closely linked to presenilins (Li et al. 2000; Wolfe et al. 1999) and that presenilins may become a therapeutic target. However, the importance of presenilins in the critical Notch pathway may limit the applicability of C-secretase inhibitors. In vivo studies have demonstrated the ability

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of C-secretase inhibitor to reduce brain >-amyloid levels in transgenic animals. (Dovey et al. 2001). An alternative therapeutic approach could involve an antibody to the toxic >-amyloid. In fact, this is the basis for an Alzheimer’s “vaccine.”

Interfering With Tangle Formation Hyperphosphorylation of tau protein leads to the formation of neurofibrillary tangles (NFTs) (Alonso et al. 1996). NFTs are present in the brains of individuals with Alzheimer’s disease irrespective of cognitive status, but the density of the NFTs is correlated with the clinical severity of Alzheimer’s disease (Haroutunian et al. 1999). Tauopathies are diseases that may include Alzheimer’s disease, and an understanding of the tauopathies may also translate into therapeutic interventions (Forman et al. 2000). The cholinergic system may also interface with tangle formation. Tau is phosphorylated by glycogen synthase kinase–3> and is inhibited via protein kinase C. Many muscarinic agonists attenuate the expression of phosphorylated tau (Forlenza et al. 2000). In addition, lithium has been shown to block tau hyperphosphorylation by inhibition of glycogen synthase kinase–3> (Lovestone et al. 1999). Inhibitors of glycogen synthase kinase–3>, such as lithium and valproic acid (G. Chen et al. 1999), may be future therapeutic agents for Alzheimer’s disease.

Immunological Approaches: “Vaccine” Transgenic mice that possess the mutated human gene for APP develop intracerebral amyloid deposits. The development of these deposits was attenuated in these genetically altered mice (compared with control mice) by vaccinating the mice with >-amyloid (Bard et al. 2000; Barinaga 1999). Vaccination of mice that had already developed the amyloid deposits led to a reduction in plaque formation in the transgenic mouse group compared with control mice (Janus et al. 2000). The effectiveness of the vaccine in transgenic mice may be dependent on >-amyloid load before the vaccination; the vaccine appears to work best in mice with low or no levels of >-amyloid at the time of the vaccinations (Das et al. 2001). To determine whether the vaccine has any beneficial or deleterious effects, in one study the transgenic mice that developed learning deficits were observed for 8 months while they were receiving the vaccination (Morgan et al. 2000). During that time there were no functional changes in the vaccinated group of mice compared with the control mice. The vaccinated group performed better than the control transgenic mice on a task of spatial memory. Pre-


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liminary work in vaccinating humans (Thatte 2001) was terminated in early 2002 because 4/360 persons exposed to multiple doses of the vaccine AN-1972 developed clinical signs of CNS inflammation (Imbimbo 2002). The cause of this inflammation remains to be determined. Other unanswered questions about this approach are the degree to which elderly humans will develop and maintain an immune response to antibodies against amyloid protein, whether humans will reject the foreign epitope (see Frenkel et al. 2001), which epitope will be ideal for humans (see Klein et al. 2001), whether the vaccine will be able to (or will need to) cross the bloodbrain barrier (see Poduslo and Curran 2001), what schedule of vaccines will be optimal (e.g., giving it to subjects at risk or to subjects who already have the disease), whether reduction in amyloid plaques will result in any meaningful clinical change in presentation or course of the disease, and whether reduction in plaque burden will result in an increase in other pathology (a shift in equilibrium).

Apolipoprotein E There is a threefold higher prevalence of the apolipoprotein E (ApoE) A4 allele in persons with late-onset familial Alzheimer’s disease than in control subjects. ApoE is present in senile plaques, vascular amyloid, and neurofibrillary tangles of Alzheimer’s disease. Based on experimental data, it has been suggested that the protein generated by the ApoE A4 allele (unlike the proteins generated by the alleles ApoE A3 or ApoE A2) lacks microtubule-protective properties. Thus, the absence of the alternative alleles ApoE A3 or ApoE A2 may be amyloidogenic and associated with an increased risk for Alzheimer’s disease (Strittmatter et al. 1994). This hypothesis suggests that new pharmacological strategies in Alzheimer’s disease could consist of agents with ApoE A3- or ApoE A2-like microtubule–stabilizing properties or of compounds that alter the expression of the ApoE gene. The protein product of the ApoE A4 gene, ApoE4, is involved in lipid transport and may affect lipid balance in the brains of Alzheimer’s disease patients. Phospholipid, fatty acid, and cholesterol metabolism may be adversely affected by low apolipoprotein concentrations in ApoE A4 Alzheimer’s disease patients. Response to drug treatment in Alzheimer’s disease patients may be dependent on ApoE genotype. In addition, there is an inverse relationship between the number of ApoE A4 alleles and nicotinic receptor binding as well as choline acetyltransferase activity. For all these reasons, ApoE A4 may be a potential target for therapeutic intervention in Alzheimer’s disease (Poirier 1999).

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Statins Cholesterol has been associated with increased risk of developing Alzheimer’s disease (Marx 2001). Rabbits fed high-cholesterol diets demonstrated increased intracellular >-amyloid (Sparks et al. 1994). Guinea pigs given statin drugs demonstrated lower levels of >-amyloid 42 in CSF and brain (Fassbender et al. 2001). In another study with >-amyloid phenotype transgenic mice, a cholesterol-lowering agent (BM15.766) resulted in lower levels of plaque formation, lower serum cholesterol levels, and a correlation between serum cholesterol levels and >-amyloid levels (Refolo et al. 2001). In a cell culture experiment, another possible link in cholesterol metabolism and APP processing was observed. The drug lovastatin appeared to stimulate =-secretase and resulted in the increased production of the nontoxic, soluble =-secretase cleaved APP fragments (Kojro et al. 2001). Another study demonstrated that cholesterol acyltransferase, the enzyme responsible for altering the balance between cholesterol and cholesterol esters, may be a potential drug target in Alzheimer’s disease (Puglielli et al. 2001). A series of epidemiological studies support the possibility that statins reduce the risk of developing Alzheimer’s disease. One study found that individuals over age 50 who were taking statins had a substantially lower risk of developing dementia independent of exposure to nonstatin lipid–powering agents or hyperlipidemia (Jick et al. 2000). Another study found that the prevalence of probable Alzheimer’s disease in a cohort of persons taking statins was 60%–73% lower than the total population or compared with patients taking other medications used in the treatment of hypertension or cardiovascular disease (Wolozin et al. 2000). Basic studies have demonstrated a reduction in the secreted form of >-amyloid in various cells exposed to lovastatin. A dose response was evident in each cell type tested (Friedhoff et al. 2001). Clinical trials are planned that will test the efficacy and safety of statins for the treatment of Alzheimer’s disease. In addition, a large clinical trial with pravastatin is examining the effects of this drug on major vascular events over 3.5 years in an elderly cohort of more than 5,000 individuals. Additional analysis will examine the cognitive effects of pravastatin in these individuals (Shepherd et al. 1999).

Summary and Conclusions Multiple empirical pharmacological strategies have failed in Alzheimer’s disease, but the neurotransmission-enhancing strategies (and in particular the cholinomimetic strategies) have shown some promise. The secondgeneration cholinesterase inhibitors (donepezil, galantamine, and rivastig-


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mine) have been FDA approved for mild to moderate Alzheimer’s disease. Some evidence suggests that these agents may have not only palliative effects, but also have a disease modifying effect. Evidence that patients with more advanced disease may benefit from cholinesterase inhibitors is intriguing and requires further investigation. An Alzheimer’s disease vaccine may offer future hope of decreasing >-amyloid burden, but crucial safety and efficacy questions remain. Newer strategies are based on an increasing understanding of the pathophysiological processes involved in this illness. Strategies aimed at slowing or arresting the progression of the illness are beginning to be explored and will undoubtedly lead to therapeutic breakthroughs in the near future. Protease inhibitors, agents that block tangle formation, antioxidants, anti-inflammatory agents, cholesterolreducing agents, and cholinesterase inhibitors may be a future therapeutic cocktail for the treatment of Alzheimer’s disease.

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APPENDIX

A

Dementia Questionnaire

Patient Name _________________________ Age __________ Date __________________ Informant ___________________________________________ Relation to patient _____________________________________ MEMORY Does _________________________________________________________________________ have any problem with: Yes

No

Don’t know

Date

1) Memory

______ ______ ______ ______

2) Remembering people’s names

______ ______ ______ ______

3) Recognizing familiar faces

______ ______ ______ ______

4) Finding way about indoors

______ ______ ______ ______

5) Finding way on familiar streets

______ ______ ______ ______

6) Remembering a short list of items

______ ______ ______ ______

7) Did trouble with memory begin suddenly

______ or slowly ______

8) Has the course of the memory problems been a steady downhill progression or have there been abrupt declines ______ ______ ______ EXPRESSION 9) Ever have trouble finding the right word or expressing self ______ ______ ______ ______ 10) Talking become less over time

______ ______ ______ ______

11) Tendency to dwell in the past

______ ______ ______ ______

DAILY FUNCTIONING 12) Trouble with household tasks

______ ______ ______ ______

13) Trouble handling money

______ ______ ______ ______

14) Trouble grasping situations or explanations

______ ______ ______ ______

15) Difficulty at work (check if N/A____)

______ ______ ______ ______

16) Trouble dressing or caring for self

______ ______ ______ ______

17) Trouble feeding self

______ ______ ______ ______

18) Trouble controlling bladder and bowels

______ ______ ______ ______

19) Agitation and nervousness

______ ______ ______ ______

483

484


Yes

No

Don’t know

Date

OTHER PROBLEMS 20) High blood pressure

______ ______ ______ ______

21) Stroke

______ ______ ______ ______

22) More than one stroke

______ ______ ______ ______

23) Is one side of the body weaker than other side

______ ______ ______ ______

24) Parkinson’s disease (tremors, shuffling gait, rigidity of limbs) ______ ______ ______ ______ 25) Injury to the head resulting in a loss of consciousness for more than a second or two ______ ______ ______ ______ 26) Seizure or fits

______ ______ ______ ______

27) Syphilis

______ ______ ______ ______

28) Diabetes

______ ______ ______ ______

29) Drinking problem (describe type and amount consumed per day, duration, blackouts, DTs) _______________________________________ 30) Did memory problems coincide with drinking

______ ______ ______ ______

31) Ever depressed or sad for 2 weeks or more

______ ______ ______ ______

32) If yes, ever seek treatment

______ ______ ______ ______

33) Ever very high, euphoric, top of the world

______ ______ ______ ______

34) If yes, ever seek treatment

______ ______ ______ ______

35) Ever seek psychiatric or psychological help for any reason

______ ______ ______ ______

36) If yes, ever hospitalized for psychiatric illness

______ ______ ______ ______

Where? ____________________________________________________________ 37) Down syndrome (subject or family member)

______ ______ ______ ______

38) Other medical problems we have not talked about ________________________________________________________________ MEDICAL CONTACTS 39) Name and address of doctors seen for memory or related problems: ____________________________________________________________________________ ____________________________________________________________________________ ____________________________________________________________________________ 40) Ever receive medications

______ ______ ______ ______

41) A neurological exam or a psychiatric exam

______ ______ ______ ______

42) CAT scan or MRI scan

______ ______ ______ ______

43) What was diagnosis given for problems ___________________________________________ RECOGNITION OF PROBLEM 44) Who was the first person to notice something wrong ________________________________ 45) What was noticed ___________________________________________________________ 46) When was the last time (the subject seemed to be really well, or his old self) ____________________________________________________________________________

Dementia Questionnaire

485

MEDICATIONS 47) What medications are currently being taken ________________________________________ FAMILY HISTORY 48) Anyone else in the family with similar problems ______ Yes ______ No. If yes, what is the name of the person ______________________________________________; relationship __________________________; age __________. How can we obtain history about that person _______________________________________ _____________________________________________________________________________ Source. Adapted from Breitner JCS, Folstein MF: “Familial Alzheimer Dementia: A Prevalent Disorder With Specific Features.” Psychological Medicine 14:63–80, 1984. Used with permission.


APPENDIX

B

Mental Status Examination

Patient name _________________________________ Handedness ___ R ___ L

Age ____

Years of education_____ 1.

Sex ___

Date:___/___/___

Marital status _________

Occupation _________________________

APPEARANCE AND BEHAVIOR

Norm Abn Unk

Grooming and dress (circle one):

0

1

Hearing

0

1

9

Eyesight

0

1

9

Wandering

0

1

9

Verbal aggression

0

1

9

Sundowning

0

1

9

2.

9

BEHAVIORAL HISTORY OR OBSERVATION

Physical aggression

0

1

9

Apathy

0

1

9

Crying

0

1

9

Blunted

0

1

9

Shallow

0

1

9

Labile

0

1

9

Appropriateness

0

1

9

Other

0

1

9

3.

ORIENTATION

Time

day

date

month

Place

city

hospital

home address

Person

name

age

birth date

4.

year

EMOTION (AFFECT)

487

488

5.


MOOD

Norm Abn Unk

Depressed

0

1

9

Euphoric

0

1

9

Other

0

1

9

6.

THOUGHT PROCESS

Associations Loose

0

1

9

Klang

0

1

9

Other

0

1

9

Flow Tangential

0

1

9

Circumstantial

0

1

9

Flight of ideas

0

1

9

Blockage

0

1

9

Derailment

0

1

9

Perseveration

0

1

9

Other

0

1

9

Delusions

0

1

9

Hallucinations

0

1

9

Illusions

0

1

9

Suspicions

0

1

9

Misidentification syndrome

0

1

9

7.

8.

THOUGHT CONTENT

ATTENTION

3-7 2-4-9

Digits forward:

0

1

9

8-5-2-7 2-9-6-8-3

Digits reversed:

0

1

9

0

1

9

5-7-1-9-4-6 8-1-5-9-3-6-2 3-9-8-2-5-1-4-7 CONCENTRATION Subtraction of 3s (20, 17, 14, 11, 8, 5, 2, -1) 9. LANGUAGE Articulation

0

1

9

Fluency overall

0

1

9

increase

decrease

neologisms

paraphasias

other

delayed word finding


489

Norm Abn Unk 10. Name as many animals as you can in 1 minute:

0

1

9

(normal=18±6)

11. EXPRESSIVE LANGUAGE

None

Word finding difficulty in

Mild– mod Severe Unk

0

1

2

9

0

1

2

9

spontaneous speech: Global rating of amount of spoken language:

Norm Abn Unk 0 1 9

12. COMPREHENSION Point to floor

ceiling

desk, chair, door

Are you 150 years old?

Is the sky green?

Do you put on your coat before or after your shirt/blouse? If you cross from the north to the south side of the street, which side are you on? Is my cousin’s mother a man or a woman? 13. REPETITION walk

hospital

0

1

9

0

1

9

Mississippi River

the little boy next door I saw the train arrive yesterday 14. NAMING watch

back

crystal

band

stem

15. READING ALOUD (see p. 492) P

0

1

9

I am going to a movie

G

R

0

1

9

It is a thriller and bound to be scary

0

1

9

16. WRITING (see p. 494) Dictated sentence

0

1

9

Spontaneous sentence

0

1

9

0

1

9

book

0

1

9

chair

0

1

9

green

0

1

9

17. MEMORY Remote: Recent:

Name four presidents during your lifetime unrelated words

5 minutes

cued


490

18. PRAXIS

Norm Abn Unk

Imitation

0

1

9

Ideomotor: Salute flag

0

1

9

Comb hair

0

1

9

Blow out match

0

1

9

Construction (see p. 493):

0

1

9

intersecting rectangles

0

1

9

Greek cross

0

1

9

cube

0

1

9

0

1

9

0

1

9

Don’t cry over spilled milk.

0

1

9

People who live in glass houses shouldn’t throw stones.

0

1

9

Overall rating

0

1

9

19. HIGHER COGNITIVE FUNCTION Fund of information How many weeks in a year? Why do people have lungs? Name four states Where is Denmark? How far is it from New York to Los Angeles? Who wrote the Odyssey?

Why are light colored clothes cooler in the summer than dark colored clothes? Who was president during the American Civil War? What causes rust? What is the Koran?

20. CALCULATION 2´2=4, 2´4=8, 2´8=16, … (through 1,024) 21. PROVERBS: What do people mean when they say...

22. SIMILARITIES: An apple and a banana are similar in that they are fruits. What is the similarity between... potato cat

— carrot — rabbit

airplane — motorcycle dancing — swimming hot

— cold — tongue

nose Overall rating

0

1

9

0

1

9

0

1

9

0

1

9

0

1

9

0

1

9

0

1

9

23. JUDGMENT—What would you do if... You found a sealed, addressed, stamped envelope on the street?

0

1

9

You were in a crowded theater when a fire broke out?

0

1

9

Overall assessment

0

1

9


24. INSIGHT: 0=normal; total insight into illness and implications 1=partial awareness of disease or implications 2=unaware of or denial of symptoms or illness 3=uncertain or irrelevant response or not applicable DIAGNOSIS (DSM-IV-TR) Axis I:

Clinical syndromes or conditions that are the focus of treatment:

Axis II:

Personality or specific developmental disorders:

Axis III: Physical disorders and conditions:

491

492



493

494


Dictated sentence: Spontaneous sentence: Draw figures below:

APPENDIX

C

Neurological Examination

Patient Name: Handedness: R Age:

L Sex:

Date: __/__/__

Date: Cranial nerves

Normal

Abnormal

N/A

1.

Olfaction:

0

1

9

2.

Visual acuity:

0

1

9

3.

Pupils (ERRLA):

0

N=neurologic

9

P=physical 4.

Visual fields:

0

1

9

5.

Fund:

0

1

9

6.

EOMs:

0

1

9

7.

Facial sensation:

0

1

9

8.

Muscles of mastication:

0

1

9

9. 10.

Jaw jerk:

0

1

9

Facial muscles:

0

N=neurologic

9

P=physical 11.

Auditory acuity:

0

1=unilateral

9

2=bilateral 12.

Palate elevation:

0

N=neurologic

9

P=physical 13.

Cough, gag, swallow:

0

1

9

14.

Traps and SCM (CNXI):

0

1

9

15.

Tongue:

0

1

9

F=focal

9

Motor 16.

Bulk:

0

D=diffuse 17.

Spasticity (tone):

0

F=focal D=diffuse

495

9


496

18.

Normal

Abnormal

N/A

0

F=focal

9

Fasciculations:

D=diffuse 19.

Paratonia:

0

F=focal

9

D=diffuse 20.

“Lead pipe” rigidity

None Mild Moderate Severe N/A 0 1 2 3 9

a) Right extremities: b) Left extremities:

0

1

2

3

9

Note: Do not consider cogwheel rigidity here. 21.

Strength: 5=normal 4=reduced strength 3=unable to overcome

22.

2=unable to overcome gravity 1=trace of movement only 0=no strength 9=N/A

Muscle stretch reflexes (circle one for each side) a) Right

b) Left reflexes reduced but present

1 2

normal

1 2

3

increased reflexes

3

4

nonsustained clonus

4

5

sustained clonus

5

0

absent reflexes

0

9

N/A

9 Normal

Abnormal

N/A

Primitive reflexes (check all that apply) palmomental snout grasp suck

0

1

9

24.

Extensor plantar response:

0

1

9

25.

Finger-nose-finger:

0

1

9

26.

Heel-knee-shin:

0

1

9

27.

Luria maneuver:

0

1

9

23.

28.

Go–no-go:

0

1

9

29.

Motor impersistence:

0

1

9

30.

Perseveration:

0

1

9

31.

Reciprocal motor command:

0

1

9

32.

Rapid alternating movements Right Impairment

None Mild Moderate Severe N/A

a) Finger or hand clasps b) Heel taps

0 0

1 1

2 2

3 3

9 9

c) Prone/supine

0

1

2

3

9

Neurological Examination

Left Impairment

33.

34.

36.

None Mild Moderate Severe N/A

d) Finger or hand clasps e) Heel taps

0 0

1 1

2 2

3 3

9 9

f) Prone/supine

0

1

2

3

9

Abnormal movements

Normal

Abnormal

N/A

a) Benign essential tremor:

0

1

9

b) Myoclonus:

0

1

9

c) Dyskinesia

0

1

9

d) Rest tremor–right extremities:

0

1

9

e) Rest tremor–left extremities:

0

1

9

f) Action tremor–right extremities:

0

1

9

g) Action tremor–left extremities:

0

1

9

Normal

Abnormal

N/A

0

F=focal

9

Sensation (decreased) (mark all that apply)

35.

Light touch

Cold

Vibration Pinprick Joint position sense

Gait and station Gait and posture:

D=diffuse

Normal

Abnormal

N/A

0

1

9

Other extrapyramidal symptoms a) Body bradykinesia:

0

1

9

0

1

9

b) Postural stability:

0

1

9

c) Arising from chair:

0

1

9

d) Voice (hypovocalization):

0

1

9

e) Facial movement (hypomimia):

0

1

9

f) Turning en bloc:

0

1

9

g) Cogwheel rigidity:

0

1

9

37.

Patient cooperativeness (mark one) 0=fully cooperative 1=mildly to moderately cooperative 2=very uncooperative 9=couldn’t examine/don’t know

38.

Overall neurological assessment

39.

497

Normal

Abnormal

N/A

(excluding mental status)

0

1

9

Overall mental status

0

1

9

Notes:


APPENDIX

D 1)

Blessed Dementia Rating Scale

Memory and performance of everyday activities

Loss of ability (Score: 0=none; 0.5=sometimes; 1=frequently) A. Ability to perform household tasks B. Ability to cope with small sums of money C. Ability to remember a short list of items (e.g., shopping list) D. Ability to find way about indoors (patient's home or other familiar locations) E. Ability to find way around familiar streets F.

2)

Ability to grasp situations or explanations

0

0.5

1

0

0.5

1

0

0.5

1

0

0.5

1

0

0.5

1

0

0.5

1

G. Ability to recall recent events

0

0.5

1

H. Tendency to dwell in the past

0

0.5

1

Habits A. Eating 0=Feeds self without assistance 1=Feeds self with minor assistance 2=Feeds self with much assistance 3=Has to be fed B. Dressing 0=Unaided 1=Occasionally misplaces buttons, etc., requires minor help 2=Wrong sequence, forgets items, requires much assistance 3=Unable to dress C. Toilet 0=Clean, cares for self at toilet 1=Occasional incontinence, or needs to be reminded 2=Frequent incontinence, or much assistance 3=No control

3)

TOTAL SCORE OF ALL ITEMS (maximum score 17)

Source. Adapted from Blessed G, Tomlinson BE, Roth M: “The Association Between Quantitative Measures of Dementia and of Senile Change in the Cerebral Gray Matter of Elderly Subjects.” British Journal of Psychiatry 114:797–811, 1968. Used with permission.

499


APPENDIX

E

Washington University Clinical Dementia Rating Scale

Healthy CDR 0 Memory

Questionable dementia CDR 0.5

No memory loss or slight inconsistent forgetfulness

Orientation

Mild consistent forgetfulness, partial recollection of events; “benign” forgetfulness

Fully oriented Only doubtful impairment in solving problems, similarities, differences

Judgment—problem solving

Solves everyday problems well; judgment good in relation to past performance

Community affairs

Only doubtful or mild Independent function at usual level in job, shopping, impairment in these activities business, and financial affairs, volunteer and social groups

Home—hobbies

Life at home, hobbies, intellectual interests well maintained

Personal care

Fully capable of self-care

Score only impairment due to cognitive loss, not impairment due to other factors.

501

Life at home, hobbies, intellectual interests slightly impaired


502

Mild dementia CDR 1

Moderate dementia CDR 2

Severe dementia CDR 3

Severe memory loss: only Severe memory loss: only Moderate memory loss: fragments remain highly learned material more marked for recent retained; new material events; defect interferes rapidly lost with everyday activities Some difficulty with time Usually disoriented in time, often to place relationships: oriented for place and person at examination but may have geographic disorientation Moderate difficulty in handling complex problems; social judgment usually maintained

Orientation to person only

Unable to make Severely impaired in judgments or solve handling problems, problems similarities, differences; social judgment usually impaired

No pretense of independent function outside home Unable to function independently at these Appears well enough to be Appears too ill to be taken activities though may to functions outside a still be engaged in some; taken to functions family home outside a family home may still appear normal to casual inspection Only simple chores Mild but definite preserved; very impairment of function restricted interests, at home; more difficult chores abandoned; more poorly sustained complicated hobbies and interests abandoned

No significant function in home outside of own room

Needs prompting

Requires much help with personal care; often incontinent

Requires assistance in dressing, hygiene, keeping of personal effects

Source. Reprinted from Hughes CP, Berg L, Danziger WL: “A New Clinical Scale for the Staging of Dementia.” British Journal of Psychiatry 140:566–572, 1982. Used with permission.

APPENDIX

F

Alzheimer’s Disease Assessment Scale

The examiner is seated facing the subject across a small table. The word recall task is administered first and is followed by the remaining cognitive tasks. Some time (as long as 10 minutes) is spent in open-ended conversation to assess various aspects of expressive speech. Noncognitive behaviors are evaluated from reports of the patient and/or reliable informants and from observations made during the interview. It is best, but not absolutely necessary, to interview subject or informant separately. The rating scale of 0–5 indicates the severity of dysfunction. 0 = no impairment on a task or absence of a particular behavior 1 = very mild 2 = mild 3 = moderate 4 = moderately severe 5 = the most severe degree of impairment or a very high frequency of a behavior Ratings of many cognitive behaviors correspond to specific levels of performance on tasks.

COGNITIVE BEHAVIORS 1. WORD RECALL TASK. The subject reads 10 high-imagery words exposed for two seconds each. Each word is printed in 5/8" (16-mm) letters on a separate 4"´6" card. The subject is asked to recall the words aloud. The cards are then shuffled and re-presented. Three trials of reading and recall are given. The score equals the mean number of words NOT recalled on three trials (maximum=10). If subject is unable to comprehend or perform task, the score is 10. Note: Language abilities are evaluated throughout the interview and on specific tests. Questions eliciting “yes” and “no” answers assess basic 503

504


comprehension. Other questions should require specific information and well-developed communication skills commensurate with educational level or estimated premorbid intelligence level. Do NOT rate word finding here. 2. SPOKEN LANGUAGE ABILITY. This is a global rating of speech quality such as clarity and ability to make oneself understood. Do NOT rate quantity of speech or word-finding difficulty here. 0 = no difficulty 1 = one instance of lack of understanding 2 = subject understandable >75% of the time 3 = subject understandable 50%–75% of the time 4 = subject NOT understandable 50% of the time 5 = one or two word utterances; fluent but empty speech; mute 3. COMPREHENSION. Evaluate the subject’s ability to understand speech. Do not include responses to commands. 0 = no misunderstandings 1 = one instance of misunderstanding 2 = 3–5 instances of misunderstanding 3 = requires several repetitions and rephrasing 4 = occasional correct response, such as yes-no questions 5 = rarely responds to questions appropriately, not due to poverty of speech 4. REMEMBERING TEST INSTRUCTIONS. The subject’s ability to remember the requirements of the recognition task is evaluated. On each recognition trial, the subject is asked prior to presenting the first two words, “Did you see this word before or is it a new word?” For the third word, the subject is asked, “How about this one?” If subject responds appropriately, i.e., “yes” or “no,” recall of instructions is accurate. Failure to respond indicates that instructions have been forgotten. The instruction is then repeated. The procedure for the third word is repeated for words 4– 24; each instance of recall failure is noted. 5. WORD-FINDING DIFFICULTY IN SPONTANEOUS SPEECH. Subjects have difficulty finding the desired word in spontaneous speech. They may deal with this by circumlocution or giving explanatory phrases or nearly satisfactory synonyms. Do NOT include finger and object naming in this rating.


505

0 = remembers well 1 = forgets once 2 = must be reminded twice 3 = must be reminded 3–4 times 4 = must be reminded 5–6 times 5 = must be reminded 7 or more times 0 = none 1 = 1–2 instances 2 = noticeable circumlocution or word substitution 3 = occasional loss of words without compensation 4 = frequent loss of words without compensation 5 = nearly total loss of content words; speech sounds empty; 1- to 2-word utterances 6. COMMANDS. Receptive speech is also assessed by subject’s ability to carry out 1- to 5-step commands. 1 = Make a FIST 2 = Point to the CEILING and then to the FLOOR. Line up a pencil, watch, and 4"´6" card, in that order, on the table in front of the patient. 3 = Put the PENCIL ON TOP OF THE CARD and then PUT IT BACK. 4 = Put the WATCH on the OTHER SIDE OF THE PENCIL and then TURN OVER THE CARD. 5 = Tap EACH SHOULDER TWICE, WITH TWO FINGERS, KEEPING YOUR EYES SHUT. Each capitalized element is a single step. The command may be repeated once in its entirety. Each command is scored as a whole. The rating is the number of commands performed correctly. 0 = accomplishes 5-step command 1 = accomplishes 4-step command 2 = accomplishes 3-step command 3 = accomplishes 2-step command 4 = accomplishes 1-step command 5 = cannot follow 1-step command

506


7. NAMING OBJECTS AND FINGERS. The subject is asked to name 12 randomly presented real objects whose frequency values (2) are high, medium, and low. Then, subjects are asked to place the dominant hand on the table and to name the fingers: thumb, index (pointer, first finger forefinger), middle, ring, and little (pinky), or other culturally acceptable name. Standard clues may be used to assist subjects having difficulty. The objects, their frequency, and the clues are: High Frequency: Flower (plastic): grows in the garden Bed (dollhouse furniture): used for sleeping Whistle: makes sound when blown Pencil: used for writing Medium Frequency: Rattle: a baby’s toy Mask: hides your face Scissors: cuts paper Comb: used on hair Low Frequency: Wallet: holds your money Harmonica: a musical instrument Stethoscope: doctor uses it to listen to your heart Tongs: picks up food 0 = 0–2 objects named incorrectly (objects + fingers named) 1 = 3–5 objects named incorrectly 2 = 6–8 objects named incorrectly 3 = 9–11 objects named incorrectly 4 = 12–14 objects named incorrectly 5 = 15–17 objects named incorrectly 8. CONSTRUCTIONAL PRAXIS. The ability to copy four geometric forms is assessed. These forms, in order of presentation, are: 1. Circle, approximately 20 cm in diameter. 2. Two overlapping rectangles forming a cross. The vertical rectangle is 20´25 cm; the horizontal, 10´35 cm. 3. Rhombus, each side 20 cm, acute £50 deg, obtuse ³130 deg. 4. Cube, each side=20 cm, with internal lines present.


507

Each form is located in the upper middle of a 5"´8" sheet of white paper. The subject is asked, “Do you see this figure?” and then told, “Make one that looks like this anywhere on the paper.” Two attempts are permitted. Scoring criteria are: 1. Circle. A closed, curved figure. 2. Two overlapping rectangles. Figures must be four-sided and overlap similar to presented form. Do NOT score for size. 3. Rhombus. Figure must be four-sided, obliquely oriented, and the sides of approximately equal length. Four measurements are taken: ac, ać, bc, bć. The ratio of ac/ać ranges from 0.75 to 1.0. The ratio of bc/bć ranges from 0.6 to 1.0. The ratio of bb´/aa´ ranges from 3 to 0.75. Figure is incorrect if any ratio is outside these ranges. 4. Cube. The form is three-dimensional with front face in the correct orientation, internal lines drawn correctly between corners. Opposite sides of faces not parallel by more than 10 deg is incorrect.

9. IDEATIONAL PRAXIS. The subject is given an 8½"´11" sheet of paper and a long envelope. Subjects are instructed to pretend to send the letter to themselves. Subjects are told to fold the paper, put the paper in the envelope, seal it, address it to themselves, and to indicate where the stamp goes. If the subject forgets part of the task or has difficulty, reinstruction is given. Impairment on this task should reflect dysfunction in executing an overlearned task and NOT recall difficulty. Task components are: 1) fold letter, 2) put letter in envelope, 3) seal envelope, 4) address envelope, and 5) mark where stamp goes. Any address containing name, street, city and state (ZIP code is optional). 0 = performs all components 1 = failure to perform 1 component 2 = failure to perform 2 components 3 = failure to perform 3 components 4 = failure to perform 4 components 5 = failure to perform 5 components 10. ORIENTATION. The components of orientation are date, month, year, day of the week, season, time of day, place, and person. One point is

508


given for each INCORRECT response (maximum=8). Acceptable answers include ±1 for the date, ±1 for the hour, partial name for place, naming of upcoming season within 1 week of its beginning, and name of previous season for 2 weeks after its end. 11. WORD RECOGNITION TASK. The subject reads aloud 12 high-imagery words printed in 16-mm letters on 4" ´ 6" cards. These cards are then randomly mixed with 12 words the subject has not seen. The subject indicates whether the word was shown previously. Then two more trials of reading the original words and of recognition are given. The score is the mean number of incorrect responses for the three trials (maximum = 12). If the subject is unable to perform the task, a score of 12 is given.

NONCOGNITIVE BEHAVIORS 12. TREMORS. Subject extends both hands in front of body and extends the fingers, holding this position for approximately 10 seconds. 0 = none 1 = very slight tremor, barely noticeable 2 = noticeable tremor that does not interfere with activities 3 = tremor that interferes with activities such as holding pencil or buttoning shirt 4 = tremor that interferes with gross activities such as holding a glass of water 5 = very rapid movements with sizable displacement 13. TEARFUL. Subject/informant is asked about the frequency of tearfulness in the prior week. 0 = no tears or crying 1 = occurs one time during week or testing session 2 = occurs 2–3 times during the week 3 = occasional outbursts of short duration 4 = frequent crying spells nearly every day 5 = frequent and prolonged crying spells every day 14. DEPRESSION. Subject/informant is asked about sadness, discouragement, being down. If response is positive, inquire as to severity and pervasiveness of mood, loss of interest or pleasure in activities, and reactivity


509

to environmental events. Interviewer notes presence of depressed faces and ability to respond to encouragement and jokes. Include past week. 0 = feels good 1 = feels slightly dysphoric 2 = appears and reports mild dysphoric mood, reactivity present, some loss of interest 3 = feels moderately dysphoric often 4 = feels dysphoric almost all the time with considerable loss of reactivity and interest 5 = pervasive and severe dysphoric mood; total lack of reactivity; pervasive loss of interest and/or pleasure 15. CONCENTRATION/DISTRACTIBILITY. Rate the frequency with which subject is distracted by irrelevant stimuli and/or must be reoriented to the ongoing task. Information from informant may also be used, for example, ability to watch TV, finish meals, have conversations. A score of 1 may be given subjects who are reported by the informant as distractible but do not exhibit this behavior during the interview. 0 = concentrates well 1 = one instance of poor concentration 2 = 2–3 instances of poor concentration/distractibility 3 = 4–5 instances during interview; frequent episodes at home 4 = poor concentration; highly distractible throughout much of the interview and at home 5 = extreme difficulty in concentration; extremely distractible, unable to complete tasks 16. UNCOOPERATIVE TO TESTING. Rate the amount of subject’s resistance to various aspects of the interview. 0 = no instance of uncooperativeness 1 = one instance of uncooperativeness 2 = few instances of uncooperativeness; readily complies if asked to continue 3 = several instances of uncooperativeness 4 = needs constant cajoling to complete interview 5 = refuses to complete interview 17. DELUSIONS. Rate the subject’s belief in ideas that appear untrue, for example, persons entering house, stealing possessions. In rating severity

510


consider conviction in delusions, preoccupation, and effect on subject’s actions. Include prior week’s observations. 0 = none 1 = one transient delusional belief 2 = delusion present, but subject questions own belief 3 = patient convinced of delusion, but belief doesn’t affect behavior 4 = delusion affects behavior 5 = significant actions based on delusions 18. HALLUCINATIONS. Inquiry about visual, auditory, and tactile hallucinations. The frequency and degree of disruptiveness of hallucinations are rated. 0 = none 1 = very mild; hears voice saying one word; visual hallucination once 2 = mild 3 = moderate; hallucinates numerous times during day, which interferes with normal functioning 4 = moderately severe 5 = severe; nearly constant hallucinating, which totally disrupts normal functioning 19. PACING. Distinguish between normal physical activity and excessive walking back and forth. Include the prior week. 0 = none 1 = very rare occurrence 2 = paces for short intervals at certain times of the day 3 = paces frequently each day 4 = paces for the greater portion of the day, but can stop for activities such as meals 5 = cannot sit still and paces excessively 20. INCREASED MOTOR ACTIVITY. Rate in relation to the subject’s normal level of motor activity or a previously obtained baseline. Include the prior week. A score of 1–2 is permissible if increased motor activity is reported by the informant but does not occur during the interview.


511

0 = none 1 = very slight increase 2 = noticeable fidgeting and restlessness 3 = moves frequently; fidgets very often 4 = significant increase in movement that interferes with other activity 5 = must be moving constantly; rarely sits still 21. INCREASED/DECREASED APPETITE. Rate relative to subject’s normal appetite or previously obtained baseline. Include prior week. 0 = none 1 = slight appetite change without weight change 2 = appetite change with weight change, but eats without encouragement 3 = appetite and weight change with encouragement needed to eat OR asks for more food 4 = moderately severe 5 = will not eat/requires forced feeding OR complains of constant hunger despite adequate food intake

512


ALZHEIMER’S DISEASE ASSESSMENT SCALE SCORING Subject

Rater

Date

COGNITIVE BEHAVIORS 1. Word recall Average Error Score 2. Spoken language ability 3. Comprehension spoken language 4. Recall test instructions 5. Word finding difficulty 6. Commands: 1 2 3 4 5 7. Naming H: 1 2 3 4 Fingers: M: 1 2 3 4 TIMRP L: 1 2 3 4 8. Constructions Figures: 0 1 2 3 4 9. Ideational praxis Steps: 0 1 2 3 4 5 10. Orientation Day Year Person Time of Day Date Month Season Place 11. Word recognition . . . . . . . . . . . . . . . . . . . . Average Error Score NONCOGNITIVE BEHAVIORS 12. Tremor 13. Tearful 14. Depressed mood 15.Concentration 16. Uncooperative to testing

17. 18. 19. 20. 21.

Delusions Hallucinations Pacing Increased motor activity Increased/decreased appetite

TOTAL SCORES Word Recall (Item 1) . . . . . . . . . . . . . . . . . . . . . Word Recognition (Item 11) . . . . . . . . . . . . . . . Total Cognitive Behaviors . . . . . . . . . . . . . . . . . Other Cognitive Behaviors (Items 2–10) ....... Noncognitive Behaviors (Items 12–21) ........ Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

Source. Reprinted from Rosen WG, Mohs RC, Davis KL: “A New Rating Scale for Alzheimer’s Disease.” American Journal of Psychiatry 14:1356–1364, 1984. Used with permission. Copyright 1984 American Psychiatric Association.

APPENDIX

G

Neuropsychiatric Inventory: Community Dwelling Version

Scoring Sheet

Name (L, F, MI)

Item

Date (M/D/Y)

N/A Absent Frequency

Severity

F×S

Disruption

A. Delusions

x

0

1 2 3 4

1 2 3

___

012345

B. Hallucinations

x

0

1 2 3 4

1 2 3

___

012345

C. Agitation

x

0

1 2 3 4

1 2 3

___

012345

D. Depression/dysphoria

x

0

1 2 3 4

1 2 3

___

012345

E. Anxiety

x

0

1 2 3 4

1 2 3

___

012345

F.

x

0

1 2 3 4

1 2 3

___

012345

G. Apathy/indifference

Euphoria/elation

x

0

1 2 3 4

1 2 3

___

012345

H. Disinhibition

x

0

1 2 3 4

1 2 3

___

012345

I.

Irritability/lability

x

0

1 2 3 4

1 2 3

___

012345

J.

Aberrant motor behavior

x

0

1 2 3 4

1 2 3

___

012345

K. Night-time behavior

x

0

1 2 3 4

1 2 3

___

012345

L. Appetite/eating change

x

0

1 2 3 4

1 2 3

___

012345

1.

Informant/Caregiver

2.

Knowledge of the informant/caregiver about (S): 1)

very familiar/provides daily care

2)

somewhat familiar/often cares for (S)

3)

not very familiar, has minimal interaction with (S)

3.

If caregiver does not live with patient, how many hours per week do they see him/her?

4.

Medications of (S)

513


514

Instructions: Ask the informant/caregiver to indicate whether any of the (S)’s behaviors listed below occurred during the previous four weeks. If so, use the following scales to rate the frequency, severity, and amount of distress the behaviors caused the caregiver. A. Delusions Read to the caregiver: Does (S) have beliefs that you know are not true? For example, insisting that people are trying to harm him/her or steal from him/her. Has he/she said that family members are not who they say they are, or that the house is not their home? I’m not asking about mere suspiciousness: I am interested if (S) is convinced that these things are happening to him/her. Yes No N.A. _____ _____ _____ _____ _____ _____ _____ _____ _____

(If yes, proceed to subquestions 1–10). (If no, proceed to next screening question, “B. Hallucinations”). (Not applicable)

1. Does (S) believe that he/she is in danger—that others are planning to hurt him/ her? 2. Does (S) believe that others are stealing from him/her? 3. Does (S) believe that his/her spouse is having an affair? 4. Does (S) believe that unwelcome guests are living in his/her house? 5. Does (S) believe that his/her spouse or others are not who they claim to be? 6. Does (S) believe that his/her home is not his/her home? 7. Does (S) believe that family members plan to abandon him/her? 8. Does (S) believe that television or magazine figures are actually present in the home/room? [Does he/she try to talk or interact with them?] 9. Does (S) believe any other unusual things that I haven’t asked about? 10. Have the caregiver rate the global frequency, severity, and their own distress for the preceding items.

10a. Frequency Ratings (check one): 1. Occasionally—less than once per week. 2. Often—about once per week. 3. Frequently—several times per week, but less than every day. 4. Very frequently—once or more per day. 10b. Severity (check one): 1. Mild—delusions present but seem harmless, and do not upset (S) that much. 2. Moderate—delusions are stressful and upsetting to (S) and cause unusual or strange behavior. 3. Marked—delusions are very stressful and upsetting to (S) and cause a major amount of unusual or strange behavior. [PRN medications may be required to control them.] 10c. Caregiver Distress (How emotionally distressing do you find this behavior? Check one): 0. Not at all 1. Minimally 2. Mildly 3. Moderately 4. Severely 5. Very severely or extremely

Neuropsychiatric Inventory

515

B. Hallucinations Read to the caregiver: Does (S) have hallucinations such as false visions or voices? Does he/she see, hear, or experience things that are not present? By this we do not mean just mistaken beliefs such as stating that someone who has died is still alive; rather we are asking if (S) actually has abnormal experiences of sounds, or visions. Yes No N/A _____ 1. _____ 2. _____ 3. _____ 4. _____ 5. _____ 6. _____ 7. 8.

(If yes, proceed to subquestions 1–8). (If no proceed to next screening question, “C. Agitation/Aggression”). (not applicable)

Does (S) describe hearing voices or act as if he/she hears voices? Does (S) talk to people who are not there? Does (S) describe seeing things not seen by others, or behave as if he/she is seeing things not seen by others (people, animals, lights, etc.) Does (S) report smelling odors not smelled by others? Does (S) describe feeling things on his/her skin, or otherwise appear to be feeling things crawling or touching him/her? Does (S) describe tastes that are without known cause? Does (S) describe any other unusual sensory experiences? Have the caregiver rate the global frequency, severity, and their own distress for the preceding items.

8a. Frequency Ratings (check one): 1. Occasionally—less than once per week. 2. Often—about once per week. 3. Frequently—several times per week, but less than every day. 4. Very frequently—once or more per day. 8b. Severity (check one): 1. Mild—hallucinations are present but seem harmless and cause little distress for (S). 2. Moderate—hallucinations are distressing and are disruptive to (S). 3. Marked—hallucinations are very disruptive and are a major source of behavioral disturbance. PRN medications may be required to control them. 8c. Caregiver Distress (How emotionally distressing do you find this behavior? Check one): 0. Not at all 1. Minimally 2. Mildly 3. Moderately 4. Severely 5. Very severely or extremely C. Agitation/Aggression Read to the caregiver: Does (S) have periods when he/she refuses to cooperate or won’t let people help him/her? Is he/she hard to handle? Yes

(If yes, proceed to subquestions 1–9).

No

(If no, proceed to next screening question, “D. Depression/Dysphoria”).

N.A.

(not applicable)


516

_____ 1. _____ _____ _____ _____ _____ _____ _____

2. 3. 4. 5. 6. 7. 8. 9.

Does (S) get upset when people are trying to care for him/her or resist activities such as bathing or changing clothes? Is (S) stubborn, having to have things his/her way? Is (S) uncooperative, resistive to help from others? Does (S) have any other behaviors that make him/her hard to handle? Does (S) shout or curse angrily? Does (S) slam doors, kick furniture, throw things? Does (S) attempt to hurt or hit others? Does (S) have any other aggressive or agitated behaviors? Have the caregiver rate the global frequency, severity, and their own distress for the preceding items.

9a. Frequency Ratings (check one): 1. Occasionally—less than once per week. 2. Often—about once per week. 3. Frequently—several times per week, but less than every day. 4. Very frequently—once or more per day. 9b. Severity Ratings (check one): 1. Mild—behavior is disruptive but can be managed with redirection or reassurance. 2. Moderate—behaviors disruptive and difficult to redirect or control. 3. Marked—agitation is very disruptive and a major source of difficulty; there may be a threat of personal harm. Medications are often required. 9c. Caregiver Distress (How emotionally distressing do you find this behavior? Check one): 0. Not at all 1. Minimally 2. Mildly 3. Moderately 4. Severely 5. Very severely or extremely D. Depression/Dysphoria Read to the caregiver: Does (S) seem sad or depressed? Does he/she say that he/she feels sad or depressed? Yes No N.A. _____ _____ _____ _____ _____ _____

1. 2. 3. 4. 5. 6.

_____ 7. _____ 8. 9.

(If yes, proceed to subquestions 1–9). (If no, proceed to next screening question, “E. Anxiety”). (Not applicable)

Does (S) have periods of tearfulness or sobbing that seem to indicate sadness? Does (S) say or act as if he/she is sad or in low spirits? Does (S) put him/herself down or say that he/she feels like a failure? Does (S) say that he/she is a bad person or deserves to be punished? Does (S) seem very discouraged or say that he/she has no future? Does (S) say he/she is a burden to the family or that the family would be better off without him/her? Does (S) express a wish for death or talk about killing him/herself? Does (S) show any other signs of depression or sadness? Have the caregiver rate the global frequency, severity, and their own distress for the preceding items.


517

9a. Frequency Ratings (check one): 1. Occasionally—less than once per week. 2. Often—about once per week. 3. Frequently—several times per week, but less than every day. 4. Very frequently—essentially continuously present. 9b. Severity Ratings (check one): 1. Mild—depression is distressing, but usually responds to redirection or reassurance. 2. Moderate—depression is distressing, depressive symptoms are spontaneously voiced by (S) and difficult to alleviate. 3. Marked—depression is very distressing and a major source of suffering for (S). 9c. Caregiver Distress (How emotionally distressing do you find this behavior? Check one): 0. Not at all 1. Minimally 2. Mildly 3. Moderately 4. Severely 5. Very severely or extremely E. Anxiety Read to the caregiver: Is (S) very nervous, worried, or frightened for no reason? Does he/she seem very tense or fidgety? Is (S) afraid to be apart from you? Yes No N.A _____ 1. _____ 2. _____ 3. _____ 4. _____ 5. _____ 6. _____ 7. 8.

(If yes, proceed to subquestions 1–8). (If no, proceed to next screening question, “F. Elation/Euphoria”). (not applicable) Does (S) say that he/she is worried about planned events? Does (S) have periods of feeling shaky, unable to relax, or feeling excessively tense? Does (S) have periods of or complain of shortness of breath, gasping, or sighing for no reason other than nervousness? Does (S) complain of butterflies in his/her stomach, or of racing or pounding of the heart in association with nervous? [Symptoms not explained by ill health]. Does (S) avoid certain places or situations that make him/her more nervous such as riding in the car, meeting with friends, or being in crowds? Does (S) become nervous or upset when separated from you [or his/her caregiver]? [Does he/she cling to you to keep from being separated?] Does (S) show any other signs of anxiety? Have the caregiver rate the frequency, severity, and their own distress for the preceding items.

8a. Frequency Ratings (check one): 1. Occasionally—less than once per week. 2. Often—about once per week. 3. Frequently—several times per week, but less than every day. 4. Very frequently—once or more per day. 8b. Severity Ratings (check one): 1. Mild—anxiety is stressful for, but usually responds to redirection or reassurance. 2. Moderate—anxiety is stressful, anxiety symptoms are spontaneously voiced by (S) and difficult to alleviate. 3. Marked—anxiety is very distressing and a major source of suffering.


518

8c. Caregiver Distress (How emotionally distressing do you find this behavior? Check one): 0. Not at all 1. Minimally 2. Mildly 3. Moderately 4. Severely 5. Very severely or extremely F. Elation/Euphoria Read to the caregiver: Does (S) seem too cheerful or too happy for no reason? I don’t mean the normal happiness that comes from seeing friends, receiving presents, or spending time with family members. I am asking if (S) has a persistent and abnormally good mood or finds humor where others do not. Yes No N.A. _____ 1. _____ 2. _____ 3. _____ 4. _____ 5. _____ 6. _____ 7. 8.

(If yes, proceed to subquestions 1–8). (If no, proceed to next screening question, “G. Apathy/Indifference”). (Not applicable)

Does (S) appear to feel too good or to be too happy, different from his/her usual self? Does (S) find humor and laugh at things that others do not find funny? Does (S) seem to have a childish sense of humor with a tendency to giggle or laugh inappropriately (such as when something unfortunate happens to others)? Does (S) tell jokes or make remarks that have little humor? Does he/she play childish pranks such as pinching or playing “keep away” for the fun of it? Does (S) “talk big” or claim to have more abilities or wealth than is true? Does (S) show any other signs of feeling too good or being too happy? Have the caregiver rate the global frequency, severity, and their own distress for the preceding items.

8a. Frequency Ratings (check one): 1. Occasionally—less than once per week. 2. Often—about once per week. 3. Frequently—several times per week, but less than every day. 4. Very frequently—essentially continuously present. 8b. Severity Ratings (check one): 1. Mild—(S) is too happy at times. 2. Moderate—(S) is too happy at times, and this sometimes causes strange behavior. 3. Marked—(S) is almost always too happy and finds nearly everything to be funny. 8c. Caregiver Distress (How emotionally distressing do you find this behavior? Check one): 0. Not at all 1. Minimally 2. Mildly 3. Moderately 4. Severely 5. Very severely or extremely


519

G. Apathy/Indifference Read to the caregiver: Does (S) sit quietly without paying attention to things going on around him/ her? Has (S) lost interest in the world around him/her? Has (S) lost interest in doing things or lack motivation for participating in activities? Is it difficult to involve (S) in conversation or in doing chores? Yes No N.A. _____ _____ _____ _____ _____ _____ _____ _____

1. 2. 3. 4. 5. 6. 7. 8. 9.

(If yes, proceed to subquestions 1–9). (If no, proceed to next screening question, “H. Disinhibition”). (Not applicable)

Does (S) seem less spontaneous and less active than usual? Is (S) less likely to initiate a conversation? Is (S) less affectionate or lacking in emotions when compared to his/her usual self? Does (S) contribute less to household chores? Does (S) seem less interested in the activities and plans of others? Has (S) lost interest in friends and family members? Is (S) less enthusiastic about his/her usual interests? Does (S) show any other signs that he/she doesn’t care about doing new things? Have the caregiver rate the global frequency, severity, and their own distress for the preceding items.

9a. Frequency Ratings (check one): 1. Occasionally—less than once per week. 2. Often—about once per week. 3. Frequently—several times per week, but less than every day. 4. Very frequently—nearly always present. 9b. Severity Ratings (check one): 1. Mild—apathy is notable but produces little interference with daily routines; only mildly different from (S)’s usual behavior; (S) responds to suggestions to engage in activities. 2. Moderate—apathy is very evident; may be overcome with coaxing and encouragement; responds spontaneously only to powerful events such as visits from close relatives or family members. 3. Marked—apathy is very evident and usually fails to respond to any encouragement or external events. 9c. Caregiver Distress (How emotionally distressing do you find this behavior? Check one): 0. Not at all 1. Minimally 2. Mildly 3. Moderately 4. Severely 5. Very severely or extremely H. Disinhibition Read to the caregiver: Does (S) seem to act impulsively without thinking? Does he/she do or say things that are not usually done or said in public? Does he/she say things that are embarrassing to you or others? Yes (If yes, proceed to subquestions 1–8). No (If no, proceed to next screening question, “I. Irritability/Lability”). N. A. (Not applicable)


520 _____ _____ _____ _____

1. 2. 3. 4.

_____ 5. _____ 6. _____ 7. 8.

Does (S) act impulsively without appearing to consider the consequences? Does (S) talk to total strangers as if he/she knew them? Does (S) say things to people that are insensitive or hurt their feelings? Does (S) say crude things or make sexual remarks that they would not usually have said? Does (S) talk openly about very personal or private matters not usually discussed in public? Does (S) take liberties or touch or hug others in a way that is out of character for him/her? Does (S) show any other signs of loss of control of his/her impulses? Have the caregiver rate the global frequency, severity, and their own distress for the preceding items.

8a. Frequency Ratings (check one): 1. Occasionally—less than once per week. 2. Often—about once per week. 3. Frequently—several times per week, but less than every day. 4. Very frequently—essentially continuously present. 8b. Severity Ratings (check one): 1. Mild—disinhibition is notable, but usually responds to redirection and guidance. 2. Moderate—disinhibition is very evident and difficult to overcome by the caregiver. 3. Marked—disinhibition usually fails to respond to any interventions by the caregiver and is a source of embarrassment or social distress. 8c Caregiver Distress (How emotionally distressing do you find this behavior? Check one): 0. Not at all 1. Minimally 2. Mildly 3. Moderately 4. Severely 5. Very severely or extremely I. Irritability/Lability Read to the caregiver: Does (S) get irritated and easily disturbed? Are his/her moods very changeable? Is he/she abnormally impatient? We do not mean frustration over memory loss or inability to perform usual tasks; we are interested to know if (S) has abnormal irritability, impatience, or rapid emotional changes different from his/her usual self. Yes No N.A. _____ 1. _____ 2. _____ _____ _____ _____ _____

3. 4. 5. 6. 7. 8.

(If yes, proceed to subquestions 1–8). (If no, proceed to next screening question, “J. Aberrant Motor Behavior”). (Not applicable)

Does (S) have a bad temper, “flying off the handle” easily over little things? Does (S) rapidly change moods from one to another, being fine one minute and angry the next? Does (S) have sudden flashes of anger? Is (S) impatient, having trouble coping with delays or waiting for planned activities? Is (S) cranky and irritable? Is (S) argumentative and difficult to get along with? Does (S) show any other signs of irritability? Have the caregiver rate the global frequency, severity, and their own distress for the preceding items.


521

8a. Frequency (check one): 1. Occasionally—less than once per week. 2. Often—about once per week. 3. Frequently—several times per week, but less than every day. 4. Very frequently—essentially continuously present. 8b. Severity (check one): 1. Mild—irritability or lability is notable but usually responds to redirection and reassurance. 2. Moderate—irritability and lability are very evident and difficult to overcome by the caregiver. 3. Marked—irritability and lability are very evident, they usually fail to respond to any intervention by the caregiver, and they are a major source of distress. 8c. Caregiver Distress (How emotionally distressing do you find this behavior? Check one): 0. Not at all 1. Minimally 2. Mildly 3. Moderately 4. Severely 5. Very severely or extremely J. Aberrant Motor Behavior Read to the caregiver: Does (S) pace, do things over and over such as opening closets or drawers, or repeatedly pick at things, or wind string or threads? Yes No N.A. _____ _____ _____ _____ _____

1. 2. 3. 4. 5.

_____ 6. _____ 7. 8.

(If yes, proceed to subquestions 1–8). (If no, proceed to next screening question, “K. Sleep”) (Not applicable)

Does (S) pace around the house without purpose? Does (S) rummage around opening and unpacking drawers or closets? Does (S) repeatedly put on and take off clothing? Does (S) have repetitive activities or “habits” that he/she performs over and over? Does (S) engage in repetitive activities such as handling buttons, picking, wrapping string, etc.? Does (S) fidget excessively, seem unable to sit still, or bounce his/her feet or tap his/her fingers a lot? Does (S) do any other activities over and over? Have the caregiver rate the global frequency, severity, and their own distress for the preceding items.

8a. Frequency (check one): 1. Occasionally—less than once per week. 2. Often—about once per week. 3. Frequently—several times per week, but less than every day. 4. Very frequently—essentially continuously present. 8b. Severity (check one): 1. Mild—abnormal motor activity is notable but produces little interference with daily routines. 2. Moderate—abnormal motor activity is very evident; can be overcome by the caregiver. 3. Marked—abnormal motor activity is very evident, it usually fails to respond to any intervention by the caregiver, and is a major source of distress.


522

8c. Caregiver Distress (How emotionally distressing do you find this behavior? Check one): 0. Not at all 1. Minimally 2. Mildly 3. Moderately 4. Severely 5. Very severely or extremely K. Sleep Read to the caregiver: Does (S) have difficulty sleeping (do not count as present if (S) simply gets up once or twice per night to go to the bathroom and falls back asleep immediately)? Is he/she up at night? Does he/she wander at night, get dressed, or disturb your sleep? Yes No N.A. _____ 1. _____ 2. _____ 3. _____ 4. _____ 5. _____ 6. _____ 7. _____ 8. 9.

(If yes, proceed to subquestions 1–9). (If no, proceed to next screening question, “L. Appetite and Eating Disorders”). (Not applicable)

Does (S) have difficulty falling asleep? Does (S) get up during the night (do not count if the patient gets up once or twice per night only to go to the bathroom and falls back asleep immediately.) Does (S) wander, pace, or get involved in inappropriate activities at night? Does (S) awaken you during the night? Does (S) wake up at night, dress, and plan to go out, thinking that it is morning and time to start the day? Does (S) wake up too early in the morning (earlier than was his/her habit)? Does (S) sleep excessively during the day? Does (S) have any other night-time behaviors that bother you that we haven’t talked about? Have the caregiver rate the global frequency, severity, and their own distress for the preceding items.

9a. Frequency (check one): 1. Occasionally—less than once per week. 2. Often—about once per week. 3. Frequently—several times per week, but less than every day. 4. Very frequently—essentially continuously present. 9b. Severity (check one): 1. Mild—night-time behaviors occur but they are not particularly disruptive. 2. Moderate—night-time behaviors occur and disturb (S) and the sleep of the caregiver; more than one type of night-time behavior may be present. 3. Marked—night-time behaviors occur; several types of behavior may be present; (S) is very distressed during the night and the caregiver’s sleep is markedly disturbed. 9c. Caregiver Distress (How emotionally distressing do you find this behavior? Check one): 0. Not at all 1. Minimally 2. Mildly 3. Moderately 4. Severely 5. Very severely or extremely


523

L. Appetite and Eating Disorders Read to the caregiver: Has he/she had any changes in appetite, weight, or eating habits? (Count as NA if (S) is incapacitated and has to be fed.) Has there been any change in type of food he/she prefers? Yes No N.A. _____ _____ _____ _____ _____

1. 2. 3. 4. 5.

_____ 6. _____ 7. _____ 8. 9.

(If yes, proceed to subquestions 1–9). (Not applicable)

Does (S) have a poor appetite (loss of appetite). Does (S) have an abnormally good appetite (increase in appetite)? Has (S) lost weight? Has (S) gained weight? Does (S) have unusual eating behavior, such as putting too much food in his/her mouth at once? Has (S) had a change in the kind of food he/she likes, such as wanting too many sweets or other specific types of food? Has (S) developed eating behaviors, such as eating exactly the same types of food each day, or eating the food in exactly the same order? Have there been any other changes in appetite or eating that I haven’t asked about? Have the caregiver rate the global frequency, severity, and their own distress for the preceding items.

9a. Frequency (check one): 1. Occasionally—less than once per week. 2. Often—about once per week. 3. Frequently—several times per week, but less than every day. 4. Very frequently—essentially continuously present. 9b. Severity (check one): 1. Mild—irritability or lability is notable but usually responds to redirection and reassurance. 2. Moderate—irritability and lability are very evident and difficult to overcome by the caregiver. 3. Marked—irritability and lability are very evident, they usually fail to respond to any intervention by the caregiver, and they are a major source of distress. 9c. Caregiver Distress (How emotionally distressing do you find this behavior? Check one): 0. Not at all 1. Minimally 2. Mildly 3. Moderately 4. Severely 5. Very severely or extremely Source. Copyright J.L. Cummings, 1994. Used with permission. The Neuropsychiatric Inventory is copyrighted and its use must be negotiated with the author, Jeffrey L. Cummings, UCLA School of Medicine, 710 Westwood Plaza, Los Angeles, CA 90097-1769.


APPENDIX

H

Agitated Behavior in Dementia Scale

Instructions for Administration and Scoring of Agitated Behavior in Dementia Scale (ABID) The ABID is administered to the caregiver about the Alzheimer’s disease patient. Instructions should be read to the caregiver, and the interviewer should ensure that the caregiver understands the instructions. Each item is rated according to its occurrence during the past week, and according to its occurrence during the week before last, using the following format: Was (subject) verbally threatening or aggressive towards others during the past week? If yes, mark the frequency, according to instructions. How about the week before last? If yes, mark the frequency. If the behavior occurred during either of the past 2 weeks, ask the caregiver to rate how much the behavior bothered him/her, according to instructions. If the behavior did not occur during either week, mark the reaction as “9” (not applicable). Continue for each item. Scoring Algorithm for Outpatient Agitation Inventory: Reaction total: sum (r0l to r16) range=0 to 64 items scored as “9” (not applicable) receive a reaction score of “0” Frequency total: first, compute composite score for each item (f01 to f16) by adding (week 1+week 2) for each item range for item scores=0 to 6 then, sum composite scores (f01 to f16) range for total score=0 to 96 Interview Date:

Month___________ Day ___________ Year__________________

Instructions: The following is a list of problems people/patients sometimes have. Please indicate if any of these problems have occurred during the last two weeks. If so, how much has this bothered or upset you when it happened? Use the following scales for the frequency of the problem and your reaction to it. Please read the description of the ratings carefully.

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Frequency Ratings: 0=did not occur in the week 1=occurred 1 to 2 times in the week 2=occurred 3 to 6 times in the week 3=occurred daily or more often 9=don’t know/not applicable

Reaction Ratings: 0=not at all 1=a little 2=moderately 3=very much 4=extremely 9=don’t know/not applicable

Please answer all the questions below. Check one box from 0–9 for both Frequency and Reaction. WEEK 1 WEEK 2

WEEK 1

Refers to the past week Refers to the week before last Frequency

Reaction

0 1 2 3 9

0 1 2 3 4 9

WEEK 2

WEEK 1

0 1 2 3 9

0 1 2 3 4 9

WEEK 2

WEEK 1

0 1 2 3 9

0 1 2 3 4 9

WEEK 2

WEEK 1

0 1 2 3 9

0 1 2 3 4 9

WEEK 2

WEEK 1

0 1 2 3 9

WEEK 1

0 1 2 3 4 9

WEEK 2

WEEK 1

0 1 2 3 9

WEEK 2

2. Physically threatening or aggressive toward others.

3. Harmful to self (e.g., biting, pinching self).

4. Inappropriate screaming or crying out.

5. Destroying property.

0 1 2 3 4 9

WEEK 2

0 1 2 3 9

1. Verbally threatening or aggressive toward others.

0 1 2 3 4 9

6. Refusing to accept appropriate help (e.g., with personal care).

7. Trying to leave (or leaving) home inappropriately.

Agitated Behavior in Dementia Scale

WEEK 1

0 1 2 3 9

WEEK 1

0 1 2 3 4 9

WEEK 2

WEEK 1

0 1 2 3 9

0 1 2 3 4 9

WEEK 2

WEEK 1

0 1 2 3 9

0 1 2 3 4 9

WEEK 2

WEEK 1

0 1 2 3 9

0 1 2 3 4 9

WEEK 2

WEEK 1

0 1 2 3 9

WEEK 1

0 1 2 3 4 9

WEEK 2

WEEK 1

0 1 2 3 9

0 1 2 3 4 9

WEEK 2

WEEK 1

0 1 2 3 9

WEEK 2

9. Socially inappropriate behavior (e.g., loud offensive remarks).

10. Inappropriate sexual behavior (e.g., unwanted sexual advances, public sexual behavior).

11. Restlessness, fidgetiness, inability to sit still.

12. Worrying, anxiety, and/or fearfulness.

13. Easily agitated or upset.

0 1 2 3 4 9

WEEK 2

0 1 2 3 9

8. Arguing, irritability, or complaining.

0 1 2 3 4 9

WEEK 2

0 1 2 3 9

527

0 1 2 3 4 9

14. Waking and getting up at night (other than trips to the bathroom).

15. Incorrect, distressing beliefs or delusions (e.g., about being threatened or harmed).

16. Seeing, hearing, or sensing distressing people or things that are not really present (e.g., a strange man in the house, insects crawling on the walls—hallucinations).

Source. Reprinted from Logsdon RG, Teri L, Weiner MF, et al.: “Assessment of Agitation in Alzheimer’s Disease: The Agitated Behavior in Dementia Scale: Alzheimer’s Disease Cooperative Study. Journal of the American Geriatrics Society 47:1354–1358, 1999. Used with permission.


APPENDIX

I

Quality of Life in Alzheimer’s Disease Scale

Instructions for Interviewers The QOL-AD is administered in interview format to caregivers of individuals with dementia, following the instructions below. Hand the form to the caregiver, so that he or she may look at it as you give the following instructions (instructions should closely follow the wording given in bold type): I want to ask you some questions about [S’s] quality of life and have you rate different aspects of [S’s] life using one of four words: poor, fair, good, or excellent Point to each word (poor, fair, good, and excellent) on the form as you say it. When you think about [S’s] life, there are different aspects, like physical health, energy, family, money, and others. I’m going to ask you to rate each of these areas. We want to find out what you think [S]feels about his/her current situation in each area. If you’re not sure about what a question means, you can ask me about it. If you have difficulty rating any item, just give it your best guess. It is usually apparent whether an individual understands the questions, and most individuals who are able to communicate and respond to simple questions can understand the measure. If the caregiver answers all questions the same, or says something that indicates a lack of understanding, the interviewer is encouraged to clarify the question. However, under no circumstances should the interviewer suggest a specific response. Each of the four possible responses should be presented, and the caregiver should pick one of the four. 529

530


If a caregiver is unable to choose a response to a particular item or items, this should be noted in the comments. If the caregiver is unable to comprehend and/or respond to two or more items, the testing may be discontinued and this should be noted in the comments. As you read the items listed below, ask the caregiver to circle her/his response. If the caregiver has difficulty circling the word, you may ask her/ him to point to the word or say the word, and you may circle it for him or her. You should let the participant hold his or her own copy of the measure and follow along as you read each item. 1. First of all, how do you think [S] feels about [S’s] physical health? Would you say it’s poor, fair, good, or excellent? Circle whichever word you think best describes [S’s] estimate of his/her physical health right now. 2. How do you think [S] feels about [S’s] energy level? Do you think it is poor, fair, good, or excellent? If the participant says that some days are better than others, ask him or her to rate how she/he thinks [S] has been feeling most of the time lately. 3. How would [S] describe [S’s] mood lately? Would [S] say [S’s] spirits have been good, or would [S] report feeling down? Would [S] rate [S’s] mood as poor, fair, good, or excellent? 4. How do you think [S] feels about [S’s] living situation; the place where [S] lives now? Would you say it’s poor, fair, good, or excellent? 5. How about [S’s] feelings about [S’s] memory? Would [S] describe it as poor, fair, good, or excellent? 6. How about [S’s] family and [S’s] relationship with family members? Would you describe it as poor, fair, good, or excellent? If the respondent says [S] has no family, ask about brothers, sisters, children, nieces, nephews. 7. How do you think [S] would rate [S’s] (your ) marriage? Do you feel [S] would describe the relationship as poor, fair, good, or excellent? Some patients will be accompanied by a non-spousal caregiver. In that case, ask [S’s] rating of the relationship with him/her. When this is the case, ask the caregiver how they seem to feel about him/her. 8. How would you think [S] would describe [S’s] current relationship with friends? Would you say it’s poor, fair, good, or excel-


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lent? If the respondent answers that [S] has no friends, or all their friends have died, probe further. Is there anyone [S] appears to enjoy being with besides family? Would you call that person a friend? If the respondent still says [S] has no friends, ask how does [S] feel about having no friends—poor, fair, good, or excellent? 9. How do you think [S] feels about him/herself—when [S] thinks of [S’s] whole self, and all the different things about him/her, would you say it’s poor, fair, good, or excellent? 10. How do you think [S] feels about [S’s] ability to do things like chores around the house or other things [S] needs to do? Would you say it’s poor, fair, good, or excellent? 11. How about [S’s] feelings about [S’s] ability to do things for fun, that [S] enjoys? Would you say it’s poor, fair, good, or excellent? 12. How do you think [S] feels about [S’s] current situation with money; [S’s] financial situation? Would [S] rate it as poor, fair, good, or excellent? If the respondent hesitates, explain that you don’t want to know what [S’s] situation is (as in amount of money), just how they feel about it. 13. How do you think [S] would rate [S’s] life as a whole; everything together. Would you say it’s poor, fair, good, or excellent? SCORING INSTRUCTIONS FOR THE QOL: Points are assigned to each item as follows: poor = 1, fair = 2, good = 3, excellent=4. The total score is the sum of all 13 items.

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Patient ID# Patient Initials Visit Type Date

_________________ _________________ _________________ _________________

Quality of Life (Informant Version) Please rate [S’s] current situation, as you see it. Circle your responses. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Physical health. Energy. Mood. Living situation. Memory. Family. Marriage. Friends. Self as a whole. Ability to do chores around the house. Ability to do things for fun. Money. Life as a whole.

Poor Poor Poor Poor Poor Poor Poor Poor Poor Poor Poor Poor Poor

Fair Fair Fair Fair Fair Fair Fair Fair Fair Fair Fair Fair Fair

Good Good Good Good Good Good Good Good Good Good Good Good Good

Excellent Excellent Excellent Excellent Excellent Excellent Excellent Excellent Excellent Excellent Excellent Excellent Excellent

Comments: _________________________________________________________ ____________________________________________________________________ ____________________________________________________________________ Thank You!


Patient ID# Patient Initials Visit Type Date

533

_________________ _________________ _________________ _________________

Quality of Life (Patient Version) Please rate current situation, as you see it. Circle your responses. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Physical health. Energy. Mood. Living situation. Memory. Family. Marriage. Friends. Self as a whole. Ability to do chores around the house. Ability to do things for fun. Money. Life as a whole.

Poor Poor Poor Poor Poor Poor Poor Poor Poor Poor Poor Poor Poor

Fair Fair Fair Fair Fair Fair Fair Fair Fair Fair Fair Fair Fair

Good Good Good Good Good Good Good Good Good Good Good Good Good

Excellent Excellent Excellent Excellent Excellent Excellent Excellent Excellent Excellent Excellent Excellent Excellent Excellent

Comments: ________________________________________________________ ____________________________________________________________________ ____________________________________________________________________ Thank You! Source. Reprinted from Logsdon RG, Gibbons LE, McCurry SM, et al.: “Quality of Life in Alzheimer’s Disease: Patient and Caregiver Reports.” Journal of Mental Health and Aging 5:21–32, 1999. Copyright 1999, Springer Publishing Company, Inc., New York 10012. Used with permission.


APPENDIX

J

Quality of Life in LateStage Dementia (QUALID) Scale

The Quality of Life in Late-Stage Dementia (QUALID) is administered in interview format to an informant following the instructions below. Informants may be either a family member or professional caregiver who by having regular contact is familiar with the subject’s general behavior. Informants must, in addition to being familiar with the subject, have spent a significant portion of at least 3 days out of the last 7 days with the subject, in order to accurately rate the items on the scale. The scale is scored by summing the responses. The possible scores range from 11 to 55, with 11 representing the highest quality of life. The final items on the scale require that the interviewer make a judgment about the validity of the interview. Provide both a rating of the overall quality of the interview, which includes the informant’s ability to understand the items and responses and the effort the informant put forth in answering questions, and the familiarity of the informant with the subject. These items are not included in the score, but offer information about the validity and usefulness of the ratings for that subject. Informants are handed a blank copy of the scale so that they may look at the items as they are read aloud, and the following instructions are given: I want to ask you some questions about quality of life. I want you to rate his/ her behaviors using the responses under each question on this page. (Point to the responses on the first question.) There is no one right or wrong answer. I just want to know how you would rate his/her behavior from your observations. Specifically, I want to know about his/her behavior over the past week only, not how he/she previously behaved. Remember that your answers should reflect his/her behavior over the past seven days. If you are not sure what the question means, you can ask me about it. If you have difficulty choosing a rating for an item, just make your best guess. Again, indicate your observation about his/her behavior over the past week.

Which response best describes ______________ over the past week? A. [S] smiles 1. spontaneously once or more each day 2. spontaneously less than once each day 3. only in response to external stimuli; at least once each day 4. only in response to external stimuli; less than once each day 5. rarely, if at all

535

536


B. [S] appears sad 1. rarely or never 2. only in response to external stimuli; less than once each day 3. only in response to external stimuli; at least once each day 4. for no apparent reason less than once each day 5. for no apparent reason once or more each day C. [S] cries 1. rarely or never 2. only in response to external stimuli; less than once each day 3. only in response to external stimuli; at least once each day 4. for no apparent reason less than once each day 5. for no apparent reason once or more each day D. [S] has a facial expression of discomfort—appears unhappy or in pain (looks worried, grimaces, furrowed or turned-down brow) 1. rarely or never 2. less than once each day 3. at least once each day 4. nearly half of each day 5. most of each day E. [S] appears physically uncomfortable—he/she squirms, writhes, frequently changes position 1. rarely or never 2. less than once each day 3. at least once each day 4. nearly half of each day 5. most of each day F.

[S] makes statements or sounds that suggest discontent, unhappiness, or discomfort (complains, groans, screams) 1. rarely or never 2. only in response to external stimuli; less than once each day 3. only in response to external stimuli; at least once each day 4. without cause less than once each day 5. without cause once or more each day

G. [S] is irritable or aggressive (becomes angry, curses, pushes, or attempts to hurt others) 1. rarely or never 2. only in response to external stimuli; less than once each day 3. only in response to external stimuli; at least once each day 4. without cause less than once each day 5. without cause once or more each day H. [S] enjoys eating 1. at most meals and snacks 2. twice a day 3. at least once a day 4. less than once each day 5. rarely or never

Quality of Life in Late-Stage Dementia Scale

537

I.

[S] enjoys touching/being touched 1. almost always; almost always initiates touching 2. more than half the time; sometimes initiates touching 3. half the time; never initiates touching, but doesn’t resist touching 4. less than half the time; often or frequently resists touching/being touched 5. rarely or never; almost always resists touching/being touched

J.

[S] enjoys interacting or being with others 1. almost always; almost always initiates interaction with others 2. more than half the time; sometimes initiates interaction with others 3. half the time; never initiates interaction, but doesn’t resist interaction with others 4. less than half the time; often or frequently resists interacting with others 5. rarely or never; almost always resists interacting with others

K. [S] appears emotionally calm and comfortable 1. most of each day 2. more than half of each day 3. half of each day 4. less than half of each day 5. rarely or never __________Total Score (sum of all items; scores range from 11 to 55 with lower scores representing higher quality of life) Quality of Interview (Administrator’s judgment): 0 Interview appeared valid 1 Some questions about interview, but probably acceptable 2 Information from interview of doubtful validity Knowledge/familiarity of caregiver with subject: 0 Very familiar; provides daily care 1 Somewhat familiar; often provides some care 2 Not very familiar; only dispenses meds, minimal contact Source.

Copyright 2000 Myron F. Weiner, M.D.


APPENDIX

K

Abnormal Involuntary Movement Scale (AIMS)

Before conducting the formal examination below, observe patients unobtrusively at rest in a hard, firm, armless chair. Then ask the following questions or make the following requests: 1. “Is there anything in your mouth such as gum or candy? If so, please remove it.” 2. “How are your teeth?” “Do you wear dentures?” “Do your teeth or dentures bother you?” 3. “Do you notice any movements in your mouth, face, hands, or feet? If so, describe them.” “How much do they bother you at present, and how much do they interfere with your activities?” 4. “Please sit with your hands on your knees, legs slightly apart and feet flat on the floor.” (Observe for large body movements) 5. “Please let your hands to hang down between your legs” or (if wearing a dress) “Let your hands hang over your knees.” (Observe hands and other body areas) 6. “Please open your mouth.” (Do twice, observing tongue at rest) 7. “Please stick out your tongue.” (Do twice, noting abnormalities of tongue movement) 8. “Tap your thumb with each finger of the same hand as fast as you can.” (Do 15 seconds for each finger of both hands, one hand at a time. Observe face and leg movements) 9. “Please stand up.” (Observe all body areas, including hips, in profile) 10. “Please stretch your arms out in front of you with your palms down.” (Observe trunk, legs, and mouth) 11. “Please walk a few steps, turn, and walk back to the chair.” (Do twice, observing hands and gait)

539

540


Circle the highest severity noted. 0 = none; 1 = minimal; 2 = mild; 3 = moderate; 4 = severe. 1. Muscles of facial expression (frowning, blinking, grimacing)

0 1 2 3 4

2. Lips and perioral area (puckering, pouting, smacking)

0 1 2 3 4

3. Jaw (chewing, clenching, mouth opening, lateral motion)

0 1 2 3 4

4. Tongue

0 1 2 3 4

5. Upper extremities (choreic [rapid, purposeless, spontaneous, irregular] and athetoid [slow, irregular, complex, serpentine] movements only)

0 1 2 3 4

6. Lower extremities

0 1 2 3 4

7. Trunk (squirming, rocking, twisting)

0 1 2 3 4

8. Global severity of abnormal movements

0 1 2 3 4

9. Incapacity from abnormal movements

0 1 2 3 4

10. Patient’s awareness of abnormal movements

0 1 2 3 4

0 = NONE; 1 = AWARE, NO DISTRESS; 2 = AWARE, MILD DISTRESS; 3 = AWARE, MODERATE DISTRESS; 4 = AWARE, SEVERE DISTRESS 11. Current problem with teeth or dentures? Source. Adapted from Guy 1976.

No 0

Yes 1

APPENDIX

L

Resources

National Agencies Administration on Aging, U.S. Department of Health and Human Services 330 Independence Avenue, SW Washington, DC 20201 1-800-677-1116 Web site: http://www.aoa.dhhs.gov The Administration on Aging (AOA) supports a nationwide network providing services to the elderly, especially to enable them to remain independent. AOA supports some 240 million meals for the elderly each year, including home-delivered “meals on wheels,” helps provide transportation and at-home services, supports ombudsman services for the elderly, and provides policy leadership on aging issues.

Alzheimer’s Association (National Office) 919 North Michigan Avenue, Suite 1100 Chicago IL 60611-1676 1-800-272-3900 or 1-313-335-8700; fax: 1-312-335-1110 Web site: http://www.alz.org E-mail: [email protected] A privately funded national voluntary organization with chapters nationwide. The national office can be contacted for information on many issues regarding Alzheimer’s disease, as well as referral to the nearest local chapter.

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Alzheimer’s Disease Education and Referral (ADEAR) Center P.O. Box 8250 Silver Spring, MD 20907-8250 1-800-438-4380 Web site: http://www.alzheimers.org This agency is contracted through the National Institute on Aging. ADEAR maintains an on-line database and functions as a clearinghouse for publications and information on Alzheimer’s disease. It has publications from the federally funded Alzheimer’s Disease Centers and other sources.

American Association of Retired Persons (AARP) Programs Resources Dept./BS 601 E Street, NW Washington, DC 20049 1-800-424-3410 Web site: http://www.aarp.org AARP distributes resource kits consisting of several publications about aging and caregiving.

Brain Injury Association of America 105 North Alfred Street Alexandria, VA 22314 703-236-6000; fax: 703-236-6001 Web site: http://www.biausa.org/ An advocacy organization whose mission is to improve the quality of life for persons with head injures and their families, and to develop programs to prevent head injuries. To fulfill its mission, the BIAA focuses its efforts on education, support and information, public awareness, prevention, research, and training.

National Association of Professional Geriatric Care Managers 1604 N. County Club Road Tucson, AZ 85716-3102 1-520-881-8008 Web site: http://www.caremanager.org Private case managers are certified to provide an array of assessment and social services ranging from obtaining in-home health help to linking with financial, legal, and other long-term care services.

Resources

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The National Council on the Aging, Inc. 409 3rd Street SW, Suite 200 Washington, DC 20024 1-202-479-1200 Web site: http://www.ncoa.org A private, nonprofit organization that serves as a resource for information, training, technical assistance, advocacy, and leadership in all aspects of aging.

National Health Information Center P.O. Box 133 Washington, DC 20013-1133 1-800-336-4797 Web site: http://www.health.gov/nhic Healthfinder series provides a starting point for consumers and health professionals looking for information on home health care. Currently available books and additional organizations that can provide further information are cited. Financial issues and how to find home health care providers are discussed.

National Stroke Association (NSA) 9707 E. Easter Lane Englewood, CO 80112 1-800-787-6537 or 1-303-649-9299; fax: 1-303-649-1328 Web site: http://www.stroke.org A nonprofit organization whose mission is to reduce the incidence and impact of stroke on individuals and on society. It supports stroke research in all areas, develops and distributes educational materials, and is an information and referral clearinghouse.

Huntington’s Disease Society of America (HDSA) 158 W. 29th Street, 7th Floor New York, NY 10001-5300 1-800-345-4372; fax: 1-212-239-3430 Web site: http://www.hdsa.org A national voluntary organization providing support and services to patients and families. HDSA also supports research and education and disseminates information. There is also a network of local chapters across the United States.

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National Organization for Rare Disorders (NORD) 55 Kenosia Avenue P.O. Box 1968 Danbury, CT 06813-1968 1-800-999-6673 or 1-203-744-0100 Web site: http://www.rarediseases.org A federation of voluntary health organizations dedicated to helping people with rare “orphan” diseases. NORD is a clearinghouse for information and is committed to the identification, treatment, and cure of rare disorders through programs of education, advocacy, research, and service.

National Parkinson Foundation (NPF) Bob Hope Parkinson Research Center 1501 NW 9th Avenue Miami, FL 33136-1494 1-800-327-4545 or 1-305-547-6666 Web site: http://www.parkinson.org Provides educational services and information in the form of support groups, publications, and workshops. NPF also supports Parkinson’s disease research.

The American Parkinson Disease Association, Inc. (APDA) 1250 Hylan Blvd., Suite 4B Staten Island, NY 10305-1946 1-800-223-2732 or 1-718-981-8001 Web site: http://www.apdaparkinson.com/ APDA supports research and produces educational materials including a newsletter and various pamphlets covering issues such as nutrition in Parkinson’s disease and mobility aids.

State Agencies State Department on Aging (See state governmental listing in local telephone directories) These agencies in each state funnel federal dollars to local area agencies on aging for disbursement to community agency services and programs for elders. Some programs may be dementia specific. This agency is a good entry point for information and referral for aging services.

Resources

545

State Department of Human Services Provide linkage to state-administered and subsidized programs, including community care and adult day care, elder abuse and neglect programs, and nursing home and other residential care programs under Title XX. Web site: http://www.dhs.state.[2 letter state code].us

State Alzheimer’s Programs Several states have Alzheimer’s programs within their state Department of Human Services that provide a variety of services, including information and referral. These states include California, Connecticut, Delaware, Florida, Kansas, Massachusetts, Missouri, New Hampshire, New Jersey, New York, North Carolina, Pennsylvania, Texas, and Wisconsin.

Nursing Home Ombudsman Programs Information available regarding quality of care in nursing homes, lists of nursing homes, checklists, etc. Contact the nearest Area Agency on Aging for information on the ombudsman program in your area.

Other Sources of Information Alzheimer’s Forum Web site: http://www.alzforum.org A compendium of information for researchers, physicians, and the general public, the site includes news, articles, discussion forums, interviews, diagnostic and treatment guide, directory of drugs and clinical trials, and research advances. It also provides access to such unique tools as directory of genetic mutations, antibodies, patents, and conferences.

Caregiver’s Handbook Web site: http://www.biostat.wustl.edu/ALZHEIMER/care.html Although this handbook is not specific to Alzheimer’s disease, it is easily applicable to Alzheimer’s disease, provides good coverage on care for the caregiver, and is copyright free, making it an excellent training tool.

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Planning for Long-Term Care Web site: http://www.alzheimers.org/pubs/longterm.html This Web site from the National Institute on Aging explores the options for long-term care, with articles on planning ahead, making the right choice, and making a smooth transition.

Clinical Trials.gov Web site: http://www.clinicaltrials.gov Persons with Alzheimer’s disease, family members, and members of the public can find current trials and research. The searchable database provides information on the name of the study, the purpose, eligibility, and contact information. In addition, the site indicates whether the study is recruiting and includes citations from published works.

Index Page numbers printed in boldface type refer to tables or figures.

Acting out, as defense mechanism, 57, 190 Activities of daily living (ADL) Alzheimer’s disease and, 140 caregivers and, 329 nursing homes and, 382–389 Activity therapy, and management of cognitive impairment, 212 Acute intermittent porphyria, 158–159 Adenbrooke’s Cognitive Examination (ACE), 145–146 Adenosine triphosphate (ATP), and neuroimaging, 113 Administration on Aging (AOA), 541 Adrenoleukodystrophy, 167 Adult polyglucosan body disease, 167 Adult Protective Services, 337 Advance directives, and end-of-life issues, 366 Age and aging cognitive changes and normal process of, 1, 10–11, 286–287 concept of aging in place, 410–411 elderly as growing segment of society, 285 onset of Alzheimer’s disease and, 438 psychotropic drugs and considerations related to, 221 Age-associated memory impairment (AAMI), 11–13 Agency for Healthcare Research and Quality, 381, 391 Agent-based ethics, 346 Aggression. See also Behavior; Violent behavior Alzheimer’s disease and, 141 lithium and, 249

ABC approach, to management of cognitive impairment , 200–201, 203, 211 Abdominal examination, 86 Abnormal Involuntary Movement Scale (AIMS), 244, 539–540 Abstract attitude, and Alzheimer’s disease, 12 Abstract thought, and mental status examination, 35–36 Abulia, 70–71 Acceptance, and management of cognitive impairment, 192 Accessibility, and living environment, 414 Access to care, and community resources, 376 Accusations, and cognitive impairment, 189–190, 206. See also Suspiciousness Acetazolamide, 267 Acetylcholine, and Alzheimer’s disease, 260 Acetylcholinesterase inhibitors, and Alzheimer’s disease, 454–455 Acetyl-L-carnitine, 260 Acquired hepatocerebral degeneration, 154 Acquired imbecility, 13 Acquired immunodeficiency syndrome (AIDS). See also Human immunodeficiency virus (HIV) cognitive dysfunction and, 2 family of patients with, 324, 333 psychotropic drugs for delirium and, 235 reversible dementia and, 159

547

548


Aggression (continued) management of, 188, 190 nursing homes and, 396–397 Agitated Behavior in Dementia (ABID) Scale, 42, 525–527 Agitation. See also Behavior management of, 204 nursing homes and, 396–397 psychological and behavioral concomitants of dementing illness and, 65–66 psychotropic drugs and, 238–252 Agnosias, 141 Alcoholism and alcohol abuse cognitive dysfunction and, 2 patient history of, 308–309 reversible dementia and, 154–155, 160 Alcohol-related dementia, 5–6, 308–309 Alertness. See Hyperalertness Alprazolam, 237, 239–240 Altruism, and coping, 54, 189 Aluminum, and Alzheimer’s disease, 463 Alzheimer, Alois, 138, 145, 181 Alzheimer’s Association, 335, 541 Alzheimer’s disease (AD). See also Caregivers; Community resources; Dementia of the Alzheimer’s type; Management; Nursing homes; Safety; Treatment advances in research on, 433–447 advances in treatment of, 453–471 apathy and, 71 awareness of deficits in, 56 behavioral symptoms of, 141, 181 case examples of, 56, 57, 58–59, 220 as cause of death, 2, 141 Charles Bonnet syndrome and, 70 cognitive patterns of, 304–305 depression and, 27–28, 29, 59, 60, 141, 211, 311 Down syndrome and, 27

differential diagnosis of, 137–142, 306, 311 driving and, 208 electroencephalography and, 94 genetic testing and, 349 Lewy body variant of, 143 medications for, 259–267, 362 mild cognitive impairment and development of, 12 neuroimaging and, 103, 110–111, 114, 115, 122, 124 Parkinson’s disease and, 148–149 prevalence of, 1 progression of, 49 sleep and, 66 sundowning and, 20, 140 support groups for, 210–211 tests for incipient, 12 Alzheimer’s Disease Assessment Scale (ADAS-Cog), 40, 41, 259, 262, 264, 458, 503–512 Alzheimer’s Disease Education and Referral (ADEAR) Center, 542 Alzheimer’s Disease: A Handbook for Caregivers (Hamdy et al. 1998), 321 Alzheimer’s Early Stages: First Steps in Caring and Treatment (Kuhn and Bennett 1999), 321 Alzheimer’s Forum, 545 Amantadine, 242 American Academy of Neurology, 89, 92, 96, 104, 353 American Association of Retired Persons (AARP), 416, 542 American Geriatrics Society, 353 American Parkinson Disease Association, Inc. (APDA), 544 American Psychiatric Association, 3 Amitriptyline, 220, 229 Amnesia and amnestic disorders Alzheimer’s disease and, 304 clinical diagnosis of, 20 DSM-IV-TR classification of, 5 DSM-IV-TR criteria for, 21

Index Amphetamine-related disorders, 6 Amyloid biomarkers, for Alzheimer’s disease, 442–443 Amyloid processing, in Alzheimer’s disease, 434–437, 467–468 Amyotrophic lateral sclerosis (ALS), 147 Anemia, 89, 161 Anger, and stress in caregivers, 334 Angiography, 93 Anomic aphasia, 32 Anoxia, and reversible dementia, 159 Antiandrogens, 257 Anticholinergic agents delirium and, 230 Parkinson’s disease and, 149 Anticholinesterases, and Alzheimer’s disease, 260–264, 265–266 Anticipation, and coping, 54–55 Anticoagulants, and vascular dementia, 151 Anticonvulsants, and agitation, 249–251 Antidepressants. See also Medications; Tricylic antidepressants depression in elderly and, 29, 202 vascular dementia and, 151 Antihistamines, 220, 253 Antioxidants, and Alzheimer’s disease, 267, 462 Antiparkinson drugs, and tardive dyskinesia, 244 Antiplatelet drugs, and cerebrovascular disease, 267–268 Antipsychotics. See also Neuroleptics agitation and, 239, 240–244 depression in elderly and, 223–224 Anxiety. See also Behavior management of cognitive impairment and, 199, 203–204 psychological and behavioral concomitants of dementing illness and, 65 psychotropic drugs and, 236–238

549

Anxiety disorder due to a general medical condition, 22, 24–25 Apathy. See also Behavior; Social withdrawal management of cognitive impairment and, 207–208 psychological or behavioral concomitants of dementing illness, 70–71 psychotropic drugs and, 256 Apathy Evaluation Scale, 71 Aphasias, 31–32, 141 Apolipoprotein E (ApoE), and Alzheimer’s disease, 119–120, 434, 438–439, 441, 443–444, 447, 469 Apraxias, 302,m Aspergillosis, 170 Aspirin, 267–268 Assisted-living settings, 405, 417–421, 426 Atherosclerosis, 269 Attention, and neuropsychological tests, 290, 293–294 A2M polymorphisms, and Alzheimer’s disease, 447 Atypical neuroleptics, 224, 244–247. See also Neuroleptics Australia, and hostels for elderly, 406 Automobiles. See Driving Autonomy. See also Independence environment of older adult and, 408 management of cognitive impairment and, 193–194 personality and, 53 Awareness, and assisted-living settings, 418 Azotemia, 155 >-Adrenergic blockers, and agitation, 251 > -Amyloid. See Amyloid biomarkers; Amyloid processing Babinski reflex, 88 Baclofen, 165

550


Barbiturates reversible dementia and, 154 sleep and, 253 withdrawal from medication and delirium, 235 Barrier interventions, and wandering, 397 Bathing, and nursing care, 384 Beck Depression Inventory (BDI), 303 Behavior. See also Agression; Agitation; Anxiety; Apathy; Irritability; Violent behavior ABC approach to management of, 200–201 Alzheimer’s disease and, 141, 181 control as ethical issue, 346, 365 executive functions and dyscontrol of, 65 explanation of dementia to family and, 322–324 measures of symptoms of dementing illness, 41–42 medical evaluation and, 83–84 nursing homes and, 395–399 psychotropic drugs and, 220, 258–269 Behavioral Pathology in Alzheimer’s Disease (BEHAVE-AD), 245 Beliefs, cognitive impairment and mistaken, 189–190 Benzodiazepines agitation and, 240 anxiety and, 236, 237 delirium and, 235–236 falls and, 390 reversible dementia and, 154 sleep-wake disturbance and, 253–254 tardive dyskinesia and, 244 Benztropine, 235, 242 Best interests of patient, and legal issues, 338 Binswanger’s disease, 149 Bioethics, 346

Biological integrity, and coping ability, 52 Biological vulnerability, to depression, 61 Bipolar disorder, and reversible dementia, 153 Blessed Dementia Rating Scale (BDRS), 14, 40, 140, 499 Blood oxygenation level dependent (BOLD) fMRI, 125, 126 Blood tests, and laboratory studies, 89–91. See also Cerebral blood flow Blood viscosity reducers, and cerebrovascular disease, 267–268 Body mass index (BMI), 385 Boston Naming Test, 300 Brain. See also Brain damage; Brain disorders atrophy and Alzheimer’s disease, 142 biopsy of, 93 maps of and neuroimaging, 117–119 volume of and neuroimaging, 111 Brain damage. See also Head injury depression and subclinical, 61 reversible dementia and traumatic, 163–164 Brain disorders, and reversible dementia, 162–164 Brain Injury Association of America, 542 Brief Psychiatric Rating Scale, 247, 249 Bright light therapy, 394, 397, 426. See also Lighting; Phototherapy Broca’s aphasia, 32 Bromocriptine, 165, 242 Bupropion, 228–229, 231, 232 Buschke Selective Reminding Test, 296 Buspirone, 238, 390 Butyrylcholinesterase, 456–457

Index Caffeine, and insomnia, 67 Caffeine-related disorders, 6 Calcium, reversible dementia and blood levels of, 157–158 California, and legal issues, 361, 420 California Verbal Learning Test (CVLT), 296, 297, 298 Cambridge Examination for Mental Disorders of the Elderly, 1 Campbell v. Groves (1989), 343 Canada Cree tribe and Alzheimer’s disease, 443 guidelines for medical evaluations and, 96 special care units in, 423 Candidiasis, 170 Cannabis-related disorders, 6 Capacity to Consent to Treatment Instrument (CCTI), 354–359 Capgras’ syndrome, 59, 69 Carbamazepine, 249 Cardiovascular disease, and vascular dementia, 151 Cardiovascular examination, 86 Caregivers. See also Family; Nursing homes behavior control and continuity of, 365 communication and, 186, 382 community resources and, 376 digital technology and, 417 education for, 321–327 ethical issues for, 337–338 impact of dementia on, 330–333 insomnia and, 67 living environment and, 414 management of cognitive impairment and, 187, 189–201, 203–204 neuropsychological evaluation and interviews, 289 nursing homes and, 336–337 psychological point of view, 327–329

551

reports of deterioration in cognitive function, 373 sexuality and, 335–336 stress and, 334–335, 373–374 surrogates and relief for, 201 views of difficult patients, 50–51 Caregiver’s Handbook, 545 Carotid and transcranial sonography, 93–94 Case examples of ABC approach to behavior management, 201 of assisted living settings, 417–418 of caregiving environment, 411 of cognitive impairment, 50–51 of competency as legal issue, 342–343 of defense mechanisms in Alzheimer’s disease, 56, 57, 58–59 of delirium, 64 of depression, 62 of explanation of dementia to family, 322–324 of frontotemporal dementia, 37 of informed consent, 351 of medical evaluation, 80, 97 of nursing home as living environment, 421–422 of personality change due to a general medical condition, 25–26 of proxy decision makers, 364 of psychotic defense mechanisms, 57–58 of psychotic disorder due to a general medical condition, 21, 23 of psychotropic drugs and Alzheimer’s disease, 220 of subcortical dementia, 38–39 of temporoparietal dementia, 38 Catastrophic reactions, and defense mechanisms, 56–57 Catatonic disorder due to a general medical condition, 22–23

552


Category Test, 295 Central nervous system disorders, and reversible dementia, 152 Cerebral blood flow, and neuroimaging, 113, 125 Cerebrolysin (FPF-1070), 460–461 Cerebrospinal fluid (CSF) Alzheimer’s disease and, 91 computed tomography and, 105 Cerebrovascular disease drugs for prevention and treatment of, 267–269 vascular dementia and, 149–150 Ceroid lipofuscinosis, 167 Certified nursing assistants (CNAs), 384–385, 386, 399 Charles Bonnet syndrome, 70 Chelating agents, 463–464 Chemical poisoning, and reversible dementia, 155 Childhood abuse, and adult depression, 60–61 Children, dementia and adult, 332–333. See also Family Chlordiazepoxide, 237 Chlorpromazine, 225 Chlorpropamide, 156 Choices, reduction of, 197 Cholesterol, and Alzheimer’s disease, 447, 469–470 Cholinergic hypothesis, of Alzheimer’s disease, 453–459. See also Cholinergic system Cholinergic-monoaminergic combinations, and Alzheimer’s disease, 460–464 Cholinergic system, drugs affecting, 259–264. See also Cholinergic hypothesis Cholinesterase inhibitors Alzheimer’s disease and, 142, 453–459 hallucinations and, 255 Parkinson’s disease and, 149 Chromosome 21, and Alzheimer’s disease, 436

Chromosome 17, and familial FTD, 147 Chronic obstructive pulmonary disease (COPD), 159, 254 Cisapride, 391 Cisternogram, 92–93 Citalopram, 222–223, 227, 231, 232, 252 Clinical care, and informed consent, 350–351 Clinical Dementia Rating (CDR) Scale, 40, 208, 260 Clinical Global Impression of Change, 250, 251, 259, 266 Clinical Practice Guideline on Urinary Incontinence in Adults: Acute and Chronic Management (Agency for Healthcare Quality and Research), 391 Clinical Trials.gov, 546 Clock drawing test, 298 Clomipramine, 223 Clonazepam, 239, 254 Clonidine, 460 Clopidogrel, 268 Clozapine agitation and, 244 dosage of, 225 hallucinations and, 255–256 side effects of, 225, 247 Cocaine-related disorders, 7 Coccidioidomycosis, 170 Cochrane Database of Systematic Reviews, 381 Code of Federal Regulations (CFR), 351–352 Cognitive-behavioral therapy, for Alzheimer’s disease, 211 Cognitive disorders. See also Cognitive functioning; Cognitive impairment clinical diagnosis of, 32–36 cognitive disorder not otherwise specified and, 26 DSM-IV-TR classification of, 5

Index Cognitive functioning. See also Cognitive disorders; Cognitive impairment; Executive functions; Neuropsychological evaluation characterization of, 286 families of dementia patients and, 323–324 measures of, 40–41 model of, 50 patterns of various types of dementia, 304–313 Cognitive impairment. See also Cognitive disorders; Cognitive functioning; Executive functions; Memory case example of, 50–51 causes of in youth or early adulthood, 2 depression and, 28 medical evaluation of, 78, 79 medical illness and management of, 212–214 mild forms of, 11–13 normal aging process and, 1, 10–11, 286–287 personal environment and, 408–411 severity of as issue in management, 183–186 sleep-wake disturbances and, 66 Cohen-Mansfield Agitation Inventory (CMAI), 66, 241, 250, 396 Color schemes, and dementia care environments, 422–423 Communication. See also Language cognitive impairment and, 183, 194 neurolinguistic analysis of discourse and, 300–301 nursing homes and, 381–382 Community resources access to care and, 376 for caregivers, 334, 335 factors influencing utilization of, 374–376 informed decisions and, 376–378

553

recognition of need for help, 371–374, 372–373 services needed by patients and families, 372 Comorbidity, of depression and Alzheimer’s disease, 27–28, 29, 59, 60, 141, 211, 311 Compensatory mechanisms, and coping, 55 Competency. See also Decision making; Judgment housing and, 407 as legal issue, 341–345, 355, 356–357 Competitive inhibition, and cholinesterase inhibitors, 457 Complete Guide to Alzheimer’s Proofing Your Home, The (Warner 2000), 415 Compliance, and post-hospital medical treatment, 213–214 Comprehension, and mental status examination, 35 Computed tomography (CT), 104–106, 107, 142, 151, 165 Concentration, and neuropsychological tests, 293–294 Concrete operations, and cognitive maturation, 185 Concussive brain injury, 164 Confabulation, and memory impairment, 68–69 Conflict, and living environment, 414 Conflict-based ethics, 346 Congenital imbecility, 13 Congruence model, of personal environment, 407 Consent capacity, assessment of, 355–357 Conservation withdrawal, and depression, 61 Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), 266, 293

554


Continuity model, of person and environment, 407–408 Continuum, of levels of care, 410–411 Contract, and capacity as legal issue, 344 Controlled Word Association Test, 307 Control, and living environments, 407, 419 Conversation, and walking programs, 389 Coping humor and, 55, 189 management of dementia and, 188–189 personality function in dementia and, 52, 54–55 Copper chelating agents and Alzheimer’s disease, 464 Wilson’s disease and metabolism of, 90, 158 Corpus callosum, and Alzheimer’s disease, 110–111 Corsellis, J., 138 Cortical dementia, 36, 296, 307–308 Corticobasal degeneration (CBD), 147–148 Corticotropin-releasing hormone, 460 Cortisol concentration, and reversible dementia, 158 Cotard’s syndrome, 69 Cranial nerves, and neurological examination, 86–87 Creutzfeldt-Jakob disease brain biopsy and, 93 eletroencephalography and, 95 laboratory studies and diagnosis of, 91 neurological symptoms of, 165–166 progression of to dementia, 49 Cruzan v. Director, Missouri Dept. of Health (1990), 338 Cryptococcosis, 169–170 Culture, and end-of-life decisions, 366 Cushing’s syndrome, 158

Cyanocobalamin, 161–162 Cyclin-dependent kinase 5 (Cdk5), 442 Cycloergometer, 388 Cycloserine, 461 Dantrolene, 242 Day-care programs, 195 Death. See also Suicide Alzheimer’s disease as cause of, 2, 141 end-of-life decisions and ethical or legal issues, 338, 346–347, 364, 365–367 Decision making. See also Competency; Judgment assessment of capacity for, 354–359, 362 management of cognitive impairment and, 189 proxy decision makers and, 363–364 Defense mechanisms, and personality, 54, 56–59. See also Denial; Projection Delayed recall, 297 Delirium clinical diagnosis of, 16–20 coexistence of with dementia, 19 DSM-IV-TR and, 4, 19 hospitalization for medical illness and, 213 management of, 202–203 psychological and behavioral concomitants of dementing illness and, 63–64 psychotropic drugs and, 234–236 Delirium tremens, 235–236 Delis-Kaplan Executive Function Test, 295 Delusional projection, 57, 328 Delusions Alzheimer’s disease and, 141 as defense mechanisms, 58 management of cognitive impairment and, 205–206 nursing homes and, 398–399

Index psychological and behavioral concomitants of dementing illness and, 68, 69 psychotropic drugs and, 254–255 Dementia and dementing illness. See also Alzheimer’s disease; Behavior; Caregivers; Case examples; Cognitive impairment; Community resources; Management; Medical evaluation; Psychotropic drugs; Nursing homes; Safety; Treatment characterization of, 36–39 clinical diagnosis of, 13–16 cognitive patterns of various types, 304–313 delirium and coexistence of, 19 depression-related cognitive impairment and, 28 differential diagnosis of, 137–171 DSM-IV-TR classification of, 4 DSM-IV-TR diagnostic criteria for, 15–16, 17–18 ethical issues and, 346–367 family and, 322, 330–333 individual differences in, 14, 49 legal issues and, 341–345 neuroimaging and, 103–131 neuropsychological testing and, 290 Parkinson’s disease and, 149 personality function in, 51–59 prevalence of, 1–2 psychological and behavioral management of, 181–214 as psychological process, 53–71 qualifying aspects of, 39–43 Dementia with Lewy bodies (LBV) cognitive patterns of, 306 differential diagnosis of, 142–144, 306 Dementia Questionnaire, 483–485 Dementia Rating Scale, 292, 299 Demonstrations, and management of cognitive impairment, 196

555

Denial Alzheimer’s disease and, 141 caregivers and, 327–329 as defense mechanism, 56 Dependence, and management of cognitive impairment, 193 Deprenyl, 459–460 Depression Alzheimer’s disease and, 27–28, 29, 59, 60, 141, 211, 311 apathy and, 71 behavioral interventions for, 211 in caregivers, 334, 373–374 clinical diagnosis of, 27–31 cognitive patterns of, 310–311 DSM-IV-TR criteria for, 29, 30 family of dementia patient and, 323 insomnia and, 67 management of, 202 medical conditions as cause of, 23 neuropsychological evaluation and, 303, 310–311 psychological and behavioral concomitants of, 59–62 psychotropic drugs and, 222–234 reversible dementia and, 153 stroke and, 28, 59, 163 suicidal ideation and, 62 vascular dementia and, 151 Desipramine, 229, 231, 232 Developmental disorders, and differential diagnosis of dementia, 27 Developmental history, and neuropsychological evaluation, 288 Dexamethasone suppression test, 29, 31 Dextroamphetamine, 234, 256–257 Diagnosis. See also Differential diagnosis; Medical evaluation; Mental status examination; Neuropsychological evaluation advantage of threshold diagnoses, 3 of Alzheimer’s disease, 104, 138, 140

556


Diagnosis (continued) of amnestic disorder, 20 of anxiety disorder due to a general medical condition, 24–25 of cognitive disorder not otherwise specified, 26 of cognitive dysfunction, 32–36 of delirium, 16–20 of dementia, 13–16, 36–43 of depression, 27–31 DSM-IV-TR and classification of mental disorders, 3–10 of language disorders, 31–32 legal issues and, 344–345 of mental retardation, 26–27 of mood disorder due to a general medical condition, 23 neuroimaging and, 114 of personality change due to a general medical condition, 25–26 persons at risk for dementing illness and, 348–350 of psychotic disorder due to a general medical condition, 20, 23 of substance-induced mood disorder, 24 Diazepam, 237 Dicyano-dimethylamino-naphthalenpropene (DDNP), 122 Diet. See also Eating behavior; Nutritional status; Vitamin deficiencies monoamine oxidase inhibitors and, 233 vitamin C and E supplements and Alzheimer’s disease, 462–463 Differential diagnosis of Alzheimer’s disease, 137–142, 306, 311 of corticobasal degeneration, 147–148 of dementia with Lewy bodies, 142–144

of frontotemporal dementia, 144–147 of mixed dementia, 151 of progressive supranuclear palsy, 148 of Parkinson’s disease, 148–149 of reversible dementias, 151–170 of vascular dementia, 149–151 Digital technology, and living environments, 416–417, 426 Dilemma-based ethics, 346 Diphenhydramine, 220, 235, 242 Dipyridamole, 268 Disinhibition, and family of dementia patient, 323 Displacement, and Alzheimer’s disease, 56 Disruptive vocalizations, and nursing homes, 398 Dissociative disorder not otherwise specified, 31 Distortion, as defense mechanism, 57 Distraction, and management of cognitive impairment, 200 Distress, and dementia, 25 Diuretics, and reversible dementia, 156 Divalproex, 240, 249–250 Donepezil, 261–262, 265–266, 454 Dosage, of psychotropic drugs. See also specific drugs of antipsychotics, 241 of beta-adrenergic blockers, 251 of benzodiazepines, 237 neuroleptics and, 225, 235 of tricyclic antidepressants, 230–233 Down syndrome, 27, 127–130, 436 Doxepin, 229 Drawings, and neuropsychological tests, 298–299 Dressing, and management of cognitive impairment, 189, 194, 384–385, 421 Driving, of automobiles caregivers and, 328 ethical and legal issues in, 361–362 management of cognitive impairment and, 208

Index Drug-drug interactions, and monoamine oxidase inhibitors, 233 DSM-IV-TR Alzheimer’s disease and, 138, 140 amnestic disorder and, 20, 21 classification of mental disorders in, 3–10 dementia and, 14, 15–16, 17–18 delirium and, 19 depression and, 29, 30 memory loss and, 287 mental disorders due to a general medical condition and, 22–23 personality disorders and, 52 psychotic disorder and, 20, 22 substance-induced mood disorder and, 24 Durable powers of attorney, 345 Duration, of Alzheimer’s disease, 141 Dysnomia, 300 Dysphoria, 25 Dystonia, and antipsychotic drugs, 243, 247–248 Eating behavior, and management of cognitive impairment, 197, 385–386. See also Diet Education. See also Learning for caregivers and family, 321–327 for nursing home staffs, 399 Electroconvulsive therapy (ECT), 224, 226–227 Electroencephalography (EEG) Creutzfeldt-Jakob disease and, 166 delirium and, 18 medical evaluation and, 94–95 Emotions measures of symptoms of dementing illness, 41–42 neuropsychological evaluation and, 303 Encephalitis, and reversible dementia, 170

557

End of life, and ethical issues, 338, 346–347, 364, 365–367. See also Death Endocrine disorders, and anxiety, 24–25 Environment assisted living settings and, 417–421 digital technology and, 416–417, 426 ethical issues in long term care and, 359–363 incontinence and, 392 management of cognitive impairment and constancy or predictability of, 195 medical evaluation and stress from, 83 nursing homes and, 421–426 private residences and, 411–416 theories of effects on cognitively impaired, 408–411 theories of effects on older adults, 406–408 Epilepsy, and electroencephalography, 95. See also Seizures Episodic memory, 296 Esquirol, J. E. D., 13 Estate plan, and legal issues, 345 Estrogen therapy Alzheimer’s disease and, 465–466 hypersexuality and, 257 Ethical issues assessment of decision-making capacity and, 354–359 at-risk situations and, 347–350 behavior control and, 365 for caregivers, 337–338 end-of-life care and, 365–367 informed consent and, 346, 350–354 long-term-care environment and, 359–363 models of, 346–347 proxy decision makers and, 363–364 Ethics committees, 366

558


Etiologies, of reversible dementia, 152 European Community, and living environments for cognitively impaired, 415–416 Evaluation. See Medical evaluation; Neuropsychological evaluation Excitatory amino acid (EAA)-mediated toxicity, 461, 462 Executive functions. See also Cognitive functioning; Cognitive impairment Alzheimer’s disease and, 140 behavioral dyscontrol and, 65 neuropsychological tests and, 290, 294–295, 307 stimuli and context of, 183 Exercise, and nursing homes, 387–389, 392, 397 Expressive language, 299–300 Extrapyramidal symptoms, and parkinsonism, 87 Eye diseases, 395 Facial muscles, and neurological examination, 86–87 Failure-Free Activities for the Alzheimer’s Patient (Sheridan 1987), 198 Falls. See also Safety living environment and, 412 in nursing homes, 389–391 Familial fatal insomnia, 166 Familial Mediterranean fever, 467 Familial multiple system tauopathy, 147 Family. See also Caregivers; Children; Family history; Grandparents and grandchildren; Parents end-of-life issues and, 366 explanation of dementia to, 322 genetic testing and, 349–350 impact of dementia on, 330–333 living settings and, 405 neuropsychological evaluation and, 289, 312

Family history. See also Genetics medical evaluation and, 84 neuropsychological evaluation and, 288–289 Fantasy, as defense mechanism, 57 Fatigue, and stress in caregivers, 334 Fear, and hallucinations, 207 Fecal incontinence, 393 Feeding. See Eating behavior; Tube feedings Fever, and reversible dementias, 152 Financial issues, and family, 326–327 Finger tapping tests, 301 Floor effect, of psychotropic drugs, 239 Floor plans, for living environments, 414, 415 Fluctuations, in cognitive dysfunction, 82–83 Fluoxetine, 226, 231, 232 Fluphenazine decanoate, 242 Flurazepam, 154, 253–254 Folic acid, 162 Folsom, C. F., 137 Food and Drug Administration, 258, 455 Formal operations, and cognitive maturation, 185 Free radicals, and Alzheimer’s disease, 462 Free recall, 311. See also Recall Freud, Anna, 52 Frontal Assessment Battery, 145, 146 Frontal Behavioral Inventory, 145 Frontotemporal dementia (FTD) aphasias and, 32 case example of, 37 characterization of, 36 cognitive patterns of, 306–307, 308 differential diagnosis of, 144–147 neuroimaging and, 114, 116–117 Frontotemporal lobar degeneration, 144, 145 Functional Fitness for Long-Term Care (FFLTC), 389

Index Functionality, and environment of older adult, 408 Functional magnetic resonance imaging (fMRI), 124–126 Functional neuroimaging, 112–130 Fund of information, and mental status examination, 35 Funduscopic examination, 86 Gabapentin, 250–251 Gadolinium-enhanced MRI, 108–110 Gait, and neurological examination, 88 Galantamine, 261, 263–264, 455, 457–458 Ganser syndrome, 31, 83 Gender of caregiver, 373–374 feeding and nursing home patients, 385 Generalized anxiety disorder, 65 Genetics. See also Family history Alzheimer’s disease and, 138, 433–447 genetic testing for dementing illness, 348–349 Huntington’s disease and, 164–165 medical evaluation and markers, 92 metabolic diseases and, 167 Pick’s disease and, 147 risk to family of dementia patients, 325 Geriatric Depression Scale, 303 Gerstmann-Straussler-Scheinker disease, 166 Ginkgo biloba, 259, 463 Global aphasia, 32 Global function, measures of, 40, 290, 291–293 Global Positioning System (GPS), 417 Glutamatergic drugs, and Alzheimer’s disease, 461–462 Glycine, 461 Gottfries-Brane-Steen dementia rating scale, 223, 227

559

Grandchildren and grandparents, 333. See also Family Guanfacine, 460 Guardianship, as legal issue, 343, 344, 345 Guidelines. See also Standards for human-subjects research and informed consent, 352, 353–354 medical evaluations and, 96 for nursing homes and behavior control, 365 psychotropic drugs and, 219–222, 248 Guiding, and management of cognitive impairment, 196 Guilt, and depression, 62 Hallervorden-Spatz disease, 167 Hallucinations Alzheimer’s disease and, 141 management of cognitive impairment and, 206–207 medical evaluation and, 83–84 nursing homes and, 398–399 psychological and behavioral concomitants of dementing illness and, 69–70 psychotropic drugs and, 255–256 Hallucinogen-related disorders, 7 Haloperidol agitation and, 239–240, 241, 245 delirium and, 236 dosage of, 225, 235 psychotic depression and, 224 side effects of, 225 Hamilton Rating Scale for Depression, 222, 223 Hand dynamometer, 301 Head injury. See also Brain damage apathy and, 71 cognitive dysfunction and, 2 Health care. See Clinical care; End of life; Hospitalization; Medical care; Medications; Terminal care

560


Health Care Financing Administration, 248, 365 Hearing and auditory acuity management of cognitive impairment and, 191–192 neurological examination and, 86 neuropsychological evaluation and, 302 nursing homes and, 395 Heidenhain’s variant, of CreutzfeldtJakob disease, 166 Hepatic encephalopathy, 156–157 Herbal medicines, 85 Hereditary metabolic diseases, 167 Herpes simplex virus (HSV) encephalitis, 170 Heterocyclic antidepressants, 228–229 Highly active antiretroviral therapy (HAART), 85 Hip fracture, and delirium, 16, 18 Hippocampus, and Alzheimer’s disease, 110 Histoplasmosis, 170 Histrionic personality disorder, 52 HIV-1-associated cognitive/motor complex, 168 HIV-1-associated dementia (HAD), 168–169 Home, as living setting, 405, 411–417 Homocysteine metabolism, 90 Hopkins Verbal Learning Test (HVLT), 296 Hormones. See Endocrine disorders; Estrogen therapy Hospice care, 365–366 Hospitalization for injuries from falls, 391 involuntary as legal issue, 344 management of cognitive impairment and medical illness, 213 as setting for medical evaluation, 80 Housing. See Environment; Living settings; Nursing homes

Human immunodeficiency virus (HIV). See also Acquired immunodeficiency syndrome (AIDS) apathy and, 71 medical evaluation and, 84, 85 reversible dementia and, 168–169 Human immunodeficiency virus type 1 (HIV-1)-associated dementia, 168–169, 256 Human-subject research, and informed consent, 351–354 Humor, and coping, 55, 189 Huntington’s disease electroencephalography and, 94 genetic testing for, 92, 349 reversible dementia and, 164–165 suicide and, 62–63 Huntington’s Disease Society of America (HDSA), 543 Huperzine A, 456 Hydroxycholoroquine, 467 Hyperalertness, 68 Hypercalcemia, 157 Hypercholesterolemia, 90 Hypercortisolemia, 158 Hyperglycemia, 156 Hyperhomocysteinemia, 90, 269 Hyperparathyroidism, 157–158 Hypersexuality, 257, 335. See also Sexuality Hypersomnia, 67 Hyperthyroidism, 157 Hypoglycemia, 156 Hypolipidemic agents, and cerebrovascular disease, 269 Hyponatremia, 156 Hypothyroidism, 157 Ibuprofen, 445–446 Idebenone, 462 Illusions, and cognitive impairment, 69 Imbecility, categories of, 13 Imipramine, 222, 229 Immature defense mechanisms, 57

Index Immunization therapy, for Alzheimer’s disease, 447, 468–469 Impaired attention, and delirium, 18 Impaired decision-making capacity (IDMC), 352–354 Incontinence, and nursing homes, 332, 391–393 Independence, and living environment, 360–361, 408, 414. See also Autonomy Individual differences, in dementing illness, 14, 49 Infections. See also Acquired immunodeficiency syndrome (AIDS); Creutzfeldt-Jakob disease; Human immunodeficiency virus (HIV) delirium and, 159 reversible dementias and, 152, 165–167, 169–170 Informal support systems, 374 Informed consent, 346, 350–354 Informed decisions, and community resources, 376–378 Inhalant-related disorders, 7–8 Inhalants, and reversible dementia, 155 In re Colyer (1983), 338 In re Conroy (1985), 338, 366 In re Dinnerstein (1978), 366 Insanity defense, 343–344 Insomnia, 67, 253 Intellectual ability, and neuropsychological tests, 290, 291–293 Interictal epileptiform discharges (IEDs), 95 Internet, as source of information, 545–546 Interventions. See also Management for caregiver burden and stress, 334 neuropsychological evaluation and recommendations for, 287–288

561

Interviews caregiver stress and, 334–335 neuropsychological evaluation and, 289 Inventory, of assets and liabilities, 345 I Remember When: Activity Ideas to Help People Reminisce (Thorsheim and Roberts 2000), 198 Irritability, and case example of dementia, 322–323 Joint Commission on Accreditation of Healthcare Organizations, 366 Judgment. See also Competency; Decision making mental status examination and, 35–36 psychotropic drugs and impaired, 257–258 Korsakoff’s syndrome, 20, 160–161 Kraepelin, E., 13, 153 Laboratory studies, and medical evaluation, 89–91 Landmarks, and assisted-living settings, 421 Language. See also Communication; Language disorders Alzheimer’s disease and impairments of, 141 mental status examination and, 35 neuropsychological tests and, 299–301 Language disorders, and clinical diagnosis, 31–32 Learning. See also Education; Overlearned skills management of cognitive impairment and avoidance of new, 199 neuropsychological tests and, 290

562


Legal issues at-risk situations and, 347–350 competency and testamentary capacity as, 341–345 end-of-life issues and, 366–367 for family and caregivers, 326, 338 informed consent and, 350–354 nursing homes and injuries from falls, 389 Leuprolide, 257 Lewy bodies. See Dementia with Lewy bodies Life review, and psychotherapy, 211–212 Life support, artificial maintenance of, 338 Lighting, and nursing homes, 425–426. See also Bright light therapy Limbic encephalitis, 166–167 Lipid profile, and hypercholesterolemia, 90 Lipoprotein receptor-related protein, 440–441 Lithium, and agitation, 249 Liver disease, and reversible dementia, 155, 156–157 Liver function, and psychotropic drugs, 221 Living settings, for patients with cognitive impairment, 405–406. See also Environment Long term care. See also Nursing homes caregivers and placement issues, 336–337 ethical issues and environment of, 359–363 Lorazepam age-related considerations, 221 agitation and, 240 amnestic episodes and, 20 delirium and, 235, 236 dosage of, 237 Loss, and depression, 61–62

Lovastatin, 470 Low-density lipoprotein (LDL) receptor proteins, 441–442 Loxapine, 241 Lumbar puncture, 91, 213 Magnetic resonance imaging (MRI), 106–112, 142, 151, 160, 165, 213 Magnetic resonance spectroscopy (MRS), 127–130 Malingering, and cognitive impairment, 31 Management, psychological and behavioral. See also Interventions; Treatment ABC approach to, 200–201, 203, 211 activity therapies and, 212 agitation and, 204 anxiety and, 203–204 apathy and withdrawal, 207–208 behavior control as ethical issue and, 365 delirium and, 202–203 depression and, 202 general principles of, 190–200 hallucinations and, 206–207 medical illness and, 212–214 memory training and retention, 208–210 physiological factors in, 182–187 psychological factors in, 188–190 psychotherapy and, 210–212 sleep-wake disturbances and, 205 suspiciousness and delusional thinking, 205–206 wandering and, 204–205, 365 Mania, and medical conditions, 23 Marchiafava-Bignami syndrome, 154 Marriage competence as legal issue and, 344 sexuality and elderly, 335–336 spouses as caregivers and, 331–332

Index Maryland, and nursing homes, 406 Mattis Dementia Rating Scale, 29, 85 Mecobalamin, 463 Medicaid, 418 Medical care, and ethical issues, 362–363. See also Clinical care; Compliance; Hospitalization; Medical illness; Medical records; Physicians; Terminal care Medical ethics, 346 Medical evaluation. See also Diagnosis; Neuroimaging; Neuropsychological evaluation angiography and, 93 brain biopsy and, 93 carotid and transcranial sonography, 93–94 of cognitive dysfunction, 78, 79 electroencephalography and, 94–95 frequency of, 96–97 goals of, 77 genetic markers and, 92 laboratory studies and, 89–91 level of workup and, 96 neurological examination and, 86–89 patient history and , 81–85 physical examination and, 86 reevaluation and, 97 setting for, 80 Medical illness. See also Acquired immunodeficiency syndrome (AIDS); Human immunodeficiency virus (HIV); Infections; Medical care management of cognitive impairment and, 212–214 neuropsychological evaluation and patient history of, 288 Medical powers of attorney, 345, 366 Medical records, and patient history, 33. See also Medical care; Medical illness Medicare, 326–327, 365–366

563

Medications. See also Antidepressants; Antipsychotics; Barbiturates; Benzodiazepines; Drug-drug interactions; Neuroleptics; Psychotropic drugs; Tranquilizers Alzheimer’s disease and cognitive enhancers, 362 cerebrovascular disease and, 267–269 delirium and, 64 digital technology and smart pill containers, 417 education of family and, 324 falls in nursing homes and, 390–391 insomnia and, 67 medical evaluation and, 85 medical illness and compliance, 213–214 reversible dementia and, 153–154 symptoms of dementing illness and, 220 Medroxyprogesterone, 257, 336 Memantine, 461 Memory. See also Cognitive impairment age-associated impairment of, 11–13, 286–287 Alzheimer’s disease and, 140 caregivers and, 323 confabulation and, 68–69 depression and, 311 DSM-IV-TR and loss of, 287 management of cognitive impairment and training in, 208–210 neuropsychological tests and, 290, 295–297 normal aging and, 11 prevalence of problems in elderly, 1 Mental disorder not otherwise specified due to a general medical condition, 23 Mental disorders due to a general medical condition, 22–23

564


Mental retardation, and clinical diagnosis, 26–27 Mental status examination cognitive dysfunction and, 34–36 diagnosis of dementia and, 13 malingering and, 31 standardized form for, 487–494 Meprobamate, 154 Metabolic disorders, and reversible dementia, 152, 155–159, 167 Metachromatic leukodystrophy, 167 Methylphenidate, 151, 234, 256 Metoclopramide, 391 Mild cognitive impairment (MCI) Alzheimer’s disease and, 12 cognitive patterns of, 309–310 reversibility of, 14 Mini-Mental State Exam (MMSE), 1, 40–41, 85, 138, 140, 145, 256, 262, 265, 266, 292, 356, 386 Minnesota Multiphasic Personality Inventory-2 (MMPI-2), 303 Minor cognitive/motor disorder (MCMD), 168 Mirtazapine, 229, 231, 232 Mixed dementia, 151 Molecular linkages, and Alzheimer’s disease, 443–444 Molecular therapy, for Alzheimer’s disease, 444–447 Monoamine oxidase inhibitors, 227, 233 Monoaminergic drugs, and Alzheimer’s disease, 459–460 Mood disorder due to a general medical condition, 22, 23 Motion detectors, 416 Motor system. See also Psychomotor abilities Alzheimer’s disease and, 140–141 neurological examination and, 87 neuropsychological testing and, 301–302 Multidimensional Observation Scale for Elderly Subjects, 396

Multiple cueing, and management of cognitive impairment, 195–196 Multiple sclerosis, 209 Muscarinic agonists, 461 Music therapy, 212, 396–397, 425 Mycobacterium avium, 170 Myoclonus, 87 Naming tests, 35 National Adult Reading Test-Revised (NART-R), 292 National agencies, contact information for, 541–544 National Association of Professional Geriatric Care Managers, 542 National Bioethics Advisory Commission (NBAC), 352–353 National Council on the Aging, Inc., 543 National Health Information Center, 543 National Huntington’s Disease Research Roster, 62 National Medical Expenditure Survey, 406 National Organization for Rare Disorders (NORD), 544 National Parkinson Foundation (NPF), 544 National Stroke Association (NSA), 543 Native Americans, and Alzheimer’s disease, 443 Nefazodone, 228 Neprilysin, 436 Nerve growth factor (NGF), and Alzheimer’s disease, 464–465 Neuritic plaques, and Alzheimer’s disease, 139 Neuroacanthosis, 167 Neurobiology, of depression, 61 Neurochemical changes, and neuroimaging, 122 Neurocognitive testing, 289, 290. See also Neuropsychological evaluation

Index Neurodiagnosis, and cognitive assessment, 286–287 Neurofibrillary tangles (NFTs), and Alzheimer’s disease, 139, 441, 468 Neurogenerative diseases, and reversible dementia, 164–165 Neuroimaging. See also Medical evaluation functional types of, 112–130 future directions in, 130–131 HIV patients and, 169 recent advances in, 103 structural types of, 104–112 Neuroleptic malignant syndrome (NMS), 242, 247–248 Neuroleptics. See also Antipsychotics; Atypical neuroleptics agitation and, 240 delirium and, 234–235 dosages of, 225 nursing homes and, 248 psychotic depression and, 224 side effects of, 225 Neurology and neurological symptoms. See also Neuropsychological evaluation Alzheimer’s disease and, 141–142 medical evaluation and, 84, 86–89 standardized form for examination, 495–497 Neuropeptides, and Alzheimer’s disease, 460–461 Neuropsychiatric Inventory (NPI), 41–42, 71, 246, 250, 264, 265, 266, 513–523 Neuropsychological evaluation. See also Diagnosis; Neurocognitive testing; Neurology and neurological symptoms cognitive patterns of various types of dementia and, 304–313 components of comprehensive, 288–304 goals of, 286–287

565

recommendations for interventions and, 287–288 standardized testing and, 31, 290, 291–304 value of, 312–313 Neurosyphilis, 170 New Jersey, and end-of-life decisions, 338 New learning ability, 199 Nicotine-related disorders, 8 Nicotinic acid deficiency, 162 Nicotinic mechanisms, and Alzheimer’s disease, 457–458 Noise, and sleep in nursing homes, 394 Noncholinergic neurotransmitter replacement strategies, and Alzheimer’s disease, 459–460 Noncompetitive inhibition, and cholinesterase inhibitors, 457 Nonconfrontation, and management of cognitive impairment, 192–193, 205 Non-Pick lobar atrophy, 146–147 Nonsteroidal anti-inflammatory drugs (NSAIDs), 445–446, 467 Nonverbal communication, 382 Nonviral opportunistic infections, and reversible dementia, 169–170 Normalcy, and environment of older adult, 408 North Carolina, and community resources, 375 Nortriptyline, 229–230, 231, 232, 233 Nursing homes. See also Caregivers; Long term care activities of daily living and, 382–389 apathy and withdrawal in, 207–208 caregivers and placement, 336–337 communication and, 381–382 digital technology and, 426 dysfunctional behaviors and, 395–399 ethics and environment of, 359–363 falls and, 389–391

566


Nursing homes (continued) family of dementia patients and, 326, 332, 334, 336–337 incontinence and, 332, 391–393 living environment and, 421–426 neuroleptics and, 248 sensory deficits and, 395 sleep and, 393–394 urban versus rural elders and, 375 wandering and, 205 Nursing-level dementia care (NLDC), 405, 406, 409, 410, 420, 422, 424–425 Nutritional status, of nursing home patients, 385. See also Diet; Eating behavior Olanzapine, 224, 244, 246, 247, 255 Olfaction, and neurological examination, 86 Omnibus Budget Reconciliation Act of 1987, 248 Onset, of symptoms of cognitive impairment, 81–82 Ophthalmologic examinations, 395 Opioid-related disorders, 8 Optimal autonomy, 193–194 Optimal stimulation, 197, 202–203 Organic compounds, and reversible dementia, 155 Orientation, and assisted-living settings, 418. See also Reality orientation Over-the-counter medications, 85 Overlearned skills, determining and using, 198–199, 212. See also Learning Oxazepam, 236–237, 254 Oxybutynin, 220 Panic attacks, and anxiety disorders, 24 Papaverine, 267 Paranoid ideation, and Alzheimer’s disease, 141 Parathyroid adenoma, 157

Parents, and dementia in adult child, 333. See also Family Parkinsonism, and neurological examination, 87 Parkinson’s disease competency as legal issue in, 356–358 dementia with Lewy bodies and, 143, 144 depression and, 28 differential diagnosis of, 148–149 Paroxetine, 226–227, 231, 232, 252 Pathology, of Alzheimer’s disease, 138 Patient history aphasia and, 32 diagnosis of dementia and, 13 diagnosis of mental retardation and, 27 medical evaluation and, 81–85 neuropsychological evaluation and, 288–289 personality and, 53 taking of, 33–34 PC12 neural cells, 436 Pellagrinous encephalopathy, 154 Pemoline, 234 Pentobarbital, 235 Perception, and living environments, 423. See also Sensory-perceptual abilities Pernicious anemia, 161 Personality changes in and characterization of dementia, 36 function of in dementia, 51–59 management of dementia and premorbid, 188 neuropsychological evaluation and, 303 Personality change due to a general medical condition, 23, 25–26 Personal preferences, and utilization of community resources, 374–376 Pertinent autonomy, 408 Phantom boarder syndrome, 68, 69

Index Phencyclidine-related disorders, 8–9 Phenelzine, 231, 232, 233 Phototherapy, 425. See also Bright light therapy Physical activity, and nursing homes, 386–389, 394. See also Walking programs Physical examination, and medical evaluation, 86 Physicians. See also Medical care community resources and, 376 driving and safety issues, 361 end-of-life issues and, 366 medical illness in cognitively impaired and, 213 neuroleptic use in nursing homes and, 248 neuropsychological evaluation and, 312 Physiological factors, in management of dementia, 182–187 Physiologic reaction, and depression, 61 Physostigmine, 230, 260 Piaget, J., 183, 185 Pick, Arnold, 145 Pick’s disease, 94, 145, 146, 147 Pinel, P., 13 Planning for Long-Term Care, 546 Pleasant events, and management of cognitive impairment, 198 Pleasant Events Schedule, 195, 211, 329 Polysubstance-related disorder, 9 Porphobilinogen, 159 Positron emission tomography (PET), 112–122, 142, 165 Position sense, and sensation, 87–88 Positive bonding, and surrogate caregiving, 201 Postoperative cognitive dysfunction (POCD), 26 Postoperative delirium, 236 Poststroke depression, 60 Postsynaptic agonist strategy, and cholinergic system, 458–459

567

Posture, and neurological examination, 88 Powers of attorney, 345 Praxis, and mental status examination, 35 Predominant functions, and physiological factors in management, 182–183 Preoperational stage, of cognitive maturation, 184 Presenilin genes, 437–438 Press, of environment, 407 Prevalence of Alzheimer’s disease, 1, 138 of anxiety in Alzheimer’s patients, 65 of dementia, 1–2 of dementia with Lewy bodies, 144 of depression in Alzheimer’s patients, 59 of depression in cognitively impaired, 28 Prevention programs, and falls in nursing homes, 389–390 Prichard, J. A. C., 13 Primary control, 407 Primary memory, 34 Prion diseases, and reversible dementia, 165–166 Privacy, and assisted-living settings, 418–419 Problem-solving skills, and neuropsychological testing, 295 Procedural discourse, 301 Professional Environmental Assessment Procedure (PEAP), 409, 410, 423 Prognosis, as issue for families, 324–325 Progression, of symptoms in cognitive impairment, 82–83, 186–187 Progressive multifocal leukoencephalopathy (PML), 170 Progressive supranuclear palsy (PSP), 148 Projection, as defense mechanism, 57, 327–329

568


Progopagnosia, 206 Propranolol, 251 Prospective planning, 347–348 Protective genes, and Alzheimer’s disease, 443 Protein phosphatase 2A (PP2A), 441 Proxy decision makers (PDMs), 363–364 Pseudodementia, 28 Psychiatric disorders. See also Cognitive disorders; Depression; DSM-IV-TR; Schizophrenia medical evaluation and patient history of, 83 neuropsychological evaluation and patient history of, 288 reversible dementias and, 152, 153 Psychiatric symptoms, of Alzheimer’s disease, 141 Psychological factors, in management of dementia, 188–190 Psychological point of view, and caregivers, 327–329 Psychological process, dementing illness as, 53–59 Psychological symptoms, and psychotropic drugs, 258–269 Psychomotor abilities, and neuropsychological tests, 290, 301–302. See also Motor system Psychostimulants, 256. See also Stimulants Psychotherapy, and management of cognitive impairment, 210–212 Psychotic defense mechanisms, 57–58 Psychotic depression, 224 Psychotic disorder due to a general medical condition, 20, 22, 23 Psychotropic drugs. See also Antidepressants; Antipsychotics; Barbiturates; Benzodiazepines; Dosage; Medications; Neuroleptics; Side effects; Toxicity; Tranquilizers; Withdrawal agitation and, 238–252 anxiety and, 236–238

apathy and withdrawal, 256–257 behavioral disturbances attributable to effects of, 220 delirium and, 234–236 depression and, 222–234 general principles for use of, 219–222 hallucinations and, 255–256 hypersexuality and, 257 impaired judgment and, 257–258 real world use of for behavioral and psychological symptoms, 258–269 reversible dementia and, 154 sleep-wake disturbance and, 252–254 suspiciousness and delusions, 254–255 Public housing, for elderly, 406 Pyritinol, 463 Pyrroloporphyria, Swedish type, 158–159 Quality of life as issue for family and caregivers, 326, 337–338 measures of, 42–43 Quality of Life in Alzheimer’s Disease (QOL-AD) Scale, 42–43, 529–533 Quality of Life in Dementia (QUALID) Scale, 43, 535–537 Quetiapine, 225, 246–247, 248, 255 Radioisotopes, and SPECT, 123 Range of motion (ROM) exercises, 389 Rapid eye movement (REM) sleep behavior disorder, 254 Reaction formations, as defense mechanisms, 56 Reality orientation, and management of cognitive impairment, 198–199, 395. See also Orientation Recall, and normal aging, 11–13. See also Free recall; Memory

Index Receptive language, 299 Reducing choices, and management of cognitive impairment, 197 Reevaluation, and medical evaluations, 97 Reflexes, and neurological examination, 88 Regression, as defense mechanism, 58 Rehabilitation memory-training programs and, 209 nursing homes and physical activity, 388–389 Reinforcement, and management of cognitive impairment, 196–197 Religion, and end-of-life decisions, 366 Reminiscence, and life review, 211–212, 396 Remote memory, and Alzheimer’s disease, 12 Renal function, and psychotropic drugs, 221 Repetition, and management of cognitive impairment, 196 Reporting, of cognitive evaluation results, 303–304 Residential care facilities providing specialized dementia programs (RC-SDP), 420 Resources, contact information for, 541–546. See also Community resources Restraints, and nursing homes, 399 Reversibility, of cognitive impairment, 186–187 Reversible dementias causes of, 14, 16 differential diagnosis of, 151–170 Rey Auditory Verbal Learning Test (RAVLT), 296 Rey-Osterreith Complex Figure Test, 297, 298 Risk factors for Alzheimer’s disease, 138 for dementing illness, 325, 346, 348–350

569

Risperidone, 224, 225, 245–246, 247 Rivastigmine, 261, 262–263, 266, 454–455, 456 Rocking, as therapeutic activity, 388 Rural areas, and nursing homes, 375, 376 Safety. See also Driving; Falls assisted-living settings and, 418 digital technology and, 417 as issue for family and caregivers, 326, 337–338 management of cognitive impairment and, 193, 208 screening of home environments for hazards and, 412–413, 414–415 Salt-wasting nephropathy, 156 Scapegoating, and long-term care placement, 336–337 Schizophrenia medical evaluation and cognitive impairment in, 83 onset of cognitive dysfunction in, 82 reversible dementia and, 153 Scopolamine, and memory, 260 Secondary control, 407 Secondary memory, 34–35 Secondary parkinsonism, 87 Secured Perimeters Pilot Program (California), 420 Security, and assisted-living settings, 418 Sedative-, hypnotic-, or anxiolyticrelated disorders, 9 Seizures electroencephalography and, 95 medical evaluation and neurological symptoms, 84 Selective attention, 294 Selective serotonin reuptake inhibitors (SSRIs), 226–228, 258, 336 Selegiline, 267, 459–460, 462

570


Self. See also Self-esteem assisted-living settings and identity issues, 419 orientation to, 183 Self-awareness, and coping, 55 Self-esteem. See also Self caregivers and, 329 coping mechanisms and, 55 Self-sufficiency, and environment of older adult, 408 Semantic dementia, 145 Sensation, and neurological examination, 87–88 Sensorimotor stage, of cognitive maturation, 183–184 Sensory impairment, and management of cognitive impairment, 190–192, 395 Sensory-perceptual abilities, and neuropsychological tests, 302–303. See also Perception Sensory Perceptual Examination, 302–303 Serotonin agonists, and agitation, 251–252 Serotonin reuptake inhibitors, and reversible dementia, 156 Serotonin syndrome, 227 Sertraline, 223, 226, 231, 232 Setting, of medical evaluation, 80. See also Environment; Living settings Sexuality. See also Hypersexuality caregivers and, 335–336 management of inappropriate behavior and, 188 psychotropic drugs and, 257 Side effects, of psychotropic drugs. See also Medications; specific drugs age-related considerations and, 221 of antipsychotics, 241 of benzodiazepines, 237 of monoamine oxidase inhibitors, 233 neuroleptic malignant syndrome (NMS) and, 242, 247–248

of psychostimulants, 256 serotonin syndrome and, 227 tardive dyskinesia syndromes and, 243–244, 247–248 of tricyclic antidepressants, 230, 232 Simplification, and management of cognitive impairment, 194 Simulated Presence (SimPres), 396 Single photon emission computed tomography (SPECT), 122–124, 142, 151, 160, 165 Skills. See also Coping activities of daily living and training in, 383–384 management of cognitive impairment and overlearned, 198–199, 212 Sleep and sleep-wake disturbances. See also Sleep apnea caregivers and, 332 management of cognitive impairment and, 205 nursing homes and, 393–394 psychological and behavioral concomitants of dementing illness and, 66–68 psychotropic drugs and, 252–254 Sleep apnea, 67, 253, 254, 394 Smart pill containers, 417 Smoke detectors, 416 Snoezelen, 212 Social contact, and assisted-living settings, 419 Social withdrawal. See also Apathy Alzheimer’s disease and, 71 management of cognitive impairment and, 207–208 Sodium levels, and reversible dementia, 156 Solvents, and reversible dementia, 155 Special care units (SCUs), 416, 422–424 Spinal fluid, and medical evaluation, 91

Index Splitting, as defense mechanism, 58–59 Standardized instruments assessment of decision-making capacity and, 354–359 diagnosis of dementing illness and, 39–43 neuropsychological evaluation and, 290, 291–303 Standards, for competence and testamentary capacity, 343–344. See also Guidelines State agencies, contact information for, 544–545 Statin drugs, 269, 447, 469–470 Stepwise progression, of symptoms in cognitive impairment, 82 Stimulants. See also Psychostimulants depression in elderly and, 234 sleep-wake disturbance and, 253 Stimulation, and management of cognitive impairment, 197, 202–203, 419 Stress, and caregivers, 334–335 Stroke depression after, 28, 59, 163 reversible dementia and, 162–163 vascular dementia and, 151 Stroop Color Word Test, 294 Structural neuroimaging, 104–112 Structure, and management of cognitive impairment, 195 Subcortical dementia case example of, 38–39 characterization of, 36–37 cognitive patterns of, 307–308 memory and, 296 Subdural hematoma, 163–164 Sublimation, and coping, 54 Substance-induced mood disorder, 24 Substance-induced persisting dementia, 18, 21 Substance intoxication delirium, 19 Substance-related disorders, DSM-IV-TR classification of, 5–10

571

Substance withdrawal delirium, 19 Suicide, and psychological and behavioral concomitants of dementing illness, 62–63 Sundowning Alzheimer’s disease and, 20, 140 cognitive impairment and optimal stimulation, 197 delirium and chronic obstructive pulmonary disease, 159 Support groups, and Alzheimer’s disease, 210–211 Support services. See Community resources; Resources Suppression, and coping, 54 Supreme Court, and end-of-life issues, 338 Surrogate caregiving, and management of cognitive impairment, 201 Suspiciousness. See also Accusations cognitive impairment and, 68, 205–206 psychotropic drugs and, 254–255 Symbolic communication, and cognitive impairment, 183 Syphilis, 90, 170 Tacrine, 261, 455, 456, 465 Tardive dyskinesia syndromes, 243–244, 247–248 Tau protein, 147, 441–442, 468 Telephone, cognitive impairment and communication by, 194 Temazepam, 253 Temporoparietal dementia, 36, 38 Terminal care, as ethical issue, 347 Territory, as autonomy-related issue, 194 Testamentary capacity, as legal issue, 342, 343 Tetrahydroacridinamine. See Tacrine Texas Functional Living Scale (TFLS), 293

572


Thiamine Alzheimer’s disease and dietary supplements, 463 amnestic disorder and deficiency of, 20 reversible dementia and deficiency of, 160–161 Thioridazine, 241 Thiothixene, 241 36-Hour Day, The (Mace and Rabins 1999), 321, 416 Threshold diagnosis, 3 Threshold model, of dementing illness, 50 Thrombolytic agents, and stroke, 163 Thyroid laboratory tests for function, 90 reversible dementia and disease of, 157 Ticlopidine hydrochloride, 268 Toileting strategies, in nursing homes, 392 Toluene, 155 Tomlinson, B. E., 138 Toxicity, of psychotropic drugs in elderly, 229, 242–244 Toxins cholinergic system and, 458 cognitive dysfunction and exposure to environmental, 85 laboratory tests and, 90–91 reversible dementia and, 152, 153–154, 155 Toxoplasma gondii and toxoplasmosis 169 Trail Making Test, 307 Tranquilizers, for agitation or anxiety, 236–237, 239–240 Transcranial Doppler imaging, 94 Transgenic models, of Alzheimer’s disease, 439–440 Tranylcypromine, 231, 232, 233 Trazodone, 228, 239, 252, 253 Treatable dementia-producing conditions, 14, 16

Treatment. See also Interventions; Management; Psychotropic drugs advances in for Alzheimer’s disease, 453–471 of cerebrovascular disease, 267–269 neuropsychological evaluation and effects of medical, 312–313 of Parkinson’s disease, 149 of vascular dementia, 151 Triazolam, 253 Tricyclic antidepressants (TCAs). See also Antidepressants depression in elderly and, 223, 229–233 serotonin syndrome and, 227 Trifluoperazine, 225 Triggers, for agitation, 204 Trihexyphenidyl, 242 Trizolam, 20 Tube feedings, and nursing homes, 385–386 Tuberculosis, 170 Tyramine, and monoamine oxidase inhibitors, 233 Universal design, of living environments, 412 University of Texas Southwestern Medical Center, 292, 433, 438 Urban areas, and nursing homes, 375 Uremic encephalopathy, 155 Urinalysis, and laboratory studies, 90, 91 Urinary incontinence, 391–392 Vaccine, development of for Alzheimer’s disease, 445, 468–469 Validation therapy, 211 Vascular dementia anxiety symptoms and, 65 cognitive patterns of, 305–306 differential diagnosis of, 149–151 DSM-IV-TR diagnostic criteria for, 17

Index Venlafaxine, 227, 228, 231, 232 Verbal fluency, 300 Verbal memory, 296–297 Verbal Series Attention Test (VSAT), 294 Vibration sense, and neurological examination, 87–88 Violent behavior, management of, 190. See also Aggression; Behavior Viral infections, and reversible dementia, 170 Virtue ethics, 346 Vision and visual acuity management of cognitive impairment and, 190–191, 192 neurological examination and, 86 neuropsychological tests and, 302–303 nursing homes and, 395 Visits, and nursing homes, 337 Visual memory, 297 Visuospatial skills, and neuropsychological tests, 290, 298–299 Vitamin deficiencies. See also Diet Alzheimer’s disease and, 463 medical evaluation and, 89–90 nursing homes and, 387 reversible dementia and, 152, 160–162 Vitamin C, and Alzheimer’s disease, 462–463 Vitamin E Alzheimer’s disease and, 142, 267, 462–463 tardive dyskinesia and, 244 Voidable marriage, 344 Volume depletion, and reversible dementia, 156 Voxel-based morphometry, 111

573

Walking programs, and nursing homes, 387–388, 392, 397 Wandering, and management of cognitive impairment, 204–205, 365, 397 Warfarin, 267, 268 Washington University Clinical Dementia Rating (CDR) Scale, 40, 501–502 Water intoxication, 156 Web sites, and sources of information, 545–546 Wechsler, D., 137–138 Wechsler Adult Intelligence Scale (WAIS), 291, 300 Wechsler Memory Scale (WMS), 294, 297 Wernicke-Korsakoff syndrome, 154 Wernicke’s aphasia, 32 Wernicke’s encephalopathy, 20 Wernicke’s syndrome, 160–161, 236 Wide Range Achievement Test, 3rd Edition (WRAT-3) Wills, and testamentary capacity, 343, 345 Wilson’s disease, 90, 158 Wisconsin Card Sorting Test, 295, 307 Withdrawal, from medications. See also Social withdrawal benzodiazepines and, 237 delirium and, 235 selective serotonin reuptake inhibitors and, 227–228 stimulants and, 234 Word fluency, 35 Zaleplon, 254 Zinc, and chelating agents, 464 Ziprasidone, 247 Zolpidem, 254

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