The Official Patient's Sourcebook on Alzheimer's Disease: Directory for the Internet Age

THE OFFICIAL PATIENT’S SOURCEBOOK on ALZHEIMER’S DISEASE J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E ...

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THE OFFICIAL PATIENT’S SOURCEBOOK

on

ALZHEIMER’S DISEASE J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright ©2003 by ICON Group International, Inc. Copyright ©2003 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Tiffany LaRochelle Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher’s note: The ideas, procedures, and suggestions contained in this book are not intended as a substitute for consultation with your physician. All matters regarding your health require medical supervision. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation, in close consultation with a qualified physician. The reader is advised to always check product information (package inserts) for changes and new information regarding dose and contraindications before taking any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960The Official Patient’s Sourcebook on Alzheimer’s Disease: A Revised and Updated Directory for the Internet Age/James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary and index. ISBN: 0-597-83849-6 1. Alzheimer’s Disease-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem or as a substitute for consultation with licensed medical professionals. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors or authors. ICON Group International, Inc., the editors, or the authors are not responsible for the content of any Web pages nor publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this sourcebook for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications are copyrighted. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this sourcebook.

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Dedication To the healthcare professionals dedicating their time and efforts to the study of Alzheimer’s disease.

Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this sourcebook which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which directly or indirectly are dedicated to Alzheimer’s disease. All of the Official Patient’s Sourcebooks draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this sourcebook. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for the Official Patient’s Sourcebook series published by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for the Official Patient’s Sourcebook series published by ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents INTRODUCTION ...................................................................................... 1 Overview ...............................................................................................................1 Organization .........................................................................................................3 Scope ......................................................................................................................3 Moving Forward....................................................................................................4

PART I: THE ESSENTIALS ................................................ 7 CHAPTER 1. THE ESSENTIALS ON ALZHEIMER’S DISEASE: GUIDELINES ................................................................................................................ 9 Overview ...............................................................................................................9 What Is Alzheimer’s Disease?.............................................................................10 What Causes AD? ...............................................................................................11 What Are the Symptoms of AD? ........................................................................12 How Is AD Diagnosed? ......................................................................................12 How Is AD Treated? ...........................................................................................13 Is There Help for Caregivers?..............................................................................14 Research...............................................................................................................15 For More Information..........................................................................................15 More Guideline Sources ......................................................................................16 Vocabulary Builder..............................................................................................31

CHAPTER 2. SEEKING GUIDANCE ........................................................ 33 Overview .............................................................................................................33 Associations and Alzheimer’s Disease ................................................................33 Finding Associations ...........................................................................................35 Finding Doctors...................................................................................................37 Finding a Neurologist .........................................................................................38 Selecting Your Doctor .........................................................................................38 Working with Your Doctor .................................................................................39 Broader Health-Related Resources ......................................................................40 Vocabulary Builder..............................................................................................40

CHAPTER 3. CLINICAL TRIALS AND ALZHEIMER’S DISEASE .............. 43 Overview .............................................................................................................43 Recent Trials on Alzheimer’s Disease .................................................................46 Benefits and Risks................................................................................................65 Keeping Current on Clinical Trials.....................................................................68 General References...............................................................................................69 Vocabulary Builder..............................................................................................70

PART II: ADDITIONAL RESOURCES AND ADVANCED MATERIAL................................................. 71 CHAPTER 4. STUDIES ON ALZHEIMER’S DISEASE ................................ 73

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Overview .............................................................................................................73 The Combined Health Information Database ......................................................73 Federally Funded Research on Alzheimer’s Disease ...........................................80 E-Journals: PubMed Central.............................................................................164 The National Library of Medicine: PubMed .....................................................174 Vocabulary Builder............................................................................................232

CHAPTER 5. PATENTS ON ALZHEIMER’S DISEASE ............................ 239 Overview ...........................................................................................................239 Patents on Alzheimer’s Disease ........................................................................240 Patent Applications on Alzheimer’s Disease ....................................................249 Keeping Current ................................................................................................250 Vocabulary Builder............................................................................................251

CHAPTER 6. BOOKS ON ALZHEIMER’S DISEASE ................................ 253 Overview ...........................................................................................................253 Book Summaries: Federal Agencies...................................................................253 Book Summaries: Online Booksellers ................................................................257 The National Library of Medicine Book Index ..................................................269 Chapters on Alzheimer’s Disease ......................................................................272 Directories .........................................................................................................276 General Home References ..................................................................................277 Vocabulary Builder............................................................................................278

CHAPTER 7. MULTIMEDIA ON ALZHEIMER’S DISEASE ..................... 279 Overview ...........................................................................................................279 Video Recordings...............................................................................................279 Bibliography: Multimedia on Alzheimer’s Disease...........................................281

CHAPTER 8. PERIODICALS AND NEWS ON ALZHEIMER’S DISEASE .. 285 Overview ...........................................................................................................285 News Services and Press Releases.....................................................................285 Newsletter Articles............................................................................................299 Academic Periodicals covering Alzheimer’s Disease ........................................300 Vocabulary Builder............................................................................................301

CHAPTER 9. PHYSICIAN GUIDELINES AND DATABASES ................... 303 Overview ...........................................................................................................303 NIH Guidelines .................................................................................................303 NIH Databases ..................................................................................................304 Other Commercial Databases ............................................................................311 Other Commercial Databases ............................................................................311 The Genome Project and Alzheimer’s Disease ..................................................311 Specialized References .......................................................................................316 Vocabulary Builder............................................................................................318

CHAPTER 10. DISSERTATIONS ON ALZHEIMER’S DISEASE................ 319 Overview ...........................................................................................................319 Dissertations on Alzheimer’s Disease ...............................................................319 Keeping Current ................................................................................................336

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Vocabulary Builder............................................................................................337

PART III. APPENDICES ..................................................339 APPENDIX A. RESEARCHING YOUR MEDICATIONS .......................... 341 Overview ...........................................................................................................341 Your Medications: The Basics ...........................................................................341 Learning More about Your Medications...........................................................343 Commercial Databases ......................................................................................347 Contraindications and Interactions (Hidden Dangers) ....................................348 A Final Warning ...............................................................................................349 General References.............................................................................................350 Vocabulary Builder............................................................................................351

APPENDIX B. RESEARCHING ALTERNATIVE MEDICINE .................... 353 Overview ...........................................................................................................353 What Is CAM? ..................................................................................................353 What Are the Domains of Alternative Medicine? ............................................354 Can Alternatives Affect My Treatment? ..........................................................357 Additional Web Resources.................................................................................380 General References.............................................................................................381 Vocabulary Builder............................................................................................382

APPENDIX C. RESEARCHING NUTRITION ......................................... 383 Overview ...........................................................................................................383 Food and Nutrition: General Principles............................................................383 Finding Studies on Alzheimer’s Disease...........................................................388 Federal Resources on Nutrition.........................................................................400 Additional Web Resources.................................................................................401 Vocabulary Builder............................................................................................401

APPENDIX D. FINDING MEDICAL LIBRARIES .................................... 403 Overview ...........................................................................................................403 Preparation ........................................................................................................403 Finding a Local Medical Library .......................................................................404 Medical Libraries in the U.S. and Canada ........................................................404

APPENDIX E. ALZHEIMER’S DISEASE: UNRAVELING THE MYSTERY 411 Overview ...........................................................................................................411 Introduction.......................................................................................................412 The Impact of Alzheimer's Disease ...................................................................413 A Walking Tour Through the Brain..................................................................415 Inside the Human Brain ....................................................................................416 Neurons and Their Jobs .....................................................................................419 Plaques and Tangles: The Hallmarks of AD .....................................................422 The Changing Brain in Alzheimer's Disease ....................................................426 Preclinical AD ...................................................................................................426 Mild AD ............................................................................................................427 Moderate AD.....................................................................................................428

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Severe AD..........................................................................................................429 Then and Now: the Fast Pace of Development in AD Research .......................430 The Search for Causes........................................................................................431 Genetic Factors at Work in AD.........................................................................432 Other Factors at Work in AD ...........................................................................435 New Techniques Help in Diagnosing AD ........................................................438 The Search for New Treatments ........................................................................441 Improving Support for Families and Other Caregivers ....................................445

APPENDIX F. ALZHEIMER’S DISEASE AND RELATED DEMENTIAS: ACUTE AND LONG-TERM CARE SERVICES ........................................ 451 Overview ...........................................................................................................451 Providing Care to People with ADRD..............................................................453 Current Themes Affecting ADRD Care............................................................454 Balance between Community and Institutional Care .......................................458 “New” Forms of Care for People with ADRD ..................................................462 Health Services Questions.................................................................................470 Changing Government Policies.........................................................................471 Client Preferences and Ethical Concerns ..........................................................473 Measuring Therapeutic Effectiveness ...............................................................476 Recommendations..............................................................................................477

APPENDIX G. GENETICS OF ALZHEIMER’S DISEASE ......................... 481 Overview ...........................................................................................................481 Alzheimer’s Disease: Not a Single-Gene Disorder............................................483 ApoE in Sporadic Alzheimer’s Disease .............................................................483 Research Questions ...........................................................................................486 For More Information........................................................................................487

APPENDIX H. 2000 PROGRESS REPORT ON ALZHEIMER’S DISEASE . 489 Overview ...........................................................................................................489 The Impact of Alzheimer’s Disease....................................................................490 Alzheimer’s Disease: An Urgent National Health and Research Priority .......492 The AD Research Effort.....................................................................................492 Alzheimer’s Disease: More Pieces of the Puzzle Fall into Place .......................494 What Are the Main Characteristics of AD? .....................................................494 Structure and Function of the Brain.................................................................496 What Causes AD? .............................................................................................497 What Do We Know about Diagnosing AD?.....................................................501 Chromosomes and Genes: The Database of Life ................................................503 How Can Alzheimer’s Disease Be Treated? ......................................................503 2000 AD: Research Advances: Taking the Next Steps .....................................505 Understanding the Etiology of AD ...................................................................505 Additional Genetic Links to AD........................................................................513 Alzheimer’s Disease and Parkinson’s Disease: Two Diseases or One? ............517 Prion Diseases ...................................................................................................518 Familial British Dementia and Associated Disorders .......................................518

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Possible Therapeutic Approaches for Abnormal Protein Deposition ................519 Aging and AD Development.............................................................................519 Early Life Events and Other Factors.................................................................520 Improving Early Diagnosis ...............................................................................521 Clinical-Pathological Correlations ....................................................................524 Slowing, Delaying, or Preventing the Disease..................................................527 Estrogen.............................................................................................................527 Anti-Inflammatory Agents................................................................................529 Inflammation .....................................................................................................530 Antioxidants......................................................................................................531 Nerve Growth Factor (NGF) and Other Neurotrophic Factors........................532 Alzheimer’s Disease Clinical Trials Database...................................................533 Clues to Healthy Aging Found in Lifestyles .....................................................534 Improving Support for Caregivers ....................................................................537 Pursuing Innovative Mechanisms for Funding AD Research .........................539 Enhancing the Efficiency and Effectiveness with which Research Is Conducted ...........................................................................................................................541 Support for AD Research by Other NIH Institutes..........................................544 Outlook for the Future.......................................................................................558

APPENDIX I. NIA ALZHEIMER’S DISEASE CENTERS PROGRAM DIRECTORY......................................................................................... 563 Overview ...........................................................................................................563 Alabama.............................................................................................................564 Arizona ..............................................................................................................564 Arkansas ............................................................................................................565 California ...........................................................................................................565 Georgia...............................................................................................................567 Illinois................................................................................................................567 Indiana...............................................................................................................568 Kentucky............................................................................................................569 Maryland ...........................................................................................................569 Massachusetts....................................................................................................569 Michigan............................................................................................................570 Minnesota..........................................................................................................570 Missouri.............................................................................................................571 New York...........................................................................................................571 North Carolina ..................................................................................................573 Ohio ...................................................................................................................573 Oregon ...............................................................................................................573 Pennsylvania .....................................................................................................574 Texas..................................................................................................................575 Washington .......................................................................................................575 National Alzheimer’s Coordinating Center (NACC) .......................................576

ONLINE GLOSSARIES....................................................577

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Online Dictionary Directories ..........................................................................580

ALZHEIMER’S DISEASE GLOSSARY.........................581 General Dictionaries and Glossaries .................................................................590

INDEX ..................................................................................593

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INTRODUCTION Overview Dr. C. Everett Koop, former U.S. Surgeon General, once said, “The best prescription is knowledge.”1 The Agency for Healthcare Research and Quality (AHRQ) of the National Institutes of Health (NIH) echoes this view and recommends that every patient incorporate education into the treatment process. According to the AHRQ: Finding out more about your condition is a good place to start. By contacting groups that support your condition, visiting your local library, and searching on the Internet, you can find good information to help guide your treatment decisions. Some information may be hard to find—especially if you don’t know where to look.2 As the AHRQ mentions, finding the right information is not an obvious task. Though many physicians and public officials had thought that the emergence of the Internet would do much to assist patients in obtaining reliable information, in March 2001 the National Institutes of Health issued the following warning: The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading.3

Quotation from http://www.drkoop.com. The Agency for Healthcare Research and Quality (AHRQ): http://www.ahcpr.gov/consumer/diaginfo.htm. 3 From the NIH, National Cancer Institute (NCI): http://cancertrials.nci.nih.gov/beyond/evaluating.html. 1 2

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Alzheimer’s Disease

Since the late 1990s, physicians have seen a general increase in patient Internet usage rates. Patients frequently enter their doctor’s offices with printed Web pages of home remedies in the guise of latest medical research. This scenario is so common that doctors often spend more time dispelling misleading information than guiding patients through sound therapies. The Official Patient’s Sourcebook on Alzheimer’s Disease has been created for patients who have decided to make education and research an integral part of the treatment process. The pages that follow will tell you where and how to look for information covering virtually all topics related to Alzheimer’s disease, from the essentials to the most advanced areas of research. The title of this book includes the word “official.” This reflects the fact that the sourcebook draws from public, academic, government, and peerreviewed research. Selected readings from various agencies are reproduced to give you some of the latest official information available to date on Alzheimer’s disease. Given patients’ increasing sophistication in using the Internet, abundant references to reliable Internet-based resources are provided throughout this sourcebook. Where possible, guidance is provided on how to obtain free-ofcharge, primary research results as well as more detailed information via the Internet. E-book and electronic versions of this sourcebook are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). Hard copy users of this sourcebook can type cited Web addresses directly into their browsers to obtain access to the corresponding sites. Since we are working with ICON Health Publications, hard copy Sourcebooks are frequently updated and printed on demand to ensure that the information provided is current. In addition to extensive references accessible via the Internet, every chapter presents a “Vocabulary Builder.” Many health guides offer glossaries of technical or uncommon terms in an appendix. In editing this sourcebook, we have decided to place a smaller glossary within each chapter that covers terms used in that chapter. Given the technical nature of some chapters, you may need to revisit many sections. Building one’s vocabulary of medical terms in such a gradual manner has been shown to improve the learning process. We must emphasize that no sourcebook on Alzheimer’s disease should affirm that a specific diagnostic procedure or treatment discussed in a research study, patent, or doctoral dissertation is “correct” or your best option. This sourcebook is no exception. Each patient is unique. Deciding on

Introduction

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appropriate options is always up to the patient in consultation with their physician and healthcare providers.

Organization This sourcebook is organized into three parts. Part I explores basic techniques to researching Alzheimer’s disease (e.g. finding guidelines on diagnosis, treatments, and prognosis), followed by a number of topics, including information on how to get in touch with organizations, associations, or other patient networks dedicated to Alzheimer’s disease. It also gives you sources of information that can help you find a doctor in your local area specializing in treating Alzheimer’s disease. Collectively, the material presented in Part I is a complete primer on basic research topics for patients with Alzheimer’s disease. Part II moves on to advanced research dedicated to Alzheimer’s disease. Part II is intended for those willing to invest many hours of hard work and study. It is here that we direct you to the latest scientific and applied research on Alzheimer’s disease. When possible, contact names, links via the Internet, and summaries are provided. It is in Part II where the vocabulary process becomes important as authors publishing advanced research frequently use highly specialized language. In general, every attempt is made to recommend “free-to-use” options. Part III provides appendices of useful background reading for all patients with Alzheimer’s disease or related disorders. The appendices are dedicated to more pragmatic issues faced by many patients with Alzheimer’s disease. Accessing materials via medical libraries may be the only option for some readers, so a guide is provided for finding local medical libraries which are open to the public. Part III, therefore, focuses on advice that goes beyond the biological and scientific issues facing patients with Alzheimer’s disease.

Scope While this sourcebook covers Alzheimer’s disease, your doctor, research publications, and specialists may refer to your condition using a variety of terms. Therefore, you should understand that Alzheimer’s disease is often considered a synonym or a condition closely related to the following: •

Presenile Dementia

•

Primary Degenerative Dementia

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Alzheimer’s Disease

•

Senile Dementia of the Alzheimer's Type (SDAT)

•

Senile Dementia/Alzheimer's Type (SDAT)

In addition to synonyms and related conditions, physicians may refer to Alzheimer’s disease using certain coding systems. The International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) is the most commonly used system of classification for the world’s illnesses. Your physician may use this coding system as an administrative or tracking tool. The following classification is commonly used for Alzheimer’s disease:4 •

290.0 senile dementia, uncomplicated

•

290.10 presenile dementia, uncomplicated

•

331.0 alzheimer's disease

For the purposes of this sourcebook, we have attempted to be as inclusive as possible, looking for official information for all of the synonyms relevant to Alzheimer’s disease. You may find it useful to refer to synonyms when accessing databases or interacting with healthcare professionals and medical librarians.

Moving Forward Since the 1980s, the world has seen a proliferation of healthcare guides covering most illnesses. Some are written by patients or their family members. These generally take a layperson’s approach to understanding and coping with an illness or disorder. They can be uplifting, encouraging, and highly supportive. Other guides are authored by physicians or other healthcare providers who have a more clinical outlook. Each of these two styles of guide has its purpose and can be quite useful. As editors, we have chosen a third route. We have chosen to expose you to as many sources of official and peer-reviewed information as practical, for the purpose of educating you about basic and advanced knowledge as recognized by medical science today. You can think of this sourcebook as your personal Internet age reference librarian. 4 This list is based on the official version of the World Health Organization’s 9th Revision, International Classification of Diseases (ICD-9). According to the National Technical Information Service, “ICD-9CM extensions, interpretations, modifications, addenda, or errata other than those approved by the U.S. Public Health Service and the Health Care Financing Administration are not to be considered official and should not be utilized. Continuous maintenance of the ICD-9-CM is the responsibility of the federal government.”

Introduction

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Why “Internet age”? All too often, patients diagnosed with Alzheimer’s disease will log on to the Internet, type words into a search engine, and receive several Web site listings which are mostly irrelevant or redundant. These patients are left to wonder where the relevant information is, and how to obtain it. Since only the smallest fraction of information dealing with Alzheimer’s disease is even indexed in search engines, a non-systematic approach often leads to frustration and disappointment. With this sourcebook, we hope to direct you to the information you need that you would not likely find using popular Web directories. Beyond Web listings, in many cases we will reproduce brief summaries or abstracts of available reference materials. These abstracts often contain distilled information on topics of discussion. While we focus on the more scientific aspects of Alzheimer’s disease, there is, of course, the emotional side to consider. Later in the sourcebook, we provide a chapter dedicated to helping you find peer groups and associations that can provide additional support beyond research produced by medical science. We hope that the choices we have made give you the most options available in moving forward. In this way, we wish you the best in your efforts to incorporate this educational approach into your treatment plan. The Editors

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PART I: THE ESSENTIALS

ABOUT PART I Part I has been edited to give you access to what we feel are “the essentials” on Alzheimer’s disease. The essentials of a disease typically include the definition or description of the disease, a discussion of who it affects, the signs or symptoms associated with the disease, tests or diagnostic procedures that might be specific to the disease, and treatments for the disease. Your doctor or healthcare provider may have already explained the essentials of Alzheimer’s disease to you or even given you a pamphlet or brochure describing Alzheimer’s disease. Now you are searching for more in-depth information. As editors, we have decided, nevertheless, to include a discussion on where to find essential information that can complement what your doctor has already told you. In this section we recommend a process, not a particular Web site or reference book. The process ensures that, as you search the Web, you gain background information in such a way as to maximize your understanding.

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CHAPTER 1. THE ESSENTIALS ON ALZHEIMER’S DISEASE: GUIDELINES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines on Alzheimer’s disease. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. The great advantage of guidelines over other sources is that they are often written with the patient in mind. Since new guidelines on Alzheimer’s disease can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

The National Institutes of Health (NIH)5 The National Institutes of Health (NIH) is the first place to search for relatively current patient guidelines and fact sheets on Alzheimer’s disease. Originally founded in 1887, the NIH is one of the world’s foremost medical research centers and the federal focal point for medical research in the United States. At any given time, the NIH supports some 35,000 research grants at universities, medical schools, and other research and training institutions, both nationally and internationally. The rosters of those who have conducted research or who have received NIH support over the years include the world’s most illustrious scientists and physicians. Among them are 97 scientists who have won the Nobel Prize for achievement in medicine.

5

Adapted from the NIH: http://www.nih.gov/about/NIHoverview.html.

10 Alzheimer’s Disease

There is no guarantee that any one Institute will have a guideline on a specific disease, though the National Institutes of Health collectively publish over 600 guidelines for both common and rare diseases. The best way to access NIH guidelines is via the Internet. Although the NIH is organized into many different Institutes and Offices, the following is a list of key Web sites where you are most likely to find NIH clinical guidelines and publications dealing with Alzheimer’s disease and associated conditions: •

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

•

National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines available at http://www.nlm.nih.gov/medlineplus/healthtopics.html

•

National Institute on Aging (NIA); guidelines at http://www.nih.gov/nia/health/

Among those listed above, the National Institute on Aging is particularly noteworthy. The National Institute on Aging (NIA), one of the 25 institutes and centers of the National Institutes of Health, leads a broad scientific effort to understand the nature of aging and to extend the healthy, active years of life. In 1974, Congress granted authority to form the National Institute on Aging to provide leadership in aging research, training, health information dissemination, and other programs relevant to aging and older people. Subsequent amendments to this legislation designated the NIA as the primary federal agency on Alzheimer’s disease research. The NIA provides the following guideline on Alzheimer’s disease.6

What Is Alzheimer’s Disease?7 Dementia is a brain disorder that seriously affects a person's ability to carry out daily activities. The most common form of dementia among older people is Alzheimer's disease (AD), which involves the parts of the brain that control thought, memory, and language. Although scientists are learning more every day, right now they still do not know what causes AD, and there is no cure.

6 This and other passages have been adapted from the National Institute on Aging: http://www.nia.nih.gov/about/history.htm. “Adapted” signifies that the text has been reproduced with attribution, with some or no editorial adjustments. 7 Adapted from the National Institute on Aging: http://www.niapublications.org/adearnia/adfact.asp.

Guidelines 11

Scientists think that up to 4 million Americans suffer from AD. The disease usually begins after age 60, and risk goes up with age. While younger people also may get AD, it is much less common. About 3 percent of men and women ages 65 to 74 have AD, and nearly half of those age 85 and older may have the disease. It is important to note, however, that AD is not a normal part of aging. AD is named after Dr. Alois Alzheimer, a German doctor. In 1906, Dr. Alzheimer noticed changes in the brain tissue of a woman who had died of an unusual mental illness. He found abnormal clumps (now called amyloid plaques) and tangled bundles of fibers (now called neurofibrillary tangles). Today, these plaques and tangles in the brain are considered signs of AD. Scientists also have found other brain changes in people with AD. Nerve cells are lost in areas of the brain that are vital to memory and other mental abilities. There also are lower levels of chemicals in the brain that carry complex messages back and forth between nerve cells. AD may disrupt normal thinking and memory by blocking these messages between nerve cells.

What Causes AD? Scientists do not yet fully understand what causes AD. There probably is not one single cause, but several factors that affect each person differently. Age is the most important known risk factor for AD. The number of people with the disease doubles every 5 years beyond age 65. Family history is another risk factor. Scientists believe that genetics may play a role in many AD cases. For example, familial AD, a rare form of AD that usually occurs between the ages of 30 and 60, is inherited. However, in the more common form of AD, which occurs later in life, no obvious inheritance pattern is seen. One risk factor for this type of AD is a gene that makes a protein called apolipoprotein E (apoE). Everyone has apoE, which helps carry cholesterol in the blood. The apoE gene has three forms. One seems to protect a person from AD, and another seems to make a person more likely to develop the disease. It is likely that other genes also may increase the risk of AD or protect against AD, but they remain to be discovered. Scientists still need to learn a lot more about what causes AD. In addition to genetics and apoE, they are studying education, diet, environment, and viruses to learn what role they might play in the development of this disease.


What Are the Symptoms of AD? AD begins slowly. At first, the only symptom may be mild forgetfulness. In this stage, people may have trouble remembering recent events, activities, or the names of familiar people or things. They may not be able to solve simple math problems. Such difficulties may be a bother, but usually they are not serious enough to cause alarm. However, as the disease goes on, symptoms are more easily noticed and become serious enough to cause people with AD or their family members to seek medical help. For example, people in the middle stages of AD may forget how to do simple tasks, like brushing their teeth or combing their hair. They can no longer think clearly. They begin to have problems speaking, understanding, reading, or writing. Later on, people with AD may become anxious or aggressive, or wander away from home. Eventually, patients need total care.

How Is AD Diagnosed? An early, accurate diagnosis of AD helps patients and their families plan for the future. It gives them time to discuss care while the patient can still take part in making decisions. Early diagnosis also offers the best chance to treat the symptoms of the disease. Today, the only definite way to diagnose AD is to find out whether there are plaques and tangles in brain tissue. To look at brain tissue, however, doctors must wait until they do an autopsy, which is an examination of the body done after a person dies. Therefore, doctors can only make a diagnosis of "possible" or "probable" AD while the person is still alive. At specialized centers, doctors can diagnose AD correctly up to 90 percent of the time. Doctors use several tools to diagnose "probable" AD, including: •

Questions about the person's general health, past medical problems, and any difficulties the person has carrying out daily activities.

•

Medical tests - such as tests of blood, urine, or spinal fluid.

•

Tests of memory, problem solving, attention, counting, and language.

•

Brain scans.

These test results help the doctor find other possible causes of the person's symptoms. For example, thyroid problems, drug reactions, depression, brain

Guidelines 13

tumors, and blood vessel disease in the brain can cause AD-like symptoms. Some of these other conditions can be treated success-fully. Recently, scientists have focused on a type of memory change called mild cognitive impairment (MCI), which is different from both AD and normal age-related memory change. People with MCI have ongoing memory problems, but they do not have other losses like confusion, attention problems, and difficulty with language. Scientists funded by the National Institute on Aging (NIA) are studying information collected from the Memory Impairment Study to learn whether early diagnosis and treatment of MCI might prevent or slow further memory loss, including the development of AD.

How Is AD Treated? AD is a slow disease, starting with mild memory problems and ending with severe brain damage. The course the disease takes and how fast changes occur vary from person to person. On average, AD patients live from 8 to 10 years after they are diagnosed, though the disease can last for as many as 20 years. No treatment can stop AD. However, for some people in the early and middle stages of the disease, the drugs tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), or galantamine (Reminyl) may help prevent some symptoms from becoming worse for a limited time. Also, some medicines may help control behavioral symptoms of AD such as sleeplessness, agitation, wandering, anxiety, and depression. Treating these symptoms often makes patients more comfortable and makes their care easier for caregivers. Developing new treatments for AD is an active area of research. Scientists are testing a number of drugs to see if they prevent AD, slow the disease, or help reduce symptoms. There is evidence that inflammation in the brain may contribute to AD damage. Some scientists believe that drugs such as nonsteroidal antiinflammatory drugs (NSAIDs) might help slow the progression of AD, although recent studies of two of these drugs, rofecoxib (Vioxx) and naproxen (Aleve), have shown that they did not delay the progression of AD in people who already have the disease. Scientists are now testing other NSAIDs to find out if they can slow the onset of the disease.


Research has shown that vitamin E slows the progress of some consequences of AD by about 7 months. Scientists now are studying vitamin E to learn whether it can prevent or delay AD in patients with MCI. Recent research suggests that ginkgo biloba may be of some help in treating AD symptoms. There is no evidence that ginkgo will cure or prevent AD. Scientists now are trying to find out whether ginkgo biloba can delay or prevent dementia in older people. Research also is under way to see if estrogen reduces the risk of AD or slows the disease. One study showed that estrogen does not slow the progression of already diagnosed disease, but more research is needed to find out if it may play another role. For example, scientists now are trying to find out whether estrogen can prevent development of AD in women with a family history of the disease. People with AD and those with MCI who want to help scientists test possible treatments may be able to take part in clinical trials, which are studies to find out whether a new treatment is both safe and effective. Healthy people also can help scientists learn more about the brain and AD. The NIA and the Food and Drug Administration (FDA) are working together to maintain the AD Clinical Trials Database, which lists AD clinical trials sponsored by the Federal government and private companies. To find out more about these studies, contact the NIA's Alzheimer's Disease Education and Referral (ADEAR) Center at 1-800-438-4380, or visit the ADEAR Center Website at www.alzheimers.org. You also can sign up for e-mail alerts on new clinical trials that have been added to the database. Many of these studies are being done at NIA-supported Alzheimer's Disease Centers located throughout the United States. These centers carry out a wide range of research, including studies of the causes, diagnosis, treatment, and management of AD. To get a list of these centers, contact the ADEAR Center.

Is There Help for Caregivers? Most often, spouses or other family members provide the day-to-day care for people with AD. As the disease gets worse, people often need more and more care. This can be hard for caregivers and can affect their physical and mental health, family life, job, and finances. The Alzheimer's Association has chapters nationwide that provide educational programs and support groups for caregivers and family

Guidelines 15

members of people with AD. For more information, contact the Alzheimer's Association listed at the end of this fact sheet.

Research Scientists have come a long way in their understanding of AD. Findings from years of research have begun to clarify differences between normal agerelated memory changes, MCI, and AD. Scientists also have made great progress in defining the changes that take place in the AD brain, which allows them to pinpoint possible targets for treatment. These advances are the foundation for the National Institutes of Health (NIH) Alzheimer's Disease Prevention Initiative, which is designed to: •

Understand why AD occurs and who is at greatest risk of developing it

•

Improve the accuracy of diagnosis and the ability to identify those at risk

•

Discover, develop, and test new treatments

•

Discover treatments for behavioral problems in patients with AD

For More Information To learn about support groups, services, research centers, and publications about AD, contact the following groups: Alzheimer's Association Suite 1100 919 North Michigan Avenue Chicago, IL 60611-1676 1-800-272-3900 Website: www.alz.org This non-profit association supports families and caregivers of patients with AD. Chapters nationwide provide referrals to local resources and services, and sponsor support groups and educational programs. Alzheimer's Disease Education and Referral (ADEAR) Center PO Box 8250 Silver Spring, MD 20907-8250 1-800-438-4380 Website: www.alzheimers.org This service of the National Institute on Aging is funded by the Federal Government. It offers information and publications on diagnosis, treatment, patient care, caregiver needs, long-term care, education and


training, and research related to AD. Staff answer telephone and written requests and make referrals to local and national resources. Eldercare Locator 800-677-1116 Website: www.eldercare.gov This service of the Administration on Aging is funded by the Federal Government. It offers information about and referrals to respite care and other home and community services offered by State and Area Agencies on Aging.

More Guideline Sources The guideline above on Alzheimer’s disease is only one example of the kind of material that you can find online and free of charge. The remainder of this chapter will direct you to other sources which either publish or can help you find additional guidelines on topics related to Alzheimer’s disease. Many of the guidelines listed below address topics that may be of particular relevance to your specific situation or of special interest to only some patients with Alzheimer’s disease. Due to space limitations these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly.

Topic Pages: MEDLINEplus For patients wishing to go beyond guidelines published by specific Institutes of the NIH, the National Library of Medicine has created a vast and patientoriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages.” You can think of a health topic page as a guide to patient guides. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following as being relevant to Alzheimer’s disease: •

Other guides Alzheimer's Caregivers http://www.nlm.nih.gov/medlineplus/alzheimerscaregivers.html Alzheimer's Disease http://www.nlm.nih.gov/medlineplus/alzheimersdisease.html

Guidelines 17

Dementia http://www.nlm.nih.gov/medlineplus/dementia.html Neurologic Diseases http://www.nlm.nih.gov/medlineplus/neurologicdiseases.html Parkinson's Disease http://www.nlm.nih.gov/medlineplus/parkinsonsdisease.html

Within the health topic page dedicated to Alzheimer’s disease, the following was recently recommended to patients: •

General/Overviews Alzheimer's: Searching for a Cure Source: Food and Drug Administration http://www.fda.gov/fdac/features/2003/403_alz.html

•

Diagnosis/Symptoms ApoE (Apolipoprotein E) Genotyping Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/apoe/test.h tml Expanding the Use of Imaging in Alzheimer's Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=HQ00914 Memory Loss: Questions to Ask the Doctor Source: Administration on Aging http://www.aoa.gov/alz/public/alzcarefam/disease_info/questions _to_ask.asp Mild Cognitive Impairment: Possible Predictor of Alzheimer's Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=AZ00014 Tau/Amyloid Beta 42 Peptide Test (Alzheimer Biomarkers) Source: American Association for Clinical Chemistry http://www.labtestsonline.org/understanding/analytes/tau/test.ht ml Understanding Alzheimer's: Getting a Diagnosis Source: Fisher Center for Alzheimer's Research Foundation http://www.alzinfo.org/understanding/diagnosis/


Understanding Alzheimer's: Warning Signs & Symptoms Source: Fisher Center for Alzheimer's Research Foundation http://www.alzinfo.org/understanding/signssymptoms/ •

Treatment Alzheimer's Disease Medications Source: National Institute on Aging http://www.alzheimers.org/pubs/medications.htm Standard Prescriptions for Alzheimer's Source: Alzheimer's Association http://www.alz.org/AboutAD/Treatment/Standard.htm Treating Behavioral Symptoms in Alzheimer's Source: Alzheimer's Association http://www.alz.org/AboutAD/Treatment/Behavioral.htm

•

Alternative Therapy Alternative Treatments in Alzheimer's Source: Alzheimer's Association http://www.alz.org/AboutAD/Treatment/Alternative.htm

•

Nutrition Nutritional Challenges of Alzheimer's Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=HQ00217

•

Coping Coping with Changes in Daily Life Source: Alzheimer's Association http://www.alz.org/IHaveAD/Coping.htm Helping Your Family and Friends Source: Alzheimer's Association http://www.alz.org/IHaveAD/Helping.htm Making Job Decisions Source: Alzheimer's Association http://www.alz.org/IHaveAD/JobDecisions.htm Modifying the Home Source: Fisher Center for Alzheimer's Research Foundation http://www.alzinfo.org/treatment/modifying/default.aspx

Guidelines 19

Taking Care of Yourself Source: Alzheimer's Association http://www.alz.org/IHaveAD/Care.htm •

Specific Conditions/Aspects Alzheimer's: When Driving Becomes an Issue Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=HO00046 Choosing Health Care Providers and Facilities Source: Alzheimer's Association http://www.alz.org/IHaveAD/Planning/Choosing.htm Facts about Agitation and Alzheimer's Disease http://www.alz.org/ResourceCenter/FactSheets/FSAgitation.pdf Facts about Sleep Changes in Alzheimer's Disease http://www.alz.org/ResourceCenter/FactSheets/FS_Sleep.pdf Financial Matters for Alzheimer's Care Source: Alzheimer's Association http://www.alz.org/IHaveAD/Planning/FinancialMatters.htm Involvement of Aluminum in the Development of Alzheimer's Disease Source: National Institute of Environmental Health Sciences http://www.niehs.nih.gov/external/faq/alum.htm Legal Issues Source: Alzheimer's Association http://www.alz.org/IHaveAD/Planning/LegalIssues.htm Spirituality and Alzheimer's Disease Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=AZ00024

•

From the National Institutes of Health Alzheimer's Disease: Unraveling the Mystery Source: National Institute on Aging http://www.alzheimers.org/unraveling/index.htm Forgetfulness: It's Not Always What You Think Source: National Institute on Aging http://www.niapublications.org/engagepages/forgetfulness.asp


•

Journals/Newsletters Advances Source: Alzheimer's Association http://www.alz.org/ResourceCenter/ByType/AssociationNewslette rs.htm

•

Latest News Brain Scans Can 'Predict' Alzheimer's Source: 11/25/2003, The Press Association http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/f ullstory_14824.html FDA Approves Memantine (Namenda) for Alzheimer's Disease Source: 10/17/2003, Food and Drug Administration http://www.fda.gov/bbs/topics/NEWS/2003/NEW00961.html Investigators Explore Selective Silencing of Disease Genes Source: 10/15/2003, National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/news_and_events/news_article_gene_sil encing.htm National Alzheimer's Disease Month November 2003 Source: 11/05/2003, Center for Mental Health Services http://www.mentalhealth.org/highlights/november2003/alzheimer s/ Psychologic Factors May Raise Alzheimer's Risk Source: 12/09/2003, Reuters Health http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/f ullstory_15045.html Vioxx Does Not Prevent Alzheimer's Source: 12/12/2003, United Press International http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/f ullstory_15103.html

•

Organizations Administration on Aging http://www.aoa.gov/ Alzheimer's Association http://www.alz.org/

Guidelines 21

Alzheimer's Disease Education and Referral (ADEAR) Center Source: National Institute on Aging http://www.alzheimers.org/ Fisher Center for Alzheimer's Research Foundation http://www.alzinfo.org/ National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/ National Institute on Aging http://www.nia.nih.gov/ •

Research “Use It Or Lose It?” Study Suggests Mentally Stimulating Activities May Reduce Alzheimer's Risk Source: National Institute on Aging http://www.nih.gov/news/pr/feb2002/nia-12.htm Effects of Alzheimerâ€™s Disease May Be Influenced by Education Source: National Institute on Aging http://www.nia.nih.gov/news/pr/2003/0623.htm Folic Acid Possibly a Key Factor in Alzheimer's Disease Prevention Source: National Institute on Aging http://www.nih.gov/news/pr/mar2002/nia-01.htm High Homocysteine Levels May Double Risk of Dementia, Alzheimer's Disease, New Report Suggests Source: National Institute on Aging http://www.nih.gov/news/pr/feb2002/nia-13.htm Human Gene Affects Memory Source: National Institute of Child Health and Human Development, National Institute of Mental Health http://www.nih.gov/news/pr/jan2003/nimh-23.htm Investigators Explore Selective Silencing of Disease Genes Source: National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/news_and_events/news_article_gene_sil encing.htm Life and Death of a Neuron Source: National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/health_and_medical/pubs/NINDS_Neu ron.htm


Lithium Shows Promise against Alzheimer's in Mouse Model Source: National Institute of Mental Health, National Institute on Aging http://www.nih.gov/news/pr/may2003/nimh-21.htm New Studies in Mice Suggest Ways to Clear Damaging Alzheimer's Amyloid Plaques Source: National Institute on Aging http://www.alzheimers.org/nianews/nianews53.htm Prevalence, Incidence, and Cumulative Risk of Alzheimer's Disease Reported Higher in African-American Community Source: Alzheimer's Association http://www.alz.org/Media/newsreleases/current/021202aareport.h tml Research Aimed at Preventing Alzheimer's Disease Source: Fisher Center for Alzheimer's Research Foundation http://www.alzinfo.org/research/prevention/default.aspx Research Brief: Cells That Live and Let Die Source: National Institute of General Medical Sciences http://www.nigms.nih.gov/news/releases/brief_steller.html Research on Causes of Alzheimer's: Risk Factors and Biology Source: Fisher Center for Alzheimer's Research Foundation http://www.alzinfo.org/research/causes/genetic/default.aspx Research: Leading the Battle in Cause, Care, Cure Source: Fisher Center for Alzheimer's Research Foundation http://www.alzinfo.org/research/battle/default.aspx Scientists Pinpoint Gene Influencing Age-at-Onset of Alzheimer’s, Parkinson’s Source: National Institute on Aging http://www.nia.nih.gov/news/pr/2003/1021b.htm What's in a Connection? A Look at Protein Patterns within Synapses Source: National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/news_and_events/news_article_synapse s.htm WHIMS Study on Estrogen/Progestin Source: Food and Drug Administration http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01226.html

Guidelines 23

•

Statistics FASTATS: Alzheimer's Disease Source: National Center for Health Statistics http://www.cdc.gov/nchs/fastats/alzheimr.htm New Prevalence Study Suggests Dramatically Rising Numbers of People with Alzheimer's Disease Source: National Institute on Aging http://www.nih.gov/news/pr/aug2003/nia-18.htm Statistics about Alzheimer's Disease Source: Alzheimer's Association http://www.alz.org/AboutAD/Statistics.htm

•

Teenagers Talking to Children and Teens about Alzheimer's Source: Alzheimer's Association http://www.alz.org/Caregivers/Coping/childrenteens.htm

You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search.

The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on Alzheimer’s disease and related conditions. One of the advantages of CHID over other sources is that it offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive:


•

Let Us Help You Cope With Alzheimer's Disease: The Major Cause of Dementia Source: Boca Raton, FL: Alzheimer's Disease and Related Disorders Association, Palm Beach County Chapter. [6 p.]. Contact: Available from Alzheimer's Association, Palm Beach County Chapter. P.O. Box 272147, Boca Raton, FL 33427-2147. (305) 392-1363 (south) or (305) 763-2699 (north). Summary: The Palm Beach County Chapter of the Alzheimer's Association is part of a nationwide organization dedicated to fighting Alzheimer' s disease on several fronts, including family support, public awareness, advocacy of resources and services, and promotion of research. This brochure also lists characteristics of the three stages of Alzheimer's disease.

•

Alzheimer's Disease Resource Book Source: Winter Park, FL: Area Agency on Aging. 1988. 61 p. Contact: Available from Area Agency on Aging. 1011 Wymore Road, Suite 105, Winter Park, FL 32789. (407) 645-3339. Summary: This booklet gives information on Alzheimer's disease and its stages of progression. It explains the purpose of local support groups and gives their addresses and telephone numbers. It also describes community services such as respite care, day care, and nursing homes. Helpful hints on dealing with the Alzheimer person are given, along with a list of videos, films, and books on Alzheimer's.

•

Alois Alzheimer Center: Dedicated to the Care and Study of Alzheimer's Disease Source: Cincinnati, OH: Alois Alzheimer Center. [4 p.]. Contact: Available from Alois Alzheimer Center. 70 Damon Road, Cincinnati, OH 45218. (513) 825-2255. PRICE: Free. Summary: This brochure defines Alzheimer's disease, describes the philosophy of the Alois Alzheimer Center, and provides a brief summary about the center's staff, facility, and program. The Alzheimer Center is located within a noninstitutional, campus-like setting in residential Cincinnati. It consists of large, open-spaced walking areas that link furnished patient rooms with the dining room. A chapel, beauty shop, activity room, whirlpool area, and separate rooms for family-patient encounter therapy are also included in the center. The center's program involves maintaining the dignity of the patient while integrating the emotional concerns of the family. The program also includes interactive

Guidelines 25

participation between patient and family through social support groups and professional counseling services provided on a permanent basis. •

Alzheimer's Disease: A Mini-Residency for Allied Health Professionals Source: Pittsburgh, PA: University of Pittsburgh Alzheimer Disease Research Center. 199x. 6 p. Contact: University of Pittsburgh Alzheimer Disease Research Center. University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213-2582. (412) 692-2700; FAX (412) 692-2710. PRICE: Free. Summary: This brochure describes a two week educational program offered by the University of Pittsburgh Alzheimer Disease Research Center for health and social service professionals and students. The course is designed to teach the principles of working with families facing cognitive impairment, to enhance understanding of current research and the clinical and behavioral aspects of Alzheimer's disease, and to improve clinical, research and advisory skills of participants. Session topics include diagnosis and clinical evaluation, etiology, brain/behavior relationships, neurophysiology of memory, physical changes in normal aging, management of behavior problems, research administration, and accessing community resources. Lectures, conferences and working sessions at other institutions are also part of the course. Continuing education credit is available.

•

Epidemiology of Alzheimer Disease in Mental Retardation. Results and Recommendations from an International Conference. Report of the AAMR/IASSID Workgroup on Epidemiology and Alzheimer's Disease Source: Albany, NY: New York State Office of Mental Retardation and Development Disabilities Bureau of Aging Services. 1995. 16 p. Contact: New York State Office of Mental Retardation and Development Disabilities Bureau of Aging Services. 144 Holland Avenue, Albany, NY 12229. (518) 473-7855; FAX (518) 473-0775. PRICE: Free. Summary: This report considers the discussions and recommendations of an epidemiology work group, formed at an international conference convened to discuss Alzheimer's disease among people with mental retardation. Topics include the incidence and prevalence of clinical dementia in this population, risk factors for the development of Alzheimer's disease in adults with mental retardation, and a minimum data set that may be of use for future research on Alzheimer's disease in adults with mental retardation. 1 table, 1 chart, 62 references.


The National Guideline Clearinghouse™ The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search their site located at http://www.guideline.gov by using the keyword “Alzheimer’s disease” or synonyms. The following was recently posted: •

Guidelines for Alzheimer's disease management. Source: Alzheimer's Association of Los Angeles, Riverside and San Bernardino Counties - Private Nonprofit Organization; 1999 January 8 (revised 2002 Jan 1); 52 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3157&am p;nbr=2383&string=Alzheimer''s+AND+disease

Healthfinder™ Healthfinder™ is an additional source sponsored by the U.S. Department of Health and Human Services which offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •

Alzheimer's Disease Summary: A general overview of Alzheimer's Disease that includes a description and information about treatment, prognosis and research. Source: National Institute of Neurological Disorders and Stroke, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&R ecordID=1105

•

Alzheimer's Disease - Iowa Geriatric Education Center Summary: The Alzheimer's disease information on this web site was contributed by medical institutions, health practitioners and other sources and peer-reviewed by members of the Iowa Geriatric Education Source: Educational Institution--Follow the Resource URL for More Information http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&R ecordID=4714

Guidelines 27

•

Alzheimer's Disease Fact Sheet Summary: This sheet provides basic information about Alzheimer's disease, symptoms, diagnosis, and treatment. Source: Alzheimer's Disease Education and Referral Center, National Institute on Aging http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&R ecordID=6911

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Alzheimer's Disease Genetics Summary: This fact sheet summarizes current research about the role of genetics in Alzheimer's disease. Source: Alzheimer's Disease Education and Referral Center, National Institute on Aging http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&R ecordID=6916

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Alzheimer's Disease Information Summary: This fact sheet discusses Alzheimer's disease, its social and economic impact, and the federal programs and services that are available to the public. Source: U.S. Administration on Aging, U.S. Department of Health and Human Services http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&R ecordID=3863

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Alzheimer's Disease Medications Fact Sheet Summary: This fact sheet summarizes the four FDA-approved medications for treating Alzheimer's disease--Reminyl, Exelon, Aricept, and Cognex. Source: Alzheimer's Disease Education and Referral Center, National Institute on Aging http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&R ecordID=6917


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Alzheimer's Disease Research Summary: Alzheimer's disease is a progressive, irreversible brain disorder with no known cause or cure. It attacks and slowly steals the minds of its victims. Source: American Health Assistance Foundation http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&R ecordID=6683

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Caregiver Guide Summary: This guide provides practical tips for daily coping with bathing, dressing, eating, and activities for people with Alzheimer's disease. Source: Alzheimer's Disease Education and Referral Center, National Institute on Aging http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&R ecordID=6912

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Depression and Alzheimer's Disease Summary: A fact sheet that discusses depression and Alzheimer's disease and how a caregiver can recognize depression in a family member or patient with Alzheimer's disease. Source: American Academy of Family Physicians http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&R ecordID=6084

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Ginkgo Biloba Summary: This fact sheet summarizes the research findings to date regarding the effectiveness of this natural extract in treating Alzheimer's disease. Source: Alzheimer's Disease Education and Referral Center, National Institute on Aging http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&R ecordID=6920

Guidelines 29

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healthfinder® just for you: Caregivers Summary: healthfinder®'s just for you: Caregivers section features topics such as Alzheimer's disease, home health care, and terminal illness. Source: U.S. Department of Health and Human Services http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&R ecordID=7024

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Home Safety for People with Alzheimer's Disease Summary: This booklet offers tips and guidelines for creating a safe home environment for people with Alzheimer's disease. Source: Alzheimer's Disease Education and Referral Center, National Institute on Aging http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&R ecordID=6915

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News and Press Releases - Alzheimer's Disease Education and Referral (ADEAR) Center Summary: This page provides the latest press releases and announcements from this U.S. Department of Health and Human Services agency. Source: Alzheimer's Disease Education and Referral Center, National Institute on Aging http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&R ecordID=1506

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NIH Senior Health Summary: This web site is organized by health topic and currently includes information on Alzheimer's Disease, Caring for Someone with Alzheimer's, and Exercise for Older Adults. Source: National Institutes of Health, U.S. Department of Health and Human Services http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&R ecordID=7724


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NIHSeniorHealth: Alzheimer's Disease Summary: Designed especially for seniors, this page defines Alzheimer's Disease and lists its causes and risk factors, symptoms and diagnosis, treatment and research, and frequently asked questions. Source: National Institutes of Health, U.S. Department of Health and Human Services http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&R ecordID=7008

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Occupational Therapy And People With Alzheimer's Disease Summary: Alzheimer's disease, a condition that affects the brain, occurs in middle or late life, striking men and women of all races, cultures, and backgrounds. Source: American Occupational Therapy Association http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&R ecordID=7305

The NIH Search Utility After browsing the references listed at the beginning of this chapter, you may want to explore the NIH search utility. This allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEBSPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to Alzheimer’s disease. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html.

Additional Web Sources A number of Web sites that often link to government sites are available to the public. These can also point you in the direction of essential information. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats

Guidelines 31

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Family Village: http://www.familyvillage.wisc.edu/specific.htm

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Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/

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Med Help International: http://www.medhelp.org/HealthTopics/A.html

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Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

•

Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/

•

WebMD®Health: http://my.webmd.com/health_topics

Vocabulary Builder The material in this chapter may have contained a number of unfamiliar words. The following Vocabulary Builder introduces you to terms used in this chapter that have not been covered in the previous chapter: Analytes: A component of a test sample the presence of which has to be demonstrated. The term "analyte" includes where appropriate formed from the analyte during the analyses. [NIH] Estrogen: One of the two female sex hormones. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH]

33

CHAPTER 2. SEEKING GUIDANCE Overview Some patients are comforted by the knowledge that a number of organizations dedicate their resources to helping people with Alzheimer’s disease. These associations can become invaluable sources of information and advice. Many associations offer aftercare support, financial assistance, and other important services. Furthermore, healthcare research has shown that support groups often help people to better cope with their conditions.8 In addition to support groups, your physician can be a valuable source of guidance and support. Therefore, finding a physician that can work with your unique situation is a very important aspect of your care. In this chapter, we direct you to resources that can help you find patient organizations and medical specialists. We begin by describing how to find associations and peer groups that can help you better understand and cope with Alzheimer’s disease. The chapter ends with a discussion on how to find a doctor that is right for you.

Associations and Alzheimer’s Disease As mentioned by the Agency for Healthcare Research and Quality, sometimes the emotional side of an illness can be as taxing as the physical side.9 You may have fears or feel overwhelmed by your situation. Everyone has different ways of dealing with disease or physical injury. Your attitude, your expectations, and how well you cope with your condition can all 8 Churches, synagogues, and other houses of worship might also have groups that can offer you the social support you need. 9

This section has been adapted from http://www.ahcpr.gov/consumer/diaginf5.htm.


influence your well-being. This is true for both minor conditions and serious illnesses. For example, a study on female breast cancer survivors revealed that women who participated in support groups lived longer and experienced better quality of life when compared with women who did not participate. In the support group, women learned coping skills and had the opportunity to share their feelings with other women in the same situation. In addition to associations or groups that your doctor might recommend, we suggest that you consider the following list (if there is a fee for an association, you may want to check with your insurance provider to find out if the cost will be covered): •

Alzheimer's Disease Education and Referral Center Address: P.O. Box 8250, Silver Spring, MD 20907-8250 Telephone: (301) 495-3311 Toll-free: (800) 438-4380 Fax: (301) 495-3334 Email: [email protected] Web Site: http://www.alzheimers.org Background: The Alzheimer's Disease Education and Referral (ADEAR) Center is a service of the National Institute on Aging (NIA) and National Institutes of Health, dedicated to providing information about Alzheimer's disease and related disorders to the general public, patients and their families, and health professionals. Established in 1990, ADEAR seeks to investigate the basic mechanisms of Alzheimer's Disease, manage the symptoms, and help families cope with the effects of the disease. The organization maintains an online bibliographic database of Alzheimer's Disease education materials and resources. This database is available to the public as the 'Alzheimer's Disease Subfile' of the Combined Health Information Database (CHID) and is a valuable resource for health professionals, administrators, social service workers, and caregivers. CHID contains information on patient brochures, fact sheets, books, journals, audiovisuals, directories, posters, teaching manuals, government reports and documents, and more. Most publications are free. Call toll-free to talk with an information specialist.

•

Alzheimer's Association Address: 225 North Michigan Avenue, 17th Floor, Chicago, IL 60601-7633 Telephone: (312) 335-8700 Toll-free: (800) 272-3900 Fax: (312) 335-1110 Email: [email protected]

Seeking Guidance 35

Web Site: http://www.alz.org Background: The Alzheimer s Association is a national not-for-profit voluntary organization dedicated to promoting and supporting research into the causes, cure, and prevention of Alzheimer s Disease and to providing education and support services to people with Alzheimer s Disease, their families, and caregivers. Established in 1980, the Association works through a network of more than 220 local chapters, more than 2,000 support groups, and 35,000 volunteers nationwide. The goals of the Alzheimer s Association include education, chapter formation, advocacy for improved public policy and needed legislation, and patient and family services to aid present and future patients and caregivers. Activities of the Association include the promotion of fundraising for research through its Medical and Scientific Advisory Board; publication of the quarterly 'Alzheimer s Association Newsletter'; and promotion of public awareness by publicizing such national annual events as Memory Walk and the national education conference. In addition, the Association operates a 24-hour telephone hotline to assist people with Alzheimer s Disease and their families.

Finding Associations There are a several Internet directories that provide lists of medical associations with information on or resources relating to Alzheimer’s disease. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with Alzheimer’s disease.

The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about Alzheimer’s disease. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797.

DIRLINE A comprehensive source of information on associations is the DIRLINE database maintained by the National Library of Medicine. The database comprises some 10,000 records of organizations, research centers, and


government institutes and associations which primarily focus on health and biomedicine. DIRLINE is available via the Internet at the following Web site: http://dirline.nlm.nih.gov/. Simply type in “Alzheimer’s disease” (or a synonym) or the name of a topic, and the site will list information contained in the database on all relevant organizations.

The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “Alzheimer’s disease”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” By making these selections and typing in “Alzheimer’s disease” (or synonyms) into the “For these words:” box, you will only receive results on organizations dealing with Alzheimer’s disease. You should check back periodically with this database since it is updated every 3 months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by specific diseases. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “Alzheimer’s disease” (or a synonym) in the search box, and click “Submit Query.”

Online Support Groups In addition to support groups, commercial Internet service providers offer forums and chat rooms for people with different illnesses and conditions. WebMD®, for example, offers such a service at its Web site: http://boards.webmd.com/roundtable. These online self-help communities can help you connect with a network of people whose concerns are similar to yours. Online support groups are places where people can talk informally. If you read about a novel approach, consult with your doctor or other healthcare providers, as the treatments or discoveries you hear about may not be scientifically proven to be safe and effective.

Seeking Guidance 37

Finding Doctors One of the most important aspects of your treatment will be the relationship between you and your doctor or specialist. All patients with Alzheimer’s disease must go through the process of selecting a physician. While this process will vary from person to person, the Agency for Healthcare Research and Quality makes a number of suggestions, including the following:10 •

If you are in a managed care plan, check the plan’s list of doctors first.

•

Ask doctors or other health professionals who work with doctors, such as hospital nurses, for referrals.

•

Call a hospital’s doctor referral service, but keep in mind that these services usually refer you to doctors on staff at that particular hospital. The services do not have information on the quality of care that these doctors provide.

•

Some local medical societies offer lists of member doctors. Again, these lists do not have information on the quality of care that these doctors provide.

Additional steps you can take to locate doctors include the following: •

Check with the associations listed earlier in this chapter.

•

Information on doctors in some states is available on the Internet at http://www.docboard.org. This Web site is run by “Administrators in Medicine,” a group of state medical board directors.

•

The American Board of Medical Specialties can tell you if your doctor is board certified. “Certified” means that the doctor has completed a training program in a specialty and has passed an exam, or “board,” to assess his or her knowledge, skills, and experience to provide quality patient care in that specialty. Primary care doctors may also be certified as specialists. The AMBS Web site is located at 11 http://www.abms.org/newsearch.asp. You can also contact the ABMS by phone at 1-866-ASK-ABMS.

•

You can call the American Medical Association (AMA) at 800-665-2882 for information on training, specialties, and board certification for many

This section has been adapted from the AHRQ: www.ahrq.gov/consumer/qntascii/qntdr.htm. 11 While board certification is a good measure of a doctor’s knowledge, it is possible to receive quality care from doctors who are not board certified. 10


licensed doctors in the United States. This information also can be found in “Physician Select” at the AMA’s Web site: http://www.amaassn.org/aps/amahg.htm.

Finding a Neurologist The American Academy of Neurology allows you to search for member neurologists by name or location. To use this service, go to http://www.aan.com/, select “Find a Neurologist” from the toolbar. Enter your search criteria, and click “Search.” To find out more information on a particular neurologist, click on the physician’s name. If the previous sources did not meet your needs, you may want to log on to the Web site of the National Organization for Rare Disorders (NORD) at http://www.rarediseases.org/. NORD maintains a database of doctors with expertise in various rare diseases. The Metabolic Information Network (MIN), 800-945-2188, also maintains a database of physicians with expertise in various metabolic diseases.

Selecting Your Doctor12 When you have compiled a list of prospective doctors, call each of their offices. First, ask if the doctor accepts your health insurance plan and if he or she is taking new patients. If the doctor is not covered by your plan, ask yourself if you are prepared to pay the extra costs. The next step is to schedule a visit with your chosen physician. During the first visit you will have the opportunity to evaluate your doctor and to find out if you feel comfortable with him or her. Ask yourself, did the doctor: •

Give me a chance to ask questions about Alzheimer’s disease?

•

Really listen to my questions?

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Answer in terms I understood?

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Show respect for me?

•

Ask me questions?

•

Make me feel comfortable?

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Address the health problem(s) I came with?

12 This

section has been adapted from the AHRQ: www.ahrq.gov/consumer/qntascii/qntdr.htm.

Seeking Guidance 39

•

Ask me my preferences about different kinds of treatments for Alzheimer’s disease?

•

Spend enough time with me?

Trust your instincts when deciding if the doctor is right for you. But remember, it might take time for the relationship to develop. It takes more than one visit for you and your doctor to get to know each other.

Working with Your Doctor13 Research has shown that patients who have good relationships with their doctors tend to be more satisfied with their care and have better results. Here are some tips to help you and your doctor become partners: •

You know important things about your symptoms and your health history. Tell your doctor what you think he or she needs to know.

•

It is important to tell your doctor personal information, even if it makes you feel embarrassed or uncomfortable.

•

Bring a “health history” list with you (and keep it up to date).

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Always bring any medications you are currently taking with you to the appointment, or you can bring a list of your medications including dosage and frequency information. Talk about any allergies or reactions you have had to your medications.

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Tell your doctor about any natural or alternative medicines you are taking.

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Bring other medical information, such as x-ray films, test results, and medical records.

•

Ask questions. If you don’t, your doctor will assume that you understood everything that was said.

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Write down your questions before your visit. List the most important ones first to make sure that they are addressed.

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Consider bringing a friend with you to the appointment to help you ask questions. This person can also help you understand and/or remember the answers.

•

Ask your doctor to draw pictures if you think that this would help you understand.

This section has been adapted from the AHRQ: www.ahrq.gov/consumer/qntascii/qntdr.htm.

13


•

Take notes. Some doctors do not mind if you bring a tape recorder to help you remember things, but always ask first.

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Let your doctor know if you need more time. If there is not time that day, perhaps you can speak to a nurse or physician assistant on staff or schedule a telephone appointment.

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Take information home. Ask for written instructions. Your doctor may also have brochures and audio and videotapes that can help you.

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After leaving the doctor’s office, take responsibility for your care. If you have questions, call. If your symptoms get worse or if you have problems with your medication, call. If you had tests and do not hear from your doctor, call for your test results. If your doctor recommended that you have certain tests, schedule an appointment to get them done. If your doctor said you should see an additional specialist, make an appointment.

By following these steps, you will enhance the relationship you will have with your physician.

Broader Health-Related Resources In addition to the references above, the NIH has set up guidance Web sites that can help patients find healthcare professionals. These include:14 •

Caregivers: http://www.nlm.nih.gov/medlineplus/caregivers.html

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Choosing a Doctor or Healthcare Service: http://www.nlm.nih.gov/medlineplus/choosingadoctororhealthcareserv ice.html

•

Hospitals and Health Facilities: http://www.nlm.nih.gov/medlineplus/healthfacilities.html

Vocabulary Builder The following vocabulary builder provides definitions of words used in this chapter that have not been defined in previous chapters:

You can access this information at: http://www.nlm.nih.gov/medlineplus/healthsystem.html.

14

Seeking Guidance 41

Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH]

43

CHAPTER 3. CLINICAL TRIALS AND ALZHEIMER’S DISEASE Overview Very few medical conditions have a single treatment. The basic treatment guidelines that your physician has discussed with you, or those that you have found using the techniques discussed in Chapter 1, may provide you with all that you will require. For some patients, current treatments can be enhanced with new or innovative techniques currently under investigation. In this chapter, we will describe how clinical trials work and show you how to keep informed of trials concerning Alzheimer’s disease.

What Is a Clinical Trial?15 Clinical trials involve the participation of people in medical research. Most medical research begins with studies in test tubes and on animals. Treatments that show promise in these early studies may then be tried with people. The only sure way to find out whether a new treatment is safe, effective, and better than other treatments for Alzheimer’s disease is to try it on patients in a clinical trial.

The discussion in this chapter has been adapted from the NIH and the NEI: http://www.nei.nih.gov/health/clinicaltrials%5Ffacts/index.htm.

15


What Kinds of Clinical Trials Are There? Clinical trials are carried out in three phases: •

Phase I. Researchers first conduct Phase I trials with small numbers of patients and healthy volunteers. If the new treatment is a medication, researchers also try to determine how much of it can be given safely.

•

Phase II. Researchers conduct Phase II trials in small numbers of patients to find out the effect of a new treatment on Alzheimer’s disease.

•

Phase III. Finally, researchers conduct Phase III trials to find out how new treatments for Alzheimer’s disease compare with standard treatments already being used. Phase III trials also help to determine if new treatments have any side effects. These trials--which may involve hundreds, perhaps thousands, of people--can also compare new treatments with no treatment.

How Is a Clinical Trial Conducted? Various organizations support clinical trials at medical centers, hospitals, universities, and doctors’ offices across the United States. The “principal investigator” is the researcher in charge of the study at each facility participating in the clinical trial. Most clinical trial researchers are medical doctors, academic researchers, and specialists. The “clinic coordinator” knows all about how the study works and makes all the arrangements for your visits. All doctors and researchers who take part in the study on Alzheimer’s disease carefully follow a detailed treatment plan called a protocol. This plan fully explains how the doctors will treat you in the study. The “protocol” ensures that all patients are treated in the same way, no matter where they receive care. Clinical trials are controlled. This means that researchers compare the effects of the new treatment with those of the standard treatment. In some cases, when no standard treatment exists, the new treatment is compared with no treatment. Patients who receive the new treatment are in the treatment group. Patients who receive a standard treatment or no treatment are in the “control” group. In some clinical trials, patients in the treatment group get a new medication while those in the control group get a placebo. A placebo is a harmless substance, a “dummy” pill, that has no effect on Alzheimer’s disease. In other clinical trials, where a new surgery or device (not a medicine) is being tested, patients in the control group may receive a “sham

Clinical Trials 45

treatment.” This treatment, like a placebo, has no effect on Alzheimer’s disease and does not harm patients. Researchers assign patients “randomly” to the treatment or control group. This is like flipping a coin to decide which patients are in each group. If you choose to participate in a clinical trial, you will not know which group you will be appointed to. The chance of any patient getting the new treatment is about 50 percent. You cannot request to receive the new treatment instead of the placebo or sham treatment. Often, you will not know until the study is over whether you have been in the treatment group or the control group. This is called a “masked” study. In some trials, neither doctors nor patients know who is getting which treatment. This is called a “double masked” study. These types of trials help to ensure that the perceptions of the patients or doctors will not affect the study results. Natural History Studies Unlike clinical trials in which patient volunteers may receive new treatments, natural history studies provide important information to researchers on how Alzheimer’s disease develops over time. A natural history study follows patient volunteers to see how factors such as age, sex, race, or family history might make some people more or less at risk for Alzheimer’s disease. A natural history study may also tell researchers if diet, lifestyle, or occupation affects how a disease or disorder develops and progresses. Results from these studies provide information that helps answer questions such as: How fast will a disease or disorder usually progress? How bad will the condition become? Will treatment be needed? What Is Expected of Patients in a Clinical Trial? Not everyone can take part in a clinical trial for a specific disease or disorder. Each study enrolls patients with certain features or eligibility criteria. These criteria may include the type and stage of disease or disorder, as well as, the age and previous treatment history of the patient. You or your doctor can contact the sponsoring organization to find out more about specific clinical trials and their eligibility criteria. If you are interested in joining a clinical trial, your doctor must contact one of the trial’s investigators and provide details about your diagnosis and medical history. If you participate in a clinical trial, you may be required to have a number of medical tests. You may also need to take medications and/or undergo


surgery. Depending upon the treatment and the examination procedure, you may be required to receive inpatient hospital care. Or, you may have to return to the medical facility for follow-up examinations. These exams help find out how well the treatment is working. Follow-up studies can take months or years. However, the success of the clinical trial often depends on learning what happens to patients over a long period of time. Only patients who continue to return for follow-up examinations can provide this important long-term information.

Recent Trials on Alzheimer’s Disease The National Institutes of Health and other organizations sponsor trials on various diseases and disorders. Because funding for research goes to the medical areas that show promising research opportunities, it is not possible for the NIH or others to sponsor clinical trials for every disease and disorder at all times. The following lists recent trials dedicated to Alzheimer’s disease.16 If the trial listed by the NIH is still recruiting, you may be eligible. If it is no longer recruiting or has been completed, then you can contact the sponsors to learn more about the study and, if published, the results. Further information on the trial is available at the Web site indicated. Please note that some trials may no longer be recruiting patients or are otherwise closed. Before contacting sponsors of a clinical trial, consult with your physician who can help you determine if you might benefit from participation. •

A study of the safety and efficacy of multiple doses of ABT-089 in subjects with Alzheimer's disease Condition(s): Alzheimer's Disease Study Status: This study is currently recruiting patients. Sponsor(s): Abbott Laboratories Purpose - Excerpt: The purpose of this study is to compare the safety and efficacy of 2 mg, 4 mg, and 20 mg of ABT-089 BID to placebo in adults with Alzheimer's disease. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00069849

16

These are listed at www.ClinicalTrials.gov.

Clinical Trials 47

•

Alzheimer's Disease and Aging: Therapeutic potential of estrogen Condition(s): Alzheimer's Disease Study Status: This study is currently recruiting patients. Sponsor(s): Department of Veterans Affairs Medical Research Service Purpose - Excerpt: This study is designed to evaluate the potential beneficial effects of estrogen on cognitive function of women with Alzheimer's Disease. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00018343

•

Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) Condition(s): Alzheimer Disease Study Status: This study is currently recruiting patients. Sponsor(s): National Institute on Aging (NIA); Department of Veterans Affairs; University of Washington; Johns Hopkins University Purpose - Excerpt: The purpose of this trial is to test the ability of the nonsteroidal anti-inflammatory medications naproxen and celecoxib to delay or prevent the onset of AD and age-related cognitive decline. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00007189

•

Alzheimer's Disease Genetics Study Condition(s): Alzheimer Disease; Late Onset Alzheimer Disease Study Status: This study is currently recruiting patients. Sponsor(s): National Institute on Aging (NIA) Purpose - Excerpt: The purpose of the Alzheimer's Disease Genetics Study is to identify the genes that are responsible for causing Alzheimer's Disease (AD). One of the ways in which the risk factor genes for late onset AD can be investigated is by identifying and collecting genetic material from families with multiple members diagnosed with late onset (over 60 years of age) AD. Families meeting the criteria will have a sibling pair diagnosed with AD with an onset of age 60 or older and at least one other affected or unaffected relative willing to participate. Families will


be evaluated for a medical diagnosis and other factors. If eligible, blood samples will be collected to establish cell lines. If one of the identified family members is deceased, DNA will be extracted and stored from autopsy samples. Local sites will collect clinical and demographic data from the families and will send coded data (without identifiers) to the National Cell Repository for Alzheimer's Disease (NCRAD) at Indiana University. Persons interested in registering to participate in this study can call the toll-free NCRAD number 1-800-526-2839 for more information. Local study sites are located all over the United States, and arrangements may be made for eligible families who do not live near a participating site Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00064870 •

Alzheimer's Disease Treatment and Illness Perceptions Survey (TIPS) II Condition(s): Alzheimer Disease Study Status: This study is currently recruiting patients. Sponsor(s): Alzheimer's Association Purpose - Excerpt: The TIPS Study, or Treatment and Illness Perceptions Survey, is a study funded by the national Alzheimer's Association to learn more about differences between African Americans' and Whites' attitudes, beliefs, and experiences related to Alzheimer's disease (AD). The study involves a one-time 30-minute telephone survey in which participants are asked about a range of topics related to AD, including their personal experiences, their beliefs about the disease's symptoms and risk factors, and their attitude toward possible future treatment options. Information from the survey will be used to develop more culturally sensitive health education and healthcare services for persons with AD. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00059410

•

Alzheimer's Disease: Therapeutic Potential of Estrogen Condition(s): Alzheimer Disease Study Status: This study is currently recruiting patients. Sponsor(s): National Institutes of Health (NIH)

Clinical Trials 49

Purpose - Excerpt: This is a 15-month study to determine the effectiveness of hormone replacement therapy in improving memory and the ability to live independently in postmenopausal women with Alzheimer's disease. Phase(s): Phase II; Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00066157 •

Bathing persons with Alzheimer's disease aT Home (The BATH Study) Condition(s): Alzheimer Disease Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Nursing Research (NINR) Purpose - Excerpt: This study will evaluate the effectiveness of a 3-week reminiscence intervention applied during bathing persons with Alzheimer's disease (AD) in decreasing resistiveness to care (RTC), relieving patient discomfort, and improving spouse caregiver appraisals of burden, capabilities and confidence while bathing the patient. Reminiscence provides opportunities for the patient to feel good and recall pleasant memories, easily done by caregivers in a home setting. Home visits and telephone calls from trained nurses provide coaching and practice for caregivers for the preliminary phase of this study. Each couple will be enrolled in the study for approximately 9 weeks. The study will recruit 100 patient/spouse caregiver couples randomly divided into one of two groups: reminiscence with coaching, or bathing support (control). Bathing support will be provided to participants in both conditions including: individualized assessment; education regarding bathing techniques for people with dementia; and individualized problem solving. In addition to the bathing support intervention, participants in the experimental group will receive a pleasant memories interview and reminiscence script with coaching for implementation. Caregivers will keep a journal of their experiences in bathing the care recipien Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00062569

•

Brain Imaging in Alzheimer's Disease Condition(s): Alzheimer Disease


Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Mental Health (NIMH) Purpose - Excerpt: The purpose of this study is to use brain imaging technology to examine the role of certain brain chemicals in individuals with Alzheimer's disease (AD) and in healthy volunteers. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00039702 •

Brain Imaging in Elderly People and Individuals with Alzheimer's Disease Condition(s): Alzheimer's Disease; Healthy Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Mental Health (NIMH) Purpose - Excerpt: The purpose of this study is to use brain imaging technology to study the effects of aging and Alzheimer's Disease (AD) on a specific type of brain receptor. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001917

•

CATIE-Alzheimer's Disease Trial Condition(s): Alzheimer's Disease Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Mental Health (NIMH) Purpose - Excerpt: The CATIE Alzheimer's Disease Trial is part of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Project. The study is for people with Alzheimer's disease who are having trouble with their thinking or behavior. In particular, this study is trying to find out the best treatment for people who have hallucinations (seeing or hearing things that aren't there), delusions (false beliefs), or agitation. The design of the trial helps to increase the chance that participants in the study receive a medication that helps them. The study uses three medications known as atypical antipsychotics (olanzapine, quetiapine, risperidone), which are the newest medications that are currently available for treating these problems. Participants may also receive an antidepressant (citalopram). The trial lasts for 36 weeks. Participants are given a thorough evaluation at no cost to ensure that this study is

Clinical Trials 51

appropriate. In addition, the caregiver, family member, or friend who comes with the participant will be offered an educational program about Alzheimer's disease. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00015548 •

Cholesterol Lowering Agent to Slow Progression (CLASP) of Alzheimer's Disease Study Condition(s): Alzheimer Disease Study Status: This study is currently recruiting patients. Sponsor(s): National Institute on Aging (NIA) Purpose - Excerpt: CLASP is a research study to investigate the safety and effectiveness of simvastatin (a cholesterol lowering drug or statin) to slow the progression of Alzheimer's disease (AD). Statins are commonly used to treat high cholesterol levels, which increase the risk of heart disease and stroke. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00053599

•

COGNIShunt(r) System for Alzheimer's Disease Condition(s): Alzheimer Disease Study Status: This study is currently recruiting patients. Sponsor(s): Eunoe Purpose - Excerpt: This is a study of the effect on the progression of Alzheimer's Disease of a surgically implanted shunt (tube) to increase the flow of cerebrospinal fluid and improve the clearance of potential neurotoxins from the fluid bathing the brain. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00056628


•

Cognitive and Neurophysiological Effects of Raloxifene in Alzheimer's Disease Condition(s): Alzheimer Disease Study Status: This study is currently recruiting patients. Sponsor(s): University of Wisconsin Purpose - Excerpt: The aim of this study is to determine the effectiveness of treatment with raloxifene, an estrogen-like medication approved by the Food and Drug Administration for the treatment of osteoporosis, in improving memory and the ability to live independently in postmenopausal women with Alzheimer's disease. Phase(s): Phase II; Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00065767

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Effects of an Anti-Inflammatory Drug in Alzheimer's Disease Condition(s): Alzheimer's Disease Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Mental Health (NIMH) Purpose - Excerpt: The purpose of this study is to evaluate the effects of the drug cyclophosphamine (CY) on inflammation and immune responses in individuals with Alzheimer's Disease (AD). Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00013650

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Effects of Estrogen on Memory in Post-Menopausal Women and Patients With Alzheimer's Disease Condition(s): Alzheimer Disease Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); Alzheimer's Association; Pfizer; Eisai Medical Research Inc Purpose - Excerpt: The goal of this study is to examine whether the administration of estrogen to post-menopausal women and women with mild to moderate Alzheimer's disease will enhance their memory and their capacity for learning.

Clinical Trials 53

Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006399 •

Efficacy and Safety of LY451395 in Patients with Probable Alzheimer's Disease Condition(s): Alzheimer's Disease Study Status: This study is currently recruiting patients. Sponsor(s): Eli Lilly and Company Purpose - Excerpt: Study of an investigational medication for the treatment of Alzheimer's Disease in patients who are not taking Aricept, Reminyl, Exelon. Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00051909

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Evaluation of Age- and Alzheimer's Disease-Related Memory Disorder Condition(s): Alzheimer Disease; Dementia; Memory Disorder; Healthy Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Mental Health (NIMH) Purpose - Excerpt: The purpose of this study is to examine how a part of the brain called the hippocampus contributes to memory changes that occur with aging and Alzheimer's disease (AD). Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00029120

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Gene-Environment Interactions in Alzheimer's Disease Condition(s): Alzheimer's Disease Study Status: This study is currently recruiting patients. Sponsor(s): Department of Veterans Affairs Medical Research Service Purpose - Excerpt: This study will create Alzheimer 's disease risk profiles for defined combinations of genotypes and environmental exposures. This study will carry out a molecular epidemiologic study to identify genetic and environmental risks factors using state of the art techniques. The following will be done during the course of this study 1) Recruit both Alzheimer's patients and cognitively normal aged veterans. 2) Evaluate


gene interaction in Alzheimer's disease. 3) Evaluate gene-environment interactions on the risk of Alzheimer's disease. These procedures should initially address the question as to whether certain genes either independently or synergistically modify the risk of Alzheimer's disease. This study will also determine whether certain environmental factors (smoking, alcohol consumption etc.) can modify the risk of AD and whether this effect is dependent on certain genetic backgrounds. This study will provide information that will be useful in designing therapies, develop risk factor profiles to be further tested in future studies, designating patients for specific therapies based on genetic factors and providing data and genetic material for future studies. This study will also provide a cohort of older and well characterized cognitively normal veterans for prospective genetic epidemiological studies on aging. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00018473 •

High Intensity Light Therapy in Alzheimer's Disease Condition(s): Alzheimer's Disease; Dementia Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Complementary and Alternative Medicine (NCCAM); National Institute on Aging (NIA) Purpose - Excerpt: The purpose of this study is to determine whether bright light improves the sleep, mood, and behavior of persons with Alzheimer's disease and related dementias (AD) who live in long-term care settings and, if so, to determine the best timing for the light therapy. The light levels being used in the study have been shown to improve depression in persons with seasonal affective disorder (SAD) and to relieve sleep problems in persons with jet lag and other body rhythm disturbances. Because persons with AD often will not remain still in front of a fluorescent panel, this project has involved renovations in the study units that provide for even, regulated, high-intensity light in all public areas of the study settings. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00065689

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Insulin, Neurogentics and Memory in Alzheimer's Disease Condition(s): Alzheimer Disease Study Status: This study is currently recruiting patients. Sponsor(s): Department of Veterans Affairs Medical Research Service Purpose - Excerpt: This study examines the use of insulin-sensitizing compounds, as therapeutic agents for cognitive impairment in Alzheimer's disease. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00018382

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Prevention of Alzheimer's Disease by Vitamin E and Selenium (PREADVISE) Condition(s): Alzheimer Disease Study Status: This study is currently recruiting patients. Sponsor(s): National Institute on Aging (NIA); National Cancer Institute (NCI) Purpose - Excerpt: The Prevention of Alzheimer's Disease by Vitamin E and Selenium (PREADVISE) prevention trial is an important addition to the Selenium and Vitamin E Cancer Prevention Trial (SELECT). As a prevention trial, PREADVISE is trying to find out if taking selenium and/or Vitamin E supplements can help to prevent memory loss and dementia such as Alzheimer's disease. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00040378

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Prevention of cognitive decline in Alzheimer's disease by ingested interferon alpha Condition(s): Memory Disorders; Alzheimer's Disease Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); Pfizer Purpose - Excerpt: In this phase I-II parallel design, randomized, doubleblind clinical trial we will determine if 3,000 or 30,000 units ingested hrIFN-a prevents deterioration of cognitive functioning in patients with


dementia of Alzheimer's type (AD) and whether ingested hrIFN-a treatment decreases acute phase reactants and pro-inflammatory cytokine IL-6 in mild to moderate AD. We predict that the novel antiinflammatory agent ingested human recombinant interferon alpha (hrIFN-a) will modulate inflammation and inhibit the natural history of AD progression. If you are eligible, you will receive Aricept for 5 weeks (donezepil) and thereafter in addition to Aricept either placebo (inactive substance) or interferon alpha at 3,000 or 30,000 units every day for 12 months. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00031018 •

The Effect of Short-Term Statins and NSAIDs on Levels of BetaAmyloid, a Protein Associated with Alzheimer's Disease Condition(s): Alzheimer Disease Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Mental Health (NIMH) Purpose - Excerpt: The purpose of this study is to determine whether short-term use of the drugs ibuprofen and lovastatin affects levels of a protein called beta-amyloid in people who are at risk for developing Alzheimer's Disease (AD). Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00046358

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Treatment of Alzheimer's Disease with CX516 (Ampalex) Condition(s): Alzheimer's Disease; Dementia Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS) Purpose - Excerpt: Glutamate is an amino acid released by brain cells that acts to excite other cells. Glutamate attaches to special sites on cells called AMPA (alpha-amino-2,3-dihydro-5 methyl 3-oxo-4-isoxazolepropanoic acid) receptors. The brain cells responsible for releasing glutamate are damaged in Alzheimer's disease and other conditions affecting thinking

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and reasoning. Researchers would like to see if giving patients a drug that attaches to AMPA receptors improves the symptoms of Alzheimer's disease. CX516 (Ampalex) is a test drug that affects the AMPA receptors. This study will investigate the effectiveness and safety of CX516 on patients with Alzheimer's disease. Patients will be given capsules of CX516 or placebo (sugar pill that neither harms nor helps) for up to 16 weeks in different amounts. The effectiveness of the drug will be measured by neurological tests. Safety will be monitored by frequent check-ups and lab examinations. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001662 •

Treatment of Behavioral Symptoms in Alzheimer's Disease Condition(s): Alzheimer Disease Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Mental Health (NIMH) Purpose - Excerpt: Alzheimer's patients with behavioral problems (e.g., sleep disturbance, agitation) and/or psychosis are commonly treated with antipsychotic medications like haloperidol. This study focuses on the treatment of behavioral symptoms in Alzheimer's disease with haloperidol and whether long term treatment is necessary. The study is conducted in two phases: First, for five months active haloperidol is given, titrating the dose (1-4 mg. daily) for maximum effectiveness while closely monitoring side effects. Second, for those patients who respond and remain stable on the medication, we examine whether continuation medication treatment is necessary. To this end, they are treated for another 24 weeks in a randomized double-blind placebo-controlled manner. After completing the study, patients are transferred back to their primary physician once the behavioral disturbance and/or psychosis is optimally treated. Drs. D.P. Devanand and G. Pelton are conducting this project. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00009217


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VITAL - VITamins to slow ALzheimer's disease (Homocysteine study) Condition(s): Alzheimer's Disease Study Status: This study is currently recruiting patients. Sponsor(s): National Institute on Aging (NIA) Purpose - Excerpt: The purpose of this study is to determine whether reduction of homocysteine levels with high-dose folate (folic acid), B6, and B12 supplementation will slow the rate of cognitive decline in persons with Alzheimer's disease. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00056225

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Alzheimer's Disease Prevention Trial Condition(s): Alzheimer Disease; Memory Disorders Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute on Aging (NIA) Purpose - Excerpt: This is a three-year study to determine if estrogens can prevent memory loss and Alzheimer's disease in women with a family history of Alzheimer's disease. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000176

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Gene Therapy for Alzheimer's Disease Clinical Trial Condition(s): Alzheimer Disease Study Status: This study is no longer recruiting patients. Sponsor(s): The Shiley Family Trust; Institute for the Study of Aging; University of California, San Diego Purpose - Excerpt: This Phase I clinical trial is the first step in testing gene therapy. This study is called a "Safety/Toxicity" study by the Food and Drug Administration, and primarily aims to determine whether the experimental protocol is safe for humans. It will determine whether the study procedure causes side effects in humans, and may also give us a preliminary sense of whether this will be effective in combating Alzheimer's disease in humans.

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Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00017940 •

Genetic Studies in Alzheimer's Disease Condition(s): Alzheimer's Disease; Nervous System Disease Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS) Purpose - Excerpt: Alzheimer's disease is a condition marked by the deterioration of mental function. The disease usually begins in late middle life and results in death in 5 to 10 years. Patients with Alzheimer's disease typically suffer from memory loss, confusion, and disorientation. The condition has become a major medical and social problem in the United States because of the increasing number of people living beyond the age of 65. The actual cause of Alzheimer's disease is unknown. Researchers believe that Alzheimer's disease, or at least a portion of cases, may be an inherited condition. As a result, many new techniques have been developed to study the genetic causes of Alzheimer's disease and other neurological disorders. Many of these genetic techniques require blood samples and a family pedigree. A pedigree is a chart, similar to a family tree, that shows a patient's family history. The purpose of this study is to collect family and psychosocial information, blood, and biopsy samples from patients with neurological diseases, their families, and normal volunteers. This information gathered will be used to learn more about diseases that affect the brain. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001235

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Lipitor as a Treatment for Alzheimer's Disease Condition(s): Alzheimer Disease Study Status: This study is no longer recruiting patients. Sponsor(s): Institute for the Study of Aging; Pfizer Purpose - Excerpt: The purpose of this study is to assess the clinical benefit of Lipitor, a cholesterol-lowering drug, in the treatment of Alzheimer's disease.


Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00024531 •

A Multicenter Trial of Rofecoxib and Naproxen in Alzheimer's Disease (NSAID Study). Condition(s): Alzheimer Disease Study Status: This study is completed. Sponsor(s): National Institute on Aging (NIA) Purpose - Excerpt: The primary specific aim of this clinical trial is to determine whether treatment with rofecoxib or naproxen for one year will slow the rate of decline of cognitive function in patients with Alzheimer's disease (AD) as measured by ADAScog. Phase(s): Phase II; Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004845

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Agitation in Alzheimer's Disease Condition(s): Alzheimer Disease Study Status: This study is completed. Sponsor(s): National Institute on Aging (NIA) Purpose - Excerpt: Agitation affects 70 to 90 percent of patients with AD. Signs of agitation include verbal and physical aggressiveness, irritability, wandering, and restlessness. These behaviors often make caring for patients at home very difficult. Trazodone and haldol are two of the most commonly prescribed drugs for agitation in AD patients. Behavior management, a non drug approach, has been effective in reducing signs of agitation. Researchers have yet to compare the effectiveness of drug versus non drug therapy to treat agitation in AD patients and determine which is the best treatment. The Alzheimer's Disease Cooperative Study, with funding from the National Institute on Aging, is conducting an agitation treatment program at 21 sites in 16 States. This study will assess which of the above treatments is most effective. Phase(s): Phase III Study Type: Interventional

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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000179 •

Effects on sleep and attention of two currently marketed drugs for Alzheimer's disease Condition(s): Alzheimer's Disease Study Status: This study is completed. Sponsor(s): Janssen Pharmaceutica Purpose - Excerpt: Evaluate the effects of two marketed drugs on sleep and attention in patients with Alzheimer's disease. Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00035204

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Efficacy and Safety of Risperidone versus Placebo in patients with Psychosis of Alzheimer's Disease Condition(s): Dementia, Alzheimer Type Study Status: This study is completed. Sponsor(s): Johnson Development, L.L.C.

&

Johnson

Pharmaceutical

Research

and

Purpose - Excerpt: The purpose of this study is to compare the effectiveness and safety of risperidone versus placebo in patients that have been diagnosed with psychosis of Alzheimer's Disease Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00034762 •

Evaluation of Galantamine in the Treatment of Alzheimer's Disease Condition(s): Alzheimer Disease Study Status: This study is completed. Sponsor(s): Janssen Pharmaceutica Purpose - Excerpt: Galantamine is an experimental drug being evaluated in the United States for the treatment of Alzheimer's disease. Results from previous clinical trials suggest that galantamine may improve cognitive


performance in individuals with Alzheimer's disease. It is not a cure for Alzheimer's disease. Nerve cells in the brain responsible for memory and cognitive function communicate using a chemical called acetylcholine. Research has shown that deterioration of cells that produce acetylcholine in the brain affects thought processes. Galantamine is thought to work in two ways to increase the amount of acetylcholine available in the brain. It inhibits an enzyme that breaks down acetylcholine and it also stimulates the nicotinic receptors in the brain to release more acetylcholine. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000172 •

Investigation into Delay to Diagnosis of Alzheimer's Disease with Exelon (InDDEx) Condition(s): Alzheimer Disease; Cognition Disorders Study Status: This study is completed. Sponsor(s): Novartis Pharmaceuticals Purpose - Excerpt: This phase IIIb trial is a prospective, randomized, double-blind, placebo-controlled, 36-month study comparing the length of time of progression from mild cognitive impairment (MCI) to a clinical diagnosis of Alzheimer's disease (AD) in subjects taking Exelon vs. placebo. Exelon is currently under review with the U.S. Food and Drug Administration as a treatment for Alzheimer's disease. The drug has been cleared for marketing in more than 40 countries for Alzheimer's disease to date, including all 15 member states of the European Union, New Zealand, Argentina, Brazil and Mexico. Each subject with MCI will be randomly assigned to treatment with either Exelon or placebo. Subjects assigned to Exelon will receive 1.5 to 6.0 mg bid (twice daily) (3.0 to 12 mg/day) for the majority of the study. At every regular visit scheduled every three months, patients will be given basic efficacy and safety assessments. These assessments will include evaluation of adverse events, vital signs, activities of daily living, and clinical staging scales to determine if the subject may have converted to dementia. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000174

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Multicenter Trial of Prednisone in Alzheimer's Disease Condition(s): Alzheimer Disease Study Status: This study is completed. Sponsor(s): National Institute on Aging (NIA) Purpose - Excerpt: This is a randomized placebo controlled, double blind study. Patients who meet eligibility criteria and decide to participate in the study will be randomly assigned to receive either drug treatment or a placebo. Neither the patients nor the participating investigators will know who is receiving the drugs and who is receiving the placebo. Participation involves 15 outpatient clinic visits over a 68 week period. Patients take study medication at varying doses (the maximum dose is 20 mg daily), along with calcium and vitamin supplements. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000178

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Nefiracetam in the Treatment of Alzheimer's Disease Condition(s): Alzheimer's Disease Study Status: This study is completed. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS) Purpose - Excerpt: Some of the thinking difficulties of Alzheimer's patients may be due to a deficiency in a brain chemical called acetylcholine, which helps transmit messages between nerve cells. Nefiracetam is a new drug that stimulates acetylcholine. This study will test whether Nefiracetam can safely improve memory, thinking and activities of daily living in patients with mild to moderate intellectual impairment due to Alzheimer's disease. Patients in the study must have a caregiver and designated representative. Candidates will be given a medical history and physical examination that includes a complete neurologic and neuropsychologic evaluation, blood tests, and an electrocardiogram. A chest X ray and magnetic resonance imaging (MRI) test will be done on patients who have not had these tests within the previous two years. During the 20-week study, each patient will take three pills twice a day for twenty weeks of either Nefiracetame or placebo (sugar pill). Neither the patients nor the doctors will know which patients are getting the drug and which are getting the placebo. Blood and urine tests will be done frequently throughout the study. Patients will be asked


to have a spinal tap (on a voluntary basis) to measure the levels of drug in the spinal fluid, and a PET scan (a brain imaging test). At the end of the study, patients who feel they are doing well with no side effects from the drug (or placebo) may be given the option of continuing treatment for another seven months. Animal studies showed that Nefiracetam improved learning impairment and memory in rats with dementia. In a small study of humans, about one-fourth of patients who were given a low dose of the drug had improved intellectual function, and about onehalf who received a higher dose improved. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001933 •

Randomized Safety, Tolerability and Pilot Efficacy of AN-1792 in Alzheimer's Disease Condition(s): Alzheimer's Disease Study Status: This study is terminated. Sponsor(s): Elan Pharmaceuticals; Wyeth-Ayerst Research Purpose - Excerpt: A multi-center, double-blind, placebo-controlled outpatient, safety, tolerability, and pilot efficacy study of intramuscular AN1792 in patients with mild to moderate Alzheimer's disease. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00021723

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Study of Melatonin: Sleep Problems in Alzheimer's Disease Condition(s): Alzheimer Disease; Dyssomnias Study Status: This study is completed. Sponsor(s): National Institute on Aging (NIA) Purpose - Excerpt: This protocol is a multicenter clinical trial of melatonin for sleep disturbances associated with Alzheimer's disease (AD). Frequent nocturnal awakening is a common behavioral symptom of AD. Nighttime wandering and agitated behavior may result in injuries and sleep disruption for caregivers. Alternatives are sorely needed to the currently available sleep medications that have marginal efficacy and serious side effects. Melatonin is a naturally occurring hormone secreted

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by the pineal gland. It has soporific effects with oral administration and is well tolerated. It enhances sleep in normal older people. Melatonin also may help sleep disturbances associated with AD; however, this remains to be proven. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000171 •

The Safety and Efficacy of an Investigational Drug in Delaying the Progression of Alzheimer's Disease Condition(s): Alzheimer Disease Study Status: This study is terminated. Sponsor(s): Merck Purpose - Excerpt: This is a 15-month study with two phases. During the first 12-month phase of this study, patients will be randomly assigned to receive either active study drug or placebo (approximately half of all patients will be on active study drug, the other half on placebo). The second phase is a 3-month randomized withdrawal period. For this phase approximately 10% of the patients will remain on the active drug. Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006187

Benefits and Risks17 What Are the Benefits of Participating in a Clinical Trial? If you are interested in a clinical trial, it is important to realize that your participation can bring many benefits to you and society at large: •

A new treatment could be more effective than the current treatment for Alzheimer’s disease. Although only half of the participants in a clinical trial receive the experimental treatment, if the new treatment is proved to be more effective and safer than the current treatment, then those patients who did not receive the new treatment during the clinical trial may be among the first to benefit from it when the study is over.

This section has been adapted from ClinicalTrials.gov, a service of the National Institutes of Health: http://www.clinicaltrials.gov/ct/gui/c/a1r/info/whatis?JServSessionIdzone_ct=9jmun6f291.

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If the treatment is effective, then it may improve health or prevent diseases or disorders.

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Clinical trial patients receive the highest quality of medical care. Experts watch them closely during the study and may continue to follow them after the study is over.

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People who take part in trials contribute to scientific discoveries that may help other people with Alzheimer’s disease. In cases where certain diseases or disorders run in families, your participation may lead to better care or prevention for your family members. The Informed Consent

Once you agree to take part in a clinical trial, you will be asked to sign an “informed consent.” This document explains a clinical trial’s risks and benefits, the researcher’s expectations of you, and your rights as a patient.

What Are the Risks? Clinical trials may involve risks as well as benefits. Whether or not a new treatment will work cannot be known ahead of time. There is always a chance that a new treatment may not work better than a standard treatment. There is also the possibility that it may be harmful. The treatment you receive may cause side effects that are serious enough to require medical attention.

How Is Patient Safety Protected? Clinical trials can raise fears of the unknown. Understanding the safeguards that protect patients can ease some of these fears. Before a clinical trial begins, researchers must get approval from their hospital’s Institutional Review Board (IRB), an advisory group that makes sure a clinical trial is designed to protect patient safety. During a clinical trial, doctors will closely watch you to see if the treatment is working and if you are experiencing any side effects. All the results are carefully recorded and reviewed. In many cases, experts from the Data and Safety Monitoring Committee carefully monitor each clinical trial and can recommend that a study be stopped at any time. You will only be asked to take part in a clinical trial as a volunteer giving informed consent.

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What Are a Patient’s Rights in a Clinical Trial? If you are eligible for a clinical trial, you will be given information to help you decide whether or not you want to participate. As a patient, you have the right to: •

Information on all known risks and benefits of the treatments in the study.

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Know how the researchers plan to carry out the study, for how long, and where.

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Know what is expected of you.

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Know any costs involved for you or your insurance provider.

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Know before any of your medical or personal information is shared with other researchers involved in the clinical trial.

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Talk openly with doctors and ask any questions.

After you join a clinical trial, you have the right to: •

Leave the study at any time. Participation is strictly voluntary. However, you should not enroll if you do not plan to complete the study.

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Receive any new information about the new treatment.

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Continue to ask questions and get answers.

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Maintain your privacy. Your name will not appear in any reports based on the study.

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Know whether you participated in the treatment group or the control group (once the study has been completed).

What about Costs? In some clinical trials, the research facility pays for treatment costs and other associated expenses. You or your insurance provider may have to pay for costs that are considered standard care. These things may include inpatient hospital care, laboratory and other tests, and medical procedures. You also may need to pay for travel between your home and the clinic. You should find out about costs before committing to participation in the trial. If you have health insurance, find out exactly what it will cover. If you don’t have health insurance, or if your insurance company will not cover your costs, talk to the clinic staff about other options for covering the cost of your care.


What Questions Should You Ask before Deciding to Join a Clinical Trial? Questions you should ask when thinking about joining a clinical trial include the following: •

What is the purpose of the clinical trial?

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What are the standard treatments for Alzheimer’s disease? Why do researchers think the new treatment may be better? What is likely to happen to me with or without the new treatment?

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What tests and treatments will I need? Will I need surgery? Medication? Hospitalization?

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How long will the treatment last? How often will I have to come back for follow-up exams?

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What are the treatment’s possible benefits to my condition? What are the short- and long-term risks? What are the possible side effects?

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Will the treatment be uncomfortable? Will it make me feel sick? If so, for how long?

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How will my health be monitored?

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Where will I need to go for the clinical trial? How will I get there?

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How much will it cost to be in the study? What costs are covered by the study? How much will my health insurance cover?

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Will I be able to see my own doctor? Who will be in charge of my care?

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Will taking part in the study affect my daily life? Do I have time to participate?

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How do I feel about taking part in a clinical trial? Are there family members or friends who may benefit from my contributions to new medical knowledge?

Keeping Current on Clinical Trials Various government agencies maintain databases on trials. The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide patients, family members, and physicians with current information about clinical research across the broadest number of diseases and conditions.

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The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to their Web site (www.clinicaltrials.gov) and search by “Alzheimer’s disease” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/

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For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html

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For trials on aging and age-related diseases, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm

General References The following references describe clinical trials and experimental medical research. They have been selected to ensure that they are likely to be available from your local or online bookseller or university medical library. These references are usually written for healthcare professionals, so you may consider consulting with a librarian or bookseller who might recommend a particular reference. The following includes some of the most readily available references (sorted alphabetically by title; hyperlinks provide rankings, information and reviews at Amazon.com): •

A Guide to Patient Recruitment : Today’s Best Practices & Proven Strategies by Diana L. Anderson; Paperback - 350 pages (2001), CenterWatch, Inc.; ISBN: 1930624115; http://www.amazon.com/exec/obidos/ASIN/1930624115/icongroupinter na


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A Step-By-Step Guide to Clinical Trials by Marilyn Mulay, R.N., M.S., OCN; Spiral-bound - 143 pages Spiral edition (2001), Jones & Bartlett Pub; ISBN: 0763715697; http://www.amazon.com/exec/obidos/ASIN/0763715697/icongroupinter na

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The CenterWatch Directory of Drugs in Clinical Trials by CenterWatch; Paperback - 656 pages (2000), CenterWatch, Inc.; ISBN: 0967302935; http://www.amazon.com/exec/obidos/ASIN/0967302935/icongroupinter na

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Extending Medicare Reimbursement in Clinical Trials by Institute of Medicine Staff (Editor), et al; Paperback 1st edition (2000), National Academy Press; ISBN: 0309068886; http://www.amazon.com/exec/obidos/ASIN/0309068886/icongroupinter na

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Handbook of Clinical Trials by Marcus Flather (Editor); Paperback (2001), Remedica Pub Ltd; ISBN: 1901346293; http://www.amazon.com/exec/obidos/ASIN/1901346293/icongroupinter na

Vocabulary Builder The following vocabulary builder gives definitions of words used in this chapter that have not been defined in previous chapters: Consumption: Pulmonary tuberculosis. [NIH] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Delusion: A false belief, not susceptible to argument or reason, and determined, pathologically, by some form of mental disorder. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Haloperidol: Butyrophenone derivative. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Lipitor: Cholesterol-lowering drug. [NIH] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH]

Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH]

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PART II: ADDITIONAL RESOURCES AND ADVANCED MATERIAL

ABOUT PART II In Part II, we introduce you to additional resources and advanced research on Alzheimer’s disease. All too often, patients who conduct their own research are overwhelmed by the difficulty in finding and organizing information. The purpose of the following chapters is to provide you an organized and structured format to help you find additional information resources on Alzheimer’s disease. In Part II, as in Part I, our objective is not to interpret the latest advances on Alzheimer’s disease or render an opinion. Rather, our goal is to give you access to original research and to increase your awareness of sources you may not have already considered. In this way, you will come across the advanced materials often referred to in pamphlets, books, or other general works. Once again, some of this material is technical in nature, so consultation with a professional familiar with Alzheimer’s disease is suggested.

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CHAPTER 4. STUDIES ON ALZHEIMER’S DISEASE Overview Every year, academic studies are published on Alzheimer’s disease or related conditions. Broadly speaking, there are two types of studies. The first are peer reviewed. Generally, the content of these studies has been reviewed by scientists or physicians. Peer-reviewed studies are typically published in scientific journals and are usually available at medical libraries. The second type of studies is non-peer reviewed. These works include summary articles that do not use or report scientific results. These often appear in the popular press, newsletters, or similar periodicals. In this chapter, we will show you how to locate peer-reviewed references and studies on Alzheimer’s disease. We will begin by discussing research that has been summarized and is free to view by the public via the Internet. We then show you how to generate a bibliography on Alzheimer’s disease and teach you how to keep current on new studies as they are published or undertaken by the scientific community.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and Alzheimer’s disease, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the


format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type in “Alzheimer’s disease” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is a sample of what you can expect from this type of search: •

Acetyl L-Carnitine Slows Decline in Younger Patients With Alzheimer's Disease: a Reanalysis of a Double-Blind, PlaceboControlled Study Using the Source: International Psychogeriatrics. 10(2): 193-203. June 1998. Summary: This article assesses the longitudinal effects of acetyl-Lcarnitine (ALC) on patients diagnosed with Alzheimer's disease (AD). Researchers studied 334 diagnosed subjects from 24 sites across the United States by administering the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS) every 3 months for 1 year. Data showed that both the ALC group and the placebo group exhibited the same mean rate of change on the ADAS. Analysis revealed a statistically significant Age x Drug interaction characterized by younger subjects benefiting more from ALC treatment than older subjects. Further analyses suggested that the optimal, though not statistically significant, cutoff point for ALC benefits was age 61. The authors concluded that ALC slows the progression of AD in younger subjects, and the use of a trilinear approach to estimate the average rate of change may prove valuable in pharmacological trials. 3 figures, 3 tables, 20 references.

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Extrapyramidal Side Effects in Patients With Alzheimer's Disease Treated With Low-Dose Neuroleptic Medication Source: American Journal of Geriatric Psychiatry. 6(1): 75-82. Winter 1998. Summary: This article describes a study to determine whether extrapyramidal motor function, measured before the start of neuroleptic treatment, could be used to predict the development and severity of neuroleptic-induced parkinsonism (NIP) in patients with Alzheimer's disease (AD). Twenty-four community-dwelling patients with AD, mean age 75.1 years, were recruited from the Geropsychiatry Clinical Research Center at the University of California, San Diego. Sixteen patients were treated with haloperidol and eight with thioridazine, at dosages determined by their primary physicians. They were assessed before treatment and after 3 months and 9 months of treatment. Pretreatment

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extrapyramidal motor function and NIP were assessed with a modified version of the Simpson-Angus Rating Scale for Extrapyramidal Side Effects (SAS). Postural tremor, rigidity, and bradykinesia also were quantified with instrument-based measures. Sixteen patients (66.7 percent) developed NIP at some point during the 9-month followup. These patients exhibited more severe pretreatment bradykinesia on instrument-based measures, but not on the SAS, than patients who did not develop NIP. The authors conclude that instrumented measures of pretreatment motor function may be useful for identifying patients at greater risk for NIP. 1 figure, 1 table, 21 references. •

The Contribution of Gaetano Perusini to the Definition of Alzheimer's Disease Source: Italian Journal of Nerological Sciences. 19: 49-52. 1998. Summary: This article discusses Gaetano Perusini's contribution to the definition of Alzheimer's disease (AD). Shortly after Alzheimer presented the seminal case of a 51-year old woman with dementia, he suggested that Perusini undertake a more detailed study of the clinical notes and neuropathological specimens. Perusini studied that case along with three others, and subsequently produced three papers that more clearly defined the clinical and histopathological features of AD. The third paper, published in 1911, centered on the diagnostic value of the senile plaques and neurofibrillar alterations originally described by Alzheimer. Throughout his works, Perusini was careful to credit Alzheimer with his discovery and to express gratitude that Alzheimer entrusted him with further study of the disease. 2 figures, 17 references.

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Cognitive Models of Physicians' Legal Standard and Personal Judgments of Competency in Patients With Alzheimer's Disease Source: JAGS. Journal of the American Geriatrics Society. 48(8): 919- 927. August 2000. Summary: This article explores cognitive predictors of physician judgements of competency in patients with Alzheimer's disease (AD). Five physicians with extensive experience in dementia and competency assessment were asked to make judgments of 10 older controls and 21 AD patients based on videotapes of their performance on the Capacity to Consent to Treatment Instrument (CCTI). The CCTI consists of two clinical vignettes that test competency under five different, increasing difficult legal standards (LS). Each physician made a judgment of competent or incompetent under each LS as well as a personal competency judgment for both vignettes. Results showed that multiple cognitive functions predicted physicians' LS and personal competency


judgments. Declines in semantic knowledge, short-term verbal recall, and simple reasoning ability predicted physicians' judgments on the three most difficult and clinically relevant LS as well as their personal competency judgments. The findings suggest that clinical assessment of competency should include evaluation of semantic knowledge, verbal recall, and simple reasoning abilities. 3 tables, 29 references. •

Is Smoking Associated With the Risk of Developing Alzheimer's Disease? Results From Three Canadian Data Sets Source: Annals of Epidemiology. 10(7): 409-416. October 2000. Summary: This article investigates the association between smoking and Alzheimer's disease (AD). Three Canadian data sets were analyzed: the University of Western Ontario Dementia Study (200 cases, 163 controls), the Canadian Study of Health and Aging (258 cases, 258 controls), and the patient database from the Clinic for Alzheimer Disease and Related Disorders at the Vancouver Hospital and Health Sciences Center (566 cases, 277 controls). The association between smoking and AD was examined using bivariate analyses and multiple logistic regression models with adjustment for age, sex, educational level, family history of dementia, head injury, and hypertension. The results of bivariate analyses were inconsistent across the three data sets, with smoking found to be a significant protective factor, a significant risk factor, or not associated with AD. Results of the multiple logistic regression models were consistent; no significant association remained after adjusting for potential confounders. The authors conclude that failure to adjust for appropriate confounders may explain the inconsistent reports of an association between smoking and AD in the literature. 7 tables, 41 references. (AA-M).

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First International Pharmacoeconomic Conference on Alzheimer's Disease: Report and Summary Source: Alzheimer Disease and Associated Disorders. 12(4): 266-280. 1998. Summary: This article presents a report on the First International Pharmacoeconomic Conference on Alzheimer's disease (AD), which was held under the auspices of the International Working Group for Harmonization of Dementia Drug Guidelines. The conference brought together researchers, clinicians, and industry representatives. In this report, the authors discuss the role of longer life expectancy on quality of life, integrating care systems, and the economics of AD. They look at guidelines, current trends, and methodological issues of pharmacoeconomic studies in dementia as well as economic models of drug treatments for AD. The authors hope that the models described may

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become more available to politicians, clinicians, and caregivers to help them make better decisions about AD treatment. 4 tables, 73 references. •

Alzheimer's Disease International and International Working Group for Harmonization of Dementia Drug Guidelines for Research Involving Human Source: Alzheimer Disease and Associated Disorders. 13(2): 71-79. 1999. Summary: This consensus statement addresses the Working Group's mission, of global drug development efforts in dementia, focusing on the ethical considerations relevant to dementia research proposal review. The statement emphasizes that ethical review committees must consider a proposal's scientific design; it would be unethical to permit a study that presents risk to subjects with cognitive impairment if the study, whether biomedical or behavioral, is flawed in a way that would make the results invalid. Fifteen guidelines directed at the application of ethical principles to research involving human subjects are presented. The guidelines address the following categories: informed consent of subjects, selection of research subjects, confidentiality of data, compensation of research subjects for accidental injury, review procedures, and externally sponsored research. 18 references.

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Descriptive Analysis of Emergency Hospital Admissions of Patients With Alzheimer's Disease Source: Alzheimer Disease and Associated Disorders. 15(1): 21-25. 2001. Summary: This journal article describes a study that examined the reasons for emergency hospital admissions among people with dementia of the Alzheimer type (DAT) and noted patient characteristics. Information was collected prospectively on 118 patients with DAT, most from two emergency departments of one British hospital. Data analysis indicated that the two main reasons for admission were behavioral problems and falls. Patients with DAT were usually at an advanced stage of the disease and had poor nutritional status and loss of activities of daily living. Approximately one-third of the patients had been admitted to the hospital for the same reason in previous months. The main medications taken were psychotropic drugs. Discharge reports indicated that medications were a contributing factor in the disorders of 25 percent of the patients. The researchers concluded that improved information for caregivers and early management and treatment of patients with DAT are crucial. 3 tables, 21 references.


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Assessing the Impact of Neuropsychiatric Symptoms in Alzheimer's Disease: The Neuropsychiatric Inventory Caregiver Distress Scale Source: Journal of the American Geriatrics Society. 46(2): 210-215. February 1998. Summary: This journal article describes an evaluation of the Neuropsychiatric Inventory Caregiver Distress Scale (NPI-D), an adjunct scale to the Neuropsychiatric Inventory (NPI) designed to assess caregiver distress associated with neuropsychiatric symptoms in patients with Alzheimer's disease (AD. The participants were 85 patients with AD, aged 58 to 88 years, and their caregivers (54 spouses and 31 children), enrolled in ambulatory Memory Disorder Clinics at the University of California at Los Angeles and the University of Pittsburgh, Pennsylvania. The NPI was used to assess neuropsychiatric symptoms in the patients, and the NPI-D was used to assess caregiver distress related to those symptoms. Criterion validity of the NPI-D was examined in 69 participants by comparison with an abridged version of the Relatives' Stress Scale (RSS). Test-retest validity was examined in 20 caregivers, and interrater validity in 16 caregivers. The NIP-D scale had adequate testretest and interrater reliability, and NIP-D ratings were significantly correlated with RSS scores. Caregiver distress was associated more strongly with neuropsychiatric symptoms than with cognitive symptoms. The authors conclude that the NIP-D may be useful in both clinical and research settings to assess the effects of neuropsychiatric symptoms on caregiver distress. 3 tables, 42 references.

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Paradise Garden: A Model Garden Design for Those With Alzheimer's Disease Source: Activities, Adaptation, and Aging. 22(1-2): 3-16. 1997. Summary: This journal article describes the design of garden spaces for people with Alzheimer's disease (AD), using the paradise garden as a model for a restorative environment. The concept of the paradise garden originated in ancient times in the Middle East and is characterized by four key elements: an enclosing wall, water, a canopy (tree or trellis), and a hill. This article explores how these elements, together with paving, can serve the needs of people with AD. It describes how these components of the paradise garden were integrated into the design of three therapeutic gardens at the Alois Alzheimer Center in Cincinnati, Ohio. The center accommodates 82 residents with AD and dementia, and provides a continuum of care. Three garden spaces were designed to meet the unique environmental, social, and physical needs of residents at different stages of AD. All of the garden spaces feature an enclosing wall for safety and security, a trellis to filter harsh sunlight, a raised area to provide

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visual interest and variety, a small pool and fountain, and nontoxic plants for sensory stimulation. Two of the gardens have looped walkways to permit wandering by active residents; and one is configured to accommodate wheelchairs and sturdy, comfortable garden furniture for more impaired residents. 1 figure, 11 references. •

Features of Alzheimer's Disease: Crystallized and Fluid Intelligence in Elderly Patients With Mild Dementia of the Alzheimer Type Source: International Psychogeriatrics. 10(2): 147-154. June 1998. Summary: This journal article discusses a study that examined early intellectual deficits in elderly patients by using the Japanese version of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) to compare 25 elderly patients with Alzheimer's disease (AD) and 25 normal controls. The two groups were similar in age, years of education, and gender. Researchers classified the WAIS-R subtests into two categories: fluid intelligence and crystallized intelligence. Fluid intelligence describes the ability to acquire new concepts and adapt to unfamiliar situations; crystalized intelligence refers to knowledge accumulated over a lifetime. Data revealed that the AD patients had significantly lower crystallized intelligence scores; subtests for crystallized intelligence (information, comprehension, and similarities) showed the most significant deficits. The fluid intelligence scores did not differ significantly between the two groups. These results demonstrate that elderly subjects with mild AD have crystallized intelligence that is more impaired than that of subjects without dementia. These results suggest that it may be possible through a prospective cohort study, to clarify more precisely the intellectual deficits in AD. 2 tables, 40 references (AA-M).

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Apolipoprotein E Genotype and Progression of Alzheimer's Disease: The Rotterdam Study Source: Journal of Neurology. 246: 304-308. 1999. Summary: This journal article examines the effect of the apolipoprotein E4 allele on the progression of Alzheimer's disease (AD). A sample of AD patients (n=97) was drawn from a population-based study of people aged 55 years and older living in a suburb of Rotterdam, The Netherlands. All patients were free of dementia at study entry, and were followed for up to 5 years. ApoE genotyping was performed for all participants. Cognitive function was assessed with the Dutch version of the MiniMental State Examination (MMSE), and stage of AD with the Clinical Dementia Rating (CDR) scale. Changes in MMSE and CDR scores were similar in carriers and noncarriers of the apoE4 allele. Overall survival also did not differ between the two groups. The findings suggest that the


progression of AD is not related to the presence or absence of the apoE4 allele. 1 figure, 2 tables, 26 references. •

Right-Side Neglect in Alzheimer's Disease Source: Neurology. 51: 1207-1209. October 1998. Summary: This journal article reports on a 73-year-old woman with probable Alzheimer's disease (AD) who showed signs of right-side neglect and extinction. Unilateral neglect, or the inability to pay attention to events occurring on one side of space, usually occurs for left-side events after focal right-hemisphere damage. In this case, the signs of unilateral neglect for the right hemispace were consistent throughout several tasks and became more severe at retest after 1 year. Neuroimaging techniques demonstrated asymmetry of cortical involvement, with cortical atrophy and hypoperfusion predominant in the left posterior regions. The authors state that unilateral neglect should be assessed systematically in AD. This assessment could help determine more precisely the pattern of cognitive impairment in each patient and could help identify patients at risk for spatial disorientation and wandering. 2 figures, 1 table, 10 references (AA-M).

Federally Funded Research on Alzheimer’s Disease The U.S. Government supports a variety of research studies relating to Alzheimer’s disease and associated conditions. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.18 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Visit CRISP at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You can perform targeted searches by various criteria including geography, date, as well as topics related to Alzheimer’s disease and related conditions. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore Alzheimer’s disease and related conditions. In some cases, therefore, it may Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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be difficult to understand how some basic or fundamental research could eventually translate into medical practice. The following sample is typical of the type of information found when searching the CRISP database for Alzheimer’s disease: •

Project Title: A MULTIDIMENSIONAL ALZHEIMER'S DISEASE BRAIN ATLAS Principal Investigator & Institution: Toga, Arthur W.; Professor; None; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 01-MAY-1995; Project End 31-JUL2006 Summary: This competitive renewal application has an overall goal, the creation of an atlas of Alzheimer’s disease. The neuroscience and informatics efforts proposed here will result in a tool set and product that is applicable not only to the basic and clinical science of Alzheimer's disease, but to the general problem of mapping the structure and function of any dynamic process in health or disease in whole populations of subjects. Leveraging the accomplishments achieved during the last period of this project and building upon our highresolution post mortem anatomic framework, the development of atlas construction methodology and the ability to create 3D visual models of anatomy, we will construct the first multimodality probabilistic atlas of the brain representing a diseased population. Including both histologically processed post mortem tissue as well as highresolution 3D MR images acquired from subjects in various stages of Alzheimer's disease, we will generate the average geometry and 3D variability of the anatomic structures of these populations. Further, we will describe the anatomy as cytoarchitectural features from histology and gyral sulcal features from MRI. There are 7 specific aims in this project. The first will be the collection of a cohort of post mortem specimens from an Alzheimer's disease population. Second, we will create detailed individual probabilistic maps describing the architectural boundaries in AD and matched controls. Third, we will create an MRI probabilistic atlas based upon data that has been previously acquired or will be acquired with funding from other active projects. Fourth, we will develop and refine appropriate registration deformation correction atlasing strategies to create a comprehensive multimodality atlas of Alzheimer’s disease. This will enable the development of data at different spatial resolutions and representing different aspects of brain structure and function. Fifth, individualized data analysis utilizing mathematical strategies to compare individual MRI data with the probabilistic atlas will enable access by the


neuroscience community to this multimodality atlas. Sixth, we will develop dynamic 4D mapping tools to express the spatial and temporal profiles of degeneration heretofore unavailable in static single time point representations of anatomy or physiology. Seventh, these will be combined into an interactive visualizable and analytic tool set made available to the neuroscientific community. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: A PROGRAM OF COLLABORATIVE CARE FOR ALZHEIMER DISEASE Principal Investigator & Institution: Callahan, Christopher M.; Associate Professor; Medicine; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL2005 Summary: Alzheimer Disease and related disorders are common among older adults attending primary care clinics. Unfortunately, many of these vulnerable older adults do not receive an adequate diagnosis, evaluation, education treatment, or long-term management. Also, primary care practices are rarely designed to provide education and support for the caregivers of patients with dementia. Fragmentation of care within the health care system and poor communication among the health care providers and between local social support agencies contribute to frustration, poorer outcomes, and increased costs. Indeed, primary care practitioners appear to have tremendous difficulty in delivering a systematic program of care for older adults with dementia. In our earlier studies, we found that nearly 1 in 6 patients over the age 60 attending a large primary care practice suffered from cognitive impairment. Unfortunately, 75 percent of the patients with moderate to severe cognitive impairment had not been diagnosed with a dementing disorder. Patients with moderate to severe cognitive impairment were more likely to be seen in the emergency room, more likely to be hospitalized, and more likely to die over the following year. Even controlling for the impact of comorbid conditions, cognitive impairment in these older adults was significantly associated with mortality after 5-7 years of follow-up. We are proposing a four-year randomized controlled clinical trial designed to test the efficacy of an Integrated Program of Collaborative Care as compared to usual care in improving the outcomes of care for older adults with Alzheimer Disease in a primary care setting. Although guidelines for the care of patients with Alzheimer Disease and related disorders have been published, there are no clinical trials that test the impact of close adherence to these guidelines on the outcomes of care

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for a group of vulnerable older adults in an urban primary care setting. We are hypothesizing that the integrated program of collaborative care, managed by a geriatric nurse practitioner who is empowered to facilitate published guidelines for care, will result in: a reduction in psychopathology and disruptive behavior among patients; a reduction in stress and depression among caregiver; a reduction in the use of skilled nursing home services; and an improvement in satisfaction with care. The study design will also allow us to describe the prevalence of dementing disorders and associated comorbidity in primary care and to measure utilization, costs, use of community services, and the costs associated with the intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADAPT 78 IN OXIDANT STRESS, AGING AND NEURODEGENERATION Principal Investigator & Institution: Davies, Kelvin J.; Gerontology; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2001; Project Start 01-FEB-2000; Project End 31-JAN2005 Summary: We are interested in a possible link between oxidative stress, aging and neurodegenerative diseases. In recent studies of adaptation to oxidative stress we have identified several previously unknown genes (in addition to confirming the overexpression of several known genes) that appear to provide stress protection in isolated hamster cells in culture. These "adapt" genes include: adapt15, adapt33, adapt66, adapt73, adapt78, and adapt 116. Although our studies indicate that full adaptation depends upon both transcription and translation, it is not clear which genes are actually required. Although each of these newly discovered genes is worthy of detailed study, adapt78 whose mRNA levels increase more than 50 fold in adaptation, in particular stands out. In screening studies employing autopsy samples from human brains, we have now found that the human homologue of adapt78 exhibits extremely high levels of expression in brain autopsy samples from Alzheimer's disease patients, and low levels of expression in brain samples encompassing the substantia nigra from patients who died with Parkinson's disease. Recently, it has become clear that our adapt78 is identical to (or at least highly homologous with) the simultaneously independently discovered Down syndrome critical region 1 (DSCR1) gene of chromosome 21. Furthermore, two different isoforms of both adapt78 and DSCR1 are differentially expressed; corresponding to differentially spliced forms of exons 1-5, 6, 7 and exons 4-5, 6, 7. We


propose to now carefully study expression of both isoforms of the human adapt78 gene in different brain regions, using the more sensitive techniques of RT-PCR and in situ hybridization. We plan to study adapt78 expression as a function of age, in brain autopsy samples from otherwise healthy individuals, since adapt78 expression may well vary with age. We will perform detailed studies of brain samples from Alzheimer's disease patients, Parkinson's disease patients, and Down syndrome patients in order to carefully determine both qualitative and quantitative differences in expression of both isoforms of adapt78 mRNA. Localization of adapt78 mRNA expression by cell type will also be studied. We also will synthesize and characterize the (1-5, 6, 7 and 4-5, 6, 7) Adapt78 proteins and generate antibodies to them in order to study expression of the actual proteins in all cell and brain samples. In cell culture studies, with PC-12 cells, we will test the hypothesis that inducible overexpression of adapt78 may confer an oxidative stress resistance phenotype. We will also test the ability of inducible adapt78 overexpressing cells to overcome the lethal oxidizing effects of glutathione deficiency, caused by expression of antisense message to gamma glutamylcysteine synthetase. These studies will allow us to begin to investigate our hypothesis that aging, and perhaps certain neurodegenerative diseases, involving defects in the expression of adapt78 and other adaptive genes required to cope with the deleterious effects of oxidative stress. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALZHEIMER'S DISEASE AND ANIMAL MODELS Principal Investigator & Institution: Price, Donald L.; Professor of Neurology; Pathology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 28-SEP-1984; Project End 31-MAR2004 Summary: The Alzheimer's Disease Research Center (ADRC) at The Johns Hopkins Medical Institutions (JHMI) is committed to investigations of aging and Alzheimer's disease (AD). Age and genes are important risk factors for AD, and our principal goal is to examine the impact of age and mutations in the amyloid precursor protein (APP) in the cognition/memory abnormalities occurring in elderly humans and in our mouse/human-APPswe (Mo/Hu- APP) transgenic (Tg) mice. Thus, with the support of Cores A and D, Cores B and C focus on behavior-brain correlations in intact, mildly impaired, and demented aged individuals, particularly by those in the cohorts of the Baltimore Longitudinal Study of Aging (BLSA). This extraordinarily well characterized with serial

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imaging studies; many of these individuals have entered our prospective autopsy program. Supported by Cores B and C, Project 4 takes advantage of this material to examine early brain lesions focusing on: glial cell responses and the production of inflammatory mediators. complement factors, cytokines, etc.) capable of influencing neurons and synapses. These findings will be correlated with detailed assessments of the neuropathology, quantitative estates of synaptic markers, and evidence of cell death and neuronal loss. In parallel to the studies of aging and AD in humans, Projects 1-3 take advantage of our lines of Mo/Hu-APPswe Tg mice that express mutant APP at levels approximately threefold greater than endogenous MoAPP; these animals develop Abeta deposits, we hypothesize that elevated levels of Abeta42 damage synapses before over deposits of Abeta species. In project 1, we will examine the performances of these Tg mice on tasks designed to assess cognition/memory. In Project 2, we will correlate these findings with studies of biochemical marker (e.g. levels of Abeta peptide species, synaptic proteins, neurotransmitters and their enzymes) and the character/severity of the cellular pathology (e.g., abnormalities in synapses, Abeta deposition, loss of synapses, activation of glial cells, subsets of neurons, evidence of cell death, etc.) in specific regions of brain. In Project 3, we believe that these parallel clinical-neurochemical-pathological correlative studies of humans and Tg mice will help to define the biological substrates of impairments. In the intervention studies of our Tg mice, we will assess the responsivity (to age, genotype, and toxins) to the basal forebrain cholinergic and monoaminergic systems that are vulnerable in cases of AD; attempt to provoke glial cells to enhance amyloid; and to test the effects of estrogen on Abeta deposits. Finally, Core D will serve to disseminate information concerning age-associated diseases to families, caregivers, and other health professionals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALZHEIMER'S DISEASE PREVENTION TRIAL WITH ESTROGENS Principal Investigator & Institution: Sano, Mary; Professor of Neuropsychology; Psychiatry; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2003; Project Start 01-SEP-1998; Project End 31-AUG2008 Summary: (provided by applicant): This is a continuation of a double blind placebo controlled multi-center clinical trial to determine if estrogen can delay the onset of Alzheimer's Disease (AD) and reduce memory decline. The use of estrogen to prevent or delay AD is supported


by biologic, epidemiologic and clinical studies. New data are available which demonstrate that estrogen does not have a role in prevention of heart disease and stroke. However, the mechanisms through which estrogens may have a benefit in dementia are not the same as those which may mediate vascular activity. In the original proposal we postulated that estrogen had an effect on cognition and dementia, that the trial to assess dementia in a cohort with high risk of dementia was feasible and that dementia prevention was a high priority. It was designed to answer the question in a population at risk for dementia. We have carefully selected women at high risk for dementia and by careful screening we have selected to reduce the risk of the known estrogen related adverse outcomes. We propose to continue this 5 year multicenter, randomized, double blind placebo controlled trial of estrogens (Premarin or Prempro) to assess its efficacy to prevent memory loss and dementia in 900 healthy, elderly women greater than or equal to age 65 with a family history of AD recruited at 27 sites. Subjects will be assessed at 6 month intervals for safety and compliance and at annual intervals for cognitive outcomes. We believe that this trial must be completed to answer this important question. We propose the following specific aims: 1) to continue the double-blind placebo controlled 5 year trial of Premarin (.625 mg/day) or Prempro to assess the efficacy to prevent memory loss and dementia in healthy elderly women with a family history of AD; 2) To assess the safety of this regimen in this cohort with specific attention to the recently established profile of vascular adverse events; 3) To assess our use of a very sensitive neuropsychotogical battery which may permit reliable, early detection of impaired cognitive health. In an aging society, with the increasing risk of Alzheimer's disease and memory loss, and in a world of growing technological complexity requiring intact cognition, it would be short-sighted to abandon studies of an agent which has the potential to prevent cognitive loss and AD. This trial may represent the very last chance to determine if estrogen can have a benefit in dementia prevention and memory protection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALZHEIMERS DISEASE RESEARCH CENTER Principal Investigator & Institution: Thal, Leon J.; Professor and Chair; Neurosciences; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 92093 Timing: Fiscal Year 2001; Project Start 28-SEP-1984; Project End 31-MAR2004 Summary: This proposal is for a five-year renewal of the Alzheimer's Disease Research Center (ADRC) at the University of California San

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Diego in consortium with The Salk and The Burnham Institutes. The major goals of the Center over the next five years will be to expand our efforts into early clinical identification of Alzheimer's disease (AD) and studying mechanisms of neurodegeneration and repair. Projects will focus on semantic memory in AD, potential mechanisms of neurodegeneration in AD, alpha-synuclein biology, and mechanisms whereby hormones or environment may enhance neuronal survival. In addition, we will continue to carry out detailed clinicopathological correlations and studies of the course of AD. This Center will continue to maintain extremely strong Clinical and Neuropathology Cores. The Clinical Core will continue to longitudinally characterize a cohort of approximately 475-500 subjects to study early changes in cognition and semantic memory, and to provide other AD investigators and the San Diego community as a whole with a well- characterize clinical cohort of both Caucasian and Hispanic volunteer who undergo annual evaluations and are willing to participate in clinical research. The Clinical Core will also recruit special subjects and controls to support the special needs of many of the individual projects. Subjects will also participate in multicenter drug trials. Data derived from subjects will be used in collaborative research. We will place increasing emphasis in identifying genetic influence that either accelerate or protect individuals from the development of AD. In addition, we will continue to focus our studies on the 15-20% of individuals with AD who also have Lewy bodies in their cortex and represent the second most common form of dementia in the United States. The Neuropathology ore will continue to refine the diagnosis of AD and LBD, provide diagnoses, clinicopathological correlations, and brain tissue. The Center as a whole will continue to provide brain tissue, fibroblasts, plasma, DNA, and cerebrospinal fluid to investigators upon request. The ADRC provides a setting to facilitate research training of investigators and will transfer information to the profession and lay communities through our mini-residency program, conferences and other educational activities. The Biostatistics Core will continue to modernize the database and will: 1) maintain the database for the Center, 2) transmit data as requested for the Alzheimer's Disease Data Coordinating Center, 3) provide consultations and statistical expertise for projects emanating from the cores, projects and pilots. Our specific research projects in this renewal include: the role of caspase cleavage in neurodegenerative disease (Bredesen), regulation of neurogenesis in the adult mammalian hippocampus (Gage), NACP/alpha-synuclein and the mechanism of neurodegeneration in Lewy body disease (Masliah), cognitive studies of semantic memory in AD (Salmon), and estrogen mediated neuronal plasticity in the brain


(Tuszynski). A mechanism is also outlined for the awarding of pilot feasibility studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALZHEIMERS DISEASE RESEARCH CENTER Principal Investigator & Institution: Doody, Rachelle S.; Neurology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 1998; Project Start 29-SEP-1989; Project End 31-MAY2004 Summary: The Baylor College of Medicine's ADRC will now focus on detailed evaluation and longitudinal assessment of a well-characterized population of Alzheimer's disease patients and controls including related neurodegenerative disorders to be correlated with neuropathological studies and parallel research investigations of the mechanisms of selective neuronal vulnerability and prevention of cell death. The Administrative Core will coordinate and help foster the goals of the Clinical Core, the Neuropathology Core, and the Information Core and promote interactions between the Cores and the three research projects and the two pilot projects. It will help foster the growth of Alzheimer's disease clinical care and research in the Southwestern par tof the United States. The Clinical Core will promote and facilitate the recruitment, follow up, and detailed evaluation of patients with Alzheimer's disease as well as appropriate controls, including minatory populations. It will monitor rates of progression with special emphasis on defining populations with slow an with fast progression, and will encourage clinical pathologic correlations. The Neuropathology Core will establish the histopathology of Alzheimer's disease, maintain a rapid autopsy protocol, provide special histologic stains and quantitative measures, and support eh Brain Donation Program. The Information Core will provide Alzheimer's disease educational outreach program and consultation to healthcare providers, caregivers, and the Houston lay community. Data management now assures improved communication between Cores an projects under the aegis of our biostatistician. Research Project 1 will investigate mechanisms of selective vulnerability and the role of increased intracellular calcium and limited calcium buffering capacity. Specific studies will explore the direct toxic effects of IgG from amyotrophic lateral sclerosis patients on a motor neuron cell line and the toxic effects of beta amyloid on a substantia nigra cell line. Research Project 9 will test a model for neuronal rescue by implanting cells with an amplifiable regulatable gene. Cells can be activated to produce tyrosine hydroxylase in 6-OH. Dopamine lesioned animals and nerve growth factor in fimbria-fornix lesioned animals. Research Project 10 will

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investigate interactions between mononuclear phagocytes and AD plaques, and will assess possible consequences of these interactions, including neuronal cell death. Plot Project 1 is a study of implicit semantic memory, and is related to past and present interests of the Clinical Core. Pilot Project 2, further delineates the role of calcium in cell death employing electrophysiologic techniques to study beta amyloidinduced toxicity and clearly relates tot he ongoing activities of Research Projects 1 and 3. The common aims of the Cores, Research Projects and pilot Projects will enhance ongoing interactions and help translate the ADRC activity into improved care and therapy for patients afflicted with Alzheimer’s disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALZHEIMRE'S NEUROPROTECTIVE TMT

DISEASE

ANTIAMYLOID

Principal Investigator & Institution: Manyam, Bala V.; Professor of Neurology; Scott and White Memorial Hospital 2401 S 31St St Temple, Tx 76508 Timing: Fiscal Year 2002; Project Start 15-APR-2002; Project End 31-MAR2004 Summary: Alzheimer's disease (AD) is the leading cause of cognitive impairment in the geriatric population. Deposition of the beta-amyloid peptide (Abeta) in the brain parenchyma and cerebral blood vessel walls is one of the distinguishing neuropathological features of AD. Abeta has been hypothesized to be the primary culprit triggering the neurodegenerative changes responsible for the memory loss and behavioral changes in AD. Increased Abeta production and deposition occurs with mutations in all three genes linked to early onset AD, the amyloid precursor protein, Presenilin 1 and Presenilin 2. Doubly transgenic mice with mutations in the amyloid precursor protein and Presenilin 1 rapidly develop AD-like changes in the brain including fibrillar Abeta deposits, glial reactivity and dystrophic neurites and will provide a means of screening treatments that alter AD production or which ameliorate its effects in the brain. Centella asiatica (Syn. Gota Cola, Luei Gong Gen, Indian Pennywort) is an ethnophytotherapeutic agent reputed to have a beneficial effect on cognition. However, the mode of action of Centella asiatica has not been fully established. The object of this application is to test the central hypothesis that Centella asiatica extract (CAE) may exert a therapeutic effect on both cognition and neuropathology in a doubly transgenic mouse model of AD by modulating amyloid deposition in the brain. Specific aims: 1) Determine the effect of 3 different doses of CAE on learning and memory


performance at young (3 month), mature (6 month), and aging (12 month) old doubly transgenic mice when treatment is started prior to onset of Abeta deposition (2 months). 2) Assay the effect of CAE on the production and deposition of Abeta 40 and 42 isoforms using ELISA as well as antibodies to Abeta and standard histological techniques known to detect fibrillar amyloid at each of the three age groups tested. 3) Perform secondary analysis of neuronal loss, dystrophic neurite formation, glial activation and markers of oxidative stress to test the neuronal and glial response to both AD and CAE treatment with aging. The efficacy of CAE to improve working and spatial memory will be studied using the object recognition task that has previously been shown to discriminate between transgenic mice carrying mutations linked to early onset AD and controls. Expected results are improvement in performance of CAE-treated group in the behavioral task, and reduction in the levels of Abeta(3 deposition in the brain. Our proposal meets the criteria of R21 application of NCCAM that will generate preliminary data on possible mechanism of action of a traditional herbal drug for Alzheimer's disease with eventual development of a therapeutic agent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTI-ABETA IMMUNITY AGAINST ALZHEIMER'S DISEASE Principal Investigator & Institution: Ugen, Kenneth E.; Associate Professor; Medical Microbiol & Immunology; University of South Florida 4202 E Fowler Ave Tampa, Fl 33620 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL2004 Summary: (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disease characterized by overproduction of Abetaamyloid from amyloid precursor protein (APP), with the subsequent pathologic deposition of Abeta into extracellular plaques in regions of the brain which are important for memory. Recently we, as well as others, have demonstrated that vaccination of a transgenic (Tg) mouse which expresses mutant presenilin-1 and APP (and serves as a model for AD) with an Abeta(1-42) peptide, resulted in amelioration of neural pathology and protection of these mice from functional memory deficits. Others have indicated that humoral immunity plays a major role in at least ameliorating the neural pathology. However, the exact role of cellular immunity, whether beneficial or deleterious, has not been addressed. We have recently demonstrated that vaccination of Tg mice with Abeta results in the induction of antibodies indicative of a T helper 2 response. We have also shown strong T cell proliferative activity in mice vaccinated

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with Abeta stimulated with specific antigen. A chimeric mouse line has recently been developed which expresses human MHC I and II molecules and is called CHAD (chimeric human A2DR). We propose to use this mouse to cross mate with the doubly transgenic mice described above to ask important questions about human immune responses to Abeta. The specific aims of this proposal are as follows: (a) evaluation of the CD4 T cell responses to Abeta in a Tg mouse model for AD; (b) evaluation of the potential role of CD4 T cell responses after Abeta vaccination; (c) evaluation of the CD8 T cell responses in Tg mouse models; and (d) engineering of specific immune responses in AD Tg mice. These studies will comprehensively address the potential role of cellular immune responses to Abeta vaccines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: APP TRAFFICKING AND THE PATHWAYS OF A BETA FORMATION Principal Investigator & Institution: Koo, Edward H.; Professor; Neurosciences; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 92093 Timing: Fiscal Year 2001; Project Start 01-JAN-1998; Project End 31-DEC2002 Summary: Alzheimer's disease is characterized by the presence of both beta- amyloid plaques and neurofibrillary tangles in cortex. Increasing evidence favors the deposition of amyloid beta-protein (Abeta) in plaques as an early and possibley primary event in the pathogenesis of Alzheimer's disease, a process that may be related to altered expression or processing of the amyloid precursor protein (APP). Recent studies have further implicated the longer Abeta species, specifically Abeta peptides of 42 amino acids long (Abeta42) as potentially critical for amyloid deposition and fibril formation. The pathways that lead to the generation of Abeta and Abeta42 have not been clearly defined. The foundation that guides this ongoing project is that processing of APP in the endocytic pathway is important to Abeta production. Accordingly, we have formulated two working hypotheses to direct our continuing research efforts: 1) the APP internalization pathway is the primary route for Abeta production and subsequent release into the medium, and 2) familial Alzheimer's disease mutations alter APP trafficking and, in turn, Abeta production. Three Specific Aims are proposed for the next granting period to test the two working hypotheses. The first Specific Aim examines the role of endocytic processing in the production and release of Abeta42. The second Specific Aim will analyze the relationship between presenilin-1 mutations, APP trafficking and Abeta42 production.


In the third Specific Aim, the mechanism by which the APP codon 717 mutations increases Abeta42 production will be explored with regards to the relationship between internalization and gamma-secretase APP cleavage. This investigation of the APP trafficking pathways in a cell culture system will examine fundamental processes that are critical for Abeta (Abeta42) production. Results from these studies may provide important insight into the pathogenesis of Alzheimer’s disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ATTENTION AND MEMORY INFLUENCES ON NAVIGATION IN AD Principal Investigator & Institution: Mapstone, Mark E.; Neurology; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2003; Project Start 15-FEB-2003; Project End 31-JAN2008 Summary: (provided by applicant): Spatial disorientation is a primary manifestation of Alzheimer's disease (AD) greatly impacting functional independence. While the amnesic features of AD are well described, relatively little is known about the deficits underlying spatial disorientation. Spatial disorientation in AD has been attributed to pervasive memory dysfunction, but it can present without evident memory deficits. Alternatively, spatial disorientation in AD may reflect a reduction in the size of the spatial window of attention; the area of the visual field that is simultaneously accessed by cognition. Narrowing the attentional window might limit access to orientation cues in global patterns of optic flow and force reliance on less informative object motion cues. I propose to immerse myself in the study of spatial disorientation in Alzheimer's disease for the next five years. Through formal instruction, hands-on laboratory experience, and completion of the research plan described within. l will further develop skills in patient-oriented research leading to competence as an independent investigator. The strength of my approach is a core group of mentors selected for their expertise in addressing the proposed research topic and for their commitment to developing young investigators. Charles Dully, MD, PhD (visual psychophysics), Roger Kurlan, MD (neurological disease clinical trials), and Suzanne Corkin, PhD (behavioral studies of memory) have agreed to share their specific expertise and serve as mentors in my transition to independent investigator. The specific aims of the proposed research are 1 ) To quantify the size of the window of attention in patients with AD and investigate its effect on the use global motion (optic flow) and local motion (object) cues for determining heading, 2) To determine the contributions of spatial attention and memory systems for path

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integration, and 3) To explore the role of the cholinergic system as a neuro-modulator for spatial attention and global motion processing using pharmacological challenge. This funding will provide for my further development in behavioral studies of spatial attention in aging and AD and commence my programmatic approach to the study of brainbehavior relationships. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BETA AMYLOID DERIVATION IN BRAIN IN ALZHEIMERS DISEASE Principal Investigator & Institution: Dewji, Nazneen N.; Associate Professor; Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 92093 Timing: Fiscal Year 2001; Project Start 01-AUG-1989; Project End 31MAR-2003 Summary: Mutations in the genes for the beta-amyloid precursor protein (beta- APP), a type 1 single-membrane spanning integral protein, and the more recently identified closely homologous seven-membrane spanning integral proteins S182 and STM2, together account for all early-onset familial Alzheimer’s disease. The normal functions of the three proteins are not known nor do we know how their functions are implicated in the disease. They recently proposed (Science, 271, 159-160, 1996) based on precedents in other system of an integral proteins, that one or more forms of beta-APP and S182 (or STM2) may normally be components of an intercellular signaling system. Beta-APP and S182 or STM2 on the surfaces of neighboring cells would bind to one another specifically through their extra-cellular domains protruding from the dell membranes, beta-amyloid (Abeta) being a proteolytic by-product of this interaction. To test this proposal full-length cDNAs for S182 and STM2 were cloned by PCR and subcloned into pcDNA3. Beta- APP695 cDNA was also subcloned into pcDNA3 and the constructs were used to transiently transfect cultured cells. Polyclonal antibodies raised to peptide sequences of STM2 and S182 demonstrated the presence of the two proteins at the surface of transfected cells. In order to determine if STM2 or S182 on one cell interacts with beta- APP on another, transfected cells expressing STM2 or S182 were mixed with cells expressing betaAPP. Heterotypic cell aggregates were formed, as shown by double labeling with antibodies to beta-APP and STM2 (or S182). Furthermore, this aggregation could be inhibited by excess soluble beta-APP, indicating specificity of the interaction. Our work provides evidence for the direct physical interaction of beta- APP with STM2 and S182, which may be crucial to the generation of Abeta and the genesis of Alzheimer’s disease.


To further test our hypothesis, in this application we propose, among other things, to investigate if transcellular binding between beta-APP and S182/STM2 results in vesicular internalization of the two proteins, the release of more or longer form of Abeta and normal signaling. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BRAIN IMAGING & COGNITION IN SUBJECTS AT RISK FOR AD Principal Investigator & Institution: Bassett, Susan S.; Associate Professor; Psychiatry and Behavioral Scis; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 01-JUN-2000; Project End 31-MAY2005 Summary: Alzheimer's disease (AD) is a major health problem facing this country. The destruction of brain tissue in this degenerative disease likely begins decades before the onset of clinical symptoms. Identification of preclinical markers for AD would be extremely valuable for both intervention and treatment. Recent work suggests that decrements in cognition and changes on neuroimaging in asymptomatic individuals may identify those who go on to develop AD. The aim of this project is to study both cognition and structural and functional neuroimaging longitudinally in a sample of adults who are at increased risk for development of AD and contrast these findings with those of a matched control group. Specifically we will examine cognitive performance on tests of memory and learning, generalized and regional brain measures from conventional MRI and changes in activation with a memory fMRI paradigm. In a small subsample, we will investigate activation changes using olfactory fMRI. In addition, participants will be referred to NIH for assay of amyloid in cerebral spinal fluid. Participants, all at least 50 years of age, will include adult offspring (N=100) of autopsy-confirmed AD cases who are members of multiplex families with extensively characterized pedigrees, currently enrolled in a genetic study of AD, and adults matched for age and gender (N=100) who are presently followed in a study of normal aging. Approximately equal numbers of males and females will be enrolled. All participants will be evaluated twice, three years apart to examine change over time on these measures. In addition, all participants will be typed on two genetic markers (APOE, Alpha2 Macroglobulin) for correlation of allele status with the above measures. The results of this study will provide information on the identification of preclinical markers for late-onset AD. It is hoped that the findings here will prove of significant value as future interventions for Alzheimer's disease are developed. In addition, the proposed studies will provide

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valuable data for planned long-term longitudinal studies of persons atrisk for AD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CANDIDATE GENES FOR ALZHEIMER'S DISEASE RISK IN BLACKS Principal Investigator & Institution: Evans, Rebecca M.; Neurology; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2001; Project Start 19-FEB-2001; Project End 31-JAN2006 Summary: (Adapted From The Applicant's Abstract): The primary objective of this Mentored Patient-Oriented Research Career Development Award is to permit Rebecca M. Evans (the candidate) to develop her full potential as a clinical investigator in dementia research. Dr Evans has completed a 2-year fellowship in neurodegenerative disease and has initiated research into vascular aspects of dementia. She has been, and will continue to be actively involved in the hands-on examination of participants in the Indianapolis-Ibadan Dementia Study (IIDS), a cross-cultural, longitudinal, population-based study of dementia in elderly Africans and African Americans. As the APOE epsilon 4 allele is not associated with AD risk in blacks, Dr Evans' initial research project will focus on examining three candidate genes for AD risk. Given that hypertension is very prevalent in the black population, and is a major vascular risk factor, and the emerging recognition that vascular factors increase AD risk, the genetic polymorphisms chosen to study for AD risk are all associated with hypertension in blacks. Dr. Evans will study the angtiotensin I converting enzyme (ACE) gene insertion/deletion polymorphism, the angiotensinogen allele T235, and epithelial sodium channel variants for association with Alzheimer's disease (AD) in each cohort of the IIDS. During the award period, she will work with her mentors to design and implement preliminary case control studies to assess the significance of vascular risk factors in AD patients and patients with post-stroke dementia. Dr. Evans' future goal is to obtain independent grant funding to develop and implement 1.) larger studies of vascular risk factors for AD, and 2.) interventional trials of therapy to modify vascular risk factors which might prevent or delay dementia onset or slow disease progression. Didactic courses are planned in epidemiology, clinical trial design, statistical analysis, and the ethical conduct of research. This career enhancement plan will enable Dr. Evans to develop expertise in patient-oriented research, and help her accomplish her goal of becoming an independent investigator.


Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CARRIER MEDIATED UPTAKE OF ABETA IN VIVO & IN VITRO Principal Investigator & Institution: Harris-White, Marni E.; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR2008 Summary: (provided by applicant): There is increasing evidence for soluble Amyloid-beta peptide (Abeta) uptake into neurons being an early event in the pathogenesis of Alzheimer's Disease (AD). Identification of the early events leading to neurotoxicity is key to preventing or curing Alzheimer's disease. In this proposal, we examine a very specific, receptor-mediated mechanism of Abeta uptake into neurons. Aim 1 will examine the role of the Low Density Lipoprotein Receptor Related Protein (LRP) in mediating Transforming Growth Factor-beta2 (TGFbeta2) targeting of Abeta to neurons. TGFbeta2 has been shown to be upregulated in AD brain and recent evidence points to TGFbeta2 being upregulated very early in the course of the disease. In Aim 1 we will investigate the mechanism by which TGFbeta2 impacts Abeta uptake, clearance and degradation. Another protein known to be genetically linked to AD is Apolipoprotein E (ApoE). Aim 2 examines the role of ApoE, an LRP ligand, in TGFbeta2-mediated targeting of Abeta to neurons. Aim 3 completes the protocol by testing our mechanism in vivo using human ApoE transgenics and ApoE knockout mice. The Aims outlined in the proposal utilize primary cell cultures, organotypic hippocampal slice cultures (OHSC) and in vivo methods, giving us a symmetrical and powerful approach to studying receptor-mediated uptake and neurotoxicity of Abeta. Another advantage to our mouse infusion model of AD is that, as opposed to transgenic models that overproduce Abeta, we can dissect Abeta clearance away from issues of Abeta production in our mouse infusion model of Alzheimer's disease. There are few published reports that focus on receptor-mediated pathways for Abeta toxicity in Alzheimer's disease. Understanding this mechanism may help to resolve the paradox that "Abeta plaque deposition is not sufficient to cause Alzheimer's" and could lead to new and better targets of intervention in Alzheimer's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHOLESTEROL AND AMYLOIDOGENESIS Principal Investigator & Institution: Pappolla, Miguel A.; Professor; Pathology; University of South Alabama Mobile, Al 366880002 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY2008 Summary: (provided by applicant): Recent studies have shown that increased levels of Ab peptides are among the earliest detectable abnormalities in Alzheimer's disease and may mediate a chain of downstream events leading to neuronal degeneration and cognitive decline. There is increasing evidence from clinical, epidemiological and laboratory studies that cholesterol plays a role in the pathogenesis of Alzheimer’s disease. This body of evidence includes in vitro studies indicating that cellular cholesterol levels modulate Ab production and the enzymatic processing of APP, animal studies demonstrating that cholesterol levels modulate Ab accumulation in the brain (preliminary data) and several observational, clinical studies suggesting that the prevalence and incidence of probable Alzheimer's disease was significantly lower in patients taking cholesterol-lowering drugs. Taken together the studies support the hypothesis that Alzheimer's disease may be a disease in which cholesterol homeostasis is altered and that cholesterol may participate in a chain of events that modulate the disease neuropathology. The application proposes to test the following hypotheses: 1-that in the human brain increased cholesterol content contributes to amyloid accumulation by changing APP processing in a more amyloidogenic manner. 2-that there are correlative interactions between levels of apoE expression, cholesterolemia and amyloid pathology. 3-that certain apoE promoter polymorphisms act in concert with cholesterol levels influencing the extent of apoE expression and amyloid accumulation. Preliminary and recently published data from our laboratory suggest that cholesterol content in plasma and brain of Alzheimer's transgenic mice is strongly correlated with rate of development of amyloid pathology and with apoE expression. These hypotheses are amenable to testing as outlined in the corresponding sections of the proposal and their study will advance our understanding of the pathogenesis of Alzheimer’s disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CLONING OF LATE-ONSET ALZHEIMER'S DISEASE GENES Principal Investigator & Institution: Schellenberg, Gerard D.; Research Professor; Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105


Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL2007 Summary: (provided by the applicant): Alzheimer's disease (AD) is the most common cause of dementia in the elderly. In the U.S., this disease affects approximately 3-4 million persons, costing the U.S. economy more than $50 billion per year. The cause(s) of this debilitating neurodegenerative disease is/are presently unknown. However, a large body of evidence indicates that at least some, if not all, AD cases are due to genetic factors. Genetic analysis of families with multiple cases of early-onset AD has shown that 3 autosomal-dominant genes are responsible for at least some occurrences of the disease. In these families, offspring of affected persons are at least at 50% risk of inheriting a Familial AD (FAD) gene and developing AD. Late-Onset FAD (LOFAD) appears to involve other genes, and is a more complex disease. Using linkage analysis, other sophisticated statistical genetic methods and positional cloning approaches, the long-range goal of this project is to identify the underlying causes of AD by identifying the genes responsible for genetic forms of late-onset AD. Using genetic-linkage analysis, based on Monte Carlo Markov Chain methods, we identified a quantitative trait locus on chromosome-19p 13.2 that affects AD risk. This locus was identified as a quantitative trait that affects age-of-onset. The 19p locus targeted by this project is distinct from ApoE, another LOFAD gene located at 19q13. To identify this new LOFAD gene by positional cloning, the following steps will be performed. First, a physical, sequence, and gene-map of 19p13.2 spanning the region, indicated by linkage analysis, will be generated. Second, genes in this region will be screened for polymorphic sites by database analysis and DNA sequence analysis. Third, polymorphisms spanning the region will be used to test for linkage disequilibrium in the region. Polymorphic sites tested will include short tandem repeat polymorphic sites and single nucleotide polymorphism (SNP) sites. Fourth, SNP's in genes in the region will be tested as pathogenic sites in multiple familial and case-control samples to identify the true pathogenic allele. Fifth, when the gene and pathogenic alleles are found, functional assays will be devised to determine the mechanism of pathogenesis leading to AD. Identification of additional LOFAD genes should greatly enhance our understanding of AD, and potentially lead to new types of therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COMPLEMENT AND INFLAMMATORY FACTORS IN AD PATHOGENESIS Principal Investigator & Institution: Tenner, Andrea J.; Professor; Molecular Biology and Biochem; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2001; Project Start 01-FEB-1997; Project End 31-MAY2004 Summary: (Adapted from the Investigator's Abstract): Alzheimer's disease (AD) is a common dementia or loss of cognitive abilities, which is linked to degeneration of brain tissue. The cause of this neurodegeneration is under intense investigation, as a critical step toward designing therapies for this debilitating and costly disease. In a variety of test systems, fibrillar beta-amyloid displays neurotoxic properties via its direct interaction with neurons but also via its interaction(s) with microglia and its ability to activate the complement system. Multiple studies have demonstrated that reactive microglia and astrocytes and proteins of the complement system are associated with the senile plaques in AD brain, suggesting that inflammation initiated by or exacerbated by activation of the complement system may be one of the major processes involved in the generation of pathology that leads to the cognitive loss. The complement (C') system is a powerful effector mechanism of the immune system. Tissue damage can result however, from chronic or unregulated activation of this system. However, it is also becoming increasingly evident that some complement components provide protective functions in areas of injury. Thus, in this research program novel mouse models will be generated to more closely mimic the human complement system to test the hypothesis that complement plays a role in the pathogenesis of Alzheimer’s disease. Organotypic culture systems will be used to assess the ability of specific complement components to modify amyloid-induced microglia-mediated neuronal cell death/degeneration. In addition, potential protective effects of specific complement components in this disorder will be defined and the specific ligand-receptor interactions that regulate these functions will be determined. These studies should provide solid data on the significance of complement activation and inflammatory events in AD--events which could be targeted to slow the progression of the disease, as well as develop relevant animal models for testing potential therapies in vivo. Since complement has been implicated in a number of other neurodegenerative diseases, it is likely that the investigators' findings will be relevant to other diseases as well. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen


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Project Title: CONFERENCE ON NEURONAL AND VASCULAR STRESS Principal Investigator & Institution: Stern, David M.; Dean and Chief; Keystone Symposia Drawer 1630, 221 Summit Pl #272 Silverthorne, Co 80498 Timing: Fiscal Year 2001; Project Start 01-FEB-2001; Project End 31-JAN2002 Summary: Recent findings have focused attention on amyloid betapeptide (Abeta) as a key element in the pathogenicity of cell stress and, ultimately, cytotoxicity to neurons and the vasculature in Alzheimer's disease and cerebrovascular amyloid angiopathy. Although dense extracellular plaque-like deposits of Abeta are abundant late in the course of Alzheimer's disease, it has become evident that much earlier events in the generation and toxicity of Abeta, especially within the endoplasmic reticulum, will be critical to fully understand in order to design therapies that block the disease at a stage when cellular dysfunction is still reversible. Biology of the presenilins, cell surface and intracellular targets of Abeta converge on microglial-neuronal interactions and the vasculature to create a milieu of sustained and destructive inflammation, as well as an exaggerated and adverse response to ischemic stress. Insights from new animal models and clinical studies will be described, and related to an emerging cell biology of Alzheimer's disease and cerebrovascular amyloid angiopathy; namely, that of cellular dysfunction is driven by Abeta-induced engagement of specific molecular targets, rather than the previously held notion of passive cellular disruption by massive fibrils nonspecifically and inexorably destabilizing cell membranes. This altered view of the pathogenesis of Alzheimer's disease suggests multiple sites for future therapeutic interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--CLINICAL Principal Investigator & Institution: Foster, Norman L.; Professor; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 31-MAY2002 Summary: The Clinical Core promotes the goals of the MADRC and s3erves individual projects by recruiting patients for clinical research studies. Patients with Alzheimer' s disease and Alzheimer's mimics are identified at the University of Michigan with the help of collaborators in the Neurology and Geropsychiatry Clinics and the Neuropsychology

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Division and at Satellite Diagnostic and Treatment Centers located in Detroit and in rural Northern Michigan. This provides an ethnically diverse research population including rural and urban residing subjects reflecting the full range of disease severity from minimally symptomatic to severely impaired. Recruitment of normal control subjects is coordinated with the Human Subjects Core of the Pepper Older Americans Independence Center at the University of Michigan. Potential research subjects receive exclusion criteria. Demographic and caregiver data, dementia severity, neuropsychological performance, motor signs and behavior are characterized using standardized procedures. A subset of these patients who have named a health care advocate and are given provisional consent for an autopsy, and a cohort of normal individuals who have consented to an autopsy are periodically reassessed and serve as a resource for studies examining the clinical course of dementing disorders and clinico-pathological correlations Nurses and social workers help recruit patients to research studies and provide patient and caregiver support and telephone contacts that encourage research participation and the cooperation of families in obtaining postmortem brain examinations. They assure appropriate subject selection and patient safety by coordinating participation in multiple studies. The Clinical Core provides consultation about clinical aspects of dementia to investigators and other Cores and plays a major role in educational and outreach activities of the Center. It promotes collaboration with other Alzheimer Disease Centers for datasharing and joint projects such as the Alzheimer Disease Cooperative Study. Data collected are linked to ongoing epidemiological studies of aging at the University of Michigan including the Assets and Health Dynamics Study of community dwelling elderly and the National Nursing Home Resident Assessment Instrument for elderly receiving institutional care. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--CLINICAL RESEARCH Principal Investigator & Institution: Wilson, Robert S.; Associate Professor of Psychology; Rush-Presbyterian-St Lukes Medical Ctr Chicago, Il 60612 Timing: Fiscal Year 2001; Project Start 01-APR-1991; Project End 31-MAR2004 Summary: The proposed Clinical Core will identify and recruit persons who are eligible for the two proposed clinical projects, and follow a subset of participants in the clinical projects with annual clinical evaluations to identify incident cases of dementia and Alzheimer's diseases and to assess change in cognitive function. To accomplish these


goals, the Core will have the following Specific Aims. 1. Recruit the following four groups of persons: a. older persons meeting accepted clinical criteria for Alzheimer's disease, b. older persons meeting clinical criteria for mild cognitive impairment, c. older persons without cognitive impairment, d. younger persons without cognitive impairment. 2. At initial evaluation, gather uniform clinical and neuropsychological data, in a highly structured fashion, applying uniform structure diagnostic criteria for Alzheimer's disease mild cognitive impairment and non cognitive impairment. 3. Review clinical data from the initial evaluation and distribute eligible subjects to the proposed clinical projects. 4. Follow older persons meeting clinical criteria for Alzheimer's disease, mild cognitive impairment and no cognitive and non cognitive impairment with annual clinical evaluations to assess change in cognitive function and, in those with mild or no cognitive impairment, to identify incident dementia and Alzheimer’s disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--NEUROPATHOLOGY Principal Investigator & Institution: Cochran, Presbyterian-St Lukes Medical Ctr Chicago, Il 60612

Elizabeth;;

Rush-

Timing: Fiscal Year 2001; Project Start 01-APR-1991; Project End 31-MAR2004 Summary: The Neuropathology Core will provide brain tissue and diagnostic neuropathology evaluations on Alzheimer's disease patients and elderly individuals, both controls and those with mild cognitive impairment, to the researchers of the Program Project. This tissue will be obtained from subjects of the Rush Alzheimer's Disease Center Clinical and Religious Orders Study Cores. These individuals are closely following with annual neurological and neuropsychological examinations. There are four projects requiring brain tissue: project R07, Dr. J. Kordower, Dopaminergic mesocortical and nigrostrial system in mild cognitive impairment and Alzheimer's disease;; project RO8, Dr. E. Mufson, Galanin remodeling in the progression of Alzheimer's disease;; project R09, Dr. L. Binder, Tau truncation and conformation in Alzheimer's disease progression, and project RO10, Dr. J. Kuret, Protein kinase markers of Alzheimer's disease progression. Each project requires both frozen and fixed tissue from the following clinical categories: severe Alzheimer's disease, moderate Alzheimer's disease, mild Alzheimer's disease, mild cognitive impairment, and no cognitive impairment will be the Religious Orders Study Core. The Rush ADC Clinical Core and Religious Orders Study Core have provided an average of 36 and 20 cases, respectively, annually, over the last grant period. The

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Neuropathology Core will provide state-of-the-art neuropathological evaluation for Alzheimer's disease, using the NIA Consensus/Reagan diagnostic criteria. These criteria are uniformly applied and all data is directly entered into a computerized program at the time of collection. In addition, all stored tissue is indexed using a specimen tracking software program (FreezerWorks) facilitating reliable tissue distribution. The brain tissue and neuropathological data provided to the investigators of Projects 7, 8, 9, and 10 by the Neuropathology Core is critical for the success of the projects, and for the provision of seminal information about changes in the dopaminergic system and the functions of tau protein kinases and galanin in the progression of cognitive impairment in the elderly and those with Alzheimer’s disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--NEUROPATHOLOGY Principal Investigator & Institution: Carroll, Steven L.; Associate Professor; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001; Project Start 01-MAY-2001; Project End 31MAR-2002 Summary: Despite recent advances in our understanding of the clinical course, pathology and molecular underpinnings of Alzheimer's disease, the cellular events triggering the onset and progression of this dementia remain incompletely understood. Research properly collected and preserved and preserved brain tissue and other biologic samples from Alzheimer's disease patients and normal aged controls is essential for advancing our knowledge of the cellular and molecular mechanisms responsible for the development of Alzheimer’s disease. Further, the interpretation of the clinical features of Alzheimer's disease and evaluation of the effectiveness of potential therapeutic agents requires accurate diagnosis of patients participating in these studies, a goal which at present can be met only by postmortem examination of autopsy brain tissue. The long term goal of the UAB Neuropathology Core Laboratory is to support research which furthers our understanding of the molecular mechanisms of Alzheimer's disease, improves the daily life of patients with Alzheimer's disease and points to new therapeutic approaches. To achieve these goals, the UAB Neuropathology Core Laboratory proposes to: 1) to accurately diagnoses the neuropathologic abnormalities in Alzheimer's disease patients compared to normal aged- matched controls, following the NIA-Reagan Institute Working Group criteria; 2) to provide intramural and extramural investigators with precisely dissected and properly preserved brain tissues and other biological


specimens from our bank of materials collected from Alzheimer's disease patients and normal aged controls; 3) to support researchers applying an ever widening variety of molecular, cellular and genetic approaches to Alzheimer's disease by prospective collecting and preparing tissues per the individual investigator's requirements, thus expanding the range of research service provided by the Core Laboratory and; 4) to expand the Core Laboratory's research function by developing a computer database which will provide more effective communication both with outside pathologists contributing tissue to the Core Laboratory and investigators wishing to utilize tissues collected by the Core Laboratory. By aggressively working to provide service necessary to support other components of the UAB Alzheimer's Disease Research Center and facilitating Alzheimer's disease research by other investigators, both inside and outside the UAB research community, we will significantly expand the ability of these collaborating investigators to conduct both basic and clinical research into Alzheimer’s disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE-NEUROTOXICOLOGY/NEURODEGENERATIVE DISEASE RESEARCH Principal Investigator & Institution: Graziano, Joesph H.;; Columbia Univ New York Morningside 1210 Amsterdam Ave, Mc 2205 New York, Ny 10027 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR2008 Summary: The developing nervous system is vulnerable to adverse effects due to exposures to a variety of substances in the environment, particularly metals and pesticides. At the same time, chronic exposure to low levels of neurotoxicants throughout life can lead to impaired neurologic functioning later in life, particularly in the elderly. As life expectancy increases, and the baby-boom generation approaches retirement age, neurodegenerative diseases such as IPD, Essential Tremor and Alzheimer's Disease will have a significant impact on quality of life, and will represent significant financial costs to the health care system. Collectively, the investigators in this research core are interested in understanding the extent to which, and mechanisms 295 whereby, populations exposed to known quantities of neurotoxicants suffer adverse consequences on the nervous system. The populations under investigation, which include birth cohorts in Yugoslavia and northern Manhattan, populations of adults and children chronically exposed to arsenic in drinking water in Bangladesh, and populations of the elderly in northern Manhattan, represent groups of individuals who have been

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remarkably well characterized for a variety of chemical exposures and other risk factors for adverse neurologic outcomes. At the same time, laboratory based scientists are exploring the mechanisms whereby the compounds of interest alter normal function. The overall goals of the Neurotoxicology/Neurodegenerative Disease Research Core are: I) to promote and facilitate interdisciplinary neuroscience-related research that will define the magnitude of effect of exposure to substances in the environment that are believed to be involved in the etiology of neurologic disease. These substances include metals (Pb, Mn, Fe and As), pesticides (chlorpyrifos, diazinon, propoxur, and others), 13- carboline alkaloids (harmane and harmine), and other factors; and 2) to unravel the cellular and molecular mechanisms whereby these substances exert their effects. The core is responsible for furthering the development of existing and new investigations of environmental exposures that affect the incidence and/or progression of diseases of the central and peripheral nervous systems. The Specific Aims currently under investigation include: 1) to define the cellular and molecular events involved in chemical models of Parkinsonism and in IPD, with the goal of defining those that are common to each; 2) to elucidate the environmental risk factors associated with the onset of IPD, Essential Tremor, and Alzheimer's Disease;; 3) to examine, in both humans and animal models, the relationship between environmental Pb exposure and brain function, with particular interest in the possible mediating effects of Pb on thyroid hormone fate and transport; 4) to determine whether exposure to arsenic in drinking water is associated with adverse neuropsychologic effects in children, and polyneuropathy in adults; and 5) to develop biomarkers of prenatal pesticide exposure in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYCLOOXYGENASE AND ANTI-INFLAMMATORY DRUGS IN AD Principal Investigator & Institution: Pasinetti, Giulio M.; Professor; Psychiatry; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-JUL2004 Summary: Non steroidal anti-inflammatory drugs are among the most promising classes of drugs for the prevention and possibly treatment of Alzheimer's disease (AD). A rapidly increasing number of large-scale therapeutic trials of such drugs are being initiated. The most likely target of NSAIDs in the brain is cyclooxygenase (COX)-2. We found that COX-2, but not COX-1 expression, is elevated in the neurons of AD brain, where


it correlates with amyloid plaque density and neuronal atrophy. In this revised application, using a combination of in situ hybridization and immunocytochemical techniques, we will further study the regional distribution and cell-type expression of COX-2 and other inflammatory markers in the AD brain. To determine the relationship between COX-2 expression in the AD brain and clinical measures of disease activity, COX-2 expression will be correlated with antemortem assessment of dementia. Because therapeutic trials of potential disease-modifying regimens select patients at one or more stages of clinical disease, these studies will determine the relationship between AD clinical stage and COX-2 expression. In parallel studies the effect of COX inhibitors on COX-2 mediated responses in the brain will be explored using a transgenic mouse model of human (h)COX-2 overexpression in neurons. In preliminary studies using primary neuron cultures derived from these transgenic mice, we found that hCOX-2 overexpression potentiates beta amyloid (Abeta) neurotoxicity in vitro through potentiation of oxidative stress mechanisms. We will use this model system to compare the neuroprotective activity of various COX inhibitors on Abeta toxicity in vitro, and to study the mechanism of such neuroprotection. Based in part on the outcome of these studies, we will then test the brain activity of NSAID regimens administered systemically. We have established in our preliminary studies that transgenic mice with neuronal overexpression of hCOX-2 show increased lipid peroxidation in brain as measured by levels of malondialdehyde (MDA) along with elevated prostaglandin (PG)F2alpha. Preliminary studies also indicate increased expression of components of the complement cascade in the brain of hCOX-2 transgenics. Based on our evidence that COX-2 in neurons is indeed the appropriate target for NSAID regimens in AD, this transgenic model provides a unique method of measuring relevant brain activity of COX inhibitors. The outcome of the proposed studies will be immediately relevant to the design of human trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYTOSKELETAL PROTEIN PHOSPHORYLATION IN APOPTOSIS Principal Investigator & Institution: Johnson, Gail V W.; Professor; Psychiatry; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001; Project Start 30-SEP-1997; Project End 31-MAY2004 Summary: (Verbatim from the Applicant's Abstract) During apoptosis the cytoskeleton of the cell undergoes dynamic alterations which result in the

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characterisitic morphological changes common to most apoptotic cells. Recently, using the classical paradigm of inducing apoptosis differentiated PC12 cells by withdrawal of serum and nerve growth factor (NGF), we demonstrated that the neuronal cytoskeletal protein tau is hyperphosphorylated at specific epitopes during apoptosis. Further, there are associated functional changes, as the microtubule-bindng capacity of tau from apoptotic cells is significantly reduced, and it is restored after dephosphorylation. This demonstrates directly that the increased phosphorylation of tau in cells undergoing apoptosis impairs the function of tau, and thus may contribute to the microtubule instability and the cytoskeletal based morphological changes of apoptotic cells. These findings are exciting both for the insight they provide for understanding the drastic morphological changes associated with apoptosis, and for the potential links between apoptosis in Alzheimer's disease and hyperphosphorylated tau. There is increasing evidence that apoptotic-like processes may contribute to the neuronal death in Alzheimer's disease, as well as other neurodegenerative disorders. In Alzheimer's disease brain, extensively hyperphosphorylated tau forms paired helical filaments (PHFs). In addition, the microtubule binding of PHF-tau is impaired, but can be restored at least partially by dephosphorylation. Thus, apoptosis during Alzheimer's disease may contribute to the formation of hyperphosphorylated tau that accumulated in this disease, thereby further emphasising the need to clarify the mechanisms that control tau phosphorylation in these conditions. In AD brain, cdc2, casein kinase1d (CK1d ) and cdk5 are elevated, and the investigators have found them to be increased during apoptosis as well. Considering these and other findings, the comprehensive working hypothesis is that during apoptosis tau is hyperphosphorylated at specific sites by specific protein kinases and this hyperphosphorylation results in compromised tau function, which contributes to the structural changes that occur during apoptosis. Elucidation of the changes in tau phosphorylation that occur during apoptosis will contribute towards the understanding of the processes that result in the hyperphosphorylation of tau in AD and other neurodegenerative disorders. The specific aims of this proposal are to test the hypotheses that: (1) during apoptosis tau is phosphorylated at specific sites and the increases in the activities of cdc2, CK1d and cdk5 are essential components of this process, (2) that the specific sites on tau that are phosphorylated in apoptotic cells modulate tau function and localization, and (3) that during apoptosis, tau with frontal temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) mutations is differentially phosporylated and localized compared to wild type tau. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen


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Project Title: DEMENTIA IN SWEDISH TWINS Principal Investigator & Institution: Gatz, Margaret J.; Professor; Psychology; University of Southern California 2250 Alcazar Street, Csc219 Los Angeles, Ca 90033 Timing: Fiscal Year 2001; Project Start 15-FEB-1990; Project End 31-JUL2004 Summary: (Adapted from Applicant's Abstract). This application seeks continued support for the Study of Dementia in Swedish Twins to expand the sample by means of total ascertainment of all cases of Alzheimer's disease and other late-life dementias in the entire Swedish Twin Registry. The estimate is to complete data for over 200 pairs in which one or both is diagnosed with Alzheimer's disease, and 350 pairs in which one or both has any dementia diagnosis. Case identification will use telephone screening with all individuals in the sample, followed by informant interviews for those with evidence impairment, resulting in cognitive screening data from over 6000 complete pairs. Record linkage to health care utilization will be carried out as a parallel case identification strategy. Diagnostic assessment for those with a positive screening outcome will include medical evaluation, neuropsychological measures, neuroimaging, and informant interviews. Partners will receive the identical protocol, as will an independent sample of individuals who screened negative. Risk and protective factors will be obtained from the informant interview, medical records, and twin registry database, with occupational history linked to measured exposures. One longitudinal follow-up is included, and permission for autopsy will be requested. Data analyses using quantitative genetic approaches will address six questions: 1) What is the relative importance of genetic and environmental effects of Alzheimer's disease? 2) What are the best indices of the underlying genetic liability and of quantitative variability? 3) What non-genetic risk factors can be identified? 4) What influences age of onset? 5) Are there interactions between genetic and environmental risk factors? and 6) What is the covariation of liability to different types of disorder? Analytic techniques will include expansion of liability threshold models to mixed models, sex limitation models, use of measured genotype, bivariate models, and case-control methods using matched twin designs. Different diagnostic criteria will be compared. Quantitative indices will be derived from neuropsychological scores and from neuroimaging data subjected to quantitative mapping. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEMENTIA OF CLINICOPATHOLOGIC PHENOTYPE

PARKINSON

TYPE:

Principal Investigator & Institution: Galvin, James E.; Assistant Professor; Neurology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR2005 Summary: Parkinson's disease and Dementia with Lewy bodies (DLB) together comprise the second most common form of dementia after Alzheimer's Disease (AD). The signature pathologic lesions in these disorders are Lewy bodies (Lbs) found in cortical (DLB) and nigral (PD) neurons. Furthermore, a significant number of AD patients develop parkinsonian signs during the course of disease and many of these patients also are found to have Lbs on autopsy. Whether previously diagnosed with PD- associated dementia now would be classified as DLB is unknown. It is also unclear that PD alone can cause dementia occurs only in the presence of critical Lbs or AD-related pathology. The goal of this project is to characterize the clinicopathologic phenotypes of Dementia of the Parkinson Type (DPT). We propose to analyze the longitudinal studies of the Alzheimer's Disease Research Center (ADRC) for the clinical, motor, cognitive, behavioral, and pathologic characteristics of autopsy defined case of AD, PD and DLB in order to: 1) determine those clinical features that differentiate pathologically diagnosed DLB and PD from AD and from each other to establish the DPT phenotype; 2) identify differences between groups in pathologic features other than those used in the diagnosis by exploring the neuroanatomical correlates of the unique clinical symptomatology of DPT; and 3) to determine the best short set of clinical features for the diagnosis of pathologically defined DPT groups. The ADRC and the Department of Neurology at Washington University School of Medicine provide the candidate with an outstanding environment to develop his skills as an independent clinician-scientist. This K08 award will make available to the candidate protected time to complete the Specific Aims of the project and complete didactic courses in the ethical conduct of research, biostatistics and epidemiological study design. The research career development plan of the candidate is to use the mentored period to establish in the field of dementia research, specifically examining the role co-existent pathologies play in the onset, progression and unique characteristics of dementing disorders. At the completion of the award period, candidate plans to develop an independent R01 project derived from the data generated by the experiments described in this proposal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen


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Project Title: DETECTION OF PRESYMPTOMATIC ALZHEIMER'S DISEASE BY FMRI Principal Investigator & Institution: Smith, Charles D.; Neurology; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2003; Project Start 30-SEP-1997; Project End 31-DEC2007 Summary: (provided by applicant): Alzheimer's disease (AD) is preceded by a period when detectable changes in brain function occur without warning symptoms. This period may be twenty years or longer. Activation measured by functional magnetic resonance imaging is reduced during confrontation naming in normal women who have increased risk of late-onset Alzheimer's disease, at an average age of only 53 years. These same individuals have reduced activation in the posterior cingulate cortex during a memorization task, among other disparities. Our hypothesis is that the altered functional MRI responses in naming, working memory and memorization will quantifiably worsen with age, due to progressive underlying Alzheimer's disease pathology. Diseasemodifying treatments applied in this early, pre-symptomatic stage of AD could have profound impact, by preventing the onset of cognitive symptoms. Millions are currently being spent on large-scale prevention trials, with AD symptoms as end-points. By providing a biomarker of pre-symptomatic AD progression, fMRI could potentially reduce the duration and costs of such trials. This continuation proposal is designed to detect changes in brain function in high-AD risk individuals over time. We will study normal education-matched groups of high- and low-AD risk subjects in the age ranges 40-65 and 65-90 years, using fMRI stimulus tasks which have previously demonstrated regional disparities in highAD risk individuals. In addition, we will repeat the naming and fluency fMRI studies performed previously in high- and low-AD risk individuals after an interval of five years, in order to detect longitudinal changes in activation. The convergence of evidence from these cross-sectional and longitudinal studies could provide powerful evidence for a model of Alzheimer's disease as a relentless, slowly progressive brain pathology that begins early in adult life, but remains compensated until it produces clinical symptoms in its late stages. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEVELOPMENT OF NOVEL MUSCARINIC AGONISTS Principal Investigator & Institution: Messer, William S.; Medicinal & Biological Chemistry; University of Toledo 2801 W Bancroft St Toledo, Oh 43606

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Timing: Fiscal Year 2001; Project Start 08-AUG-1994; Project End 31-JUL2003 Summary: Applicant's Abstract) The neurotransmitter acetylcholine mediates a variety of responses within the central nervous system and plays an important role in memory function and cognition. Cholinergic cells within the basal forebrain denerate in Alzheimer's disease, a disorder associated with memory dysfunction and progressive cognitive decline. Research efforts have focused on developing selective M1 muscarinic agonists for the treatment of Alzheimer's disease. Over the past few years, several putative M1 agonists have been identified. The proposal focuses on the design, synthesis, and biological testing of novel compounds as selective muscarinic ligands. Chemical synthesis focuses on exploring a radically new approach to the development of muscarinic agonists, based on a novel series of bis-thiadiazole derivatives that display very high potency and activity at M1 receptors. Structure activity and molecular modeling studies will help identify the molecular features that contribute to activity and provide a basis for the rational design and synthesis of new ligands. In addition to pharmacological characterization of new compounds, biological studies will compare the affinity and efficiacy of several putative slective M1 muscarinic agonists at muscarinic receptors expressed in cultured cell lines and in the brain. Further studies will examine the ability of a few active and slective compounds to penetrate into the brain and reverse memory deficits associated with lesions of the septohippocampal cholinergic system. The overall goals of the project are to identify ligands with improved selectivity for muscarinic receptor subtypes, thereby providing important new pharmacological tools. A compound with high M1 agonists activity and the ability to penetrate into the brain also could become a drug candidate for the treatment of Alzheimer’s disease. These studies will help determine the therapeutic utility of selective muscarinic agonists in the treatment of Alzheimer’s disease. In addition the research could provide new approaches to the synthesis of compounds useful in a variety of neurological disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISSECTING PATHOGENIC DOMAINS OF APP IN TRANSGENIC MICE Principal Investigator & Institution: Ashe, Karen H.; Professor; Neurology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2001; Project Start 01-AUG-1994; Project End 31-JAN2004


Summary: The broad, long-range objective of these studies is to define the molecular basis of neuronal dysfunction in Alzheimer’s disease. We have developed transgenic mice expressing the amyloid precursor protein (APP) for animal studies of Alzheimer's disease (Hsiao et al., 1996). These mice simulate several behavioral and neuropathological features of Alzheimer’s disease. We propose to delineate the molecular domains of APP responsible for these behavioral and neuropathological abnormalities. Because hundreds of researchers around the world have begun using these mice as a model for Alzheimer's disease, we feel compelled to dispel even the slightest doubts about the reproducibility of the phenotypic traits we observed. Therefore, we shall embark upon producing another line of mice over-expressing mutant human APP exhibiting both age-related behavioral and pathological abnormalities simulating Alzheimer's disease in humans in AIM #1. In AIM #2 we shall examine the role of alphabeta in producing age-related neural dysfunction in the brain. By comparing the behavioral and neuropathological profiles of transgenic mice expressing wild-type APP and APP lacking the alphabeta domain to transgenic mice overexpressing mutant APP we shall determine which biological and behavioral abnormalities are due to alphabeta accumulation and which can be attributed solely to APP over-expression. Elucidating the role of alphabeta in functional brain abnormalities in Alzheimer's disease is a critical and timely question that can now be approached by studying neural dysfunction in transgenic APP mice. We shall also distinguish between the more and less amyloidogenic forms of alphabeta, alphabeta40 and alphabeta42(43), by comparing, by comparing behavioral and neuropathological profiles of transgenic mice expressing APP with the Swedish (KM670/671 NL) and London (V717I) mutations. In Aim #3 we shall determine whether the KPI domain in APP influences the onset and rate of amyloid formation. In different laboratories APP isoforms with or without KPI domains have both been used to generate transgenic mice developing amyloid plaques (Games et al., 1995; Hsiao et al., 1996; Sturchler-Pierrat et al., 1997). Although the topographical and morphological features of the amyloid deposits are remarkably similar in these mice, the presence or absence of the KPI domain in the APP transgene might account for differences in the chronological appearance and amount of alpha/beta deposition. Whether the KPI domain alone can explain these differences remains unresolved because of slight potential variations in APP levels and differences in promoters used to drive APP expression in the two lines of mice. To answer this question we shall compare alphabeta levels, temporal patterns and extent of alphabeta deposits, as well as profiles of behavioral impairment in transgenic mice,

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expressing mutated APP with and without the KPI domain driven at comparable levels by the identical promoter. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EARLY EVENTS IN ALZHEIMER PATHOGENESIS Principal Investigator & Institution: Griffin, Sue T.; Professor; Geriatrics; University of Arkansas Med Scis Ltl Rock 4301 W Markham St Little Rock, Ar 72205 Timing: Fiscal Year 2001; Project Start 01-JUN-1995; Project End 31-MAY2002 Summary: The objective of this Program Project is to critically evaluate a hypothesized cytokine cycle of molecular and cellular events that we propose is important in the pathogenesis of Alzheimer disease. Effectorstimulated microglial activation with synthesis and release of the glial inflammatory cytokine interleukin-1 (IL-1) is seminar in this cycle. IL- 1based actions include (i) induction of over-expression and processing of beta-amyloid precursor protein (betaAPP) in neurons (leading to betaamyloid deposition, cell death and release of secreted APP, stimulating further expression of IL-1); and (ii) activation of astrocytes and release of S100beta (increasing the potential for cell death by promoting increases in intraneuronal calcium, by promoting synthesis of beta-APP, and by inducing overgrowth of dystrophic neurites) and with synthesis and release of ApoE (which may bind to beta-amyloid and stabilize it). Alzheimer's disease is inherently progressive, and any sequence of events hypothesized to significantly contribute to the pathogenesis of this disease must explain this progression., and any sequence of events hypothesized to significantly contribute to the pathogenesis of this disease must explain this progression. We postulate, in view of IL-1 based actions, and the potential of chronic IL-1 over-expression to promote neuronal injury and death, that the progression of Alzheimer's disease may be driven by this potentially self propagating, self sustaining sequence events. We will determine the role of glial inflammatory processes in neuronal cell injury and death in Alzheimer's disease and in epilepsy, which predisposes to early Alzheimer-type changes. We will also determine temporal and spatial relationships between glial inflammatory processes and neuronal cell injury and death in Down's syndrome and following head injury, and the modulating effects of genotype on these processes. We will also use transgenic animals overexpressing S100beta or betaAPP to define mechanisms responsible for these relationships. Cell culture models will be used to define mechanisms by which glial inflammatory proteins modulate neuronal cell injury and death. Accomplishment of the goals of this Program will


yield results of direct benefit to the identification of basic elements in Alzheimer pathogenesis and provide targets for development of therapeutic strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENVIRONMENTAL ALZHEIMER'S DISEASE

CAUSES

OF

SPORADIC

Principal Investigator & Institution: Charlton, Clivel G.; Professor and Chairman; Meharry Medical College 1005-D B Todd Blvd Nashville, Tn 37208 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL2007 Summary: This study will test a proposition that environmental toxins are involved in the cause of Sporadic AIzheimer's disease (AD) by inducing, early in life, a less resilient but functional set of Nucleus Basalis of Meynert (NBM) acetylcholinergic (Ach) neurons that cannot withstand the stress placed on them later in life. Two stages of afflictions, therefore, are involved. The 1st is a predisposing or sensitizing stage that occurs early in life, causes mostly epigenetic changes that impair the phenotype and/or reduce the number of the NBM Ach neurons. The 2nd superimposing/precipitating stage occurs when age-related wear-andtear or other interventions damage the already susceptible NBM neurons and precipitate AD. The project will identify interventions that will mimic the two stages. The plant-derived tubulin assembling inhibitors, colchicines; the fungal-derived protein synthesis inhibitor, puromycin, and the fungal and plants-derived mitochondrial toxin, 3-nitroproprionic acid (3-NP) will be administered during the period of differentiation of the NBM Ach neurons of the embryos in timed-pregnant mice to induce the 1st stage. Age-related studies will verify the trans-placental or indirect in utero changes related to memory functions and the anatomy and histochemistry of the NBM Ach neurons, thus testing the vulnerability of the neurons to the wear-and-tear of life. The anticholinergic agent, scopolamine, that causes amnesia will be used, also, to mimic the 2nd stage and rationally to precipitate Alzheimer's disease-like changes in the pups. It is proposed that the ED50 for the induction of amnesia will be lower in the 1st stage treated mice, as compare to control. A new model for AD may be identified, based on chemically producing a less resilient but functional NBM Ach neuronal phenotype early in life and stressing those susceptible neurons later in life. Interventions that prevent or delay the toxic responses will be tested. This concept is relevant to the role of the environmental in about 90% of AD cases, and it may be used to study other neurodegenerative disorders

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but focusing on other neuronal sets. The mechanisms that underlie the proposed sensitization and precipitating stages, such as DNA and RNA editing and protein modifications, will be studied in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EPIDEMIOLOGY, PARKINSONISM IN AGING

PATHOLOGY,

AND

Principal Investigator & Institution: Schneider, Julie A.;; RushPresbyterian-St Lukes Medical Ctr Chicago, Il 60612 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR2005 Summary: This 5-year clinical scientist development award proposes the use of quantitative epidemiologic principles to relate post-mortem findings to neurologic conditions associated with aging. A spectrum of parkinsonian signs, including bradykinesia, rigidity, tremor, and gait imbalance are common in older persons without Parkinson's disease, and are associated with increased morbidity and mortality. The nigrostriatal system also shows a spectrum of change with age. Preliminary data suggest that nigral neurofibrillary pathology is more common than previously recognized and is related to parkinsonian signs in older persons with and without Alzheimer’s disease. The proposed studies will relate nigral neurofibrillary pathology and biochemical nigrostriatal changes to quantitative measures of global and specific parkinsonian signs in older persons with and without Alzheimer’s disease. We will test the hypotheses that neurofibrillary pathology, specifically within the pars compacta of the substantia nigra, rather than the ventral tegmental or retrorubral areas, accounts for parkinsonian signs in older persons with and without AD, and that the mechanism by which neurofibrillary pathology produces parkinsonian signs involves decreased gene expression of tyrosine hydroxylase and a reduction in striatal dopamine, but not neuronal loss. We will also determine the role of mitochondrial mutations in the pathogenesis of neurofibrillary pathology and parkinsonian signs. The proposed project will use brain tissue of 80 older persons, without Parkinson's disease, in The Religious Order Study, a longitudinal study of over 650 catholic clergy who have agreed to annual examinations and brain donation after death. The proposed study will provide the Candidate in the opportunity to work with senior colleagues and allow the development of a unique research area that integrates the clinical neurology and neuropathology training. Through the course of these studies and analyses, through didactic sessions with her sponsors and consultants, and related course work, the candidate will develop the skills necessary to become an independent investigator.


Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ERP INVESTIGATIONS OF NOVELTY PROCESSING IN AGING AND AD Principal Investigator & Institution: Daffner, Kirk R.; Chief, Division of Cognitive and Behavio; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR2007 Summary: (provided by applicant) Attention to novel events facilitates adaptation to a changing environment and may increase engagement with one?s surroundings and enhance cognitive abilities. Despite its importance, there has been limited study of age- and disease-related changes in how the brain processes novel events. Based on the PI?s research, a provisional model of a neurally-based novelty processing system is presented. Building upon this work, the proposed research will investigate age-related changes in the novelty P3 response and subsequent allocation of attention to novel stimuli (as measured by viewing durations) in order to elucidate the relationship between responsiveness to novelty and different patterns of cognitive aging. The research aims to distinguish between changes in response to novelty that appear to be inevitable (observed with even the most successful cognitive aging), changes that are most commonly seen with usual cognitive aging, and changes that are associated with the most frequent degenerative disease of the brain (Alzheimer?s disease). A carefully designed series of experiments will test hypotheses about: 1) age-related changes in response to novelty among groups of cognitively high performing individuals; 2) differences in response to novelty between cognitively high and mid performing older individuals; 3) age-related changes in response to novelty among groups of individuals that differ in level of cognitive performance; 4) differences in response to novelty between cognitively normal individuals and cognitively impaired ones (with mild Alzheimer?s disease); and 5) the relationship between the novelty P3 response and subsequent attention to novel events in the laboratory and level of engagement in daily activities. These integrative functional and cognitive neuroscientific studies will extend previous work on the neurology of attention to novel events and provide new insights into the ways in which this fundamental aspect of human behavior is related to normal aging and disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FUNCTIONAL ANALYSIS OF ASTROCYTE DERIVED APOE3 AND APOE4 Principal Investigator & Institution: Niven, Anne F.; Neurology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 15-AUG-1998; Project End 31-JUL2003 Summary: (Adapted from the application) The candidate (Anne Fagan Niven) received her Ph.D. in Neuroscience from the University of California, San Diego in 1992, and has a history of productive research investigating neuronal plasticity in the developing and injured nervous system. The candidate has expertise in cognitive neuroscience, neuronal development, neuroanatomy, and molecular neurobiology. Recent work at Washington University School of Medicine (WUSM) has fostered an interest in the etiology of neurodegenerative disease, in particular, the mechanism(s) by which apolipoprotein (ApoE) E4 is a risk factor for Alzheimer's disease (AD). Since ApoE is known to be an important regulator of plasma cholesterol metabolism, proper investigation of its role in AD, as well as in the normal brain, will require knowledge of: 1) AD, 2) cell biology, and 3) cholesterol/lipid metabolism, areas in which the candidate has little background. The proposed plan will provide the candidate with an additional period of mentored research in order to gain expertise in these three areas. The immediate career goal is to initiate a research program investigating the connection between ApoE4 and AD. Importantly, the scientific and technical expertise gained in the course of these studies will allow the candidate to attain her long-term goal; to establish an independent, multidisciplinary research career in neuroscience, with an emphasis on neuronal growth and repair as it relates to neurodegenerative disease. In the proposed study, it is hypothesized that brain-derived lipoproteins containing ApoE4 are inherently different in their composition/structure than those containing ApoE3, which in turn affects their ability to transport cholesterol/lipid, and/or affect AB metabolism. Utilizing transgenic mice which express human ApoE3 or ApoE4 by astrocytes, the candidate will characterize the composition/structure of astrocyte-derived lipoprotein particles and test their ability to transport cholesterol/lipid and affect AB metabolism in vitro and in vivo. David M. Holtzman, M.D (mentor) will provide training in AD, models of neurodegenerative disease, and cell biology; Alan L. Schwartz, M.D., Ph.D. (co-mentor), cell biology; and consultants, cell biology and lipid metabolism. WUSM, the Department of Neurology, and its associated Alzheimer's Disease Research Center has wellestablished research programs and a renowned group of faculty committed to research, education, and training. The many educational


and technical resources available to the candidate at WUSM, in combination with the strong research programs of the mentor, co-mentor, and consultants, will provide the comprehensive training necessary to achieve her career goals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC KNOWLEDGE AND ATTITUDES IN ALZHEIMER'S DISEASE Principal Investigator & Institution: Blacker, Deborah L.; Associate Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-JUL2004 Summary: This is a resubmission of Genetic Knowledge and Attitudes in Alzheimer's Disease (1 R01 HG0183), which addresses the ethical, legal, and social implications Alzheimer's disease (AD) genetics from the critical perspective of a group at high risk for the disease: currently unaffected relatives in families with AD. The applicants--at Mass General Hospital/Harvard Medical School and the University of Alabama--have been working together since 1990 as part of the NIMH Genetics Initiative to identify families with Alzheimer's disease for a genetic linkage study. Nearly 350 such families, predominantly affected sibling pairs and over 300 of their unaffected siblings, have been collected. Regular follow- up of unaffected subjects is in process in order to monitor them for disease onset and assess the role of risk factors for AD, and there are approximately 200 additional unaffected siblings in study families. In the present proposal, the two centers will study knowledge, attitudes, and behavior related to genetic studies and genetic testing in the unaffected individuals in these AD families and their primary care physicians, and will develop and pilot educational materials designed to address their needs for genetic information. Information about the ethical, legal, and social implications is just as critical as that about inheritance patterns and risk probabilities. We will employ a broad approach including qualitative as well as quantitative methods in order to capture the complexity, uncertainty, and subjectivity in this new realm. Given the growing prevalence, devastating symptoms, and prodigious social cost of AD, the recent flurry of developments in AD genetics has received extensive attention both from the popular press and from advertisers touting putative genetic tests. Those whose family history puts them at increased risk for AD are especially vulnerable to misinformation. Their primary care physicians are also ill-prepared to address these issues. The genetic educational materials for laypeople and physicians to be developed and tested in the present proposal strive to meet their current needs for

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accurate information, to prepare them for future challenges, and to supply models for genetic education in other complex diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENOMIC SCREEN TO IDENTIFY ALZHEIMERS DISEASE GENES Principal Investigator & Institution: Vance, Jeffery M.; Professor; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2003; Project Start 20-FEB-1997; Project End 31-JAN2008 Summary: (provided by applicant): To identify genes influencing age at onset (AAO) in two common neurodegenerative diseases, we performed a genomic screen for AAO in families with Alzheimer disease (AD;) and Parkinson disease (PD. (Li et al, AJHG, April, 2002). Heritabilities between 40 percent-60 percent were found in both the AD and PD datasets. For PD, significant evidence for linkage to AAO was found on chromosome 1p (LOD =3.41). In addition, evidence for AAO linkage on chromosomes 6 and 10 was identified independently in both the AD and PD data sets. Subsequent unified analyses of these regions identified a single peak on chromosome 10q between D10S 1239 and D10S 1237, with a maximum LOD score of 2.62. These data suggest that a common gene affects AAO in these two common complex neurodegenerative diseases. We propose to further map and identify the genes contributing to this age-of-onset effect. We will continue to collect new AD and PD families to further map the peaks, and test candidate genes within the region for association to age of onset in these two disorders. Candidates will be prioritized using initially obvious biological candidates, then candidates that lie within the linkage peaks that are identified through Serial Analysis of Gene Expression and Microarray studies in both AD and PD (being performed in our lab in concurrent studies) and finally through fine mapping of the linkage peak for high areas of association using a DNA pooling approach and a new Single base pair- denaturing high performance liquid chromatography methodology. Candidates lying within these high association areas will be investigated further. Once identified, the genes will be investigated in collaboration with known mouse models, at present the Parkin model of Dr. Jian Feng and the APOE models of Dr. Don Schmechel of the DUMC Alzheimer Disease Research Center. Identifying age-of-onset genes may lead to treatment and delay of these late-onset disorders and a better understanding of the pathological processes they share. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen


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Project Title: GENOMIC SCREEN TO IDENTIFY ALZHEIMERS DISEASE GENES Principal Investigator & Institution: Pericak-Vance, Margaret A.; Professor; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2001; Project Start 20-FEB-1997; Project End 31-JAN2003 Summary: This proposal is a continuation of our grant to delineate the genetics of Alzheimer disease [AD], the most common form of dementia after age 40. Within the past five years, four AD genes have been described. APP, PS-I and II are autosomal dominant causative loci in early (

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