Alzheimer Disease - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

ALZHEIMER DISEASE A

3-in-1

Medical

Reference

A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers TO INTERNET REFERENCES

ALZHEIMER DISEASE A BIBLIOGRAPHY AND DICTIONARY FOR PHYSICIANS, PATIENTS, AND GENOME RESEARCHERS

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. 7404 Trade Street San Diego, CA 92121 USA Copyright ©2007 by ICON Group International, Inc. Copyright ©2007 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: Philip Parker, Ph.D. 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 for the diagnosis or treatment of a health problem. 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. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing 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., 1960Alzheimer Disease: A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers/ James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-11325-2 1. Alzheimer 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. 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, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. 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 book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on Alzheimer disease. Books in this series 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 book. 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 health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Chaired Professor of Management Science 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 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. 7404 Trade Street San Diego, CA 92121 USA Fax: 858-635-9414 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON ALZHEIMER DISEASE ................................................................................ 3 Overview........................................................................................................................................ 3 Genetics Home Reference ............................................................................................................... 3 What Is Alzheimer Disease? .......................................................................................................... 3 How Common Is Alzheimer Disease?............................................................................................ 4 What Genes Are Related to Alzheimer Disease? ........................................................................... 4 How Do People Inherit Alzheimer Disease? .................................................................................. 5 Where Can I Find Additional Information about Alzheimer Disease?.......................................... 5 References....................................................................................................................................... 8 What Is the Official Name of the APP Gene? ................................................................................ 9 What Is the Normal Function of the APP Gene?........................................................................... 9 What Conditions Are Related to the APP Gene? .......................................................................... 9 Where Is the APP Gene Located? ................................................................................................ 10 References..................................................................................................................................... 10 What Is the Official Name of the PSEN1 Gene?.......................................................................... 12 What Is the Normal Function of the PSEN1 Gene? .................................................................... 12 What Conditions Are Related to the PSEN1 Gene? .................................................................... 12 Where Is the PSEN1 Gene Located? ............................................................................................ 12 References..................................................................................................................................... 13 What Is the Official Name of the PSEN2 Gene?.......................................................................... 14 What Is the Normal Function of the PSEN2 Gene? .................................................................... 14 What Conditions Are Related to the PSEN2 Gene? .................................................................... 14 Where Is the PSEN2 Gene Located? ............................................................................................ 14 References..................................................................................................................................... 15 What Is the Official Name of the APOE Gene? ........................................................................... 16 What Is the Normal Function of the APOE Gene? ..................................................................... 16 What Conditions Are Related to the APOE Gene? ..................................................................... 16 Where Is the APOE Gene Located? ............................................................................................. 17 References..................................................................................................................................... 17 Federally Funded Research on Alzheimer Disease....................................................................... 18 The National Library of Medicine: PubMed ................................................................................ 83 CHAPTER 2. ALTERNATIVE MEDICINE AND ALZHEIMER DISEASE .............................................. 130 Overview.................................................................................................................................... 130 National Center for Complementary and Alternative Medicine................................................ 130 Additional Web Resources ......................................................................................................... 137 General References ..................................................................................................................... 142 CHAPTER 3. DISSERTATIONS ON ALZHEIMER DISEASE ................................................................ 143 Overview.................................................................................................................................... 143 Dissertations on Alzheimer Disease........................................................................................... 143 Keeping Current ........................................................................................................................ 144 CHAPTER 4. PATENTS ON ALZHEIMER DISEASE ........................................................................... 145 Overview.................................................................................................................................... 145 Patent Applications on Alzheimer Disease ................................................................................ 145 Keeping Current ........................................................................................................................ 147 CHAPTER 5. BOOKS ON ALZHEIMER DISEASE .............................................................................. 148 Overview.................................................................................................................................... 148 Book Summaries: Online Booksellers......................................................................................... 148 The National Library of Medicine Book Index ........................................................................... 156 CHAPTER 6. MULTIMEDIA ON ALZHEIMER DISEASE.................................................................... 158 Overview.................................................................................................................................... 158

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Bibliography: Multimedia on Alzheimer Disease ...................................................................... 158 APPENDIX A. HELP ME UNDERSTAND GENETICS ....................................................................... 161 Overview.................................................................................................................................... 161 The Basics: Genes and How They Work..................................................................................... 161 Genetic Mutations and Health................................................................................................... 172 Inheriting Genetic Conditions ................................................................................................... 178 Genetic Consultation ................................................................................................................. 186 Genetic Testing .......................................................................................................................... 188 Gene Therapy ............................................................................................................................. 194 The Human Genome Project and Genomic Research................................................................. 197 APPENDIX B. PHYSICIAN RESOURCES ........................................................................................... 200 Overview.................................................................................................................................... 200 NIH Guidelines.......................................................................................................................... 200 NIH Databases........................................................................................................................... 201 Other Commercial Databases..................................................................................................... 204 The Genome Project and Alzheimer Disease.............................................................................. 204 APPENDIX C. PATIENT RESOURCES .............................................................................................. 209 Overview.................................................................................................................................... 209 Patient Guideline Sources.......................................................................................................... 209 Finding Associations.................................................................................................................. 215 Resources for Patients and Families........................................................................................... 215 ONLINE GLOSSARIES................................................................................................................ 217 Online Dictionary Directories ................................................................................................... 218 ALZHEIMER DISEASE DICTIONARY .................................................................................... 219 INDEX .............................................................................................................................................. 279

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FORWARD 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.”1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with Alzheimer disease is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about Alzheimer disease, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to Alzheimer disease, from the essentials to the most advanced areas of research. Special attention has been paid to present the genetic basis and pattern of inheritance of Alzheimer disease. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on Alzheimer disease. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to Alzheimer disease, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. We hope these resources will prove useful to the widest possible audience seeking information on Alzheimer disease. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/.

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CHAPTER 1. STUDIES ON ALZHEIMER DISEASE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on Alzheimer disease. For those interested in basic information about Alzheimer disease, we begin with a condition summary published by the National Library of Medicine.

Genetics Home Reference Genetics Home Reference (GHR) is the National Library of Medicine’s Web site for consumer information about genetic conditions and the genes or chromosomes responsible for those conditions. Here you can find a condition summary on Alzheimer disease that describes the major features of the condition, provides information about the condition’s genetic basis, and explains its pattern of inheritance. In addition, a summary of the gene or chromosome related to Alzheimer disease is provided. 2 The Genetics Home Reference has recently published the following summary for Alzheimer disease:

What Is Alzheimer Disease?3 Alzheimer disease is a degenerative disease of the brain that causes dementia, which is a gradual loss of memory, judgment, and ability to function. This disorder usually appears in people older than age 65, but less common forms of the disease appear earlier in adulthood. Memory loss is the most common sign of Alzheimer disease. Forgetfulness may be subtle at first, but the loss of memory worsens over time until it interferes with most aspects of daily living. Even in familiar settings, a person with Alzheimer disease may get lost or become confused. Routine tasks such as preparing meals, doing laundry, and performing other 2 3

This section has been adapted from the National Library of Medicine: http://ghr.nlm.nih.gov/.

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/condition=alzheimerdisease.

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Alzheimer Disease

household chores can be challenging. Additionally, it may become difficult to recognize people and name objects. Affected people may increasingly require help with dressing, eating, and personal care. As the disorder progresses, some people with Alzheimer disease experience personality and behavioral changes and have trouble interacting in a socially appropriate manner. Other common symptoms include agitation, restlessness, withdrawal, and problems with speech. People with this disease usually require comprehensive care during the advanced stages of the disease. After the appearance of symptoms, affected individuals usually survive 8 to 10 years, but the course of the disease can range from 1 to 25 years. Death usually results from pneumonia, malnutrition, or general body wasting (inanition). Four major types of familial Alzheimer disease have been identified. Types 1, 3, and 4 are classified as early-onset Alzheimer disease because their signs and symptoms appear before age 65. Type 2 is classified as late-onset Alzheimer disease because its signs and symptoms appear after age 65.

How Common Is Alzheimer Disease? Alzheimer disease currently affects an estimated 4.2 million to 5.8 million Americans. Because more people are living longer, the number of people with this disease is expected to more than triple by 2050.

What Genes Are Related to Alzheimer Disease? Mutations in the APP (http://ghr.nlm.nih.gov/gene=app), PSEN1 (http://ghr.nlm.nih.gov/gene=psen1), and PSEN2 (http://ghr.nlm.nih.gov/gene=psen2) genes cause Alzheimer disease. Variations of the APOE (http://ghr.nlm.nih.gov/gene=apoe) gene increase the risk of developing Alzheimer disease. About 75 percent of Alzheimer disease cases are classified as sporadic, which means they occur in people with no history of the disorder in their family. Although the cause of these cases is unknown, genetic changes are likely to play a role. Virtually all sporadic Alzheimer disease begins after age 65, and the risk of developing this condition increases as a person gets older. The remaining cases of Alzheimer disease are familial, which means they are found in multiple members of a family. Familial Alzheimer disease can be divided into early-onset disease (symptoms begin before age 65) and late-onset disease (symptoms begin after age 65). The early-onset forms of Alzheimer disease are caused by gene mutations that can be passed from parent to child. Researchers have identified three genes that cause these forms of the disorder. Mutations in the APP gene cause Alzheimer disease type 1. Changes in the PSEN1 gene are responsible for Alzheimer disease type 3, while PSEN2 mutations lead to Alzheimer disease type 4. As a result of mutations in any of these genes, large amounts of a toxic protein fragment called amyloid beta peptide are produced in the brain. This toxic

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peptide can build up in the brain to form clumps called amyloid plaques, which are characteristic of Alzheimer disease. Amyloid plaques may lead to the death of nerve cells and the progressive signs and symptoms of this disorder. Some evidence indicates that people with Down syndrome have an increased risk of developing type 1 Alzheimer disease. Down syndrome, a condition characterized by mental retardation and other health problems, occurs when a person is born with an extra copy of chromosome 21 in each cell. As a result, people with Down syndrome have three copies of many genes in each cell, including the APP gene, instead of the usual two copies. Although the connection between Down syndrome and Alzheimer disease is unclear, the production of more amyloid beta peptide in cells may account for the increased risk. People with Down syndrome account for fewer than 1 percent of all cases of Alzheimer disease. The genetic causes of late-onset (type 2) familial Alzheimer disease are less clear. This disorder is probably related to mutations in one or more risk factor genes in combination with lifestyle and environmental factors. A gene called APOE has been studied extensively as a risk factor for the disease. In particular, a variant of this gene called the epsilon 4 (e4) allele seems to increase an individual's risk for developing type 2 Alzheimer disease.

How Do People Inherit Alzheimer Disease? The early-onset familial forms of Alzheimer disease (types 1, 3, and 4) are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the altered gene from one affected parent. The inheritance pattern of late-onset (type 2) familial Alzheimer disease is uncertain. People who inherit one copy of the APOE e4 allele have an increased chance of developing the disease; those who inherit two copies of the allele are at even greater risk. It is important to note that people with the APOE e4 allele inherit an increased risk of developing Alzheimer disease, not the disease itself. Not all people with Alzheimer disease have the e4 allele, and not all people who have the e4 allele will develop the disease.

Where Can I Find Additional Information about Alzheimer Disease? You may find the following resources about Alzheimer disease helpful. These materials are written for the general public. NIH Publications - National Institutes of Health •

National Center for Biotechnology Information: Genes and Disease: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View.ShowSection&rid=gn d.section.193

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National Institute of Neurological Disorders and Stroke: http://www.ninds.nih.gov/disorders/alzheimersdisease/alzheimersdisease.htm

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National Institute on Aging: Alzheimer's Disease Education and Referral (ADEAR) Center: http://www.alzheimers.org

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NIH SeniorHealth: http://nihseniorhealth.gov/alzheimersdisease/toc.html

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NIH Word on Health: New Fronts in Alzheimer's Research: http://www.nih.gov/news/WordonHealth/apr2004/alzheimers.htm MedlinePlus - Health Information

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Encyclopedia: Alzheimer's Disease: http://www.nlm.nih.gov/medlineplus/ency/article/000760.htm

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Health Topic: Alzheimer's Caregivers: http://www.nlm.nih.gov/medlineplus/alzheimerscaregivers.html

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Health Topic: Alzheimer's Disease: http://www.nlm.nih.gov/medlineplus/alzheimersdisease.html Educational Resources - Information Pages

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Administration on Aging: http://www.aoa.gov/alz/

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Alzheimer's Disease Research Center, Washington University School of Medicine: http://alzheimer.wustl.edu/

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American Psychiatric Association: http://healthyminds.org/mentalhealthofelderly.cfm

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Ask the Geneticist: Inheritance of Alzheimer disease: http://www.askthegen.org/question.php?question_id=1077

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Centre for Genetics Education: http://www.genetics.com.au/factsheet/51.htm

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Cleveland Clinic Health Information Center: http://www.clevelandclinic.org/health/search/showdocuments.asp?mediaID=5&topicId=860&sortId=2

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Duke Center for Human Genetics: http://www.chg.duke.edu/diseases/alzheimer.html

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Emory University School of Medicine: http://www.genetics.emory.edu/pdf/Emory_Human_Genetics_Family_History_Alzhei mer_Disease.PDF

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Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center: http://adrc.mc.duke.edu

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Mayo Clinic: http://www.mayoclinic.org/alzheimers-disease/

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Merck Manual of Medical Information, Second Home Edition: http://www.merck.com/mmhe/sec06/ch083/ch083c.html

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New York Online Access to Health: http://www.noah-health.org/en/bns/disorders/alzheimer/

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Orphanet: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=1020

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The Wellcome Trust: http://genome.wellcome.ac.uk/doc_WTD020860.html

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University Memory and Aging Center, Case Western Reserve University: http://www.memoryandagingcenter.org/

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Patient Support - for Patients and Families •

Alzheimer's Association: http://www.alz.org/

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Alzheimer's Foundation of America: http://www.alzfdn.org/

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Alzheimer Research Forum: http://www.alzforum.org/

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National Organization for Rare Disorders: http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Alzheimer\ Professional Resources

You may also be interested in these resources, which are designed for healthcare professionals and researchers. •

Gene Reviews - Clinical summary: http://ghr.nlm.nih.gov/condition=alzheimerdisease/show/Gene+Reviews;jsessionid= 630A541530D0532C1B46151504F52A39

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Gene Tests - DNA tests ordered by healthcare professionals: http://ghr.nlm.nih.gov/condition=alzheimerdisease/show/Gene+Tests;jsessionid=630 A541530D0532C1B46151504F52A39

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Genetic Tools - Teaching cases: http://www.genetests.org/servlet/access?fcn=y&filename=/tools/cases/dementia15/

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ClinicalTrials.gov - Linking patients to medical research: http://clinicaltrials.gov/search/condition=%22Alzheimer+disease%22+OR+%22Alzhei mer+Disease%22?recruiting=false

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PubMed - Recent literature: http://ghr.nlm.nih.gov/condition=alzheimerdisease/show/PubMed;jsessionid=630A54 1530D0532C1B46151504F52A39

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Online Books - Medical and science texts: http://books.mcgrawhill.com/getommbid.php?isbn=0071459960&template=ommbid&c=234

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OMIM - Genetic disorder catalog: http://ghr.nlm.nih.gov/condition=alzheimerdisease/show/OMIM;jsessionid=630A541 530D0532C1B46151504F52A39

References These sources were used to develop the Genetics Home Reference condition summary on Alzheimer disease. •

Ashford JW. APOE genotype effects on Alzheimer's disease onset and epidemiology. J Mol Neurosci. 2004;23(3):157-65. Review. PubMed citation

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Bird TD. Genetic factors in Alzheimer's disease. N Engl J Med. 2005 Mar 3;352(9):862-4. No abstract available. PubMed citation

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Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, ThomasAnterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed citation

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Cummings JL. Alzheimer's disease. N Engl J Med. 2004 Jul 1;351(1):56-67. Review. No abstract available. PubMed citation

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Gene Review: Early-Onset Familial Alzheimer Disease

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Harman D. Alzheimer's disease pathogenesis: role of aging. Ann N Y Acad Sci. 2006 May;1067:454-60. Review. PubMed citation

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Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, Houlden H, Rossor MN, Collinge J. Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed citation

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Kamboh MI. Molecular genetics of late-onset Alzheimer's disease. Ann Hum Genet. 2004 Jul;68(Pt 4):381-404. Review. PubMed citation

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Lott IT, Head E. Alzheimer disease and Down syndrome: factors in pathogenesis. Neurobiol Aging. 2005 Mar;26(3):383-9. Review. PubMed citation

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Lott IT, Head E. Down syndrome and Alzheimer's disease: a link between development and aging. Ment Retard Dev Disabil Res Rev. 2001;7(3):172-8. Review. PubMed citation

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Mattson MP. Pathways towards and away from Alzheimer's disease. Nature. 2004 Aug 5;430(7000):631-9. Review. PubMed citation

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Nussbaum RL, Ellis CE. Alzheimer's disease and Parkinson's disease. N Engl J Med. 2003 Apr 3;348(14):1356-64. Review. No abstract available. Erratum in: N Engl J Med. 2003 Jun 19;348(25):2588. PubMed citation

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Papassotiropoulos A, Fountoulakis M, Dunckley T, Stephan DA, Reiman EM. Genetics, transcriptomics, and proteomics of Alzheimer's disease. J Clin Psychiatry. 2006 Apr;67(4):652-70. Review. PubMed citation

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Rocchi A, Pellegrini S, Siciliano G, Murri L. Causative and susceptibility genes for Alzheimer's disease: a review. Brain Res Bull. 2003 Jun 30;61(1):1-24. Review. PubMed citation

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Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001 Apr;81(2):741-66. Review. PubMed citation

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St George-Hyslop PH. Genetic factors in the genesis of Alzheimer's disease. Ann N Y Acad Sci. 2000;924:1-7. Review. PubMed citation

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A summary of the genes related to Alzheimer disease is provided below:

What Is the Official Name of the APP Gene?4 The official name of this gene is “amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease).” APP is the gene's official symbol. The APP gene is also known by other names, listed below.

What Is the Normal Function of the APP Gene? The APP gene provides instructions for making a protein called amyloid precursor protein. This protein is located in many tissues and organs, including the brain and spinal cord (the central nervous system). Within cells, the amyloid precursor protein is cut by enzymes to create smaller fragments (peptides), some of which are released outside the cell. Two of these fragments are called soluble amyloid precursor protein (sAPP) and amyloid beta peptide. Recent evidence suggests that sAPP has growth-promoting properties and may play a role in the formation of nerve cells in both embryonic and adult brain tissue. Other functions of sAPP and amyloid beta peptide are under investigation.

What Conditions Are Related to the APP Gene? Alzheimer Disease - Caused by Mutations in the APP Gene Approximately 20 different mutations in the APP gene cause type 1 Alzheimer disease. These mutations are responsible for about 10 to 15 percent of all early-onset familial Alzheimer disease cases. The most common APP mutation changes one of the protein building blocks (amino acids) in the amyloid precursor protein. This mutation replaces the amino acid valine with the amino acid isoleucine at protein position 717 (written as Val717Ile or V717I). Mutations in the APP gene can lead to an increased amount of the amyloid beta peptide, or to the production of more of a slightly longer and stickier form of the peptide. When these protein fragments are released from the cell, they can accumulate in the brain and form clumps called amyloid plaques. These plaques are characteristic of Alzheimer disease. The accumulation of amyloid beta peptide and the formation of amyloid plaques are associated with the signs and symptoms of this disorder.

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Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=app;jsessionid=630A541530D0532C1B46151504F52A39.

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Alzheimer Disease

Other Disorders - Caused by Mutations in the APP Gene Approximately 20 different mutations in the APP gene cause type 1 Alzheimer disease. These mutations are responsible for about 10 to 15 percent of all early-onset familial Alzheimer disease cases. The most common APP mutation changes one of the protein building blocks (amino acids) in the amyloid precursor protein. This mutation replaces the amino acid valine with the amino acid isoleucine at protein position 717 (written as Val717Ile or V717I). Mutations in the APP gene can lead to an increased amount of the amyloid beta peptide, or to the production of more of a slightly longer and stickier form of the peptide. When these protein fragments are released from the cell, they can accumulate in the brain and form clumps called amyloid plaques. These plaques are characteristic of Alzheimer disease. The accumulation of amyloid beta peptide and the formation of amyloid plaques are associated with the signs and symptoms of this disorder.

Where Is the APP Gene Located? Cytogenetic Location: 21q21 Molecular Location on chromosome 21: base pairs 26,174,731 to 26,465,002

The APP gene is located on the long (q) arm of chromosome 21 at position 21. More precisely, the APP gene is located from base pair 26,174,731 to base pair 26,465,002 on chromosome 21.

References These sources were used to develop the Genetics Home Reference gene summary on the APP gene. •

Bornebroek M, De Jonghe C, Haan J, Kumar-Singh S, Younkin S, Roos R, Van Broeckhoven C. Hereditary cerebral hemorrhage with amyloidosis Dutch type (AbetaPP 693): decreased plasma amyloid-beta 42 concentration. Neurobiol Dis. 2003 Dec;14(3):619-23. PubMed citation

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Caille I, Allinquant B, Dupont E, Bouillot C, Langer A, Muller U, Prochiantz A. Soluble form of amyloid precursor protein regulates proliferation of progenitors in the adult

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subventricular zone. Development. 2004 May;131(9):2173-81. Epub 2004 Apr 08. PubMed citation •

Conti L, Cattaneo E. Controlling neural stem cell division within the adult subventricular zone: an APPealing job. Trends Neurosci. 2005 Feb;28(2):57-9. PubMed citation

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Cordy JM, Hooper NM, Turner AJ. The involvement of lipid rafts in Alzheimer's disease. Mol Membr Biol. 2006 Jan-Feb;23(1):111-22. Review. PubMed citation

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Edwards-Lee T, Ringman JM, Chung J, Werner J, Morgan A, St George Hyslop P, Thompson P, Dutton R, Mlikotic A, Rogaeva E, Hardy J. An African American family with early-onset Alzheimer disease and an APP (T714I) mutation. Neurology. 2005 Jan 25;64(2):377-9. PubMed citation

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Fernandez-Madrid I, Levy E, Marder K, Frangione B. Codon 618 variant of Alzheimer amyloid gene associated with inherited cerebral hemorrhage. Ann Neurol. 1991 Nov;30(5):730-3. PubMed citation

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Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002 Jul 19;297(5580):353-6. Review. PubMed citation

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Harman D. Alzheimer's disease pathogenesis: role of aging. Ann N Y Acad Sci. 2006 May;1067:454-60. Review. PubMed citation

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Kerr ML, Small DH. Cytoplasmic domain of the beta-amyloid protein precursor of Alzheimer's disease: Function, regulation of proteolysis, and implications for drug development. J Neurosci Res. 2005 Jan 25; [Epub ahead of print]. PubMed citation

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Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, Bots GT, Luyendijk W, Frangione B. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science. 1990 Jun 1;248(4959):1124-6. PubMed citation

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Maat-Schieman M, Roos R, van Duinen S. Hereditary cerebral hemorrhage with amyloidosis-Dutch type. Neuropathology. 2005 Dec;25(4):288-97. Review. PubMed citation

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Majersik JJ, Skalabrin EJ. Single-gene stroke disorders. Semin Neurol. 2006 Feb;26(1):3348. Review. PubMed citation

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Papassotiropoulos A, Fountoulakis M, Dunckley T, Stephan DA, Reiman EM. Genetics, transcriptomics, and proteomics of Alzheimer's disease. J Clin Psychiatry. 2006 Apr;67(4):652-70. Review. PubMed citation

•

Rocchi A, Pellegrini S, Siciliano G, Murri L. Causative and susceptibility genes for Alzheimer's disease: a review. Brain Res Bull. 2003 Jun 30; 61(1): 1-24. Review. PubMed citation

•

Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001 Apr;81(2):741-66. Review. PubMed citation

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Alzheimer Disease

What Is the Official Name of the PSEN1 Gene?5 The official name of this gene is “presenilin 1 (Alzheimer disease 3).” PSEN1 is the gene's official symbol. The PSEN1 gene is also known by other names, listed below.

What Is the Normal Function of the PSEN1 Gene? The PSEN1 gene provides instructions for making a protein called presenilin 1. Presenilin 1 helps process certain proteins that are important for transmitting biochemical signals from the cell membrane into the nucleus of the cell. In the nucleus, these signals turn on (activate) particular genes that are important for cell growth and maturation. Presenilin 1 is also involved in processing amyloid precursor protein, which is made in the brain and other tissues. Research suggests that presenilin 1 works as part of an enzyme complex that cuts amyloid precursor protein into smaller segments (peptides). One of these peptides is called soluble amyloid precursor protein (sAPP) and another is called amyloid beta peptide. Recent evidence suggests that sAPP has growth-promoting properties and may play a role in the formation of nerve cells in both embryonic and adult brain tissue. Other functions of sAPP and amyloid beta peptide are under investigation.

What Conditions Are Related to the PSEN1 Gene? Alzheimer Disease - Caused by Mutations in the PSEN1 Gene More than 140 PSEN1 mutations have been identified in patients with type 3 Alzheimer disease. Mutations in the PSEN1 gene are the most common cause of early-onset familial Alzheimer disease, accounting for up to 70 percent of cases. Almost all of the PSEN1 mutations substitute one building block of DNA (a nucleotide) for another nucleotide in a particular segment of the PSEN1 gene. These mutations result in an abnormal presenilin 1 protein. Defective presenilin 1 affects the processing of amyloid precursor protein, which leads to increased production of a protein fragment called the amyloid beta peptide. This peptide can build up in the brain and form clumps (amyloid plaques) that are characteristic of Alzheimer disease.

Where Is the PSEN1 Gene Located? Cytogenetic Location: 14q24.3 Molecular Location on chromosome 14: base pairs 72,672,931 to 72,756,861

5

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=psen1.

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The PSEN1 gene is located on the long (q) arm of chromosome 14 at position 24.3. More precisely, the PSEN1 gene is located from base pair 72,672,931 to base pair 72,756,861 on chromosome 14.

References These sources were used to develop the Genetics Home Reference gene summary on the PSEN1 gene. •

Bertram L, Tanzi RE. The current status of Alzheimer's disease genetics: what do we tell the patients? Pharmacol Res. 2004 Oct;50(4):385-96. Review. PubMed citation

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Cordy JM, Hooper NM, Turner AJ. The involvement of lipid rafts in Alzheimer's disease. Mol Membr Biol. 2006 Jan-Feb;23(1):111-22. Review. PubMed citation

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George-Hyslop PS, Rossor M. Alzheimer's disease. Unravelling the disease process. Lancet. 2001 Dec;358 Suppl:S1. No abstract available. PubMed citation

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Harman D. Alzheimer's disease pathogenesis: role of aging. Ann N Y Acad Sci. 2006 May;1067:454-60. Review. PubMed citation

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Larner AJ, Doran M. Clinical phenotypic heterogeneity of Alzheimer's disease associated with mutations of the presenilin-1 gene. J Neurol. 2006 Feb;253(2):139-58. Epub 2005 Nov 4. Review. PubMed citation

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Papassotiropoulos A, Fountoulakis M, Dunckley T, Stephan DA, Reiman EM. Genetics, transcriptomics, and proteomics of Alzheimer's disease. J Clin Psychiatry. 2006 Apr;67(4):652-70. Review. PubMed citation

•

Rocchi A, Pellegrini S, Siciliano G, Murri L. Causative and susceptibility genes for Alzheimer's disease: a review. Brain Res Bull. 2003 Jun 30; 61(1): 1-24. Review. PubMed citation

•

Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001 Apr;81(2):741-66. Review. PubMed citation

•

St George-Hyslop PH. Genetic factors in the genesis of Alzheimer's disease. Ann N Y Acad Sci. 2000;924:1-7. Review. PubMed citation

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Thinakaran G, Parent AT. Identification of the role of presenilins beyond Alzheimer's disease. Pharmacol Res. 2004 Oct;50(4):411-8. Review. PubMed citation

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Alzheimer Disease

What Is the Official Name of the PSEN2 Gene?6 The official name of this gene is “presenilin 2 (Alzheimer disease 4).” PSEN2 is the gene's official symbol. The PSEN2 gene is also known by other names, listed below.

What Is the Normal Function of the PSEN2 Gene? The PSEN2 gene provides instructions for making a protein called presenilin 2. Presenilin 2 helps process certain proteins that are important for transmitting biochemical signals from the cell membrane into the nucleus of the cell. In the nucleus, these signals turn on (activate) particular genes that are important for cell growth and maturation. Presenilin 2 is also involved in processing amyloid precursor protein, which is found in the brain and other tissues. Research suggests that presenilin 2 works as part of an enzyme complex that cuts amyloid precursor protein into smaller segments (peptides). One of these peptides is called soluble amyloid precursor protein (sAPP) and another is called amyloid beta peptide. Recent evidence suggests that sAPP has growth-promoting properties and may play a role in the formation of nerve cells in both embryonic and adult brain tissue. Other functions of sAPP and amyloid beta peptide are under investigation

What Conditions Are Related to the PSEN2 Gene? Alzheimer Disease - Caused by Mutations in the PSEN2 Gene Approximately 11 mutations in the PSEN2 gene have been shown to cause type 4 Alzheimer disease. Mutations in this gene account for less than 5 percent of cases of early-onset familial Alzheimer disease. Two of the most common PSEN2 mutations that cause type 4 Alzheimer disease change one of the building blocks (amino acids) used to make presenilin 2. One mutation replaces the amino acid asparagine with the amino acid isoleucine at position 141 (written as Asn141Ile or N141I). The other mutation changes the amino acid methionine to the amino acid valine at position 239 (written as Met239Val or M239V). These mutations appear to affect the processing of amyloid precursor protein, leading to the increased formation of a protein fragment called amyloid beta peptide. This peptide can form clumps in the brain (amyloid plaques) that are characteristic of Alzheimer disease.

Where Is the PSEN2 Gene Located? Cytogenetic Location: 1q31-q42 Molecular Location on chromosome 1: base pairs 225,125,585 to 225,150,421

6

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=psen2;jsessionid=630A541530D0532C1B46151504F52A39.

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The PSEN2 gene is located on the long (q) arm of chromosome 1 between positions 31 and 42. More precisely, the PSEN2 gene is located from base pair 225,125,585 to base pair 225,150,421 on chromosome 1.

References These sources were used to develop the Genetics Home Reference gene summary on the PSEN2 gene. •

Bertram L, Tanzi RE. The current status of Alzheimer's disease genetics: what do we tell the patients? Pharmacol Res. 2004 Oct;50(4):385-96. Review. PubMed citation

•

Cordy JM, Hooper NM, Turner AJ. The involvement of lipid rafts in Alzheimer's disease. Mol Membr Biol. 2006 Jan-Feb;23(1):111-22. Review. PubMed citation

•

George-Hyslop PS, Rossor M. Alzheimer's disease. Unravelling the disease process. Lancet. 2001 Dec;358 Suppl:S1. No abstract available. PubMed citation

•

Harman D. Alzheimer's disease pathogenesis: role of aging. Ann N Y Acad Sci. 2006 May;1067:454-60. Review. PubMed citation

•

Papassotiropoulos A, Fountoulakis M, Dunckley T, Stephan DA, Reiman EM. Genetics, transcriptomics, and proteomics of Alzheimer's disease. J Clin Psychiatry. 2006 Apr;67(4):652-70. Review. PubMed citation

•

Rocchi A, Pellegrini S, Siciliano G, Murri L. Causative and susceptibility genes for Alzheimer's disease: a review. Brain Res Bull. 2003 Jun 30; 61(1): 1-24. Review. PubMed citation

•

Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001 Apr;81(2):741-66. Review. PubMed citation

•

St George-Hyslop PH. Genetic factors in the genesis of Alzheimer's disease. Ann N Y Acad Sci. 2000;924:1-7. Review. PubMed citation

•

Thinakaran G, Parent AT. Identification of the role of presenilins beyond Alzheimer's disease. Pharmacol Res. 2004 Oct;50(4):411-8. Review. PubMed citation

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Alzheimer Disease

What Is the Official Name of the APOE Gene?7 The official name of this gene is “apolipoprotein E.” APOE is the gene's official symbol. The APOE gene is also known by other names, listed below.

What Is the Normal Function of the APOE Gene? The APOE gene provides instructions for making a protein called apolipoprotein E. This protein combines with fats (lipids) in the body and is known as a lipoprotein. Lipoproteins are responsible for packaging cholesterol and other fats, carrying them through the bloodstream, and delivering them to the appropriate locations in the body for processing and use. In particular, apolipoprotein E is a major component of specific lipoproteins called very low-density lipoproteins (VLDLs). A key function of very low-density lipoproteins is to remove excess cholesterol from the blood and carry it to the liver for processing. Maintaining normal levels of cholesterol is essential for the prevention of disorders that affect the heart and blood vessels (cardiovascular diseases), including heart attack and stroke. There are at least three slightly different versions (alleles) of the APOE gene. The major alleles are called e2, e3, and e4. The most common allele is e3, which is found in more than half of the population.

What Conditions Are Related to the APOE Gene? Alzheimer Disease - Increased Risk from Variations of the APOE Gene The e4 version of the APOE gene seems to increase an individual's risk for developing type 2 Alzheimer disease, the late-onset form of this disorder. People who inherit one copy of the APOE e4 allele have an increased chance of developing the disease; those who inherit two copies of the allele are at even greater risk. It is not known how this allele affects a person's risk of Alzheimer disease. Researchers, however, have found that the APOE e4 allele is associated with an increased number of protein clumps, called amyloid plaques, in the brain tissue of people with Alzheimer disease. It is important to note that not all people with Alzheimer disease have the e4 allele, and not all people who have the e4 allele will develop Alzheimer disease. Other Disorders - Associated with the APOE Gene The e4 version of the APOE gene seems to increase an individual's risk for developing type 2 Alzheimer disease, the late-onset form of this disorder. People who inherit one copy of the APOE e4 allele have an increased chance of developing the disease; those who inherit two copies of the allele are at even greater risk. It is not known how this allele affects a person's risk of Alzheimer disease. Researchers, however, have found that the APOE e4 allele is 7

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=apoe.

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associated with an increased number of protein clumps, called amyloid plaques, in the brain tissue of people with Alzheimer disease. It is important to note that not all people with Alzheimer disease have the e4 allele, and not all people who have the e4 allele will develop Alzheimer disease.

Where Is the APOE Gene Located? Cytogenetic Location: 19q13.2 Molecular Location on chromosome 19: base pairs 50,100,878 to 50,104,489

The APOE gene is located on the long (q) arm of chromosome 19 at position 13.2. More precisely, the APOE gene is located from base pair 50,100,878 to base pair 50,104,489 on chromosome 19.

References These sources were used to develop the Genetics Home Reference gene summary on the APOE gene. •

Ashford JW. APOE genotype effects on Alzheimer's disease onset and epidemiology. J Mol Neurosci. 2004;23(3):157-65. Review. PubMed citation

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Deary IJ, Whiteman MC, Pattie A, Starr JM, Hayward C, Wright AF, Carothers A, Whalley LJ. Cognitive change and the APOE epsilon 4 allele. Nature. 2002 Aug 29;418(6901):932. PubMed citation

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Djousse L, Pankow JS, Arnett DK, Eckfeldt JH, Myers RH, Ellison RC. Apolipoprotein E polymorphism modifies the alcohol-HDL association observed in the National Heart, Lung, and Blood Institute Family Heart Study. Am J Clin Nutr. 2004 Dec;80(6):1639-44. PubMed citation

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Eichner JE, Dunn ST, Perveen G, Thompson DM, Stewart KE, Stroehla BC. Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol. 2002 Mar 15;155(6):487-95. Review. PubMed citation

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Feussner G, Piesch S, Dobmeyer J, Fischer C. Genetics of type III hyperlipoproteinemia. Genet Epidemiol. 1997;14(3):283-97. PubMed citation

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Alzheimer Disease

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Heeren J, Beisiegel U, Grewal T. Apolipoprotein E recycling: implications for dyslipidemia and atherosclerosis. Arterioscler Thromb Vasc Biol. 2006 Mar;26(3):442-8. Epub 2005 Dec 22. Review. PubMed citation

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Huang Y. Apolipoprotein E and Alzheimer disease. Neurology. 2006 Jan 24;66(2 Suppl 1):S79-85. PubMed citation

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Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease. Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5644-51. Epub 2006 Mar 27. Review. PubMed citation

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Raber J, Huang Y, Ashford JW. ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol Aging. 2004 May-Jun;25(5):641-50. Review. PubMed citation

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Rocchi A, Pellegrini S, Siciliano G, Murri L. Causative and susceptibility genes for Alzheimer's disease: a review. Brain Res Bull. 2003 Jun 30; 61(1): 1-24. Review. PubMed citation

•

Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001 Apr;81(2):741-66. Review. PubMed citation

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Song Y, Stampfer MJ, Liu S. Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease. Ann Intern Med. 2004 Jul 20;141(2):137-47. PubMed citation

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St George-Hyslop PH. Genetic factors in the genesis of Alzheimer's disease. Ann N Y Acad Sci. 2000;924:1-7. Review. PubMed citation

Federally Funded Research on Alzheimer Disease The U.S. Government supports a variety of research studies relating to Alzheimer disease. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.8 CRISP (Computerized Retrieval of Information on Scientific Projects) CRISP is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to Alzheimer disease. 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 disease. The following is typical of the type of information found when searching the CRISP database for Alzheimer disease:

8

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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Project Title: 4 IRON-4SULFUR CLUSTERS IN AGING AND ALZHEIMER'S DISEASE Principal Investigator & Institution: Longo, Valter D.; Assistant Professor; Gerontology; University of Southern California Department of Contracts and Grants Los Angeles, Ca 90033 Timing: Fiscal Year 2004; Project Start 30-SEP-2001; Project End 31-AUG-2005 Summary: DESCRIPTON (Provided by applicant): The candidate was trained as a biochemist at UCLA where he specialized in studies of oxidative damage in yeast. Dr. Longo has spent the past three years as a PI of a funded yeast laboratory and as a Research Associate/Assistant Professor working on Alzheimer?s Disease-related projects. The candidate?s long-term career goals are to be a faculty member in a neuroscience program and to continue research on aging. He is applying for the K01 Award in Aging to develop his research skills and knowledge in the neuroscience field with particular focus on the fundamental mechanisms of oxidative damage in aging and neurodegenerative diseases. Dr. Caleb. Finch, Prof. of Gerontology, Neuroscience, and Molecular Biology at the Andrus Gerontology Center, will act as Dr. Longo?s mentor along with Prof. Kelvin Davies. The international stature of these faculty members in the field of aging, oxidative stress, and neurodegenerative diseases, make this environment ideal for the development of Dr. Longo expertise in these fields. Dr Longo will participate in the bimonthly chalk talks in the Neurobiology and Endocrinology of Aging, will attend the weekly research seminars and journal clubs in USC?s multidisciplinary neuroscience program, and will attend a course on the responsible conduct of research. The candidate will also be exposed to clinical studies on cognitive changes during normal aging and during Alzheimer disease (AD). The research project "4 Iron-4 Sulfur Clusters in Aging and Alzheimer?s Disease" proposes to test the hypothesis that the 4Fe-4S clusters, contained in certain dehydratase enzymes sensitive to superoxide toxicity, are a major source of the redox-active iron that mediates oxidative damage during aging and in Alzheimer?s Disease. This hypothesis will be tested by measuring redox-active iron in animal models for AD and by determining the contribution of 4Fe-4S clusters to the pool of redox-active iron and to oxidative damage and death in neurons and neuronal cell lines exposed to oxidants and beta amyloid. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: 9TH INTL CONF ON ALZHEIMER'S DISEASE & RELATED DISORDERS Principal Investigator & Institution: Thies, William H.; Alzheimer's Association 225 N Michigan Ave, 17Th Fl Chicago, Il 60601 Timing: Fiscal Year 2004; Project Start 01-JUN-2004; Project End 31-MAY-2005 Summary: (provided by applicant): Alzheimer's disease is one of the major areas of research in neuroscience. There has been a tremendous major areas increase in the rate of excellent publications on Alzheimer's disease and related disorders. The International Conference on Alzheimer's Disease and Related Disorders started in 1988 in Las Vegas, Nevada and attracted over 350 scientists from around the world. Over the years it has grown significantly--1990, Toronto, Canada (750); 1992, Padva, Italy (1,000); 1994, Minneapolis, Minnesota (1,220); 1996, Osaka, Japan (1,600); 1998, Amsterdam, Netherlands (2,500); 2000, Washington, DC (3,000); 2002, Stockholm, Sweden (3,800)-and has become THE conference on Alzheimer's disease and related disorders research. Since the last conference in Stockholm, important advances continue to take place regarding etiology, clinical course, differential diagnosis, epidemiology and risk factors,

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Alzheimer Disease

histopathological course, genetics, molecular genetics, model systems, therapeutics and related neurodegeneration. This application specifically requests funds to help support the cost of travel for talented junior investigators, who will be selected on a competitive basis. The funding of this application will make a major contribution to the success of this international conference and the advancement of research, specifically by allowing support to be provided to a higher percentage of young researchers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: A COMMUNITY-BASED STUDY OF THE COURSE AND OUTCOMES OF ALZHEIMER'S DISEASE Principal Investigator & Institution: Stern, Yaakov; Professor; Columbia University Health Sciences Research Administration New York, Ny 100323702 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 30-JUN-2009 Summary: There have been very few studies of progression of Alzheimer's disease (AD) that have been based in community populations. Typical studies, including some of our owaa previous reports, use clinical populations, often recruited at psychiatric or AD centers. Clinical populations are not representative of the true distribution of the disease and these studies are necessarily biased by the nature of the referral and recruitment patterns particular to the clinical setting. In addition, it is not known what proportion of patients with AD actually is seen in clinical settings. In this project we are conducting a prospective, community based study of a representative sample of patients with AD to investigate determinants of disease course and outcomes. In the previous study period, we identified and initiated prospective follow-up of 903 AD patients, including 356 incident cases. We propose to continue follow-up of the surviving patients and to initiate follow-up of an additional group of incident cases in order to test specific hypotheses regarding determinants of disease course and outcomes. We will have the unprecedented opportunity to test all of our major hypotheses in a multi-ethnic cohort of incident dementia patients. We will characterize rapidity of disease course in AD by applying generalized estimating equations and random effects models to prospectively obtained measures of cognitive function and ability to perform activities of daily living. We will also determine the timing and occurrence of specific disease endpoints: change in CDR stage, use of paraprofessional care, increase in hours of ADL care, admission to nursing home, need for the equivalent of institutional care, and mortality. We will explore factors hypothesized to be associated with increased relative risk for the occurrence of the disease endpoints or with more rapid disease course: demographic features, particularly ethnicity, comorbid medical and sociocultural factors, behavioral manifestations, genetic and molecular data, as well as the rate of cognitive and functional decline and estrogen use information acquired prior to the incident dementia. We will compare hospitalization and mortality in demented patients to that observed in nondemented community patients. We will also identify what level of change in particular cognitive domains is associated with alteration in the functional task performance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: A MULTIDIMENSIONAL ALZHEIMER'S DISEASE BRAIN ATLAS Principal Investigator & Institution: Toga, Arthur W.; Director; None; University of California Los Angeles Office of Research Administration Los Angeles, Ca 90024 Timing: Fiscal Year 2004; Project Start 01-MAY-1995; Project End 31-JUL-2006

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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 high-resolution 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 high- resolution 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.; Professor & Director; Medicine; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2004; Project Start 01-AUG-2001; Project End 31-JUL-2006 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

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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 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: ACADEMIC CAREER LEADERSHIP AWARD IN ALZHEIMER'S DISEASE Principal Investigator & Institution: Asthana, Sanjay; Professor; Medicine; University of Wisconsin Madison Suite 6401 Madison, Wi 537151218 Timing: Fiscal Year 2006; Project Start 15-APR-2006; Project End 31-JAN-2011 Summary: (provided by applicant): The present Academic Leadership Award (K07) application is to request support for Sanjay Asthana, MD to integrate the remarkable resources of the University of Wisconsin (UW)-Madison, and develop a comprehensive, translational, interdisciplinary, and campus-wide research program in Alzheimer's disease (AD). The UW has a long and distinguished history of conducting cutting edge research in neuroscience. However, there is currently no academic program in AD at UW. Establishing a preeminent research program in AD is one of the top strategic priorities for UW. To that end, recruitment of Dr. Asthana into a leadership position and commitment of substantial institutional resources is expected to facilitate establishment of an AD research program at UW. Furthermore, establishing such a program will provide the infrastructure to eventually develop a NIA-funded Alzheimer's Disease Research Center (ADRC) at UW. The major objectives of the proposed AD research Program at UW are as follows: 1) to bring together the remarkable resources of UW toward developing a campus-wide, interdisciplinary, and collaborative research program in AD, 2) to develop "research cores" which will form the basic structure of the proposed AD program, and provide an infrastructure for future funding of an Alzheimer's Disease Research Center (ADRC) at UW, 3) to develop a comprehensive training program covering all aspects of AD from its neurobiology to the diagnosis and management of patients with the disease 4) to attract investigators and other faculty members from across UW to the field of AD research and related illnesses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ADVANCED GLYCATION END PRODUCTS AND ALZHEIMER'S DISEASE Principal Investigator & Institution: Schnaider Beeri, Michal M.; Psychiatry; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2005; Project Start 01-AUG-2005; Project End 31-JUL-2010 Summary: (provided by applicant): Michal Schnaider Beeri is a psychologist with research experience in geriatrics and neuropsychology. Her long-term goal is to identify modifiable risk and protective factors for Alzheimer's disease (AD) and cognitive decline. Several risk factors for cardiovascular disease and diabetes in particular, have also been associated with risk for the occurrence of AD. Advanced Glycation End (AGE) products have been proposed as an explanation for the association between diabetes and AD and are the focus of the research project proposed in this application. This award will provide time and resources for Dr. Beeri to prepare for a career as an independent scientist, by acquiring knowledge and expertise in the following eight areas: 1) Epidemiology of AD, 2) Longitudinal statistical techniques, 3) Physiology of cardiovascular risk factors, 4) Epidemiology of cardiovascular risk factors, 5) AGEs, 6) The oldest old, 7) Differential diagnosis, and 8) Treatments for diabetes and AGEs. The Mount Sinai School of Medicine is an ideal environment for this training experience. The Psychiatry Department conducts extensive longitudinal research on AD, including risk factors research led by Dr. Jeremy Silverman, the principal mentor of this application. The Division of Diabetes and Aging of the Department of Medicine, directed by Dr. Helen Vlassara, a co-mentor, has pioneered AGE research in diabetes and will provide the infrastructure for large scale AGE studies. The objective of this project is to examine the role of AGEs in cognitive decline and AD incidence in 500 subjects participating in an ongoing longitudinal cardiovascular risk factors study for AD in the very old. Subjects' serum and urine AGEs (methylglycoxal, N-carboxymethyllysine (CML), and low molecule weight CML) and dietary AGEs will be assessed on a semi annual basis for up to 4 years, complementing their comprehensive cognitive and cardiovascular assessment. Identification of AGEs as a modifiable risk factor may lead to real public health gains among the elderly, by delaying or decreasing incidence of AD and cognitive decline. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ALZHEIMER DISEASE RESEARCH CENTER Principal Investigator & Institution: Chui, Helena C.; Professor; Gerontology; University of Southern California Department of Contracts and Grants Los Angeles, Ca 90033 Timing: Fiscal Year 2004; Project Start 15-APR-1997; Project End 31-MAR-2009 Summary: (provided by applicant): The USC Alzheimer's Disease Research Center (ADRC) focuses on basic mechanisms and the cognitive/behavioral impact of Alzheimer's disease (AD) and cerebrovascular disease (CVD) among ethnically diverse populations. Administrative Core: (Helena Chui, Dir.; Caleb Finch, Co-Dir.; Elena Munoz, Admin.) Provides scientific direction and administration of Center, including solicitation of pilots, new investigators, and external advice. Data Management Core (Wendy Mack, Dir.) Responsible for Web-based database, resource for statistical design ant analytic support, sharing of data with National Alzheimer's Coordinating Center (NACC). Education Information and Transfer Core: (Margaret Gatz Dir.) Assists in minority subject recruitment, provides community education, and studies the conceptualization of dementia among minorities. Clinical Core: (Helena Chui M.D, Dir.; Lon Schneider, Co-Dir.) Evaluates, enrolls, follows, and refers subjects with AD, VD,

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and other dementias to research projects. Spanish-Speaking Satellite: (Xavier Salazar, Dir.) Evaluates, enrolls, follows, and refers Spanish speaking subjects with AD, VD, and other dementias to research projects. Pathology Core: (Carol Miller, Dir.) Provides neuropathological diagnoses, distributes tissues, and obtains genotypes. Imaging Core: (Manbir Singh, Dir.) Provides technical support to investigators, develops new techniques, refines methodologies, archives MRI. Project 16: Diffusion tensor tractography in AD and SVD (Manbir Singh, Dir.) Uses diffusion tensor MRI to map white matter pathways in AD and SVD. Project 17: Vascular risk and cognitive status in a Latino population (Wendy Mack Dir.; Rohit Varma, CoDir.) Defines the contributions of AD and VD to cognitive impairment in a community-based survey of a Mexican population. Project 18: Structural studies of a-synuclein and fibril assembly (Ralf Langen, Dir.) Uses site-directed spin labeling to define the structural characteristics of alpha-synuclein. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALZHEIMER'S DISEASE GENES, CELLULAR PATHWAYS AND THERAPIES Principal Investigator & Institution: Tanzi, Rudolph E.; Professor and Director; Keystone Symposia Drawer 1630, 221 Summit Pl #272 Silverthorne, Co 80498 Timing: Fiscal Year 2005; Project Start 01-JUL-2005; Project End 30-JUN-2006 Summary: (provided by applicant): Alzheimer's disease (AD), a progressive neurodegenerative disease, is the most common form of dementia in the elderly. Over the past two decades, studies of AD at the genetic, molecular, and cell biological level have revealed a host of genes, proteins, and biological pathways that impact on the pathogenesis of this disease. Characterization of these pathogenic pathways has suggested several promising therapeutic strategies for treating and preventing AD based on curbing the accumulation of the Abeta peptide in brain, regulating tau hyperphosphorylation, modulating inflammatory responses, and enhancing neurotransmitter function. This meeting will cover updates of the genetics of AD, Abeta generation and clearance pathways, regulation of tau, relevant animal models, novel therapeutic strategies, and advances in imaging and biomarkers for AD diagnosis. Alzheimer's disease (AD) and related disorders are the most common forms of dementia in the elderly population. The two greatest risk factors for AD are advancing age and family history. As the average lifespan continues to increase, particularly in the Western world, AD represents one of the single greatest burdens on the healthcare system. This symposium will focus on genetic risk factors, relevant cellular pathways and emerging therapies for AD and frontal temporal dementia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ALZHEIMER'S DISEASE PREVENTION TRIAL WITH ESTROGENS Principal Investigator & Institution: Sano, Mary; Phd.; Psychiatry; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2004; Project Start 01-SEP-1998; Project End 31-AUG-2008 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

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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: ALZHEIMER'S DISEASE RESEARCH CENTER Principal Investigator & Institution: Dekosky, Steven T.; Professor; Neurology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2005; Project Start 01-MAY-1997; Project End 31-MAR-2010 Summary: (provided by applicant): From its beginnings as a center which focused on behavioral, neuropsychological and neuropsychiatric changes versus the course of the disease, the University of Pittsburgh Alzheimer Disease Research Center (ADRC) has evolved into a broadly based, full-service dementia research center, fulfilling its missions in excellent patient care and follow-up, clinical, basic, and translational research, and education of students, residents, fellows, faculty, community physicians, and the lay community. Our areas of research specialization include neuropsychiatric symptoms and manifestations of Alzheimer's disease and other dementias, neuroimaging and new neuroimaging modalities, genetics, and overlap of Alzheimer's disease with other neurodegenerative disorders. A wide range of basic and clinical research studies are supported by patients, data, or biological materials from the ADRC. In this current renewal, the Center will support 6 cores (including the requisite Data Management and Statistics Core) research projects, and 2 pilot studies. One project will assess the ability to image amyloid in the brains of patients with autosomal dominant familial Alzheimer's disease; a second will evaluate gene therapy of targeted neprilysin enzymes which destroy or accelerate metabolism of beta amyloid, and the third will attempt to develop subhuman primate and human differentiated neural precursors from stem cells for use as models of AD and initiate the development of a transgenic Alzheimer's monkey to advance translational studies of therapies and establish a better animal model of AD. The Pitt ADRC has also provided national and international

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leadership to the Centers program and other collaborative efforts in Alzheimer's disease, in the ADC directors group, the ADC administrators group, the AD Cooperative Study, and the NACC. Members of the Pittsburgh ADRC sit on or chair advisory committees for a variety of other Alzheimer's centers as well as the national Alzheimer's Association. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALZHEIMER'S 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 920930934 Timing: Fiscal Year 2004; Project Start 01-APR-1997; Project End 31-MAR-2009 Summary: (provided by applicant): This proposal is for a five-year renewal of the Alzheimer's Disease Research Center (ADRC) at the University of California San Diego in consortium with The Buck Institute. The major goals of the Center over the next five years will be to expand our efforts into studying the conversion from normal aging to dementia through the intermediary step of Mild Cognitive Impairment (MCI) and to study mechanisms of neurodegeneration Projects will focus on functional MRI of the elderly at risk for Alzheimer's disease (Bondi, Project 1), testing of the role of axonal disturbances in Alzheimer's disease (Goldstein, Project 2), and studying the cytoplasmic domain of APP and its interacting proteins in synapse damage (Koo, Project 3). This Center will continue to maintain extremely strong Clinical and Neuropathological Cores. The Clinical Core will continue to longitudinally characterize a cohort of approximately 500 subjects to study early changes in cognition and semantic memory, and to provide other investigators and the San Diego community as a whole with a well characterized clinical cohort of both Caucasian and Hispanic volunteers. The Clinical Core will also recruit subjects and controls to support the special needs of many of the individual projects. The Center will also continue its participation in collaborative projects with other ADCs funded through the NACC or directly from NIA. Subjects will also participate in multi-center drug trials. Data derived from subjects will be used in collaborative research. In addition we will continue to carry out detailed clinicopathological correlations in Alzheimer's disease and other related neurodegenerative diseases: Lewy Body Variant of AD and fronto-temporal dementia. The Neuropath Core has taken a lead role in this endeavor. The Center as a whole will continue to provide brain tissue, plasma, serum, 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 professional and lay communities through our miniresidency program, conferences and other educational activities. The Data Management and Biostatistics Core will continue to provide statistical design and analysis services to ADRC investigators, prepare the minimum data set for submission to the NACC, as well as coordinate the entry, quality control, management and analysis of data generated by the Clinical and Neuropathology Cores. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ALZHEIMER'S DISEASE RESEARCH CENTER Principal Investigator & Institution: Harrell, Lindy E.; Professor; Neurology; University of Alabama at Birmingham 1530 3Rd Avenue South Birmingham, Al 35294 Timing: Fiscal Year 2004; Project Start 01-APR-1999; Project End 31-MAR-2009 Summary: (provided by applicant): The past four years have been a time of development and growth of the Alzheimer's Disease Research Center (ADRC) at UAB.

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This application represents a request to continue our ADRC for an additional five years. This ADRC is composed of 5 Cores and 3 small projects. The Administrative Core will provide the implementation of all goals of the ADRC including budgets, meetings of the Executive and Internal and External Advisory Committees, enhancing visibility through pilot grants (i.e. bring new investigators to AD research), a monthly seminar series and interactions with other Alzheimer's Disease Centers. The Clinical Core will continue to follow previously recruited patients and recruit 30 controls, 30 mild cognitive impairment (MCI), 30 mild AD, and 30 Parkinson's Disease with dementia (PDD) patients annually. Annual neuropsychological assessments and arrangement for autopsy will be performed. The Data Management and Biostatistics Core will provide statistical consultation, data management and send all required information to the NACC. The Neuropathology Core will provide new techniques for diagnosis, process and store tissue (brain, CSF) and make these available to investigators at UAB and other institutions. The Education and Information Transfer Core will provide education to physicians, paraprofessionals and lay communities (with emphasis on AfricanAmericans), maintain a Speakers Bureau, caregivers' newsletters, packets of information on AD, continue our annual CME courses with every other one done in conjunction with the Roybal Center, maintain our web page and disseminate ADRC research through multimedia. The 3 Projects are thematically linked by studying behavioral, longitudinal and functional change in AD, PDD and MCI patients and in caregivers. One Project will examine functional (e.g. driving) change in MCI patients as compared to normal older adults. A Second Project will examine the loss of medical decision making capacity in AD, PDD and controls. A Third Project will determine if interventions with caregivers while their "loved one" still has mild AD will improve caregivers' adjustment when their "loved one" progresses to moderate/severe AD. The Administration strongly supports the ADRC both philosophically and financially, paying the salary of the Administrator as well as renovating multiply areas for the ADRC. Continuation of an ADRC at UAB would allow us to continue both clinical and basic research efforts in AD and would allow us to expand into new research areas (e.g. PDD, MCI). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALZHEIMER'S DISEASE RESEARCH CENTER AT COLUMBIA UNIV. Principal Investigator & Institution: Shelanski, Michael L.; Professor and Chairman; Pathology; Columbia University Health Sciences Research Administration New York, Ny 100323702 Timing: Fiscal Year 2005; Project Start 15-JUN-1997; Project End 31-MAY-2010 Summary: (provided by applicant): The ADRC at Columbia seeks to advance and disseminate knowledge of the causes, prevention and treatment of Alzheimer's Disease and other age-related neurodegenerative and dementing disorders. Toward this end, we maintain and follow a multi-ethnic and multi-racial patient population of normal elderly and the elderly with cognitive disorders to establish the natural history of the disease as a function of age and of genetic makeup. In this application we propose to use a variety of neuropsychological, neurological and imaging tools to examine the earliest stages of AD and to follow these subjects throughout their lives. At death a comprehensive neuropathologic examination will be performed and the clinical, radiological and pathological views of the disease correlated. Tissues and DNA obtained from these subjects will be available for research on the biology and genetics of the disease. Individual research projects within the ADRC will examine various aspects of the cellular and molecular biology of AD as well as an in-depth analysis of brain function in

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human subjects using MRI. Patients enrolled in the ADRC will have the opportunity to participate in trials of new drugs and treatments for dementing diseases as they become available. The well-documented cognitive status of these patients makes them highly suitable for inclusion in clinical trials. The Education and Information Core of the Columbia ADRC endeavors to educate both lay and medical communities about AD, about the latest advances in research and about the care of the AD patient. The ADRC serves as a resource for scientists with Columbia as well as outside of it, encouraging new research avenues by the award of pilot grants, by providing tissues and other biological samples, by providing access to a carefully documented patient population and by numerous seminars and Clinical Pathological Correlation Conferences. The Genetics Core serves as the major organizer of family recruitment and identification across the ADRCs and ADCs. HIPAA compliant data organization and statistical consulting services are provided under the ADRC to the research community at Columbia and external to it. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AMINERGIC FUNCTION BRAIN AGING AND ALZHEIMER'S DISEASE Principal Investigator & Institution: Bickford, Paula C.; Professor; Neurosurgery; University of South Florida 3650 Spectrum Blvd., Suite 160 Tampa, Fl 33612 Timing: Fiscal Year 2006; Project Start 01-APR-1997; Project End 30-JUN-2011 Summary: (provided by applicant): This Program Project Grant is focused on understanding physiological and biochemical alterations in the brain underlying changes in cognition during aging and Alzheimer's disease. There are several themes that weave throughout the Program Project. A major theme is to examine the role of oxidative stress and inflammation in aging. There are 2 major sources of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the brain and these are from the glia (primarily the microglia) and the mitochondrion. All projects will examine this question from varying angles, for example projects 5, 3,and 1 will examine a mouse with defective mitochondrial (mt) DNA polymerase that show signs of premature aging. A second focus of the grant is to examine aspects of microglial function as a source of ROS and RNS as well as other biological triggers of neurodegeneration. There is increasing evidence that microglia have multiple phenotypes in the activated state ranging from classical activation states to an alternative activation state. One of the goals of the application is to understand the dynamics of the phenotype of microglia and the potential influence on CNS function and AD progression. All projects will examine microglial function. The final theme that weaves throughout the Program Project is a continuing theme of a role for monoamines, and specifically norepinephrine (NE) in age-related declines in CNS function. A new aspect of the role of NE examined in this renewal is the neuroprotective role of the locus coeruleus (LC) in aging and disease. Many neurodegenerative diseases including AD share a loss of LC neurons as an early aspect of disease progression. It has been suggested that LC-NE neurons play a specific role in protection against insults such as neuroinflammation and oxidative stress. This idea will be specifically addressed in Project 4 as well as Projects 1, 3, and 5. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AMYLOID-BETA METABOLISM/HUMANS/ALZHEIMER'S DISEASE Principal Investigator & Institution: Bateman, Randall J.; Neurology; Washington University 1 Brookings Dr, Campus Box 1054 Saint Louis, Mo 631304899

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Timing: Fiscal Year 2005; Project Start 30-SEP-2005; Project End 31-AUG-2008 Summary: (provided by applicant): The candidate is an MD trained clinical neurologist whose career goal is to investigate the pathophysiologic causes of Alzheimer's disease, with emphasis on studying Amyloid-Beta metabolism in humans. The proposed period of mentored scientific training in the laboratory of Dr. David Holtzman and clinical research training with Dr. John Morris at Washington University will allow the candidate to develop the skills necessary to become an independent investigator. The central hypotheses that will be tested during the proposed project are as follows: 1) Alzheimer's disease is associated with increased synthesis and/or decreased clearance of the amyloid-beta peptide (A?) in humans. 2) The risk factor of increased age is associated with increased synthesis and/or decreased clearance of Abeta in humans. 3) The risk factor of ApoE4 genotype is associated with decreased clearance of Abeta in humans. The candidate proposes to test these hypotheses using a recently developed method to measure the synthesis and clearance rate of A? in vivo in humans. Participants from the Washington University Alzheimer's Disease Research Center will be enrolled in the above studies to compare groups of 1) AD versus non-demented controls, 2) older age, middle age, vs. younger age, and 3) ApoE4 positive vs. ApoE4 negative. A detectable change in Abeta metabolism in humans that is associated with AD may ultimately lead to better diagnostic and therapeutic options. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AN FMRI INDEX AS A RISK MARKER FOR ALZHEIMER'S DISEASE Principal Investigator & Institution: Li, Shi-Jiang; Professor; Biophysics; Medical College of Wisconsin 8701 Watertown Plank Rd Milwaukee, Wi 532260509 Timing: Fiscal Year 2004; Project Start 01-JUL-2002; Project End 30-JUN-2007 Summary: The goal of this proposal is to develop and validate an early, non-invasive, quantitative marker for the pre-clinical stage of Alzheimer's disease (risk marker) using functional magnetic resonance imaging (fMRI). Such a sensitive marker for AD will have significant advantages in identifying people at risk, facilitating early assessment and providing effective disease management. Recent developments in fMRI technology allow us to indirectly observe neuronal activity with high spatial and temporal resolution. We and others have observed spontaneous low frequency (SLF) fluctuations in the BOLD contrast-weighted neurophysiological signal in subjects at rest. We have developed an index, the COSLOF index, to quantify changes of SLF signal. The results of numerous published neuropathological studies suggest that the hippocampal formation is the initial locus in the disease processes of AD. In addition, the progression of neurodegenerative changes is remarkably uniform across individuals, is predictable, and shows little inter-patient variation. In AD, the lesions eventually lead to severe damage to the hippocampus (referred to as the "floor effect") and clinical expression of dementia. Our preliminary results demonstrate that the COSLOF index has the ability to distinguish between probable/possible AD patients and cognitively healthy controls. Based on all these results, we propose a prospective and longitudinal study to test the hypothesis that the COSLOF index in the hippocampal formation can predict the onset of AD dementia in subjects with mild cognitive impairment (MCI). We chose to study MCI subjects because of their high incidence (yearly 10-12 percent) of AD development. At the end of the five-year period, we can determine retrospectively the sensitivity of the COSLOF index to predict the pre-clinical onset of AD progression and to distinguish those MCI subjects who are destined to develop AD from those who are undergoing normal aging processes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANDROGENS AND ALZHEIMER'S DISEASE Principal Investigator & Institution: Pike, Christian J.; Assistant Professor; None; University of Southern California Department of Contracts and Grants Los Angeles, Ca 90033 Timing: Fiscal Year 2005; Project Start 01-JAN-2005; Project End 31-DEC-2009 Summary: Abundant evidence suggests that the depletion of estrogen in postmenopausal women is a significant risk factor for the development of Alzheimer's disease (AD). As a normal consequence of aging, men also exhibit depletion of their primary sex steroid hormone, testosterone. The reduction in men's androgen levels is manifested clinically as impaired function in numerous androgen-sensitive tissues throughout the body, including the brain. Based on recent evidence from our laboratory, we propose that two neural functions of androgens are promotion of neuron viability and regulation of beta-amyloid protein (A-beta). We predict that impairment of these androgen functions occurring as a result of normal, age-related androgen depletion will place the brain at increased risk for the development of Alzheimer's disease. To investigate this hypothesis, we propose three Specific Aims that utilize complementary cell culture, animal model, and human subjects paradigms. In the Aim 1, we will investigate our hypothesis that androgens are endogenous regulators of neuron viability. Proposed studies will assess the role of androgen receptor in neuroprotection as well as elucidate the responsible downstream signaling cascades. Further, we will examine how age-related androgen depletion affects neuronal vulnerability to injury. In Aim 2, we investigate the hypothesized role of androgens as endogenous modulators of AE, levels. By experimental manipulation of androgen status in animal models, we will evaluate our hypothesis that androgen depletion will result in increased levels of Abeta. Mechanistic studies will evaluate the contributions of androgen receptor activation and androgen regulation of A- beta-catabolizing enzymes. Together, we anticipate that Aims 1 and 2 will establish that androgens have beneficial, protective actions in brain and that androgen depletion places the brain at risk for degeneration and disease. In Aim 3, we will further evaluate this hypothesis by both investigating how manipulation of androgen status affects progression of AD-like neuropathology in a transgenic mouse model of Alzheimer's disease. and examining the relationships between human aging, brain levels of A-beta and androgens, and AD status. Together, we believe these novel and timely studies will begin an important evaluation of interactions between normal male aging events, neuroprotection, A-beta regulation, and the risk of developing Alzheimer's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANTIOXIDANT APPROACHES TO ALZHEIMER'S DISEASE THERAPY Principal Investigator & Institution: Beal, M Flint.; Professor; Neurology and Neuroscience; Weill Medical College of Cornell Univ 1300 York Avenue New York, Ny 10021 Timing: Fiscal Year 2006; Project Start 15-MAR-2006; Project End 31-JAN-2008 Summary: (provided by applicant): There is increasing evidence that oxidative damage may contribute to the pathogenesis of neurodegenerative diseases such as Alzheimer's Disease (AD). A number of recent studies have suggested that oxidative damage may precede and be causally linked to the deposition of beta-amyloid. Conversely, betaamyloid may induce oxidative damage. There are two major classes of oxidants and biological systems; reactive oxygen intermediates and reactive nitrogen intermediates. A

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number of studies have shown that there are increased reactive oxygen intermediates in AD postmortem brain tissue as assessed by oxidative damage markers. There also appears to be increased reactive nitrogen intermediates as assessed by biochemical and immunocytochemical measurements of 3-nitrotyrosine. Our data, which has been confirmed by others, shows that there is an increase in inducible nitric oxide synthase (NOS2) immunoreactivity within neurons in both AD postmortem brain tissue, as well as in transgenic mouse models. Genetic reduction of NOS2 activity markedly reduced beta-amyloid deposition in a transgenic mouse model of AD. The goals of the present application are to utilize two compounds, which can block reactive oxygen species and reactive nitrogen intermediates. We will utilize coenzyme Q10 and L-iminoethyl-Llysine (L-NIL) in transgenic mouse models of AD. CoQ10 is a cofactor of the electron transport gene, which has strong antioxidant properties. It is extremely well tolerated in human subjects and is under clinical development for treatment of Parkinson's Disease, Huntington's Disease and amyotrophic lateral sclerosis. We will also look at the effects of L-iminoethyl-L-lysine, which is a relatively specific inhibitor of NOS2. We will determine whether treatment with either CoQ10 or L-NIL can exert neuroprotective effects against beta-amyloid deposition and oxidative damage, and improve memory in transgenic mouse models of AD. If we can demonstrate significant effects of CoQ10 and L-NIL, this could lead to rapid development of new therapies for slowing the progression of AD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTI-OXIDANT THERAPY IN ALZHEIMER'S DISEASE Principal Investigator & Institution: Bacskai, Brian J.; Assistant Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2006; Project Start 15-FEB-2006; Project End 31-DEC-2010 Summary: (provided by applicant): Alzheimer's disease (AD) is a devastating neurological illness with no known cure, yet a central hypothesis implicating oxidative stress as a cause of the disease has been postulated for more than a decade. AD is characterized in post-mortem tissue by the presence of senile plaques that result from the progressive brain accumulation of amyloid-a (Aa) peptides; thus Aa is the principle therapeutic target for treating Alzheimer's disease. There are numerous studies with anti-oxidant therapy; however none examine the AD-specific contribution quantitatively. Clinical trials with anti-oxidant therapy have also shown limited efficacy. Our approach provides quantitative readouts of AD-specific oxidative stress to optimize an anti-oxidant treatment. While we have shown that oxidative stress results from the senile plaques of AD themselves, it is likely that other p species, such as small diffusible aggregates, oligomers, or Aa derived diffusible ligands (ADDLs) are also a source of reactive oxygen species. This grant application proposes to identify aggregated and soluble Aa components that are sources of oxidative stress, and evaluate anti-oxidant treatments for protective activity both in vitro and in vivo using transgenic mouse models of Alzheimer's disease. Our strength lies in the utilization of sophisticated imaging techniques based on multiphoton microscopy that allow us to image senile plaques structurally and functionally in vitro and in vivo. Small diffusible aggregates of Aa like oligomers and ADDLs can be analyzed and characterized using highthroughput plate-reader assays or multiphoton fluorescence correlation spectroscopy (PCS). Anti-oxidants can be tested for their ability to reduce or prevent the oxidative stress resulting from these small toxic Aa species. In combination, these experimental paradigms will be used to screen potential anti-oxidants from both traditional and alternative sources to systematically evaluate whether compounds like Ginkgo biloba

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extract, vitamin E, or grape seed extract are effective anti- oxidants for Alzheimer's disease treatment. The results will bridge the gap between the description of oxidative stress in Alzheimer's disease to direct determination of the anti-oxidant ability of natural and synthetic products that should hold promise for treatment of AD patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIOXIDANT VITAMINS IN MODELS OF ALZHEIMER'S DISEASE Principal Investigator & Institution: May, James M.; Professor of Medicine; Medicine; Vanderbilt University Medical Center Nashville, Tn 372036869 Timing: Fiscal Year 2004; Project Start 15-JAN-2004; Project End 31-DEC-2008 Summary: (provided by applicant): Alzheimer's disease is the most common dementia in aging humans, but its etiology is poorly understood. There is consensus that it relates in part to the toxicity and deposition of beta-amyloid fragments of the amyloid precursor protein. A key finding of beta-amyloid toxicity, even early in the clinical course of the disease, is oxidant stress. This manifests as lipid peroxidation and DNA damage in select cortical areas, followed by neuronal cell death. It follows that antioxidants, and particularly antioxidant vitamins such as ascorbic acid and alphatocopherol, should delay or prevent oxidant damage associated with beta-amyloid toxicity. However, this hypothesis has received little study. We propose to test it at the level of cultured neuronal cells and in animal models of Alzheimer's disease. Since neurons have the highest ascorbate content of any cell in the body, and since ascorbate is important as both a neuromodulator and antioxidant, we will focus on its role in preventing oxidant injury to cortical neurons. The first aim uses cultured SHSY5Y neurons to establish mechanisms of ascorbate uptake and recycling, to test whether ascorbate prevents lipid peroxidation and spares alpha-tocopherol, and to determine whether intracellular ascorbate either lessens beta-amyloid-induced oxidant stress or modifies beta-amyloid secretion. The second aim assesses the role of oxidant stress in the tissue damage and memory deficits in transgenic mice carrying mutations in key proteins implicated in human Alzheimer's disease. We expect to find that oxidant stress in these animals decreases cortical neuron concentrations of ascorbate, and that ascorbate supplements slow progression of cognitive defects by reversing local "scurvy." We will also crossbreed the transgenic mouse model of Alzheimer's disease with a knockout mouse that cannot synthesize ascorbate. If ascorbate prevents neuronal cell oxidant damage, moderate ascorbate deficiency due to dietary restriction should hasten the onset and worsen the severity of oxidant stress and cognitive deficits. In the third aim, we will use cortical neurons cultured from neonatal transgenic mice to determine at the cell level the mechanisms by which antioxidant vitamins lessen lipid peroxidative damage. If antioxidant vitamins ameliorate toxicity in cell and animal models of Alzheimer's disease, then oxidant stress is involved in disease progression, and antioxidant vitamin supplements may be beneficial. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOLOGY OF ALZHEIMER AMYLOID IN NEURONS Principal Investigator & Institution: Gouras, Gunnar K.; Neurology and Neuroscience; Weill Medical College of Cornell Univ 1300 York Avenue New York, Ny 10021 Timing: Fiscal Year 2006; Project Start 30-SEP-2006; Project End 31-JUL-2011 Summary: (provided by applicant): Beta-amyloid is a major constituent of the plaques found in the brains of patients afflicted by Alzheimer's disease and reduction in beta-

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amyloid is currently a major target of therapeutic strategies for the disease. We reported electron microscopy studies to better define the subcellular localization of beta-amyloid in the brain and to determine how plaques form in a well-established transgenic mouse model of beta-amyloidosis. We found that beta-amyloid localized especially to small intracellular organelles, called multivesicular bodies, and smaller vesicles, and that this beta-amyloid accumulates with aging within Alzheimer's disease vulnerable neurons within these organelles until associated morphological alterations appear, especially within distal nerve cell processes and synaptic compartments. Multivesicular bodies are currently being actively studied for their role in recycling and degradation of among others, important membrane receptors, and for their transport along axons of vital cargo proteins, including nerve growth factors and their receptors. Aberrant protein accumulation has become a common theme in neurodegenerative diseases and we propose biological and pathological studies to explore the accumulation and modulation of beta-amyloid in multivesicular bodies within neurons. Specifically, we hypothesize that accumulating beta-amyloid may cause alterations in recycling and/or degradation of important synaptic receptors, in the ubiquitin proteasome system and/or in retrograde transport within neurites. In addition, we hypothesize that our preliminary evidence on synaptic activity reducing intraneuronal beta-amyloid provides a potential explanation for an emerging paradox in the field relating to elevation of beta-amyloid secretion with synaptic activity. A better understanding of beta-amyloid accumulation in multivesicular bodies within neurons, which are associated with early beta-amyloid related changes with Alzheimer disease pathogenesis, may be important in developing more effective treatments for Alzheimer's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOMARKERS IN EARLY ALZHEIMER'S DISEASE Principal Investigator & Institution: De Leon, Mony J.; Professor; Psychiatry; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2004; Project Start 15-JUN-2004; Project End 31-MAY-2009 Summary: (provided by applicant): The goal of this project is to use MRI and CSF biomarkers to identify in cognitively normal (NL) subjects, the earliest clinically detectable brain changes of Alzheimer's disease (AD). Neuropathology studies show, in mild cognitive impairment (MCI) and some NL individuals, neurofibrillary and plaque pathology that is associated with neuronal and volume losses in the entorhinal cortex (EC) and hippocampus. Our recent in vivo MRI and PET studies of the EC show that volume and metabolism reductions predict the conversion of NL to future MCI. However, in vivo imaged changes lack disease specificity. Our most recent studies and those of our collaborators show that tangle-related abnormal tau proteins, hyperphosphorylated at threonine 231 (P-tau231), are: 1) elevated in the CSF in MCI; 2) useful in predicting further cognitive decline; and 3) diagnostically specific for AD. Our crosssectional diagnosis and longitudinal data demonstrate that P-tau231 significantly adds to the MRI hippocampal volume in the diagnosis of MCI. Moreover, we recently published an MRI-based technique that improves detection of longitudinal P-tau231 increases in MCI by controlling for progressive ventricular CSF volume dilution. Our pilot studies also show that amyloid beta 1-40 (Abeta40) levels are elevated in MCI. Overall, these findings suggest that a sensitive and specific recognition of AD in the normal stages of cognition is close at hand. We plan to complete over 5-years a longitudinal MRI and CSF study consisting of a baseline and two 18-month follow-up exams on 80 elderly NL subjects currently active in a longitudinal MRI study of aging and memory. To enrich the sample with individuals at increased risk for progressive

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cognitive decline, 50 of the subjects will be selected on the basis of subjective memory complaints. Longitudinally studied FTD patients are available to examine specificity. We will use quality controlled and standardized protocols at each observation to collect norm-referenced neuropsychological data; high-resolution MRI; and CSF. Our major hypothesis is that CSF P-tau231 measurement improves the accuracy (specificity) of MRI EC atrophy and CSF Abeta measurements in prediction of the conversion from NL to MCI. All the required imaging and clinical components for this study are active. Ample numbers of subjects are available, and we already completed the proposed three evaluations on 8 eligible NL subjects. There is adequate statistical power for testing the hypotheses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BOLD AND PERFUSION FMRI OF ALZHEIMER'S DISEASE RISK Principal Investigator & Institution: Fleisher, Adam S.; Medical Director; Neurosciences; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934 Timing: Fiscal Year 2004; Project Start 15-AUG-2004; Project End 31-JUL-2009 Summary: (provided by applicant): The primary goal of this five-year training award is to further the development of the candidate's expertise as a researcher and medical clinician in the following areas: 1) Imaging of functional brain systems in Alzheimer's disease and other dementias; 2) relationships between risk for Alzheimer's Disease (AD), functional brain system patterns, and neuropchycholgical test performance; and 3) clinical research design, methodologies, and statistical analysis techniques used in the evaluation of these relationships. The superceding career goals of this candidate are to improve the understanding of brain systems involved in dementia, develop diagnostic tools for early intervention in degenerative dementing diseases while functioning as a clinician researcher. The proposed training will include structured coursework and expert mentoring in clinical dementia, functional imaging, statistics and neuropsychology. The research project that will be adjunct to this training has an overall aim of conducting a five-year study of non-demented adults over a wide age range (3050yrs) in an effort to identify reliable patterns of altered brain function and correlate those changes to the underlying hemodynamic response in individuals at higher risk for AD. The primary aims of this study are to answer the following questions: 1) What is the age variances of Blood Oxygen Level Dependency (BOLD) signal in AD risk? 2) Does this BOLD signal correlate to differences in underlying cerebral blood perfusion?, and 3) Does the variance in BOLD signal therefore representative pathology in underlying neuronal activity? The proposed study will evaluate variance in activation BOLD signal in relationship to baseline and activation perfusion, measured by Arterial Spin Labeling Functional MRI. Neuropsychological testing will be performed to evaluate for substantial group differences. Based on our previous pilot studies each participant will be imaged on a 3T MRI scanner while performing a verbal associate episodic memory task. This training program will allow this candidate to transition from a postdoctoral research fellow to an independent investigator and clinician in the field of geriatric neurology in the UCSD Department of Neurosciences, and provide the foundation for a clinical and research career focused on dementia pathology, treatment and diagnosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CALCINEURIN AND INFLAMMATORY SIGNALING PROCESSES IN AGING AND ALZHEIMER'S DISEASE Principal Investigator & Institution: Norris, Christopher M.; Molecular & Biomedical Pharmacology; University of Kentucky 109 Kinkead Hall Lexington, Ky 405060057

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Timing: Fiscal Year 2006; Project Start 01-SEP-2006; Project End 30-JUN-2011 Summary: (provided by applicant): Alzheimer's disease (AD) is a devastating and irreversible neurological disease that progressively alters personality and behavior, and destroys cognitive function. With an annual price tag exceeding 100 billion dollars, AD is also one of the nation's most costly diseases. In recent years, anti-inflammatory agents have emerged as promising compounds for delaying the onset of AD symptoms. Yet, our understanding of the mechanisms underlying neuro-immune/inflammatory (im/inf) signaling in the brain remains incomplete. The Ca2+/calmodulin dependent protein phosphatase, calcineurin, plays a critical role in im/inf signaling cascades in lymphocytes and other cell types, but has received little consideration for a similar role in nervous tissue. In the past year, we found that calcineurin activation in neuron-glia co-cultures was sufficient for recapitulating several components of the im/inf response found consistently with aging and AD, including astrocyte activation and the induction of numerous im/inf-related gene cascades. We also observed a marked and selective upregulation of calcineurin in activated astrocytes surrounding amyloid deposits in AD model mice. The long-term goal of this project is to therefore test the hypothesis that calcineurin is a critical component for the activation of im/inf signaling processes associated with AD. The first two aims will test whether activation of calcineurin and/or the calcineurin-dependent transcription factor, NFAT is necessary for im/inf signaling in astrocytes. Biologically relevant inflammatory mediators will be delivered to astrocyte- specific cultures in the presence or absence of potent calcineurin and NFAT inhibitors. The induction of im/inf markers will be assessed with Western blots, RTPCR, and cytokine arrays. Potential Ca2+ sources for calcineurin activation in astrocytes will also be examined, along with the possibility that calcineurin amplifies its own activity by up-regulating these Ca2+ sources. Aim three will use cell fractionation, immunoprecipitation, Western blot, phosphatase activity assays, immunohistochemistry, and in situ hybridization to qualitatively and quantitatively assess changes in calcineurin signaling in AD brain specimens and/or in a rodent model of AD. Completion of these studies will greatly increase our knowledge of the role of calcineurin in neuroinflammation and AD, and may lead to the development of novel treatment strategies for this disease and other degenerative conditions where neuroinflammation is prominent. 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 UnivPurdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2004; Project Start 19-FEB-2001; Project End 31-JAN-2006 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, populationbased 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

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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: CARDIORESPIRATORY FITNESS IN ALZHEIMER'S DISEASE Principal Investigator & Institution: Burns, Jeffrey M.; Neurology; University of Kansas Medical Center Msn 1039 Kansas City, Ks 66160 Timing: Fiscal Year 2005; Project Start 15-AUG-2005; Project End 30-JUN-2007 Summary: (provided by applicant): Effective strategies for promoting healthy brain aging and preventing Alzheimer's disease (AD) are increasingly important given the growth of the elderly population and the resulting increase in the incidence of AD. Accumulating evidence suggests that exercise and cardiorespiratory (CR) fitness may protect against cognitive decline and age-related brain changes in non-demented aging. CR fitness has not been studied in the early stages of AD. Neuroimaging surrogate measures of brain aging and brain disease are increasingly used lo detect disease associations, explore causal mechanisms, and establish an intervention's diseasemodifying effect. Thus, our long-term goal is to investigate CR fitness in AD and its relationship to structural brain changes associated with early-stage AD and nondemented aging. Our overall hypothesis is that increased CR fitness will be inversely associated with neuroimaging markers of brain aging. We will assess maximal oxygen consumption (VO2 max), the gold-standard measure of CR fitness, in a cohort (n = 64) of non-demented controls and early-stage AD subjects completing clinical and neuroimaging assessments as part of the University of Kansas (KU) Brain Aging Project. Brain aging markers include MRI measures of whole brain atrophy, hippocampal atrophy, white matter lesions, and infarcts. We will test our hypothesis with three specific aims. Aim 1: Assess for group differences in CR fitness in a cohort of nondemented controls and early-stage AD participants. Aim 2: Evaluate the relationship of CR fitness and hippocampal volume in non-demented aging and early-stage AD. Aim 3: Assess CR fitness in relation to MRI markers of brain aging: atrophy, white matter lesions, and infarcts. This preliminary, multidisciplinary study will generate crosssectional pilot data assessing the relation between CR fitness, brain aging and ADrelated brain injury. Utilizing well-characterized subjects with clinical and neuroimaging assessments through the KU Brain Aging Project enables this project to be feasible in a discrete time-frame. Exercise is already a key prevention strategy for health issues beyond preventing brain aging and cognitive decline. Despite this, an estimated 40-50 million adults in the US do not currently obtain the recommended amount of physical activity. A clear demonstration of the beneficial effects of exercise on brain

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aging and AD would be important for public health policy and effective for encouraging the public to adapt more active lifestyles. If our hypotheses are correct, we would pursue longitudinal interventional studies to better establish causality and assess increasing CR fitness as a way to promote healthy brain aging and moderate AD-related brain changes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLONING OF LATE-ONSET ALZHEIMER'S DISEASE GENES Principal Investigator & Institution: Schellenberg, Gerard D.; Research Professor; Medicine; University of Washington Office of Sponsored Programs Seattle, Wa 98105 Timing: Fiscal Year 2004; Project Start 15-AUG-2002; Project End 31-JUL-2007 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: CNS STEM CELLS FOR ALZHEIMER'S DISEASE THERAPY Principal Investigator & Institution: Carlson, George A.; Director; Stemcells, Inc. 3155 Porter Dr Palo Alto, Ca 943031213 Timing: Fiscal Year 2004; Project Start 30-SEP-2004; Project End 31-MAR-2006 Summary: (provided by applicant): Alzheimer's disease (AD) is a progressive neurodegenerative disease. It is prevalent among the elderly, affecting approximately 4 million Americans. Alzheimer's is a heterogeneous disease involving a number of

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components, including genetics. Although the accumulation of beta-amyloid peptide (AB) has been associated with both familial and sporadic forms of Alzheimer's, our current understanding of the role of AB and the mechanisms leading to the decline of cognitive function and neuronal loss are speculative. Transgenic mouse lines that over express AB peptides develop amyloid plaques and show age-related memory deficits have been created. Unfortunately, these mouse models for AD do not result in progressive neuronal loss as seen in humans. Whether this is due to species differences between mouse and human neurons can now be addressed directly by examining the fate of human neural cells transplanted into these AD mouse models. The ability to identify, isolate and expand human neural stem cells provides the opportunity to generate well-characterized cells for transplantation. In vivo properties of these cells have been extensively tested in the experimental NOD-Scid xenogeneic transplant mouse system. The striking features of the human CNS-SC is their capacity to engraft, migrate within the brain, and phenotypically differentiate into the three major cell types, neurons, astrocytes, and oligodendrocytes. Here we propose to examine the fate of human CNS-SC derived neural cells in the mouse models that recapitulate features of AD to assess the utility of neural cell transplants in the treatment of AD. Moreover, one can envision that these stem cells by their very biological property could produce and replace lost or dysfunctional neurons. The objectives of this grant are to test human neural stern cells as candidate therapeutics for the treatment of Alzheimer's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COMPUTERIZED ALZHEIMER'S DISEASE ASSESSMENT SCALE Principal Investigator & Institution: O'halloran, James P.; Neurocomp Systems, Inc. 1370 Reynolds Ave Irvine, Ca 92614 Timing: Fiscal Year 2004; Project Start 01-SEP-2001; Project End 31-MAY-2006 Summary: (provided by applicant): Alzheimer's Disease (AD) is a degeneratve disorder of the central nervous system that affects between 4-6% of all elderly US residents over the age of 65 with annual associated costs over $100 billion. Research and development of new treatments is critically dependent on accurate and reliable assessment methods that address multiple cognitive domains. The Alzheimer's Disease Assessment Scale or ADAS was among the first comprehensive cognitive/behavioral batteries designed specifically for Alzheimer's disease assessment and is today the most widely accepted and used in research and clinical trials of new antidementia pharmacologic agents. The project objective is to develop a computerized version of the ADAS that is equivalent to the standard paper-and-pencil version while conferring the advantages of contemporary information technologies. The primary advantages of computerization include: standardized presentation, immediate electronic data capture, error-free tabulation and scoring; and storage in a powerful, fully relational database. The computer platform to be utilized is uniquely suited to assessment of the elderly and impaired subjects due to its interactive dual-display and control architecture, which integrates a human examiner. This enables an examiner to score verbal report and overt behavioral performance (e.g. praxis tasks), otherwise not possible with single display systems. The proposed hardware-software ensemble will include not only a computerized ADAS but also a suite of powerful software utilities to assist implementation and management of clinical trials as well as to comply with recently issued regulatory agency guidelines. In addition to software development, Phase II will implement a longitudinal comparison of the cADAS with the standard ADAS at two established AD research centers. The proposed new technology would find application in nearly all clinical trials as well as

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research and development of new pharmaceutical agents aimed at reducing the cognitive deficits and/or underlying neuropathology of Alzheimer's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISCLOSURE OF GENETIC RISK FOR ALZHEIMER'S DISEASE Principal Investigator & Institution: Roberts, J Scott.; Health Behavior and Health Education; University of Michigan at Ann Arbor 3003 South State Street, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2006; Project Start 01-SEP-2006; Project End 31-AUG-2008 Summary: (provided by applicant): Understanding how people respond to genetic risk information will be critical in allowing discoveries from genomic research to be effectively translated into clinical care. Alzheimer's disease (AD), for which one form of the apolipoprotein E (APOE) genotype serves as a significant risk factor, provides an instructive paradigm in which to examine the process and impact of genetic testing for a common, complex disease. The parent grant in this application, the NHGRI/NIAfunded Risk Evaluation and Education for Alzheimer's Disease (REVEAL) Study, is a multi-site, randomized clinical trial of a genetic counseling and education program that includes disclosure of APOE genotype information. This clinical trial examines the psychological and behavioral impact of the counseling and education program on a racially diverse sample of first-degree relatives of people with AD. We will expand upon the already novel design and content of the REVEAL Study through several methodological innovations. First, we will use the Roter Interaction Analysis System (RIAS) coding method to analyze over 225 audiotaped REVEAL risk disclosure sessions. The RIAS has been utilized successfully in many clinical contexts but has never been applied to actual genetic risk disclosure sessions. Its use will permit for rigorous analysis of the process of risk disclosure for AD susceptibility. Second, we will examine physicians as providers of risk disclosure, in order to explore provider differences in provision of genetic risk assessment. Given these additions to the REVEAL Study design, we will be able to: 1) examine how the quality of provider-patient interactions during risk disclosure sessions predicts key patient and provider outcomes following genetic risk assessment; 2) examine differences in provider-patient interactions between risk disclosure sessions in which negative vs. positive test results for the APOE-e4 genotype are disclosed; and 3) explore differences in provider-patient interactions based on both patient and provider characteristics (e.g., race, provider profession). Study findings will inform the development and implementation of genetic risk assessment programs across numerous disease contexts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DRUG DISCOVERY FOR ALZHEIMER'S DISEASE Principal Investigator & Institution: Das, Arpita; Neuronautics, Inc. Evanston, Il 602013135 Timing: Fiscal Year 2004; Project Start 01-JUL-2000; Project End 31-JUL-2005 Summary: (provided by applicant): NNI seeks to ameliorate neurodegeneration seen in Alzheimer's disease and other dementias. Toward this end, NNI scientists have targeted neurofibrillary tangle (NFT) formation for drug discovery. These lesions appear in concert with the onset of memory loss in AD, and are in fact the best markers for AD neurodegeneration known in the scientific literature. Thus NNI has pursued agents that interfere with NFT formation. As part of Phase I effort, the feasibility of inhibiting tau filament formation and driving filament depolymerization in vitro using small, drug-

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like ligands was demonstrated. Moreover, the ability of one such molecule to halt progression of neurodegeneration in an animal model of disease was shown. The goal of Phase II effort is to extend these results by validating tau fibrillization as a drug target, and proving that in vitro screening technology can successfully identify compounds that are active in animal models of tau-induced neurodegeneration. There are three Aims. First, NNI will expand its screening effort to identify additional classes of molecules with anti tau polymerization activity. NNI has shown the feasibility of using its screening technology to identify such molecules. Second, NNI will characterize the mechanism of action of its compounds, establishing a structure activity relationship for members of the existing structural family. Finally, NNI will examine the activity of active compounds in vivo, demonstrating entry into the brain, and determining a structure activity relationship for in vivo activity. At the end of the project, NNI will be in position to establish neuritic lesions (e.g., NFTs) as an authentic target for intensive preclinical development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECTS OF VISUAL SIGNAL STRENGTH ON ALZHEIMER COGNITION Principal Investigator & Institution: Cronin-Golomb, Alice M.; Associate Professor; Psychology; Boston University 881 Commonwealth Avenue Boston, Ma 02215 Timing: Fiscal Year 2005; Project Start 01-AUG-1999; Project End 31-MAY-2009 Summary: (provided by applicant): Identification of factors that keep individuals with Alzheimer's disease (AD) from functioning optimally in their daily lives is of singular importance. Most aspects of visual cognition are impaired in AD, including the abilities to recognize and discriminate objects, faces, and patterns. The inability to recognize the face of a loved one or the danger in inappropriately identifying an object are some of the most devastating features of AD for both the patient and the caregiver. These visual deficits arise from pathological changes in highorder association areas of the brain but also from defective input from lower-level visual processing areas. Impairments in basic vision are prevalent in AD and can strongly predict deficits in visual cognition. We plan to apply our knowledge of the cognitive consequences of visual dysfunction in AD to designing visual-system manipulations with the goal of ameliorating cognitive deficits in this disorder. These results will indicate which cognitive and memory domains are most accessible to visual interventions and allow us to develop a visually-fair neuropsychological test battery for clinical and research use. This work continues our dual-site study with the Alzheimer Disease Centers of Boston and Cleveland. Key features of the new study are its focus on the effect of contrast manipulation on memory, and the expansion of examined levels of visual processing "downward" to include retinal change and "upward" to include the relation of visual abilities to daily activities assessed under naturalistic conditions. Another point of expansion is in the examination of nondemented individuals with Parkinson's disease (PD). Our Specific Aims are: (1) To perform experimental manipulations of contrast sensitivity and to document changes in memory and cognition as a function of normal aging, AD and PD. (2) To examine retinal and optic nerve function with frequency-doubling technology and optical coherence tomography and relate findings to visual cognition, memory, and daily activities. (3) To assess motion detection with the goal of establishing which factors are most salient to performance. (4) To relate visual abilities to daily function, as assessed by naturalistic tasks and by successful engagement in vision-dependent leisure activities and instrumental activities of daily living. Using innovative techniques, our findings will span the multiple levels of retina, basic vision, visual cognition, visual memory, and

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daily function, and we will attain new and more comprehensive insights into improving the quality of life of normal elderly adults and those with AD and PD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FISH OIL & ALPHA LIPOIC ACID IN MILD ALZHEIMER'S DISEASE Principal Investigator & Institution: Shinto, Lynne H.; Neurology; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2004; Project Start 30-SEP-2003; Project End 31-AUG-2007 Summary: (provided by applicant): The heterogeneous nature of the biological mechanisms associated with Alzheimer's disease (AD) pathology make therapies that can target multiple mechanisms of action rather than a single mechanism attractive candidates to delay or prevent disease progression. Oxidative stress has been highly implicated in Alzheimer's disease pathology and recent studies show there is also an association between an increase in inflammation and cholesterol (respectively), and AD pathology. Fish oil and alpha lipoic also have the ability to decrease oxidative stress, inflammation, and lipid levels, making them strong candidates as therapeutic agents in slowing the progression of Alzheimer's disease. These supplements also have few reported side effects. Based on their mechanisms of action, a combination of the two supplements has the potential to maximize the therapeutic benefit in delaying the progression in AD. The proposed study will be a pilot trial designed to collect preliminary data to aid in the design of a larger clinical trial powered to assess both treatments' effect on mechanisms associated with AD pathology and clinical markers of AD pathology. This pilot study is designed as a 3-arm, parallel group, double-blind placebo-controlled trial. Subjects >55 yrs. diagnosed with probable AD and having mild cognitive impairment will be randomized to one of three groups (13 subjects/group): 1. fish oil alone, 2. fish oil plus alpha lipoic acid, 3. placebo. The treatment intervention will be for 1-year. Our primary objective, Aim 1, is to assess the treatments' effect on oxidative stress by measuring urine F2-isoprotane levels. We will also collect preliminary data on the treatments' effect on plasma lipid levels and high-sensitivity Creactive protein. Our secondary objective, Aim 2, is to collect preliminary data on ADrelated clinical outcome measures which will include: the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Clinical Dementia Rating scale (CDR), Mini Mental State Examination (MMSE), Alzheimer's Disease Cooperative Study Activities of Daily Living Scale, SF-36, and Logical Memory I1.Our tertiary objective, Aim 3, is to assess treatment safety by a monthly monitoring of adverse events and laboratory tests (metabolic panel, including liver function tests and platelet function assay). Compliance of fish oil supplementation will be assessed by red blood cell membrane fatty acid analysis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FLORIDA ALZHEIMER'S DISEASE RESEARCH Principal Investigator & Institution: Potter, Huntington; Professor; Molecular Medicine; University of South Florida 3650 Spectrum Blvd., Suite 160 Tampa, Fl 33612 Timing: Fiscal Year 2005; Project Start 01-MAY-2005; Project End 31-MAR-2010 Summary: (provided by applicant): There are an estimated 430,000 Alzheimer's disease patients in Florida, with the Tampa Bay and Miami/Dade County areas having a large, ethnically diverse and growing population with this illness. Indeed, Florida is the fourth largest state in the country in terms of population, and the second largest in total number of Alzheimer's disease patients. Clearly Florida would be ideal place to site an

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NIA-funded Alzheimer's disease Research Center (ADRC). Yet no such Florida-based ADRC exists. Therefore, a group of researcher s and physicians from across the state have joined together to design and seek funding for the Florida ADRC (FADRC) described in this application. The general goals of the proposed FADRC are represented by the three Projects which aim: 1. To better understand the process of transition from normal to MCI to AD by determining which combinations of clinical, epidemiologic, imaging, neuropsychological, and biological markers best identify individuals who will experience a rapid rate of cognitive decline toward AD or other dementing illnesses. 2. To investigate the ability of cognitive rehabilitation to intervene in and slow disease progression in MCI and early AD patients. 3. To use mouse models of AD to determine which aspects of environmental enrichment (including cognitive rehabilitation) best slow or reverse cognitive impairment and might be similarly applied to human patients. These projects are mutually supportive and synergistic because markers found in Project 1 can be used to measure success and/or to distinguish populations in Project 2, and model results obtained in Project 3 can be used to help decide which type of intervention may be most successful in humans. The three projects are supported by 5 Cores- Clinical, Data Management, Neuropathology, Education, and Mouse Behavior and Neuropathology. The end result of the synergy inherent in the design of the FADRC may be the development a novel therapeutic intervention that can slow the clinical course of the disease. To aid in the development, administration and financial support of the planned FADRC, in 2002, the Florida Legislature established and funded the Johnnie B. Byrd Sr. Alzheimer's Center and Research Institute on the campus of the University of South Florida. Byrd Institute funds and personnel will be used to supplement the NIA grant in a State-Federal collaboration that will help assure the success of the proposed FADRC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE DETECTION IN REGIONS LINKED TO ALZHEIMER'S DISEASE Principal Investigator & Institution: Avramopoulos, Dimitrios; Psychiatry and Behavioral Sciences; Johns Hopkins University W400 Wyman Park Building Baltimore, Md 212182680 Timing: Fiscal Year 2005; Project Start 01-FEB-2005; Project End 31-JAN-2010 Summary: (provided by applicant): Of all the regions that have been detected in genome scans for late onset Alzheimer's disease (LOAD) only a few have consistently provided positive findings, suggesting that they likely harbor a LOAD susceptibility gene. One such region is close to the centromere on chromosome 10. We recently reported a strong linkage finding in this region in our subset of the NIMH genetics initiative pedigrees, accompanied by a parent of origin effect. We have now investigated an additional independent subset of pedigrees, those collected by the University of Alabama, and replicated the parental origin effect in the region. In the combined maternal pedigree set after fine mapping the multipoint LOD score is 3.53 reaching the conservative threshold for genome-wide significance. Our 1-LOD interval is 15 cM wide with our current density of 1.4 cM per marker (information content =0.7). Our first aim is to perform an association analysis comparing cases from our families with controls that are cognitively healthy and have no family history of Alzheimer's disease. We will genotype 242 cases and 242 controls for 3,000 SNPs selected from those genotyped for the HapMap project and found to be non-redundant (not in perfect LD) in Caucasians and including 50 genomic control markers for correction of population substructure. We expect this aim to narrow down the finding to a few disease associate regions. Those will be followed

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up with a family based association analysis in an independent sample in order to be confirmed or rejected. In aim 2 we will further analyze the confirmed or convincing associated region(s) by genotyping more known variation within them and variation detected through nucleotide sequencing in expressed, conserved and known functional areas. We will also genotype additional SNPs in areas where the coverage in aim 1 was inadequate due to low linkage disequilibrium. Finally in aim 3 we will analyze the confirmed and convincing region(s) to detect expression in the brain of sequences known or predicted to be transcribed and we will examine the presence of expression variation between cases and controls and between positively and negatively associated alleles/haplotypes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC CONSORTIUM FOR LATE ONSET ALZHEIMER'S DISEASE Principal Investigator & Institution: Mayeux, Richard; Gertrude H. Sergievsky Professor of Neur; Gertrude H Sergievsky Center; Columbia University Health Sciences Research Administration New York, Ny 100323702 Timing: Fiscal Year 2005; Project Start 30-SEP-2005; Project End 30-JUN-2010 Summary: (provided by applicant): Over the past two years the NIA-Late-Onset Alzheimer's Disease (NIA-LOAD) Study was developed for the recruitment of individuals from families with late onset familial Alzheimer's disease and supported through supplements to 18 Alzheimer's Disease Centers. This group, led by a Genetics Coordinating Core (GCC) at Columbia University has developed, circulated and refined a procedures manual and has overseen the collection of 1,885 samples from 422 families for which data has been transmitted to the National Cell Repository for Alzheimer's Disease (NCRAD) located at Indiana University. The intent of this Resource-Related Research Project-Cooperative Agreement is to complete the collection of new families, recruit appropriate members in existing families and initiate and complete follow-up in all participating families. Five of the original Centers (Columbia University, Indiana University, Mayo Clinic, University of Washington and Washington University) will form a consortium with the existing GCC at Columbia University and will also coordinate follow-up of existing families through small targeted subcontracts with the remaining 13 Centers. The aims of this proposal are to: l)Complete the current collection of 1,000 families; 2) Identify newly affected family members and appropriate unaffected members by expanding pedigrees in participating families; 3) Develop and implement standardized follow-up procedures for the participating families and family members; 4) Improve statistical power of the sample for genetic linkage analysis by implementing methods for standardized assessment of a series of quantitative traits at the time of follow-up for all families; 5) Complete the recruitment and begin follow-up of 1,000 individuals unrelated to the participating families without dementia to form a "control" group; 6) Apply to the Center for Inherited Disease Research to have genotyping completed in the first 500 families. At the conclusion of this five year proposal we will have created a rich resource of 1,000 well-characterized families with late-onset, familial Alzheimer's disease, which is essential for the success of genetics research in this area. The NIA-LOAD Study has added specific criteria for the inclusion of families with lateonset disease and has used standardized methods to identify affected and unaffected individuals across Centers. This collection of families will be complimented by a similar number of unrelated controls. The need for additional, well characterized families is essential for identifying the remaining genetic variants and role in the disease. This application proposes to work with the network of NIA supported Alzheimer's Disease

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Centers to provide the resources critical to Alzheimer's disease researchers that will allow the elucidation of susceptibility genes. BACKGROUND, SIGNIFICANCE, AND INNOVATION Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC EPIDEMIOLOGICAL STUDIES OF ALZHEIMER DISEASE Principal Investigator & Institution: Farrer, Lindsay A.; Chief, Genetics Program; Neurology; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 021182394 Timing: Fiscal Year 2004; Project Start 01-MAY-1991; Project End 30-JUN-2007 Summary: (provided by applicant): There is a growing body of evidence from pathological, epidemiological and genetic studies that risk factors for vascular disease also enhance risk of Alzheimer disease (AD). However, epidemiological studies usually lack neuroimaging studies and it is unclear whether the apparent association between vascular risk factors and AD is mediated via ischemic injury to the brain, acceleration of the primary Alzheimer neurodegenerative process, or some other process. Some vascular risk factors are more prevalent in African American and Japanese American populations than in Caucasians. We propose to build upon our earlier work by evaluating the association between APOE, genes involved in vascular function, and other indicators of cerebrovascular health including blood pressure and structural brain imaging (MRI) and susceptibility to AD in these ethnic groups. In order to carry out this project successfully, we will ascertain a total sample of 1000 patients (500 Caucasian, 300 African American, 200 Japanese American) who meet NINCDS/ADRDA criteria for probable or definite AD from 11 centers in the U.S., Canada and Germany. Many patients will be identified from our existing family registry. Family history, medical history, and epidemiological information will be obtained from AD probands and their first-degree relatives using standardized questionnaire instruments and established protocols. A cognitive screening test will be administered to and blood samples will be collected from the proband's living sibs, spouses and children over the age of 50 years. DNA, plasma ABeta isoforms and MRI of the brain will be evaluated in probands and sibs. The scientific aims of this project are to: (1) examine recently discovered associations between risk of AD and magnetic resonance imaging (MRI) variables, adjusting for APOE genotype and other known risk factors; (2) examine the association between single nucleotide polymorphisms (SNPs) in 100 genes posited to have a role in vascular function and AD in 1000 sibships using high throughput genotyping technology, and sib-pair linkage and family-based association methodologies; and (3) compare the relative contributions of these SNPs and non-genetic factors including blood pressure, treatment for hypertension, and plasma ABeta on disease and imaging outcomes in Caucasian, African American and Japanese American sibships. Our familybased design is uniquely suited for disentangling complex gene-environment interactions. Our registry will provide DNA resources and baseline data for studies beyond the next funding period. The ultimate goal of this study is to find new targets, genetic and non-genetic, for therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC EPIDEMIOLOGY OF ALZHEIMER'S DISEASE IN TWINS Principal Investigator & Institution: Plassman, Brenda L.; Assistant Research Professor; Psychiatry; Duke University 2424 Erwin Rd. Durham, Nc 27705 Timing: Fiscal Year 2003; Project Start 01-SEP-1999; Project End 31-AUG-2007

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Summary: (Adapted from the Investigator's Abstract) The National Academy of Sciences/National Research Council Twin Registry ("the Registry") contains approximately 4,300 living pairs of white male twins who will be aged 72-83 in 2000. This competing renewal application proposes studies in the Registry that, combined with work to date, will yield 240 twin pairs in which one or both members have Alzheimer's disease (AD). This population-based panel will enable the continued investigation of four broad aims: 1) Estimate the magnitude of genetic influences on the development and age of onset of AD by contrasting concordance rates and the similarity of onsets within monozygotic (MZ) and dizygotic (DZ) pairs; 2) Characterize the environmental contribution of variability of onset of AD. For example, variability of onset within MZ pairs defines the maximum degree to which the environmental influences can modify the onset of AD; 3) Evaluate the role of specific genes on the development and age of onset of AD using the Sibling Transmission/Disequilibrium Test approach to investigate the association between candidate genes such as alpha-2 macroglobulin (A2M) and AD; and 4) Identify environmental factors that are associated with the risk of developing AD, using the co-twin control method. The research will capitalize upon recent developments in the genetics of AD, specifically the influence of apolipoprotein E (APOE) genotype and candidate gene A2M on both liability to AD and its timing of onset. Such findings can be used to refine the classical twin paradigm of investigating broad (but heterogeneous) genetic and environmental influences. Thus, one can not only estimate the heritability of AD in general, but also undertake partitioned analyses to estimate the phenotypic variance attributable to genotypes at APOE or other marker systems, as these are identified. However, until all of the genes that predispose to AD are identified, the twin method has several advantages over other approaches in identifying the extent of the genetic and environmental contribution to AD. Several MZ twin pairs have been described with widely divergent onsets of AD. Environmental factors may therefore alter the onset, and hence the populations risk, of some genetically defined forms of AD. This study will analyze the environmental contribution to variability of onset, and will characterize the divergence in onset within sets of genetically matched individuals. Since comprehensive information on environmental factors has been collected on all participating members of the twin registry, this study will also employ the co-twin control method to seek the specific environmental factors that may be responsible for this variation. A population-based twin design remains the ideal approach to these sorts of investigations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETICS OF ALZHEIMER'S DISEASE IN ISRAELI ARABS Principal Investigator & Institution: Friedland, Robert Paul.; Associate Professor and Chief; Neurology; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2005; Project Start 30-SEP-2000; Project End 31-JUL-2010 Summary: (provided by applicant): We found a very high prevalence of Alzheimer disease (AD) (20% of those 60 years or older) in an inbred Arab community in northern Israel. This observation is apparently unrelated to the APOE c4 allele which has a frequency of Questions to Ask the Doctor Summary: causes of your memory loss symptoms, especially those which are treatable, beforeyou and your doctor settle on a diagnosis of Alzheimer's disease or dementia. Source: www.aoa.gov http://www.aoa.gov/ALZ/Public/alzcarefam/disease_info/questions_to_ask.asp

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Alzheimers Resource Room>Stages of Alzheimer's Disease Summary: Home > Elders and Caregivers > Facts About Alzheimer's Disease > Stages of Alzheimer'sDisease, Elders & Caregivers. Alzheimer's Disease Information. Source: www.aoa.gov http://www.aoa.gov/ALZ/Public/alzcarefam/disease_info/facts_alz/stages_alz.asp

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Amyotrophic Lateral Sclerosis Fact Sheet: National Institute of. Summary: Neurological disorders such as multiple sclerosis, post-polio syndrome, multifocalmotor. conditions such as Parkinson's disease and Alzheimer's disease and is. Source: www.ninds.nih.gov http://www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis/detail_amyotrophic lateralsclerosis.htm

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Dementia and Alzheimer's Disease Summary: Dementia and Alzheimer's Disease. Allen Douma, MD. Eventually, total care is required.How Is Alzheimer's Disease Diagnosed in Someone with Dementia?. Source: www.aarp.org http://www.aarp.org/health/comparedrugs/alzheimer.html/?drug=chei&date= &branch=2

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Dementia and Alzheimer's Disease Summary: Dementia and Alzheimer's Disease. Allen Douma, MD. Eventually, total care is required.How Is Alzheimer's Disease Diagnosed in Someone with Dementia?. Source: www.aarp.org http://www.aarp.org/health/comparedrugs/alzheimer.html/?step=2&drug=&a mp;date=&branch=1

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NIHSeniorHealth: Alzheimer's Disease Source: nihseniorhealth.gov http://nihseniorhealth.gov/alzheimersdisease/faq/faq7b.html

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NIHSeniorHealth: Alzheimer's Disease - Alzheimer's Disease Defined Summary: Alzheimer's Disease Alzheimer's Disease Defined Dementia. Alzheimer's diseaseis the most common form of dementia among older people. It. Source: nihseniorhealth.gov http://nihseniorhealth.gov/alzheimersdisease/defined/01.html

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NIHSeniorHealth: Alzheimer's Disease - Causes and Risk Factors Summary: For example, familial Alzheimer's disease, a rare form of Alzheimer's diseasethat occurs between the ages of 30 and 60, can be inherited. Source: nihseniorhealth.gov http://nihseniorhealth.gov/alzheimersdisease/causes/02.html The NIH Search Utility

The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. 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 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://health.nih.gov/index.asp. Under Search Health Topics, type Alzheimer disease (or synonyms) into the search box, and click Search. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

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/

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

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WebMD®Health: http://www.webmd.com/diseases_and_conditions/default.htm

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Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to Alzheimer disease. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with Alzheimer 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 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. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://sis.nlm.nih.gov/dirline.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. Simply type in Alzheimer disease (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://healthhotlines.nlm.nih.gov/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. 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 health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type Alzheimer disease (or a synonym) into the search box, and click Submit Query.

Resources for Patients and Families The following are organizations that provide support and advocacy for patient with genetic conditions and their families29:

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Adapted from the National Library of Medicine: http://ghr.nlm.nih.gov/ghr/resource/patients.

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Genetic Alliance: http://geneticalliance.org

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Genetic and Rare Diseases Information Center: http://rarediseases.info.nih.gov/html/resources/info_cntr.html

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Madisons Foundation: http://www.madisonsfoundation.org/

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March of Dimes: http://www.marchofdimes.com

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National Organization for Rare Disorders (NORD): http://www.rarediseases.org/ For More Information on Genetics

The following publications offer detailed information for patients about the science of genetics: •

What Is a Genome?: http://www.ncbi.nlm.nih.gov/About/primer/genetics_genome.html

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A Science Called Genetics: http://publications.nigms.nih.gov/genetics/science.html

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Genetic Mapping: http://www.genome.gov/10000715

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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

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MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

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Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

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Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

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On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

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Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

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Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/archive//20040831/nichsr/ta101/ta10108.html

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on Alzheimer disease: •

Basic Guidelines for Alzheimer Disease Alzheimer's disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000760.htm

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Diagnostics and Tests for Alzheimer Disease Computed Tomography Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm Magnetic resonance imaging Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003335.htm

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Background Topics for Alzheimer Disease Autosomal dominant Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002049.htm

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Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

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Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

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Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

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ALZHEIMER DISEASE DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 3-dimensional: 3-D. A graphic display of depth, width, and height. Three-dimensional radiation therapy uses computers to create a 3-dimensional picture of the tumor. This allows doctors to give the highest possible dose of radiation to the tumor, while sparing the normal tissue as much as possible. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Ablation: The removal of an organ by surgery. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetylcholinesterase: An enzyme that catalyzes the hydrolysis of acetylcholine to choline and acetate. In the CNS, this enzyme plays a role in the function of peripheral neuromuscular junctions. EC 3.1.1.7. [NIH] Actin: Essential component of the cell skeleton. [NIH] Activities of Daily Living: The performance of the basic activities of self care, such as dressing, ambulation, eating, etc., in rehabilitation. [NIH] Acute lymphoblastic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphocytic leukemia. [NIH] Acute lymphocytic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphoblastic leukemia. [NIH] Acylation: The addition of an organic acid radical into a molecule. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU]

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Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenosine Triphosphate: Adenosine 5'-(tetrahydrogen triphosphate). An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

Age Groups: Persons classified by age from birth (infant, newborn) to octogenarians and older (aged, 80 and over). [NIH] Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Aged, 80 and Over: A person 80 years of age and older. [NIH] Ageing: A physiological or morphological change in the life of an organism or its parts, generally irreversible and typically associated with a decline in growth and reproductive vigor. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring

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substances. [EU] Alexia: The inability to recognize or comprehend written or printed words. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Aluminum: A metallic element that has the atomic number 13, atomic symbol Al, and atomic weight 26.98. [NIH] Ameliorated: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amnesia: Lack or loss of memory; inability to remember past experiences. [EU] Amnion: The extraembryonic membrane which contains the embryo and amniotic fluid. [NIH]

Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Amygdala: Almond-shaped group of basal nuclei anterior to the inferior horn of the lateral ventricle of the brain, within the temporal lobe. The amygdala is part of the limbic system. [NIH]

Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH]

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Amyloidosis: A group of diseases in which protein is deposited in specific organs (localized amyloidosis) or throughout the body (systemic amyloidosis). Amyloidosis may be either primary (with no known cause) or secondary (caused by another disease, including some types of cancer). Generally, primary amyloidosis affects the nerves, skin, tongue, joints, heart, and liver; secondary amyloidosis often affects the spleen, kidneys, liver, and adrenal glands. [NIH] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Aneuploidy: The chromosomal constitution of cells which deviate from the normal by the addition or subtraction of chromosomes or chromosome pairs. In a normally diploid cell the loss of a chromosome pair is termed nullisomy (symbol: 2N-2), the loss of a single chromosome is monosomy (symbol: 2N-1), the addition of a chromosome pair is tetrasomy (symbol: 2N+2), the addition of a single chromosome is trisomy (symbol: 2N+1). [NIH] Angiopathy: Disease of the blood vessels (arteries, veins, and capillaries) that occurs when someone has diabetes for a long time. There are two types of angiopathy: macroangiopathy and microangiopathy. In macroangiopathy, fat and blood clots build up in the large blood vessels, stick to the vessel walls, and block the flow of blood. In microangiopathy, the walls of the smaller blood vessels become so thick and weak that they bleed, leak protein, and slow the flow of blood through the body. Then the cells, for example, the ones in the center of the eye, do not get enough blood and may be damaged. [NIH] Angiotensinogen: An alpha-globulin of which a fragment of 14 amino acids is converted by renin to angiotensin I, the inactive precursor of angiotensin II. It is a member of the serpin superfamily. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anisotropy: A physical property showing different values in relation to the direction in or along which the measurement is made. The physical property may be with regard to thermal or electric conductivity or light refraction. In crystallography, it describes crystals whose index of refraction varies with the direction of the incident light. It is also called

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acolotropy and colotropy. The opposite of anisotropy is isotropy wherein the same values characterize the object when measured along axes in all directions. [NIH] Anomalies: Birth defects; abnormalities. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticholinergic: An agent that blocks the parasympathetic nerves. Called also parasympatholytic. [EU] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiserum: The blood serum obtained from an animal after it has been immunized with a particular antigen. It will contain antibodies which are specific for that antigen as well as antibodies specific for any other antigen with which the animal has previously been immunized. [NIH] Antispasmodic: An agent that relieves spasm. [EU] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH] Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apolipoproteins A: Lipoproteins found in human blood serum in the high-density and very-high-density lipoprotein fraction (HDL, VHDL). They consist of several different

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polypeptides, the most important of which are apolipoprotein A-I and A-II. They maintain the structural integrity of the HDL particles and are activators of lecithin:cholesterol acyltransferase (LCAT). Atherosclerotic patients show low apolipoprotein A levels and these apolipoproteins are either absent or present in extremely low plasma concentration in Tangier disease. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Apraxia: Loss of ability to perform purposeful movements, in the absence of paralysis or sensory disturbance, caused by lesions in the cortex. [NIH] Aqueous: Having to do with water. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Ascorbic Acid: A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. [NIH] Aspartate: A synthetic amino acid. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Atherogenic: Causing the formation of plaque in the lining of the arteries. [NIH] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU]

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Auditory: Pertaining to the sense of hearing. [EU] Autacoids: A chemically diverse group of substances produced by various tissues in the body that cause slow contraction of smooth muscle; they have other intense but varied pharmacologic activities. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autopsy: Postmortem examination of the body. [NIH] Avidity: The strength of the interaction of an antiserum with a multivalent antigen. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Back Pain: Acute or chronic pain located in the posterior regions of the trunk, including the thoracic, lumbar, sacral, or adjacent regions. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Metabolism: Heat production, or its measurement, of an organism at the lowest level of cell chemistry in an inactive, awake, fasting state. It may be determined directly by means of a calorimeter or indirectly by calculating the heat production from an analysis of the end products of oxidation within the organism or from the amount of oxygen utilized. [NIH] Basalis: Chiasmatic cistern. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Base Sequence: The sequence of purines and pyrimidines in nucleic acids and polynucleotides. It is also called nucleotide or nucleoside sequence. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Bewilderment: Impairment or loss of will power. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological Markers: Measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, environmental

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exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiologic studies, etc. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biotinylation: Incorporation of biotinyl groups into molecules. [NIH] Bivalent: Pertaining to a group of 2 homologous or partly homologous chromosomes during the zygotene stage of prophase to the first metaphase in meiosis. [NIH] Bladder: The organ that stores urine. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood-Brain Barrier: Specialized non-fenestrated tightly-joined endothelial cells (tight junctions) that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Body Fluids: Liquid components of living organisms. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH]

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Bone scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Diseases: Pathologic conditions affecting the brain, which is composed of the intracranial components of the central nervous system. This includes (but is not limited to) the cerebral cortex; intracranial white matter; basal ganglia; thalamus; hypothalamus; brain stem; and cerebellum. [NIH] Brain Stem: The part of the brain that connects the cerebral hemispheres with the spinal cord. It consists of the mesencephalon, pons, and medulla oblongata. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Budgets: Detailed financial plans for carrying out specific activities for a certain period of time. They include proposed income and expenditures. [NIH] Bulbar: Pertaining to a bulb; pertaining to or involving the medulla oblongata, as bulbar paralysis. [EU] Butyrylcholinesterase: An aspect of cholinesterase (EC 3.1.1.8). [NIH] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Calcineurin: A calcium- and calmodulin-binding protein present in highest concentrations in the central nervous system. Calcineurin is composed of two subunits. A catalytic subunit, calcineurin A, and a regulatory subunit, calcineurin B, with molecular weights of about 60 kD and 19 kD, respectively. Calcineurin has been shown to dephosphorylate a number of phosphoproteins including histones, myosin light chain, and the regulatory subunit of cAMP-dependent protein kinase. It is involved in the regulation of signal transduction and is the target of an important class of immunophilin-immunosuppressive drug complexes in T-lymphocytes that act by inhibiting T-cell activation. EC 3.1.3.-. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. [NIH] Calorimeter: Measures the amounts of heat absorbed or given off by a solid, a liquid, or a

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gas. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carcinogenic: Producing carcinoma. [EU] Carcinogens: Substances that increase the risk of neoplasms in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. [NIH] Cardiac: Having to do with the heart. [NIH] Cardiorespiratory: Relating to the heart and lungs and their function. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Causality: The relating of causes to the effects they produce. Causes are termed necessary when they must always precede an effect and sufficient when they initiate or produce an effect. Any of several factors may be associated with the potential disease causation or outcome, including predisposing factors, enabling factors, precipitating factors, reinforcing factors, and risk factors. [NIH] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids,

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proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centromere: The clear constricted portion of the chromosome at which the chromatids are joined and by which the chromosome is attached to the spindle during cell division. [NIH] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebral Hemorrhage: Bleeding into a cerebral hemisphere of the brain, including lobar, subcortical white matter, and basal ganglia hemorrhages. Commonly associated conditions include hypertension; intracranial arteriosclerosis; intracranial aneurysm; craniocerebral trauma; intracranial arteriovenous malformations; cerebral amyloid angiopathy; and cerebral infarction. [NIH] Cerebral Infarction: The formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction). [NIH]

Cerebral Palsy: Refers to a motor disability caused by a brain dysfunction. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Chaos: Complex behavior that seems random but actually has some hidden order. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chelation: Combination with a metal in complexes in which the metal is part of a ring. [EU] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH]

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Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Chloroform: A commonly used laboratory solvent. It was previously used as an anesthetic, but was banned from use in the U.S. due to its suspected carcinogenecity. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Cholinesterase Inhibitors: Drugs that inhibit cholinesterases. The neurotransmitter acetylcholine is rapidly hydrolyzed, and thereby inactivated, by cholinesterases. When cholinesterases are inhibited, the action of endogenously released acetylcholine at cholinergic synapses is potentiated. Cholinesterase inhibitors are widely used clinically for their potentiation of cholinergic inputs to the gastrointestinal tract and urinary bladder, the eye, and skeletal muscles; they are also used for their effects on the heart and the central nervous system. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chromosome Fragility: Susceptibility of chromosomes to breakage and translocation or other aberrations. Chromosome fragile sites are regions that show up in karyotypes as a gap (uncondensed stretch) on the chromatid arm. They are associated with chromosome break sites and other aberrations. A fragile site on the X chromosome is associated with fragile X syndrome. Fragile sites are designated by the letters "FRA" followed by the designation for the specific chromosome and a letter which refers to the different fragile sites on a chromosome (e.g. FRAXA). [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic Obstructive Pulmonary Disease: Collective term for chronic bronchitis and emphysema. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Cirrhosis: A type of chronic, progressive liver disease. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public,

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interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clathrin: The main structural coat protein of coated vesicles which play a key role in the intracellular transport between membranous organelles. Clathrin also interacts with cytoskeletal proteins. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coated Vesicles: Vesicles formed when cell-membrane coated pits invaginate and pinch off. The outer surface of these vesicles are covered with a lattice-like network of coat proteins, such as clathrin, coat protein complex proteins, or caveolins. [NIH] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Colonoscopy: Endoscopic examination, therapy or surgery of the luminal surface of the colon. [NIH] Comorbidity: The presence of co-existing or additional diseases with reference to an initial

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diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complement Activation: The sequential activation of serum components C1 through C9, initiated by an erythrocyte-antibody complex or by microbial polysaccharides and properdin, and producing an inflammatory response. [NIH] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT)

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scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Concentric: Having a common center of curvature or symmetry. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constriction: The act of constricting. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Contrast Sensitivity: The ability to detect sharp boundaries (stimuli) and to detect slight changes in luminance at regions without distinct contours. Psychophysical measurements of this visual function are used to evaluate visual acuity and to detect eye disease. [NIH] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Corpus: The body of the uterus. [NIH] Corpus Luteum: The yellow glandular mass formed in the ovary by an ovarian follicle that has ruptured and discharged its ovum. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU]

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Corticosteroids: Hormones that have antitumor activity in lymphomas and lymphoid leukemias; in addition, corticosteroids (steroids) may be used for hormone replacement and for the management of some of the complications of cancer and its treatment. [NIH] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] C-Peptide: A 31-amino acid peptide which connects the A and B chains of proinsulin. The exact composition of the peptide is species dependent. In beta cells proinsulin is enzymatically converted to insulin with the liberation of the C-peptide. An immunoassay has been developed for assessing pancreatic beta cell secretory function in diabetic patients in whom circulating insulin antibodies and exogenous insulin interfere with insulin immunoassay. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Creatine: An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. [NIH]

Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Cross-Sectional Studies: Studies in which the presence or absence of disease or other health-related variables are determined in each member of the study population or in a representative sample at one particular time. This contrasts with longitudinal studies which are followed over a period of time. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cystathionine beta-Synthase: A multifunctional pyridoxal phosphate enzyme. In the second stage of cysteine biosynthesis it catalyzes the reaction of homocysteine with serine to form cystathionine with the elimination of water. Deficiency of this enzyme leads to hyperhomocysteinemia and homocystinuria. EC 4.2.1.22. [NIH] Cysteinyl: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytogenetics: A branch of genetics which deals with the cytological and molecular behavior of genes and chromosomes during cell division. [NIH] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a

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continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Death Certificates: Official records of individual deaths including the cause of death certified by a physician, and any other required identifying information. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Delusions: A false belief regarding the self or persons or objects outside the self that persists despite the facts, and is not considered tenable by one's associates. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dentate Gyrus: Gray matter situated above the gyrus hippocampi. It is composed of three layers. The molecular layer is continuous with the hippocampus in the hippocampal fissure. The granular layer consists of closely arranged spherical or oval neurons, called granule cells, whose axons pass through the polymorphic layer ending on the dendrites of pyramidal cells in the hippocampus. [NIH] Deoxyribonucleic: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleic acid: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleotides: A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or

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concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Diffusivity: Of a reverberant sound field. The degree to which the directions of propagation of waves are random from point to point. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disease Susceptibility: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the individual more than usually susceptible to certain diseases. [NIH] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] Donepezil: A drug used in the treatment of Alzheimer's disease. It belongs to the family of drugs called cholinesterase inhibitors. It is being studied as a treatment for side effects caused by radiation therapy to the brain. [NIH] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for

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its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Drug Design: The molecular designing of drugs for specific purposes (such as DNAbinding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis. [NIH] Drug Evaluation: Any process by which toxicity, metabolism, absorption, elimination, preferred route of administration, safe dosage range, etc., for a drug or group of drugs is determined through clinical assessment in humans or veterinary animals. [NIH] Duct: A tube through which body fluids pass. [NIH] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dyslexia: Partial alexia in which letters but not words may be read, or in which words may be read but not understood. [NIH] Dyslipidemia: Disorders in the lipoprotein metabolism; classified as hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, and low levels of high-density lipoprotein (HDL) cholesterol. All of the dyslipidemias can be primary or secondary. Both elevated levels of low-density lipoprotein (LDL) cholesterol and low levels of HDL cholesterol predispose to premature atherosclerosis. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Electric Conductivity: The ability of a substrate to allow the passage of electrons. [NIH] Electroencephalography: Recording of electric currents developed in the brain by means of electrodes applied to the scalp, to the surface of the brain, or placed within the substance of the brain. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]

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Elementary Particles: Individual components of atoms, usually subatomic; subnuclear particles are usually detected only when the atomic nucleus decays and then only transiently, as most of them are unstable, often yielding pure energy without substance, i.e., radiation. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endorphins: One of the three major groups of endogenous opioid peptides. They are large peptides derived from the pro-opiomelanocortin precursor. The known members of this group are alpha-, beta-, and gamma-endorphin. The term endorphin is also sometimes used to refer to all opioid peptides, but the narrower sense is used here; opioid peptides is used for the broader group. [NIH] Endosomes: Cytoplasmic vesicles formed when coated vesicles shed their clathrin coat. Endosomes internalize macromolecules bound by receptors on the cell surface. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] Energy Intake: Total number of calories taken in daily whether ingested or by parenteral routes. [NIH] Enkephalins: One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla. [NIH] Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme-Linked Immunosorbent Assay: An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the

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antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiologic Studies: Studies designed to examine associations, commonly, hypothesized causal relations. They are usually concerned with identifying or measuring the effects of risk factors or exposures. The common types of analytic study are case-control studies, cohort studies, and cross-sectional studies. [NIH] Epidemiological: Relating to, or involving epidemiology. [EU] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epistasis: The degree of dominance exerted by one gene on the expression of a non-allelic gene. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Estrogen: One of the two female sex hormones. [NIH] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Excrete: To get rid of waste from the body. [NIH] Exocytosis: Cellular release of material within membrane-limited vesicles by fusion of the vesicles with the cell membrane. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] Extracellular: Outside a cell or cells. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Eye Color: Color of the iris. [NIH] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Eye Movements: Voluntary or reflex-controlled movements of the eye. [NIH]

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Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fathers: Male parents, human or animal. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibril: Most bacterial viruses have a hollow tail with specialized fibrils at its tip. The tail fibers attach to the cell wall of the host. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fossa: A cavity, depression, or pit. [NIH] Fourth Ventricle: An irregularly shaped cavity in the rhombencephalon, between the medulla oblongata, the pons, and the isthmus in front, and the cerebellum behind. It is continuous with the central canal of the cord below and with the cerebral aqueduct above, and through its lateral and median apertures it communicates with the subarachnoid space. [NIH]

Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Frail Elderly: Older adults or aged individuals who are lacking in general strength and are unusually susceptible to disease or to other infirmity. [NIH] Frameshift: A type of mutation which causes out-of-phase transcription of the base sequence; such mutations arise from the addition or delection of nucleotide(s) in numbers other than 3 or multiples of 3. [NIH] Frameshift Mutation: A type of mutation in which a number of nucleotides not divisible by three is deleted from or inserted into a coding sequence, thereby causing an alteration in the reading frame of the entire sequence downstream of the mutation. These mutations may be induced by certain types of mutagens or may occur spontaneously. [NIH]

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Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Functional magnetic resonance imaging: A noninvasive tool used to observe functioning in the brain or other organs by detecting changes in chemical composition, blood flow, or both. [NIH]

Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gap Junctions: Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Products, rev: Trans-acting nuclear proteins whose functional expression are required for HIV viral replication. Specifically, the rev gene products are required for processing and translation of the HIV gag and env mRNAs, and thus rev regulates the expression of the viral structural proteins. rev can also regulate viral regulatory proteins. A cis-acting antirepression sequence (CAR) in env, also known as the rev-responsive element (RRE), is responsive to the rev gene product. rev is short for regulator of virion. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genes, env: DNA sequences that form the coding region for the viral envelope (env) proteins in retroviruses. The env genes contain a cis-acting RNA target sequence for the rev protein (= gene products, rev), termed the rev-responsive element (RRE). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus,

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transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]

Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Geriatric: Pertaining to the treatment of the aged. [EU] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Germline mutation: A gene change in the body's reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; germline mutations are passed on from parents to offspring. Also called hereditary mutation. [NIH] Ginseng: An araliaceous genus of plants that contains a number of pharmacologically active agents used as stimulants, sedatives, and tonics, especially in traditional medicine. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Gliosis: The production of a dense fibrous network of neuroglia; includes astrocytosis, which is a proliferation of astrocytes in the area of a degenerative lesion. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Gonadal: Pertaining to a gonad. [EU] Governing Board: The group in which legal authority is vested for the control of health-

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related institutions and organizations. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Granule: A small pill made from sucrose. [EU] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanine: One of the four DNA bases. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Hair Color: Color of hair or fur. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haplotypes: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the major histocompatibility complex. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemophilia: Refers to a group of hereditary disorders in which affected individuals fail to make enough of certain proteins needed to form blood clots. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hepatic: Refers to the liver. [NIH]

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Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Hereditary mutation: A gene change in the body's reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; hereditary mutations are passed on from parents to offspring. Also called germline mutation. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heritability: The proportion of observed variation in a particular trait that can be attributed to inherited genetic factors in contrast to environmental ones. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum, and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Histones: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homozygote: An individual in which both alleles at a given locus are identical. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called endocrine therapy. [NIH] Horseradish Peroxidase: An enzyme isolated from horseradish which is able to act as an antigen. It is frequently used as a histochemical tracer for light and electron microscopy. Its antigenicity has permitted its use as a combined antigen and marker in experimental immunology. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive

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isotope tritium. [NIH] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperhomocysteinemia: An inborn error of methionone metabolism which produces an excess of homocysteine in the blood. It is often caused by a deficiency of cystathionine betasynthase and is a risk factor for coronary vascular disease. [NIH] Hyperlipidemia: An excess of lipids in the blood. [NIH] Hyperlipoproteinemia: Metabolic disease characterized by elevated plasma cholesterol and/or triglyceride levels. The inherited form is attributed to a single gene mechanism. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [NIH] Hypothalamic: Of or involving the hypothalamus. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Imaging procedures: Methods of producing pictures of areas inside the body. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH]

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Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunophilin: A drug for the treatment of Parkinson's disease. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Indomethacin: A non-steroidal anti-inflammatory agent (NSAID) that inhibits the enzyme cyclooxygenase necessary for the formation of prostaglandins and other autacoids. It also inhibits the motility of polymorphonuclear leukocytes. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infant, Newborn: An infant during the first month after birth. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Informed Consent: Voluntary authorization, given to the physician by the patient, with full

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comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH] Intermediate Filaments: Cytoplasmic filaments intermediate in diameter (about 10 nanometers) between the microfilaments and the microtubules. They may be composed of

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any of a number of different proteins and form a ring around the cell nucleus. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Intestinal: Having to do with the intestines. [NIH] Intestines: The section of the alimentary canal from the stomach to the anus. It includes the large intestine and small intestine. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intracranial Aneurysm: A saclike dilatation of the walls of a blood vessel, usually an artery. [NIH]

Intracranial Arteriosclerosis: Vascular diseases characterized by thickening, hardening, and remodeling of the walls of intracranial arteries. There are three subtypes: (1) atherosclerosis, marked by fatty depositions in the innermost layer of the arterial walls, (2) Monckeberg's sclerosis, which features calcium deposition in the media and (3) arteriolosclerosis, which refers to sclerosis of small caliber arteries. Clinically, this process may be associated with transient ischemic attack, brain infarction, intracranial embolism and thrombosis, or intracranial aneurysm. [NIH] Intracranial Hypertension: Increased pressure within the cranial vault. This may result from several conditions, including hydrocephalus; brain edema; intracranial masses; severe systemic hypertension; pseudotumor cerebri; and other disorders. [NIH] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isoleucine: An essential branched-chain amino acid found in many proteins. It is an isomer of LEUCINE. It is important in hemoglobin synthesis and regulation of blood sugar and energy levels. [NIH] Isoprenoid: Molecule that might anchor G protein to the cell membrane as it is hydrophobic. [NIH]

Karyotype: The characteristic chromosome complement of an individual, race, or species as

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defined by their number, size, shape, etc. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Kidney Cortex: The outer zone of the kidney, beneath the capsule, consisting of kidney glomerulus; kidney tubules, distal; and kidney tubules, proximal. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH] Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Lag: The time elapsing between application of a stimulus and the resulting reaction. [NIH] Latency: The period of apparent inactivity between the time when a stimulus is presented and the moment a response occurs. [NIH] Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Lesion: An area of abnormal tissue change. [NIH] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]

Leukemia: Cancer of blood-forming tissue. [NIH] Libido: The psychic drive or energy associated with sexual instinct in the broad sense (pleasure and love-object seeking). It may also connote the psychic energy associated with instincts in general that motivate behavior. [NIH] Life Expectancy: A figure representing the number of years, based on known statistics, to which any person of a given age may reasonably expect to live. [NIH] Ligaments: Shiny, flexible bands of fibrous tissue connecting together articular extremities of bones. They are pliant, tough, and inextensile. [NIH] Ligands: A RNA simulation method developed by the MIT. [NIH] Limbic: Pertaining to a limbus, or margin; forming a border around. [EU] Limbic System: A set of forebrain structures common to all mammals that is defined functionally and anatomically. It is implicated in the higher integration of visceral, olfactory, and somatic information as well as homeostatic responses including fundamental survival

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behaviors (feeding, mating, emotion). For most authors, it includes the amygdala, epithalamus, gyrus cinguli, hippocampal formation (see hippocampus), hypothalamus, parahippocampal gyrus, septal nuclei, anterior nuclear group of thalamus, and portions of the basal ganglia. (Parent, Carpenter's Human Neuroanatomy, 9th ed, p744; NeuroNames, http://rprcsgi.rprc.washington.edu/neuronames/index.html (September 2, 1998)). [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Linkage Disequilibrium: Nonrandom association of linked genes. This is the tendency of the alleles of two separate but already linked loci to be found together more frequently than would be expected by chance alone. [NIH] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [NIH] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Locus Coeruleus: Bluish region in the superior angle of the fourth ventricle floor, corresponding to melanin-like pigmented nerve cells which lie lateral to the pontomesencephalic central gray (griseum centrale). It is also known as nucleus pigmentosus pontis. [NIH] Longitudinal Studies: Studies in which variables relating to an individual or group of individuals are assessed over a period of time. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Long-Term Care: Care over an extended period, usually for a chronic condition or disability,

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requiring periodic, intermittent, or continuous care. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphocytes: White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each); those with characteristics of neither major class are called null cells. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Macroglia: A type of neuroglia composed of astrocytes. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Magnetic Resonance Spectroscopy: Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (magnetic resonance imaging). [NIH] Magnetoencephalography: The measurement of magnetic fields over the head generated by electric currents in the brain. As in any electrical conductor, electric fields in the brain are accompanied by orthogonal magnetic fields. The measurement of these fields provides information about the localization of brain activity which is complementary to that provided by electroencephalography. Magnetoencephalography may be used alone or together with electroencephalography, for measurement of spontaneous or evoked activity, and for research or clinical purposes. [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Mammography: Radiographic examination of the breast. [NIH] Mania: Excitement of psychotic proportions manifested by mental and physical hyperactivity, disorganization of behaviour, and elevation of mood. [EU]

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Manic: Affected with mania. [EU] Manic-depressive psychosis: One of a group of psychotic reactions, fundamentally marked by severe mood swings and a tendency to remission and recurrence. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Memantine: Amantadine derivative that has some dopaminergic effects. It has been proposed as an antiparkinson agent. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH]

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Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]

Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mesencephalic: Ipsilateral oculomotor paralysis and contralateral tremor, spasm. or choreic movements of the face and limbs. [NIH] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metallothionein: A low-molecular-weight (approx. 10 kD) protein occurring in the cytoplasm of kidney cortex and liver. It is rich in cysteinyl residues and contains no aromatic amino acids. Metallothionein shows high affinity for bivalent heavy metals. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microglia: The third type of glial cell, along with astrocytes and oligodendrocytes (which together form the macroglia). Microglia vary in appearance depending on developmental stage, functional state, and anatomical location; subtype terms include ramified, perivascular, ameboid, resting, and activated. Microglia clearly are capable of phagocytosis and play an important role in a wide spectrum of neuropathologies. They have also been suggested to act in several other roles including in secretion (e.g., of cytokines and neural growth factors), in immunological processing (e.g., antigen presentation), and in central nervous system development and remodeling. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microtubule-Associated Proteins: High molecular weight proteins found in the microtubules of the cytoskeletal system. Under certain conditions they are required for tubulin assembly into the microtubules and stabilize the assembled microtubules. [NIH] Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Minority Groups: A subgroup having special characteristics within a larger group, often bound together by special ties which distinguish it from the larger group. [NIH] Miscarriage: Spontaneous expulsion of the products of pregnancy before the middle of the second trimester. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH]

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Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monosomy: The condition in which one chromosome of a pair is missing. In a normally diploid cell it is represented symbolically as 2N-1. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Mosaicism: The occurrence in an individual of two or more cell populations of different chromosomal constitutions, derived from a single zygote, as opposed to chimerism in which the different cell populations are derived from more than one zygote. [NIH] Motility: The ability to move spontaneously. [EU] Motor Activity: The physical activity of an organism as a behavioral phenomenon. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Multivalent: Pertaining to a group of 5 or more homologous or partly homologous chromosomes during the zygotene stage of prophase to first metaphasis in meiosis. [NIH] Muscular Diseases: Acquired, familial, and congenital disorders of skeletal muscle and smooth muscle. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Myelin: The fatty substance that covers and protects nerves. [NIH] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myositis: Inflammation of a voluntary muscle. [EU]

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Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Neocortex: The largest portion of the cerebral cortex. It is composed of neurons arranged in six layers. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neprilysin: Enzyme that is a major constituent of kidney brush-border membranes and is also present to a lesser degree in the brain and other tissues. It preferentially catalyzes cleavage at the amino group of hydrophobic residues of the B-chain of insulin as well as opioid peptides and other biologically active peptides. The enzyme is inhibited primarily by EDTA, phosphoramidon, and thiorphan and is reactivated by zinc. Neprilysin is identical to common acute lymphoblastic leukemia antigen (CALLA), an important marker in the diagnosis of human acute lymphocytic leukemia. EC 3.4.24.11. [NIH] Nerve Growth Factor: Nerve growth factor is the first of a series of neurotrophic factors that were found to influence the growth and differentiation of sympathetic and sensory neurons. It is comprised of alpha, beta, and gamma subunits. The beta subunit is responsible for its growth stimulating activity. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neurites: In tissue culture, hairlike projections of neurons stimulated by growth factors and other molecules. These projections may go on to form a branched tree of dendrites or a single axon or they may be reabsorbed at a later stage of development. "Neurite" may refer to any filamentous or pointed outgrowth of an embryonal or tissue-culture neural cell. [NIH] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [NIH] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neurofibrillary Tangles: Abnormal structures located in various parts of the brain and composed of dense arrays of paired helical filaments (neurofilaments and microtubules). These double helical stacks of transverse subunits are twisted into left-handed ribbon-like filaments that likely incorporate the following proteins: (1) the intermediate filaments: medium- and high-molecular-weight neurofilaments; (2) the microtubule-associated

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proteins map-2 and tau; (3) actin; and (4) ubiquitin. As one of the hallmarks of Alzheimer disease, the neurofibrillary tangles eventually occupy the whole of the cytoplasm in certain classes of cell in the neocortex, hippocampus, brain stem, and diencephalon. The number of these tangles, as seen in post mortem histology, correlates with the degree of dementia during life. Some studies suggest that tangle antigens leak into the systemic circulation both in the course of normal aging and in cases of Alzheimer disease. [NIH] Neurofilaments: Bundle of neuronal fibers. [NIH] Neuroglia: The non-neuronal cells of the nervous system. They are divided into macroglia (astrocytes, oligodendroglia, and schwann cells) and microglia. They not only provide physical support, but also respond to injury, regulate the ionic and chemical composition of the extracellular milieu, participate in the blood-brain and blood-retina barriers, form the myelin insulation of nervous pathways, guide neuronal migration during development, and exchange metabolites with neurons. Neuroglia have high-affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitters, but their role in signaling (as in many other functions) is unclear. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neurologist: A doctor who specializes in the diagnosis and treatment of disorders of the nervous system. [NIH] Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Diseases: A general term encompassing lower motor neuron disease; peripheral nervous system diseases; and certain muscular diseases. Manifestations include muscle weakness; fasciculation; muscle atrophy; spasm; myokymia; muscle hypertonia, myalgias, and musclehypotonia. [NIH] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neuronal Plasticity: The capacity of the nervous system to change its reactivity as the result of successive activations. [NIH] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuropil: A dense intricate feltwork of interwoven fine glial processes, fibrils, synaptic terminals, axons, and dendrites interspersed among the nerve cells in the gray matter of the central nervous system. [NIH] Neuropil Threads: Abnormal structures located chiefly in distal dendrites and, along with neurofibrillary tangles and senile plaques, constitute the three morphological hallmarks of Alzheimer disease. Neuropil threads are made up of straight and paired helical filaments which consist of abnormally phosphorylated microtubule-associated tau proteins. It has been suggested that the threads have a major role in the cognitive impairment seen in Alzheimer disease. [NIH] Neuropsychology: A branch of psychology which investigates the correlation between experience or behavior and the basic neurophysiological processes. The term neuropsychology stresses the dominant role of the nervous system. It is a more narrowly defined field than physiological psychology or psychophysiology. [NIH]

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Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]

Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutrophils: Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. [NIH] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear Envelope: The membrane system of the cell nucleus that surrounds the nucleoplasm. It consists of two concentric membranes separated by the perinuclear space. The structures of the envelope where it opens to the cytoplasm are called the nuclear pores (nuclear pore). [NIH] Nuclear Pore: An opening through the nuclear envelope formed by the nuclear pore complex which transports nuclear proteins or RNA into or out of the cell nucleus and which, under some conditions, acts as an ion channel. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH]

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Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nurse Practitioners: Nurses who are specially trained to assume an expanded role in providing medical care under the supervision of a physician. [NIH] Odds Ratio: The ratio of two odds. The exposure-odds ratio for case control data is the ratio of the odds in favor of exposure among cases to the odds in favor of exposure among noncases. The disease-odds ratio for a cohort or cross section is the ratio of the odds in favor of disease among the exposed to the odds in favor of disease among the unexposed. The prevalence-odds ratio refers to an odds ratio derived cross-sectionally from studies of prevalent cases. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Omega-3 fatty acid: A type of fat obtained in the diet and involved in immunity. [NIH] Opioid Peptides: The endogenous peptides with opiate-like activity. The three major classes currently recognized are the enkephalins, the dynorphins, and the endorphins. Each of these families derives from different precursors, proenkephalin, prodynorphin, and proopiomelanocortin, respectively. There are also at least three classes of opioid receptors, but the peptide families do not map to the receptors in a simple way. [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [NIH]

Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Overweight: An excess of body weight but not necessarily body fat; a body mass index of 25 to 29.9 kg/m2. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]

Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological

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oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative Phosphorylation: Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds. [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Palsy: Disease of the peripheral nervous system occurring usually after many years of increased lead absorption. [NIH] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Paralysis: Loss of ability to move all or part of the body. [NIH] Paraparesis: Mild to moderate loss of bilateral lower extremity motor function, which may be a manifestation of spinal cord diseases; peripheral nervous system diseases; muscular diseases; intracranial hypertension; parasagittal brain lesions; and other conditions. [NIH] Parenchyma: The essential elements of an organ; used in anatomical nomenclature as a general term to designate the functional elements of an organ, as distinguished from its framework, or stroma. [EU] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Parietal: 1. Of or pertaining to the walls of a cavity. 2. Pertaining to or located near the parietal bone, as the parietal lobe. [EU] Parietal Lobe: Upper central part of the cerebral hemisphere. [NIH] Particle: A tiny mass of material. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Paternity: Establishing the father relationship of a man and a child. [NIH] Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural

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and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] PDQ: Physician Data Query. PDQ is an online database developed and maintained by the National Cancer Institute. Designed to make the most current, credible, and accurate cancer information available to health professionals and the public, PDQ contains peer-reviewed summaries on cancer treatment, screening, prevention, genetics, and supportive care; a registry of cancer clinical trials from around the world; and directories of physicians, professionals who provide genetics services, and organizations that provide cancer care. Most of this information is available on the CancerNet Web site, and more specific information about PDQ can be found at http://cancernet.nci.nih.gov/pdq.html. [NIH] Pedigree: A record of one's ancestors, offspring, siblings, and their offspring that may be used to determine the pattern of certain genes or disease inheritance within a family. [NIH] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide Fragments: Partial proteins formed by partial hydrolysis of complete proteins. [NIH] Perceived risk: Estimate or evaluation of risk as observed through personal experience or personal study, and personal evaluation of consequences. [NIH] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Periodontitis: Inflammation of the periodontal membrane; also called periodontitis simplex. [NIH]

Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peripheral Nervous System Diseases: Diseases of the peripheral nerves external to the brain and spinal cord, which includes diseases of the nerve roots, ganglia, plexi, autonomic nerves, sensory nerves, and motor nerves. [NIH] Perirhinal: Transitional region between the older and newer cortex. [NIH] Perivascular: Situated around a vessel. [EU] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Pharmacokinetics: Dynamic and kinetic mechanisms of exogenous chemical and drug absorption, biotransformation, distribution, release, transport, uptake, and elimination as a

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function of dosage, and extent and rate of metabolic processes. It includes toxicokinetics, the pharmacokinetic mechanism of the toxic effects of a substance. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phloroglucinol: 1,3,5-Benzenetriol. A trinitrobenzene derivative with antispasmodic properties that is used primarily as a laboratory reagent. [NIH] Phosphodiesterase: Effector enzyme that regulates the levels of a second messenger, the cyclic GMP. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Physostigmine: A cholinesterase inhibitor that is rapidly absorbed through membranes. It can be applied topically to the conjunctiva. It also can cross the blood-brain barrier and is used when central nervous system effects are desired, as in the treatment of severe anticholinergic toxicity. [NIH] Pigments: Any normal or abnormal coloring matter in plants, animals, or micro-organisms. [NIH]

Pilot study: The initial study examining a new method or treatment. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid

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and diploid generations. [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] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government

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agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precipitating Factors: Factors associated with the definitive onset of a disease, illness, accident, behavioral response, or course of action. Usually one factor is more important or more obviously recognizable than others, if several are involved, and one may often be regarded as "necessary". Examples include exposure to specific disease; amount or level of an infectious organism, drug, or noxious agent, etc. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Prion: Small proteinaceous infectious particles that resist inactivation by procedures modifying nucleic acids and contain an abnormal isoform of a cellular protein which is a major and necessary component. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Proinsulin: The substance made first in the pancreas that is then made into insulin. When insulin is purified from the pancreas of pork or beef, all the proinsulin is not fully removed. When some people use these insulins, the proinsulin can cause the body to react with a rash, to resist the insulin, or even to make dents or lumps in the skin at the place where the insulin is injected. The purified insulins have less proinsulin and other impurities than the other types of insulins. [NIH] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Proneness: Susceptibility to accidents due to human factors. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed

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over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandins: A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. [NIH] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Proteome: The protein complement of an organism coded for by its genome. [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] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Psychopathology: The study of significant causes and processes in the development of mental illness. [NIH] Psychophysiology: The study of the physiological basis of human and animal behavior.

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[NIH]

Psychosis: A mental disorder characterized by gross impairment in reality testing as evidenced by delusions, hallucinations, markedly incoherent speech, or disorganized and agitated behaviour without apparent awareness on the part of the patient of the incomprehensibility of his behaviour; the term is also used in a more general sense to refer to mental disorders in which mental functioning is sufficiently impaired as to interfere grossly with the patient's capacity to meet the ordinary demands of life. Historically, the term has been applied to many conditions, e.g. manic-depressive psychosis, that were first described in psychotic patients, although many patients with the disorder are not judged psychotic. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quadriplegia: Severe or complete loss of motor function in all four limbs which may result from brain diseases; spinal cord diseases; peripheral nervous system diseases; neuromuscular diseases; or rarely muscular diseases. The locked-in syndrome is characterized by quadriplegia in combination with cranial muscle paralysis. Consciousness is spared and the only retained voluntary motor activity may be limited eye movements. This condition is usually caused by a lesion in the upper brain stem which injures the descending cortico-spinal and cortico-bulbar tracts. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [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] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from

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radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Reality Testing: The individual's objective evaluation of the external world and the ability to differentiate adequately between it and the internal world; considered to be a primary ego function. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflective: Capable of throwing back light, images, sound waves : reflecting. [EU] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH]

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Registries: The systems and processes involved in the establishment, support, management, and operation of registers, e.g., disease registers. [NIH] Relative risk: The ratio of the incidence rate of a disease among individuals exposed to a specific risk factor to the incidence rate among unexposed individuals; synonymous with risk ratio. Alternatively, the ratio of the cumulative incidence rate in the exposed to the cumulative incidence rate in the unexposed (cumulative incidence ratio). The term relative risk has also been used synonymously with odds ratio. This is because the odds ratio and relative risk approach each other if the disease is rare ( 5 percent of population) and the number of subjects is large. [NIH] Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Research Design: A plan for collecting and utilizing data so that desired information can be obtained with sufficient precision or so that an hypothesis can be tested properly. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respite Care: Patient care provided in the home or institution intermittently in order to provide temporary relief to the family home care giver. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal Ganglion Cells: Cells of the innermost nuclear layer of the retina, the ganglion cell layer, which project axons through the optic nerve to the brain. They are quite variable in size and in the shapes of their dendritic arbors, which are generally confined to the inner plexiform layer. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retrograde: 1. Moving backward or against the usual direction of flow. 2. Degenerating, deteriorating, or catabolic. [EU] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH]

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Reverberant: The sound field prevailing in a large enclosure with moderately reflecting surfaces. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [NIH] Ribonucleic acid: RNA. One of the two nucleic acids found in all cells. The other is deoxyribonucleic acid (DNA). Ribonucleic acid transfers genetic information from DNA to proteins produced by the cell. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rod: A reception for vision, located in the retina. [NIH] Rural Population: The inhabitants of rural areas or of small towns classified as rural. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Satellite: Applied to a vein which closely accompanies an artery for some distance; in cytogenetics, a chromosomal agent separated by a secondary constriction from the main body of the chromosome. [NIH] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [NIH] Scatter: The extent to which relative success and failure are divergently manifested in qualitatively different tests. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of

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thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Scurvy: A deficiency disease due to lack of vitamin C in the diet. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Self Care: Performance of activities or tasks traditionally performed by professional health care providers. The concept includes care of oneself or one's family and friends. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Senile Plaques: Spherical masses consisting of amyloid fibrils and neuronal processes. [NIH] Sequence Analysis: A multistage process that includes the determination of a sequence (protein, carbohydrate, etc.), its fragmentation and analysis, and the interpretation of the resulting sequence information. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Sequester: A portion of dead bone which has become detached from the healthy bone tissue, as occurs in necrosis. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled

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to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Social Support: Support systems that provide assistance and encouragement to individuals with physical or emotional disabilities in order that they may better cope. Informal social support is usually provided by friends, relatives, or peers, while formal assistance is provided by churches, groups, etc. [NIH] Social Work: The use of community resources, individual case work, or group work to promote the adaptive capacities of individuals in relation to their social and economic environments. It includes social service agencies. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic cells: All the body cells except the reproductive (germ) cells. [NIH] Somatic mutations: Alterations in DNA that occur after conception. Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children. These alterations can (but do not always) cause cancer or other diseases. [NIH] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle

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displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Spastic: 1. Of the nature of or characterized by spasms. 2. Hypertonic, so that the muscles are stiff and the movements awkward. 3. A person exhibiting spasticity, such as occurs in spastic paralysis or in cerebral palsy. [EU] Spasticity: A state of hypertonicity, or increase over the normal tone of a muscle, with heightened deep tendon reflexes. [EU] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectroscopic: The recognition of elements through their emission spectra. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spinal Cord Diseases: Pathologic conditions which feature spinal cord damage or dysfunction, including disorders involving the meninges and perimeningeal spaces surrounding the spinal cord. Traumatic injuries, vascular diseases, infections, and inflammatory/autoimmune processes may affect the spinal cord. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Standardize: To compare with or conform to a standard; to establish standards. [EU] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones,

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bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stillbirth: The birth of a dead fetus or baby. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subiculum: A region of the hippocampus that projects to other areas of the brain. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Support group: A group of people with similar disease who meet to discuss how better to cope with their cancer and treatment. [NIH] Supportive care: Treatment given to prevent, control, or relieve complications and side effects and to improve the comfort and quality of life of people who have cancer. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but,

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according to the general view, there is no direct contiguity. [NIH] Synapsis: The pairing between homologous chromosomes of maternal and paternal origin during the prophase of meiosis, leading to the formation of gametes. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synaptic Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] Synaptic Vesicles: Membrane-bound compartments which contain transmitter molecules. Synaptic vesicles are concentrated at presynaptic terminals. They actively sequester transmitter molecules from the cytoplasm. In at least some synapses, transmitter release occurs by fusion of these vesicles with the presynaptic membrane, followed by exocytosis of their contents. [NIH] Synaptophysin: A 38-kDa integral membrane glycoprotein of the presynaptic vesicles in neuron and neuroendocrine cells. It is expressed by a variety of normal and neoplastic neuroendocrine cells and is therefore used as an immunocytochemical marker for neuroendocrine differentiation in various tumors. In Alzheimer disease and other dementing disorders there is an important synapse loss due in part to a decrease of synaptophysin in the presynaptic vesicles. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tacrine: A cholinesterase inhibitor that crosses the blood-brain barrier. Tacrine has been used to counter the effects of muscle relaxants, as a respiratory stimulant, and in the treatment of Alzheimer's disease and other central nervous system disorders. [NIH] Tau Proteins: One of the two major classes of microtubule-associated proteins isolated from the brain. The proteins have two domains: one that binds to microtubules and a second that binds to other cell components. By binding to several unpolymerized tubulin molecules simultaneously, tau proteins speed up the nucleation process in tubulin polymerization. Chemically modified tau proteins also appear to be involved in the formation and/or composition of the neurofibrillary tangles and neuropil threads found in Alzheimer disease. [NIH]

Taurine: 2-Aminoethanesulfonic acid. A conditionally essential nutrient, important during mammalian development. It is present in milk but is isolated mostly from ox bile and strongly conjugates bile acids. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Temporal Lobe: Lower lateral part of the cerebral hemisphere. [NIH] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU]

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Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thiorphan: A potent inhibitor of membrane metalloendopeptidase (enkephalinase). Thiorphan potentiates morphine-induced analgesia and attenuates naloxone-precipitated withdrawal symptoms. [NIH] Thoracic: Having to do with the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH]

Dictionary 275

Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Tracer: A substance (such as a radioisotope) used in imaging procedures. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Tricyclic: Containing three fused rings or closed chains in the molecular structure. [EU] Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [NIH] Trinucleotide Repeat Expansion: DNA region comprised of a variable number of repetitive, contiguous trinucleotide sequences. The presence of these regions is associated with diseases such as Fragile X Syndrome and myotonic dystrophy. Many chromosome fragile sites (chromosome fragility) contain expanded trinucleotide repeats. [NIH] Trinucleotide Repeats: Microsatellite repeats consisting of three nucleotides dispersed in the euchromatic arms of chromosomes. [NIH] Trisomy: The possession of a third chromosome of any one type in an otherwise diploid cell.

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[NIH]

Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Ultraviolet radiation: Invisible rays that are part of the energy that comes from the sun. UV radiation can damage the skin and cause melanoma and other types of skin cancer. UV radiation that reaches the earth's surface is made up of two types of rays, called UVA and UVB rays. UVB rays are more likely than UVA rays to cause sunburn, but UVA rays pass deeper into the skin. Scientists have long thought that UVB radiation can cause melanoma and other types of skin cancer. They now think that UVA radiation also may add to skin damage that can lead to skin cancer and cause premature aging. For this reason, skin specialists recommend that people use sunscreens that reflect, absorb, or scatter both kinds of UV radiation. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Valine: A branched-chain essential amino acid that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. [NIH]

Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasodilators: Any nerve or agent which induces dilatation of the blood vessels. [NIH]

Dictionary 277

Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Very low-density lipoprotein: The lipoprotein particles that initially leave the liver, carrying cholesterol and lipid. VLDLs contain 10 to 15 percent of the total serum cholesterol along with most of the triglycerides in the fasting serum; VLDLs are precursors of LDL, and some forms of VLDL, particularly VLDL remnants, appear to be atherogenic. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visual Acuity: Acuteness or clearness of vision, especially of form vision, which is dependent mainly on the sharpness of the retinal focus. [NIH] Visual Perception: The selecting and organizing of visual stimuli based on the individual's past experience. [NIH] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection

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and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

279

INDEX 3 3-dimensional, 168, 199, 219 A Abdomen, 219, 227, 250, 260, 271, 272, 277 Abdominal, 116, 219, 259 Aberrant, 33, 51, 74, 219 Ablation, 75, 219 Acceptor, 219, 250, 259 Acetylcholine, 58, 80, 219, 230, 257 Acetylcholinesterase, 80, 82, 147, 219 Actin, 126, 169, 219, 254, 256 Activities of Daily Living, 20, 40, 41, 96, 219 Acute lymphoblastic leukemia, 219, 255 Acute lymphocytic leukemia, 219, 255 Acylation, 81, 219 Adaptability, 219, 228, 229 Adaptation, 117, 219, 262 Adenine, 162, 220, 265 Adenosine, 163, 220, 261 Adenosine Triphosphate, 163, 220, 261 Adenovirus, 195, 220 Adjustment, 27, 219, 220 Adrenal Cortex, 220, 234, 263 Adrenal Glands, 220, 222 Adrenal Medulla, 220, 238, 239, 257 Adverse Effect, 58, 220, 269 Aerobic, 220, 253 Affinity, 220, 224, 253, 256, 270 Agar, 220, 262 Age Groups, 61, 220 Age of Onset, 45, 46, 220, 276 Aged, 80 and Over, 220 Ageing, 123, 146, 220 Agonist, 81, 82, 220, 237, 257 Alexia, 65, 221, 237 Algorithms, 221, 226 Alkaline, 221, 227 Alkaloid, 221, 257 Alleles, 16, 37, 43, 76, 164, 181, 221, 244, 250 Alpha-1, 177, 181, 221 Alternative medicine, 149, 221 Aluminum, 80, 221 Ameliorated, 76, 221 Ameliorating, 40, 221 Amino Acid Sequence, 221, 223, 239 Amino Acids, 9, 10, 14, 139, 164, 168, 174, 221, 222, 231, 253, 260, 264, 268, 275

Amnesia, 124, 221 Amnion, 221 Amniotic Fluid, 190, 192, 221 Amplification, 50, 221 Amygdala, 111, 113, 221, 250 Amyloidosis, 10, 11, 33, 48, 64, 138, 222 Anaesthesia, 222, 246 Anal, 21, 23, 222, 239, 250 Analogous, 222, 237, 275 Anaphylatoxins, 222, 232 Anatomical, 222, 230, 246, 253, 259, 269 Androgens, 30, 220, 222 Anemia, 176, 177, 180, 181, 186, 222, 240 Aneuploidy, 174, 175, 222 Angiopathy, 93, 95, 111, 114, 149, 222, 229 Angiotensinogen, 36, 222, 267 Animal model, 19, 24, 25, 30, 32, 40, 54, 59, 76, 98, 222 Anisotropy, 95, 222 Anomalies, 223, 273 Antibacterial, 223, 271 Antibiotic, 223, 260, 271, 274 Antibodies, 113, 169, 223, 234, 244, 245, 262 Antibody, 169, 220, 223, 232, 238, 244, 245, 246, 252, 266, 271 Anticholinergic, 223, 261 Anticoagulant, 223, 264 Antigen, 220, 223, 225, 232, 239, 244, 245, 246, 252, 253, 255 Antigen-Antibody Complex, 223, 232 Anti-inflammatory, 35, 50, 54, 110, 146, 223, 242, 246 Anti-Inflammatory Agents, 35, 110, 223 Antioxidant, 31, 32, 47, 61, 146, 223, 224, 258, 259 Antiserum, 223, 225 Antispasmodic, 223, 261 Anuria, 223, 249 Anus, 222, 223, 231, 248 Apolipoproteins, 75, 223, 250 Apolipoproteins A, 75, 223 Apoptosis, 65, 85, 163, 172, 224, 228, 234 Apraxia, 108, 152, 224 Aqueous, 61, 224, 225, 235, 245 Arginine, 222, 224, 244, 257 Arterial, 34, 108, 224, 229, 230, 245, 248, 264, 273 Arteries, 222, 224, 226, 233, 248, 251

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Arterioles, 224, 226 Arteriovenous, 224, 229 Artery, 91, 92, 224, 229, 248, 265, 268 Ascorbic Acid, 32, 224 Aspartate, 96, 224 Assay, 41, 65, 74, 94, 224, 245 Astrocytes, 35, 38, 50, 224, 242, 251, 253, 256 Atherogenic, 224, 277 Atrophy, 34, 36, 77, 91, 106, 127, 128, 224, 255, 256 Attenuated, 224, 236 Atypical, 185, 224 Auditory, 225 Autacoids, 225, 246 Autoimmune disease, 225, 254 Autologous, 71, 225 Autopsy, 27, 59, 67, 77, 120, 225 Avidity, 113, 225 Axons, 33, 225, 235, 256, 258, 267 B Back Pain, 58, 225 Bacteria, 161, 169, 173, 223, 225, 239, 253, 266, 271, 275, 276 Bacterial Physiology, 219, 225 Basal Ganglia, 225, 227, 229, 250 Basal Metabolism, 55, 225 Basalis, 58, 225 Base Sequence, 173, 225, 240 Beta-pleated, 221, 225 Bewilderment, 225, 233 Bilateral, 225, 259 Bile, 225, 241, 250, 272, 273 Bile Acids, 225, 272, 273 Bioavailability, 61, 225 Biological Markers, 42, 115, 225 Biological response modifier, 226, 247 Biological Transport, 226, 236 Biomarkers, 24, 33, 48, 55, 66, 88, 117, 226 Biotechnology, 5, 83, 86, 156, 168, 195, 197, 202, 226 Biotinylation, 56, 226 Bivalent, 226, 253 Bladder, 226, 230, 232, 246, 254, 264, 276 Blastocyst, 226, 233, 261 Blood Coagulation, 226, 227, 274 Blood Glucose, 226, 243, 247 Blood pressure, 44, 61, 79, 180, 226, 228, 245, 254, 270 Blood-Brain Barrier, 84, 226, 261, 273 Blot, 35, 226 Body Fluids, 226, 227, 237, 270, 276

Body Mass Index, 60, 226, 258 Bone Marrow, 196, 219, 226, 241, 245, 251, 254 Bone scan, 227, 268 Bowel, 222, 227, 272 Bradykinin, 227, 257 Brain Diseases, 227, 265 Brain Stem, 227, 229, 256, 265 Breeding, 64, 227 Bronchitis, 227, 230 Buccal, 190, 192, 227 Budgets, 27, 227 Bulbar, 227, 265 Butyrylcholinesterase, 80, 82, 227 Bypass, 91, 92, 227 C Calcineurin, 35, 227 Calcium, 63, 227, 232, 248, 269 Calmodulin, 35, 227 Calorimeter, 225, 227 Carbohydrate, 228, 242, 269 Carcinogenic, 228, 247, 263, 272 Carcinogens, 228, 258 Cardiac, 228, 239, 271 Cardiorespiratory, 36, 228 Cardiovascular, 16, 17, 23, 54, 74, 77, 121, 199, 228, 269 Cardiovascular disease, 16, 17, 23, 74, 199, 228 Carotene, 139, 148, 228, 267 Caspase, 65, 91, 228 Caudal, 228, 245, 262 Causal, 36, 55, 228, 239 Causality, 37, 228 Cause of Death, 228, 235 Cell Cycle, 171, 172, 228 Cell Death, 32, 63, 172, 224, 228, 255 Cell Differentiation, 228, 269 Cell Division, 11, 164, 171, 172, 184, 185, 225, 228, 229, 234, 243, 252, 253, 261, 263 Cell membrane, 12, 14, 41, 56, 226, 228, 235, 239, 241, 248, 261 Cell proliferation, 58, 229, 269 Cell Respiration, 229, 253, 267 Cell Survival, 229, 243 Centromere, 42, 164, 167, 229 Cerebellum, 63, 227, 229, 240 Cerebral, 10, 11, 34, 57, 65, 67, 77, 84, 89, 90, 93, 95, 99, 111, 114, 117, 127, 128, 149, 225, 226, 227, 229, 239, 240, 255, 259, 271, 273 Cerebral Cortex, 227, 229, 255

Index 281

Cerebral Hemorrhage, 10, 11, 229 Cerebral Infarction, 229 Cerebral Palsy, 229, 271 Cerebrospinal, 26, 88, 97, 106, 109, 120, 229 Cerebrospinal fluid, 26, 88, 97, 106, 109, 120, 229 Cerebrovascular, 23, 44, 54, 77, 78, 90, 114, 121, 150, 228, 229 Cerebrum, 229 Chaos, 144, 229 Character, 229, 235 Chelation, 229 Chemotactic Factors, 229, 232 Chin, 230, 252 Chloroform, 146, 230 Cholesterol Esters, 230, 250 Choline, 80, 219, 230 Cholinergic, 58, 59, 80, 82, 101, 149, 230, 257 Cholinesterase Inhibitors, 58, 125, 127, 230, 236 Choroid, 230, 267 Chromatin, 224, 230, 251, 257 Chromosomal, 45, 69, 172, 174, 175, 185, 186, 187, 189, 221, 222, 230, 244, 254, 268 Chromosome Fragility, 230, 275 Chronic, 50, 66, 72, 81, 89, 117, 146, 147, 212, 225, 230, 236, 246, 249, 250, 272 Chronic Disease, 146, 147, 230 Chronic Obstructive Pulmonary Disease, 81, 230 Chylomicrons, 230, 250 Cirrhosis, 230, 243 CIS, 230, 241, 267 Clamp, 59, 231 Clathrin, 231, 238 Clinical Medicine, 198, 231, 263 Clinical study, 231, 233 Cloning, 37, 226, 231 Coated Vesicles, 231, 238 Codon, 11, 169, 231 Coenzyme, 31, 78, 139, 224, 231 Cofactor, 31, 231, 264, 274 Cognition, 25, 26, 28, 33, 40, 58, 68, 124, 128, 231 Collagen, 231, 240, 262, 263 Colloidal, 231, 237 Colon, 178, 231 Colonoscopy, 180, 231 Comorbidity, 22, 231

Complement, 53, 55, 71, 91, 137, 222, 232, 241, 248, 251 Complement Activation, 71, 91, 222, 232 Complementary and alternative medicine, 130, 142, 232 Complementary medicine, 130, 232 Compliance, 25, 41, 232 Computational Biology, 202, 232 Computed tomography, 232, 233, 268 Computerized axial tomography, 232, 233, 268 Concentric, 233, 257 Conception, 171, 233, 240, 270 Cones, 233, 267 Confusion, 178, 233, 236, 276 Conjunctiva, 233, 261 Connective Tissue, 224, 226, 231, 233, 240, 241 Consciousness, 233, 235, 236, 264, 265 Constriction, 164, 167, 233, 248, 268 Consultation, 27, 186, 187, 190, 191, 233 Contraindications, ii, 233 Contrast Sensitivity, 40, 233 Controlled clinical trial, 22, 233 Coordination, 52, 229, 233, 254 Coronary, 18, 91, 92, 228, 233, 245 Coronary heart disease, 18, 228, 233 Corpus, 233, 263, 277 Corpus Luteum, 233, 263 Cortex, 72, 80, 91, 224, 233, 238, 260 Cortical, 32, 65, 80, 92, 96, 127, 233 Corticosteroids, 234, 242 Cortisol, 72, 234 C-Peptide, 55, 234 Cranial, 229, 234, 248, 258, 260, 265 Creatine, 100, 234 Creatinine, 234, 249 Cross-Sectional Studies, 55, 234, 239 Curative, 63, 234, 274 Cyclic, 138, 227, 234, 243, 257, 261 Cystathionine beta-Synthase, 234, 245 Cysteinyl, 234, 253 Cytochrome, 234, 259 Cytogenetics, 234, 268 Cytokine, 35, 50, 75, 234 Cytoplasm, 161, 162, 163, 169, 224, 228, 234, 235, 238, 243, 251, 253, 254, 256, 257, 268, 273 Cytosine, 162, 235, 265 Cytoskeleton, 156, 235, 253 Cytotoxic, 235, 270

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D Data Collection, 81, 235 De novo, 172, 235 Death Certificates, 180, 235 Degenerative, 3, 34, 35, 57, 68, 71, 118, 235, 242 Deletion, 36, 174, 224, 235 Delusions, 93, 235, 265 Dendrites, 235, 255, 256 Dendritic, 51, 235, 267 Dentate Gyrus, 235, 244 Deoxyribonucleic, 162, 235, 268 Deoxyribonucleic acid, 162, 235, 268 Deoxyribonucleotides, 235 Depolarization, 235, 270 Diabetes Mellitus, 235, 243 Diagnostic procedure, 82, 145, 235 Diastolic, 235, 245 Diffusion, 24, 95, 125, 226, 235, 236 Diffusivity, 95, 236 Digestion, 225, 227, 236, 250, 272, 276 Dihydrotestosterone, 236, 266 Dilution, 33, 236 Diploid, 222, 236, 254, 262, 275 Direct, iii, 32, 68, 112, 190, 191, 192, 231, 236, 237, 266, 273 Discrete, 36, 236 Discrimination, 97, 192, 193, 198, 236 Disease Progression, 28, 32, 36, 41, 42, 50, 54, 58, 59, 67, 68, 71, 122, 125, 236 Disease Susceptibility, 46, 56, 236 Disorientation, 52, 233, 236 Dissociation, 94, 95, 151, 220, 236 Dissociative Disorders, 236 Distal, 33, 236, 249, 256, 264 Dominance, 236, 239 Donepezil, 83, 87, 140, 151, 236 Dopamine, 236, 257, 261 Dorsal, 237, 262 Double-blind, 25, 41, 237 Drug Design, 60, 237 Drug Evaluation, 60, 237 Duct, 237, 268 Dyes, 221, 237, 257 Dyslexia, 65, 237 Dyslipidemia, 18, 237 E Effector, 219, 232, 237, 261 Efficacy, 22, 25, 31, 48, 54, 81, 96, 102, 237 Electric Conductivity, 222, 237 Electroencephalography, 237, 251 Electrolyte, 237, 249, 270

Electrons, 223, 225, 237, 248, 251, 258, 259, 265 Electrophoresis, 68, 237 Elementary Particles, 237, 238, 251, 264 Embryo, 171, 172, 173, 181, 221, 226, 228, 238, 246 Emphysema, 230, 238 Endemic, 238, 271 Endocytosis, 74, 75, 238 Endogenous, 30, 64, 75, 236, 238, 258, 275 Endorphins, 238, 257, 258 Endosomes, 74, 238 Endothelial cell, 226, 238, 274 Endothelium, 238, 257 Endothelium-derived, 238, 257 Endotoxins, 232, 238 Energy Intake, 47, 238 Enkephalins, 238, 257, 258 Entorhinal Cortex, 33, 238, 244 Environmental Exposure, 58, 226, 238 Environmental Health, 201, 202, 238 Enzymatic, 65, 227, 228, 232, 238, 267 Enzyme-Linked Immunosorbent Assay, 48, 238 Epidemic, 239, 271 Epidemiologic Studies, 226, 239 Epidemiological, 44, 47, 51, 64, 78, 239 Epinephrine, 236, 239, 257, 276 Epistasis, 70, 239 Epithelial, 36, 226, 239 Erythrocytes, 222, 226, 239, 266 Estrogen, 20, 24, 30, 67, 99, 239 Ethnic Groups, 44, 78, 186, 189, 239 Eukaryotic Cells, 239, 246, 258, 276 Excitation, 239, 257 Excrete, 223, 239, 249 Exocytosis, 239, 273 Exogenous, 234, 238, 239, 260, 276 Exon, 72, 239 Extracellular, 50, 54, 65, 71, 221, 224, 233, 238, 239, 240, 256, 270 Extremity, 239, 259 Eye Color, 173, 239 Eye Infections, 220, 239 Eye Movements, 239, 265 F Family Planning, 202, 240 Fat, 47, 222, 226, 228, 233, 240, 250, 254, 258, 270, 275 Fathers, 181, 240 Fatigue, 147, 240 Fatty acids, 240, 264

Index 283

Fetus, 189, 190, 192, 196, 240, 261, 263, 272, 276 Fibril, 24, 73, 240 Fibroblasts, 240, 247 Fibrosis, 173, 176, 180, 181, 240, 269 Fluorescence, 31, 68, 72, 73, 240 Folate, 64, 107, 240 Fold, 52, 68, 147, 240 Folic Acid, 240 Forearm, 226, 240 Fossa, 229, 240 Fourth Ventricle, 240, 250 Fractionation, 35, 240 Frail Elderly, 82, 240 Frameshift, 100, 174, 240 Frameshift Mutation, 174, 240 Free Radicals, 223, 236, 241 Functional magnetic resonance imaging, 29, 108, 241 G Gallbladder, 219, 241 Ganglia, 219, 241, 255, 260 Gap Junctions, 241, 273 Gas, 228, 235, 241, 244, 257 Gastrin, 241, 244 Gastrointestinal, 227, 230, 239, 241, 269, 272, 276 Gastrointestinal tract, 230, 241, 269, 276 Gene Expression, 46, 94, 101, 169, 170, 241 Gene Products, rev, 241 Gene Therapy, 25, 58, 105, 194, 195, 196, 220, 241 Genes, env, 180, 241 Genetic Engineering, 226, 231, 241 Genetic Markers, 82, 242 Genetic testing, 39, 157, 183, 187, 188, 189, 190, 191, 192, 193, 198, 242 Genomics, 199, 242 Genotype, 8, 17, 18, 29, 39, 42, 44, 45, 47, 62, 70, 86, 104, 242, 261 Germ Cells, 172, 196, 242, 252, 270 Germline mutation, 172, 242, 244 Ginseng, 57, 142, 242 Gland, 220, 242, 259, 264, 269, 272, 274 Gliosis, 71, 242 Glucocorticoid, 71, 242 Glucose, 49, 89, 106, 126, 224, 226, 235, 242, 243, 247, 268 Glucose tolerance, 49, 242 Glucose Tolerance Test, 242 Glutamic Acid, 240, 242, 257, 263 Glycine, 242, 257

Glycoprotein, 242, 273, 274 Gonadal, 242, 271 Governing Board, 242, 263 Graft, 243, 246 Graft Rejection, 243, 246 Grafting, 91, 92, 243, 246 Granule, 235, 243, 268 Granulocytes, 243, 249, 270, 278 Growth factors, 243, 253, 255 Guanine, 162, 243, 265 Guanylate Cyclase, 243, 257 H Hair Color, 173, 243 Haploid, 243, 261 Haplotypes, 43, 243 Heart attack, 16, 228, 243 Hemochromatosis, 189, 243 Hemodialysis, 243, 249 Hemoglobin, 163, 222, 239, 243, 248 Hemoglobinopathies, 241, 243 Hemophilia, 181, 243 Hemorrhage, 243, 272 Hepatic, 242, 243 Hereditary, 10, 11, 161, 162, 172, 181, 187, 242, 243, 244, 255, 267 Hereditary mutation, 172, 242, 244 Heredity, 109, 164, 241, 242, 244 Heritability, 45, 105, 244 Heterogeneity, 8, 13, 52, 96, 106, 220, 244 Hippocampus, 29, 33, 59, 63, 68, 72, 80, 94, 100, 108, 113, 116, 235, 244, 250, 256, 272 Histology, 21, 244, 256 Histones, 164, 227, 230, 244 Homeostasis, 74, 244 Homogeneous, 67, 244 Homologous, 221, 226, 241, 244, 254, 273 Homozygote, 50, 244 Hormonal, 224, 244 Hormone, 30, 67, 102, 169, 225, 234, 239, 241, 244, 247, 252, 263, 269, 274 Hormone therapy, 67, 244 Horseradish Peroxidase, 238, 244 Hybridomas, 244, 247 Hydrogen, 107, 219, 225, 228, 244, 245, 250, 254, 259, 264 Hydrogen Peroxide, 245, 250 Hydrolysis, 219, 245, 260, 261, 264 Hydrophobic, 245, 248, 250, 255 Hypercholesterolemia, 78, 237, 245 Hyperhomocysteinemia, 64, 234, 245 Hyperlipidemia, 54, 237, 245 Hyperlipoproteinemia, 17, 245

284

Alzheimer Disease

Hypertension, 35, 44, 46, 54, 78, 108, 228, 229, 245, 248 Hypertriglyceridemia, 237, 245 Hypothalamic, 71, 245 Hypothalamus, 227, 245, 250 I Idiopathic, 154, 245 Imaging procedures, 245, 275 Immune response, 102, 223, 225, 243, 245, 246, 251, 272, 276, 277 Immune Sera, 245 Immune system, 71, 89, 245, 246, 251, 254, 260, 276, 277 Immunity, 245, 258, 275 Immunization, 69, 84, 152, 245, 246 Immunoassay, 234, 238, 245 Immunohistochemistry, 35, 53, 108, 109, 245 Immunologic, 229, 245, 246 Immunophilin, 227, 246 Immunosuppressive, 227, 242, 246 Immunosuppressive therapy, 246 Immunotherapy, 85, 246 Implantation, 233, 246 In situ, 35, 246 In Situ Hybridization, 35, 246 In vitro, 31, 39, 48, 51, 57, 60, 62, 64, 65, 74, 94, 123, 241, 246, 274 In vivo, 29, 31, 33, 38, 40, 48, 57, 58, 60, 62, 64, 65, 68, 89, 97, 123, 241, 246, 258 Incision, 246, 248 Incontinence, 81, 246 Indomethacin, 54, 246 Induction, 35, 50, 222, 246 Infancy, 199, 246 Infant, Newborn, 220, 246 Infection, 50, 120, 226, 229, 239, 245, 246, 251, 256, 260, 272, 277 Inflammation, 28, 41, 64, 71, 110, 195, 223, 227, 239, 240, 246, 254, 260, 262 Informed Consent, 190, 193, 198, 246 Infusion, 48, 58, 115, 247 Ingestion, 242, 247, 262 Inhalation, 247, 262 Initiation, 70, 247, 275 Inositol, 96, 141, 247 Insight, 51, 59, 101, 247 Insulator, 247, 254 Insulin, 49, 55, 60, 94, 234, 242, 247, 255, 263, 276 Insulin-dependent diabetes mellitus, 247 Insulin-like, 60, 247

Interferon, 146, 247 Interferon-alpha, 247 Interleukin-1, 50, 109, 247 Interleukin-2, 247 Interleukin-6, 50, 247 Intermediate Filaments, 247, 255 Intermittent, 248, 251 Intestinal, 228, 242, 248 Intestines, 219, 241, 248 Intoxication, 248, 278 Intracellular, 32, 33, 54, 65, 74, 75, 110, 231, 246, 248, 252, 257, 269 Intracellular Membranes, 248, 252 Intracranial Aneurysm, 229, 248 Intracranial Arteriosclerosis, 229, 248 Intracranial Hypertension, 248, 259 Intravascular, 48, 248 Intravenous, 115, 247, 248, 259 Invasive, 29, 245, 248, 251 Ion Channels, 224, 248, 256, 273 Ionizing, 238, 248 Ions, 225, 227, 236, 237, 244, 248, 254 Iris, 239, 248 Ischemia, 224, 248 Isoleucine, 9, 10, 14, 248 Isoprenoid, 51, 248 K Karyotype, 166, 248 Kb, 46, 249 Kidney Cortex, 249, 253 Kidney Failure, 175, 249 Kidney Failure, Acute, 249 Kidney Failure, Chronic, 249 Kinetic, 80, 81, 248, 249, 260 L Labile, 232, 249 Lag, 147, 249 Latency, 249 Lectin, 249, 252 Lesion, 65, 242, 249, 250, 265 Leucocyte, 221, 249 Leukemia, 241, 249 Libido, 222, 249 Life Expectancy, 58, 249 Ligaments, 233, 249 Ligands, 31, 40, 75, 76, 249 Limbic, 221, 249 Limbic System, 221, 249 Linkage, 37, 42, 43, 44, 46, 109, 112, 116, 242, 250 Linkage Disequilibrium, 37, 43, 46, 250

Index 285

Lipid, 11, 13, 15, 32, 41, 49, 62, 64, 74, 75, 78, 110, 118, 223, 230, 247, 250, 254, 259, 275, 277 Lipid Peroxidation, 32, 49, 62, 64, 110, 118, 250, 259 Lipopolysaccharide, 146, 250 Lipoprotein, 16, 79, 223, 237, 250, 251, 277 Liver, 16, 41, 74, 170, 219, 222, 225, 230, 240, 241, 242, 243, 250, 253, 268, 277 Liver scan, 250, 268 Lobe, 101, 229, 250 Localization, 33, 74, 108, 245, 250, 251 Localized, 33, 222, 246, 250, 261, 262 Locomotion, 250, 261 Locus Coeruleus, 28, 250 Longitudinal Studies, 55, 61, 234, 250 Longitudinal study, 29, 52, 112, 250 Long-Term Care, 19, 80, 250 Low-density lipoprotein, 16, 78, 237, 250, 251 Lumbar, 225, 251 Lymphatic, 238, 246, 251, 271, 274 Lymphocytes, 35, 124, 223, 227, 244, 245, 247, 249, 251, 271, 274, 278 Lymphoid, 223, 234, 249, 251 Lysine, 31, 244, 251 M Macroglia, 251, 253, 256 Macrophage, 172, 247, 251 Magnetic Resonance Imaging, 44, 70, 119, 125, 251, 268 Magnetic Resonance Spectroscopy, 89, 251 Magnetoencephalography, 119, 251 Major Histocompatibility Complex, 243, 251 Malignant, 67, 251 Malnutrition, 4, 224, 251 Mammography, 180, 251 Mania, 147, 251, 252 Manic, 252, 265 Manic-depressive psychosis, 252, 265 Manifest, 64, 66, 67, 252 Medial, 128, 252, 258 Mediate, 25, 54, 64, 66, 236, 252 Mediator, 51, 247, 252, 269 Medical Records, 180, 193, 252 Medicament, 147, 252 MEDLINE, 202, 252 Meiosis, 171, 226, 252, 254, 273 Melanin, 248, 250, 252, 261, 276 Melanoma, 252, 276

Memantine, 83, 87, 124, 153, 252 Membrane Proteins, 54, 252 Meninges, 229, 252, 271 Menopause, 68, 138, 252, 262 Menstrual Cycle, 252, 263 Menstruation, 252 Mental Disorders, 252, 264, 265 Mental Health, iv, 18, 201, 203, 252, 265 Mental Processes, 236, 253, 264 Mental Retardation, 5, 185, 187, 189, 253 Mentors, 36, 66, 253 Mesencephalic, 250, 253 Meta-Analysis, 93, 253 Metallothionein, 98, 253 Microbe, 253, 275 Microbiology, 219, 224, 253 Microglia, 28, 50, 54, 224, 253, 256 Microorganism, 231, 253, 277 Microscopy, 31, 33, 56, 73, 244, 253 Microtubule-Associated Proteins, 253, 256, 273 Microtubules, 73, 247, 253, 255, 273 Minority Groups, 52, 253 Miscarriage, 192, 253 Mitochondria, 162, 163, 175, 181, 182, 253, 258 Mitosis, 171, 224, 253 Modeling, 237, 254 Modification, 62, 241, 254, 265 Molecular Structure, 254, 275 Monitor, 72, 234, 254, 257 Monocytes, 54, 247, 254 Mononuclear, 254 Monosomy, 175, 222, 254 Morphological, 33, 56, 120, 220, 238, 254, 256 Morphology, 108, 122, 254 Mosaicism, 172, 254 Motility, 81, 246, 254, 269 Motor Activity, 254, 265 Multiple sclerosis, 114, 123, 213, 254 Multivalent, 225, 254 Muscular Diseases, 254, 256, 259, 265 Mutagens, 240, 254 Myelin, 254, 256 Myosin, 227, 254 Myositis, 109, 254 Myotonic Dystrophy, 184, 255, 275 N NCI, 1, 200, 231, 255, 260 Necrosis, 224, 229, 255, 269 Neocortex, 87, 255, 256

286

Alzheimer Disease

Neonatal, 32, 255 Neprilysin, 25, 93, 255 Nerve Growth Factor, 33, 58, 255 Nervous System, 9, 38, 58, 66, 69, 184, 219, 227, 229, 230, 241, 242, 252, 253, 254, 255, 256, 257, 258, 260, 261, 269, 272, 273 Networks, 65, 255 Neural, 11, 25, 30, 38, 48, 68, 97, 135, 221, 253, 255 Neurites, 33, 255 Neuroblastoma, 65, 255 Neurodegenerative Diseases, 19, 26, 28, 30, 33, 46, 56, 255 Neuroendocrine, 115, 255, 273 Neurofibrillary Tangles, 49, 69, 72, 76, 80, 119, 124, 255, 256, 273 Neurofilaments, 255, 256 Neuroglia, 242, 251, 256 Neurologic, 65, 256 Neurologist, 29, 256 Neuromuscular, 219, 256, 265 Neuromuscular Diseases, 256, 265 Neuromuscular Junction, 219, 256 Neuronal, 19, 29, 30, 32, 33, 34, 38, 51, 55, 57, 58, 75, 76, 97, 115, 117, 153, 156, 256, 269 Neuronal Plasticity, 51, 56, 256 Neurons, 19, 28, 31, 32, 33, 38, 48, 55, 58, 71, 72, 74, 75, 80, 119, 153, 235, 241, 255, 256, 257, 272, 273 Neuropathy, 181, 256 Neuropil, 256, 273 Neuropil Threads, 256, 273 Neuropsychology, 23, 34, 90, 108, 119, 256 Neurotoxic, 50, 257 Neurotoxicity, 48, 65, 257 Neurotransmitter, 24, 219, 220, 227, 230, 236, 242, 248, 257, 269, 272, 273 Neutrophils, 146, 243, 257 Nicotine, 58, 147, 257 Nitric Oxide, 31, 102, 257 Nitrogen, 28, 30, 221, 222, 249, 257 Norepinephrine, 28, 236, 257 Nuclear, 154, 162, 225, 237, 239, 241, 250, 255, 257, 267 Nuclear Envelope, 162, 257 Nuclear Pore, 257 Nuclei, 221, 237, 241, 242, 244, 250, 251, 253, 257, 258, 264 Nucleic acid, 225, 235, 246, 254, 257, 263, 265, 268 Nurse Practitioners, 190, 258

O Odds Ratio, 258, 267 Oliguria, 249, 258 Omega-3 fatty acid, 143, 258 Opioid Peptides, 238, 255, 258 Opsin, 258, 267, 268 Optic Chiasm, 245, 258 Optic Nerve, 40, 258, 267 Organelles, 33, 161, 162, 231, 235, 254, 258, 262 Ovaries, 189, 258, 269 Overweight, 61, 258 Ovum, 233, 258, 263, 278 Oxidants, 19, 30, 31, 63, 258 Oxidation, 63, 219, 223, 225, 234, 250, 258, 259 Oxidation-Reduction, 258, 259 Oxidative Phosphorylation, 163, 259 Oxidative Stress, 19, 28, 31, 41, 49, 63, 64, 111, 154, 259 Oxygen Consumption, 36, 259, 267 Oxygenase, 104, 259 P Palliative, 80, 156, 259, 274 Palsy, 72, 259 Pancreas, 219, 226, 243, 247, 259, 263, 276 Pancreatic, 234, 259 Paralysis, 224, 227, 253, 259, 265, 271 Paraparesis, 88, 259 Parenchyma, 71, 259 Parenteral, 238, 259 Parietal, 96, 113, 259 Parietal Lobe, 259 Particle, 259, 270, 275 Patch, 59, 259 Paternity, 189, 259 Pathologic, 90, 112, 224, 227, 233, 259, 260, 271 Pathologic Processes, 224, 260 Pathophysiology, 52, 65, 66, 260 PDQ, 200, 260 Pedigree, 42, 70, 109, 260 Pelvis, 219, 251, 258, 260, 276 Penicillin, 260, 276 Peptide Fragments, 48, 260 Perceived risk, 103, 260 Perfusion, 34, 260 Periodontitis, 50, 260 Peripheral blood, 117, 247, 260 Peripheral Nervous System, 238, 255, 256, 257, 259, 260, 265, 272

Index 287

Peripheral Nervous System Diseases, 256, 259, 260, 265 Perirhinal, 89, 260 Perivascular, 253, 260 Peroxide, 107, 260 Phagocyte, 258, 260 Phagocytosis, 253, 260 Pharmacokinetics, 237, 260 Pharmacologic, 38, 80, 212, 225, 261, 275 Phenotype, 28, 54, 64, 104, 112, 122, 225, 261 Phenylalanine, 169, 261, 276 Phloroglucinol, 146, 261 Phosphodiesterase, 55, 261 Phospholipases, 261, 269 Phospholipids, 240, 247, 250, 261 Phosphorus, 227, 261 Phosphorylated, 33, 88, 231, 256, 261 Phosphorylation, 73, 163, 261 Physical Examination, 187, 261 Physiologic, 220, 252, 261, 266 Physiology, 21, 23, 58, 63, 225, 261 Physostigmine, 115, 261 Pigments, 228, 261, 262, 267 Pilot study, 41, 117, 261 Placenta, 261, 263 Plants, 146, 221, 227, 230, 242, 249, 254, 257, 261, 268, 275 Plaque, 33, 49, 50, 54, 62, 72, 75, 76, 155, 224, 262 Plasma cells, 223, 262 Plasticity, 51, 68, 112, 262 Plastids, 258, 262 Platelet Activation, 262, 270 Platelet Aggregation, 222, 257, 262 Platelets, 257, 262, 269 Pneumonia, 4, 233, 262 Poisoning, 82, 248, 262 Polymerase, 28, 262 Polymorphic, 37, 235, 262 Polymorphism, 17, 36, 37, 50, 104, 122, 123, 191, 262 Posterior, 127, 222, 225, 229, 230, 237, 248, 259, 262 Postmenopausal, 30, 262 Postnatal, 262, 271 Postsynaptic, 262, 269, 273 Potentiates, 247, 262, 274 Potentiation, 230, 262, 270 Practice Guidelines, 150, 153, 203, 212, 262 Precipitating Factors, 228, 263 Preclinical, 40, 58, 62, 76, 82, 127, 263

Prenatal, 189, 192, 238, 263 Presynaptic, 257, 263, 273 Prevalence, 8, 22, 45, 51, 58, 70, 74, 75, 82, 96, 115, 129, 154, 177, 258, 263 Prion, 97, 263 Progesterone, 67, 263, 271 Proinsulin, 234, 263 Projection, 257, 258, 263 Proline, 72, 231, 263 Promoter, 50, 69, 263 Prone, 175, 184, 263 Proneness, 70, 263 Prophase, 226, 254, 263, 273 Prophylaxis, 263, 276 Prospective study, 50, 82, 94, 96, 250, 263 Prostaglandins, 246, 264 Prostate, 226, 264, 276 Protease, 49, 63, 65, 264 Proteolytic, 48, 57, 63, 69, 221, 232, 264 Proteome, 68, 264 Protocol, 195, 264 Protons, 244, 248, 251, 264, 265 Proximal, 236, 249, 263, 264 Psychiatric, 6, 20, 61, 124, 153, 225, 252, 264 Psychic, 249, 252, 264 Psychoactive, 264, 278 Psychology, 40, 236, 256, 264 Psychopathology, 22, 264 Psychophysiology, 256, 264 Psychosis, 92, 105, 118, 119, 121, 265 Public Health, 23, 37, 47, 48, 54, 70, 203, 265 Public Policy, 155, 202, 265 Pulmonary, 226, 249, 265, 277 Pulmonary Artery, 226, 265, 277 Pulmonary Edema, 249, 265 Pulse, 254, 265 Purines, 225, 265 Pyrimidines, 225, 265 Q Quadriplegia, 144, 265 Quality of Life, 41, 58, 82, 105, 107, 125, 154, 211, 265, 272 R Race, 39, 70, 248, 265 Radiation, 219, 236, 238, 240, 241, 248, 265, 266, 268, 276, 278 Radiation therapy, 219, 236, 240, 265 Radioactive, 227, 244, 246, 250, 257, 266, 268 Radioisotope, 266, 275

288

Alzheimer Disease

Radiological, 27, 266 Radiology, 119, 266 Randomized, 22, 25, 39, 41, 95, 96, 237, 266 Randomized clinical trial, 39, 266 Reactive Oxygen Species, 28, 31, 266 Reagent, 261, 266 Reality Testing, 265, 266 Receptor, 30, 54, 68, 81, 83, 90, 178, 219, 223, 236, 266, 269 Recombinant, 195, 266, 277 Recombination, 241, 242, 266 Rectum, 223, 231, 241, 246, 264, 266 Red blood cells, 239, 259, 266, 268 Reductase, 70, 78, 266 Refer, 1, 167, 171, 173, 178, 196, 227, 232, 238, 250, 255, 265, 266 Reflective, 84, 266 Refraction, 222, 266, 271 Regimen, 25, 237, 266 Registries, 82, 267 Relative risk, 20, 267 Renin, 222, 267 Reproductive cells, 174, 185, 186, 242, 244, 267 Research Design, 34, 267 Respiration, 254, 267 Respite Care, 82, 267 Retina, 40, 230, 233, 256, 258, 267, 268, 277 Retinal, 40, 120, 258, 267, 268, 277 Retinal Ganglion Cells, 258, 267 Retinoblastoma, 177, 267 Retinol, 267, 268 Retrograde, 33, 267 Retroviral vector, 241, 267 Reverberant, 236, 268 Rheumatoid, 258, 268 Rhodopsin, 258, 267, 268 Ribonucleic acid, 169, 268 Ribose, 220, 268 Ribosome, 169, 268, 275 Rigidity, 261, 268 Rod, 231, 268 Rural Population, 62, 268 S Saliva, 268 Salivary, 72, 268 Saponins, 268, 272 Satellite, 24, 77, 268 Scans, 42, 49, 67, 268 Scatter, 268, 276 Schizoid, 268, 278

Schizophrenia, 81, 147, 150, 182, 268, 269, 278 Schizotypal Personality Disorder, 268, 278 Sclerosis, 31, 107, 178, 213, 248, 254, 269 Screening, 25, 40, 44, 77, 82, 93, 94, 126, 180, 189, 190, 192, 231, 260, 269 Scurvy, 32, 269 Secretion, 32, 33, 50, 54, 59, 75, 247, 253, 269, 276 Secretory, 234, 269, 273 Self Care, 219, 269 Senile, 31, 49, 54, 138, 256, 269 Senile Plaques, 31, 54, 256, 269 Sequence Analysis, 37, 269 Sequencing, 43, 46, 197, 269 Sequester, 269, 273 Serotonin, 257, 269 Serum, 23, 26, 64, 72, 78, 106, 113, 121, 222, 223, 232, 245, 249, 251, 269, 277 Sex Characteristics, 222, 269, 274 Side effect, 41, 196, 199, 220, 236, 269, 272, 275 Signal Transduction, 54, 153, 157, 227, 247, 269 Signs and Symptoms, 4, 5, 9, 10, 183, 184, 189, 270 Skeletal, 222, 230, 231, 254, 270 Skeleton, 219, 270 Skull, 270, 273 Small intestine, 230, 244, 248, 270 Smooth muscle, 126, 222, 225, 254, 270, 272 Social Environment, 265, 270 Social Support, 21, 270 Social Work, 149, 186, 270 Sodium, 36, 95, 270 Soft tissue, 226, 270 Solvent, 146, 230, 270 Soma, 270 Somatic, 172, 175, 186, 249, 252, 253, 260, 270 Somatic cells, 172, 175, 186, 252, 253, 270 Somatic mutations, 175, 270 Sound wave, 266, 270 Spastic, 88, 271 Spasticity, 271 Specialist, 190, 215, 271 Species, 28, 31, 38, 69, 71, 142, 155, 199, 234, 239, 248, 252, 253, 265, 266, 271, 272, 275, 277, 278 Specificity, 33, 80, 122, 220, 271 Spectroscopic, 96, 251, 271

Index 289

Spectrum, 8, 28, 41, 47, 59, 66, 96, 253, 271 Sperm, 171, 172, 174, 175, 184, 185, 186, 189, 196, 222, 230, 242, 244, 267, 270, 271, 276 Spinal cord, 9, 224, 227, 229, 230, 252, 255, 256, 259, 260, 265, 271 Spinal Cord Diseases, 259, 265, 271 Spleen, 222, 251, 271 Sporadic, 4, 38, 67, 72, 85, 113, 255, 267, 271 Staging, 268, 271 Standardize, 53, 271 Steel, 231, 271 Stem Cells, 25, 38, 271 Steroid, 30, 68, 234, 268, 271 Stillbirth, 187, 272 Stimulant, 272, 273, 276 Stimulus, 239, 248, 249, 272, 274 Stomach, 219, 241, 242, 244, 248, 270, 271, 272 Stool, 231, 246, 272 Strand, 162, 262, 272 Stress, 22, 28, 31, 32, 41, 61, 64, 70, 71, 82, 97, 117, 149, 210, 234, 259, 272 Stroke, 5, 11, 16, 24, 36, 55, 78, 90, 99, 108, 128, 180, 201, 228, 272 Stroma, 248, 259, 272 Subacute, 124, 246, 272 Subclinical, 246, 272 Subiculum, 244, 272 Subspecies, 271, 272 Substrate, 51, 65, 237, 239, 272 Superoxide, 19, 146, 272 Supplementation, 41, 143, 272 Support group, 56, 272 Supportive care, 260, 272 Sympathomimetic, 237, 239, 257, 272 Symptomatic, 58, 272 Synapse, 26, 256, 263, 272, 273, 275 Synapsis, 273 Synaptic, 33, 55, 57, 58, 66, 68, 75, 112, 256, 257, 270, 273 Synaptic Transmission, 55, 59, 257, 273 Synaptic Vesicles, 56, 273 Synaptophysin, 119, 273 Synergistic, 42, 273 Systemic, 222, 226, 239, 246, 248, 256, 266, 273, 275 Systolic, 245, 273 T Tacrine, 80, 142, 273 Tau Proteins, 33, 256, 273

Taurine, 61, 273 Temporal, 21, 24, 26, 29, 60, 72, 91, 95, 123, 128, 221, 244, 273 Temporal Lobe, 128, 221, 273 Teratogenic, 58, 273 Terminator, 231, 274 Testosterone, 30, 266, 274 Tetracycline, 69, 274 Therapeutics, 11, 20, 38, 48, 63, 66, 274 Thermal, 222, 236, 274 Thiorphan, 255, 274 Thoracic, 225, 274, 278 Threonine, 33, 274 Threshold, 42, 245, 274 Thrombin, 262, 264, 274 Thrombomodulin, 264, 274 Thrombosis, 248, 264, 272, 274 Thymus, 245, 251, 274 Thyroid, 189, 274, 276 Thyroid Gland, 189, 274 Thyroid Hormones, 274, 276 Tissue Culture, 255, 274 Tolerance, 219, 242, 274 Tomography, 40, 67, 126, 217, 232, 233, 251, 274 Tooth Preparation, 219, 274 Toxic, iv, 4, 31, 48, 161, 238, 245, 256, 257, 261, 275 Toxicity, 19, 32, 48, 49, 60, 80, 195, 237, 261, 275 Toxicology, 50, 58, 67, 202, 275 Toxins, 223, 238, 246, 275 Tracer, 80, 244, 275 Trachea, 274, 275 Traction, 231, 275 Transcription Factors, 54, 170, 275 Transduction, 54, 269, 275 Transfection, 226, 241, 275 Transfer Factor, 245, 275 Translation, 169, 170, 212, 241, 275 Translational, 22, 25, 124, 275 Transmitter, 219, 224, 236, 248, 252, 256, 257, 273, 275 Transplantation, 38, 245, 249, 251, 275 Trauma, 229, 255, 275 Tricyclic, 82, 275 Triglyceride, 245, 275 Trinucleotide Repeat Expansion, 184, 275 Trinucleotide Repeats, 275 Trisomy, 175, 222, 275 Tubulin, 253, 273, 276 Tumor marker, 226, 276

290

Alzheimer Disease

Type 2 diabetes, 49, 276 Tyrosine, 54, 113, 141, 236, 276 U Ubiquitin, 33, 256, 276 Ultraviolet radiation, 172, 276 Uremia, 249, 276 Urethra, 264, 276 Urinary, 81, 230, 246, 258, 276 Urine, 23, 41, 223, 226, 234, 246, 249, 258, 276 Uterus, 189, 233, 252, 258, 263, 276 V Vaccination, 76, 102, 276 Vaccine, 264, 276 Vacuoles, 238, 258, 276 Valine, 9, 10, 14, 276 Vasodilators, 257, 276 Vector, 58, 194, 195, 275, 277 Vein, 224, 248, 257, 268, 277 Venous, 224, 229, 264, 277 Ventricle, 221, 244, 245, 265, 273, 277 Ventricular, 33, 277 Venules, 226, 277 Vertebrae, 271, 277 Very low-density lipoprotein, 16, 277 Vesicular, 75, 277

Veterinary Medicine, 202, 277 Viral, 124, 194, 241, 275, 277 Virulence, 224, 275, 277 Virus, 58, 194, 241, 247, 262, 267, 275, 277 Viscera, 270, 277 Visual Acuity, 233, 277 Visual Perception, 66, 277 Vitreous, 267, 277 Vitreous Body, 267, 277 Vitro, 31, 40, 49, 60, 149, 189, 277 Vivo, 31, 33, 40, 48, 49, 58, 65, 75, 277 W White blood cell, 172, 219, 223, 251, 262, 277 Windpipe, 274, 278 Withdrawal, 4, 274, 278 Womb, 276, 278 X Xenograft, 222, 278 X-ray, 232, 233, 240, 257, 265, 266, 268, 278 Y Yeasts, 261, 278 Z Zygote, 233, 254, 278 Zymogen, 264, 278