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

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

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THE OFFICIAL PATIENT’S SOURCEBOOK

on

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Alzheimer’s Disease

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

Introduction

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

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

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

Presenile Dementia

•

Primary Degenerative Dementia

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Alzheimer’s Disease

•

Senile Dementia of the Alzheimer's Type (SDAT)

•

Senile Dementia/Alzheimer's Type (SDAT)

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

290.0 senile dementia, uncomplicated

•

290.10 presenile dementia, uncomplicated

•

331.0 alzheimer's disease

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

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

Introduction

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

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PART I: THE ESSENTIALS

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

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

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

5

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

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

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

•

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

•

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

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

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

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

Guidelines 11

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

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

12 Alzheimer’s Disease

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

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

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

•

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

•

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

•

Brain scans.

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

Guidelines 13

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

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

14 Alzheimer’s Disease

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

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

Guidelines 15

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

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

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

•

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

•

Discover, develop, and test new treatments

•

Discover treatments for behavioral problems in patients with AD

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

16 Alzheimer’s Disease

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

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

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

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

Guidelines 17

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

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

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

•

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

18 Alzheimer’s Disease

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

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

•

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

•

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

•

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

Guidelines 19

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

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

•

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

20 Alzheimer’s Disease

•

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

•

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

•

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

Guidelines 21

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

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

22 Alzheimer’s Disease

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

Guidelines 23

•

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

•

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

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

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

24 Alzheimer’s Disease

•

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

•

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

•

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

Guidelines 25

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

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

•

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

26 Alzheimer’s Disease

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

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

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

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

•

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

Guidelines 27

•

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

•

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

•

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

•

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

28 Alzheimer’s Disease

•

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

•

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

•

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

•

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

Guidelines 29

•

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

•

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

•

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

•

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

30 Alzheimer’s Disease

•

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

•

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

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

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

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

Guidelines 31

•

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

•

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/

•

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

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

33

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

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

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

34 Alzheimer’s Disease

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

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

•

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

Seeking Guidance 35

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

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

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

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

36 Alzheimer’s Disease

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

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

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

Seeking Guidance 37

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

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

•

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

•

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

•

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

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

Check with the associations listed earlier in this chapter.

•

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

•

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

•

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

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

38 Alzheimer’s Disease

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

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

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

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

•

Really listen to my questions?

•

Answer in terms I understood?

•

Show respect for me?

•

Ask me questions?

•

Make me feel comfortable?

•

Address the health problem(s) I came with?

12 This

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

Seeking Guidance 39

•

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

•

Spend enough time with me?

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

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

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

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

13

40 Alzheimer’s Disease

•

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

•

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

•

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

•

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

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

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

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

•

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

•

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

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

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

14

Seeking Guidance 41

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

43

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

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

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

15

44 Alzheimer’s Disease

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

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

•

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

•

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

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

Clinical Trials 45

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

46 Alzheimer’s Disease

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

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

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

16

These are listed at www.ClinicalTrials.gov.

Clinical Trials 47

•

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

•

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

•

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

48 Alzheimer’s Disease

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

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

•

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

Clinical Trials 49

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

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

•

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

50 Alzheimer’s Disease

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

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

•

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

Clinical Trials 51

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

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

•

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

52 Alzheimer’s Disease

•

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

•

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

•

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

Clinical Trials 53

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

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

•

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

•

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

54 Alzheimer’s Disease

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

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

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•

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

•

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

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

56 Alzheimer’s Disease

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

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

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

Clinical Trials 57

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

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

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

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

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

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

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

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

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

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

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

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

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

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

&

Johnson

Pharmaceutical

Research

and

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

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

62 Alzheimer’s Disease

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

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

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•

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

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

64 Alzheimer’s Disease

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

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

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

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

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

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

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

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

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•

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

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

•

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

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

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

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

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

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

•

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

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Know what is expected of you.

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Know any costs involved for you or your insurance provider.

•

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

•

Talk openly with doctors and ask any questions.

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

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

•

Receive any new information about the new treatment.

•

Continue to ask questions and get answers.

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

•

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

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

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

What is the purpose of the clinical trial?

•

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

•

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

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

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

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

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How will my health be monitored?

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

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

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

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

•

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

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

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

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

•

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

•

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

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

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

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•

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

•

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

•

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

•

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

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

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

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PART II: ADDITIONAL RESOURCES AND ADVANCED MATERIAL

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Project Title: A MULTIDIMENSIONAL ALZHEIMER'S DISEASE BRAIN ATLAS Principal Investigator & Institution: Toga, Arthur W.; Professor; None; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 01-MAY-1995; Project End 31-JUL2006 Summary: This competitive renewal application has an overall goal, the creation of an atlas of Alzheimer’s disease. The neuroscience and informatics efforts proposed here will result in a tool set and product that is applicable not only to the basic and clinical science of Alzheimer's disease, but to the general problem of mapping the structure and function of any dynamic process in health or disease in whole populations of subjects. Leveraging the accomplishments achieved during the last period of this project and building upon our highresolution post mortem anatomic framework, the development of atlas construction methodology and the ability to create 3D visual models of anatomy, we will construct the first multimodality probabilistic atlas of the brain representing a diseased population. Including both histologically processed post mortem tissue as well as 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Project Title: ALZHEIMRE'S NEUROPROTECTIVE TMT

DISEASE

ANTIAMYLOID

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Elizabeth;;

Rush-

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

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

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

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

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

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

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

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

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

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

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

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Project Title: DEMENTIA OF CLINICOPATHOLOGIC PHENOTYPE

PARKINSON

TYPE:

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

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

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

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

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

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

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

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

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

Project Title: ENVIRONMENTAL ALZHEIMER'S DISEASE

CAUSES

OF

SPORADIC

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

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

Project Title: EPIDEMIOLOGY, PARKINSONISM IN AGING

PATHOLOGY,

AND

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

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

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

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

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

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

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

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

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Project Title: GENOMIC SCREEN TO IDENTIFY ALZHEIMERS DISEASE GENES Principal Investigator & Institution: Pericak-Vance, Margaret A.; Professor; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2001; Project Start 20-FEB-1997; Project End 31-JAN2003 Summary: This proposal is a continuation of our grant to delineate the genetics of Alzheimer disease [AD], the most common form of dementia after age 40. Within the past five years, four AD genes have been described. APP, PS-I and II are autosomal dominant causative loci in early (<60) familial AD but represent <2% of all AD cases. The vast majority of cases are late- onset familial or sporadic AD. Through the present grant, the laboratories of Drs. Pericak-Vance and Haines were the first to describe the increased risk related to the APOE-4 allele and the protective effect of the APOE-2 allele. By all estimations, APOE accounts for approximately 50% of the total predicted genetic effect and is the single most important biological risk factor yet identified in AD. Although this finding has dramatically changed the focus of AD research, another 50% of genetic etiology of AD remains unexplained. In addition to delineating the APOE effect, we have completed a genome screen using our initial set of extended late-onset pedigrees and have identified several regions deserving more scrutiny. We have now expanded our data set from 52 to 200+ multiplex late-onset AD families (250+ sampled affected sibpairs) and have 500+ sporadic AD patients and 300+ spouse controls. We also have identified the genetically isolated Indiana Amish population who, despite having a lower prevalence of AD and a decreased frequency of APOE-4, maintain familial aggregation. The above resources permit a more detailed and sophisticated genome screening and analyses to identify all major and moderate genetic effects in AD, something not possible even three years ago. We will use newly described sibpair and affected- relative-pair analyses in conjunction with lod score analysis to make greatest use of the screening data. We will also examine gene/gene interactions between the regions we (or others) conform as harboring AD genes. The ultimate goal of our proposal is the identification of all major loci involved in AD, the first step in combating this devastating neurodegenerative disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENOMIC ALZHEIMER DISEASE

SEARCH

FOR

SUSCEPTIBILITY--

Principal Investigator & Institution: Goate, Alison M.; Professor; Psychiatry; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 01-APR-1999; Project End 31-MAR2003 Summary: Studying the genetics of Alzheimer's Disease (AD) has added significantly to our understanding of the disease. During the last six years it has been established that familial early onset Alzheimer's disease (FAD) is a genetically heterogenous disease that can be caused by mutations in at least three different genes: the beta-amyloid protein precursor (APP) gene on chromosome 21, the presenilin 1 (PS-1) gene on chromosome 14 and the presenilin 2 (PS-2) gene on chromosome 1 (1-3). Since other families exist that do not carry mutations within any of these genes it is very likely that there are other as yet unidentified FAD genes. In vitro experiments suggest that mutations in each of the known genes cause AD through changes in APP processing that lead to elevated levels of total Abeta or specifically increase Abeta42 (4). This provides strong support for the "Amyloid Hypothesis" of AD pathogenesis. The study of the genetics of late onset AD has also led to the identification of the first genetic risk factor for AD. The epsilon 4 allele of the apolipoprotein E (ApoE) gene has been shown to increase risk for AD in every population studied although the magnitude of the increase in risk varies between populations. Although it is still uncertain how the ApoE4 allele increases risk for AD there is some evidence to support the hypothesis that ApoE4 modifies amyloid deposition by an unknown mechanism. However, since there are many individuals with AD who have no ApoE4 alleles there must be other risk factors for late onset AD. We hypothesize that at least some of these risk factors are genetic and that they may also modify amyloid deposition. The aim of this proposal is to use a genetic linkage strategy to identify new genetic risk factors for late onset AD. As our test sample we will use three hundred caucasian sib pairs with an age of onset of AD over the age of sixty five years to perform a 20cM genomewide screen using microsatellite markers. Genomic regions showing evidence of linkage will be followed up with flanking markers in the same sample and in a second sample of equivalent size also selected on the basis of racial origin and age of onset. It is anticipated that by restricting the racial origin and age of onset of our initial samples we will reduce the likely genetic heterogeneity and increase our chances of detecting a second risk factor. Candidate genes in genomic regions that continue to show evidence of linkage will then be followed up using a

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case control association approach in caucasians and in other ethnic groups. Finally, we will complete a 20cM genome screen in the replication sample increasing the effective sample size to 600 sib pairs, enabling us to look for genes of smaller effect size. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GLIAL CYTOKINES AND NEURONAL DEATH Principal Investigator & Institution: Van Eldik, Linda J.; Professor; Northwestern University Office of Sponsored Programs Chicago, Il 60611 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR2008 Summary: This Project will examine the link between selected glial neuroinflammatory responses and neuronal cell death. The hypothesis to be tested is: Overproduction or sustained production of potentially detrimental biomolecules (NO and pro-inflammatory cytokines) by activated glia contribute to neuronal death. Insight into which of these pathways can be readily modulated by endogenous factors or synthetic ligands will provide a firm foundation for future drug discovery efforts towards developing new therapeutics for Alzheimer's Disease (AD). We will address several fundamental questions about glial cytokine production and its linkage to neuronal cell death. These include: what glial cytokines contribute to neuronal death and what pathways are potential targets for inhibition of cytokine-dependent neuronal cell death? The focus will be on: (i) beta-amyloid (Abeta)-induced upregulation of inducible nitric oxide synthase (iNOS), and its potentially neurotoxic product, nitric oxide (NO) and NO metabolites such as peroxynitrite; (ii) the Abeta-induced increases in proinflammatory cytokines interleukin (IL)-1beta, tumor necrosis factor (TNF)alpha, and S 100B; (iii) comparison of the neurotoxic effects of these glial derived products to those of direct Abeta effects on neurons; and (iv) discovery of ligand modulators of signaling pathways key to neuronal cell death. In aim 1, we will define at the molecular level what is meant by glial cytokine-dependent neuronal cell death. Glial/neuronal co-culture models, in vivo administration of cytokines, and animal models of neuroinflammation and disease will be utilized. We will determine the potential common and distinct elements between cytokine-dependent and -independent neuronal death by focusing on key elements of standard themes that have been implicated previously in cell death mechanisms, particularly MAP kinase (MAPK)-regulated pathways and death domain signaling pathways involving death receptors like TNF receptorl (TNFR1) and death kinases like death associated protein kinase (DAPK). In aim 2, we will discover ligand modulators of cytokine-

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dependent neuronal cell death. Chemical genomics approaches will allow the discovery of small molecule modulators of neuronal cell death and death kinases. Pathway selective inhibitors will allow probing of the relative contribution of distinct signaling pathways to common biological end points. Potentially efficacious synthetic compounds will be tested in animal models of neuroinflammation and disease. Our results will have a potential broad impact on basic restarch in areas such as signal transduction and glialneuronal interactions as well as provide insight into possible new therapeutic approaches to neurodegenerative disorders such as Alzheimer’s disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GLIAL NEURONAL INTERACTION IN ALZHEIMERS DISEASE Principal Investigator & Institution: Griffin, W S.;; University of Arkansas Med Scis Ltl Rock 4301 W Markham St Little Rock, Ar 72205 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 31-MAY2002 Summary: The objective of Project 1 is to address the idea that glial inflammatory changes with over-expression of glia-derived cytokines, in particular interleukin-1 (IL-1) and S100beta, are primer movers in a cascade of events that lead to neuronal cell injury and death in the early pathogenesis of Alzheimer's disease (AD). These cytokine-driven cascades of neuronal dysfunctions include early over-expression of betaAPP, accumulation of neurofibrillary tangles, overgrowth of betaAPP- over-expressing neurites, appearance of neuropil threads, and eventually cell death. Chronic activation of these cytokine-drive neurodegenerative cascades can in turn promote further over-expression of IL-1. In this way these cytokine-driven cascades may become selfpropagating as illustrated in the "cytokine cycle". To elucidate aspects of this cycle, we will use molecular techniques to: 1) Define the relationship of glial inflammation to neuronal cell injury (as evidenced by betaAPP over- expression and neurofibrillary tangle formation in neurons, neurites and in neuropil threads, as well as by synaptic changes) and neuronal cell death (as evidenced by TUNEL positivity) in Alzheimer’s disease. These will be correlated with the incidence of: i) associated activated microglial over-expression IL-i); ii) associated activated microglia over-expressing IL-1; ii) associated activated astrocytes overexpressing S100beta; iii) associated beta-amyloid plaques of different types; and iv) stages of neurofibrillary tangle formation. 2) Define the temporal and spatial relationships of glial inflammation to neuronal cell injury and death in conditions predisposing to Alzheimer's disease or to

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accelerated Alzheimer-type senile changes. For this we will use material from patients with Braak and Braak stages of I-IV of Alzheimer- related changes, with Down's syndrome, with head injury, and with epilepsy. 3) Examine the extent and nature of altered glial cytokine expression and of neuronal cell injury and death in genetic animal models with altered expression of cytokine cycle elements. These include betaAPP transgenic mice and S100beta transgenic mice. 4) Assess the local and remote effects of exogenous glial cytokines in vivo, using intracerebral implants of timed-release pellets containing specific glial cytokines and other cytokine cycle molecules. Successful completion of these specific aims will provide information regarding the progression of neuropathological changes and highlight targets for therapeutic strategies to slow the clinical progression of Alzheimer’s disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GSK3BETA: SIGNALING AND APOPTOSIS Principal Investigator & Institution: Jope, Richard S.; Psychiatry; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-AUG2008 Summary: (provided by applicant): Glycogen synthase kinase-3beta (GSK3b) is linked to most key aspects of Alzheimer’s disease. These include: GSK3b phosphorylates tau and amyloid precursor protein, Abeta peptide activates GSK3b and inhibition of GSK3b protects from Abtoxicity, and presenilin-1 binds and regulates the activity of GSK3b, actions altered by mutant presenilin-l. Also, GSK3b impairs neural plasticity, facilitates apoptotic signaling cascades, and inhibits the activities of multiple transcription factors (CREB, AP-1, NFkB, myc, bcatenin, and others), all actions likely important in Alzheimer’s disease. These actions and associations indicate that GSK3b may be an important modulator of neuropathological processes associated with Alzheimer's disease as well as other neurodegenerative conditions, but much remains to be learned about the actions of GSK3b. The overall goal of this project is to investigate mechanisms regulating GSK3b and to delineate its effects on cell function, especially neural plasticity and apoptosis. The aims are based on our findings that (i) thapsigargin, which increases intracellular calcium levels and causes endoplasmic reticulum (ER)-stress, conditions associated with Alzheimer's disease, activates GSK3b, and GSK3b is obligatory for thapsigargin-induced apoptosis, (ii) apoptotic stimuli cause intranuclear accumulation of GSK3b, and (iii) GSK3b inhibits the function of the key transcription factor CREB. Specific Aim 1 will test the hypothesis that GSK3b is activated by, and is a critical mediator of,

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toxicity induced by thapsigargin and other agents perturbing calcium or the ER, and will identify the mechanisms involved in GSK3b activation and assess the regulatory roles of GSK3b-binding proteins. Specific Aim 2 will test the hypothesis that apoptotic stimuli induce nuclear accumulation of GSK3b, identify the mechanisms controlling the intranuclear distribution of GSK3b, and test if nuclear GSK3b contributes to apoptotic signaling. Specific Aim 3 will test the hypothesis that GSK3b has dual functions in apoptosis, both attenuating antiapoptotic signals, with a focus on survival-promoting transcription factors, and facilitating proapoptotic signals connecting ER stress to caspase activation. Overall, these experiments will clarify mechanisms regulating GSK3b and its effects on neural plasticity and survival. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IL-1 INDUCED INFLAMMATION AND AD-- COX-

MEDIATORS

OF

CNS

Principal Investigator & Institution: O'banion, Michael Kerry.; Associate Professor; Neurology; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2001; Project Start 28-APR-2000; Project End 31-MAR2003 Summary: (adapted from applicant's abstract): Inflammation-related changes are a prominent part of the CNS response to acute injury, infection, and chronic neurodegenerative disease. Numerous studies indicate that attenuation of CNS inflammation may be beneficial in treating CNS disorders, including Alzheimer's disease (AD). Microglia and astrocytes play a significant role in the initiation and maintenance of CNS inflammation by producing a wide-range of inflammation-related gene products. Elaboration of inflammatory responses elicited by both acute and chronic stimuli depends on key molecular players that drive interactions among cells. One of these players is IL-1 beta proinflammatory cytokine strongly implicated in acute CNS inflammation as well as AD. Based on studies of peripheral inflammation, another key player is likely to be prostaglandin E2 (PGE2) produced by the inflammation-responsive protein, cyclooxygenase-2 (COX-2), one of two isoforms of the obligate enzyme for prostaglandin biosynthesis. COX-2 is made in brain and can be induced by IL-1 beta and other proinflammatory cytokines in astrocytes and microglia. Moreover, preliminary studies indicate that selective inhibition of COX-2 attenuates the expression of inflammation-related genes following acute CNS injury. Based on these findings and epidemiological evidence that inhibitors of cyclooxygenase may be beneficial in AD, this competitive

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renewal focuses on the role of COX-2 in CNS inflammation. The hypothesis that COX-2 derived prostaglandins are required for elaboration of acute as well as chronic local inflammatory responses in the central nervous system will be tested in three different model systems. The first specific aim will characterize direct influences of COX-2 and PGE2 on expression of IL-1 beta responsive genes in primary cultures of human and murine astrocytes. In the second specific aim, the contributions of COX-2 and PGE2 to an acute inflammatory cascade elicited by cortical injection of IL-1 beta will be established. In the third and fmal specific aim, COX-2 specific inhibitors will be employed in double transgenic PS-1/APP mice to ascertain the role of COX-2 in chronic CNS inflammation secondary to Abeta deposition. Together, these studies examine the role of COX-2 and increased prostaglandin production in CNS inflammation and a model of Alzheimer’s disease. This work will provide a clearer understanding of the mechanisms by which anti-inflammatory drugs influence AD and may reveal new avenues for therapeutic intervention. Moreover, these studies have relevance to pathological processes occurring in head trauma, stroke, and other neurodegenerative diseases where gliosis and inflammation-related changes take place. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNOTHERAPY OF ALZHEIMER'S DISEASE Principal Investigator & Institution: Raso, Victor A.; Senior Scientist; Boston Biotechnology Corporation Watertown, Ma 02472 Timing: Fiscal Year 2001; Project Start 15-APR-1998; Project End 31-DEC2003 Summary: The beta-amyloid peptide and the cerebral plaques that it forms are likely either the direct or indirect cause of Alzheimer’s disease. This peptide is produced in both the brain and peripheral tissues by cleavage from a common cell-surface precursor protein. Soluble betaamyloid exists free in the blood and cerebrospinal fluid while "insoluble" aggregates are deposited in the brain as amyloid plaques. The soluble and insoluble forms of beta-amyloid present within Alzheimer's patients appear to be in dynamic equilibrium. In the Phase I proposal we described how to displace this equilibrium away from the brain by generating peptide-specific antibodies in a transgenic mouse model of Alzheimer’s disease. Recent studies have shown that, as we predicted, this beta-amyloid vaccine approach can prevent plaque formation in young mice and dissipate preestablished plaques in older mice. Those preclinical experiments used complete Freund's adjuvant to help elicit an immune response but such preparations are not approved for use in

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humans. Therefore Phase II will focus on producing and testing in animals several alternative adjuvant and antigen formulations which are compatible with clinical standards. Our expressly designed beta-amyloid antigens and adjuvants would form a basis for the immunotherapy of Alzheimer's disease using highly specific beta-amyloid vaccines. PROPOSED COMMERCIAL APPLICATIONS: The high-potency, human-compatible vaccines produced in this Phase II project have tremendous potential for use in either treating or preventing Alzheimer’s disease. If successful the vaccine approach could help the large number of patients who are already suffering from the disease. It might also be used to prevent or delay the onset of disease in those who are at high risk. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IN VITRO IN VIVO MODELS OF ALZHEIMER'S DISEASE Principal Investigator & Institution: Lee, Virginia M.; Professor; Pathology and Lab Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 01-SEP-1997; Project End 31-AUG2008 Summary: (provided by applicant): The competing renewal of this Program Project grant (PPG) builds on important research conducted during the last 10 years in the development of in vitro and in vivo models of Alzheimer's Disease (AD) amyloidosis for the purpose of elucidating mechanisms leading to the regulation of amyloid beta (Abeta) pathogenesis. These studies are sharply focused on addressing a novel hypothesis that emerged from studies conducted in the previous funding cycle of this PPG to account for the neurotoxicity of Abeta. A "two hit" hypothesis is proposed which states that the "first hit" (i.e., elevation of full length Abeta) is necessary but not sufficient to induce neurodegeneration, and that a "second hit" (i.e. genetic and epigenetic factors) is required to render neurons susceptible to the toxic effects of Abeta. In addition to being plausible and compatible with our own preliminary data and the published literature on the biological effects of Abeta in vitro and in vivo, this hypothesis can be rigorously tested by accomplishing the goals of Projects 1-4 in this PPG application where socalled "second hit" events that augment Abeta toxicity could be oxidative stress, lipid peroxidation, traumatic brain injury, the involvement of other Abeta fragments in senile plaque formation, neurofibrillary tangles, Lewy bodies or other processes identified to occur in the AD brain. To test this hypothesis, the investigators use complementary research

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strategies to pursue four separate projects: 1) Cell Biology of Abeta Production (RW Doms); 2) Novel Abeta Fragments as Mediators of Alzheimer's Disease (V. M.-Y. Lee); 3) Lipid peroxidation and Alzheimer's disease phenotypes (D. Pratico); and 4) Traumatic Brain Injury and Alzheimer's Disease (J. Q. Trojanowski). With the support of the Administrative and Neuroscience Cores, the investigators will use a multi-disciplinary approach to work synergistically to advance understanding of mechanisms of Abeta-mediated neuron degeneration in AD at the molecular, cellular and in vivo levels. It is anticipated that information derived from this research could provide a rationale for the development of novel therapeutic interventions for AD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INFLUENCE OF APOLIPOPROTEIN E2 & E4 ON DVPMT OF HALLMARKS OF ALZHEIMER'S DISEASE Principal Investigator & Institution: Martinez, Andrew O.; Professor; University of Texas San Antonio San Antonio, Tx 78249 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL2006 Summary: Transgenic mouse models for Alzheimer's disease (AD) offer the best hope for understanding and developing effective means of treating this dreadful disease. A number of laboratories, including ours, are working to develop useful models for this polygenic disease. Familial AD is often associated with mutations in the amyloid precursor protein (APP); one of the mutations is found in a Swedish population (APPSWED). Several groups have developed transgenic mice carrying the APPSWED gene but to date the most successful model is one developed by Hsaio/Ashe et al. (1995) called Tg2576. The proposed work is to cross the Tg2576 mice with mice generated in our laboratory that carry two common alleles for human apolipoprotein E (APOE), APOE-2 and APOE-4. APOE-4 is a risk factor for AD, and APOE-2 is reported to be beneficial in somehow retarding the development of AD. The ultimate goal is to obtain two mouse lines that each carry three transgenes; one carrying APOE-4, APPSWED, and mouse APOE-knockout (E-KO); the other carrying APOE-2, APPSWED, and E-KO. In addition, we also plan to similarly use a new APPSWED transgenic line recently developed in our laboratory to cross with APOE-2 and APOE-4 mouse lines. The new APPSWED line may be needed to elucidate any defects that may be due to mouse background strain. Once the proper crosses are obtained, the mice will be tested for (1) memory deficits and the age at which any deficits occur, (2) presence in brain of amyloidosis and content of bamyloid peptide which is derived from APP and strongly implicated in

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the pathogenesis of AD, and (3) the presence of cerebral angiopathy which is found in AD. After demonstration of neuropathology in the mice, the effects of both diet restriction and high cholesterol diets will be tested to determine if the course of the pathology can be altered. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN, ALZHEIMER'S DISEASE

COGNITIVE

IMPAIRMENT

AND

Principal Investigator & Institution: Qiu, Wei Q.;; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG2008 Summary: (provided by applicant): Despite the fact that there are multiple etiologies of Alzheimer's disease (AD), all AD cases share the neuropathological hallmark of amyloid-Beta peptide (Abeta) plaques and neurofibrillary tangles in brain, indicating a possible common pathway of AD pathogenesis. Apolipoprotein E4 (ApoE4) has been identified as a major risk factor of late-onset AD, but approximately 50% of cases do not carry the ApoE4 allele. Interestingly, hyperinsulinaemia is found to be associated with AD cases in the absence of ApoE 4 influence. 37% of AD subjects suffer from impaired glucose tolerance, presumably also having elevated plasma insulin, compared to 19.9% of non-AD subjects in the same population. The major hypothesis of the proposed study is that hyperinsulinaemia is another risk factor of late-onset AD in the absence of ApoE4. Insulin and AB, the major component in AD pathology, share biochemical features. Both are short peptides with amyloidogenic properties, and both are degraded by a common protease, insulindegrading enzyme (IDE). To explore the mechanism of how hyperinsulinaemia might contribute to AD, our secondary hypothesis is that in hyperinsulinaemia insulin competes with AB for IDE, increasing the amount AB and thus causing AD pathology. To translate the candidate's basic research on IDE and ABeta into clinical research on AD, this proposal presents a multi-faceted and collaborative study. By collaborating in a project that will recruit 1600 homebound elderly in Boston, subjects will be available to evaluate the relationship between insulin levels with cognitive impairment and AD. Subjects who do not carry ApoE4 and have not received insulin treatment will meet study criteria. Quantitative correlation will be evaluated between fasting plasma insulin level and cognitive impairment in the absence of ApoE4. Clinical examination and MRI scans will be performed on a subset of 473 subjects to evaluate the association of hyperinsulinaemia in AD vs. nonAD subjects. Hyperinsulinaemia is present in some but not all cases of

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type 2 diabetes. Because hyperinsulinaemia rather than type 2 diabetes alone may be the relevant risk factor of AD, the association of AD with hyperinsulinaemia vs. type 2 diabetes will also be analyzed. We will determine whether levels of insulin and cognitive function are correlated with Aa levels and IDE activity. Results from this study should provide a rationale to determine if elevated insulin increases the incidence of AD in a prospective study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LEADERSHIP AWARD FOR ALZHEIMER'S DISEASE RESEARCH Principal Investigator & Institution: Mirra, Suzanne S.; Professor and Chair; Pathology; Suny Downstate Medical Center 450 Clarkson Ave New York, Ny 11203 Timing: Fiscal Year 2001; Project Start 01-FEB-2000; Project End 31-JAN2005 Summary: The overall goal of this Academic Career Leadership Award is to develop an outstanding research and educational program on Alzheimer's disease (AD) and other neurodegenerative disorders at the State University of New York, Health Science Center at Brooklyn (Downstate). We plan to build upon the existing strengths at Downstate and the unique demographics of its surrounding community. These include the neuroscience program with its emphasis on hippocampal pathophysiology, the large population of Caribbean American, African American, and other minority groups in Brooklyn, and the special interests of the PI, including the overlap and heterogeneity of AD, Parkinson's disease and other neurodegenerative disorders. Our specific aims are to (1) establish an infrastructure to support the development of an institutional research center on AD and related neurodegenerative disorders; (2) develop mechanisms that will bring new investigators to the field, enable established investigators to channel their expertise towards the field, encourage collaborations, and support pilot studies; (3) stimulate interest and collaborations in AD-related research within the scientific community through educational programs and related experiences; and (4) promote awareness of AD in the lay and professional community through outreach and educational programs. The candidate, Dr. Suzanne Mirra, is well qualified to lead this initiative. An experienced and respected neuropathologist working on AD and other neurodegenerative disorders, Dr. Mirra was the director and principal investigator of the Alzheimer's Disease Center at her former institution. She led the neuropathology arm of CERAD (Consortium to Establish a Registry for AD), the NIA longitudinal study, in standardizing the

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neuropathological evaluation of AD. A nationally recognized leader in neuropathology, she is Founding Chair of the Neuropathology Committee of the College of American Pathologists and President-Elect of the American Association of Neuropathologists. Dr. Mirra has forged strong ties in the lay community, such as her involvement with the national board and regional chapters of the Alzheimer's Association. Moreover, she is an outstanding communicator as well as a committed and innovative educator with a demonstrated track record of outreach to non-white minorities. This Academic Career Leadership Award, along with strong institutional commitment, will enable Dr. Mirra and collaborators to build a thriving research program on Alzheimer's disease and related neurodegenerative disorders at Downstate. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF NEUROTROPHIN-IMPROVED COGNITION IN AGING Principal Investigator & Institution: Granholm, Ann-Charlotte E.; Associate Professor; Physiology and Neuroscience; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2003; Project Start 29-SEP-1991; Project End 31-AUG2008 Summary: (provided by applicant): Aging and Alzheimer's disease are correlated with a progressive loss of cognitive function. Even though a significant increase in resources and research emphasis have been spent on investigating memory loss, it is still not known which biological events in the brain that lead to age-related cognitive impairment. Studies have demonstrated that altered function of the neurotrophic factors nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) may lead to age-related cognitive impairment. Likewise, many investigators believe that faulty processing of the amyloid precursor protein (APP), leading to production of the deadly beta-amyloid, is the culprit in agerelated neuronal loss and cognitive dysfunction, especially in Alzheimer’s disease. Amyloid is formed by gamma-secretase mediated cleavage of the APP pre-protein. In the past grant period we investigated effects of NGF upon cholinergic neurotransmission during aging. We would like to continue this work, and expand our focus to include BDNF, since this growth factor has been shown to be involved in memory. We propose a hypothesis that NGF and BDNF play important roles in neurotransmission in the hippocampus. In addition, we postulate that this neurotrophic influence is altered by APP and/or amyloid processing during aging, leading to lost neurotrophic function and, eventually, memory loss. In order to investigate this hypothesis we propose the

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following specific aims: 1. To determine if release, uptake, or retrograde transport of BDNF and/or NGF are altered in aged animals. 2. To determine if amyloid synthesis and/or gamma-secretase activity is altered in aged rodents, and if so: if this is correlated with age-related memory impairment or neurotrophic loss. The overall goal is to determine if NGF and BDNF activity is altered during aging because of altered release, uptake, or transport, and also to determine if this altered neurotrophic activity is related to alterations in amyloid-enzyme activities. We hope that these findings will ultimately lead to better treatment paradigms for patients with neurodegenerative diseases, in particular Alzheimer's disease, and provide a more mechanistic base for knowledge regarding this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MICHIGAN ALZHEIMERS DISEASE RESEARCH CENTER Principal Investigator & Institution: Gilman, Sid; Director, Michigan Alzheimer's Disease c; Neurology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2001; Project Start 29-SEP-1989; Project End 31-MAY2004 Summary: In this application for continuation of the MADRC, we propose to initiate new projects and extend two ongoing projects and maintain research cores. All projects involve investigations of Alzheimer's disease (AD) and AD mimics. The proposed projects include positron emission tomography (PET) studies of glucose metabolism and monoaminergic pathways in AD and dementia with Lewy disease (DLB); presynaptic neurochemical markers in AD, Parkinson's disease, and DLB; strategies for inhibition of Abeta protein aggregation; protein-protein interactions in amyloid precursor protein processing; and telephone counseling intervention to promote caregiver self-care behavior. Pilot projects are included in the proposal to stimulate innovative research in AD. The proposed Clinical, Neuropathology, Education and Information Transfer, and Biostatistics Cores will support these and a large number of other continuing and externally funded AD projects. Two successful satellite diagnostic and treatment centers in Detroit and Norther Michigan will continued to recruit under-represented urban, predominantly African American, and rural-resident patients to research studies The scientific approaches utilize major strengths in neurology and neuroscience at the longitudinal studies with autopsy verification, biostatistics, PET, molecular biology, molecular pharmacology, and survey research. The MADRC interacts with multiple components of the

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University to achieve its scientific and educational objectives, particularly the Schools of Medicine, Public Health, and Nursing, the Pepper Older Americans Independence Center, the Institute of Gerontology, the Geriatrics Center, and the Geriatric Research Education and Clinical Center at the Ann Arbor Veterans Medical Center. It collaborates with other ADCs on research projects and in datasharing. It plays a leadership role in statewide dementia initiatives and works closely with Michigan chapters of the Alzheimer Association. The scientific program proposed involves interdisciplinary collaboration of scientists and educators with many backgrounds and a strong training environment for predoctoral and postdoctoral students, medical students, and visiting scholars. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MICROGLIAL ALZHEIMER'S DISEASE

SIGNALING

MECHANISMS

IN

Principal Investigator & Institution: Landreth, Gary E.; Professor; Neurology; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2001; Project Start 01-MAR-2000; Project End 31-JAN2005 Summary: (adapted from applicant's abstract) Alzheimer's Disease (AD) is characterized by the extracellular deposition of compacted fibrillar forms of B-amyloid (AB) protein within the brain. These senile plaques are the focus of a complex cellular reaction, the most prominent which is the presence of abundant reactive microglial cells that are found adjacent to and invest in the senile plaques. Microglia are derived from a monocytic lineage and are the sole immune cell in the brain. Microglial activation is accompanied by enhanced expression of numerous cell surface proteins an elaboration of a complex array of proinflammatory and acute phase products. There is compelling evidence that there is a significant inflammatory component in Alzheimer's disease as evidenced by a diverse range of clinical studies which have shown that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) substantially reduces the incidence of AD-related dementia delays disease progression. The central hypothesis guiding these studies is that microglia can detect and respond to fibrillar forms of amyloid by activation of intracellular signaling pathways which subserve the "activation" of the cells and the consequent secretion of proinflammatory products. The Specific Aims of this proposal are: 1. The characterization of membrane proteins that interact with AB fibrils and serve as primary signal transducing elements linked to intracellular signaling pathways. We demonstrate that the Bclass scavenger receptor, CD36, and an integrin mediate the adhesion of

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monocytes to AB fibrils and activation of tyrosine kinase based signaling cascades. We propose to identify the relevant integrin and ascertain how these cell surface molecules are linked to intracellular signal transduction complexes. 2. Identification of the signal transduction pathways activated in response to AB which subserve the production of proinflammatory products and the acquisition of an activated phenotype by the microglia. Specifically, we will investigate signaling pathways that mediate the activation of the transcription factors NFkB and the peroxisome proliferation activated receptor, PPARy. We will also investigate ABinducted expression of cyclooxygenase-2. 3. We propose to employ an animal model of Alzheimer's disease to the effects of anti-inflammatory drugs on microglial activation. Transgenic mice expressing mutant forms of both the amyloid precursor gene and the presenelin 1 gene develop amyloid plaques and exhibit dramatic activation of plaque-associated microglia. We will test the efficacy of the classical NSAID, indomethacin, as well a PPARy agonists and a COX-2 specific inhibitor in blocking the acquisition of a reactive phenotype by microglial cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MODELS OF ALZHEIMER'S DISEASE Principal Investigator & Institution: Andreasson, Katrin I.; Neurology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 01-AUG-2000; Project End 31-JUL2003 Summary: adapted from applicant's abstract): Alzheimer's disease is a neurodegenerative disorder affecting the elderly and accounts for two thirds of all dementia. Recent epidemiological studies suggest that the use of non-steroidal anti-inflammatory agents is associated with a significantly lower risk of developing Alzheimer’s disease. The primary targets of NSAIDs are the prostaglandin synthases, also known as cyclooxygenases. The cyclooxygenases catalyze the conversion of arachidonic acid to PGH2, which becomes the substrate for prostaglandin and thromboxane synthases. The conclusion raised by the recent epidemiological studies is that inhibition of cyclooxygenases activity is protective against development of Alzheimer’s disease. There are two isoforms of cyclooxygenase (cox). Cox-1 is expressed constitutively in most tissues and at very low levels in the brain. Cox-2 is expressed in neurons of hipppocampus, amygdala and layers II/III of cortex. From our previous studies of genes involved in the adaptive responses of neurons to synaptic activity, we have identified cox-2 as an N-methyl Daspartate (NMDA)-dependent activity-regulated gene in brain. Cox-2 is also highly expressed in neurons in paradigms of excitotoxicity, such as

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ischemia, trauma, and kindling. Because of its regulation by excitatory synaptic activity, and because of recent evidence implicating excitotoxic mechanisms in neurodegenerative diseases, we propose to study the role of cox-2 in the pathogenesis of Alzheimer’s disease. We have generated transgenic C57Bl6/J founder mice that express the human form of cox-2 driven by the neuronal specific thy-1. An initial line of transgenic hcox-2 mice demonstrates immunoreactive hcox-2 and an 8 to 12-fold increase in PGE2 synthesis. In Aim 1 we will complete our immunohistochemical and biochemical characterization of remaining lines generated from our founder mice and select 3-5 additional lines for further study. In Aim 2 we will examine the contribution of cox-2 activity to the pathogenesis of Alzheimer's disease by crossing hcox-2 mice to a murine model of familial Alzheimer's disease that overexpresses mutant APP and PS-1 and analyzing the pathological phenotype of resultant double and triple transgenic mice. In Aim 3, we will test the effect of a selective cox-2 inhibitor on the development of a pathological AD phenotype in single, bigenic and trigenic mice generated in Aims 1 and 2. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MODULATION OF ALZHEIMER'S AMYLOIDOSIS BY STATINS Principal Investigator & Institution: Petanceska, Suzana S.; Assistant Professor; Nathan S. Kline Institute for Psych Res Psychiatric Research Orangeburg, Ny 10962 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR2006 Summary: (provided by applicant): Cerebral accumulation of Amyloid beta (Abeta) peptides is an early event in establishing of Alzheimer's disease (AD) pathology. Based on the epidemiological evidence pointing to a link between cholesterol metabolism and AD and the numerous laboratory studies implicating cholesterol in the process of Abeta production and accumulation, it is now believed that cholesterollowering therapies will be of value as disease modifying agents. Several epidemiological studies revealed that statin use for the treatment of coronary arterial disease is associated with a decreased prevalence or a decreased risk of developing AD. The major objectives of this proposal are: to test the ability of different statins to delay the onset or retard the progression of brain Abeta deposition in the PSAPP transgenic mouse model of Alzheimer's amyloidosis, and to investigate the mechanisms by which statin treatment modulates brain Abeta accumulation. Our goal is to examine how the lipid-lowering as well as the antiinflammatory/immunomodulatory activities of statins contribute to their

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effect on brain Abeta accumulation. To this end we will employ in vivo experimental paradigms using the PSAPP transgenic mouse model of Alzheimer's amyloidosis, as well as in vitro experimental paradigms using microglial and neuronal cultures. In the first specific aim we will compare the relative efficacy with which statins with different BBB permeability attenuate early as well as advanced Abeta deposition. We will then examine how statin treatments modulate APP processing and ApoE expression in brain (specific aim 2). Finally, we will evaluate the effects of statins on the inflammatory response in brain in the context of different paradigms of microglial activation and we will test their ability to prevent or attenuate Abeta-induced microglial neurotoxicity (specific aim 3). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MRI BIOMARKERS OF RISK AND PROGRESSION IN ALZHEIMER'S Principal Investigator & Institution: Jack, Clifford R.; Professor of Radiology; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2003; Project Start 01-JUN-1993; Project End 31-JUL2008 Summary: (provided by applicant): The overall aims of this renewal application are to prove that magnetic resonance imaging and magnetic resonance spectroscopy (MRI/MRS) measurements can predict development of Alzheimer's Disease (AD), and that serial MRI/MRS measurements are valid biomarkers of AD disease progression. We will study three clearly distinguishable clinical groups: 1) cognitively normal elderly subjects, 2) patients with probable AD and 3) patients with a mild cognitive impairment (MCI). Patients and normals will be drawn from the Mayo Alzheimer's Disease patient registry (AGO6786) and Alzheimer's Disease Research Center (AG16574). We will employ five different MR measures: medial temporal lobe structural measures; 1H MRS; leukoaraiosis volume; whole brain and ventricular volume, and lobar volume measures. In addition to established imaging technology, we will use a very promising new method of image registration and subtraction, and a new method for non-linear deformation (warping) of structural MRI. The grant contains three specific aims. Aim 1- to test the hypothesis that MRI/MRS measurements at baseline can predict the development of AD in normals and MCIs. Specific Aim 2 - to test the hypothesis that rates of change in MRI/MRS measurements derived from serial imaging studies are valid biomarkers of AD disease progression in normals and MCIs. Specific Aim 3 - to test the hypothesis that MRI/MRS measures are associated with change in performance on formal tests of

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cognition in normals, MCIs, and subjects with AD; where the dependent variables are continuous measures of cognitive performance rather than clinical group transitions. Currently no absolute diagnostic marker exists for AD. In anticipation of the coming era of therapeutic prevention and treatment for AD, better methods are needed to identify the risk of developing the disease and to track progression of the disease. Results from this project will provide new information that address an area identified as high priority for research by both the National Institute on Aging and the FDA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROBIOLOGY OF ALZHEIMER'S DISEASE AND AGING Principal Investigator & Institution: Rosenberg, Roger N.; Professor; Neurology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2001; Project Start 01-MAY-1994; Project End 31MAR-2005 Summary: The Alzheimer's Disease Center (ADC) has as its long-range goal to continue to develop and expand its Clinical Core functions to evaluate and follow comprehensively, selected patients with memory loss, Alzheimer's Disease (AD), and other dementias, and similarly to longitudinally follow and evaluate control subjects and encode pertinent data in a central database. Patients will be assigned to appropriate followup and study protocols and a computerized tracking system to monitor and document progress will be employed. Minority recruitment has been emphasized to increase our number of patients who are AfricanAmerican, Hispanic, and Native-American. It is our plan to evaluate potential predisposing events to AD, clinical course and complications of AD, clinical course and complications of AD, quantify emotional/behavioral symptoms and quality of life, utilization of imaging studies in the diagnosis of AD, and obtain clinical pathologic correlations. It will be our intent to achieve an 80% follow-up rate for persons designated for long-term studies. Well-studied subjects, clinical data and body fluids will be supplied to investigators, and in particular ante- mortem and perimortem information to investigators using postmortem tissues from our controls and patients. Patients and control subjects will be evaluated with comprehensive neuropsychological testing, brain imaging, CSF and neuropathologic findings, in order to detect and assess preclinical and early AD. A Memory Disorders for Native Americans will be developed in Dallas to study their prevalence and clinical features of AD. The collaboration with the Alzheimer's Disease Clinical Studies Unit will continue. ADC patients and controls

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will be autopsied to provide an accurate diagnosis of AD or other basis of dementia. The Brain Bank will be expanded over the next five years from these autopsy studies and banked tissues will be made available to be utilized by investigators on our campus and at other ADC's. The Clinical Core will also supply information about the ante mortem state of control and AD patients for correlation with cellular and molecular analyses. Genotyping of AD autopsied cases for apolipoprotein E will be conducted as will ELISA assays for synaptophysin and tau proteins, and quantification of neocortical neuritic dystrophy in immunostained sections using image analysis. It is our intent as well to expand the isolation and banking of DNA from frozen and fixed autopsied tissue samples to facilitate ongoing and new studies of molecular alterations in AD and aging. The Statistics and Data Management Core will enter, store and analyze additional new patient data for comparative studies. The functionality of the existing centralized database will be enhanced with appropriate security over a central network to authorized ADC investigators at our institutions. The Education Core has extensive plans that have been developed over the past five years to extend knowledge about AD and specifically, availability of patient services to minority populations and also to primary health care providers. Educational videotapes and TV announcements will be developed both in English and Spanish. The Alzheimer's Researcher Newsletter will be published semi-annually and distributed to our 5000 subscribers in this five-state region. The number and scope of research projects will be increased during the next five years. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROGENOMICS OF ALZHEIMER'S DISEASE AND AGING Principal Investigator & Institution: Stephan, Dietrich A.; Assistant Professor; Translational Genomics Research Inst 400 N 5Th St, Ste 1600 Phoenix, Az 85004 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG2008 Summary: (provided by applicant): Alzheimer's disease (AD) affects a large proportion of the world's population and is primarily a disease of old age. There is little known about the early molecular pathogenesis of AD leading to the characteristic dementia. Increased knowledge of the etiologic processes leading to dementia would allow improved diagnostics and targeted therapeutics. This proposal is multifaceted and seeks to elucidate 1) what differentiates AD from normal aging processes and other dementias of old age, 2) why individuals with certain genetic

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backgrounds (ApoE4 alleles) are more likely to become affected (interindividual differences), 3) and what happens at the cellular and subcellular level in response to dementia-inducing stimuli (plaques and tangles)(intra-individual differences). Taken together the expression profiling data set generated on laser capture microdissected (LCM) cells from carefully stratified patient cohorts should provide unique insight into the AD phenotype. Specific hypotheses related to energy metabolism will be validated by multiple techniques (by immunohistochemistry on independent tissues and at the functional level using neuronal cell cultures and siRNAs). These results will be made available to the general public within 6 months of generation via the most established relational database for array data, the NINDS/NIMH array consortium repository. The applicants are uniquely qualified to perform a large-scale collaborative study of this type. Working closely in collaboration with 3 Alzheimer's Disease Centers (ADCs), the PIs will have access to tissue sections from the appropriate cohorts. The use of tissue sections (as opposed to large heterogeneous pieces of brain) and LCM as the starting reagents for the expression profiling will allow generation of high quality data while not depleting the banked national resource of brains. The PI is the Chairman of a National consortium of expression profiling facilities which generate extremely high quality data on large numbers of neurological phenotypes. Integration of this data set into that repository will increase the value of the AD data set exponentially because of the increased number of comparisons which can be generated using preexisting data. The group also has access to sophisticated validation technologies. In all, the partnership of leaders in the AD field, the national resources within the ADCs, and the genomics expertise at TGen should allow rapid progress in understanding the etiology of AD dementia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROPEPTIDES 2003 SYMPOSIUM: ALZHEIMER'S DISEASE Principal Investigator & Institution: Seroogy, Kim B.; Neurology; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2003; Project Start 15-JUN-2003; Project End 31-MAY2004 Summary: (provided by applicant): On behalf of the American Summer Neuropeptide Conference request is being made from the National Institute on Aging to partially sponsor the symposium titled "Alzheimer's Disease" to be held as part of NEUROPEPTIDES 2003, the 3rd Joint Meeting of the American Summer Neuropeptide Conference and the

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European Neuropeptide Club. This joint international meeting will be held in Montauk, New York, USA from June 8-12, 2003. The goal of the symposium is to bring together leaders in the field of peptides and aging disorders to discuss their latest findings on the roles of neuropeptides in Alzheimer’s disease. This symposium will provide important, state-ofthe-art research on the pathophysiology and biochemical basis of AIzheimer's disease in the context of neuropeptides. Topics will range from basic molecular mechanisms to potential neuroprotective and therapeutic applications of neuropeptides in neurodegenerative disorders, with an emphasis on Alzheimer’s disease. Specifically, we are requesting funds to help defray meeting expenses of several invited speakers in this symposium and of several graduate student and postdoctoral trainees who will participate in the conference and interact with established leaders in fields related to the mission of the National Institute on Aging. The total amount requested is $11,650. The American Summer Neuropeptide Conference, now in its thirteenth year, and its counterpart the European Neuropeptide Club. The conferences highlight major new advances in neuropeptide research and attract a good mixture of senior and junior participants from academia and industry from throughout the world. Active participation by graduate and postdoctoral trainees, as well as by women and minority scientists, is strongly encouraged. The format of the present joint conference involves morning, afternoon and evening symposia, poster sessions Club, also in its thirteenth year, have become the premier international meetings for neuropeptide research, an award ceremony and conference banquet, and special lectures by distinguished international scientists. This format, coupled with the informal setting, provides an ideal forum for the dissemination and exchange of current information and the development of new collaborations among the participants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEW INHIBITORS OF BETA-AMYLOID TOXICITY Principal Investigator & Institution: Murphy, Regina M.; Professor; Chemical Engineering; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2001; Project Start 10-APR-2000; Project End 31-MAR2004 Summary: (From the applicant's abstract): Alzheimer's disease is a devastating neurodegenerative disease that afflicts over 4 million people in the United States. Two defining pathological features of the disease are extracellular senile plaques and intraneuronal fibrillary tangles, both abnormal features found in the brain of patients upon autopsy. The senile

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plaques consist of a proteinaceous amyloid deposit surrounded by degenerating neurites. The predominant protein component of the amyloid deposit is beta-amyloid (Abeta), a 4 kDa peptide derived from a much larger transmembrane precursor protein. Abeta deposits are fibrillar, with a diameter of 5-10 nm and a cross-beta structural motif. Mounting in vitro and transgenic mouse data support the hypothesis that Abeta, and more specifically, aggregated (fibrillar) Abeta, is neurotoxic and thus likely plays an essential role in the onset and/or progression of Alzheimer's pathology. This hypothesis leads to a proposed strategy for therapeutic intervention: compounds which can interfere with assembly of Abeta monomer into toxic fibrils should provide protection from Abeta toxicity. Abeta is an amphiphilic self-associating peptide whose sequence is known. To self-associate, Abeta must be able to "recognize" other copies of itself. This leads to the intriguing possibility that molecules which borrow partial sequences from Abeta could also associate specifically with, or recognize, Abeta. Such sequences would be useful as means to target Abeta. These recognition elements could then be coupled to elements that were capable of disrupting Abeta aggregation. The hybrid compounds, containing both recognition and disrupting functionality, could potentially prevent Abeta neurotoxicity. In preliminary work, four such hybrid compounds were synthesized. These compounds disrupted Abeta aggregation and protected cells in vitro from Abeta toxicity. In the proposed research, this modular design strategy is explored in much greater depth. A library of peptidyl and organopeptidyl compounds will be synthesized, drawing on knowledge of the amino acids in Abeta that are responsible for the Abeta-Abeta interaction. Those compounds which prove to be effective recognition elements will be coupled to a palette of peptide- or saccharide-based disrupting elements. Such compounds will be evaluated extensively for their effect on Abeta aggregation and their ability to interfere with Abeta cellular toxicity. By repeated rounds of synthesis and evaluation, compounds which are highly effective at interfering with Abeta aggregation will be generated. Such compounds may serve as useful probes of the role of Abeta aggregation in neurotoxicity and may provide leads for developing clinically effective therapies for the treatment of Alzheimer’s disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OLFACTION AND EARLY DIAGNOSIS OF AD:FMRI STUDIES Principal Investigator & Institution: Tabert, Matthias H.; Psychiatry; Columbia University Health Sciences New York, Ny 10032

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Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG2008 Summary: (provided by applicant): This is an application for a Mentored Research Scientist Development Award. In Alzheimer's disease (AD), degeneration due to amyloid plaques and neurofibrillary tangles occurs early in the entorhinal-hippocampal-subicular complex as well as in the olfactory bulb and tract. AD patients consistently show deficits in olfactory identification compared to age-matched controls, as do patients with mild cognitive impairment (MCI), who are thought to be in the preclinical stages of the illness. While progress is being made in understanding the neuroanatomical and neurophysiological basis of olfaction, there has been a lack of clinical studies examining the neural correlates of AD-related olfactory deficits. The primary goal of the current research project will be to examine the degree to which odorantinduced brain activation in olfactory-related brain regions can be used as a reliable index that differentiates mild AD patients, MCI patients, and healthy age-matched elders. To implement this goal, the proposed project will conduct an olfactory fMRI study. The focus will be on cross-sectional analyses of the fMRI response to odorants in olfactory-related brain regions. Ultimately, the clinical goal is to use differential odorant-induced activation profiles in MCI patients as an early diagnostic marker of AD. Such markers are critical for the development of effective treatments that can slow disease progression early in its course. The proposal provides for a staged training schedule designed to build on the candidate's background in neuropsychology and develop expertise in olfaction and neuroimaging, within a clinical research context. The career development activities and research plan capitalize on the resources of Columbia University to aid in achieving the candidate's long-term goal of becoming an independent investigator, focusing on early detection of psychiatric and neurological disease, limbic system functions, and brain imaging. In the training plan, he will receive expert mentorship in key areas, including psychophysics and neuroscience of olfaction, technical and theoretical aspect of fMRI, research design and quantitative methods, clinical assessment and diagnosis, and in the ethical treatment of patients and research conduct. This will be complemented by a comprehensive didactic program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OREGON ALZHEIMER DISEASE CENTER Principal Investigator & Institution: Kaye, Jeffrey A.; Professor and Director of Adcc; Neurology; Oregon Health & Science University Portland, or 972393098

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Timing: Fiscal Year 2001; Project Start 06-JUL-1990; Project End 31-MAR2005 Summary: The overall mission of the Oregon Alzheimer's Disease Center (OADC) is to facilitate and advance research in Alzheimer's disease (AD) and related dementias. This will be achieved by maintaining 6 core facilities in associated with expert Core personnel to support both current research strengths, as well as to be responsive to the developing potential of new knowledge and discoveries in the field. The Center is organized and coordinated by the Administrative ore to be an efficient unit, working in concert with the research community to facilitate investigations in several major thematic areas such as studies of preclinical or incipient dementia in the very elderly, the genetics of AD, and the relationship between AD and Parkinson's disease. The Clinical Core provides well-characterized, longitudinally followed research subjects of several kinds: 1) AD and related dementias; 2) Healthy elderly at high risk for developing dementia, emphasizing those older than 85 years of age; 3) Dementia of Parkinson's disease; and 4) Subjects reflecting social and racial diversity (African American, Native American, and isolated rural populations). The Clinical Core is linked to the Neuropathology Core through programs such as the Community Brain Donor Program designed to enhance tissue donation. The Neuropathology Core uses modern histopathologic and morphometric techniques to characterized donated tissues which in turn are utilized by a diverse array of basic and clinical scientists both locally and nationally. The Genetics Core response to the needs of both Clinical and Neuropathology Cores and their missions of sophisticated characterization of research subjects and tissues by family history and genotype. The Genetics Core is also responsive to basic scientists in potential ability to facilitate study of candidate genes causing AD or genes which are protective and promote successful aging. Liking all these units is the Data Core which maintains an efficient relational database containing a unique catalogue record system allowing easy revision and modification of protocols as is inevitable in any longitudinal program. The Data Core further provides important assistance and advice in design and statistical analysis to investigators developing new projects. New information and knowledge of the field is disseminated through the Education and Information Transfer Core. This Core provides regular educational forums of many types ranging from small seminars to interactive television broadcasts. The Core's professional education programs and curricula are informed by new research spearheaded by this Core on how primary care physicians diagnose dementia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PET STUDIES OF CHOLINERGIC MODULATION IN ALZHEIMERS Principal Investigator & Institution: Smith, Gwenn S.; Associate Professor; Long Island Jewish Medical Center 270-05 76Th Ave New Hyde Park, Ny 11040 Timing: Fiscal Year 2000; Project Start 01-APR-1997; Project End 31-MAR2004 Summary: Primary symptomatology in Alzheimer~s disease (AD) has been attributed to a presynaptic cholinergic deficit, based mainly on postmortem examination of the brain at the end stages of the illness. Pharmacologic enhancement of the cholinergic system has not been consistently efficacious and does not stop disease progression. Animal and human models of AD based on inducted cholinergic hypofunction only mimic some aspects of symptomatology in AD. More recent neuropathologic studies have reported deficits in other neurotransmitter systems (e.g. dopamine, serotonin, norepinephrine). As an integration of the present knowledge concerning the neurochemistry of AD and the observation that neurotransmitter systems function synergistically, not in isolation, the proposed studies will test the novel hypothesis that the cognitive and behavioral symptomatology in AD represents a failure of acetylcholine to modulate other functionally-linked neurotransmitters, and that these deficits occur prior to the clinical diagnosis of AD. A recently developed research approach with Positron Emission Tomography (PET) will be used to combine neuroreceptor radiotracer studies with pharmacologic challenges to measure cholinergic modulation (Smith et al., 1996, Dewey et al., 1993). This approach is the most direct, non-invasive and quantitative method of measuring neurotransmitter activity and modulation in the living brain. These studies will measure cholinergic modulation of monoamine function (serotonin, dopamine) in the normal elderly, and in AD patients. A wellcharacterized pharmacologic challenge paradigm (administration of the selective muscarinic cholinegic antagonist scopolamine) will be used with PET and radiotracers for dopaminergic (D2, [1]C]- raclopride) and serotonergic (5-HT2A, [18F]-altanserin) receptors. Having performed the proposed studies, unique information will be obtained regarding cholinergic modulation of dopamine and serotonin receptor systems. These studies will provide a baseline for subsequent longitudinal followup of patients and for correlation with genetics and post-mortem findings (by the Alzheimer~s Disease Research Center) to determine how differences in monoaminergic responsiveness relate to AD subgroups (e.g. Lewy Body Dementia) A better understanding of the neurochemical deficits in AD may direct the development of novel treatment

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interventions that would improve symptomatology and perhaps stop disease progression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: POST-TRANSCRIPTIONALLY ACTING ALZHEIMER'S DRUGS Principal Investigator & Institution: Utsuki, Tada; Scientist; Message Pharmaceuticals, Inc. 30 Spring Mill Dr Malvern, Pa 19355 Timing: Fiscal Year 2001; Project Start 15-AUG-1997; Project End 31-DEC2002 Summary: Alzheimer's disease (AD) is a major concern as the population ages, with no truly effective treatments available. One of the hallmarks of the disease is the deposition of insoluble plaques composed of a peptide derived from Amyloid Precursor Protein (APP). Message has established a drug discovery program focused on regulating protein expression by altering the interaction of an RNA binding protein with its target RNA. The overall goal of this project is to use this technology to develop drugs that decrease levels of APP. The current proposal seeks to (1) identify all the necessary components involved in these interactions; (2) screen for compounds that alter the interactions; (3) analyze effects of the compounds in cell culture; and (4) determine the in vivo efficacy in animal models of AD. Successful completion of this work will result in preclinical drug candidates and ultimately in a novel treatment targeting AD progression. To date, we have demonstrated that Message is regulated at the post-transcriptional level and that phenserine can block translation of the APP mRNA in a specific fashion. Analogs are currently being tested for more potent molecules and a high throughput screen will be developed once the regulatory regions are better understood. PROPOSED COMMERCIAL APPLICATION: Successful completion of this project will provide compounds for preclinical development as AD therapeutics. All current treatments for AD treat the symptoms (cognition) whereas this strategy would target a key factor believed to play a role in causing the disease. In addition, validation of posttranscriptional drug targeting would have broad implications for the treatment of other diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PROTEIN RADICAL, MITOCHONDRIA, AND AD

PROTEIN

NITRATION,

Principal Investigator & Institution: Chen, Yeong-Renn; Internal Medicine; Ohio State University 1960 Kenny Road Columbus, Oh 43210

146 Alzheimer’s Disease

Timing: Fiscal Year 2002; Project Start 13-SEP-2002; Project End 31-JUL2005 Summary: (Taken from the Investigator's Abstract) The causative factors of Alzheimer's disease (AD) involve aging, genetics, and environmental exposures. At the neuronal level, a defect of energy metabolism associated with mitochondrial cytochrome C oxidase (CcO) deficiency was marked in AD brain. The mitochondrial abnormality caused by oxidative damage of CcO has been suggested as a part of causative events in AD. The long-term objective of this proposed research is to identify the molecular mechanism related to oxidative damage of AD-associated mitochondrial CcO. The proteincentered radical(s) in CcO, as detected with ESR spin-trapping technique, is formed by reacting with peroxides, such as hydrogen peroxide, organic peroxides, and lipid peroxides. Available evidence indicates that a specific tyrosine in mitochondrial cytochrome C may be nitrated to form 3- nitrotyrosine. The candidate hypothesizes that a specific amino acid residue(s) in CcO is involved in the radical formation and that 3- nitrotyrosine can be detected when the purified CcO is exposed to a reactive nitrogen species (RNS) such as nitric oxide (NO) or peroxynitrite. The radioisotope-labeled spin trap, [14C]labeled 2-methyl-2-nitrosopropane (MNP), will be synthesized and used to trap the protein-centered radical(s) in CcO. The subunit (location) of CcO associated with the spin trap will be visualized by SDS-PAGE and radioisotope distribution. NO and peroxynitrite will be used to test the nitration of tyrosine in purified CcO. The nitration of CcO will be characterized by immunoblotting using the antibody against 3nitrotyrosine. Peptide chemistry/mapping and mass spectrometry will be used to identify specific amino residue(s) associated with the above events of oxidative damage. The functional domains involved in the above radical formation and nitration will be identified. The essential role of the identified domains will be studied by immunochemistry. The results will provide fundamental information concerning the pathological relevance of neurodegenerative disease, such as AD, associated with mitochondrial dysfunction caused by oxidative damage. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROTEOME MARKERS FOR ALZHEIMER'S DISEASE DIAGNOSIS Principal Investigator & Institution: Lee, Kelvin H.; Associate Professor; Chemical and Biomedical Engineering; Cornell University Ithaca Office of Sponsored Programs Ithaca, Ny 14853 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR2005

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Summary: (Adapted from applicant's abstract): The objective of this project is to identify CSF molecular markers associated with the antemortem diagnosis of Alzheimer's disease which can be used as a measure for disease pathology. In contrast to brain based studies of the molecular mechanism of disease progression, this investigation with use proteomics technology to identify and characterize CSF proteins of interest. This information can be used to categorize disease pathology or can be used to develop immunoassays for diagnosis. In order to achieve these long-term objectives, the investigator plans to: identify and obtain CSF blood samples and clinical information from an appropriate sample population of patients with different forms of dementia, probable Alzheimer's disease at various stages and controls (Specific Aim 1). Analyze the samples for AD specific protein markers used in proteome analysis that includes high solution two-dimensional electrophoresis, laser densitometry, fluorescence imaging, and computer aided in each analysis (Specific Aim 2). He employs multivariate statistics to establish a correlation between relevant changes in disease diagnosis and establish qualitative and quantitative bar code for diagnosis of Alzheimer’s disease. This includes the validation of other proposed CSF markers such as tau and Abeta 42 as well as the preliminary identification of other major differential diagnosis such as vascular dementia, dementia with Lewy bodies (Specific Aim 3). Use microchemical characterization of important proteins to elucidate the genetic basis of the molecular markers and other reference proteins. This information can also be used to develop immunoassays (Specific Aim 4). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REVEALING EPISTASIS IN ALZHEIMER DISEASE Principal Investigator & Institution: Martin, Eden R.; Assistant Research Professor; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR2007 Summary: Alzheimer disease (AD) is a leading cause of dementia in the elderly. Identifying susceptibility genes for AD will aid in risk assessment, diagnosis and understanding the etiology of the disease. Several chromosomal regions have been identified as harboring genes for late-onset AD, but only one gene, APOE, has been demonstrated consistently to be directly involved in disease risk. While APOE may explain up to half of the genetic effect in late-onset AD, the remaining susceptibility genes have been difficult to identify. A large number of candidate genes have been tested for association using either case-control tests in unrelated individuals or family-based association tests, but the

148 Alzheimer’s Disease

results have varied greatly between studies. It is our hypothesis that epistatic effects among multiple genes play a more important role in determining risk of AD than the independent effects of any single gene. The multiple positive and negative reports for numerous candidate gene association studies may in fact be due to study designs that only evaluate each candidate gene for main effects that are independent of all other genes. The goal of this proposal is to determine the role of epistasis or nonadditive gene-gene interactions on the risk of late-onset AD. To accomplish this goal, we propose to identify and genotype several single nucleotide polymorphisms in ten AD candidate genes for which there have been conflicting association studies. We will use a family-based design using affected and unaffected siblings and propose to study 800 sibships containing approximately 1600 individuals. We will extend the recently developed pedigree disequilibrium test (PDT) to test for associations at the genotypic level and allow its incorporation into the new multifactor dimensionality reduction (MDR) method. To test for complex genetic interactions in these data, we will use this modified MDR-PDT method. We anticipate that these results will explain at least some of the inconsistency arising from Alzheimer disease candidate gene association studies. Further, knowledge gained from the proposed research will be invaluable for public health efforts to prevent and treat the initiation, progression, and severity of Alzheimer disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RISK FACTORS FOR INCIDENT ALZHEIMERS DISEASE Principal Investigator & Institution: Evans, Denis A.; Director, Rush Institute for Healthy Agi; Rush-Presbyterian-St Lukes Medical Ctr Chicago, Il 60612 Timing: Fiscal Year 2001; Project Start 01-MAR-1993; Project End 31MAY-2004 Summary: (Adapted from the Investigator's Abstract) This is a revision of a previous application that was not funded. It proposes to continue the Chicago Health and Aging Project (CHAP), a study of incident clinically diagnosed Alzheimer's Disease among 6,162 residents of a geographically defined, urban, biracial community of the south side of Chicago. Recent data from the studies suggest that prevalence of Alzheimer's Disease is 2.65-fold higher among blacks than whites after adjustment for age, education and APOE genotype. The proposed work examines potentially modifiable risk factors, especially ones that might explain racial differences in risk. The primary questions are: (1) whether vascular factors, especially elevated blood pressure, increase risk of

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clinically manifest Alzheimer's Disease itself, in addition to their accepted role in predicting risk of vascular dementia, (2) whether this is mediated through small brain infarcts and non-infarct related white matter changes, and (3) to what extent do vascular factors account for racial differences in risk of disease? Secondary issues include potential protective effects of anti-inflammatory drugs and estrogens, effects of early life exposure on risk of Alzheimer's Disease, and the extent to which vascular factors predict risk of vascular dementia. To achieve these goals, a proposed second follow up (incidence) data collection cycle will detect Alzheimer's Disease occurring in the three year interval since the previous cycle, and all clinical evaluations will include magnetic resonance imaging and magnetic resonance and geography. In addition, enrollment of successive age cohorts of community residents as they reach age 65 is proposed to enable the study, in the future, to examine three important issues that cannot be examined by existing studies: whether effects of risk factors for Alzheimer's Disease vary greatly with age, the need for exposure information at multiple points over an extended period of time, and differences in the occurrence and effects of risk factors in different age cohorts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF CASPASE NEURODEGENERATIVE DISEASES

CLEAVAGE

IN

Principal Investigator & Institution: Bredesen, Dale E.; Director; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 92093 Timing: Fiscal Year 2001; Project Start 15-APR-2001; Project End 31-MAR2002 Summary: The mechanisms that contribute to death of neurons in Alzheimer's disease remain to be defined. This is a particularly important process because loss of neurons and synapses likely play a critical role in cognitive impairment and indeed, may even precede clinical manifestations of the disease. Recent studies consistently showed that many mutations associated with neurodegenerative disease result in a pro-apoptotic phenotype in culture and, furthermore, many of the neurodegeneration-associated gene products are generally believed to be the "executioners" of the cell death program. We have recently found that the mutant androgen receptor associated with Kennedy's syndrome (spinobulbar muscular atrophy) is a caspase substrate, and, more importantly, that mutation of the caspase cleavage site blocks the proapoptotic effects of the mutant gene. This result argues that caspase cleavage in this case is an important event in the induction of cell death.

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Recently, it has been shown that three important Alzheimer's disease associated-genes, amyloid precursor protein, presenilin-1, and presenilin2, are all caspase substrates. Therefore, the working hypothesis that guides this project is that caspase cleavage of these three gene products is required for cell death promoting properties associated with the familial Alzheimer's disease (FAD) mutations. In this application, we propose to explore the relationship between caspase cleavage of these three proteins and cell death. The results of these studies should help determine whether caspase cleavage represents an important signaling event in cell death in culture included by these mutant proteins. Furthermore, an understanding of this relationship will affect the development of new therapeutic strategies to treat Alzheimer disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF NO SYNTHASE-2 IN MURINE ALZHEIMER'S DISEASE Principal Investigator & Institution: Nathan, Carl F.; Professor & Chair; Medicine; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2001; Project Start 19-SEP-2000; Project End 31-JUL2005 Summary: Alzheimer's disease (AD) can be viewed as a chronic degenerative and inflammatory disease leading to neuronal dysfunction and loss that are critically linked to accumulation of fibrillogenic fragments (Abeta[1-42/43]) of beta-amyloid precursor protein (APP). One leading possibility to explain how Abeta accumulation leads to neurotoxicity is that Abeta triggers oxidative and/or nitrosative injury. Fibrillogenic Abeta can generate oxidants in vitro and can elicit production of reactive nitrogen intermediates (RNI) and reactive oxygen intermediates (ROI) from microglia, astrocytes, neurons and monocytes in vitro (alone or with cytokines) and when injected into the brain. Biochemical and histochemical hallmarks of oxidative/nitrosative injury have been documented in lesions of AD. Among these, expression of the inducible isoform of nitric oxide synthase (NOS2; iNOS) is of special interest because its presence in brain is abnormal and implies inflammation; its production of NO is usually more sustained and destructive than that of other NOS's; it can produce ROI simultaneously with RNI, both by its own enzymatic action and by damaging mitochondria; and the resulting production of NO and superoxide in the same time and place favors the formation of peroxynitrite. Peroxynitrite is more toxic than either of its precursors, and there is strong histochemical evidence for its formation in AD. The PI has collaborated in demonstrating the presence of NOS2 in brains of patients with AD,

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associated with tangle-bearing neurons and neuropil. The advent of mice bearing AD-associated transgenes and the PI's generation of mice with disrupted alleles for NOS2 now permit a genetic test of the hypothesis that NOS2 may be an important enzymatic contributor to the oxidative/nitrosative neuronal injury characteristic of AD. Preliminary studies in 4 transgenic mouse models of AD using well-characterized antibodies for NOS2 have demonstrated NOS2 immunoreactivity in each type of AD-prone mouse. In contrast, cyclooxygenase 2 was scarcely detectable. In this proposal, mice carrying two AD-associated transgenes will be bred to retain or lose functional alleles of NOS2. These two strains will be compared with each other and with littermate- derived wild type mice as a function of age. If inability to express NOS2 decreases, delays, slows, or reduces the incidence, onset, progression or severity of neuronal loss or oxidative injury in mice with AD-associated transgenes, then NOS2 will emerge as an important target for experimental therapy in AD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE AMYLOIDOSIS

OF

TGF

B1

IN

CEREBROVASCULAR

Principal Investigator & Institution: Wyss-Coray, Tony; Assistant Professor; J. David Gladstone Institutes 365 Vermont St San Francisco, Ca 94103 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-JUL2003 Summary: (From Abstract): Cerebrovascular deposition of amyloid, or cerebral amyloid angiopathy (CAA), is a prime cause of normotensive intracerebral hemorrhages in the elderly. CAA is also a major neuropathological lesion in Alzheimer's disease (AD) and is accompanied by degenerating cells of the vascular wall. Because cerebrovascular amyloidosis has implications for the pathogenesis of Alzheimer's disease and for central nervous system (CNS) function in general, understanding its etiology is of great importance. Although it is known that single amino acid substitutions in several different proteins can cause rare autosomal dominant forms of CAA and that the apolipoprotein (apo) E e4 allele is a genetic risk factor for CAA, the cause of this disease in the majority of cases remains elusive. Through studies addressing the role of injury in neurodegenterative diseases, we have identified transforming growth factor (TGF)-ß1 as an inducer of cerebrovascular amyloidosis and as a potential pathogenic factor for CAA in human Alzheimer's disease cases. The cytokine TGF-ß1 is rapidly produced after all forms of CNS injury and may function as an organizer of the responses to brain injury. Overexpression of TGF-

152 Alzheimer’s Disease

ß1 in astrocytes of transgenic mice caused cerebrovasular amyloid deposition and prominent perivascular astrocyte activation along with a degeneration of cortical capillaries reminiscent of Alzheimer’s disease. Here we propose experiments to define the role of TGF-ß1 in cerebrovascular amyloidosis at the molecular level. We will determine whether chronic activation of astrocytes by TGF-ß1 is necessary and sufficient to cause cerebrovascular amyloidosis in vivo and whether this process is modulated by different human apoe isoforms. We will use transgenic mice that overexpress dominant-active or dominant-negative TGF-ß receptors in astrocytes or comparable levels of apoE3 or apoE4 in neurons. In addition, we will initiate studies to determine if chronic TGF-ß1 production and astrocytosis cause the capillary degeneration that precedes amyloid deposition and whether these processes can be modulated by apoE3 or apoE4. The proposed studies will allow us to better understand the etiology and pathogenesis of cerebrovascular amyloidosis in vivo and clarify the roles of TGF-ß1, CNS injury, and astrocyte activation in this process. Our findings will have implications for the pathogenesis of human CAA and Alzheimer's disease in general and will help to assess whether TGF-ß1 could be a future target of therapeutic interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SCREENING FOR NOVEL ALZHEIMER'S DISEASE DRUGS Principal Investigator & Institution: Marques, Marcos A.;; Apologic, Inc. 3130 Highland Ave, Ste 3265 Cincinnati, Oh 45219 Timing: Fiscal Year 2001; Project Start 01-AUG-1998; Project End 31MAR-2002 Summary: There are four million people with Alzheimer's disease (AD) in the U.S. alone and the cost of their care is currently estimated at 100 billion dollars. Available therapy is limited to symptomatic relief without affecting the underlying cause of the disease. Recent evidence indicates that apolipoprotein E (apoE) may play a direct role in neuropathological changes that occur in AD. In particular, apoE has been shown to exhibit neurotoxic activity with isoform specificity that parallels the risk of disease. We have found that the neurotoxic activity of apoe can be blocked by specific compounds, suggesting a novel approach to the design of new therapeutic agents for treatment of Alzheimer’s disease. Phase I has been successful. The feasibility of screening novel compounds has been demonstrated. Many of these show efficacy in an in vitro assay designed to mimic the proposed neurotoxic properties associated with apoE. The goals of phase II are to: accelerate in vitro screening, carry out

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refined analysis of positive compounds, synthesize novel compounds based on positive results, and screen for non-target properties of effective compounds. PROPOSED COMMERCIAL APPLICATION: There are currently no effective treatments for Alzheimer’s disease. The identification and development of an agent that significantly delays either the onset or progression of the disease would address a current healthcare cost of several billion dollars. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TARGETED MOUSE MODELS OF ALZHEIMER DISEASE Principal Investigator & Institution: Fukuchi, Ken-Ichiro; Genomics and Pathobiology; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR2002 Summary: Alzheimer Disease (AD) is a neurodegenerative disorder characterized by the progressive loss of memory and cognitive functions. Cardinal pathological changes found in the brain of patients with AD are neurofibrillary tangles and deposits of aggregated amyloid protein (Abeta) in neuritic plaques and cerebral vessels (cerebrovascular amyloid angiopathy). The pathogenetic mechanisms that lead to development of AD are not clearly understood. There is no satisfactory treatment for AD. Approximately 10% of AD cases are classified as early onset familial AD (FAD) and show autosomal dominant inheritance. Inherited mutations in the gene coding for presenilin 1 (PS1) cause 18 to 50% of the early onset FAD cases. Although PS1 may be a transmembrane aspartyl protease that generates Abeta by cleaving its precursor proteins, neither the physiological functions nor normal metabolism of PS1 are fully understood. Such understanding is essential to establishing the logical basis for therapy and prevention of the disease. Attempts to clarify the physiological functions of PS1 by constructing PS1 deficient (knockout) mice resulted in embryonic lethality. Thus, it is impossible to study the physiological functions and pathogenetic roles of PS1 in the adult using the "conventional" knockout mice. The primary goal of this pilot project is to establish new lines of PS1 knockout mice where expression of the PS1 gene is tightly regulated by the tetracycline (Tc) controllable transactivator system. The Specific Aims of the current research project are to: (Aim 1) isolate targeted embryonic stem (ES) cell lines with a PS1 gene under control of the Tc transactivator system and (Aim 2) establish mutant mouse lines for the PS1 gene using the targeted ES cell lines established in Aim 1 and test the tight regulation of the targeted PS1

154 Alzheimer’s Disease

genes in the mice. In these new lines of mice, expression of the PS1 gene will be turned on during embryogenesis and completely turned off by administration of doxycycline (a derivative of Tc) when the mice become adult. The long-term goal of this research is to elucidate the role of PS1 in the pathogenesis of AD via a thorough understanding of the physiological functions and normal metabolism of PS1. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ROLE OF CASPASE-8 IN ALZHEIMER'S DISEASE Principal Investigator & Institution: Rohn, Troy T.; Biology; Boise State University 1910 University Dr Boise, Id 83725 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL2004 Summary: (Adapted from applicant's abstract): A prominent feature of Alzheimer's disease (AD) is the loss of neurons by apoptotic cell death. Apoptosis is characterized by plasma membrane blebbing, nuclear condensation, and DNA fragmentation and is initiated by the activation of caspases, a family of aspartate proteases. The initiation of apoptosis involves the sequential activation of pro-caspases to their active form by proteolysis. Two key members of this family are caspase-8, the most apical member of the caspases, and caspase-3 that is commonly referred to as the executioner member of this family. Because caspases are specific, cleaving after aspartic residues, this generates caspase cleavage products (CCPs) that are antigenically distinct and therefore, represent desirable targets for cleavage site-directed antibodies. Using this approach, we designed an antibody to CCPs of fodrin, a neuronal cytoskeleton protein, and showed widespread accumulation of these products in Alzheimer’s disease. Thus, while no staining was observed in control cases, labeling of neurons was observed in the hippocampus and entorhinal cortex of all AD cases, which increased as a function of disease progression. This study along with others has demonstrated a prominent role for the activation of apoptotic mechanisms in neurons of the AD brain. Presently, there are two major pathways of apoptosis: the death receptor pathway in which caspase-8 plays a critical initiator role and the mitochondrial pathway involving oxidative stress and activation of caspase-9. Induction of cell death via the Fas/TNFR super family of death receptors is mediated by adapter proteins (e.g., Fas-associated death domain, FADD) and initiation caspases (e.g., caspase-8). In the present application we test the role of the death receptor pathway and caspase-8 in Alzheimer’s disease. To examine the role of caspase-8 in Alzheimer's disease we will propose to 1) develop cleavage site-directed antibodies against the active fragments of caspase-8; 2) characterize these antibodies

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using model systems of apoptosis; 3) use this antibody together with the fodrin CCP antibody to determine the role of caspase-8 in mediating the activation of caspase-3 in neurons of the AD brain. Elucidation of the exact apoptotic pathway involved in the eventual activation of caspase-3 will lead to the identification of newer, more specific targets for pharmacological intervention that may be useful for the treatment of Alzheimer’s disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSGENIC MODELS OF ALZHEIMERS DISEASE Principal Investigator & Institution: Irizarry, Michael C.;; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 01-AUG-1997; Project End 31MAY-2002 Summary: Alzheimer's disease (AD) is a progressive neurodegenerative dementing disorder affecting over 3.5 million Americans for which there is not known effective therapy. Genetic, cell culture, and animal studies support a key role of the amyloid precursor protein (APP) and amyloid beta protein (alpha beta) in the pathogenesis of AD, and related disorder, congophilic amyloid angiopathy (CAA). The applicant proposes to study two existing transgenic mouse models of cerebral amyloid deposition and to contribute the development of a transgenic model of vascular APP production to examine specific hypotheses relevant to the pathophysiology and neuropathology of AD and CAA. The objective of this Mentored Clinical Scientist proposal is to study whether APP transgene expression and/or Abeta deposition is associated with neuronal loss, vascular damage, synaptic alterations, gliotic changes, or loss of functional integrity of neural systems. Stereologically based statistically unbiased techniques will be used to assess neuronal counts, amyloid burden, and vascular amyloid in the entorhinal cortex, cingulate cortex, and hippocampal subfields to transgenic mice an non-transgenic littermate controls. The regional distribution and morphology of amyloid plaques will be analyzed immunohistochemically with light and confocal microscopy. The relation of transgene APP splice form expression to Abeta deposition will be assessed through in situ hybridization. Functional integrity of neural systems will be evaluated by cytochrome oxidase histochemistry and in situ hybridization, and synaptic integrity will be evaluated by immunohistochemistry and in situ hybridization. The applicant proposes to assess the effects of APP over-expression in vascular smooth muscle by producing and evaluating a new transgenic model of cerebral amyloid angiopathy. The candidate is a board certified neurologist who has completed two productive years of fellowship

156 Alzheimer’s Disease

training in the well established neuroscience laboratory of Bradley T. Hyman. The laboratory includes experience and facilities for stereological techniques, molecular biology, immunohistochemistry, and confocal microscopy as well as access to human pathological specimens through the Alzheimer Disease Research Center. The additional basic science training in an exciting and novel project with direct clinical relevance will allow the candidate to develop into an independent academic neuroscientist. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSGENIC MODELS TO STUDY ALZHEIMER'S DISEASE Principal Investigator & Institution: Mucke, Lennart; Associate Professor; J. David Gladstone Institutes 365 Vermont St San Francisco, Ca 94103 Timing: Fiscal Year 2002; Project Start 01-SEP-1992; Project End 31-MAR2007 Summary: (Adapted from applicant's abstract): Alzheimer' s disease (AD) is the main cause of dementia in the elderly. Its increasing prevalence and enormous cost threaten the health and economic stability of people in the United States and many other nations. Thus, there is an urgent need to deepen our understanding of this illness and to develop better strategies to treat and prevent it. In this project, we use transgenic (tg) mouse models to study the roles of amyloid proteins and apolipoprotein (apo) E in the pathogenesis of Alzheimer’s disease. During the last funding cycle, we overexpressed human amyloid protein precursors (APPs) and APP-derived amyloid peptides (A13) in neurons of tg mice. Similar to people with AD, APP mice showed progressive deposition of At3 in amyloid plaques and degeneration of neurons and synapses. Plaque formation depended not only on absolute levels of the fibrillogenic AB142 peptide but also on a number of key modifiers. High AB1-4O/AB1-42 ratios and ablation of apoE prevented neuritic plaques, whereas a1antichymotrypsin doubled the plaque load. The cytokine transforming growth factor Bi had complex effects, decreasing the overall plaque burden while promoting amyloid deposition in blood vessels. Synaptic deficits correlated with AB levels but not with plaque load, suggesting a plaque-independent role for AB in Alzheimer’s disease. Expression of apoE3, but not of apoE4, prevented or delayed synaptic deficits and memory impairments in APP/apoE doubly tg mice, consistent with observations by others that apoE4 increases AD risk, accelerates AD onset, and is found in the majority of people with Alzheimer’s disease. This application follows up on our previous results, extends our project from AD pathogenesis to treatments, and addresses several important

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unanswered questions. We propose to determine whether nondeposited forms of AB such as AB-derived diffusible ligands (ADDLs) cause the plaque-independent neuronal deficits we identified in APP tg mice; whether these deficits can be prevented and ameliorated by vaccination with ADDLs; whether apoE3 suppresses ADDLs more effectively than apoE4 in APP/apoE mice, tg glial cultures, and cell-free conditions; and whether transient expression of apoE3 in adult regulatable APP/apoE mice can decrease ADDL levels and inhibit neuronal deficits. We also propose to use DNA microarrays to identify additional mechanisms by which apoE isoforms might affect AB/ADDL-induced neuronal deficits. Achieving these aims could shed light on the molecular pathways that culminate in AD-associated cognitive decline and assist in the preclinical evaluation of novel treatments for the most common neurodegenerative disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSGENIC RAT MODELS OF ALZHEIMER'S DISEASE Principal Investigator & Institution: Herrera, Victoria L.; Profesor of Medicine; Medicine; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2001; Project Start 15-FEB-2000; Project End 31-JAN2003 Summary: Animal models are proven investigative tools for study of complex human diseases such as Alzheimer s Disease (AD) and atherosclerosis. Trangenic and bigenic mouse models for presenilin-1 (PS1) and amyloid precursor protein (APP) human gene variants have been instrumental in delineating their roles in AD pathogenesis. However, to date these mouse models have not exhibited key AD pathology such as neurofibrillary tangles, neuronal loss and ADassociated cognitive/neurobehavioral deficits. We hypothesize that a more phenotypically robust and experimentally accessible model of Alzheimer s disease will be obtained in the rat based on key observations: a) rat ApoE is more homologous to human ApoE4 compared with mouse; b) rat complement, like the human has greater levels compared with the mouse and might be a key determinant to the development of neurofibrillary tangles; c) neurobehavioral studies assessing aging and hippocampal-specific learning and memory deficits have been validated in the rat; d) the size of the rat allows lesioning and imaging studies; f) the more robust atherosclerotic phenotype in transgenic rats compared with mice given the same human cholesteryl ester transfer (hCETP) transgene indicates valid modeling for complex diseases. This proposal

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focuses on the following specific aims. (1) Develop three key inbred Fischer 344 rat AD models with the highest probability for a robust AD phenotype: a) homozygous high-expresser of mutant human APPSWE AD gene, TgAPP, b) homozygous bigenic with both mutant human PSIM146L and hAPPSWE, 2TG[PS1xAPP], and a trigenic rat model, 3Tg]PS1 x APAP x hCETP], which imposes, if not test, hypercholesterolemia-induced exacerbaytion of amyloidogenic APP processing in vivo. (2) Investigate the degree of cognitive deficits in the combinational transgenic rat AD models by measuring hippocampaldependent working memory and spatial learning and memory at 12, 18, 24 months. 3) Correlate observed hippocampal-dependent neurobehavioral alterations with AD- associated neuropathological alterations at 12, 18, and 24 months. (4) Correlate key neurobehavioral and neuropathological alterations with molecular and cellular markers of AD pathogenesis at 12, 18, and 24 months. Comparative analysis of the proposed rat models will not only address an accessible AD model for mechanistic dissection and therapy development, but also provide insight into the role of complement- and hypercholesterolemia-mediated disease paradigms in AD pathogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSMITTER NEUROANATOMY IN ALZHEIMERS DISEASE Principal Investigator & Institution: Armstrong, David M.; Scientific Review Administrator; Lankenau Institute for Medical Research Wynnewood, Pa 19096 Timing: Fiscal Year 2001; Project Start 01-AUG-1988; Project End 31-DEC2002 Summary: (Applicant's Abstract): The proposed studies will address the issue of selective vulnerability of neurons in Alzheimer’s disease. Underlying these studies is the hypothesis that excitotoxicity, particularly that which is mediated via stimulation of ionotropic glutamate receptors, contributes to the neuro-degeneration of Alzheimer’s disease. Moreover, we predict that in Alzheimer's disease the perturbation of specific glutamate receptor subunits, particularly those involved in the gating of calcium, may contribute significantly to the viability of the cell. The current investigation focuses on the N-methyl- D-aspartate (NMDA) receptor. Notably, previous work of ours has focused on the distribution and expression of specific non-NMDA (i.e. AMPA) receptor subunits in the hippocampus of patients with Alzheimer's disease pathology. Collectively, these investigations attempt to provide a comprehensive understanding of the anatomy of the ionotropic glutamate receptor in the

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hippocampus of normal subjects and in subjects with Alzheimer’s disease. In this application, we propose a series of highly correlated immunohistochemical (Specific Aims 1&2), biochemical (Specific Aim 3) and in situ hybridization studies investigating the distribution and level of expression of specific NMDA receptor subunits (e.g., NMDAR1, NR2A, NR2B, & NR2D). Studies will focus on the human hippocampus, in part, because this region is known to be affected very early within the progression of the disease. Subjects representing a broad range of neuropathologic severity (i.e. Braak stages I-VI) will be studied thus providing us with the opportunity of examining alterations in glutamate receptor expression throughout various stages of the disease. Moreover, the use of specific antibodies identifying early events in the evolution of neurofibrillary pathology provides an additional opportunity of correlating alterations in NMDA receptor subunit expression with initiating events of neurodegeneration. An understanding of the anatomical organization of NMDA and AMPA receptors and the mechanism underlying glutamate-mediated excitotoxicity is important before appropriate drugs aimed at halting Alzheimer's disease-associated neuronal degeneration can be developed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRIPLE TRANSGENIC MODEL OF ALZHEIMER'S DISEASE Principal Investigator & Institution: Vitek, Michael P.; Associate Professor; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 15-JUN-2002; Project End 31-MAY2007 Summary: (Adapted from applicant's abstract): The National Institutes on Aging and Reagan Institute consensus criteria for the diagnosis of Alzheimer's disease includes a clinical evaluation of progressive dementia and a post-mortem observation of both amyloid plaques and neurofibrillary tangles in the brains of AD patients. Age of the patient is the largest risk for the presence of AD followed by the presence of one or more epsilon-4 alleles of the apolipoprotein-E gene (APOE4) in about 45 percent of all AD patients. The presence of APOE4 is also associated with an increase in the numbers of neurofibrillary tangles and amyloid plaques compared to those AD patients that lack APOE4 alleles. These data imply that increased numbers of plaques and tangles are associated with a gain of Alzheimer's dementia. An animal model that displays progressive dementia, amyloid plaques and neurofibrillary tangles is a critical step forward toward developing a safe and effective drug for the treatment of Alzheimer’s disease. Based on reported studies of AD

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patients, an animal model should also display increased numbers of neurofibrillary tangles and amyloid plaques when APOE4 gene products are present. We propose to make a mouse model of Alzheimer's disease to meet the National Institute of Aging-Reagan Institute criteria for Alzheimer’s disease. This triple transgenic mouse (APP + TAU + APOE) is designed to display both neurofibrilary tangles and amyloid plaques in their brains. To be an accurate model of human AD, we hypothesize that the numbers of neurofibrillary tangles and amyloid plaques should increase in the presence of human APOE4 gene products compared to human APOE3 gene products. Although work on plaque-only or tangleonly mice needs to continue, if we are really going to develop a mouse model of Alzheimer's disease, we must have progressive dementia, plaques, and tangles. Such a model would facilitate exploration of the basic mechanisms that cause neurodegeneration and dementia, in the 'presence of plaques, tangles and apoE proteins, and thus, greatly facilitate the finding of a safe and effective drug to block Alzheimer's dementia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: UCLA ALZHEIMERS DISEASE RESEARCH CENTER Principal Investigator & Institution: Cummings, Jeffrey L.; Director; Neurology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 05-APR-1999; Project End 31-MAR2004 Summary: This application proposes the establishment of an Alzheimer's Disease Research Center (ADRC) at UCLA. The theme of the ADRC is "understanding the mechanisms and optimizing the treatment of Alzheimer's disease". An ADRC would add a basic science dimension to established activities of the current UCLA Alzheimer's Disease Core Center (ADCC), use tissues and antibodies from the ADCC Neuropathology Core, and facilitate an invigorating interchange between clinical scientists and the growing cadre of basic scientists at UCLA. The ADCC has accomplished its original goals and established a flow of well characterized patients that are being followed longitudinally (Clinical Core); accessioned 148 brains into the ADCC brain bank (Neuropathology Core); created an imaging archive with sophisticated image analysis techniques available to investigators (Imaging Subcore of Imaging and Genetics Core); developed mechanisms for routine genotyping and established a DNA bank for genetic investigations (Genetics Subcore of Imaging and Genetics Core); and engaged ore than 3600 clinicians in education programs (Education/Information Transfer

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Core). The ADCC database contains information on 1261 patients and control, in the past year we have achieved an annualized follow-up rate of 90%. In the past five years, we have awarded funding for 12 Pilot Projects; these projects have contributed to 10 funded grants and 22 publications. The ADCC has three clinical sites, each serving a different ethnic population: UCLA (primarily majority culture patients), Martin Luther King Medical Center/Drew Medical School (primarily an AfricanAmerican population), and Olive View Medical Center (an Hispanic population). UCLA investigators using data from the Cores have advanced understanding of frontotemporal dementias, dementia with Lewy bodies, behavioral aspects of AD, the role of vascular disease in AD and vascular dementia, and the role of imaging and genetics in the diagnosis and characterization of AD. ADCC investigators published 375 articles and 338 abstracts on dementia-related topics between 1993 and 1997. Three basic science projects are being proposed: 1) apolipoprotein influences on amyloid deposition (Greg Cole, Ph.D.), 2) amyloid deposition, toxicity, and inflammation in an amyloid infusion model of AD (Sally Frautschy Ph.D.) and intracellular amyloid signaling (Istvan Mody, Ph.D.). The activities of the Cores will be continued an expanded in the ADRC and the Project Leaders will be integrated into all aspects of the ADRC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: UHC/CWRU ALZHEIMER'S DISEASE RESEARCH CENTER Principal Investigator & Institution: Herrup, Karl F.; Professor; Neurology; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2001; Project Start 21-SEP-1988; Project End 31-MAY2005 Summary: The three-part of the Alzheimer Center of University Hospitals of Cleveland/Case Western Reserve University Medical School is 1) to provide clinical service, 2) to promote research and 3) to educate health professionals and the lay public into the causes and treatments of Alzheimer's disease (AD). We have learned much about the biological basis of AD in the past six years, yet the disease persists. The pace of discovery gives us hope, but the persistence of the disease is a reminder that much more needs to be done. To approach this task, this application proposes four research projects. Dr. Lamb will investigate the behavioral and pathological deficits of mice engineered to mimic early onset forms of AD. Dr. Landreth will explore the role of inflammatory processes and ectopic cell cycle components in the neurodegenerative processes of AD.

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Dr. Smyth will examine the dynamics and effectiveness of various forms of computer-mediated support to caregivers of persons with AD. Dr. Whitlatch will study the congruence between the treatment preferences of persons with dementia and their caregivers. These four studies plus the projects of many researchers throughout Greater Cleveland depend on the support services offered by the eight Cores. Dr. Herrup will direct the Administration Core that oversees the operations of the entire ADRC. The Clinical Core, under Dr. Geldmacher, will recruit and characterize AD research subjects. The Neuropathology Core, under Dr. Gambetti, will perform pathological diagnosis of dementia cases and controls and assist in the analyses of animal models. Dr. Neundorfer will run our Minority Recruitment Satellite. Dr. Smyth will lead the Management and Analysis Core that stores and helps to analyze the data sets collected during the previous 12 years. Dr. Stuckey will direct the Education & Information Transfer Core to disseminate reliable information on AD and its treatment to students, professionals and the public. Dr. Herrup will run the Laboratory Services Core that will offer access to a range of AD animal models. This renewal application describes the structure of an ADRC aimed at further our knowledge of Alzheimer's disease itself and developing the most effective means of easing the burden of AD for both its sufferers and their caregivers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: UROKINASE-TYPE ACTIVATOR/ALZHEIMER'S DISEASE

PLASMINOGEN

Principal Investigator & Institution: Estus, Steven S.; Associate Professor; Physiology; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-MAY2005 Summary: (provided by applicant): Genetic factors that contribute to Alzheimer's disease (AD) susceptibility are critical to our understanding and early diagnosis of the disease. A chromosome 10 region contains at least one susceptibility locus for late onset Alzheimer's disease, and is associated with increased amyloid-B (ADi) plasma levels. The gene encoding urokinase-type plasminogen activator (uPA) is within this implicated region. UPA is induced by AB-treated neurons in vitro and in the Hsiao mouse model of AB burden in vivo. Moreover, uPA converts plasminogen to the active protease plasmin, which degrades both nonaggregated and aggregated AB with physiologic efficiency. In summation, ADi induces uPA, which can in turn lead to AB degradation, suggesting a self-regulated system for clearance of AB aggregates.

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Considering these data overall we hypothesize that the chromosome 10 loci includes a uPA polymorphism(s) that modulates uPA's ability to contribute to AD clearance. To evaluate this hypothesis, we propose to (i) identify uPA polymorphisms that segregate with Alzheimer’s disease. In preliminary work we have identified two uPA polymorphisms that significantly segregate with AD susceptibility and are in strong linkage disequilibrium, including (i) a substitution of leu for pro at position 141 within uPA, which alters binding of the uPA zymogen to aggregated fibrin and (ii) a SNP two basepairs 3' to an AP-I site that is known to be critical for uPA induction. We also propose to (ii) Gain insight into the possible role of the at-risk uPA haplotype by comparing individuals homozygous for each genotype for relevant clinical and neuropathologic markers of Alzheimer's disease, (iii) Evaluate the effect of the uPA polymorphisms associated with AD risk on uPA expression and function, and (iv) Evaluate the role of uPA in AB clearance in vivo by quantifying AB accumulation in mice that are wildtype or genetically deficient for uPA. Overall, the focused approach proposed here will (i) directly evaluate the possible role of uPA polymorphisms as a risk factor(s) for Alzheimer's disease, and (ii) provide insights into possible mechanisms underlying differential uPA actions. These studies are significant in that the identification of additional genetic risk factors for Alzheimer's disease will aid in early AD diagnosis, and thereby facilitate drug discovery by identifying patients at high risk for AD prior to symptomology. Moreover, by evaluating possible mechanisms underlying the enhanced susceptibility to Alzheimer's disease, these studies may lead to the discovery of novel insights into the molecular mechanisms underlying Alzheimer's disease, and thereby suggest new therapeutic approaches. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: UTILITY ALZHEIMER'S DISEASE

OF

MUSCARINIC

AGONISTS

Principal Investigator & Institution: Ghosh, Debasis;; Pharmaceuticals, Ltd 333 14Th St Toledo, Oh 43624

FOR

Cognitive

Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 31-OCT2003 Summary: (provided by applicant): The purpose of the present study is to assess the utility of muscarinic agonists in treating Alzheimer’s disease. Levels of acetylcholine decrease in Alzheimer's disease, resulting in memory deficits. Efforts to treat Alzheimer's disease have been based on compounds that mimic acetylcholine without producing side effects such as salivation or diarrhea. Unfortunately, muscarinic agonists have shown

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limited clinical utility due to low efficacy, poor selectivity or high toxicity. Recent studies suggest however, that muscarinic agonists might be useful in treating not only memory impairments, but also the underlying causes of Alzheimer’s disease. In particular, muscarinic agonists promote asecretase activity, thereby limiting the production of b-amyloid, and stimulate Akt , which prevents the phosphorylation of tau proteins. Thus administration of efficacious, selective and safe muscarinic agonists could be beneficial in the early stages of Alzheimer’s disease. 5-(3-Ethyl-1,2 4oxadiazol-5-yl)-1 ,4,5,6-tetrahydropyrimidine (CDD-0 102) activates muscarinic receptors in brain and improves memory function with few side effects and low toxicity in the present study, CDD-01 02 will be examined for its ability to promote a-secretase and Akt activity. Metabolites of CDD-0102 will be determined and examined for receptor activity to assess safety. Together, the studies will assess the utility of CDD-01 02 in treating not only cognitive and memory deficits, but also the progression of Alzheimer’s disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

E-Journals: PubMed Central19 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).20 Access to this growing archive of e-journals is free and unrestricted.21 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “Alzheimer’s disease” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for Alzheimer’s disease in the PubMed Central database:

Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html. 20 With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 21 The value of PubMed Central, in addition to its role as an archive, lies the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print. 19

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[beta]-Amyloid peptides enhance [alpha]-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. by Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M, Mucke L.; 2001 Oct 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=59799

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A polymorphic gene nested within an intron of the tau gene: Implications for Alzheimer's disease. by Conrad C, Vianna C, Freeman M, Davies P.; 2002 May 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=124341

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A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and A[beta]. by Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, Kita Y, Kawasumi M, Kouyama K, Doyu M, Sobue G, Koide T, Tsuji S, Lang J, Kurokawa K, Nishimoto I.; 2001 May 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=33469

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Advances in the pharmacotherapy of Alzheimer's disease. by Gauthier S.; 2002 Mar 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=99406

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Aggravated decrease in the activity of nucleus basalis neurons in Alzheimer's disease is apolipoprotein E-type dependent. by Salehi A, Dubelaar EJ, Mulder M, Swaab DF.; 1998 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=21662

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Agrin in Alzheimer's disease: Altered solubility and abnormal distribution within microvasculature and brain parenchyma. by Donahue JE, Berzin TM, Rafii MS, Glass DJ, Yancopoulos GD, Fallon JR, Stopa EG.; 1999 May 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=26905

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Alzheimer's disease and herpes. by Itzhaki RF, Dobson CB.; 2002 Jul 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=116625

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Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. by Huang Y, Liu XQ, Wyss-Coray T, Brecht WJ, Sanan DA, Mahley RW.; 2001 Jul 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=37522

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Apolipoprotein E is essential for amyloid deposition in the APP V717F transgenic mouse model of Alzheimer's disease. by Bales KR, Verina T, Cummins DJ, Du Y, Dodel RC, Saura J, Fishman CE, DeLong CA, Piccardo P, Petegnief V, Ghetti B, Paul SM.; 1999 Dec 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=24803

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Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. by Holtzman DM, Bales KR, Tenkova T, Fagan AM, Parsadanian M, Sartorius LJ, Mackey B, Olney J, McKeel D, Wozniak D, Paul SM.; 2000 Mar 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=16026

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Apparent mtDNA heteroplasmy in Alzheimer's disease patients and in normals due to PCR amplification of nucleus-embedded mtDNA pseudogenes. by Hirano M, Shtilbans A, Mayeux R, Davidson MM, DiMauro S, Knowles JA, Schon EA.; 1997 Dec 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=25134

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Canadians' awareness of Alzheimer's disease lacking. by Martin S.; 2003 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=152713

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Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. by Small GW, Ercoli LM, Silverman DH, Huang SC, Komo S, Bookheimer SY, Lavretsky H, Miller K, Siddarth P, Rasgon NL, Mazziotta JC, Saxena S, Wu HM, Mega MS, Cummings JL, Saunders AM, Pericak-Vance MA, Roses AD, Barrio JR, Phelps ME.; 2000 May 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=18554

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Cingulate cortex hypoperfusion predicts Alzheimer's disease in mild cognitive impairment. by Huang C, Wahlund LO, Svensson L, Winblad B, Julin P.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=128832

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Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease. by DeMattos RB, O'dell MA, Parsadanian M, Taylor JW, Harmony JA, Bales KR, Paul SM, Aronow BJ, Holtzman DM.; 2002 Aug 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=125060

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Correlates of response to acetylcholinesterase inhibitor therapy in Alzheimer's disease. by Lanctot KL, Herrmann N, LouLou MM.; 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=161722

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Current pharmacologic options for patients with Alzheimer's disease. by Reichman WE.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=149431

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Declining brain activity in cognitively normal apolipoprotein E [var epsilon]4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease. by Reiman EM, Caselli RJ, Chen K, Alexander GE, Bandy D, Frost J.; 2001 Mar 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=30654

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Detection of Alzheimer's disease and dementia in the preclinical phase: population based cohort study. by Palmer K, Backman L, Winblad B, Fratiglioni L.; 2003 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=140758

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Detection of neuritic plaques in Alzheimer's disease by magnetic resonance microscopy. by Benveniste H, Einstein G, Kim KR, Hulette C, Johnson GA.; 1999 Nov 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=24193

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Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studies. by Etminan M, Gill S, Samii A.; 2003 Jul 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=165707

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Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. by Lanctot KL, Herrmann N, Yau KK, Khan LR, Liu BA, LouLou MM, Einarson TR.; 2003 Sep 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=191283

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Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial. by Wilcock GK, Lilienfeld S, Gaens E.; 2000 Dec 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=27547

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Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial. by Rosler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, Stahelin HB, Hartman R, Gharabawi M.; 1999 Mar 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=27767

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Epitope and isotype specificities of antibodies to [beta]-amyloid peptide for protection against Alzheimer's disease-like neuropathology. by Bard F, Barbour R, Cannon C, Carretto R, Fox M, Games D, Guido T, Hoenow K, Hu K, Johnson-Wood K, Khan K, Kholodenko D, Lee C, Lee M, Motter R, Nguyen M, Reed A, Schenk D, Tang P, Vasquez N, Seubert P, Yednock T.; 2003 Feb 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=149952

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Evidence for defective retinoid transport and function in late onset Alzheimer's disease. by Goodman AB, Pardee AB.; 2003 Mar 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=151438

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Expression profiles of multiple genes in single neurons of Alzheimer's disease. by Chow N, Cox C, Callahan LM, Weimer JM, Guo L, Coleman PD.; 1998 Aug 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=21388

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Failure To Detect Chlamydia pneumoniae in Brain Sections of Alzheimer's Disease Patients. by Gieffers J, Reusche E, Solbach W, Maass M.; 2000 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=86233

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Familial multiple system tauopathy with presenile dementia: A disease with abundant neuronal and glial tau filaments. by Spillantini MG, Goedert M, Crowther RA, Murrell JR, Farlow MR, Ghetti B.; 1997 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=20577

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From Alzheimer's disease to skin tumors: The catenin connection. by Hartmann D.; 2001 Sep 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=58494

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Functional brain imaging to identify affected subjects genetically at risk for Alzheimer's disease. by Rapoport SI.; 2000 May 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=33991

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Functional integrity of mitochondrial genomes in human platelets and autopsied brain tissues from elderly patients with Alzheimer's disease. by Ito S, Ohta S, Nishimaki K, Kagawa Y, Soma R, Kuno SY, Komatsuzaki Y, Mizusawa H, Hayashi JI.; 1999 Mar 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=26743

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Galanin transgenic mice display cognitive and neurochemical deficits characteristic of Alzheimer's disease. by Steiner RA, Hohmann JG, Holmes A, Wrenn CC, Cadd G, Jureus A, Clifton DK, Luo M, Gutshall M, Ma SY, Mufson EJ, Crawley JN.; 2001 Mar 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=31200

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Immune hyporesponsiveness to amyloid [beta]-peptide in amyloid precursor protein transgenic mice: Implications for the pathogenesis and treatment of Alzheimer's disease. by Monsonego A, Maron R, Zota V, Selkoe DJ, Weiner HL.; 2001 Aug 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=56951

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In vivo detection of amyloid plaques in a mouse model of Alzheimer's disease. by Skovronsky DM, Zhang B, Kung MP, Kung HF, Trojanowski JQ, Lee VM.; 2000 Jun 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=16593

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Inhibition of the ubiquitin-proteasome system in Alzheimer's disease. by Lam YA, Pickart CM, Alban A, Landon M, Jamieson C, Ramage R, Mayer RJ, Layfield R.; 2000 Aug 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=27620

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Interhemispheric disconnection syndrome in Alzheimer's disease. by Lakmache Y, Lassonde M, Gauthier S, Frigon JY, Lepore F.; 1998 Jul 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=21199

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Lipoprotein profile in older patients with vascular dementia and Alzheimer's disease. by Zuliani G, Ble' A, Zanca R, Munari MR, Zurlo A, Vavalle C, Atti AR, Fellin R.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=64782

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Mapping the evolution of regional atrophy in Alzheimer's disease: Unbiased analysis of fluid-registered serial MRI. by Scahill RI, Schott JM, Stevens JM, Rossor MN, Fox NC.; 2002 Apr 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=123711

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Mechanism of the cleavage specificity of Alzheimer's disease [gamma]secretase identified by phenylalanine-scanning mutagenesis of the transmembrane domain of the amyloid precursor protein. by Lichtenthaler SF, Wang R, Grimm H, Uljon SN, Masters CL, Beyreuther K.; 1999 Mar 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=15893

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Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. by Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A.; 2001 Jun 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=32306

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Multiple luteinizing hormone receptor (LHR) protein variants, interspecies reactivity of anti-LHR mAb clone 3B5, subcellular localization of LHR in human placenta, pelvic floor and brain, and possible role for LHR in the development of abnormal pregnancy, pelvic floor disorders and Alzheimer's disease. by Bukovsky A, Indrapichate K, Fujiwara H, Cekanova M, Ayala ME, Dominguez R, Caudle MR, Wimalsena J, Elder RF, Copas P, Foster JS, Fernando RI, Henley DC, Upadhyaya NB.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=161821

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Multiplex fluorescence-based primer extension method for quantitative mutation analysis of mitochondrial DNA and its diagnostic application for Alzheimer’s disease. by Fahy E, Nazarbaghi R, Zomorrodi M, Herrnstadt C, Parker WD, Davis RE, Ghosh SS.; 1997 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&ren dertype=abstract&artid=146869

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Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. by Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B.; 1998 Jun 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=22742

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Neuropathological changes in scrapie and Alzheimer's disease are associated with increased expression of apolipoprotein E and cathepsin D in astrocytes.. by Diedrich JF, Minnigan H, Carp RI, Whitaker JN, Race R, Frey W 2nd, Haase AT.; 1991 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action =stream&blobtype=pdf&artid=248933

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Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease. by Urbanc B, Cruz L, Le R, Sanders J, Ashe KH, Duff K, Stanley HE, Irizarry MC, Hyman BT.; 2002 Oct 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=137824

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Opposite roles of apolipoprotein E in normal brains and in Alzheimer's disease. by Russo C, Angelini G, Dapino D, Piccini A, Piombo G, Schettini G, Chen S, Teller JK, Zaccheo D, Gambetti P, Tabaton M.; 1998 Dec 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=28089

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Overexpression of hAPPswe Impairs Rewarded Alternation and Contextual Fear Conditioning in a Transgenic Mouse Model of

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Alzheimer's Disease. by Corcoran KA, Lu Y, Turner RS, Maren S.; 2002 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=187133 •

Past exposure to vaccines and subsequent risk of Alzheimer's disease. by Verreault R, Laurin D, Lindsay J, Serres GD.; 2001 Nov 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=81665

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Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control-group members. by Friedland RP, Fritsch T, Smyth KA, Koss E, Lerner AJ, Chen CH, Petot GJ, Debanne SM.; 2001 Mar 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=30672

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Peripheral anti-A[beta] antibody alters CNS and plasma A[beta] clearance and decreases brain A[beta] burden in a mouse model of Alzheimer's disease. by DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM.; 2001 Jul 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=37524

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Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. by Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, Kholodenko D, Malenka RC, Nicoll RA, Mucke L.; 1999 Mar 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=15924

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Plaque-induced neurite abnormalities: Implications for disruption of neural networks in Alzheimer's disease. by Knowles RB, Wyart C, Buldyrev SV, Cruz L, Urbanc B, Hasselmo ME, Stanley HE, Hyman BT.; 1999 Apr 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=21854

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Presenilin, Notch, and the genesis and treatment of Alzheimer's disease. by Selkoe DJ.; 2001 Sep 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=58679

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Simvastatin strongly reduces levels of Alzheimer's disease [beta]amyloid peptides A[beta]42 and A[beta]40 in vitro and in vivo. by Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P,

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Runz H, Kuhl S, Bertsch T, von Bergmann K, Hennerici M, Beyreuther K, Hartmann T.; 2001 May 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=33303 •

Specific intercellular binding of the [beta]-amyloid precursor protein to the presenilins induces intercellular signaling: Its significance for Alzheimer's disease. by Dewji NN, Singer SJ.; 1998 Dec 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=24574

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Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3[beta] but not of cyclin-dependent kinase 5 and c-Jun NH2-terminal kinase and concomitantly abolishes hyperphosphorylation of [tau]: Implications for Alzheimer's disease. by Papasozomenos SC, Shanavas A.; 2002 Feb 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=122157

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The Endogenous and Cell Cycle-dependent Phosphorylation of tau Protein in Living Cells: Implications for Alzheimer's Disease. by Illenberger S, Zheng-Fischhofer Q, Preuss U, Stamer K, Baumann K, Trinczek B, Biernat J, Godemann R, Mandelkow EM, Mandelkow E.; 1998 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=25374

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The galvanization of [beta]-amyloid in Alzheimer's disease. by Bush AI, Tanzi RE.; 2002 May 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=124227

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Three-dimensional structure of the lithostathine protofibril, a protein involved in Alzheimer's disease. by Gregoire C, Marco S, Thimonier J, Duplan L, Laurine E, Chauvin JP, Michel B, Peyrot V, Verdier JM.; 2001 Jul 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=125531

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To what degree does cognitive impairment in Alzheimer's disease predict dependence of patients on caregivers? by Caro J, Ward A, Ishak K, Migliaccio-Walle K, Getsios D, Papadopoulos G, Torfs K.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=123722

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Unusual phenotypic alteration of [beta] amyloid precursor protein ([beta]APP) maturation by a new Val-715 [right arrow] Met [beta]APP770 mutation responsible for probable early-onset Alzheimer's disease.

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by Ancolio K, Dumanchin C, Barelli H, Warter JM, Brice A, Campion D, Frebourg T, Checler F.; 1999 Mar 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=22430 •

When should one stop cholinesterase inhibitors in patients with Alzheimer's disease? by Bogardus ST Jr.; 2001 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&arti d=167204

The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine. The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to the public.22 If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with Alzheimer’s disease, simply go to the PubMed Web site at www.ncbi.nlm.nih.gov/pubmed. Type “Alzheimer’s disease” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for “Alzheimer’s disease” (hyperlinks lead to article summaries):

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A large, community-based, open-label trial of donepezil in the treatment of Alzheimer's disease. Author(s): Relkin NR, Reichman WE, Orazem J, McRae T. Source: Dementia and Geriatric Cognitive Disorders. 2003; 16(1): 15-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12714795&dopt=Abstract

PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.

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Studies 175

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A randomised placebo controlled study to assess the effects of cholinergic treatment on muscarinic receptors in Alzheimer's disease. Author(s): Kemp PM, Holmes C, Hoffmann S, Wilkinson S, Zivanovic M, Thom J, Bolt L, Fleming J, Wilkinson DG. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 November; 74(11): 1567-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14617718&dopt=Abstract

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A turn of the sulfatide in Alzheimer's disease. Author(s): Irizarry MC. Source: Annals of Neurology. 2003 July; 54(1): 7-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12838515&dopt=Abstract

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Abuse of patient with Alzheimer's disease in a nursing home. Author(s): Castledine G. Source: British Journal of Nursing (Mark Allen Publishing). 2003 October 9-22; 12(18): 1065. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14581838&dopt=Abstract

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Age-dependent association between the Q7R polymorphism in the Saitohin gene and sporadic Alzheimer's disease. Author(s): Combarros O, Rodero L, Infante J, Palacio E, Llorca J, Fernandez-Viadero C, Pena N, Berciano J. Source: Dementia and Geriatric Cognitive Disorders. 2003; 16(3): 132-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12826738&dopt=Abstract

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Alzheimer's disease and angiogenesis. Author(s): Tony JC. Source: Lancet. 2003 April 12; 361(9365): 1300. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12699983&dopt=Abstract

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Alzheimer's disease and angiogenesis. Author(s): Agorogiannis EI, Agorogiannis GI. Source: Lancet. 2003 April 12; 361(9365): 1299; Author Reply 1299-300. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12699979&dopt=Abstract

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Alzheimer's disease and angiogenesis. Author(s): Strandberg TE. Source: Lancet. 2003 April 12; 361(9365): 1298-9; Author Reply 1299-300. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12699978&dopt=Abstract

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Alzheimer's disease and angiogenesis. Author(s): Rutz HP. Source: Lancet. 2003 April 12; 361(9365): 1298; Author Reply 1299-300. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12699977&dopt=Abstract

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Alzheimer's disease and Parkinson's disease. Author(s): Nussbaum RL, Ellis CE. Source: The New England Journal of Medicine. 2003 April 3; 348(14): 1356-64. Review. Erratum In: N Engl J Med. 2003 June 19; 348(25): 2588. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12672864&dopt=Abstract

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Alzheimer's disease caregiving information and skills. Part I: care recipient issues and concerns. Author(s): Farran CJ, Loukissa D, Perraud S, Paun O. Source: Research in Nursing & Health. 2003 October; 26(5): 366-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14579257&dopt=Abstract

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Alzheimer's disease, neuropeptides, neuropeptidase, and amyloid-beta peptide metabolism. Author(s): Saito T, Takaki Y, Iwata N, Trojanowski J, Saido TC. Source: Sci Aging Knowledge Environ. 2003 January 22; 2003(3): Pe1. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12844556&dopt=Abstract

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Amyloid, presenilins, and Alzheimer's disease. Author(s): Van Gassen G, Annaert W. Source: The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry. 2003 April; 9(2): 117-26. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12708616&dopt=Abstract

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Antioxidant vitamins E and C and risk of Alzheimer's disease. Author(s): Martin A. Source: Nutrition Reviews. 2003 February; 61(2): 69-73. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12674439&dopt=Abstract

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Assessment of neuroinflammation and microglial activation in Alzheimer's disease with radiolabelled PK11195 and single photon emission computed tomography. A pilot study. Author(s): Versijpt JJ, Dumont F, Van Laere KJ, Decoo D, Santens P, Audenaert K, Achten E, Slegers G, Dierckx RA, Korf J. Source: European Neurology. 2003; 50(1): 39-47. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12824711&dopt=Abstract

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Association of Alzheimer's disease onset with ginkgo biloba and other symptomatic cognitive treatments in a population of women aged 75 years and older from the EPIDOS study. Author(s): Andrieu S, Gillette S, Amouyal K, Nourhashemi F, Reynish E, Ousset PJ, Albarede JL, Vellas B, Grandjean H; EPIDOS study. Source: The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2003 April; 58(4): 372-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12663701&dopt=Abstract

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Association of the androgen receptor CAG repeat polymorphism with Alzheimer's disease in men. Author(s): Lehmann DJ, Butler HT, Warden DR, Combrinck M, King E, Nicoll JA, Budge MM, de Jager CA, Hogervorst E, Esiri MM, Ragoussis J, Smith AD. Source: Neuroscience Letters. 2003 April 10; 340(2): 87-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12668243&dopt=Abstract

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Atrophy of the substantia innominata on magnetic resonance imaging predicts response to donepezil treatment in Alzheimer's disease patients. Author(s): Tanaka Y, Hanyu H, Sakurai H, Takasaki M, Abe K. Source: Dementia and Geriatric Cognitive Disorders. 2003; 16(3): 119-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12826736&dopt=Abstract

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Attentional dynamics and visual perception: mechanisms of spatial disorientation in Alzheimer's disease. Author(s): Kavcic V, Duffy CJ. Source: Brain; a Journal of Neurology. 2003 May; 126(Pt 5): 1173-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12690056&dopt=Abstract

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Autoantibodies to amyloid beta-peptide (Abeta) are increased in Alzheimer's disease patients and Abeta antibodies can enhance Abeta neurotoxicity: implications for disease pathogenesis and vaccine development. Author(s): Nath A, Hall E, Tuzova M, Dobbs M, Jons M, Anderson C, Woodward J, Guo Z, Fu W, Kryscio R, Wekstein D, Smith C, Markesbery WR, Mattson MP. Source: Neuromolecular Medicine. 2003; 3(1): 29-39. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12665674&dopt=Abstract

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Barriers to remember: brain-targeting chemical delivery systems and Alzheimer's disease. Author(s): Bodor N, Buchwald P. Source: Drug Discovery Today. 2002 July 15; 7(14): 766-74. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12547033&dopt=Abstract

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Behavioural pathology in Alzheimer's disease with special reference to apolipoprotein E genotype. Author(s): Gabryelewicz T, Religa D, Styczynska M, Peplonska B, Pfeffer A, Wasiak B, Luczywek E, Golebiowski M, Androsiuk W, Czyzewski K, Przekop I, Barcikowska M. Source: Dementia and Geriatric Cognitive Disorders. 2002; 14(4): 208-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12411763&dopt=Abstract

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Beta-amyloid fragment 25-35 selectively damages platelets from patients with Alzheimer's disease. Author(s): Casoli T, Di Stefano G, Delfino A, Solazzi M, Fattoretti P, Bertoni-Freddari C, Guidi M, Scarpino O, Giunta S, Galeazzi L. Source: Annals of the New York Academy of Sciences. 2002 November; 977: 296-302. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12480764&dopt=Abstract

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Beta-amyloid production, aggregation, and clearance as targets for therapy in Alzheimer's disease. Author(s): De Felice FG, Ferreira ST. Source: Cellular and Molecular Neurobiology. 2002 December; 22(5-6): 545-63. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12585679&dopt=Abstract

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Beta-secretase (BACE) and GSK-3 mRNA levels in Alzheimer's disease. Author(s): Preece P, Virley DJ, Costandi M, Coombes R, Moss SJ, Mudge AW, Jazin E, Cairns NJ. Source: Brain Research. Molecular Brain Research. 2003 August 19; 116(12): 155-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12941471&dopt=Abstract

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Beta-secretase (BACE) as a drug target for Alzheimer's disease. Author(s): Vassar R. Source: Advanced Drug Delivery Reviews. 2002 December 7; 54(12): 1589-602. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12453676&dopt=Abstract

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Biochemical analysis of GABA(A) receptor subunits alpha 1, alpha 5, beta 1, beta 2 in the hippocampus of patients with Alzheimer's disease neuropathology. Author(s): Rissman RA, Mishizen-Eberz AJ, Carter TL, Wolfe BB, De Blas AL, Miralles CP, Ikonomovic MD, Armstrong DM. Source: Neuroscience. 2003; 120(3): 695-704. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12895510&dopt=Abstract

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Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Author(s): Di Matteo V, Esposito E. Source: Current Drug Targets. Cns and Neurological Disorders. 2003 April; 2(2): 95-107. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12769802&dopt=Abstract

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Biological markers for therapeutic trials in Alzheimer's disease. Proceedings of the biological markers working group; NIA initiative on neuroimaging in Alzheimer's disease. Author(s): Frank RA, Galasko D, Hampel H, Hardy J, de Leon MJ, Mehta PD, Rogers J, Siemers E, Trojanowski JQ; National Institute on Aging Biological Markers Working Group. Source: Neurobiology of Aging. 2003 July-August; 24(4): 521-36. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12714109&dopt=Abstract

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Biomarkers of Alzheimer's disease and mild cognitive impairment: are we there yet? Author(s): Turner RS. Source: Experimental Neurology. 2003 September; 183(1): 7-10. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12957483&dopt=Abstract

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Bradykinin receptor modulation in cellular models of aging and Alzheimer's disease. Author(s): Jong YJ, Dalemar LR, Seehra K, Baenziger NL. Source: International Immunopharmacology. 2002 December; 2(13-14): 1833-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12489797&dopt=Abstract

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Brain aging and Alzheimer's disease; use it or lose it. Author(s): Swaab DF, Dubelaar EJ, Hofman MA, Scherder EJ, van Someren EJ, Verwer RW. Source: Prog Brain Res. 2002; 138: 343-73. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12432778&dopt=Abstract

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Brain biopsy prior to treatment of Alzheimer's disease. Author(s): Holm A, Savolainen S, Alafuzoff I. Source: Minimally Invasive Neurosurgery : Min. 2003 June; 46(3): 161-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12872193&dopt=Abstract

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Brain cholesterol, statins and Alzheimer's Disease. Author(s): Kirsch C, Eckert GP, Koudinov AR, Muller WE. Source: Pharmacopsychiatry. 2003 September; 36 Suppl 2: S113-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14574624&dopt=Abstract

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Brain hydrogen sulfide is severely decreased in Alzheimer's disease. Author(s): Eto K, Asada T, Arima K, Makifuchi T, Kimura H. Source: Biochemical and Biophysical Research Communications. 2002 May 24; 293(5): 1485-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12054683&dopt=Abstract

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Brain perfusion in Alzheimer's disease with and without apathy: a SPECT study with statistical parametric mapping analysis. Author(s): Benoit M, Koulibaly PM, Migneco O, Darcourt J, Pringuey DJ, Robert PH. Source: Psychiatry Research. 2002 June 15; 114(2): 103-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12036510&dopt=Abstract

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Brain-membrane cholesterol in Alzheimer's disease. Author(s): Eckert GP, Kirsch C, Muller WE. Source: J Nutr Health Aging. 2003; 7(1): 18-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12679836&dopt=Abstract

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Brazilian version of the Mattis dementia rating scale: diagnosis of mild dementia in Alzheimer's disease. Author(s): Porto CS, Fichman HC, Caramelli P, Bahia VS, Nitrini R. Source: Arquivos De Neuro-Psiquiatria. 2003 June; 61(2B): 339-45. Epub 2003 July 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12894264&dopt=Abstract

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Broad therapeutic benefits in patients with probable vascular dementia or Alzheimer's disease with cerebrovascular disease treated with galantamine. Author(s): Lilienfeld S, Kurz A. Source: Annals of the New York Academy of Sciences. 2002 November; 977: 487-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12480790&dopt=Abstract

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Butyrylcholinesterase: an important new target in Alzheimer's disease therapy. Author(s): Greig NH, Lahiri DK, Sambamurti K. Source: Int Psychogeriatr. 2002; 14 Suppl 1: 77-91. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12636181&dopt=Abstract

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Canadians' awareness of Alzheimer's disease lacking. Author(s): Martin S. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 2003 April 15; 168(8): 1038. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12695411&dopt=Abstract

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Cathepsin D polymorphism in Italian elderly subjects with sporadic late-onset Alzheimer's disease. Author(s): Ingegni T, Nocentini G, Mariani E, Spazzafumo L, Polidori MC, Cherubini A, Catani M, Cadini D, Senin U, Mecocci P. Source: Dementia and Geriatric Cognitive Disorders. 2003; 16(3): 151-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12826741&dopt=Abstract

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CCR1 is an early and specific marker of Alzheimer's disease. Author(s): Halks-Miller M, Schroeder ML, Haroutunian V, Moenning U, Rossi M, Achim C, Purohit D, Mahmoudi M, Horuk R. Source: Annals of Neurology. 2003 November; 54(5): 638-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14595653&dopt=Abstract

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Cerebral atherosclerosis and mild Alzheimer's disease. Author(s): Rafael H. Source: Stroke; a Journal of Cerebral Circulation. 2003 August; 34(8): E106. Epub 2003 July 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12855821&dopt=Abstract

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Cerebral correlates of the progression rate of the cognitive decline in probable Alzheimer's disease. Author(s): Nagahama Y, Nabatame H, Okina T, Yamauchi H, Narita M, Fujimoto N, Murakami M, Fukuyama H, Matsuda M. Source: European Neurology. 2003; 50(1): 1-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12824705&dopt=Abstract

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Change in rates of cerebral atrophy over time in early-onset Alzheimer's disease: longitudinal MRI study. Author(s): Chan D, Janssen JC, Whitwell JL, Watt HC, Jenkins R, Frost C, Rossor MN, Fox NC. Source: Lancet. 2003 October 4; 362(9390): 1121-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14550701&dopt=Abstract

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Chemokines in serum and cerebrospinal fluid of Alzheimer's disease patients. Author(s): Galimberti D, Schoonenboom N, Scarpini E, Scheltens P; Dutch-Italian Alzheimer Research Group. Source: Annals of Neurology. 2003 April; 53(4): 547-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12666129&dopt=Abstract

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Cholesterol paradox: is high total or low HDL cholesterol level a risk for Alzheimer's disease? Author(s): Michikawa M. Source: Journal of Neuroscience Research. 2003 April 15; 72(2): 141-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12671988&dopt=Abstract

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Cholesterol, synaptic function and Alzheimer's disease. Author(s): Koudinov AR, Koudinova NV. Source: Pharmacopsychiatry. 2003 September; 36 Suppl 2: S107-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14574623&dopt=Abstract

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Clinical characteristics of Alzheimer's disease. Author(s): Asada T. Source: Intern Med. 2003 March; 42(3): 310-1. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12705808&dopt=Abstract

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Clinically tested drugs for Alzheimer's disease. Author(s): McGeer EG, McGeer PL. Source: Expert Opinion on Investigational Drugs. 2003 July; 12(7): 114351. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12831349&dopt=Abstract

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Commentary on Spriggs: genetically selected baby free of inherited predisposition to early onset Alzheimer's disease. Author(s): Delatycki MB. Source: Journal of Medical Ethics. 2003 April; 29(2): 120. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12672897&dopt=Abstract

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Connecting with the cognitively impaired: dementia and Alzheimer's disease. Author(s): Ledoux N. Source: Caring. 2003 August; 22(8): 30-2; Quiz 33-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14556377&dopt=Abstract

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Copper, beta-amyloid, and Alzheimer's disease: tapping a sensitive connection. Author(s): Bush AI, Masters CL, Tanzi RE. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 September 30; 100(20): 11193-4. Epub 2003 Sep 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14506299&dopt=Abstract

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Corpus callosum atrophy, white matter lesions, and frontal executive dysfunction in normal aging and Alzheimer's disease. A communitybased study: the Tajiri Project. Author(s): Meguro K, Constans JM, Shimada M, Yamaguchi S, Ishizaki J, Ishii H, Yamadori A, Sekita Y. Source: Int Psychogeriatr. 2003 March; 15(1): 9-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12834197&dopt=Abstract

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Correlation between morphological and functional retinal impairment in patients affected by ocular hypertension, glaucoma, demyelinating optic neuritis and Alzheimer's disease. Author(s): Parisi V. Source: Seminars in Ophthalmology. 2003 June; 18(2): 50-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14566623&dopt=Abstract

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Correlation of neuropsychological evaluation and SPECT imaging in patients with Alzheimer's disease. Author(s): Lampl Y, Sadeh M, Laker O, Lorberboym M. Source: International Journal of Geriatric Psychiatry. 2003 April; 18(4): 288-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12673603&dopt=Abstract

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Costs to society of family caregiving for patients with end-stage Alzheimer's disease. Author(s): Prigerson HG. Source: The New England Journal of Medicine. 2003 November 13; 349(20): 1891-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14614164&dopt=Abstract

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CSF markers for incipient Alzheimer's disease. Author(s): Blennow K, Hampel H. Source: Lancet. Neurology. 2003 October; 2(10): 605-13. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14505582&dopt=Abstract

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Cytosolic beta-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer's disease. Author(s): Goldstein LE, Muffat JA, Cherny RA, Moir RD, Ericsson MH, Huang X, Mavros C, Coccia JA, Faget KY, Fitch KA, Masters CL, Tanzi RE, Chylack LT Jr, Bush AI. Source: Lancet. 2003 April 12; 361(9365): 1258-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12699953&dopt=Abstract

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Defects in expression of genes related to synaptic vesicle trafficking in frontal cortex of Alzheimer's disease. Author(s): Yao PJ, Zhu M, Pyun EI, Brooks AI, Therianos S, Meyers VE, Coleman PD. Source: Neurobiology of Disease. 2003 March; 12(2): 97-109. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12667465&dopt=Abstract

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Delusions and hallucinations in Alzheimer's disease: review of the brain decade. Author(s): Bassiony MM, Lyketsos CG. Source: Psychosomatics. 2003 September-October; 44(5): 388-401. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12954913&dopt=Abstract

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Depression in Alzheimer's disease: heterogeneity and related issues. Author(s): Lee HB, Lyketsos CG. Source: Biological Psychiatry. 2003 August 1; 54(3): 353-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12893110&dopt=Abstract

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Development of diagnostic criteria for defining sleep disturbance in Alzheimer's disease. Author(s): Yesavage JA, Friedman L, Ancoli-Israel S, Bliwise D, Singer C, Vitiello MV, Monjan AA, Lebowitz B. Source: Journal of Geriatric Psychiatry and Neurology. 2003 September; 16(3): 131-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12967054&dopt=Abstract

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Dexamethasone inhibits TNF-alpha synthesis more effectively in Alzheimer's disease patients than in healthy individuals. Author(s): Dziedzic T, Wybranska I, Dembinska-Kiec A, Klimkowicz A, Slowik A, Pankiewicz J, Zdzienicka A, Szczudlik A. Source: Dementia and Geriatric Cognitive Disorders. 2003; 16(4): 283-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14512725&dopt=Abstract

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Diagnosis and management of Alzheimer's disease. Author(s): Coll PP, Fortinsky RH, Kaplan R, Song C. Source: Conn Med. 2003 September; 67(8): 505-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14587132&dopt=Abstract

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Diagnosis and treatment of Alzheimer's disease. Author(s): Grossberg GT. Source: The Journal of Clinical Psychiatry. 2003; 64 Suppl 9: 3-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12934967&dopt=Abstract

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Dietary lipids in the aetiology of Alzheimer's disease: implications for therapy. Author(s): Cooper JL. Source: Drugs & Aging. 2003; 20(6): 399-418. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12710861&dopt=Abstract

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Differences between African Americans and Whites in their attitudes toward genetic testing for Alzheimer's disease. Author(s): Hipps YG, Roberts JS, Farrer LA, Green RC. Source: Genetic Testing. 2003 Spring; 7(1): 39-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12820701&dopt=Abstract

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Differences in the behavioral and psychological symptoms between Alzheimer's disease and vascular dementia: are the different pharmacologic treatment strategies justifiable? Author(s): Kim JM, Lyons D, Shin IS, Yoon JS. Source: Human Psychopharmacology. 2003 April; 18(3): 215-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12672174&dopt=Abstract

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Direct determination of the proportion of intra- and extra-cellular neocortical neurofibrillary tangles in Alzheimer's disease. Author(s): Vickers JC, Tan A, Dickson TC. Source: Brain Research. 2003 May 2; 971(1): 135-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12691846&dopt=Abstract

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Do dietary antioxidants prevent Alzheimer's disease? Author(s): Sano M. Source: Lancet. Neurology. 2002 October; 1(6): 342. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12849394&dopt=Abstract

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Do leisure activities protect against Alzheimer's disease? Author(s): Fabrigoule C. Source: Lancet. Neurology. 2002 May; 1(1): 11. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12849540&dopt=Abstract

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Does participation in leisure activities lead to reduced risk of Alzheimer's disease? A prospective study of Swedish twins. Author(s): Crowe M, Andel R, Pedersen NL, Johansson B, Gatz M. Source: The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences. 2003 September; 58(5): P249-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14507930&dopt=Abstract

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Does proteasome inhibition play a role in mediating neuropathology and neuron death in Alzheimer's disease? Author(s): Ding Q, Keller JN. Source: Journal of Alzheimer's Disease : Jad. 2003 June; 5(3): 241-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12897408&dopt=Abstract

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Donepezil for dementia due to Alzheimer's disease. Author(s): Birks JS, Harvey R. Source: Cochrane Database Syst Rev. 2003; (3): Cd001190. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12917900&dopt=Abstract

Studies 189

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Donepezil is associated with delayed nursing home placement in patients with Alzheimer's disease. Author(s): Geldmacher DS, Provenzano G, McRae T, Mastey V, Ieni JR. Source: Journal of the American Geriatrics Society. 2003 July; 51(7): 93744. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12834513&dopt=Abstract

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Donepezil use for advanced Alzheimer's disease--a case study from a long-term care facility. Author(s): Tariot PN, Jakimovich L. Source: Journal of the American Medical Directors Association. 2003 JulyAugust; 4(4): 216-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12837144&dopt=Abstract

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Dysphagia and aspiration pneumonia in patients with Alzheimer's disease. Author(s): Kalia M. Source: Metabolism: Clinical and Experimental. 2003 October; 52(10 Suppl 2): 36-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14577062&dopt=Abstract

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Dysregulation of calcium in Alzheimer's disease. Author(s): Brzyska M, Elbaum D. Source: Acta Neurobiol Exp (Wars). 2003; 63(3): 171-83. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14518509&dopt=Abstract

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Early and persistent alterations in prefrontal cortex MAO A and B in Alzheimer's disease. Author(s): Kennedy BP, Ziegler MG, Alford M, Hansen LA, Thal LJ, Masliah E. Source: Journal of Neural Transmission (Vienna, Austria : 1996). 2003 July; 110(7): 789-801. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12811639&dopt=Abstract

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Economic evaluation of galantamine in the treatment of mild to moderate Alzheimer's disease in the United States. Author(s): Migliaccio-Walle K, Getsios D, Caro JJ, Ishak KJ, O'Brien JA, Papadopoulos G; AHEAD Study Group. Source: Clinical Therapeutics. 2003 June; 25(6): 1806-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12860500&dopt=Abstract

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EEG synchronization in mild cognitive impairment and Alzheimer's disease. Author(s): Stam CJ, van der Made Y, Pijnenburg YA, Scheltens P. Source: Acta Neurologica Scandinavica. 2003 August; 108(2): 90-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12859284&dopt=Abstract

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Effect of advanced glycation endproducts on cell cycle and their relevance for Alzheimer's disease. Author(s): Munch G, Gasic-Milenkovic J, Arendt T. Source: Journal of Neural Transmission. Supplementum. 2003; (65): 63-71. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12946049&dopt=Abstract

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Effect of age on regional cerebral blood flow patterns in Alzheimer's disease patients. Author(s): Hanyu H, Shimuzu T, Tanaka Y, Takasaki M, Koizumi K, Abe K. Source: Journal of the Neurological Sciences. 2003 May 15; 209(1-2): 25-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12686398&dopt=Abstract

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Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studies. Author(s): Etminan M, Gill S, Samii A. Source: Bmj (Clinical Research Ed.). 2003 July 19; 327(7407): 128. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12869452&dopt=Abstract

Studies 191

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Effect of NSAIDs on risk of Alzheimer's disease: conclusions on NSAIDs and Alzheimer's disease were overstated. Author(s): Price D. Source: Bmj (Clinical Research Ed.). 2003 September 27; 327(7417): 752. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14512499&dopt=Abstract

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Effect of NSAIDs on risk of Alzheimer's disease: confounding factors were not discussed. Author(s): Robertson M. Source: Bmj (Clinical Research Ed.). 2003 September 27; 327(7417): 751; Author Reply 751-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14512494&dopt=Abstract

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Effects of acetyl-L-carnitine in Alzheimer's disease patients unresponsive to acetylcholinesterase inhibitors. Author(s): Bianchetti A, Rozzini R, Trabucchi M. Source: Current Medical Research and Opinion. 2003; 19(4): 350-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12841930&dopt=Abstract

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Effects of blood pressure on neuropsychological functioning in Alzheimer's disease. Author(s): Davis RN, Massman PJ, Doody RS. Source: Archives of Clinical Neuropsychology : the Official Journal of the National Academy of Neuropsychologists. 2003 January; 18(1): 19-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14591475&dopt=Abstract

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Effects of low-frequency cranial electrostimulation on the rest-activity rhythm and salivary cortisol in Alzheimer's disease. Author(s): Scherder E, Knol D, van Someren E, Deijen JB, Binnekade R, Tilders F, Sergeant J. Source: Neurorehabilitation and Neural Repair. 2003 June; 17(2): 101-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12814055&dopt=Abstract

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Effects of normal aging and Alzheimer's disease on emotional memory. Author(s): Kensinger EA, Brierley B, Medford N, Growdon JH, Corkin S. Source: Emotion (Washington, D.C.). 2002 June; 2(2): 118-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12899186&dopt=Abstract

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Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. Author(s): Lanctot KL, Herrmann N, Yau KK, Khan LR, Liu BA, LouLou MM, Einarson TR. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 2003 September 16; 169(6): 557-64. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12975222&dopt=Abstract

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Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer's disease. Author(s): Gauthier S, Feldman H, Hecker J, Vellas B, Ames D, Subbiah P, Whalen E, Emir B; Donepezil MSAD Study Investigators Group. Source: Int Psychogeriatr. 2002 December; 14(4): 389-404. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12670060&dopt=Abstract

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Estrogen receptor alpha-immunoreactive astrocytes are increased in the hippocampus in Alzheimer's disease. Author(s): Lu YP, Zeng M, Hu XY, Xu H, Swaab DF, Ravid R, Zhou JN. Source: Experimental Neurology. 2003 October; 183(2): 482-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14552888&dopt=Abstract

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Estrogen receptors and metabolic activity in the human tuberomamillary nucleus: changes in relation to sex, aging and Alzheimer's disease. Author(s): Ishunina TA, van Heerikhuize JJ, Ravid R, Swaab DF. Source: Brain Research. 2003 October 24; 988(1-2): 84-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14519529&dopt=Abstract

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Estrogen-induced cell signalling in a cellular model of Alzheimer's disease. Author(s): Goodenough S, Schafer M, Behl C. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 February; 84(2-3): 301-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12711016&dopt=Abstract

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Evidence linking neuronal cell death to autoimmunity in Alzheimer's disease. Author(s): D'Andrea MR. Source: Brain Research. 2003 August 22; 982(1): 19-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12915236&dopt=Abstract

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Exploring professional caregivers' perceptions. Balancing self-care with care for patients with Alzheimer's disease. Author(s): McCarty EF, Drebing C. Source: Journal of Gerontological Nursing. 2003 September; 29(9): 42-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14528748&dopt=Abstract

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Expression and distribution of carboxypeptidase B in the hippocampal subregions of normal and Alzheimer's disease brain. Author(s): Papp H, Torok I, Matsumoto A, Enomoto T, Matsuyama S, Kasa P. Source: Acta Biol Hung. 2003; 54(1): 55-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12705322&dopt=Abstract

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F175S change and a novel polymorphism in presenilin-1 gene in lateonset familial Alzheimer's disease. Author(s): Colacicco AM, Panza F, Basile AM, Solfrizzi V, Capurso C, D'Introno A, Torres F, Capurso S, Cozza S, Flora R, Capurso A. Source: European Neurology. 2002; 47(4): 209-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12037434&dopt=Abstract

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Facilitating acquisition and transfer of a continuous motor task in healthy older adults and patients with Alzheimer's disease. Author(s): Dick MB, Hsieh S, Bricker J, Dick-Muehlke C. Source: Neuropsychology. 2003 April; 17(2): 202-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12803425&dopt=Abstract

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Factor structure of a modified version of the wisconsin card sorting test: an analysis of executive deficit in Alzheimer's disease and mild cognitive impairment. Author(s): Nagahama Y, Okina T, Suzuki N, Matsuzaki S, Yamauchi H, Nabatame H, Matsuda M. Source: Dementia and Geriatric Cognitive Disorders. 2003; 16(2): 103-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12784035&dopt=Abstract

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Failure to correlate C. pneumoniae with late onset Alzheimer's disease. Author(s): Taylor GS, Vipond IB, Paul ID, Matthews S, Wilcock GK, Caul EO. Source: Neurology. 2002 July 9; 59(1): 142-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12105327&dopt=Abstract

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False recognition of pictures versus words in Alzheimer's disease: the distinctiveness heuristic. Author(s): Budson AE, Sitarski J, Daffner KR, Schacter DL. Source: Neuropsychology. 2002 April; 16(2): 163-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11949708&dopt=Abstract

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Fast axonal transport misregulation and Alzheimer's disease. Author(s): Morfini G, Pigino G, Beffert U, Busciglio J, Brady ST. Source: Neuromolecular Medicine. 2002; 2(2): 89-99. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12428805&dopt=Abstract

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Fertility and number of children in patients with Alzheimer's disease. Author(s): Ptok U, Barkow K, Heun R. Source: Archives of Women's Mental Health. 2002 October; 5(2): 83-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12510204&dopt=Abstract

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Fine mapping of susceptibility genes by Lewontin's linkage disequilibrium measure with application to Alzheimer's disease. Author(s): Gong G, Haynatzki G, Deng HW, Recker RR, Mordeson J, Cheng SC, Fong N. Source: Chinese Medical Journal. 2002 August; 115(8): 1233-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12215300&dopt=Abstract

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First clinical evaluation of ganstigmine in patients with probable Alzheimer's disease. Author(s): Jhee SS, Fabbri L, Piccinno A, Monici P, Moran S, Zarotsky V, Tan EY, Frackiewicz EJ, Shiovitz T. Source: Clinical Neuropharmacology. 2003 May-June; 26(3): 164-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12782920&dopt=Abstract

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Five-year retrospective changes in hippocampal atrophy and cognitive screening test performances in very mild Alzheimer's disease: the Tajiri Project. Author(s): Yamaguchi S, Meguro K, Shimada M, Ishizaki J, Yamadori A, Sekita Y. Source: Neuroradiology. 2002 January; 44(1): 43-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11942499&dopt=Abstract

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Focal temporoparietal slow activity in Alzheimer's disease revealed by magnetoencephalography. Author(s): Fernandez A, Maestu F, Amo C, Gil P, Fehr T, Wienbruch C, Rockstroh B, Elbert T, Ortiz T. Source: Biological Psychiatry. 2002 October 1; 52(7): 764-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12372668&dopt=Abstract

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Folic acid and Alzheimer's disease. Author(s): Tsolaki M, Kartali N. Source: International Journal of Geriatric Psychiatry. 2003 February; 18(2): 187-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12571831&dopt=Abstract

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Formation of hydrogen peroxide and hydroxyl radicals from A(beta) and alpha-synuclein as a possible mechanism of cell death in Alzheimer's disease and Parkinson's disease. Author(s): Tabner BJ, Turnbull S, El-Agnaf OM, Allsop D. Source: Free Radical Biology & Medicine. 2002 June 1; 32(11): 1076-83. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12031892&dopt=Abstract

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Fractal analysis of cerebral blood flow distribution in Alzheimer's disease. Author(s): Kuikka JT. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2002 December; 43(12): 1727-8; Author Reply 1728. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12468525&dopt=Abstract

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Frequency and characteristics of anxiety among patients with Alzheimer's disease and related dementias. Author(s): Porter VR, Buxton WG, Fairbanks LA, Strickland T, O'Connor SM, Rosenberg-Thompson S, Cummings JL. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 2003 Spring; 15(2): 180-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12724459&dopt=Abstract

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From anticholinesterase toxicity to Alzheimer's disease: important interactions of cholinergic and NMDA receptor systems. Author(s): Popke EJ. Source: Toxicological Sciences : an Official Journal of the Society of Toxicology. 2003 April; 72(2): 185-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12685427&dopt=Abstract

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From epidemiology to therapeutic trials with anti-inflammatory drugs in Alzheimer's disease: the role of NSAIDs and cyclooxygenase in betaamyloidosis and clinical dementia. Author(s): Pasinetti GM. Source: Journal of Alzheimer's Disease : Jad. 2002 October; 4(5): 435-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12446975&dopt=Abstract

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Functional ability in executive variant Alzheimer's disease and typical Alzheimer's disease. Author(s): Back-Madruga C, Boone KB, Briere J, Cummings J, McPherson S, Fairbanks L, Thompson E. Source: Clin Neuropsychol. 2002 August; 16(3): 331-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12607146&dopt=Abstract

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Functional imaging of visuospatial processing in Alzheimer's disease. Author(s): Prvulovic D, Hubl D, Sack AT, Melillo L, Maurer K, Frolich L, Lanfermann H, Zanella FE, Goebel R, Linden DE, Dierks T. Source: Neuroimage. 2002 November; 17(3): 1403-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12414280&dopt=Abstract

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Functional, cognitive and behavioral effects of donepezil in patients with moderate Alzheimer's disease. Author(s): Gauthier S, Feldman H, Hecker J, Vellas B, Emir B, Subbiah P; Donepezil MSAD Study Investigators' Group. Source: Current Medical Research and Opinion. 2002; 18(6): 347-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12442882&dopt=Abstract

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Galantamine hydrobromide: an agent for Alzheimer's disease. Author(s): Zarotsky V, Sramek JJ, Cutler NR. Source: American Journal of Health-System Pharmacy : Ajhp : Official Journal of the American Society of Health-System Pharmacists. 2003 March 1; 60(5): 446-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12635450&dopt=Abstract

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Galantamine in the treatment of cognitive decline in patients with vascular dementia or Alzheimer's disease with cerebrovascular disease. Author(s): Small G, Erkinjuntti T, Kurz A, Lilienfeld S. Source: Cns Drugs. 2003; 17(12): 905-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12962529&dopt=Abstract

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Galantamine population pharmacokinetics in patients with Alzheimer's disease: modeling and simulations. Author(s): Piotrovsky V, Van Peer A, Van Osselaer N, Armstrong M, Aerssens J. Source: Journal of Clinical Pharmacology. 2003 May; 43(5): 514-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12751272&dopt=Abstract

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Galantamine provides sustained benefits in patients with 'advanced moderate' Alzheimer's disease for at least 12 months. Author(s): Blesa R, Davidson M, Kurz A, Reichman W, van Baelen B, Schwalen S. Source: Dementia and Geriatric Cognitive Disorders. 2003; 15(2): 79-87. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12566596&dopt=Abstract

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Galantamine: a review of its use in Alzheimer's disease and vascular dementia. Author(s): Corey-Bloom J. Source: Int J Clin Pract. 2003 April; 57(3): 219-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12723727&dopt=Abstract

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Games played by rogue proteins in prion disorders and Alzheimer's disease. Author(s): Aguzzi A, Haass C. Source: Science. 2003 October 31; 302(5646): 814-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14593165&dopt=Abstract

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Gamma-secretase inhibitors and Alzheimer's disease. Author(s): Roberts SB. Source: Advanced Drug Delivery Reviews. 2002 December 7; 54(12): 1579-88. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12453675&dopt=Abstract

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Gene expression analysis in a transgenic Caenorhabditis elegans Alzheimer's disease model. Author(s): Link CD, Taft A, Kapulkin V, Duke K, Kim S, Fei Q, Wood DE, Sahagan BG. Source: Neurobiology of Aging. 2003 May-June; 24(3): 397-413. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12600716&dopt=Abstract

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Gene expression in Alzheimer's disease. Author(s): Ermak G, Davies KJ. Source: Drugs Today (Barc). 2002 July; 38(7): 509-16. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12582468&dopt=Abstract

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Gene expression profiles of cholinergic nucleus basalis neurons in Alzheimer's disease. Author(s): Mufson EJ, Counts SE, Ginsberg SD. Source: Neurochemical Research. 2002 October; 27(10): 1035-48. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12462403&dopt=Abstract

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Generalized synchronization of MEG recordings in Alzheimer's Disease: evidence for involvement of the gamma band. Author(s): Stam CJ, van Cappellen van Walsum AM, Pijnenburg YA, Berendse HW, de Munck JC, Scheltens P, van Dijk BW. Source: Journal of Clinical Neurophysiology : Official Publication of the American Electroencephalographic Society. 2002 December; 19(6): 562-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12488788&dopt=Abstract

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Genetic analysis of vascular factors in Alzheimer's disease. Author(s): Wakutani Y, Kowa H, Kusumi M, Yamagata K, Wada-Isoe K, Adachi Y, Takeshima T, Urakami K, Nakashima K. Source: Annals of the New York Academy of Sciences. 2002 November; 977: 232-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12480755&dopt=Abstract

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Glaucoma: ocular Alzheimer's disease? Author(s): McKinnon SJ. Source: Frontiers in Bioscience : a Journal and Virtual Library. 2003 September 1; 8: S1140-56. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12957857&dopt=Abstract

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Glial levels determine severity of white matter disease in Alzheimer's disease: a neuropathological study of glial changes. Author(s): Sjobeck M, Englund E. Source: Neuropathology and Applied Neurobiology. 2003 April; 29(2): 159-69. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12662323&dopt=Abstract

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Glutamatergic systems in Alzheimer's disease. Author(s): Francis PT. Source: International Journal of Geriatric Psychiatry. 2003 September; 18(Suppl 1): S15-21. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12973746&dopt=Abstract

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Glycation of the amyloid beta-protein by a nicotine metabolite: a fortuitous chemical dynamic between smoking and Alzheimer's disease. Author(s): Dickerson TJ, Janda KD. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 July 8; 100(14): 8182-7. Epub 2003 June 18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12815102&dopt=Abstract

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Glycosylation of acetylcholinesterase and butyrylcholinesterase changes as a function of the duration of Alzheimer's disease. Author(s): Saez-Valero J, Fodero LR, Sjogren M, Andreasen N, Amici S, Gallai V, Vanderstichele H, Vanmechelen E, Parnetti L, Blennow K, Small DH. Source: Journal of Neuroscience Research. 2003 May 15; 72(4): 520-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12704813&dopt=Abstract

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Glycoxidative stress creates a vicious cycle of neurodegeneration in Alzheimer's disease--a target for neuroprotective treatment strategies? Author(s): Munch G, Deuther-Conrad W, Gasic-Milenkovic J. Source: Journal of Neural Transmission. Supplementum. 2002; (62): 303-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12456073&dopt=Abstract

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G-protein alpha-subunit levels in hippocampus and entorhinal cortex of brains staged for Alzheimer's disease neurofibrillary and amyloid pathologies. Author(s): Garcia-Jimenez A, Fastbom J, Ohm TG, Cowburn RF. Source: Neuroreport. 2003 August 6; 14(11): 1523-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12960778&dopt=Abstract

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GSK3beta signalling: casting a wide net in Alzheimer's disease. Author(s): Bhat RV, Budd SL. Source: Neuro-Signals. 2002 September-October; 11(5): 251-61. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12566926&dopt=Abstract

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Haplogroup analysis of the risk associated with APOE promoter polymorphisms (-219T/G, -491A/T and -427T/C) in Colombian Alzheimer's disease patients. Author(s): Parra-Bonilla G, Arboleda G, Yunis J, Solano E, Pardo R, Arango G, Hedmont D, Arboleda H. Source: Neuroscience Letters. 2003 October 9; 349(3): 159-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12951193&dopt=Abstract

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Have cholinergic therapies reached their clinical boundary in Alzheimer's disease? Author(s): Jones RW. Source: International Journal of Geriatric Psychiatry. 2003 September; 18(Suppl 1): S7-S13. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12973745&dopt=Abstract

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Head injury and Alzheimer's disease. Author(s): Wilson JT. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 July; 74(7): 841. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12810761&dopt=Abstract

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Head injury as a risk factor for Alzheimer's disease: the evidence 10 years on; a partial replication. Author(s): Fleminger S, Oliver DL, Lovestone S, Rabe-Hesketh S, Giora A. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 July; 74(7): 857-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12810767&dopt=Abstract

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Health professionals' views on standards for decision-making capacity regarding refusal of medical treatment in mild Alzheimer's disease. Author(s): Volicer L, Ganzini L. Source: Journal of the American Geriatrics Society. 2003 September; 51(9): 1270-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12919240&dopt=Abstract

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Health service utilization by Alzheimer's disease patients: a 2-year follow-up of primary versus subspecialty care. Author(s): Aupperle PM, MacPhee ER, Coyne AC, Blume J, Sanchez B. Source: Journal of Geriatric Psychiatry and Neurology. 2003 March; 16(1): 15-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12641367&dopt=Abstract

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Hemodynamic aspects of Alzheimer's disease. Author(s): Nagata K, Sato M, Satoh Y, Watahiki Y, Kondoh Y, Sugawara M, Box G, Wright D, Leung S, Yuya H, Shimosegawa E. Source: Annals of the New York Academy of Sciences. 2002 November; 977: 391-402. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12480778&dopt=Abstract

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High b value diffusion-weighted imaging is more sensitive to white matter degeneration in Alzheimer's disease. Author(s): Yoshiura T, Mihara F, Tanaka A, Ogomori K, Ohyagi Y, Taniwaki T, Yamada T, Yamasaki T, Ichimiya A, Kinukawa N, Kuwabara Y, Honda H. Source: Neuroimage. 2003 September; 20(1): 413-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14527601&dopt=Abstract

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Hippocampal dopamine D2 receptors correlate with memory functions in Alzheimer's disease. Author(s): Kemppainen N, Laine M, Laakso MP, Kaasinen V, Nagren K, Vahlberg T, Kurki T, Rinne JO. Source: The European Journal of Neuroscience. 2003 July; 18(1): 149-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12859348&dopt=Abstract

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Hippocampal sclerosis in a case of Alzheimer's disease-like dementia with late onset intractable epilepsy. Author(s): Josephs KA, Wai DF, Parisi JE. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2003 May; 10(3): 333-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12752417&dopt=Abstract

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Homocysteine and Alzheimer's disease. Author(s): Leboeuf R. Source: Journal of the American Dietetic Association. 2003 March; 103(3): 304-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12616250&dopt=Abstract

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Homocysteine, apolipoproteine E and methylenetetrahydrofolate reductase in Alzheimer's disease and mild cognitive impairment. Author(s): Religa D, Styczynska M, Peplonska B, Gabryelewicz T, Pfeffer A, Chodakowska M, Luczywek E, Wasiak B, Stepien K, Golebiowski M, Winblad B, Barcikowska M. Source: Dementia and Geriatric Cognitive Disorders. 2003; 16(2): 64-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12784029&dopt=Abstract

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Homogeneity and heterogeneity in mild cognitive impairment and Alzheimer's disease: a cross-sectional and longitudinal study of 55 cases. Author(s): Lambon Ralph MA, Patterson K, Graham N, Dawson K, Hodges JR. Source: Brain; a Journal of Neurology. 2003 November; 126(Pt 11): 235062. Epub 2003 July 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12876147&dopt=Abstract

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Hormone replacement therapy in postmenopausal women with Alzheimer's disease: a randomized, prospective study. Author(s): Yoon BK, Kim DK, Kang Y, Kim JW, Shin MH, Na DL. Source: Fertility and Sterility. 2003 February; 79(2): 274-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12568834&dopt=Abstract

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HSP70-2 (HSPA1B) is associated with noncognitive symptoms in lateonset Alzheimer's disease. Author(s): Clarimon J, Bertranpetit J, Boada M, Tarraga L, Comas D. Source: Journal of Geriatric Psychiatry and Neurology. 2003 September; 16(3): 146-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12967056&dopt=Abstract

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Hydrogen magnetic resonance spectroscopy in Alzheimer's disease. Author(s): Rapoport SI. Source: Lancet. Neurology. 2002 June; 1(2): 82. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12849509&dopt=Abstract

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Hypertension and related factors in the etiology of Alzheimer's disease. Author(s): Skoog I, Gustafson D. Source: Annals of the New York Academy of Sciences. 2002 November; 977: 29-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12480731&dopt=Abstract

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Hypertension, hypertension-clustering factors and Alzheimer's disease. Author(s): Skoog I, Gustafson D. Source: Neurological Research. 2003 September; 25(6): 675-80. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14503023&dopt=Abstract

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Hypothalamic digoxin, hemispheric chemical dominance, and Alzheimer's disease. Author(s): Kurup RK, Kurup PA. Source: The International Journal of Neuroscience. 2003 March; 113(3): 361-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12803139&dopt=Abstract

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Hypothesis for a common basis for neuroprotection in glaucoma and Alzheimer's disease: anti-apoptosis by alpha-2-adrenergic receptor activation. Author(s): Tatton W, Chen D, Chalmers-Redman R, Wheeler L, Nixon R, Tatton N. Source: Survey of Ophthalmology. 2003 April; 48 Suppl 1: S25-37. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12852432&dopt=Abstract

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Identification of peptides that specifically bind Abeta1-40 amyloid in vitro and amyloid plaques in Alzheimer's disease brain using phage display. Author(s): Kang CK, Jayasinha V, Martin PT. Source: Neurobiology of Disease. 2003 October; 14(1): 146-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=13678675&dopt=Abstract

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Identifying severely atrophic cortical subregions in Alzheimer's disease. Author(s): Halliday GM, Double KL, Macdonald V, Kril JJ. Source: Neurobiology of Aging. 2003 October; 24(6): 797-806. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12927762&dopt=Abstract

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Idiom comprehension in Alzheimer's disease: the role of the central executive. Author(s): Papagno C, Lucchelli F, Muggia S, Rizzo S. Source: Brain; a Journal of Neurology. 2003 November; 126(Pt 11): 241930. Epub 2003 August 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12902312&dopt=Abstract

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Imaging of Alzheimer's disease. Author(s): Lee BC, Mintun M, Buckner RL, Morris JC. Source: Journal of Neuroimaging : Official Journal of the American Society of Neuroimaging. 2003 July; 13(3): 199-214. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12889165&dopt=Abstract

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Imaging of the 5-HT2A system: age-, gender-, and Alzheimer's diseaserelated findings. Author(s): Versijpt J, Van Laere KJ, Dumont F, Decoo D, Vandecapelle M, Santens P, Goethals I, Audenaert K, Slegers G, Dierckx RA, Korf J. Source: Neurobiology of Aging. 2003 July-August; 24(4): 553-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12714112&dopt=Abstract

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Immunotherapeutic approaches to Alzheimer's disease. Author(s): Monsonego A, Weiner HL. Source: Science. 2003 October 31; 302(5646): 834-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14593170&dopt=Abstract

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Immunotherapy for Alzheimer's disease. Author(s): Dodel RC, Hampel H, Du Y. Source: Lancet. Neurology. 2003 April; 2(4): 215-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12849209&dopt=Abstract

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Increased concentrations of homocysteine and asymmetric dimethylarginine and decreased concentrations of nitric oxide in the plasma of patients with Alzheimer's disease. Author(s): Selley ML. Source: Neurobiology of Aging. 2003 November; 24(7): 903-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12928048&dopt=Abstract

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Increased neuronal metabolic activity and estrogen receptors in the vertical limb of the diagonal band of Broca in Alzheimer's disease: relation to sex and aging. Author(s): Ishunina TA, Swaab DF. Source: Experimental Neurology. 2003 September; 183(1): 159-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12957499&dopt=Abstract

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Increased plasma levels of matrix metalloproteinase-9 in patients with Alzheimer's disease. Author(s): Lorenzl S, Albers DS, Relkin N, Ngyuen T, Hilgenberg SL, Chirichigno J, Cudkowicz ME, Beal MF. Source: Neurochemistry International. 2003 August; 43(3): 191-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12689599&dopt=Abstract

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Inflammatory markers in matched plasma and cerebrospinal fluid from patients with Alzheimer's disease. Author(s): Sun YX, Minthon L, Wallmark A, Warkentin S, Blennow K, Janciauskiene S. Source: Dementia and Geriatric Cognitive Disorders. 2003; 16(3): 136-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12826739&dopt=Abstract

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Inflammatory processes in Alzheimer's disease. Author(s): McGeer EG, McGeer PL. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2003 August; 27(5): 741-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12921904&dopt=Abstract

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Initial findings from the evaluation of the Alzheimer's Disease Demonstration Grants to States Program. Author(s): Montgomery RJ, Kosloski K, Karner TX, Schaefer JP. Source: Home Health Care Services Quarterly. 2002; 21(3-4): 5-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12665070&dopt=Abstract

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Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer's disease: interactions with apolipoprotein E genotype. Author(s): Craft S, Asthana S, Cook DG, Baker LD, Cherrier M, Purganan K, Wait C, Petrova A, Latendresse S, Watson GS, Newcomer JW, Schellenberg GD, Krohn AJ. Source: Psychoneuroendocrinology. 2003 August; 28(6): 809-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12812866&dopt=Abstract

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Intentional and automatic measures of specific-category effect in the semantic impairment of patients with Alzheimer's disease. Author(s): Perri R, Carlesimo GA, Zannino GD, Mauri M, Muolo B, Pettenati C, Caltagirone C. Source: Neuropsychologia. 2003; 41(11): 1509-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12849769&dopt=Abstract

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Interleukin-1B polymorphism is associated with age at onset of Alzheimer's disease. Author(s): Sciacca FL, Ferri C, Licastro F, Veglia F, Biunno I, Gavazzi A, Calabrese E, Martinelli Boneschi F, Sorbi S, Mariani C, Franceschi M, Grimaldi LM. Source: Neurobiology of Aging. 2003 November; 24(7): 927-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12928052&dopt=Abstract

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Interleukin-6 gene alleles affect the risk of Alzheimer's disease and levels of the cytokine in blood and brain. Author(s): Licastro F, Grimaldi LM, Bonafe M, Martina C, Olivieri F, Cavallone L, Giovanietti S, Masliah E, Franceschi C. Source: Neurobiology of Aging. 2003 November; 24(7): 921-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12928051&dopt=Abstract

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Intrathecal inflammation precedes development of Alzheimer's disease. Author(s): Tarkowski E, Andreasen N, Tarkowski A, Blennow K. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 September; 74(9): 1200-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12933918&dopt=Abstract

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Is Alzheimer's disease a vascular disorder? Author(s): Jellinger KA. Source: Journal of Alzheimer's Disease : Jad. 2003 June; 5(3): 247-50; Discussion 251-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12897409&dopt=Abstract

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Is DNA repair compromised in Alzheimer's disease? Author(s): Davydov V, Hansen LA, Shackelford DA. Source: Neurobiology of Aging. 2003 November; 24(7): 953-68. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12928056&dopt=Abstract

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JKK1, an upstream activator of JNK/SAPK, is activated in Alzheimer's disease. Author(s): Zhu X, Ogawa O, Wang Y, Perry G, Smith MA. Source: Journal of Neurochemistry. 2003 April; 85(1): 87-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12641730&dopt=Abstract

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Kinematic analysis of handwriting movements in patients with Alzheimer's disease, mild cognitive impairment, depression and healthy subjects. Author(s): Schroter A, Mergl R, Burger K, Hampel H, Moller HJ, Hegerl U. Source: Dementia and Geriatric Cognitive Disorders. 2003; 15(3): 132-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12584428&dopt=Abstract

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Lack of association of the interleukin-1beta gene polymorphism with Alzheimer's disease in a Chinese population. Author(s): Ma SL, Tang NL, Lam LC, Chiu HF. Source: Dementia and Geriatric Cognitive Disorders. 2003; 16(4): 265-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14512722&dopt=Abstract

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Lack of influence of the apolipoprotein E genotype on the outcome of selegiline treatment in Alzheimer's disease. Author(s): Kalman J, Juhasz A, Rimanoczy A, Palotas A, Palotas M, Szabo Z, Boda K, Marki-Zay J, Janka Z. Source: Dementia and Geriatric Cognitive Disorders. 2003; 16(1): 31-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12714797&dopt=Abstract

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Late onset Alzheimer's disease and apolipoprotein association in the Irish population: relative risk and attributable fraction. Author(s): Hawi Z, Sheehan K, Lynch A, Evans I, Lowe N, Lawlor B, Gill M. Source: Ir J Med Sci. 2003 April-June; 172(2): 74-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12930057&dopt=Abstract

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Left hippocampal volume loss in Alzheimer's disease is reflected in performance on odor identification: a structural MRI study. Author(s): Murphy C, Jernigan TL, Fennema-Notestine C. Source: Journal of the International Neuropsychological Society : Jins. 2003 March; 9(3): 459-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12666770&dopt=Abstract

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Lewy body pathology is a frequent co-pathology in familial Alzheimer's disease. Author(s): Trembath Y, Rosenberg C, Ervin JF, Schmechel DE, Gaskell P, Pericak-Vance M, Vance J, Hulette CM. Source: Acta Neuropathologica. 2003 May; 105(5): 484-8. Epub 2003 February 11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12677449&dopt=Abstract

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Life situation, coping and quality of life in people with high and low risk of developing Alzheimer's disease. Author(s): Axelman K, Lannfelt L, Almkvist O, Carlsson M. Source: Dementia and Geriatric Cognitive Disorders. 2003; 16(4): 220-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14512717&dopt=Abstract

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Lifetime symptoms of depression in Alzheimer's disease. Author(s): Heun R, Kockler M, Ptok U. Source: European Psychiatry : the Journal of the Association of European Psychiatrists. 2003 March; 18(2): 63-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12711401&dopt=Abstract

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Limbic hypometabolism in Alzheimer's disease and mild cognitive impairment. Author(s): Nestor PJ, Fryer TD, Smielewski P, Hodges JR. Source: Annals of Neurology. 2003 September; 54(3): 343-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12953266&dopt=Abstract

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Lipoproteins and lipid peroxidation in Alzheimer's disease. Author(s): Bassett CN, Montine TJ. Source: J Nutr Health Aging. 2003; 7(1): 24-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12679837&dopt=Abstract

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Loneliness and depression in spousal caregivers of those with Alzheimer's disease versus non-caregiving spouses. Author(s): Beeson RA. Source: Archives of Psychiatric Nursing. 2003 June; 17(3): 135-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12840806&dopt=Abstract

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Long-term cholinesterase inhibitor therapy for Alzheimer's disease: implications for long-term care. Author(s): Brangman SA. Source: Am J Alzheimers Dis Other Demen. 2003 March-April; 18(2): 7984. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12708222&dopt=Abstract

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Management of Alzheimer's disease. Author(s): Grossberg GT, Desai AK. Source: The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2003 April; 58(4): 331-53. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12663697&dopt=Abstract

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Managing Alzheimer's disease in the new health care economy. Author(s): Kettl P. Source: Administration and Policy in Mental Health. 2003 January; 30(3): 267-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12854681&dopt=Abstract

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Memantine in moderate-to-severe Alzheimer's disease. Author(s): Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ; Memantine Study Group. Source: The New England Journal of Medicine. 2003 April 3; 348(14): 1333-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12672860&dopt=Abstract

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Microtubule reduction in Alzheimer's disease and aging is independent of tau filament formation. Author(s): Cash AD, Aliev G, Siedlak SL, Nunomura A, Fujioka H, Zhu X, Raina AK, Vinters HV, Tabaton M, Johnson AB, Paula-Barbosa M, Avila J, Jones PK, Castellani RJ, Smith MA, Perry G. Source: American Journal of Pathology. 2003 May; 162(5): 1623-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12707046&dopt=Abstract

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Mitochondria and vascular lesions as a central target for the development of Alzheimer's disease and Alzheimer disease-like pathology in transgenic mice. Author(s): Aliev G, Seyidova D, Lamb BT, Obrenovich ME, Siedlak SL, Vinters HV, Friedland RP, LaManna JC, Smith MA, Perry G. Source: Neurological Research. 2003 September; 25(6): 665-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14503022&dopt=Abstract

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Mitochondrial dysfunction, apoptotic cell death, and Alzheimer's disease. Author(s): Eckert A, Keil U, Marques CA, Bonert A, Frey C, Schussel K, Muller WE. Source: Biochemical Pharmacology. 2003 October 15; 66(8): 1627-34. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14555243&dopt=Abstract

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Molecular genetics of Alzheimer's disease: presenilin 1 gene analysis in a cohort of patients from the Poznan region. Author(s): Kowalska A, Wender M, Florczak J, Pruchnik-Wolinska D, Modestowicz R, Szczech J, Rossa G, Kozubski W. Source: Journal of Applied Genetics. 2003; 44(2): 231-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12817569&dopt=Abstract

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Molecular pathogenesis of Alzheimer's disease. Author(s): Iwatsubo T. Source: Intern Med. 2003 March; 42(3): 312. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12705809&dopt=Abstract

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MR spectroscopy in Alzheimer's disease: gender differences in probabilistic learning capacity. Author(s): Colla M, Ende G, Bohrer M, Deuschle M, Kronenberg G, Henn F, Heuser I. Source: Neurobiology of Aging. 2003 July-August; 24(4): 545-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12714111&dopt=Abstract

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Muscarinic receptors in basal ganglia in dementia with Lewy bodies, Parkinson's disease and Alzheimer's disease. Author(s): Piggott MA, Owens J, O'Brien J, Colloby S, Fenwick J, Wyper D, Jaros E, Johnson M, Perry RH, Perry EK. Source: Journal of Chemical Neuroanatomy. 2003 March; 25(3): 161-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12706204&dopt=Abstract

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Nature of personal semantic memory: evidence from Alzheimer's disease. Author(s): Kazui H, Hashimoto M, Hirono N, Mori E. Source: Neuropsychologia. 2003; 41(8): 981-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12667533&dopt=Abstract

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Nerve growth factor: structure, function and therapeutic implications for Alzheimer's disease. Author(s): Lad SP, Neet KE, Mufson EJ. Source: Current Drug Targets. Cns and Neurological Disorders. 2003 October; 2(5): 315-34. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14529363&dopt=Abstract

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Neuropsychological performance in Alzheimer's disease and vascular dementia: comparisons in a memory clinic population. Author(s): Baillon S, Muhommad S, Marudkar M, Suribhatla S, Dennis M, Spreadbury C, Munro D, Lindesay J. Source: International Journal of Geriatric Psychiatry. 2003 July; 18(7): 6028. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12833304&dopt=Abstract

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Neuropsychological study of familial Alzheimer's disease caused by mutation E280A in the presenilin 1 gene. Author(s): Arango Lasprilla JC, Iglesias J, Lopera F. Source: Am J Alzheimers Dis Other Demen. 2003 May-June; 18(3): 137-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12811988&dopt=Abstract

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Neuroscience. Insulin insults may spur Alzheimer's disease. Author(s): Taubes G. Source: Science. 2003 July 4; 301(5629): 40-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12843374&dopt=Abstract

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Neurosteroids: Cerebrospinal fluid levels for Alzheimer's disease and vascular dementia diagnostics. Author(s): Kim SB, Hill M, Kwak YT, Hampl R, Jo DH, Morfin R. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 November; 88(11): 5199-206. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14602750&dopt=Abstract

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New learning and remote memory in atypical Alzheimer's disease. Author(s): Thompson JC, Beswick T, Foster JK, Snowden JS. Source: Cortex. 2003 September-December; 39(4-5): 751-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14584551&dopt=Abstract

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New website for Alzheimer's disease launched in Spain. Author(s): Bosch X. Source: Lancet. Neurology. 2003 January; 2(1): 3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12849280&dopt=Abstract

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Nicotinic receptors and Alzheimer's disease. Author(s): Bourion M, Ripoll N, Dailly E. Source: Current Medical Research and Opinion. 2003; 19(3): 169-77. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12814128&dopt=Abstract

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No association between Glu298Asp endothelial nitric oxide synthase polymorphism and Italian sporadic Alzheimer's disease. Author(s): Monastero R, Cefalu AB, Camarda C, Buglino CM, Mannino M, Barbagallo CM, Lopez G, Camarda LK, Travali S, Camarda R, Averna MR. Source: Neuroscience Letters. 2003 May 8; 341(3): 229-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12697290&dopt=Abstract

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Of mice and men: The relevance of transgenic mice Abeta immunizations to Alzheimer's disease. Author(s): Roher AE, Kokjohn TA. Source: Journal of Alzheimer's Disease : Jad. 2002 October; 4(5): 431-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12446974&dopt=Abstract

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Olanzapine as a treatment of neuropsychiatric disorders of Alzheimer's disease and other dementias: a 24-month follow-up of 68 patients. Author(s): Moretti R, Torre P, Antonello RM, Cazzato G, Griggio S, Bava A. Source: Am J Alzheimers Dis Other Demen. 2003 July-August; 18(4): 20514. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12955785&dopt=Abstract

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Older women caring for spouses with Alzheimer's disease at home: making sense of the situation. Author(s): Paun O. Source: Health Care for Women International. 2003 April; 24(4): 292-312. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12746002&dopt=Abstract

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Omental transposition to the brain as a surgical method for treating Alzheimer's disease. Author(s): Goldsmith HS, Wu W, Zhong J, Edgar M. Source: Neurological Research. 2003 September; 25(6): 625-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14503017&dopt=Abstract

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On disentangling states versus traits: demonstration of a new technique using the Alzheimer's disease assessment scale. Author(s): Taylor JL, Kraemer HC, Noda A, Friedman L, Zarcone V, Tinklenberg JR, Yesavage JA. Source: Alzheimer Disease and Associated Disorders. 2002 OctoberDecember; 16(4): 254-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12468900&dopt=Abstract

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Outcomes of Alzheimer's disease treatment: the Italian CRONOS project. Author(s): Bianchetti A, Padovani A, Trabucchi M. Source: International Journal of Geriatric Psychiatry. 2003 January; 18(1): 87-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12497562&dopt=Abstract

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Overexpression of wild-type presenilin 2 or its familial Alzheimer's disease-associated mutant does not induce or increase susceptibility to apoptosis in different cell lines. Author(s): Gamliel A, Teicher C, Hartmann T, Beyreuther K, Stein R. Source: Neuroscience. 2003; 117(1): 19-28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12605888&dopt=Abstract

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Oxidative stress, perturbed calcium homeostasis, and immune dysfunction in Alzheimer's disease. Author(s): Mattson MP. Source: Journal of Neurovirology. 2002 December; 8(6): 539-50. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12476348&dopt=Abstract

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Oxidative stress-mediated DHEA formation in Alzheimer's disease pathology. Author(s): Brown RC, Han Z, Cascio C, Papadopoulos V. Source: Neurobiology of Aging. 2003 January-February; 24(1): 57-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12493551&dopt=Abstract

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Oxidized neprilysin in aging and Alzheimer's disease brains. Author(s): Wang DS, Iwata N, Hama E, Saido TC, Dickson DW. Source: Biochemical and Biophysical Research Communications. 2003 October 10; 310(1): 236-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14511676&dopt=Abstract

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P38 MAP kinase is activated at early stages in Alzheimer's disease brain. Author(s): Sun A, Liu M, Nguyen XV, Bing G. Source: Experimental Neurology. 2003 October; 183(2): 394-405. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14552880&dopt=Abstract

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Pathogenesis of Alzheimer's disease and the role of heme oxygenase: new perspectives and hypothesis. Author(s): Celec P, Prihodova M. Source: Folia Neuropathol. 2003; 41(3): 155-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14604297&dopt=Abstract

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Pharmacologic treatment of Alzheimer's disease: an update. Author(s): DeLaGarza VW. Source: American Family Physician. 2003 October 1; 68(7): 1365-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14567491&dopt=Abstract

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Pharmacotherapy for Alzheimer's disease: 2002. Author(s): Knopman D. Source: Clinical Neuropharmacology. 2003 March-April; 26(2): 93-101. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12671529&dopt=Abstract

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Polymorphism in the BACE gene influences the risk for Alzheimer's disease. Author(s): Kirschling CM, Kolsch H, Frahnert C, Rao ML, Maier W, Heun R. Source: Neuroreport. 2003 July 1; 14(9): 1243-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12824768&dopt=Abstract

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Polymorphisms of the gene encoding the inflammatory cytokine interleukin-6 determine the magnitude of the increase in soluble interleukin-6 receptor levels in Alzheimer's disease. Results of a pilot study. Author(s): Bagli M, Papassotiropoulos A, Hampel H, Becker K, Jessen F, Burger K, Ptok U, Rao ML, Moller HJ, Maier W, Heun R. Source: European Archives of Psychiatry and Clinical Neuroscience. 2003 February; 253(1): 44-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12664314&dopt=Abstract

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Possible involvement of Wiskott-Aldrich syndrome protein family in aberrant neuronal sprouting in Alzheimer's disease. Author(s): Kitamura Y, Tsuchiya D, Takata K, Shibagaki K, Taniguchi T, Smith MA, Perry G, Miki H, Takenawa T, Shimohama S. Source: Neuroscience Letters. 2003 August 7; 346(3): 149-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12853106&dopt=Abstract

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Prediction of the rate of decline in cognitive function in Alzheimer's disease: a model based on simple demographic data and widely used rating scales. Author(s): Johnsen S, Hughes S, Bullock R, Hindmarch I. Source: Dementia and Geriatric Cognitive Disorders. 2003; 16(4): 276-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14512724&dopt=Abstract

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Progressive degeneration of nonphosphorylated neurofilament protein-enriched pyramidal neurons predicts cognitive impairment in Alzheimer's disease: stereologic analysis of prefrontal cortex area 9. Author(s): Bussiere T, Giannakopoulos P, Bouras C, Perl DP, Morrison JH, Hof PR. Source: The Journal of Comparative Neurology. 2003 August 25; 463(3): 281-302. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12820162&dopt=Abstract

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Psychopathological features in Alzheimer's disease: course and relationship with cognitive status. Author(s): Holtzer R, Tang MX, Devanand DP, Albert SM, Wegesin DJ, Marder K, Bell K, Albert M, Brandt J, Stern Y. Source: Journal of the American Geriatrics Society. 2003 July; 51(7): 95360. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12834515&dopt=Abstract

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Qualitative performance characteristics differentiate dementia with Lewy bodies and Alzheimer's disease. Author(s): Doubleday EK, Snowden JS, Varma AR, Neary D. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2002 May; 72(5): 602-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11971046&dopt=Abstract

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Qualitative performance characteristics differentiate dementia with Lewy bodies and Alzheimer's disease. Author(s): Ballard C, O'Brien J, Tovee M. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2002 May; 72(5): 565-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11971037&dopt=Abstract

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Quantification of regional glial fibrillary acidic protein levels in Alzheimer's disease. Author(s): Ross GW, O'Callaghan JP, Sharp DS, Petrovitch H, Miller DB, Abbott RD, Nelson J, Launer LJ, Foley DJ, Burchfiel CM, Hardman J, White LR. Source: Acta Neurologica Scandinavica. 2003 May; 107(5): 318-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12713522&dopt=Abstract

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Quantitative assessment of DNA fragmentation and beta-amyloid deposition in insular cortex and midfrontal gyrus from patients with Alzheimer's disease. Author(s): Colurso GJ, Nilson JE, Vervoort LG. Source: Life Sciences. 2003 August 22; 73(14): 1795-803. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12888118&dopt=Abstract

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Quantitative EEG abnormalities and cognitive dysfunctions in frontotemporal dementia and Alzheimer's disease. Author(s): Lindau M, Jelic V, Johansson SE, Andersen C, Wahlund LO, Almkvist O. Source: Dementia and Geriatric Cognitive Disorders. 2003; 15(2): 106-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12566600&dopt=Abstract

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Quantitative EEG and dynamic susceptibility contrast MRI in Alzheimer's disease: a correlative study. Author(s): Mattia D, Babiloni F, Romigi A, Cincotti F, Bianchi L, Sperli F, Placidi F, Bozzao A, Giacomini P, Floris R, Grazia Marciani M. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2003 July; 114(7): 1210-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12842717&dopt=Abstract

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Rate of cognitive decline in preclinical Alzheimer's disease: the role of comorbidity. Author(s): Backman L, Jones S, Small BJ, Aguero-Torres H, Fratiglioni L. Source: The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences. 2003 July; 58(4): P228-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12878651&dopt=Abstract

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Reactivation of atrophic neurons in Alzheimer's disease. Author(s): Swaab DF. Source: Neurological Research. 2003 September; 25(6): 652-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14503020&dopt=Abstract

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Reduced glutamate neurotransmission in patients with Alzheimer's disease -- an in vivo (13)C magnetic resonance spectroscopy study. Author(s): Lin AP, Shic F, Enriquez C, Ross BD. Source: Magma (New York, N.Y.). 2003 February; 16(1): 29-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12695884&dopt=Abstract

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Re-evaluation of tropicamide in the pupillary response test for Alzheimer's disease. Author(s): Iijima A, Haida M, Ishikawa N, Ueno A, Minamitani H, Shinohara Y. Source: Neurobiology of Aging. 2003 October; 24(6): 789-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12927761&dopt=Abstract

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Regional brain atrophy in patients with mild Alzheimer's disease and delusions. Author(s): Geroldi C, Bresciani L, Zanetti O, Frisoni GB. Source: Int Psychogeriatr. 2002 December; 14(4): 365-78. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12670058&dopt=Abstract

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Regional cerebral blood flow and EEG in clinically diagnosed dementia with Lewy bodies and Alzheimer's disease. Author(s): Londos E, Passant U, Brun A, Rosen I, Risberg J, Gustafson L. Source: Archives of Gerontology and Geriatrics. 2003 May-June; 36(3): 231-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12849079&dopt=Abstract

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Regional cerebral glucose metabolism in monozygotic twins discordant for Alzheimer's disease. Author(s): Jarvenpaa T, Raiha I, Kaprio J, Koskenvuo M, Laine M, Kurki T, Vahlberg T, Viljanen T, Ahonen K, Rinne JO. Source: Dementia and Geriatric Cognitive Disorders. 2003; 16(4): 245-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14512720&dopt=Abstract

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Relationship between positive and negative symptoms and neuropsychological scores in frontotemporal dementia and Alzheimer's disease. Author(s): Boone KB, Miller BL, Swartz R, Lu P, Lee A. Source: Journal of the International Neuropsychological Society : Jins. 2003 July; 9(5): 698-709. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12901776&dopt=Abstract

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Response patterns of EGb 761 in Alzheimer's disease: influence of neuropsychological profiles. Author(s): Le Bars PL. Source: Pharmacopsychiatry. 2003 June; 36 Suppl 1: S50-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=13130389&dopt=Abstract

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Response-monitoring dysfunction in aging and Alzheimer's disease: an event-related potential study. Author(s): Mathalon DH, Bennett A, Askari N, Gray EM, Rosenbloom MJ, Ford JM. Source: Neurobiology of Aging. 2003 September; 24(5): 675-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12885575&dopt=Abstract

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Secretases as targets for the treatment of Alzheimer's disease: the prospects. Author(s): Dewachter I, Van Leuven F. Source: Lancet. Neurology. 2002 November; 1(7): 409-16. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12849363&dopt=Abstract

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Self-reported memory compensation: similar patterns in Alzheimer's disease and very old adult samples. Author(s): Dixon RA, Hopp GA, Cohen AL, de Frias CM, Backman L. Source: J Clin Exp Neuropsychol. 2003 May; 25(3): 382-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12916651&dopt=Abstract

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Serotonin transporters are preserved in the neocortex of anxious Alzheimer's disease patients. Author(s): Tsang SW, Lai MK, Francis PT, Wong PT, Spence I, Esiri MM, Keene J, Hope T, Chen CP. Source: Neuroreport. 2003 July 18; 14(10): 1297-300. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12876460&dopt=Abstract

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Should home screening tests for Alzheimer's disease be regulated? Author(s): Kapp MB. Source: The Gerontologist. 2003 June; 43(3): 292-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12810891&dopt=Abstract

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Spatial and temporal distribution of intracellular free cholesterol in brains of a Niemann-Pick type C mouse model showing hyperphosphorylated tau protein. Implications for Alzheimer's disease. Author(s): Treiber-Held S, Distl R, Meske V, Albert F, Ohm TG. Source: The Journal of Pathology. 2003 May; 200(1): 95-103. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12692847&dopt=Abstract

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Spatial patterns of mammalian brain aging: distribution of cathepsin D-immunoreactive cell bodies and dystrophic dendrites in aging dogs resembles that in Alzheimer's disease. Author(s): Bi X, Head E, Cotman CW, Lynch G. Source: The Journal of Comparative Neurology. 2003 September 22; 464(3): 371-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12900930&dopt=Abstract

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Special care for persons with Alzheimer's disease and related dementias in Virginia adult care residences. Author(s): Cotter JJ, Leon J, Akers AJ, Smith WR. Source: Am J Alzheimers Dis Other Demen. 2003 March-April; 18(2): 10513. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12708226&dopt=Abstract

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Spelling via semantics and phonology: exploring the effects of age, Alzheimer's disease, and primary semantic impairment. Author(s): Cortese MJ, Balota DA, Sergent-Marshall SD, Buckner RL. Source: Neuropsychologia. 2003; 41(8): 952-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12667531&dopt=Abstract

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Subicular dendritic arborization in Alzheimer's disease correlates with neurofibrillary tangle density. Author(s): Falke E, Nissanov J, Mitchell TW, Bennett DA, Trojanowski JQ, Arnold SE. Source: American Journal of Pathology. 2003 October; 163(4): 1615-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14507668&dopt=Abstract

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Susceptibility testing for Alzheimer's disease: race for the future. Author(s): Barber M, Whitehouse PJ. Source: Lancet. Neurology. 2002 May; 1(1): 10. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12849539&dopt=Abstract

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T cell response to amyloid-beta and to mitochondrial antigens in Alzheimer's disease. Author(s): Giubilei F, Antonini G, Montesperelli C, Sepe-Monti M, Cannoni S, Pichi A, Tisei P, Casini AR, Buttinelli C, Prencipe M, Salvetti M, Ristori G. Source: Dementia and Geriatric Cognitive Disorders. 2003; 16(1): 35-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12714798&dopt=Abstract

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The efficacy of galantamine in the treatment of Alzheimer's disease: comparison of patients previously treated with acetylcholinesterase inhibitors to patients with no prior exposure. Author(s): Mintzer JE, Kershaw P. Source: International Journal of Geriatric Psychiatry. 2003 April; 18(4): 292-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12673604&dopt=Abstract

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The metallobiology of Alzheimer's disease. Author(s): Bush AI. Source: Trends in Neurosciences. 2003 April; 26(4): 207-14. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12689772&dopt=Abstract

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The relationship between neuropsychological performance and daily functioning in individuals with Alzheimer's disease: ecological validity of neuropsychological tests. Author(s): Farias ST, Harrell E, Neumann C, Houtz A. Source: Archives of Clinical Neuropsychology : the Official Journal of the National Academy of Neuropsychologists. 2003 August; 18(6): 655-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14591439&dopt=Abstract

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The role of acetylcholinesterase in the pathogenesis of Alzheimer's disease. Author(s): Rees TM, Brimijoin S. Source: Drugs Today (Barc). 2003 January; 39(1): 75-83. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12669110&dopt=Abstract

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The role of cholesterol in pathogenesis of Alzheimer's disease: dual metabolic interaction between amyloid beta-protein and cholesterol. Author(s): Michikawa M. Source: Molecular Neurobiology. 2003 February; 27(1): 1-12. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12668899&dopt=Abstract

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The secretases of Alzheimer's disease. Author(s): Wolfe MS. Source: Curr Top Dev Biol. 2003; 54: 233-61. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12696752&dopt=Abstract

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The topography of metabolic deficits in posterior cortical atrophy (the visual variant of Alzheimer's disease) with FDG-PET. Author(s): Nestor PJ, Caine D, Fryer TD, Clarke J, Hodges JR. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 November; 74(11): 1521-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14617709&dopt=Abstract

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Tolerance to tacrine, arterial hypotension and leuko-araiosis in Alzheimer's disease. Author(s): Lebert F, Mouly C, Pasquier F. Source: Age and Ageing. 1998 September; 27(5): 654. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12675108&dopt=Abstract

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Treatment with simvastatin in patients with Alzheimer's disease lowers both alpha- and beta-cleaved amyloid precursor protein. Author(s): Sjogren M, Gustafsson K, Syversen S, Olsson A, Edman A, Davidsson P, Wallin A, Blennow K. Source: Dementia and Geriatric Cognitive Disorders. 2003; 16(1): 25-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12714796&dopt=Abstract

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Upper and lower face and ideomotor apraxia in patients with Alzheimer's disease. Author(s): Capone JG, Della Sala S, Spinnler H, Venneri A. Source: Behavioural Neurology. 2003; 14(1-2): 1-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12719633&dopt=Abstract

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Up-regulation of glycohydrolases in Alzheimer's Disease fibroblasts correlates with Ras activation. Author(s): Emiliani C, Urbanelli L, Racanicchi L, Orlacchio A, Pelicci G, Sorbi S, Bernardi G, Orlacchio A. Source: The Journal of Biological Chemistry. 2003 October 3; 278(40): 38453-60. Epub 2003 July 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12878600&dopt=Abstract

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Up-regulation of mitogen-activated protein kinases ERK1/2 and MEK1/2 is associated with the progression of neurofibrillary degeneration in Alzheimer's disease. Author(s): Pei JJ, Braak H, An WL, Winblad B, Cowburn RF, Iqbal K, Grundke-Iqbal I. Source: Brain Research. Molecular Brain Research. 2002 December 30; 109(1-2): 45-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12531514&dopt=Abstract

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Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease. Author(s): An WL, Cowburn RF, Li L, Braak H, Alafuzoff I, Iqbal K, Iqbal IG, Winblad B, Pei JJ. Source: American Journal of Pathology. 2003 August; 163(2): 591-607. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12875979&dopt=Abstract

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US Alzheimer's disease prevention study under attack. Author(s): Larkin M. Source: Lancet. Neurology. 2002 November; 1(7): 397. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12849347&dopt=Abstract

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Use of artificial networks in clinical trials: a pilot study to predict responsiveness to donepezil in Alzheimer's disease. Author(s): Mecocci P, Grossi E, Buscema M, Intraligi M, Savare R, Rinaldi P, Cherubini A, Senin U. Source: Journal of the American Geriatrics Society. 2002 November; 50(11): 1857-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12410907&dopt=Abstract

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Use of cholinesterase inhibitors in Alzheimer's disease. Author(s): Slawson D. Source: American Family Physician. 2003 May 15; 67(10): 2203. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12776972&dopt=Abstract

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Use of in vivo models to study the role of cholesterol in the etiology of Alzheimer's disease. Author(s): Burns M, Duff K. Source: Neurochemical Research. 2003 July; 28(7): 979-86. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12737522&dopt=Abstract

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Use of neuroimaging to detect early brain changes in people at genetic risk for Alzheimer's disease. Author(s): Small GW. Source: Advanced Drug Delivery Reviews. 2002 December 7; 54(12): 1561-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12453673&dopt=Abstract

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Utility and limits of the mini mental state examination in evaluating consent capacity in Alzheimer's disease. Author(s): Kim SY, Caine ED. Source: Psychiatric Services (Washington, D.C.). 2002 October; 53(10): 1322-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12364686&dopt=Abstract

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Vaccines for Alzheimer's disease: how close are we? Author(s): Janus C. Source: Cns Drugs. 2003; 17(7): 457-74. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12751917&dopt=Abstract

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Validity of direct assessment of functional status as a tool for measuring Alzheimer's disease severity. Author(s): Zanetti O, Frisoni GB, Rozzini L, Bianchetti A, Trabucchi M. Source: Age and Ageing. 1998 September; 27(5): 615-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12675100&dopt=Abstract

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Variation in the DCP1 gene, encoding the angiotensin converting enzyme ACE, is not associated with increased susceptibility to Alzheimer's disease. Author(s): Carbonell J, Allen R, Kalsi G, McQuillin A, Livingston G, Katona C, Walker Z, Katz A, Rands G, Stevens T, Crossan I, Curtis D, Gurling H. Source: Psychiatric Genetics. 2003 March; 13(1): 47-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12605101&dopt=Abstract

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Vasoactive effects of A beta in isolated human cerebrovessels and in a transgenic mouse model of Alzheimer's disease: role of inflammation. Author(s): Paris D, Humphrey J, Quadros A, Patel N, Crescentini R, Crawford F, Mullan M. Source: Neurological Research. 2003 September; 25(6): 642-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14503019&dopt=Abstract

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Vigilance. Evolution and definition for caregivers of family members with Alzheimer's disease. Author(s): Mahoney DF. Source: Journal of Gerontological Nursing. 2003 August; 29(8): 24-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=13677157&dopt=Abstract

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Visual identification and spatial location in Alzheimer's disease. Author(s): Stehli Nguyen A, Chubb C, Jacob Huff F. Source: Brain and Cognition. 2003 July; 52(2): 155-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12821097&dopt=Abstract

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Visual memory predicts Alzheimer's disease more than a decade before diagnosis. Author(s): Kawas CH, Corrada MM, Brookmeyer R, Morrison A, Resnick SM, Zonderman AB, Arenberg D. Source: Neurology. 2003 April 8; 60(7): 1089-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12682311&dopt=Abstract

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Visual object recognition in early Alzheimer's disease: deficits in semantic processing. Author(s): Laatu S, Revonsuo A, Jaykka H, Portin R, Rinne JO. Source: Acta Neurologica Scandinavica. 2003 August; 108(2): 82-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12859283&dopt=Abstract

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Visuospatial impairment in dementia with Lewy bodies and Alzheimer's disease: a process analysis approach. Author(s): Simard M, van Reekum R, Myran D. Source: International Journal of Geriatric Psychiatry. 2003 May; 18(5): 387-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12766913&dopt=Abstract

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Volume reduction in cerebral blood flow in patients with Alzheimer's disease: a sonographic study. Author(s): Maalikjy Akkawi N, Borroni B, Agosti C, Pezzini A, Magoni M, Rozzini L, Prometti P, Romanelli G, Vignolo LA, Padovani A. Source: Dementia and Geriatric Cognitive Disorders. 2003; 16(3): 163-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12826743&dopt=Abstract

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What can our nose tell us about possible treatments for Alzheimer's disease? Author(s): Weiss S. Source: The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques. 2003 February; 30(1): 3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12619775&dopt=Abstract

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What can rodent models tell us about cognitive decline in Alzheimer's disease? Author(s): Davis S, Laroche S. Source: Molecular Neurobiology. 2003 June; 27(3): 249-76. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12845151&dopt=Abstract

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What evidence would prove the amyloid hypothesis? Towards rational drug treatments for Alzheimer's disease. Author(s): Morgan D, Keller RK. Source: Journal of Alzheimer's Disease : Jad. 2002 June; 4(3): 257-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12226546&dopt=Abstract

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What's new in Alzheimer's disease? Author(s): Long CO, Dougherty J. Source: Home Healthcare Nurse. 2003 January; 21(1): 8-14; Quiz 15. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12544456&dopt=Abstract

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When parsimony backfires: neglecting DNA repair may doom neurons in Alzheimer's disease. Author(s): Nouspikel T, Hanawalt PC. Source: Bioessays : News and Reviews in Molecular, Cellular and Developmental Biology. 2003 February; 25(2): 168-73. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12539243&dopt=Abstract

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Why would caregivers not want to treat their relative's Alzheimer's disease? Author(s): Karlawish JH, Casarett DJ, James BD, Tenhave T, Clark CM, Asch DA. Source: Journal of the American Geriatrics Society. 2003 October; 51(10): 1391-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14511158&dopt=Abstract

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Will a healthy lifestyle help prevent Alzheimer's disease? Author(s): Pope SK, Shue VM, Beck C. Source: Annual Review of Public Health. 2003; 24: 111-32. Epub 2001 November 06. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12415146&dopt=Abstract

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Wilms' tumor suppressor (WT1) is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer's disease. Author(s): Lovell MA, Xie C, Xiong S, Markesbery WR. Source: Brain Research. 2003 September 5; 983(1-2): 84-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12914969&dopt=Abstract

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Wives' struggle in living through treatment decisions for husbands with advanced Alzheimer's disease. Author(s): Robinson EM. Source: J Nurs Law. 2000 May; 7(1): 21-39. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12545984&dopt=Abstract

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Working memory in mild Alzheimer's disease and early Parkinson's disease. Author(s): Kensinger EA, Shearer DK, Locascio JJ, Growdon JH, Corkin S. Source: Neuropsychology. 2003 April; 17(2): 230-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12803428&dopt=Abstract

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Yellow glasses improve contrast sensitivity of a patient with a visual variant of Alzheimer's disease. Author(s): Sakai S, Hirayama K, Iwasaki S, Fujii T, Hashimoto R, Yamadori A. Source: European Neurology. 2002; 48(4): 224-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12422073&dopt=Abstract

Vocabulary Builder Ablation: The removal of an organ by surgery. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [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] Ameliorated: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH]

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Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH]

Apraxia: Loss of ability to perform purposeful movements, in the absence of paralysis or sensory disturbance, caused by lesions in the cortex. [NIH] Aspartate: A synthetic amino acid. [NIH] Aspartic: The naturally occurring substance is L-aspartic acid. One of the acidic-amino-acids is obtained by the hydrolysis of proteins. [NIH] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Axonal: Condition associated with metabolic derangement of the entire neuron and is manifest by degeneration of the distal portion of the nerve fiber. [NIH] Basalis: Chiasmatic cistern. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Cataracts: In medicine, an opacity of the crystalline lens of the eye obstructing partially or totally its transmission of light. [NIH] CD8: A protein embedded in the cell surface of killer and suppresser Tlymphocytes. [NIH] CDC2: It is crucial for entry into mitosis of eukaryotic cells. [NIH] CDNA: Synthetic DNA reverse transcribed from a specific RNA through the action of the enzyme reverse transcriptase. DNA synthesized by reverse transcriptase using RNA as a template. [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] Compacta: Part of substantia nigra. [NIH] Competency: The capacity of the bacterium to take up DNA from its surroundings. [NIH] Confounder: A factor of confusion which blurs a specific connection between a disease and a probable causal factor which is being studied. [NIH] Continuum: An area over which the vegetation or animal population is of constantly changing composition so that homogeneous, separate communities cannot be distinguished. [NIH] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the

234 Alzheimer’s Disease

body's response to stress. [NIH] Crawford: Variation of the luminosity of a light stimulus with position of entry of the light pencil through the pupil. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Davidson: Light seen through the pupil when a light source is held in the mouth. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dissection: Cutting up of an organism for study. [NIH] Duke: A lamp which produces ultraviolet radiations for certain ophthalmologic therapy. [NIH] Dystrophic: Pertaining to toxic habitats low in nutrients. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] ELISA: A sensitive analytical technique in which an enzyme is complexed to an antigen or antibody. A substrate is then added which generates a color proportional to the amount of binding. This method can be adapted to a solid-phase technique. [NIH] Embryogenesis: The process of embryo or embryoid formation, whether by sexual (zygotic) or asexual means. In asexual embryogenesis embryoids arise directly from the explant or on intermediary callus tissue. In some cases they arise from individual cells (somatic cell embryoge). [NIH] Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Epistasis: The degree of dominance exerted by one gene on the expression of a non-allelic gene. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Excitotoxicity: Excessive exposure to glutamate or related compounds can kill brain neurons, presumably by overstimulating them. [NIH]

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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] Fold: A plication or doubling of various parts of the body. [NIH] Fornix: A bundle of nerves connected to the hippocampus. [NIH] Galanin: A neurotransmitter. [NIH] Greig: A very rare inherited disorder characterized by physical abnormalities affecting the fingers and toes (digits) and the head and facial (craniofacial) area. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Harmony: Attribute of a product which gives rise to an overall pleasant sensation. This sensation is produced by the perception of the product components as olfactory, gustatory, tactile and kinaesthetic stimuli because they are present in suitable concentration ratios. [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] Heterozygotes: Having unlike alleles at one or more corresponding loci on homologous chromosomes. [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Initiator: A chemically reactive substance which may cause cell changes if ingested, inhaled or absorbed into the body; the substance may thus initiate a carcinogenic process. [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] Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Ligands: A RNA simulation method developed by the MIT. [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] Lod: The lowest analyte content which, if actually present, will be detected with reasonable statistical certainty and can be identified according to the identification criteria of the method. If both accuracy and precision are constant over a concentration range. [NIH] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH]

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Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Mononuclear: A cell with one nucleus. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH]

MRNA: The RNA molecule that conveys from the DNA the information that is to be translated into the structure of a particular polypeptide molecule. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neuritis: Inflammation of a nerve or nerves. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Olfaction: Function of the olfactory apparatus to perceive and discriminate between the molecules that reach it, in gas form from an external environment, directly or indirectly via the nose. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Phenotypes: An organism as observed, i. e. as judged by its visually perceptible characters resulting from the interaction of its genotype with the environment. [NIH] Phosphorylates: Attached to a phosphate group. [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] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Potentiate: 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] Premarin: A hormone replacement therapy drug developed by AHP (USA). [NIH]

Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an

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elongated instrument for exploring or sounding body cavities. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Protease: Any enzyme that catalyzes hydrolysis of a protein. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [NIH] Salivary: The duct that convey saliva to the mouth. [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] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] 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] 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] Superoxide: Derivative of molecular oxygen that can damage cells. [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] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [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] 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] 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

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the protein through a cell or organelle membrane. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [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] 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]

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CHAPTER 5. PATENTS ON ALZHEIMER’S DISEASE Overview You can learn about innovations relating to Alzheimer’s disease by reading recent patents and patent applications. Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.23 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available to patients with Alzheimer’s disease within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available to patients with Alzheimer’s disease. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information.

23Adapted

from The U. S. Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

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Patents on Alzheimer’s Disease By performing a patent search focusing on Alzheimer’s disease, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on Alzheimer’s disease: •

4-substituted piperidine analogs and their use as subtype selective NMDA receptor antagonists Inventor(s): Bigge; Christopher F. (Ann Arbor, MI), Cai; Sui Xiong (Foothill, CA), Keana; John F.W. (Eugene, OR), Lan; Nancy C. (South Pasadena, CA), Weber; Eckard (Laguna Beach, CA), Woodward; Richard (Aliso Viejo, CA), Wright; Jonathan (Ann Arbor, MI), Zhou; Zhang-Lin (Irvine, CA) Assignee(s): Cocensys, Incorporated (irvine, Ca), Warner-lambert Company (morris Plains, Nj) Patent Number: 6,448,270 Date filed: June 13, 2000 Abstract: Novel 4-substituted piperidine analogs, pharmaceutical compositions containing the same and the method of using the 4substituted piperidine analogs as selectively active antagonists of Nmethyl-D-aspartate (NMDA) receptor subtypes for treating conditions such as cerebral ischemia, central nervous system trauma, hypoglycemia, neurodegenerative disorders, anxiety, migraine headaches, convulsions, aminoglycoside antibiotics-induced hearing loss, chronic pain, psychosis, glaucoma, CMV retinitis, opioid tolerance or withdrawal, urinary incontinence and neurodegenerative disorders such as lathyrism, Alzheimers' Disease, Parkinsonism, and Huntington's Disease are described. Also described are novel methods for preparing 4-substituted piperidine analogs and novel intermediates of the 4-substituted piperidine analogs. Excerpt(s): This invention is related to 4-substituted piperidine analogs, including hydroxypiperidine and tetrahydropyridine analogs, as well as

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novel intermediates of the 4-substituted analogs. The analogs are selectively active as antagonists of N-methyl-D-aspartate (NMDA) receptor subtypes. The invention is also directed to the use of 4substituted piperidine analogs as neuroprotective agents for treating conditions such as stroke, cerebral ischemia, central nervous system trauma, hypoglycemia, anxiety, convulsions, aminoglycoside antibioticsinduced hearing loss, migraine headache, chronic pain, glaucoma, CMV retinitis, psychosis, urinary incontinence, opioid tolerance or withdrawal, or neuro-degenerative disorders such as lathyrism, Alzheimer's Disease, Parkinsonism and Huntington's Disease.... Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA) glutamate and aspartate at the N-methyl-D-Aspartate (NMDA) receptor. This excitotoxic action is considered responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery and cerebral trauma, as well as lathyrism, Alzheimer's Disease, Parkinson's Disease and Huntington's Disease.... Ar.sup.1 and Ar.sup.2 are each independently substituted or unsubstituted aryl, a heteroaromatic ring, or a heteroaromatic bicylic ring. The tetrahydropyridines and hydroxypiperidines of this reference are indicated to be useful as central nervous system agents, particularly as dopaminergic, antipsychotic and antihypertensive agents, and for treating central nervous system disorders such as Parkinson Disease, Huntington Disease and depression. The particular 4-substituted piperidines, including the 4-hydroxypiperdines and tetrahydropyridines of this invention are not exemplified. In addition, there is no disclosure or suggestion of treating disorders with selective NMDA receptor subtype antagonists and the advantages of such treatment. Web site: http://www.delphion.com/details?pn=US06448270__

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•

Chromosome 14 and familial Alzheimers disease genetic markers and assays Inventor(s): Bird; Thomas D. (Seattle, WA), Schellenberg; Gerard D. (Seattle, WA), Wijsman; Ellen M. (Seattle, WA) Assignee(s): University of Washington (seattle, Wa) Patent Number: 5,449,604 Date filed: October 21, 1992 Abstract: Method for isolating a DNA segment indicative of an Alzheimer's disease trait in a family population, wherein said family population consists essentially of a plurality of blood relatives of an individual having a chromosome 14 Alzheimer's disease trait, by: preparing a test sample of immobilized separated genomic DNA fragments from a plurality of the blood relatives, contacting each of the test samples with a test oligonucleotide under conditions permitting hybridization of complementary single stranded DNA molecules, wherein the test oligonucleotide is complementary with at least a portion of a genetic marker located between band q11.2 and band q32.1 in chromosome 14, identifying a plurality of hybridized molecules so formed as alleles of the genetic marker in the family population, identifying one of the genetic marker alleles as indicative of the Alzheimer's disease trait in the family population by either determining by pedigree analysis a segregation value for each of the genetic markers alleles and the Alzheimer's disease trait, and selecting an indicative genetic marker allele that co-segregates with the Alzheimer's disease trait in the family population, or measuring genetic linkage between each of the genetic marker alleles and the Alzheimer's disease trait, and selecting a genetic marker allele as indicative of the Alzheimer's disease trait in the family population if the selected genetic marker allele has a maximal LOD score of at least 3 at a recombination fraction of about 0.0 to about 0.1 for genetic linkage with the Alzheimer's disease trait in the family population, and isolating a chromosome 14 DNA segment containing the indicative genetic marker allele. Excerpt(s): The invention relates to gene probes and molecular genetic assays for early detection of Alzheimer's disease, as well as for identifying individuals who are at an increased relative risk of developing the disease.... Alzheimer's disease (AD) is a progressive neurodegenerative disorder which in some (if not all) cases is inherited as an autosomal dominant trait. The first symptoms of AD can occur as early as the fourth to fifth decades of life. Alzheimer's disease is a major disease affecting over 3 million individuals in the U.S. alone at an annual cost of over $30 billion.... The role of inheritance in the more common

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late-onset AD is not presently resolved. Evidence that defective genes may be responsible for some or possibly all late-onset AD has been suggested by clustering of late-onset cases in individual pedigrees (8,14,22), family history data from case-control studies (23-26), and the concordance rates for mono- and di-zygotic twins (27-29). Certain data also suggest the possibility of "sporadic" AD, i.e., where no family history of disease is observed, that could result, for example, from noninherited genetic mechanisms such as somatic recombination or mutation. Web site: http://www.delphion.com/details?pn=US05449604__ •

Diagnostic test for alzheimers disease Inventor(s): Alkon; Daniel L. (Bethesda, MD), Favit; Antonelle R. (Bethesda, MD), Grimaldi; Maurizio (Bethesda, MD) Assignee(s): The United States of America AS Represented by the Department of Health (washington, Dc) Patent Number: 6,107,050 Date filed: May 11, 1998 Abstract: The present invention provides methods for the diagnosis of Alzheimer's disease using human cells. Specifically, one method detects differences between potassium channels in cells from Alzheimer's patient and normal donors, and differences in intracellular calcium concentrations between Alzheimer's and normal cells in response to chemicals known to increase intracellular calcium levels. Other methods detect differences between the memory associated GTP binding Cp20 protein levels between Alzheimer's and normal cells. Another method utilizes the differential effects of.beta.-amyloid protein on levels of the protein kinase C isoenzymes PKC.alpha. and PKC.gamma. in Alzheimer's and normal cells. Yet another method detects Eu-TTA fluorescence differences between Alzheimer's and normal cells treated with an activator of a receptor-mediated metabolic pathway. In addition a diagnostic index for improved assessment between Alzheimer's and non Alzheimer's cells is provided. Excerpt(s): The present invention relates to methods for diagnosing Alzheimer’s disease. The methods utilize newly discovered differences between cells from healthy donors and those with Alzheimer’s disease. In one method, differences in the existence of functional potassium channels are assessed. In another method, differences in intracellular calcium levels in response to depolarization by a potassium channel blocker are assessed. In yet another method, differences in intracellular calcium levels in response to a chemical known to increase intracellular

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calcium levels by releasing calcium from intracellular stores are assessed. In another method, differences in the levels of a memory associated GTPbinding protein (Cp20) between cells from healthy donors and Alzheimer's patients are assessed. This invention also relates to the amino acid sequence for the Cp20 protein. In yet another method, differential effects of.beta.-amyloid on levels of the protein kinase C isoenzymes PKC.alpha. and PKC.gamma. in control and Alzheimer's cells are assessed. The invention further relates to another method in which differences in Europium (III) thenoyltrifluoro-acetate (Eu-TAA) fluorescence of cells from healthy donors and Alzheimer's patients are assessed following treatment of the cells with an activator of a receptormediated metabolic pathway. In addition, diagnostic indexes that utilize two or more of the above methods to distinguish Alzheimer's patients' cells from control non-AD cells are also provided.... Alzheimer's disease is associated with extensive loss of specific neuronal subpopulations in the brain (Sims, N. R., et al. (1987) Annals of Neurology 21:451), with memory loss being the most universal symptom. (Katzman, R. (1986) New England Journal of Medicine 314:964). Alzheimer's disease has been linked to a genetic origin. (Schellenberg, G. D., et al. (1992) Science 258:668; Li, G., et al. (1991) Psychiatric Clinics of North America 14:267; St. George-Hyslop, P. H., et al. (1989) Neurobiology of Aging 10:417; St. George-Hyslop, P. H., et al. (1987) Science 235:885). Early-onset familial forms of the disease exhibit a genetic defect on chromosome 21. (St. George-Hyslop, P. H., et al. (1987)).... Cellular changes, leading to neuronal loss and the underlying etiology of the disease, remain unknown. Proposed causes include environmental factors, (Perl, D. P. (1985) Environmental Health Perspective 63:149; Katzman, R. (1986)), including metal toxicity, (Perl, D. P., et al. (1980) Science 208:297), defects in.beta.-amyloid protein metabolism, (Shoji, M., et al. (1992) Science 258:126; Joachim, C. L. and Selkoe, D. J. (1992) Alzheimer Disease Assoc. Disord. 6:7; Kosik, K. S. (1992) Science 256:780; Selkoe, D. J. (1991) Neuron 6:487; Hardy, H. and Allsop, D. (1991) Trends in Pharmacological Science 12:383), and abnormal calcium homeostasis and/or calcium activated kinases. (Mattson, M. P., et al. (1992) Journal of Neuroscience 12:376; Borden, L. A., et al. (1991) Neurobiology of Aging 13:33; Peterson, E., et al. (1989) Annals of New York Academy of Science 568:262; Peterson, C., et al. (1988) Neurobiology of Aging 9:261; Peterson, C., et al. (1986) Proceedings of the National Academy of Science 83:7999). Web site: http://www.delphion.com/details?pn=US06107050__

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Preventive or therapeutic agents for alzheimers disease a screening method of alzheimers disease and tau-protein kinase I originated from human being Inventor(s): Hoshino; Toshimitsu (Machida, JP), Imahori; Kazutomo (Meguro-ku, JP), Saito; Ken-ichi (Asao-ku, JP), Sato; Showbu (Machida, JP), Shiratsuchi; Akiko (Sagamihara, JP), Takashima; Akihiko (Machida, JP) Assignee(s): Mitsubishi Chemical Corporation (tokyo, Jp) Patent Number: 5,837,853 Date filed: February 20, 1996 Abstract: A preventive or therapeutic agent for Alzheimer's disease which comprises a substance exhibiting an inhibitory action to tauprotein kinase I as an effective component is provided. A pharmaceutical composition comprising said agent and a method of inhibiting neuronal cell death in the brain are also provided. Excerpt(s): The present invention relates to a preventive or a therapeutic agent for Alzheimer's disease, a method of screening Alzheimer's disease and tau-protein kinase I which is originated from a human being. More particularly, it relates to a preventive or a therapeutic agent for Alzheimer's disease using a tau-protein kinase I inhibitor; a method of screening for a preventive or a therapeutic agent for Alzheimer's disease utilizing an amyloid beta-protein; a human-originated tau-protein kinase I which phosphorylates tau-protein, partial peptides thereof or peptides similar thereto; a gene which encodes the kinase; and a method of producing the same.... Alzheimer's disease is a progressive dementia which develops in late middle ages (45 to 65 years old) and its etiological changes are shrinkage of cerebral cortex due to a neuronal cell loss and degeneration of the neurons while, from the pathological view, many senile plaques and neurofibrillary tangles are noted in the brain. There is no pathologically substantial difference between the disease and senile dementia caused by the so-called natural aging which develops in the senile period of 65 years and older ages and, therefore, this disease is called senile dementia of Alzheimer type.... The numbers of the patients having this disease are increasing with an increase in the population of aged people, and so the disease is becoming an increasing health concern of society. There are various theories on the cause of this disease, but the cause is still ambiguous and, accordingly, there has been a demand for more information about the disease. Web site: http://www.delphion.com/details?pn=US05837853__

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Radiopharmaceutical agents for the detection of Alzheimers disease Inventor(s): Efange; Simon Mbua Ngale (Plymouth, MN), Parsons; Stanley M. (Santa Barbara, CA) Assignee(s): Regents of the University of Minnesota (minneapolis, Mn) Patent Number: 5,721,243 Date filed: June 13, 1994 Abstract: Novel anticholinergics which are related to vesamicol are particularly useful when radiolabeled for evaluating cholinergic innervation in the living human brain. The cholinergic deficit in the Alzheimer's brain should be identifiable with these radioligands. Excerpt(s): This invention relates to a chemical compound that is an anticholinergic. This compound may be labeled and used to track brain nerve cell production of acetylcholine as an indicator of Alzheimer’s disease.... In U.S. Pat. No. 4,522,965 which issued Nov. 12, 1985 to Stanley M. Parsons, a vesamicol derivative is described for use in blocking conduction at the neuromuscular junction in mammals. Parsons notes that it is desirable to produce a more effective compound than vesamicol for blocking presynaptic release of acetylcholine.... The hydroxylated phencyclidine (PCP) isomer trans-2-(4-phenylpiperidino)cyclohexanol (vesamicol, AH5183) induces respiratory paralysis and death in rodents and other laboratory animals (Brittain et al., 1969). Subsequent investigations have revealed that the biological activity of vesamicol is mediated in part by its ability to inhibit both the uptake of ACh into cholinergic synaptic vesicles and quantal release of this neurotransmitter from cholinergic neuron (for review, see Marshall and Parsons, 1987). Web site: http://www.delphion.com/details?pn=US05721243__

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Transdermal propentofylline compositions for the treatment of Alzheimers disease Inventor(s): Venkateshwaran; Srinivasan (Salt Lake City, UT) Assignee(s): Theratech, Inc. (salt Lake City, Ut) Patent Number: 5,762,953 Date filed: August 22, 1996 Abstract: Patients suffering from Alzheimer's disease are treated by transdermally administering an effective amount of propentofylline in the form of an occulsive device containing a delivery composition comprising a carrier vehicle having uniformly distributed therein effective amounts of propentofylline and, optionally, a penetration

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enhancer. The occulsive device may be a matrix type patch in which the carrier vehicle is a pressure sensitive adhesive or a reservoir type patch in which the carrier vehicle is a liquid of controlled viscosity, i.e. a gel, wherein the reservoir system contains means for maintaining it in a propentofylline transferring relationship with the derma when applied. Daily dosages of between about 5 and 49 mg/day are sufficient to maintain adequate plasma propentofylline levels. Excerpt(s): The present invention relates to a method for the delivery of a pharmaceutical agent for the treatment of memory disfunctions. More particularly, this invention relates to non-oral and noninvasive methods of delivery of a therapeutic agent used for the treatment of memory disfunctions. Specifically, this invention relates to a transdermal method of delivery of 1,2,3,6-tetrahydro-3-methyl-1-(3-oxohexyl)-7-propylpurine2,6-dio ne (hereinafter referred to as propentofylline).... Various potential routes for the delivery of pharmaceutical agents have been considered: invasive (e.g. direct injection: intravenous, subcutaneous, intramuscular and depot systems) and non-invasive (e.g. pulmonary, oral, nasal, buccal, ocular, rectal, vaginal and transdermal). Administration of drugs by injection is not suitable for ambulatory patients and is not generally acceptable to patients undergoing drug therapy for chronic diseases. Also this route is far from being an ideal route of administration of molecules with short biological half-lives which necessitate repeated injections.... The oral delivery route is often proposed as being superior to all others. However, the delivery of some drugs using the oral route is fraught with difficulties which center around low bioavailability. Some of the factors responsible for low bioavailability are chemical and proteolytic degradation in the GI tract, low permeability of the absorbing tissues due to the size, hydrophilicity and charge characteristics of the drugs, and first pass metabolism in the liver. For drugs with short half-lives, multiple daily dosing would be required. Fluctuations in plasma concentrations due to a combination of low bioavailability and frequent dosing regimen cause wide fluctuations in plasma levels that can lead to pharmacological extremes ranging from drug (and metabolite) associated side effects to significant periods of therapeutically inadequate dosing. Web site: http://www.delphion.com/details?pn=US05762953__

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Use of presenilin-1 for diagnosis of alzheimers disease Inventor(s): Cataldo; Anne M. (Nanuet, NY), Kao; Benjamin H. (New York, NY), Mathews; Paul M. (Irvington, NY), Nixon; Ralph A. (Tarrytown, NY) Assignee(s): The Mclean Hospital Corporation (belmont, Ma) Patent Number: 5,985,581 Date filed: July 17, 1997 Abstract: The invention provides a method of diagnosing Alzheimer’s disease. The method utilizes presenilin-1, whose level is found to be substantially decreased in Alzheimer's patients. Included in the invention are diagnostic kits for Alzheimer's disease and methods of screening for effective therapeutics for the disease. The invention also provides a method of studying the function and regulation of presenilin-1 in brain by the use of primate retinoblastoma cells. Excerpt(s): This invention relates to diagnosis of Alzheimer’s disease.... Alzheimer's disease (AD) is a devastating impairment of cognitive function prevalent in individuals generally forty-five or older. The cause of AD is not known, nor is there a treatment for AD. However, AD is the first common disease for which allelic variation or mutations at multiple genetic loci are linked to the development of disease in affected families (Roses, Annu. Rev. Med. 47: 387, 1996; Schellenberg, Proc. Natl. Acad. Sci. USA, 92: 8552, 1995). The majority (70-80%) of heritable, early-onset AD maps to chromosome 14 and appears to result from one of more than 20 different amino-acid substitutions within presenilin-1 (PS1) (Schellenberg et al., Science, 258: 668, 1992; Alzheimer's Disease Collaborative Group, Nature Genet, 11: 219, 1995; Sobi et al., Lancet., 346: 439, 1995; Van Broeckhoven, Nature Genet., 11: 230, 1995; Wasco et al., Nature Med., 1: 848, 1995; Sherrington et al., Nature, 375: 754, 1995), the product of the recently identified S182 gene (Sherrington et al., 1995). A similar, although less common, AD-risk locus on chromosome 1 encodes the highly homologous presenilin-2 (Levy-Lahad et al., Science, 269: 970, 1995; Levy-Lahad et al., Science, 269: 973, 1995; Li et al., Proc. Natl. Acad. Sci. USA, 92: 12180, 1995; Rogaev et al., Nature, 376: 775, 1995). Several amino-acid substitutions have been identified within PS2 that appear to be causative for early-onset AD (Levy-Lahad et al., Science, 269: 973, 1995; Li et al., Proc. Natl. Acad. Sci. USA, 92: 12180, 1995; Rogaev et al., Nature, 376: 775, 1995). Based upon mRNA detection, the presenilins appear to be ubiquitously expressed, suggesting that they are housekeeping proteins required by many cell types.... The two mammalian presenilins share 67% amino-acid identity and apparently belong to a larger gene-family of multimembrane spanning proteins that

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includes the C. elegans spe-4 and sel-12 genes. Mutations in the spe-4 gene disrupt the formation of a Golgi-derived storage and delivery organelle required for spermatogenesis in the nematode (L'Hernault et al., J. Cell Bio., 119: 55, 1992). SEL-12 has been shown to facilitate signaling by lin-12, a member of the Notch family of transmembrane receptors critical for cell surface to nucleus signaling during development (Levitan et al., Nature, 377: 351, 1995). A possible ER and/or Golgi localization of epitope-tagged constructs overexpressed in cultured cells and a similar immunolabeling pattern reported in mouse pyramidal neurons are consistent with the presenilins being integral membrane proteins found within compartments of the secretory pathway (Kovacs et al., Nature Med., 224: 224, 1996; Moussaoui et al., FEBS Letters, 383: 219, 1996). This, in conjunction with the spe-4 phenotype and the known importance of membrane proteins and their compartmentalization in AD, has led to the conjecture that the presenilins play a role in membrane protein trafficking and/or processing along the secretory pathway (Kovacs et al., Nature Med., 224: 224, 1996; Pellegrew et al., in Alzheimer disease, eds. R. D. Terry, R. Katzman, and K. L. Bick, Raven Press, New York, 1994; Harrison, Lancet, 346: 388, 1995). However, no direct evidence currently exists ascribing such a function to the presenilins, nor is there evidence suggesting any specialized role for presenilins in the brain. Finally, the broad distribution of the identified AD-causing mutations throughout PS1 and PS2 has yet to suggest any clear mechanistic link between these mutations and the disease process (Van Broeckhoven, Nature Genet., 11: 230, 1995). Web site: http://www.delphion.com/details?pn=US05985581__

Patent Applications on Alzheimer’s Disease As of December 2000, U.S. patent applications are open to public viewing.24 Applications are patent requests which have yet to be granted (the process to achieve a patent can take several years). The following patent applications have been filed since December 2000 relating to Alzheimer’s disease:

24

This has been a common practice outside the United States prior to December 2000.

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Methods for detecting Alzheimers disease Inventor(s): Diamandis, Eleftherios P.; (Toronto, CA) Correspondence: Merchant & Gould PC; P.o. Box 2903; Minneapolis; MN; 55402-0903; US Patent Application Number: 20020182644 Date filed: October 26, 2001 Abstract: Methods for diagnosing and monitoring Alzheimer's Disease in a subject comprising measuring hK6 in a sample from the subject. hK6 may be measured using a reagent that detects or binds to hK6, preferably antibodies reactive with hK6. Excerpt(s): The invention relates to methods for detecting Alzheimer’s disease.... Alzheimer's disease (AD) is the major cause of dementia in the elderly. Although rare genetic forms of AD exist, most patients are classified as having sporadic AD, since no family history is usually identified. Pathologically, AD is characterized by neuronal and synaptic degeneration with an increased number of senile plaques and neurofibrillary tangles compared to non-demented individuals of comparable age (1-3).... The senile plaques, characteristic of Alzheimer's disease, are composed of a central core of aggregated beta-amyloid, a breakdown product of amyloid precursor protein (APP) (2). The neurofibrillary tangles are insoluble intracellular thread-like structures made up of a hyberphospholated form of a protein called tau, which is associated with microtubles (4). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with Alzheimer’s disease, you can access the U.S. Patent Office archive via the Internet at http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “Alzheimer’s disease” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on Alzheimer’s disease. You can also use this procedure to view pending patent applications concerning Alzheimer’s disease. Simply go back to the following Web

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address: http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

Vocabulary Builder Antibiotic: A substance usually produced by vegetal micro-organisms capable of inhibiting the growth of or killing bacteria. [NIH] Breakdown: A physical, metal, or nervous collapse. [NIH] CMV: A virus that belongs to the herpes virus group. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Epilepticus: Repeated and prolonged epileptic seizures without recovery of consciousness between attacks. [NIH] Gould: Turning of the head downward in walking to bring the image of the ground on the functioning position of the retina, in destructive disease of the peripheral retina. [NIH] Isoenzyme: Different forms of an enzyme, usually occurring in different tissues. The isoenzymes of a particular enzyme catalyze the same reaction but they differ in some of their properties. [NIH] Paralysis: Loss or impairment of muscle function or sensation. [NIH] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Potassium: It is essential to the ability of muscle cells to contract. [NIH] Radiopharmaceutical: Any medicinal product which, when ready for use, contains one or more radionuclides (radioactive isotopes) included for a medicinal purpose. [NIH] 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] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH]

Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH]

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CHAPTER 6. BOOKS ON ALZHEIMER’S DISEASE Overview This chapter provides bibliographic book references relating to Alzheimer’s disease. You have many options to locate books on Alzheimer’s disease. The simplest method is to go to your local bookseller and inquire about titles that they have in stock or can special order for you. Some patients, however, feel uncomfortable approaching their local booksellers and prefer online sources (e.g. www.amazon.com and www.bn.com). In addition to online booksellers, excellent sources for book titles on Alzheimer’s disease include the Combined Health Information Database and the National Library of Medicine. Once you have found a title that interests you, visit your local public or medical library to see if it is available for loan.

Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “Alzheimer’s disease” (or synonyms) into the “For these words:” box. You will only receive results on books. You should check back periodically with this database which is updated every 3 months. The following is a typical result when searching for books on Alzheimer’s disease:

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Early Story of Alzheimer's Disease (Translation of the Historical Papers by Alois Alzheimer, Oskar Fischer, Francesco Bonfiglio, Emil Kraepelin, and Gaetano Perusini) Source: Padova, ITALY: Liviana Press. 1987. 147 p. Contact: Available from Raven Press. 1185 Avenue of the Americas, New York, NY 10036. (212) 886-1200. PRICE: $55.00. ISBN: 8876754237. Summary: These translations of the publications on Alzheimer's disease (AD) is the first effort by the World Federation of Neurology Research Group on Dementias and the Italian Study Group on Brain Aging to bring the thinking of the early researchers to current investigators involved in research on AD and related disorders. Following the key paper describing AD by Alois Alzheimer reporting on a characteristic disease of the cerebral cortex, five additional historic research papers are presented. These include: special findings in a case of probable cerebral syphilis (by Francesco Bonfiglio); miliary necrosis with nodular proliferation of the neurofibrils as a common change of the cerebral cortex in senile dementia (Oskar Fischer); descriptions of senile and presenile dementias (Emil Kraepelin); histology and clinical findings of several psychiatric diseases of older people (Gaetano Perusini); and the nosographic value of some histopathological findings in senility (Gaetano Perusini).

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When Someone You Love Has Alzheimer's Disease: The Caregiver's Journey Source: Boston, MA: Beacon Press. 1996. 163 p. Contact: Available from Houghton Mifflin. 181 Ballardvale Street, Wilmington, MA 01887. (800) 225-3365. FAX: (800) 634-7568. PRICE: $22.00. ISBN: 0807027200. Summary: This book is designed for families and friends of Alzheimer's disease patients. The authors provide insights based on their own experiences. The book reviews the symptoms and diagnosis of Alzheimer' s disease and the range of emotions that families and loved ones may experience. The authors provide guidelines for caring for Alzheimer's disease patients as well as caregiver support strategies; discuss spiritual and emotional issues among patients and caregivers; and respond to frequently asked questions about symptoms, disease progression, patient care, genetic factors, and safety. References included.

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Broken Connections: Alzheimer's Disease: Part II: Practical Guidelines for Caring for the Alzheimer Patient Source: Amsterdam, Netherlands: Swets and Zeitlinger B. V. Lisse. 1994. 325 p. Contact: Available from Taylor and Francis. 1900 Frost Road, Suite 101, Bristol, PA 19007-1598. (215) 785-5800. PRICE: $30.00. ISBN: 9026513712. Summary: This book is the second part of a two-part guide for the daily care and nursing of patients with Alzheimer's disease (AD) (see AZBK04766 for part 1). Six chapters describe concrete tasks that enable caregivers to give AD patients professional and compassionate care as the disease progresses. Using a series of practical guidelines and suggestions, this book shows how caregivers can work constructively with AD patients. With respect to nursing care, AD is divided into four stages: (1) stimulation and encouragement; (2) intervention; (3) partial take-over of the patient's daily activities by the caregiver; and (4) complete take-over of the patient's daily activities by the caregiver. In each chapter, detailed schemes are given for each stage. They deal personal care and hygiene; household, social, and recreational activities; and financial affairs. Chapters describe early symptoms, how to stimulate activity, intervention, partial take-over actions, and how to take over the patient's activities completely. The final chapter describes a test that helps assess AD patients.

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Successful Communication with Alzheimer's Disease Patients: An InService Manual Source: Boston, MA: Butterworth-Heinemann. 1997. 288 p. Contact: Available from Butterworth-Heinemann. 225 Wildwood Avenue, Woburn, MA 01801. (800) 366-2665. Fax (800) 446-6520. E-mail: [email protected]. Website: www.bh.com. PRICE: $39.50 plus shipping and handling. ISBN: 0750695641. Summary: This book offers a series of inservice instructional units written for professionals who care for persons with Alzheimer's disease (AD). Every unit focuses on a specific aspect of communication in long term care (LTC) settings, including: communication in the nursing home; communication problems and strengths of patients with AD and related disorders; other communication disorders in AD; effects of the physical environment on communication; effects of the psychosocial environment on communication; communication strengths and problems of professionals who care for patients with AD; multicultural issues in nursing homes; verbal abuse and communication neglect; positive techniques for successful conversation with AD patients; positive

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techniques for handling difficult communication situations; positive techniques for communicating with families of AD patients; and direct intervention programs for AD patients. Each unit recommends effective techniques that show how to become a better communicator, how to support patients' best communication efforts, and how to minimize or avoid disastrous communication breakdowns. Appendices include quizzes on the material in each chapter, and masters for making overheads of the instructional concepts. A subject index concludes the volume. •

Of Two Minds: A Guide to the Care of People With the Dual Diagnosis of Alzheimer's Disease and Mental Retardation Source: Malden, MA: Alzheimer Support Services Cooperative for Human Services, Inc. 1995. 167 p. Contact: Available from Antonangeli, J.M., Director, Alzheimer Support Services Cooperative for Human Services, Inc. 110 Pleasant Street, Malden, MA 02148. (617) 324-4303; FAX (617) 397-9411. PRICE: $19.95. Summary: This guidebook offers practical suggestions and techniques for caregivers of people with the dual diagnosis of Alzheimer's disease (AD) and mental retardation. It provides an overview of AD and its manifestations in people with mental retardation and suggests how to structure physical environments in a home and in a day program. It also suggests strategies for evaluating and optimizing safety, preventing wandering, and communicating with persons who have impaired memories. Guidelines are detailed for helping these persons with all activities of daily living. Behavior management strategies are given for dealing with such common problems as depression, inappropriate expressions of sexuality, and catastrophic reactions, and so-called nuisance' behaviors such as pacing. Also highlighted are strategies for medical conditions and engaging persons in failure-free activities. A section on caring for the caregiver discusses educational support, helping housemates understand AD, and helping staff cope with grief and loss. Tables, reading list, selected index, and table guide.

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Clinical Diagnosis and Management of Alzheimer's Disease Source: Woburn, MA: Butterworth-Heinemann. 1996. 372 p. Contact: Available from Butterworth-Heinemann Fulfillment Center. 225 Wildwood Avenue, Woburn, MA 081801-9606. (617) 928-2500; FAX (617) 933-6333. PRICE: $125.00 ISBN: 0750698454. Summary: This textbook is intended to guide health care professionals in the diagnosis and management of Alzheimer's disease (AD). Section One

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introduces the disease process, presents definitions and diagnostic criteria, and explains the pathophysiology of the Alzheimer syndrome. Focusing on diagnosis, Section Two reviews typical clinical features, nonAlzheimer dementias, neuropsychological assessment, brain imaging, and electrophysiological tests. Section Three examines the natural evolution of AD, including prognostic factors, global staging, cognition, mood and behavior, and functional autonomy. Section Four explores the medical management of AD, with attention to mood and behavior management, the use of AD symptomatic drugs (including tacrine [cognex]), and AD symptomatic drugs under development. Discussion also focuses on conditions, and quality of life measurements in intervention studies (mainly drug trials). Section Five, on community and institutional management, examines support of families, communitybased formal support services, and institutional care. Ethical and legal issues are delineated in Section Six, with attention to determination of competence and genetic counseling. Section Seven on the future diagnosis and treatment of AD, concludes this book. 44 tables, 24 figure, chapter references.

Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes & Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print®). The following have been recently listed with online booksellers as relating to Alzheimer’s disease (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

Alzheimer's Angels: A Compilation of Poetry Honoring Caregivers and Victims of Alzheimer's Disease by Dorothy Womack (2002); ISBN: 0595245501; http://www.amazon.com/exec/obidos/ASIN/0595245501/icongroupin terna

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Alzheimer's Disease by Ralph, W. Richter, Richter & Richter (2002); ISBN: 0723432635; http://www.amazon.com/exec/obidos/ASIN/0723432635/icongroupin terna

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Alzheimer's Disease by William Molloy (Contributor), Paul Dr. Caldwell (1998); ISBN: 1552092410;

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http://www.amazon.com/exec/obidos/ASIN/1552092410/icongroupin terna •

Alzheimer's Disease (Diseases and Disorders) by Linda Jacobs Altman (2000); ISBN: 1560066954; http://www.amazon.com/exec/obidos/ASIN/1560066954/icongroupin terna

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Alzheimer's Disease (Diseases and People) by Edward Willett (2002); ISBN: 0766015963; http://www.amazon.com/exec/obidos/ASIN/0766015963/icongroupin terna

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Alzheimer's Disease (Facts Research and Intervention in Geriatrics) by L. J. Fitten (Editor), et al (1996); ISBN: 0826196225; http://www.amazon.com/exec/obidos/ASIN/0826196225/icongroupin terna

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Alzheimer's Disease : Activity-Focused Care, 2nd Ed. by Carly R. Hellen (1998); ISBN: 0750699086; http://www.amazon.com/exec/obidos/ASIN/0750699086/icongroupin terna

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Alzheimer's Disease and Marriage by Lore K. Wright (Author) (1993); ISBN: 0803945221; http://www.amazon.com/exec/obidos/ASIN/0803945221/icongroupin terna

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Alzheimer's Disease and Related Disorders Annual, 2004 by Serge Gauthier (Editor), et al (2004); ISBN: 1841843482; http://www.amazon.com/exec/obidos/ASIN/1841843482/icongroupin terna

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Alzheimer's Disease Sourcebook: Basic Consumer Health Information About Alzheimer's Disease, Other Dementias, and Related Disorders (Health Reference Series) by Karen Bellenir (Editor) (2003); ISBN: 0780806662; http://www.amazon.com/exec/obidos/ASIN/0780806662/icongroupin terna

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Alzheimer's Disease: A Compendium of Current Theories by Zaven S. Khachaturian (Editor), M.-Marsel Mesulam (Editor) (2002); ISBN: 0801868343; http://www.amazon.com/exec/obidos/ASIN/0801868343/icongroupin terna

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Alzheimer's Disease: A Guide to Diagnosis, Treatment, and Management by James E. Soukup (Author) (1996); ISBN: 0275954609;

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http://www.amazon.com/exec/obidos/ASIN/0275954609/icongroupin terna •

Alzheimer's Disease: Activities That Work by Catherine A. Abrignani (1991); ISBN: 1877735345; http://www.amazon.com/exec/obidos/ASIN/1877735345/icongroupin terna

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Alzheimer's Disease: Amyloid Precursor Proteins, Signal Transduction, and Neuronal Transplantation (Annals of the New York Academy of Sciences, Vol) by Roger M. Nitsch, et al (1993); ISBN: 0897668545; http://www.amazon.com/exec/obidos/ASIN/0897668545/icongroupin terna

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Alzheimer's Disease: Caregivers Speak Out by Pam Haisman (1998); ISBN: 0966227204; http://www.amazon.com/exec/obidos/ASIN/0966227204/icongroupin terna

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Alzheimer's Disease: Methods and Protocols (Methods in Molecular Medicine, Vol 32) by N. M. Hooper (Editor) (2000); ISBN: 0896037371; http://www.amazon.com/exec/obidos/ASIN/0896037371/icongroupin terna

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Alzheimer's Disease: Questions and Answers by Paul S. Aisen (Editor), et al (1999); ISBN: 1873413521; http://www.amazon.com/exec/obidos/ASIN/1873413521/icongroupin terna

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Alzheimer's Disease: The Physician's Guide to Practical Management by Ralph W., Md. Richter (Editor), et al (2003); ISBN: 0896038912; http://www.amazon.com/exec/obidos/ASIN/0896038912/icongroupin terna

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Alzheimer's Disease: Vascular Etiology and Pathology (Annals of the New York Academy of Sciences, V. 977) by World Congress on Vascular Factors in Alzheimer's Disease 2002 Kyoto, J. C. De LA Torre (2002); ISBN: 1573314412; http://www.amazon.com/exec/obidos/ASIN/1573314412/icongroupin terna

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Apolipoprotein E and Alzheimer's Disease (Research and Perspectives in Alzheimer's Disease) by Allen D. Roses (Editor), et al (1996); ISBN: 3540607986; http://www.amazon.com/exec/obidos/ASIN/3540607986/icongroupin terna

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Apolipoprotein E Genotyping in Alzheimer's Disease (Annals of the New York Academy of Science, Vol 802) by Norman R. Relkin (Editor),

260 Alzheimer’s Disease

et al (1996); ISBN: 1573310484; http://www.amazon.com/exec/obidos/ASIN/1573310484/icongroupin terna •

Behavioral Complications in Alzheimer's Disease by Brian A. Lawlor (Editor) (1995); ISBN: 0880484772; http://www.amazon.com/exec/obidos/ASIN/0880484772/icongroupin terna

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Biological Markers of Alzheimer's Disease (Research and Perspectives in Alzheimer's Disease) by F. Boller, et al (1990); ISBN: 0387516697; http://www.amazon.com/exec/obidos/ASIN/0387516697/icongroupin terna

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Broken Circuits: A Memoir of Alzheimer's Disease in Four Voices by Marilyn Mehr, et al (2003); ISBN: 1410799425; http://www.amazon.com/exec/obidos/ASIN/1410799425/icongroupin terna

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Calcium, Membranes, Aging, and Alzheimer's Disease (Annals of the New York Academy of Sciences, Vol 568) by Zaven S. Khachaturian, et al (1989); ISBN: 0897665473; http://www.amazon.com/exec/obidos/ASIN/0897665473/icongroupin terna

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Can Do Activities for Adults With Alzheimer's Disease: Strength-Based Communication and Programming by Eileen Eisner (2001); ISBN: 0890798621; http://www.amazon.com/exec/obidos/ASIN/0890798621/icongroupin terna

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Candle and Darkness: Current Research in Alzheimer's Disease by Joseph Rogers (1998); ISBN: 1566250951; http://www.amazon.com/exec/obidos/ASIN/1566250951/icongroupin terna

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Caregiving to Family Members With Alzheimer's Disease (Garland Studies on the Elderly in America) by Pauline Jivanjee (1995); ISBN: 0815320256; http://www.amazon.com/exec/obidos/ASIN/0815320256/icongroupin terna

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Caring for a Loved One With Alzheimer's Disease: A Christian Perspective (Haworth Religion and Mental Health.) by Elizabeth T. Hall (2000); ISBN: 0789008734; http://www.amazon.com/exec/obidos/ASIN/0789008734/icongroupin terna

Books 261

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Cerebrovascular Pathology in Alzheimer's Disease (Annals of the New York Academy of Sciences, Vol 826) by J. C. De LA Torre (Editor), et al (1997); ISBN: 1573310867; http://www.amazon.com/exec/obidos/ASIN/1573310867/icongroupin terna

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Cholinesterase Inhibitors in Alzheimer's Disease by Gordon Mallarkey (Editor) (1999); ISBN: 0864710666; http://www.amazon.com/exec/obidos/ASIN/0864710666/icongroupin terna

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Contingent Valuation Method in Health Care: An Economic Evaluation of Alzheimer's Disease by Sandra Nocera, et al (2004); ISBN: 1402077181; http://www.amazon.com/exec/obidos/ASIN/1402077181/icongroupin terna

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Coping When a Grandparent Has Alzheimer's Disease (Coping Series) by Beth Wilkinson (1995); ISBN: 0823919471; http://www.amazon.com/exec/obidos/ASIN/0823919471/icongroupin terna

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Coping With Alzheimer's Disease and Other Dementing Illnesses by Mary Norton Kindig, Molly Carnes (1993); ISBN: 1565930975; http://www.amazon.com/exec/obidos/ASIN/1565930975/icongroupin terna

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Cytochrome Oxidase in Neuronal Metabolism and Alzheimer's Disease by F. Gonzalez-Lima (Editor) (1998); ISBN: 0306460246; http://www.amazon.com/exec/obidos/ASIN/0306460246/icongroupin terna

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Day Is Ending: A Doctor's Love Shattered by Alzheimer's Disease by Richard W., Md Zalar, et al (2003); ISBN: 0974055808; http://www.amazon.com/exec/obidos/ASIN/0974055808/icongroupin terna

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Decoding Darkness: The Search for the Genetic Causes of Alzheimer's Disease by Rudolph E. Tanzi, Ann B. Parson (2001); ISBN: 0738205265; http://www.amazon.com/exec/obidos/ASIN/0738205265/icongroupin terna

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Defense Against Alzheimer's Disease: A Rational Blueprint for Prevention by H. J. Roberts (1995); ISBN: 1884243002; http://www.amazon.com/exec/obidos/ASIN/1884243002/icongroupin terna

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Designing for Alzheimer's Disease : Strategies for Creating Better Care Environments by Elizabeth C. Brawley (Author) (1997); ISBN: 0471139203;

262 Alzheimer’s Disease

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Developing Support Groups for Individuals with Early-Stage Alzheimer's Disease: Planning, Implementation, and Evaluation by Robyn Yale (1995); ISBN: 1878812262; http://www.amazon.com/exec/obidos/ASIN/1878812262/icongroupin terna

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Doing Things: A Guide to Programming Activities for Persons With Alzheimer's Disease and Related Disorders by Jitka M. Zgola, Nancy L. Mace (Designer) (1987); ISBN: 0801834678; http://www.amazon.com/exec/obidos/ASIN/0801834678/icongroupin terna

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Dying for a Hamburger : How Modern Meat-Packing Led to an Epidemic of Alzheimer's Disease by Murray Waldman (Author), Marjorie Lamb (Author) (2004); ISBN: 0771087659; http://www.amazon.com/exec/obidos/ASIN/0771087659/icongroupin terna

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Early Diagnosis and Treatment of Alzheimer's Disease by Simon Lovestone (1998); ISBN: 1853175803; http://www.amazon.com/exec/obidos/ASIN/1853175803/icongroupin terna

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Early Markers in Parkinson's and Alzheimer's Diseases (New Vistas in Drug Research, Vol 1) by P. Dostert, et al (1991); ISBN: 0387822232; http://www.amazon.com/exec/obidos/ASIN/0387822232/icongroupin terna

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Forgetting Whose We Are: Alzheimer's Disease and the Love of God by David Keck (1996); ISBN: 0687020883; http://www.amazon.com/exec/obidos/ASIN/0687020883/icongroupin terna

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Gentlecare: Changing the Experience of Alzheimer's Disease in a Positive Way by Moyra Jones (1999); ISBN: 0881791717; http://www.amazon.com/exec/obidos/ASIN/0881791717/icongroupin terna

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Glimmers: A Journey into Alzheimer's Disease by Heidi Hamilton, Marie Foley (2003); ISBN: 188399179X; http://www.amazon.com/exec/obidos/ASIN/188399179X/icongroupi nterna

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God Never Forgets: Faith, Hope, and Alzheimer's Disease by Donald K. McKim (Editor) (1998); ISBN: 0664257046;

Books 263

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He Used to Be Somebody, 1995: A Journey into Alzheimer's Disease Through the Eyes of a Caregiver by Beverly Bigtree Murphy (1996); ISBN: 0943909147; http://www.amazon.com/exec/obidos/ASIN/0943909147/icongroupin terna

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I Can't Remember: Family Stories of Alzheimer's Disease by Esther Strauss Smoller, Kathleen O'Brien (1997); ISBN: 1566395550; http://www.amazon.com/exec/obidos/ASIN/1566395550/icongroupin terna

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Immunization Against Alzheimer's Disease and Other Neurodegenerative Disorders (Research and Perspectives in Alzheimer's Disease) by France)/ Christen, Yves Medical Research Colloquium 2002 Paris, et al (2003); ISBN: 3540007075; http://www.amazon.com/exec/obidos/ASIN/3540007075/icongroupin terna

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Immunology and Alzheimer's Disease (Research and Perspectives in Alzheimers Disease) by A. Pouplard-Barthelaix (Editor), et al (1988); ISBN: 0387191879; http://www.amazon.com/exec/obidos/ASIN/0387191879/icongroupin terna

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Interventions for Alzheimer's Disease: A Caregiver's Complete Reference by Ruth M. Tappen (1997); ISBN: 1878812394; http://www.amazon.com/exec/obidos/ASIN/1878812394/icongroupin terna

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Journey With Grandpa: Our Family's Struggle With Alzheimer's Disease by Rosalie Walsh Honel (1988); ISBN: 0801837219; http://www.amazon.com/exec/obidos/ASIN/0801837219/icongroupin terna

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Life Out of Focus: Alzheimer's Disease and Related Disorders (Encyclopedia of Psychological Disorders) by Dan Harmon, Carol C. Nadelson (Editor) (1999); ISBN: 0791048969; http://www.amazon.com/exec/obidos/ASIN/0791048969/icongroupin terna

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Living With Alzheimer's Disease: One Couple's Journey by Frances Siegel (2000); ISBN: 1889059811; http://www.amazon.com/exec/obidos/ASIN/1889059811/icongroupin terna

264 Alzheimer’s Disease

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Living With John: Caring for a Loved One With Alzheimer's Disease by Nellie Kidd-Madison (2000); ISBN: 1587410613; http://www.amazon.com/exec/obidos/ASIN/1587410613/icongroupin terna

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Love Is Ageless: Stories About Alzheimer's Disease (2nd Edition) by Jessica Bryan (Editor) (2002); ISBN: 0961931116; http://www.amazon.com/exec/obidos/ASIN/0961931116/icongroupin terna

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Managing Alzheimer's Disease in Primary Care by Brodaty, H. Brodaty (1999); ISBN: 1858733588; http://www.amazon.com/exec/obidos/ASIN/1858733588/icongroupin terna

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Mayo Clinic on Alzheimer's Disease by Ronald C., M.D. Petersen (Editor), Mayo Clinic (2002); ISBN: 1893005224; http://www.amazon.com/exec/obidos/ASIN/1893005224/icongroupin terna

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Mild Cognitive Impairment: Aging to Alzheimer's Disease by Ronald C., Ph.D., M.D. Petersen (Editor), et al (2003); ISBN: 0195123425; http://www.amazon.com/exec/obidos/ASIN/0195123425/icongroupin terna

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Muscarinic Agonists and the Treatment of Alzheimer's Disease by Abraham Fisher (Editor) (1996); ISBN: 0412103311; http://www.amazon.com/exec/obidos/ASIN/0412103311/icongroupin terna

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My Journey into Alzheimer's Disease by Robert Davis (1989); ISBN: 0842346457; http://www.amazon.com/exec/obidos/ASIN/0842346457/icongroupin terna

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Nana's New Home: A Comforting Story Explaining Alzheimer's Disease to Children by Kristi Cargill, et al (1997); ISBN: 0966056604; http://www.amazon.com/exec/obidos/ASIN/0966056604/icongroupin terna

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Neurochemistry of Alzheimer's Disease (Neuroscience Perspectives) by Bowen (2000); ISBN: 0121205401; http://www.amazon.com/exec/obidos/ASIN/0121205401/icongroupin terna

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Neuronal Signal Transduction & Alzheimer's Disease by C. O'Neill, Biochemical Society (2001); ISBN: 1855781336; http://www.amazon.com/exec/obidos/ASIN/1855781336/icongroupin terna

Books 265

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Neuropsychology of Alzheimer's Disease and Other Dementias by Randolph W. Parks (Editor), et al (1993); ISBN: 019506612X; http://www.amazon.com/exec/obidos/ASIN/019506612X/icongroupi nterna

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New Directions in Understanding Dementia and Alzheimer's Disease (Advances in Experimental Medicine and Biology, 282) by Taher Zandi, Richard J. Ham (Editor) (1991); ISBN: 0306437287; http://www.amazon.com/exec/obidos/ASIN/0306437287/icongroupin terna

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Non-Neuronal Cells in Alzheimer's Disease by Paolo Zatta (Editor), M. Nicolini (Editor) (1995); ISBN: 9810220928; http://www.amazon.com/exec/obidos/ASIN/9810220928/icongroupin terna

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Old Timers: A Son Witnesses His Mother's One-Way Journey into the Darkness of Alzheimer's Disease by Jack Turley (2002); ISBN: 0759674167; http://www.amazon.com/exec/obidos/ASIN/0759674167/icongroupin terna

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One Step at a Time: A Definitive Study of Alzheimer's Disease and a Practical Guide for Caregivers by Lorena Shell Eaker (1996); ISBN: 0965300005; http://www.amazon.com/exec/obidos/ASIN/0965300005/icongroupin terna

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Pathobiology of Alzheimer's Disease by Alison Goate (Author), Frank Ashall (Author) (1995); ISBN: 0122869656; http://www.amazon.com/exec/obidos/ASIN/0122869656/icongroupin terna

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Presenilins and Alzheimer's Disease (Research and Perspectives in Alzheimer's Disease) by S. G. Younkin (Editor), et al (1998); ISBN: 3540639977; http://www.amazon.com/exec/obidos/ASIN/3540639977/icongroupin terna

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Proteases and Protease Inhibitors in Alzheimer's Disease Pathogenesis (Annals of the New York Academy of Sciences, Vol 674) by Carl D. B. Banner (Editor), Ralph A. Nixon (Editor) (1992); ISBN: 0897667786; http://www.amazon.com/exec/obidos/ASIN/0897667786/icongroupin terna

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Psychiatric Treatment of Alzheimer's Disease (Report) (1988); ISBN: 0876305192;

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Research and Practice in Alzheimer's Disease by Bruno, Md, Ph.D Vellas (Editor), et al (2001); ISBN: 0826117430; http://www.amazon.com/exec/obidos/ASIN/0826117430/icongroupin terna

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Stolen Memories: One Family's Experience with Alzheimer's Disease by Marie Cloud, Compagno (2000); ISBN: 0595000754; http://www.amazon.com/exec/obidos/ASIN/0595000754/icongroupin terna

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Taking Care of Caregivers: For Families and Others Who Care for People With Alzheimer's Disease and Other Forms of Dementia by D. Jeanne Roberts (1991); ISBN: 0923521097; http://www.amazon.com/exec/obidos/ASIN/0923521097/icongroupin terna

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The Alzheimer's Health Care Handbook: How to Get the Best Medical Care for Your Relative with Alzheimer's Disease, in and out of the Hospital by Mary S. Mittelman, Cynthia Epstein (2003); ISBN: 1569244456; http://www.amazon.com/exec/obidos/ASIN/1569244456/icongroupin terna

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The Book---Alzheimer's Disease: Caregiver's Home Management by Robert H. Rogge (1996); ISBN: 1570871825; http://www.amazon.com/exec/obidos/ASIN/1570871825/icongroupin terna

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The Changing Brain: Alzheimer's Disease and Advances in Neuroscience by Ira B. Black (2002); ISBN: 0195156978; http://www.amazon.com/exec/obidos/ASIN/0195156978/icongroupin terna

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The Clinical Management of Early Alzheimer's Disease: A Handbook by Reinhild Mulligan (Editor), et al (2003); ISBN: 0805833706; http://www.amazon.com/exec/obidos/ASIN/0805833706/icongroupin terna

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The Encyclopedia of Alzheimer's Disease by Carol Turkington (2003); ISBN: 0816048185; http://www.amazon.com/exec/obidos/ASIN/0816048185/icongroupin terna

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The Epidemiology of Alzheimer's Disease and Related Disorders by Anthony J. Jorm, Anthony F. Jorm (1991); ISBN: 0412315203;

Books 267

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The Experience of Alzheimer's Disease: Life Through a Tangled Veil by Steven R. Sabat (2001); ISBN: 0631216669; http://www.amazon.com/exec/obidos/ASIN/0631216669/icongroupin terna

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The Loss of Self: A Family Resource for the Care of Alzheimer's Disease and Related Disorders by Donna, Ph.D Cohen, Carl, Ph.D Eisdorfer (2002); ISBN: 0393323331; http://www.amazon.com/exec/obidos/ASIN/0393323331/icongroupin terna

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The Memory Cure: How to Protect Your Brain Against Memory Loss and Alzheimer's Disease [ABRIDGED] by Majid, Md. Fotuhi, Simon Vance (Narrator) (2003); ISBN: 1932378022; http://www.amazon.com/exec/obidos/ASIN/1932378022/icongroupin terna

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The Neuropsychiatry of Alzheimer's Disease and Related Dementias by Jeffrey L. Cummings, et al (2002); ISBN: 1841842192; http://www.amazon.com/exec/obidos/ASIN/1841842192/icongroupin terna

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The Person With Alzheimer's Disease: Pathways to Understanding the Experience by Phyllis Braudy, Ph.D Harris (Editor) (2002); ISBN: 0801868777; http://www.amazon.com/exec/obidos/ASIN/0801868777/icongroupin terna

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The Positive Interactions Program of Activities for People With Alzheimer's Disease by Sylvia Nissenboim, Christine Vroman (1998); ISBN: 1878812408; http://www.amazon.com/exec/obidos/ASIN/1878812408/icongroupin terna

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The Rakhma Story: Unconditional Love and Caring for People With Alzheimer's Disease and Dementia by Shirley Joy Shaw, Lynn Baskfield (1999); ISBN: 188009083X; http://www.amazon.com/exec/obidos/ASIN/188009083X/icongroupi nterna

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The Stranger I Call Grandma: A Story About Alzheimer's Disease by Swanee Ballman, Stephanie Brunson (Illustrator) (2002); ISBN: 0970295944; http://www.amazon.com/exec/obidos/ASIN/0970295944/icongroupin terna

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Therapeutic Activities With Persons Disabled by Alzheimer's Disease and Related Disorders by Carol Bowlby Sifton (1998); ISBN: 0834211629; http://www.amazon.com/exec/obidos/ASIN/0834211629/icongroupin terna

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Understanding Alzheimer's Disease (Understanding Health and Sickness Series) by Neal R. Cutler, John J. Sramek (Contributor) (1997); ISBN: 0878059113; http://www.amazon.com/exec/obidos/ASIN/0878059113/icongroupin terna

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Vanishing Mind: A Practical Guide to Alzheimer's Disease and Other Dementias (Series of Books in Psychology) by Leonard L. Heston, June A. White (1991); ISBN: 0716721929; http://www.amazon.com/exec/obidos/ASIN/0716721929/icongroupin terna

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Vascular Factors in Alzheimer's Disease (Annals of the New York Academy of Sciences, Vol 903) by Raj N. Kalaria (Editor), Paul Ince (Editor) (2000); ISBN: 1573312517; http://www.amazon.com/exec/obidos/ASIN/1573312517/icongroupin terna

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Waiting for the Morning: A Mother and Daughter's Journey Through Alzheimer's Disease by Brenda Parris Sibley (2001); ISBN: 059518782X; http://www.amazon.com/exec/obidos/ASIN/059518782X/icongroupi nterna

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We'll Be Married in Fremantle: Alzheimer's Disease and the Everyday Act of Storying by Julie Goyder (2001); ISBN: 1863683119; http://www.amazon.com/exec/obidos/ASIN/1863683119/icongroupin terna

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When Alzheimer's Disease Strikes by James S. Sapp, Stephen Sapp (1996); ISBN: 0914733125; http://www.amazon.com/exec/obidos/ASIN/0914733125/icongroupin terna

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Will I Be Next?: Bea Gorman's Life Story - The Terror of Living With Familial Alzheimer's Disease by Lois Bristow (1995); ISBN: 0964888505; http://www.amazon.com/exec/obidos/ASIN/0964888505/icongroupin terna

Books 269

The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select “Search LOCATORplus.” Once you are in the search area, simply type “Alzheimer’s disease” (or synonyms) into the search box, and select “books only.” From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine:25 •

Advancing frontiers in Alzheimer's disease research Author: Glenner, George G.,; Year: 1970; Austin: University of Texas Press, 1987; ISBN: 0292776020 http://www.amazon.com/exec/obidos/ASIN/0292776020/icongroupin terna

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Aging of the brain and Alzheimer's disease: proceedings of the 14th International Summer School of Brain Research, held at the Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands, 26-30 August 1985 Author: Swaab, D. F. (Dick Frans); Year: 1987; Amsterdam; New York: Elsevier; New York, NY, USA: Sole distributors for the USA and Canada, Elsevier Science Pub. Co., 1986; ISBN: 0444807934 http://www.amazon.com/exec/obidos/ASIN/0444807934/icongroupin terna

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Alzheimer's disease Author: Reisberg, Barry.; Year: 1985; New York: Free Press, c1983; ISBN: 0029262305 http://www.amazon.com/exec/obidos/ASIN/0029262305/icongroupin terna

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Alzheimer's disease: a report of progress in research Author: Corkin, Suzanne.; Year: 1982; New York: Raven Press, c1982; ISBN: 0890046859 http://www.amazon.com/exec/obidos/ASIN/0890046859/icongroupin terna

In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a “Books” button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.

25

270 Alzheimer’s Disease

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Alzheimer's disease: a scientific guide for health practitioners Author: National Institute of Neurological and Communicative Disorders and Stroke. Office of Scientific and Health Reports.; Year: 1985; [Bethesda, Md.]: U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health, [1980]

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Alzheimer's disease: an information paper Author: United States. Congress. House. Select Committee on Aging. Subcommittee on Health and Long-Term Care.; Year: 1983; Washington: U.S. G.P.O., 1983

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Alzheimer's disease: early recognition of potentially reversible deficits Author: Glen, A. I. M.; Year: 1981; Edinburgh; New York: Churchill Livingstone, 1979; ISBN: 0443020809 http://www.amazon.com/exec/obidos/ASIN/0443020809/icongroupin terna

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Alzheimer's disease: is there an acid rain connection?: hearing before the Subcommittee on Human Services of the Select Committee on Aging, House of Representatives, Ninety-eighth Congress, first session, August 8, 1983, Bangor, Maine. Author: United States. Congress. House. Select Committee on Aging. Subcommittee on Human Services.; Year: 1993; Washington: U.S. G.P.O., 1983

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Alzheimer's disease: joint hearing before the Subcommittee on Health and Long-Term Care of the Select Committee on Aging and the Subcommittee on Health and the Environment of the Committee on Energy and Commerce, House of Representatives,Ninety-eighth Congress, first session, Washington, D.C., August 3, 1983. Author: United States. Congress. House. Select Committee on Aging. Subcommittee on Health and Long-Term Care.; Year: 1983; Washington: U.S. G.P.O., 1984

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Alzheimer's disease: report of the Secretary's Task Force on Alzheimer's Disease. Author: United States. Dept. of Health and Human Services. Task Force on Alzheimer's Disease.; Year: 1984; Rockville, MD (5600 Fishers Lane, Rockville 20857): U.S. Dept. of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration; Washington, D.C.: For sale by the Supt. of Docs., U.S. G.P.O., [1984]

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Alzheimer's disease: senile dementia and related disorders Author: Workshop Conference on Alzheimer's Disease: Senile Dementia and Related Disorders, Bethesda, Md., 1977.; Year: 1979; New York: Raven Press, 1978; ISBN: 089004225X http://www.amazon.com/exec/obidos/ASIN/089004225X/icongroupi nterna

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Alzheimer's disease and related conditions. A Ciba Foundation Symposium. Edited by G. E. W. Wolstenholme and Maeve O'Connor.

Books 271

Author: O'Connor, Maeve.; Year: 1978; London, Churchill, 1970; ISBN: 700014845 •

Alzheimer's disease and related disorders: research and management Author: Kelly, William E.; Year: 1983; Springfield, Ill., U.S.A.: Thomas, c1984; ISBN: 0398048959 http://www.amazon.com/exec/obidos/ASIN/0398048959/icongroupin terna

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Alzheimer's disease handbook Author: Lindeman, David A.; Year: 1986; Washington, D.C.: U.S. Dept. of Health and Human Services, Office of Human Development Services, Administration on Aging, [1984]

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Alzheimer's Disease Society day care: projects funded by the Ladbroke Group plc Author: Brownfoot, Jan.; Year: 1995; London: The Society, [1993]

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Alzheimer's disease, Down's syndrome, and aging Author: Sinex, F. Marott.; Year: 1980; New York, N.Y.: New York Academy of Sciences, 1982; ISBN: 0897661826 http://www.amazon.com/exec/obidos/ASIN/0897661826/icongroupin terna

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Biological aspects of Alzheimer's disease Author: Katzman, Robert.; Year: 1983; [Cold Spring Harbor, N.Y.]: Cold Spring Harbor Laboratory, 1983; ISBN: 0879692138 http://www.amazon.com/exec/obidos/ASIN/0879692138/icongroupin terna

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Clinical aspects of Alzheimer's disease and senile dementia Author: Cohen, Gene D.; Year: 1980; New York: Raven Press, 1981; ISBN: 0890043264 http://www.amazon.com/exec/obidos/ASIN/0890043264/icongroupin terna

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Coping and helping with Alzheimer's disease. Author: Lyons, Walter H.; Year: 1984; Ottawa, Ont.: National Advisory Council on Aging, [1984]; ISBN: 0662129687

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Current perspectives of geriatric psychopathology and Alzheimer's disease: proceedings of a symposium Author: Geyer, Harry M.; Year: 1986; New York: Liss, [1985]

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Dementia, a practical guide to Alzheimer's disease and related illnesses Author: Heston, Leonard L.; Year: 1984; New York: Freeman, c1983; ISBN: 0716715686 http://www.amazon.com/exec/obidos/ASIN/0716715686/icongroupin terna

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Impact of Alzheimer's disease on the nation's elderly: joint hearing before the Subcommittee on Aging of the Committee on Labor and

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Human Resources, United States Senate, and the Subcommittee on Labor, Health, Education, and Welfare of the Committee on Appropriations, House of Representatives, Ninety-sixth Congress, second session, on to analyze the impact of Alzheimer's disease and other dimentias [i. e. dementias] of aging on our society, July 15, 1980. Author: United States. Congress. Senate. Committee on Labor and Human Resources. Subcommittee on Aging.; Year: 1983; Washington, D.C.: U.S. G.P.O., 1980 •

National Eldercare Institute on Long Term Care and Alzheimer's Disease [microform]: final report Author: Pfeiffer, Eric,; Year: 2002; Tampa, Fla.: University of South Florida, Suncoast Gerontology Center, [1995]

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Senile dementia of the Alzheimer type: proceedings of the Fifth Tarbox Symposium: the Norman Rockwell Conference on Alzheimer's Disease held in Lubbock, Texas, October 18-20, 1984 Author: Hutton, J. Thomas.; Year: 1984; New York: Liss, c1985; ISBN: 0845127209 http://www.amazon.com/exec/obidos/ASIN/0845127209/icongroupin terna

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State and area agency instructional guide for Alzheimer's disease family support groups Author: United States. Administration on Aging.; Year: 1986; San Francisco, CA: Aging Health Policy Center, University of California, San Francisco; Washington, D.C.: U.S. Dept. of Health and Human Services, Office of Human Development Services, Administration on Aging, [1984]

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The 36-hour day: a family guide to caring for persons with Alzheimer's disease, related dementing illnesses, and memory loss in later life Author: Mace, Nancy L.; Year: 1984; Baltimore: Johns Hopkins University Press, c1981; ISBN: 0801826594 http://www.amazon.com/exec/obidos/ASIN/0801826594/icongroupin terna

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The Biological substrates of Alzheimer's disease Author: Scheibel, Arnold B.; Year: 1984; Orlando: Academic Press, 1986; ISBN: 0126231303 http://www.amazon.com/exec/obidos/ASIN/0126231303/icongroupin terna

Chapters on Alzheimer’s Disease Frequently, Alzheimer’s disease will be discussed within a book, perhaps within a specific chapter. In order to find chapters that are specifically dealing with Alzheimer’s disease, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search

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to book chapters and Alzheimer’s disease using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” By making these selections and typing in “Alzheimer’s disease” (or synonyms) into the “For these words:” box, you will only receive results on chapters in books. The following is a typical result when searching for book chapters on Alzheimer’s disease: •

Genetic Epidemiology of Alzheimer's Disease Source: in Battistin, L.; Gerstenbrand, F., eds. Aging Brain and Dementia: New Trends in Diagnosis and Therapy. Proceedings of A Symposium held in Padova, Italy, September 22-24, 1988. New York, NY: Alan R. Liss, Inc. 1990. p. 57-78. Contact: Available from Alan R. Liss, Inc. 41 East 11th Street, New York, NY 10003. (212) 741-2515. ISBN: 0471562114. Summary: Alzheimer's disease (AD) is the most common cause of old age associated dementia, accounting for as much as 50 to 80 percent of the total dementia population. Genetic factors appear to play a significant role in determining risk for AD. This paper discusses theories of genetic transmission and heterogeneity based on a review of studies of: (1) multigenerational families with many affected members studied by pedigree analysis; (2) smaller families with several affected members; (3) twins; and (4) middle-aged and older individuals with Down syndrome, who represent a unique population that invariably develops Alzheimer type neuropathology before they reach 40 years of age. The preponderance of evidence supports a genetic transmission with variability in age of onset and clinical characteristics, but whether this variability reflects a spectrum of expression related to disease severity or represents etiologically distinct subtypes is not yet clear. 86 references.

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Amyloidosis of Alzheimer's Disease Source: in Platt, D., ed. Gerontology, 4th International Symposium: Present State and Research Perspectives in the Experimental and Clinical Gerontology. New York, NY: Springer-Verlag. 1989. p. 159-174. Contact: Available from Springer-Verlag. 44 Hartz Way, Secaucus, NJ 07094. (201) 348-4033. PRICE: $70.60. ISBN: 0387515445. Summary: Definitive lesions in Alzheimer's disease (AD) are the senile plaques in the neuropil and the intraneuronal neurofibrillary tangles; both of these have the staining properties of amyloid (including

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argyrophilia and birefringement congophilia), although the paired helical filaments characteristic of the tangles are morphologically distinct from all other amyloid filaments. This paper presents the morphological information available for each form of cerebral amyloid under separate headings, although the chemical information will draw together the common features of the extracellular amyloid. Topics include: the morphology and protein chemistry of the amyloid in senile plaques and of the cerebrovascular amyloid (CA); the immunochemistry of A4 amyloid deposits; the chemical nature of the A4 amyloid precursor protein; gaps in the protein chemical data; the morphology and chemistry of neurofibrillary tangles; and other syndromes with plaques, tangles, or cerebrovascular amyloid. Speculations on the generation of Alzheimer amyloid also are presented. 76 references. •

Psychopathological Perspectives: Differential Diagnosis of Alzheimer's Disease and Related Disorders Source: in Poon, L.W., ed. Handbook for Clinical Memory Assessment of Older Adults. Hyattsville, MD: American Psychological Association. 1986. p. 81-88. Contact: This publication may be available in your local medical library. Call for information. ISBN: 091270442X. Summary: Differential diagnosis of dementias of later life is an interdisciplinary challenge, with cognitive assessment one of several essential evaluations used to distinguish diseases of the Alzheimer type, vascular dementias, and related disorders. Psychological testing also provides the empirical basis to devise a treatment plan for patients with different forms of dementia. However, it is argued that cognitive and behavioral information is underutilized in patient care. This paper discusses specific research priorities, including information needed to develop an adequate classification to overcome limitations of DSM-III, to test the hypothesis of the heterogeneity of dementia, and to improve the ability to care for people, maximizing their functional effectiveness and quality of life. 58 references.

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Chemical Neuroanatomy of Alzheimer's Disease Source: in Iversen, L.L.; Iversen, S.D.; and Snyder, S.H., eds. Psychopharmacology of the Aging Nervous System, Volume 20. New York, NY: Plenum Press. 1988. p. 131-155. Contact: Available from Plenum Press. 233 Spring Street, New York, NY 10013. (800) 221-9369. PRICE: $85.00. ISBN: 0306427443.

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Summary: During the past few years experimental neuroanatomical studies have shed considerable light on the potential significance of the distribution of degenerative changes in Alzheimer's disease (AD). These studies give some insight into the significance of specific neurotransmitter deficits in AD, both for the pathogenesis of the dementia and for its potential treatment. This review addresses four principal areas: the relationship of neural connections and neurotransmitters with Alzheimer pathology; limbic and cortical connections and neurotransmitters in AD; cortical connections and neurotransmitters in AD with respect to the brain stem and basal forebrain; and implications for the pathogenesis and treatment of AD. 126 references. •

Alzheimer's Disease: Aluminum and Fibrinous Proteins Source: in De Broe, M.E. and Coburn, J.W. Aluminum and Renal Failure. Norwell, MA: Kluwer Academic Publishers. 1990. p. 127-137. Contact: Available from Kluwer Academic Publishers. 101 Philip Drive, Norwell, MA 02061. (617) 871-6600. PRICE: $139.00. ISBN: 0792303474. Summary: This book chapter discusses the controversy concerning the possible role of aluminum in Alzheimer's disease. The controversy has arisen, in part, as a result of the observation that aluminum concentrations in some cerebral cortical regions in tissue affected with Alzheimer's disease approach those found lethal to aluminum sensitive animals. However, no cause and effect relationship between any of the morphological or biochemical changes reported in Alzheimer's disease have been directly attributable to aluminum. There are two known risk factors for Alzheimer's disease: Down's syndrome and a family history of the disease. Approximately 10 percent of Alzheimer's disease cases appear to be familial. Topics discussed include research on Alzheimer amyloid in the human brain and aluminum and aluminum's involvement in senile plaques, amyloid proteins, fibrinous proteins of neurofibrillary degeneration, and aluminum accumulation in the brain. Researchers are attempting to discover how aluminum crosses membrane barriers in the brain. 43 references.

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Association Between Clinical and Neuro-Biological Findings in Alzheimer's Disease Source: in Courtois, Y., Faucheux, B., Forette, B., Knook, D.L., and Treton, J.A., eds. Modern Trends in Aging Research. London, England: John Libbey and Company, Limited. 1986. p. 421-434.

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Contact: Available from John Libbey and Company, Limited. 80/84 Bondway, London SW8 1SF, UNITED KINGDOM. (01) 582-5266. ISBN: 086916103X. Summary: This book chapter presents some neuropathological features of senile dementia of the Alzheimer type (SDAT). Emphasis is placed on cortical atrophy, mainly due to 'shrinkage' of the length of the cortical ribbon, with thickness remaining constant, on the location of senile plaques, mainly in layers II and III of the neocortex, and on recent data concerning the formation of neurofibrillary tangles. This paper does not intend to be a review of the neuropathology of SDAT; rather, its goal is to pinpoint what currently appears to be the most salient features of SDAT. 31 references. •

Colocalisation of Somatostatin, Neuropeptide Y and Neurofibrillary Tangles in Old Age and Alzheimer's Disease: Histological Evidence for the Loss of Peptidergic Neurons Source: in Bes, A., et al. Senile Dementias: Early Detection. London, England: John Libbey and Company Limited. 1986. p. 569-573. Contact: Available from John Libbey and Company Limited. 80/84 Bondway, London SW8 1SF, ENGLAND. (71) 582-5266. ISBN: 0861960947. PRICE: $90.00. Summary: This book chapter reports the results of a study that measured the coexistence of somatostatin (SOM) and neuropeptide Y (NPY) in various cortical regions of the brain of an Alzheimer patient and of a normal elderly control subject. The results suggest an early specific degeneration of those SOM neurons which contain little NPY immunoreactivity and are localized in clusters of perikarya in the superficial layers of the temporal cortex. It was also found that some pepidergic neurons contained neurofibrillary tangles, as demonstrated by consecutive immunohistological stainings. 11 references. (AA-M).

Directories In addition to the references and resources discussed earlier in this chapter, a number of directories relating to Alzheimer’s disease have been published that consolidate information across various sources. These too might be useful in gaining access to additional guidance on Alzheimer’s disease. The

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Combined Health Information Database lists the following, which you may wish to consult in your local medical library:26 •

Survey of North American and European Dementia Brain Banks: A 1994 Directory Source: Alzheimer Disease and Associated Disorders. 9(4): 193-202. 1995. Summary: This journal article updates a previous list of U.S. Alzheimer's disease brain banks and adds Canadian and European brain banks to the list. Brain banks serve two purposes: providing definitive diagnoses of dementing disorders, and providing brain and related tissues for research. A 1994 survey showed 48 brain banks in the United States, 3 in Canada, 2 in Austria, 3 in France, 1 in Germany, 1 in The Netherlands, 1 in Northern Ireland, 1 in Spain, 1 in Sweden, and 8 in Great Britan. Increased brain banking activity results from growth in the number of State and privately funded banks, funding by the U.S. National Institutes of Health of new Alzheimer's Disease Centers with integral brain banks, and the formation and funding of the European Brain Bank Network and the American Brain Bank Network. The entry for each brain bank includes its address and telephone number and the fax and telephone numbers of principal administrators. 1 table, 21 references.

General Home References In addition to references for Alzheimer’s disease, you may want a general home medical guide that spans all aspects of home healthcare. The following list is a recent sample of such guides (sorted alphabetically by title; hyperlinks provide rankings, information, and reviews at Amazon.com): •

Adams & Victor’s Principles Of Neurology by Maurice Victor, et al; Hardcover - 1692 pages; 7th edition (December 19, 2000), McGraw-Hill Professional Publishing; ISBN: 0070674973; http://www.amazon.com/exec/obidos/ASIN/0070674973/icongroupinter na

You will need to limit your search to “Directories” and Alzheimer’s disease using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find directories, use the drop boxes at the bottom of the search page where “You may refine your search by”. For publication date, select “All Years”, select language and the format option “Directory”. By making these selections and typing in “Alzheimer’s disease” (or synonyms) into the “For these words:” box, you will only receive results on directories dealing with Alzheimer’s disease. You should check back periodically with this database as it is updated every three months.

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Clinical Neuroanatomy Made Ridiculously Simple (MedMaster Series, 2000 Edition) by Stephen Goldberg; Paperback: 97 pages; 2nd edition (February 15, 2000), Medmaster; ISBN: 0940780461; http://www.amazon.com/exec/obidos/ASIN/0940780461/icongroupinter na

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It’s Not a Tumor!: The Patient’s Guide to Common Neurological Problems by Robert Wiedemeyer; Paperback: (January 1996), Boxweed Pub; ISBN: 0964740796; http://www.amazon.com/exec/obidos/ASIN/0964740796/icongroupinter na

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Neurology for the Non-Neurologist by William J. Weiner (Editor), Christopher G. Goetz (Editor); Paperback (May 1999), Lippincott, Williams & Wilkins Publishers; ISBN: 0781717078; http://www.amazon.com/exec/obidos/ASIN/0781717078/icongroupinter na

Vocabulary Builder Bowen: Intraepithelial epithelioma affecting the skin and sometimes the mucous membranes. [NIH] Compassionate: A process for providing experimental drugs to very sick patients who have no treatment options. [NIH] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Epstein: Failure of the upper eyelid to move downward on downward movement of the eye, occurring in premature and nervous infants. [NIH]

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CHAPTER 7. MULTIMEDIA ON ALZHEIMER’S DISEASE Overview Information on Alzheimer’s disease can come in a variety of formats. Among multimedia sources, video productions, slides, audiotapes, and computer databases are often available. In this chapter, we show you how to keep current on multimedia sources of information on Alzheimer’s disease. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine. If you see an interesting item, visit your local medical library to check on the availability of the title.

Video Recordings Most diseases do not have a video dedicated to them. If they do, they are often rather technical in nature. An excellent source of multimedia information on Alzheimer’s disease is the Combined Health Information Database. You will need to limit your search to “video recording” and “Alzheimer’s disease” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find video productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Videorecording (videotape, videocassette, etc.).” By making these selections and typing “Alzheimer’s disease” (or synonyms) into the “For these words:” box, you will only receive results on video productions. The following is a typical result when searching for video recordings on Alzheimer’s disease:

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Solving Bathing Problems in Persons With Alzheimer's Disease and Related Disorders Source: Chapel Hill, NC: Departments of Family Medicine and Psychology University of North Carolina. 1996. (videocassette). Contact: Available from Terra Nova Films. 9848 S. Winchester Avenue, Chicago, IL 60643. (800) 779-8491; (773) 881-8491; FAX (773) 881-3368. PRICE: $ 129.00 (purchase); $45.00 (rental); plus $9.00 shipping and handling. Order number: ED 259Z. Summary: This videotape shows different bathing situations, problems that can arise while bathing someone who has Alzheimer s disease (AD), and how to prevent or solve those problems. It focuses on individualized care. The introduction describes agitation and aggression and how those behaviors differ. The authors encourage caregivers to: learn about the person (level of dementia, physical problems, bathing preferences); learn about the problem behavior (what is triggering or causing the behavior); and develop a plan for bathing the individual (focus on the person, be flexible). According to the authors, once a caregiver has learned what an AD patient prefers and what factors reduce problems while bathing, the caregiver should provide that information in the patient s record to inform other staff members who may bathe that patient.

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Alzheimer's Disease: Natural Feeding Techniques Source: Chicago, IL: Terra Nova Films. 1996. (videocassette). Contact: Terra Nova Films. 9848 S. Winchester Avenue, Chicago, IL 60643. (800) 779-8491; (773) 881- 8491; FAX (773) 881- 3368. Internet: http://www.terranova.org. PRICE: $105.00 (purchase), $39.00 (rental) plus $9.00 for shipping. Summary: This videotape uses three case studies to show how natural oral feeding, instead of tube feeding, is administered to and may benefit people who are in the later stages of Alzheimer s disease (AD). The introduction describes how AD affects eating behaviors and what can be done to ensure the person still maintains proper nutrition. Suggested changes in feeding techniques include individualizing the meal to the patient s needs, increasing staff size during meal times, making breakfast and lunch the large meals of the day, modifying food consistency and flavor, and providing the AD patient with verbal and physical cues to chew and swallow. The authors have found that when natural oral feeding techniques are used to replace tube feeding, there is a decrease in infection and an increase in patient comfort and quality of life.

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Bibliography: Multimedia on Alzheimer’s Disease The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select “Search LOCATORplus.” Once in the search area, simply type in Alzheimer’s disease (or synonyms). Then, in the option box provided below the search box, select “Audiovisuals and Computer Files.” From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on Alzheimer’s disease. For more information, follow the hyperlink indicated: •

Alzheimer's disease [electronic resource] Source: written by Jean Wesley; Year: 1986; Format: Electronic resource; Edwardsville, KS: MediSim, c1986

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Alzheimer's disease [videorecording] Source: produced by Delmar Publishers, Inc.; production by Panagraph Incorporated; Year: 1989; Format: Videorecording; [Albany, N.Y]: Delmar, c1989

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Alzheimer's disease [videorecording] Source: Marshfield Video Network, in cooperation with Marshfield Clinic, St. Joseph's Hospital, and Marshfield Medical Research Foundation; Year: 1988; Format: Videorecording; Marshfield, WI: The Network, c1988

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Alzheimer's disease [videorecording] Source: presented by the Medical Learning Center Network at Saint Thomas Hospital; Year: 1989; Format: Videorecording; Nashville, TN: The Network, 1989

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Alzheimer's disease [videorecording] Source: presented as an educational service by Allen & Hanburys, division of Glaxo Inc. [and] Glaxo Pharmaceuticals, division of Glaxo Inc.; a Vision Associates/Medical Vision production; Year: 1988; Format: Videorecording; [Research Triangle Park, N.C.]: Glaxo, c1988

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Alzheimer's disease [videorecording]: coping with confusion Source: HSN, Hospital Satellite Network program of continuing education; Year: 1985; Format: Videorecording; [Los Angeles, Calif.]: The Network, c1985

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Alzheimer's disease [videorecording]: effects on communication Source: [presented by] MEES; a Video Services production; Year: 1986; Format: Videorecording; [Los Angeles, Calif.]: Hospital Satellite Network, c1986

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Alzheimer's disease [videorecording]: is today's science tomorrow's management? Source: Howard A. Crystal, Peter Davies; Year: 1991; Format: Videorecording; Secaucus, N.J.: Network for Continuing Medical Education, c1991

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Alzheimer's disease [videorecording]: managing the later stages in a health care setting Source: produced by Medical Media Production Service, VA Medical Center, Northport, NY, in cooperation with Geriatric Research, Education & Clinical Center, VA Medical Cen; Year: 1989; Format: Videorecording; [Washington, D.C.]: Dept. of Veterans Affairs, 1989

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Alzheimer's disease [videorecording]: managing the later stages in the home Source: produced by Medical Media Production Service, VA Medical Center, Northport, NY, in cooperation with Geriatric Research, Education & Clinical Center, VA Medical Center, Bedford,; Year: 1988; Format: Videorecording; [Washington, D.C.: Dept. of Veterans Affairs, 1988]

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Alzheimer's disease [videorecording]: pieces of the puzzle Source: produced by Arizona Long Term Care Gerontology Center and Biomedical Communications, Arizona Health Sciences Center, College of Medicine, the University of Arizona; Year: 1990; Format: Videorecording; Tucson, AZ: The University, c1990

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Alzheimer's disease [videorecording]: stolen tomorrows Source: produced by Lincoln General Hospital; Year: 1986; Format: Videorecording; Lincoln, Neb.: The Hospital, c1986

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Alzheimer's disease [videorecording]: the loss of self: a teleconference Source: presented by the Laurence A. Grossman Medical Learning Center at Saint Thomas Hospital; Year: 1988; Format: Videorecording; Nashville, Tenn.: The Center, c1988

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Alzheimer's disease and other memory disorders [videorecording] Source: produced by Macmillan Healthcare Information/Symposiums International and by the Annenberg Center for Health Sciences at Eisenhower Medical Center; Year: 1986; Format: Videorecording; [Florham Park, N.J.: Macmillan], [1986]

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Alzheimer's disease and the family [electronic resource] Source: developed by University of Rochester Medical School, Department of Pediatrics; Year: 1988; Format: Electronic resource; Chapel Hill, NC: Health Sciences Consortium, 1988

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Alzheimer's disease, a clinical update [videorecording] Source: with Barry Reisberg; Year: 1986; Format: Videorecording; Secaucus, N.J.: Network for Continuing Medical Education, 1986

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Alzheimer's disease, discharge planning [videorecording] Source: HSN, Hospital Satellite Network program of continuing education; Year: 1985; Format: Videorecording; [Los Angeles, Calif.]: The Network, c1985

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Dealing with Alzheimer's disease [videorecording]: a common sense approach to communication Source: production/post production facility,

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Gillette Children's Hospital; Year: 1990; Format: Videorecording; [St. Paul, Minn.]: Ramsey Foundation, c1990 •

Diagnosis of Alzheimer's disease [videorecording] Source: [presented by] Marshfield Clinic, Saint Joseph's Hospital, [and] Marshfield Medical Research Foundation; Year: 1992; Format: Videorecording; Marshfield, WI: Marshfield Regional Video Network, [1992]

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Geriatrics [videorecording]: Alzheimer's disease and other dementias Source: an AREN production; [produced at the facilities of WQED/Pittsburgh by QED Enterprises]; Year: 1986; Format: Videorecording; Pittsburgh, Pa.: AREN, c1986

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Managing and understanding behavior problems in Alzheimer's disease and related disorders [videorecording]: the ABCs of behavior management in dementia Source: training program developed by Linda Teri; produced in the facilities of Instructional Media Service; Year: 1990; Format: Videorecording; Seattle, WA: [University of Washington], c1990

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Molecular, biological, and neurobiologic contributions to our understanding of Alzheimer's disease [videorecording] Source: produced by the Department of Psychiatry and Behavioral Sciences and the Health Communications Network; Year: 1990; Format: Videorecording; Charleston, S.C.: Medical University of South Carolina, c1990

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Mr. Buttons, a gentleman with Alzheimer's disease [electronic resource] Source: by Sharon Gomez; Year: 1989; Format: Electronic resource; Philadelphia, PA: J.B. Lippincott, c1989

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Not alone in the world-- caring for someone with Alzheimer's disease [videorecording] Source: executive producer, Mary Barringer; contributing producer, James Kvale; Year: 1987; Format: Videorecording; [Springfield, Ill.]: Southern Illinois University School of Medicine, c1987

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Nursing care of the client with Alzheimer's disease [electronic resource]. Year: 1986; Format: Electronic resource; Edwardsville, KS: Medi-Sim, c1986

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The Challenge of Alzheimer's disease [videorecording] Source: Geriatric Education Center; Year: 1990; Format: Videorecording; Richmond, VA: Virginia Commonwealth University, c1990

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Understanding Alzheimer's disease [videorecording] Source: University of Pittsburgh, Alzheimer Disease Research Center; produced by WQEX/16, Pittsburgh; Year: 1993; Format: Videorecording; [Pittsburgh, Pa.]: University of Pittsburgh, c1993

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CHAPTER 8. PERIODICALS AND NEWS ON ALZHEIMER’S DISEASE Overview Keeping up on the news relating to Alzheimer’s disease can be challenging. Subscribing to targeted periodicals can be an effective way to stay abreast of recent developments on Alzheimer’s disease. Periodicals include newsletters, magazines, and academic journals. In this chapter, we suggest a number of news sources and present various periodicals that cover Alzheimer’s disease beyond and including those which are published by patient associations mentioned earlier. We will first focus on news services, and then on periodicals. News services, press releases, and newsletters generally use more accessible language, so if you do chose to subscribe to one of the more technical periodicals, make sure that it uses language you can easily follow.

News Services and Press Releases Well before articles show up in newsletters or the popular press, they may appear in the form of a press release or a public relations announcement. One of the simplest ways of tracking press releases on Alzheimer’s disease is to search the news wires. News wires are used by professional journalists, and have existed since the invention of the telegraph. Today, there are several major “wires” that are used by companies, universities, and other organizations to announce new medical breakthroughs. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing.

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The following is a specific Web list relating to Alzheimer’s disease; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

General Overview Age-related Cognitive Decline Source: Healthnotes, Inc.; www.healthnotes.com Alzheimer's Disease Source: Healthnotes, Inc.; www.healthnotes.com Alzheimer's Disease Source: Integrative Medicine Communications; www.drkoop.com Amyloidosis Source: Integrative Medicine Communications; www.drkoop.com Cyclic Mastalgia Alternative names: Cyclic Mastitis, Fibrocystic Breast Disease Source: Prima Communications, Inc.www.personalhealthzone.com Dementia Source: Integrative Medicine Communications; www.drkoop.com Depression (mild to Moderate) Source: Prima Communications, Inc.www.personalhealthzone.com High Homocysteine Source: Healthnotes, Inc.; www.healthnotes.com Menopause Source: Integrative Medicine Communications; www.drkoop.com Senile Dementia Source: Integrative Medicine Communications; www.drkoop.com

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Alternative Therapy Art Therapy Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com

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Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525, 671,00.html Music Therapy Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525, 719,00.html •

Herbs and Supplements Amino Acids Overview Source: Healthnotes, Inc.; www.healthnotes.com Antioxidants Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525, 10004,00.html Ashwagandha Alternative names: Withania somniferum Source: Healthnotes, Inc.; www.healthnotes.com Beta-carotene Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525, 10103,00.html Carotenoids Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525, 763,00.html Coenzyme Q Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525, 768,00.html

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Coenzyme Q10 Source: Healthnotes, Inc.; www.healthnotes.com Dehydroepiandrosterone (DHEA) Source: Healthnotes, Inc.; www.healthnotes.com DHA Source: Integrative Medicine Communications; www.drkoop.com DHEA (Dehydroepiandrosterone) Source: Prima Communications, Inc.www.personalhealthzone.com DMAE Source: Healthnotes, Inc.; www.healthnotes.com DMAE Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525, 10023,00.html Docosahexaenoic Acid Source: Healthnotes, Inc.; www.healthnotes.com Docosahexaenoic Acid (DHA) Source: Integrative Medicine Communications; www.drkoop.com Donepezil Source: Healthnotes, Inc.; www.healthnotes.com Edta Source: Integrative Medicine Communications; www.drkoop.com Ethylenediaminetetraacetic Acid (EDTA) Source: Integrative Medicine Communications; www.drkoop.com Ginkgo Source: Prima Communications, Inc.www.personalhealthzone.com Ginkgo Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca

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Ginkgo Biloba Source: Healthnotes, Inc.; www.healthnotes.com Ginkgo Biloba Source: Integrative Medicine Communications; www.drkoop.com Ginkgo Biloba Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525, 788,00.html Gotu Kola Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525, 10031,00.html Huperzia Source: Healthnotes, Inc.; www.healthnotes.com Huperzine A Source: Prima Communications, Inc.www.personalhealthzone.com Huperzine A Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525, 10038,00.html Inositol Source: Prima Communications, Inc.www.personalhealthzone.com Lecithin Source: Prima Communications, Inc.www.personalhealthzone.com Lemon Balm Alternative names: Melissa officinalis, Melissa Source: Integrative Medicine Communications; www.drkoop.com L-tyrosine Source: Healthnotes, Inc.; www.healthnotes.com

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Maidenhair Tree Source: Integrative Medicine Communications; www.drkoop.com Melatonin Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525, 804,00.html Melissa Source: Integrative Medicine Communications; www.drkoop.com Melissa Officinalis Source: Integrative Medicine Communications; www.drkoop.com Milk Thistle Alternative names: Silybum marianum, Carduus marianus Source: Healthnotes, Inc.; www.healthnotes.com Milk Thistle Source: Prima Communications, Inc.www.personalhealthzone.com Nadh Source: Healthnotes, Inc.; www.healthnotes.com Nadh Source: Prima Communications, Inc.www.personalhealthzone.com Nadh Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525, 10047,00.html Phosphatidylserine Source: Healthnotes, Inc.; www.healthnotes.com Phosphatidylserine Source: Prima Communications, Inc.www.personalhealthzone.com Phosphatidylserine (PS) Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com

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Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525, 813,00.html Pregnenolone Source: Prima Communications, Inc.www.personalhealthzone.com S-Adenosylmethionine (SAMe) Source: Integrative Medicine Communications; www.drkoop.com SAMe Source: Healthnotes, Inc.; www.healthnotes.com SAMe Source: Integrative Medicine Communications; www.drkoop.com Siberian Ginseng Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525, 821,00.html Tacrine Source: Healthnotes, Inc.; www.healthnotes.com Trazodone Source: Healthnotes, Inc.; www.healthnotes.com Willow Bark Alternative names: There are several species of willow includingSalix alba, Salix nigra, Salix fragilis, Salix purpurea, Salix babylonica, White Willow, European Willow, Black Willow, Pussy Willow, Crack Willow, Purple Willow, Weeping Willow, Liu-zhi Source: Integrative Medicine Communications; www.drkoop.com •

Vitamins Folic Acid Source: Healthnotes, Inc.; www.healthnotes.com Folic Acid Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com

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Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525, 887,00.html Vitamin B Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525, 10067,00.html Vitamin B Complex Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525, 962,00.html Vitamin B1 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin B1 Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B12 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin B12 Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B6 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin C Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin E Source: Healthnotes, Inc.; www.healthnotes.com Vitamin E Alternative names: Alpha-Tocopherol, Beta-Tocopherol, D-AlphaTocopherol, Delta-Tocopherol, Gamma-Tocopherol Source: Integrative Medicine Communications; www.drkoop.com Vitamin E Source: Prima Communications, Inc.www.personalhealthzone.com

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•

Minerals Acetyl-l-carnitine Source: Healthnotes, Inc.; www.healthnotes.com Alpha-tocopherol Source: Integrative Medicine Communications; www.drkoop.com Beta-tocopherol Source: Integrative Medicine Communications; www.drkoop.com Carnitine Source: Prima Communications, Inc.www.personalhealthzone.com Carnitine Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525, 10012,00.html Carnitine (l-carnitine) Source: Integrative Medicine Communications; www.drkoop.com D-alpha-tocopherol Source: Integrative Medicine Communications; www.drkoop.com Delta-tocopherol Source: Integrative Medicine Communications; www.drkoop.com Gamma-tocopherol Source: Integrative Medicine Communications; www.drkoop.com Iron Source: Healthnotes, Inc.; www.healthnotes.com L-carnitine Source: Integrative Medicine Communications; www.drkoop.com Lecithin/phosphatidylcholine/choline Source: Healthnotes, Inc.; www.healthnotes.com

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Magnesium Source: Prima Communications, Inc.www.personalhealthzone.com Vinpocetine Source: Prima Communications, Inc.www.personalhealthzone.com Zinc Source: Healthnotes, Inc.; www.healthnotes.com Zinc Source: Prima Communications, Inc.www.personalhealthzone.com •

Food and Diet American Cheese Source: Healthnotes, Inc.; www.healthnotes.com Chocolate Source: Healthnotes, Inc.; www.healthnotes.com Water Source: Healthnotes, Inc.; www.healthnotes.com

Reuters Health The Reuters' Medical News and Health eLine databases can be very useful in exploring news archives relating to Alzheimer’s disease. While some of the listed articles are free to view, others can be purchased for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “Alzheimer’s disease” (or synonyms). The following was recently listed in this archive for Alzheimer’s disease: •

Clioquinol may slow cognitive decline in late-stage Alzheimer's disease Source: Reuters Medical News Date: December 15, 2003

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Neuroticism a potential risk factor for Alzheimer's disease Source: Reuters Medical News Date: December 09, 2003

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Brain arterial atherosclerosis associated with Alzheimer's disease Source: Reuters Medical News Date: December 01, 2003

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Donepezil may slow hippocampal atrophy with Alzheimer's disease Source: Reuters Medical News Date: November 17, 2003

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Memantine approved in U.S. for Alzheimer's disease Source: Reuters Medical News Date: October 17, 2003

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Ebixa, Aricept combo helps in Alzheimer's disease Source: Reuters Medical News Date: September 23, 2003

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Amyloid-binding ligand a potential biomarker for Alzheimer's disease Source: Reuters Medical News Date: September 23, 2003

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Ratio of Alzheimer's disease markers in CSF may be diagnostic Source: Reuters Medical News Date: September 15, 2003

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Alzheimer's disease cases in US expected to top 13 million by 2050 Source: Reuters Medical News Date: August 19, 2003

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Copper may play a role in Alzheimer's disease Source: Reuters Health eLine Date: August 12, 2003

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R-flurbiprofen lowers amyloid involved in Alzheimer's disease in vivo Source: Reuters Medical News Date: August 07, 2003

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Key enzyme protective against Alzheimer's disease Source: Reuters Health eLine Date: July 30, 2003

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Amyloid-beta promotes neurofibrillary tangles seen in Alzheimer's disease Source: Reuters Medical News Date: July 28, 2003

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Fish and n-3 fatty acids in diet may reduce Alzheimer's disease risk Source: Reuters Medical News Date: July 21, 2003

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Painkillers may protect against Alzheimer's disease Source: Reuters Health eLine Date: July 18, 2003

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Subacute meningoencephalitis complicates Alzheimer's disease immunization Source: Reuters Medical News Date: July 17, 2003

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Analysis supports protective effect of NSAID use against Alzheimer's disease Source: Reuters Medical News Date: July 17, 2003

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Melissa officinalis extract benefits patients with mild-to-moderate Alzheimer's disease Source: Reuters Medical News Date: July 04, 2003

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Investigational drug for Alzheimer's disease meets phase II objectives Source: Reuters Medical News Date: June 23, 2003

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Study published showing NSAIDs do not slow Alzheimer's disease progression Source: Reuters Medical News Date: June 04, 2003

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Vaccination with beta-amyloid may slow cognitive decline in Alzheimer's disease Source: Reuters Medical News Date: May 21, 2003

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Lithium reduces hallmarks of Alzheimer's disease pathology in mice Source: Reuters Medical News Date: May 21, 2003

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Depression symptoms linked to Alzheimer's disease Source: Reuters Medical News Date: May 19, 2003

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Tetrahydrocannabinol may reduce agitation in Alzheimer's disease patients Source: Reuters Medical News Date: May 16, 2003

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Progression of parkinsonian-like signs associated with Alzheimer's disease risk Source: Reuters Medical News Date: April 24, 2003

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CSF proteins could be useful markers for Alzheimer's disease Source: Reuters Medical News Date: April 22, 2003

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Apoptotic effect of monomeric aluminum may explain link to Alzheimer's disease Source: Reuters Medical News Date: April 15, 2003

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Unusual cataract associated with Alzheimer's disease Source: Reuters Medical News Date: April 11, 2003

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Form of iron raised in Alzheimer's disease: study Source: Reuters Health eLine Date: April 09, 2003

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DHEA fails to benefit patients with Alzheimer's disease Source: Reuters Medical News Date: April 07, 2003

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Drug combo improves cognition in patients with advanced Alzheimer's disease Source: Reuters Medical News Date: April 03, 2003

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Memantine slows progression of moderate-to-severe Alzheimer's disease Source: Reuters Medical News Date: April 02, 2003

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Mixed effects of Alzheimer's disease vaccine seen on autopsy of recipient Source: Reuters Medical News Date: March 17, 2003

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HRT may offer effective therapy for Alzheimer's disease Source: Reuters Medical News Date: February 26, 2003

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High intake of unsaturated fats may protect against Alzheimer's disease Source: Reuters Medical News Date: February 18, 2003

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CYP46 gene variant tied to increased risk of Alzheimer's disease Source: Reuters Medical News Date: February 07, 2003

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Alzheimer's disease costs expected to soar in UK Source: Reuters Medical News Date: January 23, 2003

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Proteins in cerebrospinal fluid predict progression to Alzheimer's disease Source: Reuters Medical News Date: November 18, 2002

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Immunotherapy for Alzheimer's disease linked to cerebral hemorrhage risk Source: Reuters Medical News Date: November 15, 2002

The NIH Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within their search engine.

Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com. You can scan the news by industry category or company name.

Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, log on to Market Wire’s Medical/Health channel at the following hyperlink http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Market Wire’s home page is http://www.marketwire.com/mw/home. From here, type “Alzheimer’s disease” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests.

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Search Engines Free-to-view news can also be found in the news section of your favorite search engines (see the health news page at Yahoo: http://dir.yahoo.com/Health/News_and_Media/, or use this Web site’s general news search page http://news.yahoo.com/. Type in “Alzheimer’s disease” (or synonyms). If you know the name of a company that is relevant to Alzheimer’s disease, you can go to any stock trading Web site (such as www.etrade.com) and search for the company name there. News items across various news sources are reported on indicated hyperlinks.

BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “Alzheimer’s disease” (or synonyms).

Newsletter Articles If you choose not to subscribe to a newsletter, you can nevertheless find references to newsletter articles. We recommend that you use the Combined Health Information Database, while limiting your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option at http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” By making these selections, and typing in “Alzheimer’s disease” (or synonyms) into the “For these words:” box, you will only receive results on newsletter articles. You should check back periodically with this database as it is updated every 3 months. The following is a typical result when searching for newsletter articles on Alzheimer’s disease: •

What Can a Pathologist Tell Us About Alzheimer's Disease? Source: Alzheimer's Disease Society Newsletter. p. 5. September 1988. Contact: Available from Alzheimer's Disease Society. Gordon House, 10 Greencoat Place, London SW1P 1PH, ENGLAND. (071) 306-0606. PRICE: Call for price information. Summary: This article reviews some recent areas of investigation into the causes of Alzheimer's disease. Relatively new techniques, such as

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immunohistology, electron microscopy, and histochemistry, are discussed, along with the older techniques that enabled Alzheimer to discover the disease. •

Genetic Factors in Alzheimer's Disease Source: Global Perspective. [Newsletter] 2(1): 6-7. April 1991. Contact: Alzheimer's Disease International. 919 North Michigan Avenue, Suite 1000, Chicago, IL 60611-1676. (800) 272-3900; (312) 335-8882 (TDD); (312) 335-1110 (FAX). PRICE: Call for price information. Summary: This newsletter article discusses a genetic theory for Alzheimer's disease, focusing on formal genetics and population genetic studies. Neither epidemiology studies nor small pedigrees support the suggestion that Alzheimer's Disease is inherited. Further, cross-cultural studies of patients from the nineteenth versus the twentieth centuries who lived in Europe or America found no age-related differences in onset of Alzheimer's disease. However, detailed, extensive pedigree studies that have examined at least three generations of affected families indicate that two types of heritable Alzheimer's disease may exist: an early onset, dominant form of the disease, and a late onset, sporadic form also referred to as senile dementia of the Alzheimer type (SDAT). When data from a large pedigree study of more than 6,000 members of a family with a pattern of early onset Alzheimer's disease were adjusted for late-onset disease (i.e., onset at age 80 rather than 42), statistical analysis revealed that most late-onset carriers, about 80 percent, will die before developing the disease. Formal genetic research studies indicate a possible linkage between early onset Alzheimer's disease and some genes on chromosome 21, including one gene defined as the familial Alzheimer's disease (FAD) gene, but no definitive genetic markers of the disease have been found yet. The author of the study concludes that genetically, based on accumulating evidence, Alzheimer's is a disease similar to thalassemia major (Cooley's anemia). The use of formal genetics is considered a futile route to study the late-onset form of the disease, and systemic crosscultural, or cross-population studies of founder effect and rare alleles (hereditary characteristics) are recommended for understanding the natural history of Alzheimer's disease.

Academic Periodicals covering Alzheimer’s Disease Academic periodicals can be a highly technical yet valuable source of information on Alzheimer’s disease. We have compiled the following list of periodicals known to publish articles relating to Alzheimer’s disease and

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which are currently indexed within the National Library of Medicine’s PubMed database (follow hyperlinks to view more information, summaries, etc., for each). In addition to these sources, to keep current on articles written on Alzheimer’s disease published by any of the periodicals listed below, you can simply follow the hyperlink indicated or go to www.ncbi.nlm.nih.gov/pubmed. Type the periodical’s name into the search box to find the latest studies published. If you want complete details about the historical contents of a periodical, you can also visit http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/ you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.” The following is a sample of periodicals which publish articles on Alzheimer’s disease:

Vocabulary Builder Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Pregnenolone: Steroid hormone. [NIH]

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CHAPTER 9. PHYSICIAN GUIDELINES AND DATABASES Overview Doctors and medical researchers rely on a number of information sources to help patients with their conditions. Many will subscribe to journals or newsletters published by their professional associations or refer to specialized textbooks or clinical guides published for the medical profession. In this chapter, we focus on databases and Internet-based guidelines created or written for this professional audience.

NIH Guidelines For the more common diseases, The National Institutes of Health publish guidelines that are frequently consulted by physicians. Publications are typically written by one or more of the various NIH Institutes. For physician guidelines, commonly referred to as “clinical” or “professional” guidelines, you can visit the following Institutes: •

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

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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/

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

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

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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.27 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:28 •

Bioethics: Access to published literature on the ethical, legal and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

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HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

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NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html

•

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

•

Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

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Cancer Information: Access to caner-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 28 See http://www.nlm.nih.gov/databases/databases.html. 27

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•

Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/

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Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

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Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html

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Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

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MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

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Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

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Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html

While all of the above references may be of interest to physicians who study and treat Alzheimer’s disease, the following are particularly noteworthy.

The Combined Health Information Database A comprehensive source of information on clinical guidelines written for professionals is the Combined Health Information Database. You will need to limit your search to “Brochure/Pamphlet,” “Fact Sheet,” or “Information Package” and Alzheimer’s disease using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For the publication date, select “All Years,” select your preferred language, and the format option “Fact Sheet.” By making these selections and typing “Alzheimer’s disease” (or synonyms) into the “For these words:” box above, you will only receive results on fact sheets dealing with Alzheimer’s disease. The following is a sample result:

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•

Ondansetron in the Treatment of Cognitive Decline in Alzheimer Dementia Source: American Journal of Geriatric Psychiatry. 10(2): 212-215. MarchApril 2002. Summary: This article describes a clinical trial of ondansetron for the treatment of cognitive decline in Alzheimer's disease (AD). The sample consisted of 185 AD patients, aged 50 years and older, with mild to moderate dementia. Participants were randomly assigned to receive either 10 micrograms per day of ondansetron, 20 micrograms per day of ondansetron, or placebo for 24 weeks. The primary outcome measures were the Alzheimer's Disease Assessment Scale-Cognitive Subscale, completed at baseline and at the ends of weeks 12 and 24, and the Clinician's Interview-Based Impression of Change, completed at the ends of weeks 12 and 24. Ondansetron was well tolerated without any serious side effects. However, there were no significant differences among groups on either the primary outcome measures or secondary measures of cognitive ability, activities of daily living, and relatives' stress. The results suggest that serotonergic agents such as ondansetron are not effective for improving cognition in patients with AD. 2 figures, 2 tables, 15 references.

•

Understanding Medicaid Long Term Care: A Primer for Alzheimer Advocates Source: Washington, DC: Alzheimer's Association. 1997. 30 p. Contact: Alzheimer's Association. Washington Public Policy Office. 1319 F Street, NW, Suite 710, Washington, DC 20004. (202) 393-7737; FAX (202) 393-2109. PRICE: Single copy free. Summary: This booklet is intended to help Alzheimer's disease (AD) advocates understand Medicaid as a potential source of funding for long term care. An introductory section provides background information about the Medicaid program, who it is designed to help, and the types of services it covers. The next three sections discuss key issues that affect the availability of Medicaid long term care services for people with AD. The first section, on financial eligibility, defines the categories of needy people covered by Medicaid and summarizes the rules concerning income and assets, spousal impoverishment, transfers of assets, and recovery of improperly paid benefits. The next section discusses other eligibility factors such as the need for care, age, disability, residency, and citizenship. The third section, on long term care services, explains Medicaid coverage for nursing home care and home and community

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care. The booklet includes a checklist for AD advocates and tables showing selected data for the 50 States. •

Alzheimer Drug Trials in Canada: December 1994 Source: Toronto, Ontario: Alzheimer Society of Canada. 1994. 1 page 4 panels. Contact: Alzheimer Society of Canada. 1320 Yonge Street, Suite 201, Toronto, Ontario M4T 1X2, CANADA. (416) 925-3552; FAX (416) 9251649. PRICE: FREE. Summary: This fact sheet, updated bi-annually, presents information on the status of the drug approval process for Alzheimer's disease (AD) in Canada. These types of fact sheets are issued during the initial recruitment/enrollment stage of the testing process and provide information on participating in trials. The sheet explains how drugs are approved in Canada and the clinical trial phases. It also provides information on how to obtain a drug outside of the approval process through the Health Protection Branch of Health Canada, Emergency Drug Release Program. A list of drugs currently under investigation for use with AD patients is provided.

•

Alzheimer Care Demonstration Evaluation Report: Senior Companion Program In-Home Respite Care Source: Chicago, IL: Alzheimer's Association. 1991. 48 p. Contact: Alzheimer's Association. 919 North Michigan Avenue, Suite 1000, Chicago, IL 60611-1676. (800) 272-3900; (312) 335-8700; (312) 3358882 (TDD); FAX (312) 335-1110. PRICE: Single copy free. Summary: This report describes a respite care demonstration project conducted by the Alzheimer's Association and the Senior Companion Program SCP, a volunteer program of the federal agency ACTION. The purpose of the demonstration was to evaluate the feasibility and benefits of using trained Senior Companion/Alzheimer's Volunteers to provide in home respite care to clients with Alzheimer's disease and their families. Nine Alzheimer's Association Chapters and SCPs participated in the 3 year project. The results demonstrated both a need for respite care services and the feasibility of the Alzheimer's Association/SCP partnership in providing such services. Evaluation responses from the families and the Senior Companion respite workers were overwhelmingly positive. The Alzheimer's Association recommends continued federal funding to take advantage of the SCP's potential as a source of respite care for patients with Alzheimer's disease and their families.

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•

Reports From the National Institute on Aging (6 Reports) Source: Aging: Clinical and Experimental Research. 2(3): 297-316. September 1990. Contact: Available from Editrice Kurtis S.R.L. Via Luigi Zoja, 30-20152 Milano, Italy. Telephone: (02) 48202740 or FAX (02) 48201219. Single issues and subscriptions available for purchase. PRICE: Contact publisher for information. Summary: This special section of this journal issue presents the third set of papers which are comprehensive reports from four of the Alzheimer's Disease Patient Registries funded by the National Institute on Aging (NIA), and details their purposes, plans, and progress. Introductory comments to this section note that the NIA commissioned a number of papers to be published in this journal that further examine issues and questions in the development of large-area, large-scale registries for dementing diseases. This section also outlines the focus of each of these four groupings of papers. The papers in the current issue cover: (1) the East Boston Alzheimers' Disease Registry, covering existing studies that supply data to the registry and discussing patient interviews, diagnostic criteria, general diagnostic inferences, and problem areas needing further studies; (2) the University of Pittsburgh Alzheimer's Disease Patient Registry, including the Monongahela Valley Independent Elders Survey (MoVIES), outlining the MoVIES cognitive screening battery and presenting descriptive demographic statistical results; (3) two projects undertaken prior to the establishment of the Iowa Registry, as well as the plans and progress of the University of Iowa Prototype Alzheimer's Disease Registry, outlining and discussing identified tasks and casefinding sources, and presenting data on demographic distributions, cognitive evaluation, etiologic categories, an evaluation of treatable causes; and (4) the Illinois Alzheimer's Patient Registry and the Prototype Alzheimer Collaborative Team (PACT), discussing the flow of case enrollment forms and providing data on selected demographic characteristics of PACT patients. The other three sets of NIAcommissioned papers discuss the development of registries for other diseases and conditions, major conceptual issues in registry development, and additional NIA-funded Alzheimer's Disease Patient Registries.

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The NLM Gateway29 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing “one-stop searching” for many of NLM’s information resources or databases.30 One target audience for the Gateway is the Internet user who is new to NLM’s online resources and does not know what information is available or how best to search for it. This audience may include physicians and other healthcare providers, researchers, librarians, students, and, increasingly, patients, their families, and the public.31 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “Alzheimer’s disease” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Items Found Journal Articles 38369 Books / Periodicals / Audio Visual 973 Consumer Health 1001 Meeting Abstracts 38 Other Collections 32 Total 40413

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x. The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 31 Other users may find the Gateway useful for an overall search of NLM’s information resources. Some searchers may locate what they need immediately, while others will utilize the Gateway as an adjunct tool to other NLM search services such as PubMed® and MEDLINEplus®. The Gateway connects users with multiple NLM retrieval systems while also providing a search interface for its own collections. These collections include various types of information that do not logically belong in PubMed, LOCATORplus, or other established NLM retrieval systems (e.g., meeting announcements and pre-1966 journal citations). The Gateway will provide access to the information found in an increasing number of NLM retrieval systems in several phases. 29 30

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HSTAT32 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.33 HSTAT’s audience includes healthcare providers, health service researchers, policy makers, insurance companies, consumers, and the information professionals who serve these groups. HSTAT provides access to a wide variety of publications, including clinical practice guidelines, quick-reference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.34 Simply search by “Alzheimer’s disease” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

Coffee Break: Tutorials for Biologists35 Some patients may wish to have access to a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. To this end, we recommend “Coffee Break,” a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.36 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.37 This site has new Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. The HSTAT URL is http://hstat.nlm.nih.gov/. 34 Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration’s Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force’s Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations. 35 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html. 36 The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 37 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process. 32 33

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articles every few weeks, so it can be considered an online magazine of sorts, and intended for general background information. You can access Coffee Break at http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other Commercial Databases Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

•

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

The Genome Project and Alzheimer’s Disease With all the discussion in the press about the Human Genome Project, it is only natural that physicians, researchers, and patients want to know about how human genes relate to Alzheimer’s disease. In the following section, we will discuss databases and references used by physicians and scientists who work in this area.

Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).38 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. 38 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

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To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “Alzheimer’s disease” (or synonyms) into the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. In particular, the option “Database Links” will search across technical databases that offer an abundance of information. The following is an example of the results you can obtain from the OMIM for Alzheimer’s disease: •

Alzheimer Disease; AD Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?104300

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Alzheimer Disease, Familial, Type 3; AD3 Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?607822

•

Amyloid Beta A4 Precursor Protein; APP Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?104760

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Alzheimer Disease 2, Late-Onset; AD2 Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?104310

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Dementia, Lewy Body; DLB Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?127750

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Presenilin 2; PSEN2 Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?600759

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Synuclein, ALPHA; SNCA Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?163890

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Alzheimer Disease, Familial, Type 5 Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?602096

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Alzheimer Disease, Susceptibility To, Mitochondrial Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?502500

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Alzheimer Disease 6 Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?605526

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Alzheimer Disease 7 Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?606187

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Alzheimer Disease 8 Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?607116

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Alzheimer Disease Neuronal Thread Protein Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?607413

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Alzheimer Disease, Early-Onset Familial, with Coexisting Amyloid and Prion Pathology Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?605055

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Alzheimer Disease without Neurofibrillary Tangles Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?604154

Genes and Disease (NCBI - Map) The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by the system of the body. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to re-visit it from time to time. The following systems and associated disorders are addressed: •

Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html

•

Nervous System: Mind and body. Examples: Alzheimer disease, Amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, Fragile X syndrome, Friedreich’s ataxia, Huntington disease, NiemannPick disease, Parkinson disease, Prader-Willi syndrome, Rett syndrome,

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Spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html •

Signals: Cellular messages. Examples: Ataxia telangiectasia, Baldness, Cockayne syndrome, Glaucoma, SRY: sex determination, Tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html

Entrez Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: •

3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

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Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books

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Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome

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NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/

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Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide

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OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

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PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset

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ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

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Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein

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PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed

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Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure

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Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy

Access the Entrez system of the NCBI at the following hyperlink: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=genom e, and then select the database that you would like to search. The databases available are listed in the drop box next to “Search.” In the box next to “for,” enter “Alzheimer’s disease” (or synonyms) and click “Go.”

Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database39 This online resource can be quite useful. It has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. You can search across syndromes using an alphabetical index at http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html, search by keyword. The Genome Database40 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 40 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html#mission. 39

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the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “Alzheimer’s disease” (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms). This database is extremely technical as it was created for specialists. The articles are the results which are the most accessible to nonprofessionals and often listed under the heading “Citations.” The contact names are also accessible to non-professionals.

Specialized References The following books are specialized references written for professionals interested in Alzheimer’s disease (sorted alphabetically by title, hyperlinks provide rankings, information, and reviews at Amazon.com): •

The Behavioral Neurology of White Matter by Christopher M. Filley; Paperback - 279 pages; 1st edition (September 15, 2001), Oxford University Press; ISBN: 019513561X; http://www.amazon.com/exec/obidos/ASIN/019513561X/icongroupinter na

•

The Cerebellum and Its Disorders by Mario-Ubaldo Manto, Massimo Pandolfo; Hardcover - 1st edition (January 2002), Cambridge University Press; ISBN: 0521771560; http://www.amazon.com/exec/obidos/ASIN/0521771560/icongroupinter na

•

Clinical Neurology by David A. Greenberg, et al; Paperback - 390 pages; 5th edition (February 9, 2002), Appleton & Lange; ISBN: 0071375430; http://www.amazon.com/exec/obidos/ASIN/0071375430/icongroupinter na

•

Clinical Neurology for Psychiatrists by David M. Kaufman; Hardcover 670 pages, 5th edition (January 15, 2001), W. B. Saunders Co.; ISBN: 0721689957;

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http://www.amazon.com/exec/obidos/ASIN/0721689957/icongroupinter na •

Comprehensive Neurology by Roger N. Rosenberg (Editor), David E. Pleasure (Editor); 1280 pages, 2nd edition (April 1998), Wiley-Liss; ISBN: 0471169587; http://www.amazon.com/exec/obidos/ASIN/0471169587/icongroupinter na

•

Emergent and Urgent Neurology by William J. Weiner (Editor), Lisa M. Shulman (Editor); Hardcover - 571 pages; 2nd edition (January 15, 1999), Lippincott, Williams & Wilkins Publishers; ISBN: 0397518579; http://www.amazon.com/exec/obidos/ASIN/0397518579/icongroupinter na

•

Neurology in Clinical Practice: Volume I: Principles of Diagnosis and Management, Volume II: The Neurological Disorders (2-Volume Set, Includes a 12-Month Subscription to the Online Edition) by W. G. Bradley, et al; Hardcover - 2413 pages, 3rd edition, Vol 1-2 (January 15, 2000), Butterworth-Heinemann; ISBN: 0750699736; http://www.amazon.com/exec/obidos/ASIN/0750699736/icongroupinter na

•

Neuroscience: Exploring the Brain by Mark F. Bear, et al; Hardcover 855 pages, 2nd edition (January 15, 2001), Lippincott, Williams & Wilkins Publishers; ISBN: 0683305964; http://www.amazon.com/exec/obidos/ASIN/0683305964/icongroupinter na

•

Office Practice of Neurology by Martain A. Samuels, Steven F. Feske; Hardcover, Churchill Livingstone; ISBN: 0443065578; http://www.amazon.com/exec/obidos/ASIN/0443065578/icongroupinter na

•

Patient-Based Approaches to Cognitive Neuroscience by Martha J. Farah (Editor), Todd E. Feinberg (Editor); Paperback - 425 pages (April 3, 2000), MIT Press; ISBN: 0262561239; http://www.amazon.com/exec/obidos/ASIN/0262561239/icongroupinter na

•

Principles of Neural Science by Eric R. Kandel (Editor), et al; Hardcover - 1414 pages, 4th edition (January 5, 2000), McGraw-Hill Professional Publishing; ISBN: 0838577016; http://www.amazon.com/exec/obidos/ASIN/0838577016/icongroupinter na

•

Review Manual for Neurology in Clinical Practice by Karl E. Misulis, et al; Paperback, Butterworth-Heinemann Medical; ISBN: 0750671920;

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http://www.amazon.com/exec/obidos/ASIN/0750671920/icongroupinter na

Vocabulary Builder Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Rett Syndrome: A neurological disorder seen almost exclusively in females, and found in a variety of racial and ethnic groups worldwide. [NIH] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH]

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CHAPTER 10. DISSERTATIONS ON ALZHEIMER’S DISEASE Overview University researchers are active in studying almost all known diseases. The result of research is often published in the form of Doctoral or Master’s dissertations. You should understand, therefore, that applied diagnostic procedures and/or therapies can take many years to develop after the thesis that proposed the new technique or approach was written. In this chapter, we will give you a bibliography on recent dissertations relating to Alzheimer’s disease. You can read about these in more detail using the Internet or your local medical library. We will also provide you with information on how to use the Internet to stay current on dissertations.

Dissertations on Alzheimer’s Disease ProQuest Digital Dissertations is the largest archive of academic dissertations available. From this archive, we have compiled the following list covering dissertations devoted to Alzheimer’s disease. You will see that the information provided includes the dissertation’s title, its author, and the author’s institution. To read more about the following, simply use the Internet address indicated. The following covers recent dissertations dealing with Alzheimer’s disease: •

A Comparison of Actual Food Consumption to Estimated Needs of Individuals with Alzheimer's Disease in a Long-term Care Facility by Heidemann, Regina Anne; Ms from D'youville College, 2002, 72 pages http://wwwlib.umi.com/dissertations/fullcit/1413007

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•

A Field Assessment of the Relationships among Interpersonal Communication Competence, Social Support, and Depression among Caregivers for Individuals with Alzheimer's Disease by Query, Jim L., Jr., Ph.D from Ohio University, 1990, 245 pages http://wwwlib.umi.com/dissertations/fullcit/9030057

•

A Financial Impact Scale for Long-term Caregivers: Application to Alzheimer Family Caregivers (alzheimer's Disease) by Todtman, Kathee L., Ph.D from Texas Tech University, 1989, 142 pages http://wwwlib.umi.com/dissertations/fullcit/9104755

•

A Formative Evaluation of Adapted Work Services for Alzheimer's Disease Victims: a Framework for Practical Evaluation in Health Care (sheltered Workplaces) by Quinn, Doris Claire, Ph.D from Vanderbilt University, 1996, 227 pages http://wwwlib.umi.com/dissertations/fullcit/9626286

•

A Functional Characterization of the Alzheimer's Disease Betasecretase by Huse, Jason Thomas; Ph.D from University of Pennsylvania, 2002, 157 pages http://wwwlib.umi.com/dissertations/fullcit/3043890

•

A Meta-analysis of the Effects of Exercise Training and Physical Activity on Health-related Physical Fitness, Cognitive and Physical Functioning, and Behavior of Individuals with Alzheimer's Disease and Related Cognitive Disorders by Heyn, Patricia; Ph.D from University of Central Florida, 2002, 243 pages http://wwwlib.umi.com/dissertations/fullcit/3069447

•

A Microeconomic Analysis of California's Alzheimer's Disease Diagnostic and Treatment Program: the Production of Care and Implications for California Policy (social Services) by Ginther, Shawn Damon, Ph.D from University of California, Berkeley, 1991, 189 pages http://wwwlib.umi.com/dissertations/fullcit/9203571

•

A Naturalistic Study of the Well-being of Caregivers to Family Members with Alzheimer's Disease (family Caregivers, Caregiver Well-being) by Jivanjee, Pauline Raye, Ph.D from University of Kansas, 1992, 369 pages http://wwwlib.umi.com/dissertations/fullcit/9323024

•

A Study of Animal-assisted Therapy and Weekday Placement of a Social Therapy Dog in an Alzheimer's Disease Unit by Martin, Daun Adair, Edd from Washington State University, 1998, 160 pages http://wwwlib.umi.com/dissertations/fullcit/9917440

•

A Study of Caregiver Burden For: Spouse Caregivers of Persons with Organic Mental Disorders of the Alzheimer's Type or Related

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Disorders (alzheimer's Disease) by Hale, Mary Anne, Dsw from Tulane University, School of Social Work, 1994, 248 pages http://wwwlib.umi.com/dissertations/fullcit/9523265 •

A Study of the Relationship between a Home Based Therapeutic Recreation Program As Implemented by a Certified Therapeutic Recreation Specialist and the Reduction of Excess Disability in Persons with Early to Mid-stage Alzheimer's Disease by Stavola Daly, Frances A.; Edd from Temple University, 2002, 417 pages http://wwwlib.umi.com/dissertations/fullcit/3057115

•

Agenda Building on Health Issues: a Focus on Alzheimer's Disease by Steckenrider, Janie S., Ph.D from University of Southern California, 1988 http://wwwlib.umi.com/dissertations/fullcit/f4136324

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Alzheimer Caregivers' Guilt Reactions to Institutionalization and Religiosity (alzheimer's Disease) by Biner, Barbara Kathryn, Ph.D from University of Colorado at Boulder, 1991, 373 pages http://wwwlib.umi.com/dissertations/fullcit/9220394

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Alzheimer's Disease As Developmental Asynchrony: a Dialectical Paradigm of the Marital Relationship of Older Couples by Wright, Lore Kathe, Ph.D from University of Georgia, 1988, 319 pages http://wwwlib.umi.com/dissertations/fullcit/8903537

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Alzheimer's Disease Caregivers: the Transition from Home Care to Formal Care by Duncan, Marie Theresa, Ph.D from Portland State University, 1992, 174 pages http://wwwlib.umi.com/dissertations/fullcit/9305303

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Alzheimer's Disease Family Caregiver Well-being a General Model by Guerriero Austrom, Mary; Ph.D from York University (canada), 1989 http://wwwlib.umi.com/dissertations/fullcit/NL51429

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Alzheimer's Disease Neuropathology in Aging and Mild Cognitive Impairment by Guillozet, Angela Lorene; Ph.D from Northwestern University, 2002, 222 pages http://wwwlib.umi.com/dissertations/fullcit/3071647

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Alzheimer's Disease Special Care Units: a Comparative Study of the Retrofit Design (nursing Home Design) by Debauge, Lucia K., Ph.D from Texas A&m University, 1990, 342 pages http://wwwlib.umi.com/dissertations/fullcit/9118215

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Alzheimer's Disease: the Nature and Chronology of the Spouse Caregiving Experience. a Retrospective Multiple-case Study Approach by Assam, Kay Swenson, Edd from University of South Dakota, 1988, 520 pages http://wwwlib.umi.com/dissertations/fullcit/8911462

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Alzheimer's Disease: the Relationship between Selected Wallcovering Patterns and Resident Behaviors in a Special Care Unit by Dobbs, Margaret Carol Nagy, Ph.D from Texas Tech University, 1990, 157 pages http://wwwlib.umi.com/dissertations/fullcit/9104762

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Alzheimer's Disease: the Social Construction of Senile Dementia by Fox, Patrick John, Ph.D from University of California, San Francisco, 1988, 293 pages http://wwwlib.umi.com/dissertations/fullcit/8809497

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An Examination of Reinforcer Identification and Stimulus Discrimination in Elderly Individuals with Alzheimer's Disease by Smith, Wanda L; Ph.D from The University of Manitoba (canada), 1986 http://wwwlib.umi.com/dissertations/fullcit/NL14750

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An Examination of the Family Leisure Experiences and Leisure Adjustments Made with a Relative Diagnosed with Alzheimer's Disease in a Long-term Care Facility by Martin, Penny-lynne; Ma from Dalhousie University (canada), 2002, 121 pages http://wwwlib.umi.com/dissertations/fullcit/MQ75519

•

An Exploratory Study of the Effects of a Training Program on the Ability to Prepare a Breakfast Meal by Clients with Mild Alzheimer's Disease by Curtin, Alicia J.; Ph.D from University of Rhode Island, 2002, 326 pages http://wwwlib.umi.com/dissertations/fullcit/3053101

•

Anti-amyloid Protein Monoclonal Antibodies for Diagnostics and Theraputics of Alzheimer's Disease by Li, Ge; Msc from University of Alberta (canada), 2002, 130 pages http://wwwlib.umi.com/dissertations/fullcit/MQ69727

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Application of Chemotactic Models to Alzheimer's Disease by Luca, Magdalena; Ph.D from The University of British Columbia (canada), 2002, 163 pages http://wwwlib.umi.com/dissertations/fullcit/NQ73199

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Art Preference in Alzheimer's Disease: Does It Remain Stable over Time? by Hickory, Meredith Ann; Psyd from Massachusetts School of Professional Psychology, 2003, 76 pages http://wwwlib.umi.com/dissertations/fullcit/3088235

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Aspects of Perceived Competency: a Study of Husbands and Wives As Caregivers for Confused and Not Confused Spouses (Alzheimer's Disease) by Wilken, Carolyn Russell, Ph.D from Purdue University, 1988, 228 pages http://wwwlib.umi.com/dissertations/fullcit/8912019

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Association between Apathy and Executive Dysfunction in Alzheimer's Disease by Arnold, Ginger Leigh Demolar; Ph.D from Fuller Theological Seminary, School of Psychology, 2002, 180 pages http://wwwlib.umi.com/dissertations/fullcit/3046361

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Becoming a Caregiver: Processes in the Career of Caring for a Family Member with Alzheimer's Disease (family Caregivers) by Blum, Nancy Sue, Ph.D from University of California, Los Angeles, 1992, 354 pages http://wwwlib.umi.com/dissertations/fullcit/9224123

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Biochemical Investigation of Tau and Map2 Polymerization: Implications for Neuropathic Filament Assembly in Alzheimer's Disease by Di Noto, Luca; Ph.D from University of Florida, 2002, 162 pages http://wwwlib.umi.com/dissertations/fullcit/3052345

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Biophysical Studies on the Met35 Oxidation of Alzheimer's Disease Amyloid Beta-peptides by Hou, Liming; Ph.D from Case Western Reserve University, 2003, 222 pages http://wwwlib.umi.com/dissertations/fullcit/3092011

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Caregiver Coping with Dementia: Relationships among Patient Characteristics, Caregiver Coping Styles, and Consequences of Caregiving (alzheimer's Disease) by Ramsey, Nina Sharp, Ph.D from University of Washington, 1990, 270 pages http://wwwlib.umi.com/dissertations/fullcit/9109822

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Caregivers for Alzheimer's Disease Patients; a Study of Religiosity and Burden by Bacik, Patricia Lee, Ph.D from The University of Toledo, 1990, 164 pages http://wwwlib.umi.com/dissertations/fullcit/9104078

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Cellular Trafficking and Metabolism of the Alzheimer's Disease Amyloid Precursor Protein (app) in the Secretory and Endocytic Pathways by Steinhilb, Michelle Leigh; Ph.D from University of Michigan, 2002, 195 pages http://wwwlib.umi.com/dissertations/fullcit/3042175

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Characteristics and Stress Levels of Hispanic and Non-hispanic Caregivers of Alzheimer's Disease Patients by Gonzalez-lima, Erika Musiol, Ph.D from Texas A&m University, 1989, 205 pages http://wwwlib.umi.com/dissertations/fullcit/9015504

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Chlamydia Pneumoniae Infection in Human Monocytes and Brain Endothelial Cells: Initiating Factors in the Development of Alzheimer's Disease by Macintyre, Angela; Ph.D from Mcp Hahnemann University, 2002, 147 pages http://wwwlib.umi.com/dissertations/fullcit/3051098

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Choices and Tradeoffs in Advanced Alzheimer's Disease: Balancing Survival, Health, Comfort, and Cost by Fabiszewski, Kathy Jean; Ph.D from University of Massachusetts Boston, 1999, 236 pages http://wwwlib.umi.com/dissertations/fullcit/9951870

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Cognitive Coping Strategies of Older Spouse Caring for One with Alzheimer's Disease (caregivers, Spouse Caregivers, Stress) by Tebb, Susan Carol Steiger, Ph.D from University of Kansas, 1992, 215 pages http://wwwlib.umi.com/dissertations/fullcit/9313182

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Cognitive Training of the Cognitively-impaired Elderly (memory, Alzheimer's Disease) by Maaser, Bruce Wayne, Ph.D from The University of Wisconsin - Madison, 1988, 400 pages http://wwwlib.umi.com/dissertations/fullcit/8822256

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Comparative Analysis of a Moderating and Mediating Model of Stress, Appraisal, and Coping in Hispanic and Non-hispanic Alzheimer's Disease Caregivers by Morano, Carmen Louis; Ph.D from Florida International University, 1999, 214 pages http://wwwlib.umi.com/dissertations/fullcit/9949326

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Comparisons of Marital Relationship Measures among Elderly Wives of Alzheimer's, Chronically Ill, and Healthy Spouses (alzheimer's Disease) by Rubin, Judith A., Ph.D from The University of Wisconsin Madison, 1991, 434 pages http://wwwlib.umi.com/dissertations/fullcit/9133413

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Conducting Differential Diagnosis of Alzheimer's Disease Utilizing Neuropsychological Assessments by Cisneros, Wendy L.; Psyd from Carlos Albizu University, 2002, 86 pages http://wwwlib.umi.com/dissertations/fullcit/3054216

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Confidence-based Calibration and the Detection of Early Cognitive Loss in Probable and Possible Alzheimer's Disease Sufferers by Minns, Joanne E.; Ma from Carleton University (canada), 2002, 73 pages http://wwwlib.umi.com/dissertations/fullcit/MQ72052

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Constructing the Dementia Process: the Identification, Definition and Management of Alzheimer's Disease (caregiving) by Manuel, Lisa Kimberley Catherine, Ph.D from University of Toronto (canada), 1995, 312 pages http://wwwlib.umi.com/dissertations/fullcit/NN02808

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Coping with Memory Problems in Normal Aging and Alzheimer's Disease: an Exploratory Field Study by Brustrom, Jennifer Elizabeth, Ph.D from University of California, Davis, 1996, 184 pages http://wwwlib.umi.com/dissertations/fullcit/9721020

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Correlates of Demoralization in a Cohort of Spousal Caregivers of Alzheimer's Victims (alzheimer's Disease, Caregivers) by Yatzkan, Elaine S., Ph.D from New York University, 1990, 190 pages http://wwwlib.umi.com/dissertations/fullcit/9023057

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Development and Evaluation of a Scale to Assess the Stress of Caring for an Older Adult with Alzheimer's Disease by Kinney, Jennifer Martin, Ph.D from Kent State University, 1987, 188 pages http://wwwlib.umi.com/dissertations/fullcit/8726977

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Development of Novel Bivalent 1,2,5,6-tetrahydropyridyl-1,2,5thiadiazole Derivatives As Selective, Potent, and Efficacious Human M1 Muscarinic Agonists for the Treatment of Alzheimer's Disease by Cao, Yang; , Ph.D from The University of Toledo, 2002, 165 pages http://wwwlib.umi.com/dissertations/fullcit/3045999

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Diagnostic Assessment and Treatment Service Utilization among Alzheimer's Disease Clients in California by Douglass, Carolinda, Ph.D from The Rand Graduate Institute, 1994, 237 pages http://wwwlib.umi.com/dissertations/fullcit/9510322

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Distress and Coping among Caregivers of Victims of Alzheimer's Disease and Related Disorders (new York) by Dundon, Margaret M., Ph.D from State University of New York at Buffalo, 1987, 129 pages http://wwwlib.umi.com/dissertations/fullcit/8710702

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Dyspragmia in Wernicke's Aphasia and Alzheimer's Disease: an Investigation in Clinical Pragmatics by Beach, Woodford Ascher; Ph.D from The University of Chicago, 2002, 416 pages http://wwwlib.umi.com/dissertations/fullcit/3070156

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Effect of a Rational-emotive Therapy-based Counseling Group on the Psychological Distress of Caregivers of Alzheimer's Disease Patients by Thompson, John Michael, Ph.D from University of Georgia, 1987, 195 pages http://wwwlib.umi.com/dissertations/fullcit/8800306

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Effectiveness of Music Therapy Intervention with Individuals Having Senile Dementia of the Alzheimer's Type (alzheimer's Disease) by Groene, Robert William, Ii, Ph.D from University of Minnesota, 1992, 205 pages http://wwwlib.umi.com/dissertations/fullcit/9306504

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Effects of an Exercise Program on Mentally Impaired Older Adults in a Long-term Care Facility (alzheimer's Disease, Dementia) by Frizzell, Linda D. Bane, Ph.D from The University of North Dakota, 1991, 182 pages http://wwwlib.umi.com/dissertations/fullcit/9220363

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Effects of Informational Support and Emotional Support on Morale of Nursing Home Staff Providing Care to Alzheimer's Disease Patients by Kline, Priscilla Mackenzie, Edd from Clemson University, 1987, 179 pages http://wwwlib.umi.com/dissertations/fullcit/8803904

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Effects of Working Memory and Semantic Impairments on Speech in Alzheimer's Disease by Altmann, Lori Jean, Ph.D from University of Southern California, 1998, 198 pages http://wwwlib.umi.com/dissertations/fullcit/9919007

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Emotional Experience, Facial Expression, and Startle Reflex Modulation in Young Adults, Healthy Older Adults, and Alzheimer's Disease by Burton, Keith Wayne; Ph.D from The University of Arizona, 2003, 93 pages http://wwwlib.umi.com/dissertations/fullcit/3089918

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Etude Geographique De La Maladie D'alzheimer Au Saguenay-lacsaint-jean (quebec) (french Text, Alzheimer's Disease) by Emard, Jeanfrancois, Ph.D from Universite De Montreal (canada), 1992, 280 pages http://wwwlib.umi.com/dissertations/fullcit/NN88880

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Experiences of Men Caring for Wives with Alzheimer's Disease by Pennington, Barbara Cheryl; Msn from University of Alaska Anchorage, 2003, 84 pages http://wwwlib.umi.com/dissertations/fullcit/1413758

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Expression and Localization of Alzheimer's Disease (ad)-related Proteins in Senescence-accelerated Mouse (sam) and Normal Mouse by Yao, Hong-bing; Ph.D from Chinese University of Hong Kong (people's Republic of China), 2002, 152 pages http://wwwlib.umi.com/dissertations/fullcit/3038012

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Factors Affecting Social Work Students' Willingness to Work with Elders with Alzheimer's Disease by Kane, Michael N., Ph.D from Barry University School of Social Work, 1997, 265 pages http://wwwlib.umi.com/dissertations/fullcit/9722252

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Familial Alzheimer's Disease Mutations Decrease Gamma-secretase Processing of Beta Amyloid Precurson Protein by Wiley, Jesse Carey; Ph.D from University of Washington, 2003, 146 pages http://wwwlib.umi.com/dissertations/fullcit/3091090

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Family Caregiving Experiences with Alzheimer's Disease: a Collective Case Study by Agee, Annabel Lee; Ph.D from The University of Tennessee, 2000, 221 pages http://wwwlib.umi.com/dissertations/fullcit/9973428

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Fighting the Living Death Through the Maintenance of Personhood: a Study on a Support Group for Early-stage Alzheimer's Disease by

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Adomako, Paul Robert Kwaku, Jr.; Msc from University of Guelph (canada), 2003, 193 pages http://wwwlib.umi.com/dissertations/fullcit/MQ76044 •

Formulaic Language in Aging and Alzheimer's Disease by De Santi, Susan M., Ph.D from City University of New York, 1993, 244 pages http://wwwlib.umi.com/dissertations/fullcit/9315456

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Fostering Effective Interaction between Nursing Home Staff and Residents Experiencing Alzheimer's Related Dementia (alzheimer's Disease, Staff Resident Interactions) by Pray, Jackie E., Ph.D from University of Kansas, 1993, 203 pages http://wwwlib.umi.com/dissertations/fullcit/9405781

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Functional Regions of the Corpus Callosum: Evidence from Alzheimer's Disease Patients by Hallam, Bradley John; Ph.D from Fuller Theological Seminary, School of Psychology, 2002, 222 pages http://wwwlib.umi.com/dissertations/fullcit/3046367

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Getting Lost Behavior and Directed Attention Impairments in Taiwanese Patients with Early Alzheimer's Disease by Chiu, Yu-hong; Ph.D from University of Michigan, 2002, 278 pages http://wwwlib.umi.com/dissertations/fullcit/3057923

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Giving Up and Giving In: Young Adolescents' Dilemmas When Caring for a Grandparent with Alzheimer's Disease by Beach, Diane Lee, Edd from University of San Diego, 1999, 124 pages http://wwwlib.umi.com/dissertations/fullcit/9930613

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Gray Matters: an Interdisciplinary Approach to Understanding the Experience of Alzheimer's Disease by Kutac, Julie Elizabeth; Ma from Rice University, 2003, 82 pages http://wwwlib.umi.com/dissertations/fullcit/1414273

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Group Counseling Experiences of Clients with Alzheimer's Disease by White, Carolyn Crabtree; Ph.D from University of New Orleans, 2002, 187 pages http://wwwlib.umi.com/dissertations/fullcit/3051368

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Husbands' Decisions to Institutionalize Wives Afflicted with Alzheimer's Disease: an Empirical Phenomenological Study by Dickerson, Paul Bryant, Ph.D from Duquesne University, 1999, 359 pages http://wwwlib.umi.com/dissertations/fullcit/9936947

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I Know Just When It Happened: a Turning Point Analysis of Communication and Change in Relationships Where One Partner Has Alzheimer's Disease by Karmon, Carolyn Lee, Ph.D from Ohio University, 1997, 212 pages http://wwwlib.umi.com/dissertations/fullcit/9804588

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Identity Loss, Moral Commitment, and Alzheimer's Disease: an Interactionist Perspective (alzheimer's Disease) by Orona, Celia J., Ph.D from University of California, San Francisco, 1989, 311 pages http://wwwlib.umi.com/dissertations/fullcit/8926413

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Impact of a Formal Education and Group Support Program on the Subjective Well-being and Burden Perceptions of Primary Caregivers for Adults with Progressive Dementia (caregivers, Alzheimer's Disease) by Stanley, Sharon A. R., Ph.D from The Ohio State University, 1989, 158 pages http://wwwlib.umi.com/dissertations/fullcit/9014492

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Improving the Dressing Skills of Persons with Alzheimer's Disease Using Picture Cues by Talbert-johnson, Carolyn, Ph.D from The Ohio State University, 1991, 171 pages http://wwwlib.umi.com/dissertations/fullcit/9201761

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Improving Transgenic Mouse Models of Alzheimer's Disease: Attempts to Enhance Acute Phase Reactions to Amyloid Deposition by Boyett, Kristal Wright; Ph.D from University of South Florida, 2002, 172 pages http://wwwlib.umi.com/dissertations/fullcit/3071291

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In Vivo Molecular Imaging Probes for Alzheimer's Disease: Molecular Requirements for Binding of 2-[1-(6-dialkylamino-2naphthyl)ethylidene]malononitrile Molecular Imaging Probes to Betaamyloid Fibrils and Senile Plaques by Agdeppa, Eric Dustin; Ph.D from University of California, Los Angeles, 2002, 165 pages http://wwwlib.umi.com/dissertations/fullcit/3076589

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Informational Supports for Caregivers Responsible for Spouses with Alzheimer's Disease by Mathews, Janet Lynn, Ph.D from Portland State University, 1995, 170 pages http://wwwlib.umi.com/dissertations/fullcit/9608482

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Intellectual Deficits Associated with Alzheimer's Disease by Pelletier, Frederick L; Ph.D from Queen's University at Kingston (canada), 1989 http://wwwlib.umi.com/dissertations/fullcit/NL50079

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Intergenerational Programming: Yesterday's Memories, Today's Moments, and Tomorrow's Hopes (alzheimer's Disease) by O'rourke, Kathleen Ann; Ph.D from The University of Tennessee, 1999, 138 pages http://wwwlib.umi.com/dissertations/fullcit/9959308

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Investigation of Cognitive Impairments Using Functional Magnetic Resonance Imaging (fmri) and Positron Emission Tomography (pet) in Patients with Mild Alzheimer's Disease by Stanonik, Mateja De Leonni; Ph.D from The University of Tennessee, 2002, 369 pages http://wwwlib.umi.com/dissertations/fullcit/3062332

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Is Pharmacological Prevention of Alzheimer's Disease a Realistic Goal? Evidence from the Cache County Study by Zandi, Peter P.; Ph.D from The Johns Hopkins University, 2002, 135 pages http://wwwlib.umi.com/dissertations/fullcit/3028352

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Kinetics of Abeta Peptide Deposition: toward in Vivo Imaging of Alzheimer's Disease Amyloid by Marshall, Jeffrey Richard; Ph.D from University of Cincinnati, 2002, 266 pages http://wwwlib.umi.com/dissertations/fullcit/3053844

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Life History of Men with Alzheimer's Disease and Their Spousal Caregivers: Relevance for Grounded Theory of Family Care (caregivers) by Flatt, Margaret Mary, Ph.D from Michigan State University, 1991, 141 pages http://wwwlib.umi.com/dissertations/fullcit/9216304

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Loneliness, Depression, and Social Support among Caregivers of Spouses with Alzheimer's Disease: the Home Versus the Nursing Home Care Experience (home Care, Family Caregivers) by Bergman, Brenda Faith, Ph.D from University of Nebraska Medical Center, 1992, 169 pages http://wwwlib.umi.com/dissertations/fullcit/9221966

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Mapping Out the Experience of Women Caregivers for Individuals with Alzheimer's Disease by Cassisi, Carmela C.; Mph from Southern Connecticut State University, 2002, 102 pages http://wwwlib.umi.com/dissertations/fullcit/1409790

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Medicalizing Intersubjectivity: Diagnostic Practices and the Self in Alzheimer's Disease by Smith, Andre Philippe; Ph.D from Mcgill University (canada), 2000, 341 pages http://wwwlib.umi.com/dissertations/fullcit/NQ69933

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Memory Training with Dementia Adults: a Nonpharmacologic Attempt to Improve Memory (alzheimer's Disease) by Winston, Marilynn Rauzin, Ph.D from Georgia State University, 1989, 107 pages http://wwwlib.umi.com/dissertations/fullcit/9015715

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Mild Cognitive Impairment: a Useful Construct for Predicting Alzheimer's Disease by Geslani, Daphne Melissa; Msc from University of Toronto (canada), 2002, 125 pages http://wwwlib.umi.com/dissertations/fullcit/MQ74106

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Mindful Attitudes in the Experience of Caring for a Spouse with Alzheimer's Disease by Schultz, Amy Susan; Ph.D from Arizona State University, 2003, 210 pages http://wwwlib.umi.com/dissertations/fullcit/3095001

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Negotiating Disease: Senile Dementia and Alzheimer's Disease, 19001980 by Holstein, Martha Beller, Ph.D from The University of Texas Graduate Sch. of Biomedical Sci. at Galveston, 1996, 352 pages http://wwwlib.umi.com/dissertations/fullcit/9700425

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No Aging in India (dementia, Alzheimer's Disease) by Cohen, Lawrence, Ph.D from Harvard University, 1992, 467 pages http://wwwlib.umi.com/dissertations/fullcit/9228327

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On the Mechanisms of Semantic Associative Processing in the Perception and Interpretation of Affective Stimuli (alzheimer's Disease) by Bortz, Jennifer Jean, Ph.D from The University of Arizona, 1992, 170 pages http://wwwlib.umi.com/dissertations/fullcit/9303313

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On-line Sentence Comprehension in Alzheimer's Disease by Small, Jeff Alan, Ph.D from University of Southern California, 1994 http://wwwlib.umi.com/dissertations/fullcit/f1879875

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Oxidative Stress in Models of Alzheimer's Disease: I. Roles of Peroxynitrite, Amyloid Beta-peptide, and 4-hydroxy-2-nonenal. Ii. Modulation by Gamma-glutamylcysteine Ethyl Ester by Drake, Jennifer Le; Ph.D from University of Kentucky, 2003, 236 pages http://wwwlib.umi.com/dissertations/fullcit/3092307

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Oxidatively-modified Proteins: I. Proteomic Identification of Specifically-oxidized Proteins in Alzheimer's Disease Brain. Ii. Modulation of Synaptosomal Membrane Lipid Bilayer Asymmetry by 4-hydroxy-2-trans-nonenal by Castegna, Alessandra; Ph.D from University of Kentucky, 2003, 170 pages http://wwwlib.umi.com/dissertations/fullcit/3092304

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Perceptual Processing Deficits and Short-term Memory in Persons with Alzheimer's Disease by Rosswurm, Mary Ann Herrity, Edd from University of Cincinnati, 1986, 108 pages http://wwwlib.umi.com/dissertations/fullcit/8612838

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Predicting Hippocampal Atrophy in a Sample of Non-demented Older Adults at Increased Risk for Alzheimer's Disease with Two Novel Memory Transfer Tests by Schnirman, Geoffrey Miles; Ph.D from Fordham University, 2002, 124 pages http://wwwlib.umi.com/dissertations/fullcit/3037229

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Predicting Lack of Awareness of Cognitive Deficits in Alzheimer's Disease by Muir, James Jeffrey; Ph.D from Georgia State University, 2002, 170 pages http://wwwlib.umi.com/dissertations/fullcit/3075428

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Predictors of Psychological Symptoms in Spouse Caregivers of Patients with Alzheimer's Disease by Forrest, Nancy Marie, Ph.D from The Herman M. Finch U. of Health Sciences - the Chicago Medical Sch., 1994, 126 pages http://wwwlib.umi.com/dissertations/fullcit/9507598

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Probing for Axonal Defects in Alzheimer's Disease by Stokin, Gorazd Bernard; Ph.D from University of California, San Diego, 2003, 95 pages http://wwwlib.umi.com/dissertations/fullcit/3094610

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Psychological Stress, Personality Characteristics, Ways of Coping, and Life Satisfaction in Caregivers of Advanced Stage Alzheimer's Disease Victims by O'brien, Marianne Scates, Ph.D from The University of Tennessee, 1990, 125 pages http://wwwlib.umi.com/dissertations/fullcit/9221789

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Semantic Memory Impairment in Patients with Alzheimer's Disease (memory) by Gresch, Anna Marie, Ph.D from The University of Wisconsin - Milwaukee, 1992, 118 pages http://wwwlib.umi.com/dissertations/fullcit/9317621

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Senility and Self in Modern America: a Cultural History of Alzheimer's Disease by Ballenger, Jesse Francis; Ph.D from Case Western Reserve University, 2000, 368 pages http://wwwlib.umi.com/dissertations/fullcit/9968137

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Serotonergic Alterations in Rats with a Cholinergic Hypofunction and in Alzheimer's Disease by Garcia Alloza, Monica; Dr from Universidad De Navarra (spain), 2002, 294 pages http://wwwlib.umi.com/dissertations/fullcit/f441297

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Service Utilization Patterns of Caregivers of People with Alzheimer's Disease by Webber, Pamela Arnsberger, Ph.D from University of California, Berkeley, 1991, 221 pages http://wwwlib.umi.com/dissertations/fullcit/9228904

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Simulated Design and Analysis of a Cognitive Prosthetic for Alzheimer's Disease by Delnegro, Rina Alice; Ms from San Jose State University, 2002, 124 pages http://wwwlib.umi.com/dissertations/fullcit/1408786

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Social Support and Coping with Spousal Alcoholism and Alzheimer's Disease by Reibstein, Ruth Joy, Edd from Boston University, 1989, 177 pages http://wwwlib.umi.com/dissertations/fullcit/8918515

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Social Support and Psychological Distress among Spouse Caregivers of Dementia Patients (alzheimer's Disease) by Fox, Mary Vyn, Ph.D from The University of Arizona, 1986, 114 pages http://wwwlib.umi.com/dissertations/fullcit/8613815

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Spiritual Well-being and Caregiver Burden in Primary Family Caregivers of Community Dwelling Persons with Alzheimer's Disease and Related Disorders by Spurlock, Wanda Raby; Dns from Louisiana State Univ. Health Sciences Center School of Nursing, 2002, 182 pages http://wwwlib.umi.com/dissertations/fullcit/3049620

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Stress in the Work of Dementia Care: a Comparison of Eight Alzheimer's Day Care Centers (alzheimer's Disease) by Lyman, Karen A., Ph.D from University of Southern California, 1989 http://wwwlib.umi.com/dissertations/fullcit/f3590612

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Structure and Cytotoxicity of the Beta Amyloid Peptide in Alzheimer's Disease by Demeester, Nathalie; Drsc from Rijksuniversiteit Te Gent (belgium), 2002, 99 pages http://wwwlib.umi.com/dissertations/fullcit/f441025

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Studies on Nitric Oxide Synthases in Age-dependent Cognitive Impairments and Alzheimer's Disease by Law, Andrew C.-k.; Ph.D from Mcgill University (canada), 2002, 304 pages http://wwwlib.umi.com/dissertations/fullcit/NQ78710

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Syntactic and Symbolic Abilities in Alzheimer's Disease (aphasia, Grammar) by Kempler, Daniel, Ph.D from University of California, Los Angeles, 1984, 165 pages http://wwwlib.umi.com/dissertations/fullcit/8428531

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Temporal Morphology and Neuropsychological Correlates in Alzheimer's Disease and Normal Aging by Hessel, Cory Dean; Ph.D from Brigham Young University, 2003, 83 pages http://wwwlib.umi.com/dissertations/fullcit/3077572

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Testing the View That the Semantic Memory Deficit in Alzheimer's Disease Reflects a Loss of Semantic Knowledge by Alathari, Lina; Ph.D from The George Washington University, 2002, 90 pages http://wwwlib.umi.com/dissertations/fullcit/3045166

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The Appraisal Process in Stress and Coping Models: Fear of Inheritability, Knowledge of Alzheimer's Disease, and Caregiver

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Burden by Kelly, Timothy Brian, Ph.D from University of Georgia, 1994, 103 pages http://wwwlib.umi.com/dissertations/fullcit/9507221 •

The Caregiving Experience of Spouses of Persons with Alzheimer's Disease by Dolan, Brigit Mary; Msn from Gonzaga University, 2002, 73 pages http://wwwlib.umi.com/dissertations/fullcit/1409466

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The Cd40/cd40l Receptor/ligand Dyad: Role in the Pathogenesis of Alzheimer's Disease by Town, Terrence Christopher; Ph.D from University of South Florida, 2002, 180 pages http://wwwlib.umi.com/dissertations/fullcit/3071328

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The Contribution of Higher-level Visual Processes to Everyday Functional Activities in Alzheimer's Disease (ad) by Jefferson, Angela Lee; Ph.D from Drexel University, 2003, 121 pages http://wwwlib.umi.com/dissertations/fullcit/3086402

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The Effect of a Leisure Education Program on the Coping Strategies and Leisure Attitudes of Caregivers of Persons with Alzheimer's Disease by Lynch, Susan Elaine, Ph.D from Texas Woman's University, 1993, 137 pages http://wwwlib.umi.com/dissertations/fullcit/9407749

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The Effect of Non-steroidal Anti-inflammatory Drugs on in Vitro Glial Apolipoprotein E Expression: Implications for the Mechanisms and Treatment of Alzheimer's Disease by Aleong, Rosanne; Msc from Mcgill University (canada), 2002, 135 pages http://wwwlib.umi.com/dissertations/fullcit/MQ78819

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The Effects of a Group Support Program on Decreasing Feelings of Burden and Depression in Relatives of Patients with Alzheimer's Disease and Other Dementing Illnesses by Kahan, Jason S., Ph.D from United States International University, 1984, 149 pages http://wwwlib.umi.com/dissertations/fullcit/8414952

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The Effects of Music Therapy Interventions on Naming and Verbal Fluency in Persons with Probable Alzheimer's Disease by York, Elizabeth Fair, Ph.D from University of Miami, 1995, 129 pages http://wwwlib.umi.com/dissertations/fullcit/9600365

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The Family Caregivers' Health Decision-making about Early Diagnosis for Alzheimer's Disease Patients by Zhao, Ping Zhong, Ph.D from Portland State University, 1991, 174 pages http://wwwlib.umi.com/dissertations/fullcit/9202279

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The Grammars of the Old Age Problem: from Activity Theory to Alzheimer's Disease (senility, Gerontology) by Lynott, Robert Joseph, Ph.D from Loyola University of Chicago, 1987, 275 pages http://wwwlib.umi.com/dissertations/fullcit/8704849

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The Gratifications, Frustrations, and Well-being of Older Women Caring at Home for Husbands with Alzheimer's Disease or a Related Disorder (family Caregivers, Dementia, Caregivers) by Motenko, Aluma K., Ph.D from Boston University, 1988, 192 pages http://wwwlib.umi.com/dissertations/fullcit/9209493

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The Impact of Alzheimer's Disease on Nursing Care: Implications for Nursing Education by Cullen, Patricia Anne, Edd from Temple University, 1994, 170 pages http://wwwlib.umi.com/dissertations/fullcit/9434661

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The Impact of Anticipatory Grief on Caregivers of Patients with Alzheimer's Disease (grief) by Walker, Rebecca Albritton, Ph.D from The University of Texas at Austin, 1994, 329 pages http://wwwlib.umi.com/dissertations/fullcit/9506122

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The Impact of Family Environment on Coping with Spouse Impairment in Alcoholism and Alzheimer's Disease (alzheimer Disease) by Golden, Lisa Anne, Edd from Boston University, 1989, 173 pages http://wwwlib.umi.com/dissertations/fullcit/8920097

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The Influence of Autobiographical Significance and Time of Acquisition on Semantic Memory: Evidence from Amnesia, Alzheimer's Disease, Semantic Dementia and Healthy Aging by Westmacott, Robyn Margaret; Ph.D from University of Toronto (canada), 2002, 341 pages http://wwwlib.umi.com/dissertations/fullcit/NQ74775

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The Influence of Frequency, Concreteness, and Grammatical Category on Semantic Processing and Word Retrieval in Probable Alzheimer's Disease by Granier, Jay Patrick; Ph.D from The University of Iowa, 2002, 196 pages http://wwwlib.umi.com/dissertations/fullcit/3058405

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The Influence of the Environment on Resistiveness to Care and the Effectiveness of an Intervention to Decrease Resistiveness to Care in People with Alzheimer's Disease Residing in Institutions by Bellar, Ann; Ph.D from Wayne State University, 2002, 275 pages http://wwwlib.umi.com/dissertations/fullcit/3071756

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The Lived Experience of Men and Women Who Have Placed a Spouse with Alzheimer's Disease in a Nursing Home by Browne, Vera Janis; Dnsc from Rush University, 2002, 187 pages http://wwwlib.umi.com/dissertations/fullcit/3042246

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The Medicalization of Alzheimer's Disease: Processes and Consequences for Public Policy by Rotwein, Suzanne, Ph.D from The University of Texas at Dallas, 1991, 205 pages http://wwwlib.umi.com/dissertations/fullcit/9135740

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The Pathological Role of Alterations in Calcineurin (protein Phosphatase 2b) Phosphatase Activity in Alzheimer's Disease by Lian, Qingyu; Ph.D from Loyola University of Chicago, 2002, 185 pages http://wwwlib.umi.com/dissertations/fullcit/3039290

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The Phoenix Rising: Self-development in Caregivers for Relatives with Alzheimer's Disease by Bar-david, Geila Naava, Ph.D from University of Toronto (canada), 1992, 365 pages http://wwwlib.umi.com/dissertations/fullcit/NN92894

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The Role of Cyclin-dependent Kinase 5 in Alzheimer's Disease Pathogenesis by Lee, Ming-sum; Ph.D from Harvard University, 2002, 267 pages http://wwwlib.umi.com/dissertations/fullcit/3051216

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The Role of Focal Adhesion Signaling in Alzheimer's Disease by Grace, Elizabeth Ann; Ph.D from The University of Connecticut, 2002, 118 pages http://wwwlib.umi.com/dissertations/fullcit/3062080

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The Role of Human Kallikrein 6 in the Pathogenesis of Alzheimer's Disease by Zarghooni, Maryam; Msc from University of Toronto (canada), 2002, 103 pages http://wwwlib.umi.com/dissertations/fullcit/MQ74047

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The Role of Mapk Pathways in Alzheimer's Disease by Zhu, Xiongwei; Ph.D from Case Western Reserve University (health Sciences), 2002, 147 pages http://wwwlib.umi.com/dissertations/fullcit/3061319

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The Role of Mononuclear Phagocyte Priming and Activation in Hiv-1associated Dementia and Alzheimer's Disease by Cotter, Robin L.; Ph.D from University of Nebraska Medical Center, 2002, 265 pages http://wwwlib.umi.com/dissertations/fullcit/3054198

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The Role of Verb Knowledge in the Sentence Comprehension Deficits of Individuals with Alzheimer's Disease and Frontotemporal Dementia by Price, Catherine E. Crenshaw; Ph.D from Drexel University, 2002, 201 pages http://wwwlib.umi.com/dissertations/fullcit/3061130

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The Search for Novel Susceptibility Loci Involved in Late Onset Alzheimer's Disease: Significant Findings on Chromosome 10 and a Possible Protective Effect of the Urokinase Plasminogen Activator Gene by Myers, Amanda Jennings; Ph.D from Washington University, 2002, 245 pages http://wwwlib.umi.com/dissertations/fullcit/3065075

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The Use of Single Photon Emission Computed Tomography (spect) Profiles to Identify Correlates of Behavioural Responses to Donepezil Therapy in Alzheimer's Disease by Lolou, Maysoon Mohamed Nasr; Msc from University of Toronto (canada), 2002, 167 pages http://wwwlib.umi.com/dissertations/fullcit/MQ68808

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The Value of Support Groups for Caregivers of a Patient with Alzheimer's Disease: a Family System's Perspective by Stanley, Renee, Ph.D from Texas Woman's University, 1987, 115 pages http://wwwlib.umi.com/dissertations/fullcit/8715024

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Theory of Mind, Empathy, and Insight in Alzheimer's Disease by Caoile, Jacqueline Daasch; Ph.D from Fuller Theological Seminary, School of Psychology, 2002, 108 pages http://wwwlib.umi.com/dissertations/fullcit/3046363

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Using Engineering Tools to Examine the Mechanisms of Alzheimer's Disease by Wang, Sheng-shih; Ph.D from Texas A&m University, 2002, 207 pages http://wwwlib.umi.com/dissertations/fullcit/3060919

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Visual Selective Attention in Alzheimer's Disease: Effects of Physical Similarity, Density, and Target-to-distractor Ratio in a Cancellation Task by Schaefer, Lynn Anne; Ph.D from City University of New York, 2002, 258 pages http://wwwlib.umi.com/dissertations/fullcit/3037441

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Wandering, Getting Lost, and Alzheimer's Disease: Influences on Precautions Taken and Levels of Supervision Provided by Caregivers by Salmons, Terri Gail; Ph.D from University of Massachusetts Boston, 1999, 135 pages http://wwwlib.umi.com/dissertations/fullcit/9951876

Keeping Current As previously mentioned, an effective way to stay current on dissertations dedicated to Alzheimer’s disease is to use the database called ProQuest Digital Dissertations via the Internet, located at the following Web address: http://wwwlib.umi.com/dissertations. The site allows you to freely access

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the last two years of citations and abstracts. Ask your medical librarian if the library has full and unlimited access to this database. From the library, you should be able to do more complete searches than with the limited 2-year access available to the general public.

Vocabulary Builder Anchorage: In dentistry, points of retention of fillings and artificial restorations and appliances. [NIH] Aphasia: An inability, caused by cerebral dysfunction, to communicate in reading, writing or speaking or to receive meaning from spoken or written words. [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] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Jefferson: A fracture produced by a compressive downward force that is transmitted evenly through occipital condyles to superior articular surfaces of the lateral masses of C1. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Senescence: The bodily and mental state associated with advancing age. [NIH]

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PART III. APPENDICES

ABOUT PART III Part III is a collection of appendices on general medical topics which may be of interest to patients with Alzheimer’s disease and related conditions.

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APPENDIX A. RESEARCHING YOUR MEDICATIONS Overview There are a number of sources available on new or existing medications which could be prescribed to patients with Alzheimer’s disease. While a number of hard copy or CD-Rom resources are available to patients and physicians for research purposes, a more flexible method is to use Internetbased databases. In this chapter, we will begin with a general overview of medications. We will then proceed to outline official recommendations on how you should view your medications. You may also want to research medications that you are currently taking for other conditions as they may interact with medications for Alzheimer’s disease. Research can give you information on the side effects, interactions, and limitations of prescription drugs used in the treatment of Alzheimer’s disease. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.

Your Medications: The Basics41 The Agency for Health Care Research and Quality has published extremely useful guidelines on how you can best participate in the medication aspects of Alzheimer’s disease. Taking medicines is not always as simple as swallowing a pill. It can involve many steps and decisions each day. The AHCRQ recommends that patients with Alzheimer’s disease take part in treatment decisions. Do not be afraid to ask questions and talk about your concerns. By taking a moment to ask questions early, you may avoid

41

This section is adapted from AHCRQ: http://www.ahcpr.gov/consumer/ncpiebro.htm.

342 Alzheimer’s Disease

problems later. Here are some points to cover each time a new medicine is prescribed: •

Ask about all parts of your treatment, including diet changes, exercise, and medicines.

•

Ask about the risks and benefits of each medicine or other treatment you might receive.

•

Ask how often you or your doctor will check for side effects from a given medication.

Do not hesitate to ask what is important to you about your medicines. You may want a medicine with the fewest side effects, or the fewest doses to take each day. You may care most about cost, or how the medicine might affect how you live or work. Or, you may want the medicine your doctor believes will work the best. Telling your doctor will help him or her select the best treatment for you. Do not be afraid to “bother” your doctor with your concerns and questions about medications for Alzheimer’s disease. You can also talk to a nurse or a pharmacist. They can help you better understand your treatment plan. Feel free to bring a friend or family member with you when you visit your doctor. Talking over your options with someone you trust can help you make better choices, especially if you are not feeling well. Specifically, ask your doctor the following: •

The name of the medicine and what it is supposed to do.

•

How and when to take the medicine, how much to take, and for how long.

•

What food, drinks, other medicines, or activities you should avoid while taking the medicine.

•

What side effects the medicine may have, and what to do if they occur.

•

If you can get a refill, and how often.

•

About any terms or directions you do not understand.

•

What to do if you miss a dose.

•

If there is written information you can take home (most pharmacies have information sheets on your prescription medicines; some even offer largeprint or Spanish versions).

Do not forget to tell your doctor about all the medicines you are currently taking (not just those for Alzheimer’s disease). This includes prescription

Researching Your Medications 343

medicines and the medicines that you buy over the counter. Then your doctor can avoid giving you a new medicine that may not work well with the medications you take now. When talking to your doctor, you may wish to prepare a list of medicines you currently take, the reason you take them, and how you take them. Be sure to include the following information for each: •

Name of medicine

•

Reason taken

•

Dosage

•

Time(s) of day

Also include any over-the-counter medicines, such as: •

Laxatives

•

Diet pills

•

Vitamins

•

Cold medicine

•

Aspirin or other pain, headache, or fever medicine

•

Cough medicine

•

Allergy relief medicine

•

Antacids

•

Sleeping pills

•

Others (include names)

Learning More about Your Medications Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications your doctor has recommended for Alzheimer’s disease. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the “U.S. Pharmacopeia (USP).” Today, the USP is a non-profit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at www.usp.org. The USP currently provides standards for over 3,700 medications. The resulting

344 Alzheimer’s Disease

USP DI® Advice for the Patient® can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database.42 While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopoeia (USP). Of course, we as editors cannot be certain as to what medications you are taking. Therefore, we have compiled a list of medications associated with the treatment of Alzheimer’s disease. Once again, due to space limitations, we only list a sample of medications and provide hyperlinks to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to Alzheimer’s disease: Benzodiazepines •

Systemic - U.S. Brands: Alprazolam Intensol; Ativan; Dalmane; Diastat; Diazepam Intensol; Dizac; Doral; Halcion; Klonopin; Librium; Lorazepam Intensol; Paxipam; ProSom; Restoril; Serax; Tranxene T-Tab; Tranxene-SD; Tranxene-SD Half Strength; Valium; Xanax http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202084.ht ml

Buspirone •

Systemic - U.S. Brands: BuSpar http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202100.ht ml

Though cumbersome, the FDA database can be freely browsed at the following site: www.fda.gov/cder/da/da.htm.

42

Researching Your Medications 345

Corticosteroids •

Dental - U.S. Brands: Kenalog in Orabase; Orabase-HCA; Oracort; Oralone http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202010.ht ml

•

Inhalation - U.S. Brands: AeroBid; AeroBid-M; Azmacort; Beclovent; Decadron Respihaler; Pulmicort Respules; Pulmicort Turbuhaler; Vanceril; Vanceril 84 mcg Double Strength http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202011.ht ml

•

Nasal - U.S. Brands: Beconase; Beconase AQ; Dexacort Turbinaire; Flonase; Nasacort; Nasacort AQ; Nasalide; Nasarel; Nasonex; Rhinocort; Vancenase; Vancenase AQ 84 mcg; Vancenase pockethaler http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202012.ht ml

•

Ophthalmic - U.S. Brands: AK-Dex; AK-Pred; AK-Tate; Baldex; Decadron; Dexair; Dexotic; Econopred; Econopred Plus; Eflone; Flarex; Fluor-Op; FML Forte; FML Liquifilm; FML S.O.P.; HMS Liquifilm; Inflamase Forte; Inflamase Mild; I-Pred; Lite Pred; Maxidex; Ocu-Dex; Ocu-Pred; Ocu-Pr http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202013.ht ml

•

Otic - U.S. Brands: Decadron http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202014.ht ml

•

Rectal - U.S. Brands: Anucort-HC; Anu-Med HC; Anuprep HC; Anusol-HC; Anutone-HC; Anuzone-HC; Cort-Dome; Cortenema; Cortifoam; Hemorrhoidal HC; Hemril-HC Uniserts; Proctocort; Proctosol-HC; Rectosol-HC http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203366.ht ml

Donepezil •

Systemic - U.S. Brands: Aricept http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203748.ht ml

346 Alzheimer’s Disease

Ergoloid Mesylates •

Systemic - U.S. Brands: Gerimal; Hydergine http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202215.ht ml

Galantamine •

Systemic - U.S. Brands: Reminyl http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500281.ht ml

Phenothiazines •

Systemic - U.S. Brands: Chlorpromazine Hydrochloride Intensol; Compazine; Compazine Spansule; Mellaril; Mellaril Concentrate; Mellaril-S; Permitil; Permitil Concentrate; Prolixin; Prolixin Concentrate; Prolixin Decanoate; Prolixin Enanthate; Serentil; Serentil Concentrate; Ste http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202457.ht ml

Risperidone •

Systemic - U.S. Brands: Risperdal http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202769.ht ml

Rivastigmine •

Systemic - U.S. Brands: Exelon http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500151.ht ml

Selegiline •

Systemic - U.S. Brands: Carbex; Eldepryl http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202519.ht ml

Tacrine •

Systemic - U.S. Brands: Cognex http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202722.ht ml

Researching Your Medications 347

Trazodone •

Systemic - U.S. Brands: Desyrel http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202573.ht ml

Valproic Acid •

Systemic - U.S. Brands: Depacon; Depakene; Depakote; Depakote Sprinkle http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202588.ht ml

Vitamin E •

Systemic - U.S. Brands: Amino-Opti-E; E-Complex-600; Liqui-E; Pheryl-E http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202598.ht ml

Zaleplon •

Systemic - U.S. Brands: Sonata http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500042.ht ml

Zolpidem •

Systemic - U.S. Brands: Ambien http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202707.ht ml

Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. You may be able to access these sources from your local medical library or your doctor’s office.

Reuters Health Drug Database The Reuters Health Drug Database can be searched by keyword at the hyperlink: http://www.reutershealth.com/frame2/drug.html.

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Mosby’s GenRx Mosby’s GenRx database (also available on CD-Rom and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Information can be obtained at the following hyperlink: http://www.genrx.com/Mosby/PhyGenRx/group.html.

PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html.

Other Web Sites A number of additional Web sites discuss drug information. As an example, you may like to look at www.drugs.com which reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. which allows users to download articles on various drugs and therapeutics for a nominal fee: http://www.medletter.com/.

Contraindications and Interactions (Hidden Dangers) Some of the medications mentioned in the previous discussions can be problematic for patients with Alzheimer’s disease--not because they are used in the treatment process, but because of contraindications, or side effects. Medications with contraindications are those that could react with drugs used to treat Alzheimer’s disease or potentially create deleterious side effects in patients with Alzheimer’s disease. You should ask your physician about any contraindications, especially as these might apply to other medications that you may be taking for common ailments. Drug-drug interactions occur when two or more drugs react with each other. This drug-drug interaction may cause you to experience an unexpected side effect. Drug interactions may make your medications less effective, cause

Researching Your Medications 349

unexpected side effects, or increase the action of a particular drug. Some drug interactions can even be harmful to you. Be sure to read the label every time you use a nonprescription or prescription drug, and take the time to learn about drug interactions. These precautions may be critical to your health. You can reduce the risk of potentially harmful drug interactions and side effects with a little bit of knowledge and common sense. Drug labels contain important information about ingredients, uses, warnings, and directions which you should take the time to read and understand. Labels also include warnings about possible drug interactions. Further, drug labels may change as new information becomes available. This is why it’s especially important to read the label every time you use a medication. When your doctor prescribes a new drug, discuss all over-thecounter and prescription medications, dietary supplements, vitamins, botanicals, minerals and herbals you take as well as the foods you eat. Ask your pharmacist for the package insert for each prescription drug you take. The package insert provides more information about potential drug interactions.

A Final Warning At some point, you may hear of alternative medications from friends, relatives, or in the news media. Advertisements may suggest that certain alternative drugs can produce positive results for patients with Alzheimer’s disease. Exercise caution--some of these drugs may have fraudulent claims, and others may actually hurt you. The Food and Drug Administration (FDA) is the official U.S. agency charged with discovering which medications are likely to improve the health of patients with Alzheimer’s disease. The FDA warns patients to watch out for43: •

Secret formulas (real scientists share what they know)

•

Amazing breakthroughs or miracle cures (real breakthroughs don’t happen very often; when they do, real scientists do not call them amazing or miracles)

•

Quick, painless, or guaranteed cures

•

If it sounds too good to be true, it probably isn’t true.

43

This section has been adapted from http://www.fda.gov/opacom/lowlit/medfraud.html.

350 Alzheimer’s Disease

If you have any questions about any kind of medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.

General References In addition to the resources provided earlier in this chapter, the following general references describe medications (sorted alphabetically by title; hyperlinks provide rankings, information and reviews at Amazon.com): •

Current Therapy in Neurologic Disease by Richard T. Johnson, et al; Hardcover - 457 pages, 6th edition (January 15, 2002), Mosby-Year Book; ISBN: 0323014720; http://www.amazon.com/exec/obidos/ASIN/0323014720/icongroupinter na

•

Emerging Pharmacological Tools in Clinical Neurology by MedPanel Inc. (Author); Digital - 66 pages, MarketResearch.com; ISBN: B00005RBN8; http://www.amazon.com/exec/obidos/ASIN/B00005RBN8/icongroupinte rna

•

Goodman & Gilman’s The Pharmacological Basis of Therapeutics by Joel G. Hardman (Editor), Lee E. Limbird; Hardcover - 1825 pages, 10th edition (August 13, 2001), McGraw-Hill Professional Publishing; ISBN: 0071354697; http://www.amazon.com/exec/obidos/ASIN/0071354697/icongroupinter na

•

Neurology and General Medicine by Michael J. Aminoff (Editor), Hardcover - 992 pages, 3rd edition (March 15, 2001), Churchill Livingstone; ISBN: 0443065713; http://www.amazon.com/exec/obidos/ASIN/0443065713/icongroupinter na

•

Neurology and Medicine by Hughes Perkins; Hardcover - 415 pages, 1st edition (December 15, 1999), B. M. J. Books; ISBN: 0727912240; http://www.amazon.com/exec/obidos/ASIN/0727912240/icongroupinter na

•

Pharmacological Management of Neurological and Psychiatric Disorders by S. J. Enna (Editor), et al; Hardcover - 736 pages, 1st edition, McGraw-Hill Professional Publishing; ISBN: 0070217645;

Researching Your Medications 351

http://www.amazon.com/exec/obidos/ASIN/0070217645/icongroupinter na

Vocabulary Builder The following vocabulary builder gives definitions of words used in this chapter that have not been defined in previous chapters: 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] Enanthate: An oily injectable contraceptive given every 8 weeks. [NIH]

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APPENDIX B. RESEARCHING ALTERNATIVE MEDICINE Overview Complementary and alternative medicine (CAM) is one of the most contentious aspects of modern medical practice. You may have heard of these treatments on the radio or on television. Maybe you have seen articles written about these treatments in magazines, newspapers, or books. Perhaps your friends or doctor have mentioned alternatives. In this chapter, we will begin by giving you a broad perspective on complementary and alternative therapies. Next, we will introduce you to official information sources on CAM relating to Alzheimer’s disease. Finally, at the conclusion of this chapter, we will provide a list of readings on Alzheimer’s disease from various authors. We will begin, however, with the National Center for Complementary and Alternative Medicine’s (NCCAM) overview of complementary and alternative medicine.

What Is CAM?44 Complementary and alternative medicine (CAM) covers a broad range of healing philosophies, approaches, and therapies. Generally, it is defined as those treatments and healthcare practices which are not taught in medical schools, used in hospitals, or reimbursed by medical insurance companies. Many CAM therapies are termed “holistic,” which generally means that the healthcare practitioner considers the whole person, including physical, mental, emotional, and spiritual health. Some of these therapies are also known as “preventive,” which means that the practitioner educates and 44

Adapted from the NCCAM: http://nccam.nih.gov/nccam/fcp/faq/index.html#what-is.

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treats the person to prevent health problems from arising, rather than treating symptoms after problems have occurred. People use CAM treatments and therapies in a variety of ways. Therapies are used alone (often referred to as alternative), in combination with other alternative therapies, or in addition to conventional treatment (sometimes referred to as complementary). Complementary and alternative medicine, or “integrative medicine,” includes a broad range of healing philosophies, approaches, and therapies. Some approaches are consistent with physiological principles of Western medicine, while others constitute healing systems with non-Western origins. While some therapies are far outside the realm of accepted Western medical theory and practice, others are becoming established in mainstream medicine. Complementary and alternative therapies are used in an effort to prevent illness, reduce stress, prevent or reduce side effects and symptoms, or control or cure disease. Some commonly used methods of complementary or alternative therapy include mind/body control interventions such as visualization and relaxation, manual healing including acupressure and massage, homeopathy, vitamins or herbal products, and acupuncture.

What Are the Domains of Alternative Medicine?45 The list of CAM practices changes continually. The reason being is that these new practices and therapies are often proved to be safe and effective, and therefore become generally accepted as “mainstream” healthcare practices. Today, CAM practices may be grouped within five major domains: (1) alternative medical systems, (2) mind-body interventions, (3) biologicallybased treatments, (4) manipulative and body-based methods, and (5) energy therapies. The individual systems and treatments comprising these categories are too numerous to list in this sourcebook. Thus, only limited examples are provided within each.

Alternative Medical Systems Alternative medical systems involve complete systems of theory and practice that have evolved independent of, and often prior to, conventional biomedical approaches. Many are traditional systems of medicine that are

45

Adapted from the NCCAM: http://nccam.nih.gov/health/whatiscam/#4.

Researching Alternative Medicine 355

practiced by individual cultures throughout the world, including a number of venerable Asian approaches. Traditional oriental medicine emphasizes the balance or disturbances of qi (pronounced chi) or vital energy in health and disease, respectively. Traditional oriental medicine consists of a group of techniques and methods including acupuncture, herbal medicine, oriental massage, and qi gong (a form of energy therapy). Acupuncture involves stimulating specific anatomic points in the body for therapeutic purposes, usually by puncturing the skin with a thin needle. Ayurveda is India’s traditional system of medicine. Ayurvedic medicine (meaning “science of life”) is a comprehensive system of medicine that places equal emphasis on body, mind, and spirit. Ayurveda strives to restore the innate harmony of the individual. Some of the primary Ayurvedic treatments include diet, exercise, meditation, herbs, massage, exposure to sunlight, and controlled breathing. Other traditional healing systems have been developed by the world’s indigenous populations. These populations include Native American, Aboriginal, African, Middle Eastern, Tibetan, and Central and South American cultures. Homeopathy and naturopathy are also examples of complete alternative medicine systems. Homeopathic medicine is an unconventional Western system that is based on the principle that “like cures like,” i.e., that the same substance that in large doses produces the symptoms of an illness, in very minute doses cures it. Homeopathic health practitioners believe that the more dilute the remedy, the greater its potency. Therefore, they use small doses of specially prepared plant extracts and minerals to stimulate the body’s defense mechanisms and healing processes in order to treat illness. Naturopathic medicine is based on the theory that disease is a manifestation of alterations in the processes by which the body naturally heals itself and emphasizes health restoration rather than disease treatment. Naturopathic physicians employ an array of healing practices, including the following: diet and clinical nutrition, homeopathy, acupuncture, herbal medicine, hydrotherapy (the use of water in a range of temperatures and methods of applications), spinal and soft-tissue manipulation, physical therapies (such as those involving electrical currents, ultrasound, and light), therapeutic counseling, and pharmacology.

356 Alzheimer’s Disease

Mind-Body Interventions Mind-body interventions employ a variety of techniques designed to facilitate the mind’s capacity to affect bodily function and symptoms. Only a select group of mind-body interventions having well-documented theoretical foundations are considered CAM. For example, patient education and cognitive-behavioral approaches are now considered “mainstream.” On the other hand, complementary and alternative medicine includes meditation, certain uses of hypnosis, dance, music, and art therapy, as well as prayer and mental healing.

Biological-Based Therapies This category of CAM includes natural and biological-based practices, interventions, and products, many of which overlap with conventional medicine’s use of dietary supplements. This category includes herbal, special dietary, orthomolecular, and individual biological therapies. Herbal therapy employs an individual herb or a mixture of herbs for healing purposes. An herb is a plant or plant part that produces and contains chemical substances that act upon the body. Special diet therapies, such as those proposed by Drs. Atkins, Ornish, Pritikin, and Weil, are believed to prevent and/or control illness as well as promote health. Orthomolecular therapies aim to treat disease with varying concentrations of chemicals such as magnesium, melatonin, and mega-doses of vitamins. Biological therapies include, for example, the use of laetrile and shark cartilage to treat cancer and the use of bee pollen to treat autoimmune and inflammatory diseases.

Manipulative and Body-Based Methods This category includes methods that are based on manipulation and/or movement of the body. For example, chiropractors focus on the relationship between structure and function, primarily pertaining to the spine, and how that relationship affects the preservation and restoration of health. Chiropractors use manipulative therapy as an integral treatment tool. In contrast, osteopaths place particular emphasis on the musculoskeletal system and practice osteopathic manipulation. Osteopaths believe that all of the body’s systems work together and that disturbances in one system may have an impact upon function elsewhere in the body. Massage therapists manipulate the soft tissues of the body to normalize those tissues.

Researching Alternative Medicine 357

Energy Therapies Energy therapies focus on energy fields originating within the body (biofields) or those from other sources (electromagnetic fields). Biofield therapies are intended to affect energy fields (the existence of which is not yet experimentally proven) that surround and penetrate the human body. Some forms of energy therapy manipulate biofields by applying pressure and/or manipulating the body by placing the hands in or through these fields. Examples include Qi gong, Reiki and Therapeutic Touch. Qi gong is a component of traditional oriental medicine that combines movement, meditation, and regulation of breathing to enhance the flow of vital energy (qi) in the body, improve blood circulation, and enhance immune function. Reiki, the Japanese word representing Universal Life Energy, is based on the belief that, by channeling spiritual energy through the practitioner, the spirit is healed and, in turn, heals the physical body. Therapeutic Touch is derived from the ancient technique of “laying-on of hands.” It is based on the premises that the therapist’s healing force affects the patient’s recovery and that healing is promoted when the body’s energies are in balance. By passing their hands over the patient, these healers identify energy imbalances. Bioelectromagnetic-based therapies involve the unconventional use of electromagnetic fields to treat illnesses or manage pain. These therapies are often used to treat asthma, cancer, and migraine headaches. Types of electromagnetic fields which are manipulated in these therapies include pulsed fields, magnetic fields, and alternating current or direct current fields.

Can Alternatives Affect My Treatment? A critical issue in pursuing complementary alternatives mentioned thus far is the risk that these might have undesirable interactions with your medical treatment. It becomes all the more important to speak with your doctor who can offer advice on the use of alternatives. Official sources confirm this view. Though written for women, we find that the National Women’s Health Information Center’s advice on pursuing alternative medicine is appropriate for patients of both genders and all ages.46

46

Adapted from http://www.4woman.gov/faq/alternative.htm.

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Is It Okay to Want Both Traditional and Alternative or Complementary Medicine? Should you wish to explore non-traditional types of treatment, be sure to discuss all issues concerning treatments and therapies with your healthcare provider, whether a physician or practitioner of complementary and alternative medicine. Competent healthcare management requires knowledge of both conventional and alternative therapies you are taking for the practitioner to have a complete picture of your treatment plan. The decision to use complementary and alternative treatments is an important one. Consider before selecting an alternative therapy, the safety and effectiveness of the therapy or treatment, the expertise and qualifications of the healthcare practitioner, and the quality of delivery. These topics should be considered when selecting any practitioner or therapy.

National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov) has created a link to the National Library of Medicine’s databases to allow patients to search for articles that specifically relate to Alzheimer’s disease and complementary medicine. To search the database, go to www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “Alzheimer’s disease” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine (CAM) that are related to Alzheimer’s disease: •

A 90-year-old monozygotic female twin pair discordant for Alzheimer's disease. Author(s): Jarvenpaa T, Raiha I, Kaprio J, Koskenvuo M, Laine M, Kurki T, Viljanen T, Rinne JO. Source: Neurobiology of Aging. 2003 November; 24(7): 941-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12928054&dopt=Abstract

•

A novel treatment for patients with Alzheimer's disease and with vascular dementia. Author(s): Kurz A.

Researching Alternative Medicine 359

Source: Annals of the New York Academy of Sciences. 2002 November; 977: 476-81. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12480788&dopt=Abstract •

A novel trivalent cation chelator Feralex dissociates binding of aluminum and iron associated with hyperphosphorylated tau of Alzheimer's disease. Author(s): Shin RW, Kruck TP, Murayama H, Kitamoto T. Source: Brain Research. 2003 January 24; 961(1): 139-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12535786&dopt=Abstract

•

A psychoeducational model for Hispanic Alzheimer's disease caregivers. Author(s): Morano CL, Bravo M. Source: The Gerontologist. 2002 February; 42(1): 122-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11815707&dopt=Abstract

•

A randomised placebo controlled study to assess the effects of cholinergic treatment on muscarinic receptors in Alzheimer's disease. Author(s): Kemp PM, Holmes C, Hoffmann S, Wilkinson S, Zivanovic M, Thom J, Bolt L, Fleming J, Wilkinson DG. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 November; 74(11): 1567-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14617718&dopt=Abstract

•

A single-photon emission computed tomography imaging study of driving impairment in patients with Alzheimer's disease. Author(s): Ott BR, Heindel WC, Whelihan WM, Caron MD, Piatt AL, Noto RB. Source: Dementia and Geriatric Cognitive Disorders. 2000 May-June; 11(3): 153-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10765046&dopt=Abstract

•

A study on the rehabilitation of cognitive function and short-term memory in patients with Alzheimer's disease using transcutaneous electrical nerve stimulation.

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Author(s): Guo Y, Shi X, Uchiyama H, Hasegawa A, Nakagawa Y, Tanaka M, Fukumoto I. Source: Frontiers of Medical and Biological Engineering : the International Journal of the Japan Society of Medical Electronics and Biological Engineering. 2002; 11(4): 237-47. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12735425&dopt=Abstract •

Acute nicotine effects on auditory sensory memory in tacrine-treated and nontreated patients with Alzheimer's disease: an event-related potential study. Author(s): Engeland C, Mahoney C, Mohr E, Ilivitsky V, Knott VJ. Source: Pharmacology, Biochemistry, and Behavior. 2002 May; 72(1-2): 457-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11900820&dopt=Abstract

•

Advances in Alzheimer's disease. Author(s): Gray-Vickrey P. Source: Nursing. 2002 November; 32(11 Pt 1): 64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12441861&dopt=Abstract

•

Animal-assisted therapy and Nutrition in Alzheimer's disease. Author(s): Edwards NE, Beck AM. Source: Western Journal of Nursing Research. 2002 October; 24(6): 697712. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12365769&dopt=Abstract

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Antioxidant strategies for Alzheimer's disease. Author(s): Grundman M, Grundman M, Delaney P. Source: The Proceedings of the Nutrition Society. 2002 May; 61(2): 191202. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12133201&dopt=Abstract

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Antioxidants in Alzheimer's disease-vitamin C demanding brain. Author(s): Quinn J, Suh J, Moore MM, Kaye J, Frei B.

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Source: Journal of Alzheimer's Disease : Jad. 2003 August; 5(4): 309-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14624026&dopt=Abstract •

APP transgenic mice Tg2576 accumulate Abeta peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer's disease senile plaques. Author(s): Kalback W, Watson MD, Kokjohn TA, Kuo YM, Weiss N, Luehrs DC, Lopez J, Brune D, Sisodia SS, Staufenbiel M, Emmerling M, Roher AE. Source: Biochemistry. 2002 January 22; 41(3): 922-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11790115&dopt=Abstract

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Association of Alzheimer's disease onset with ginkgo biloba and other symptomatic cognitive treatments in a population of women aged 75 years and older from the EPIDOS study. Author(s): Andrieu S, Gillette S, Amouyal K, Nourhashemi F, Reynish E, Ousset PJ, Albarede JL, Vellas B, Grandjean H; EPIDOS study. Source: The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2003 April; 58(4): 372-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12663701&dopt=Abstract

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Beta-amyloid plaques induce neuritic dystrophy of nitric oxideproducing neurons in a transgenic mouse model of Alzheimer's disease. Author(s): Quinn J, Davis F, Woodward WR, Eckenstein F. Source: Experimental Neurology. 2001 April; 168(2): 203-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11259108&dopt=Abstract

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Brain metabolic and clinical effects of rivastigmine in Alzheimer's disease. Author(s): Potkin SG, Anand R, Fleming K, Alva G, Keator D, Carreon D, Messina J, Wu JC, Hartman R, Fallon JH. Source: The International Journal of Neuropsychopharmacology / Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (Cinp). 2001 September; 4(3): 223-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11602028&dopt=Abstract

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Brain metabolic effects of Neotrofin in patients with Alzheimer's disease. Author(s): Potkin SG, Alva G, Keator D, Carreon D, Fleming K, Fallon JH. Source: Brain Research. 2002 September 27; 951(1): 87-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12231461&dopt=Abstract

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Brain perfusion in Alzheimer's disease with and without apathy: a SPECT study with statistical parametric mapping analysis. Author(s): Benoit M, Koulibaly PM, Migneco O, Darcourt J, Pringuey DJ, Robert PH. Source: Psychiatry Research. 2002 June 15; 114(2): 103-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12036510&dopt=Abstract

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Brain regional quantification of F-ring and D-/E-ring isoprostanes and neuroprostanes in Alzheimer's disease. Author(s): Reich EE, Markesbery WR, Roberts LJ 2nd, Swift LL, Morrow JD, Montine TJ. Source: American Journal of Pathology. 2001 January; 158(1): 293-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11141503&dopt=Abstract

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Broad therapeutic benefits in patients with probable vascular dementia or Alzheimer's disease with cerebrovascular disease treated with galantamine. Author(s): Lilienfeld S, Kurz A. Source: Annals of the New York Academy of Sciences. 2002 November; 977: 487-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12480790&dopt=Abstract

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Cerebral blood flow and cognitive responses to rivastigmine treatment in Alzheimer's disease. Author(s): Vennerica A, Shanks MF, Staff RT, Pestell SJ, Forbes KE, Gemmell HG, Murray AD. Source: Neuroreport. 2002 January 21; 13(1): 83-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11924899&dopt=Abstract

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Cerebral blood flow and metabolic abnormalities in Alzheimer's disease. Author(s): Matsuda H. Source: Ann Nucl Med. 2001 April; 15(2): 85-92. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11448080&dopt=Abstract

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Cerebral metabolic response to passive audiovisual stimulation in patients with Alzheimer's disease and healthy volunteers assessed by PET. Author(s): Pietrini P, Alexander GE, Furey ML, Dani A, Mentis MJ, Horwitz B, Guazzelli M, Shapiro MB, Rapoport SI. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2000 April; 41(4): 575-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10768555&dopt=Abstract

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Clinical Value of Neuroimaging in the Diagnosis of Dementia. Sensitivity and Specificity of Regional Cerebral Metabolic and Other Parameters for Early Identification of Alzheimer's Disease. Author(s): Silverman DH, Small GW, Phelps ME. Source: Clinical Positron Imaging : Official Journal of the Institute for Clinical P.E.T. 1999 May; 2(3): 119-130. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14516535&dopt=Abstract

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Coma in a patient with Alzheimer's disease taking low dose trazodone and gingko biloba. Author(s): Galluzzi S, Zanetti O, Binetti G, Trabucchi M, Frisoni GB. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2000 May; 68(5): 679-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10836866&dopt=Abstract

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Combination of serum markers related to several mechanisms in Alzheimer's disease. Author(s): Teunissen CE, Lutjohann D, von Bergmann K, Verhey F, Vreeling F, Wauters A, Bosmans E, Bosma H, van Boxtel MP, Maes M, Delanghe J, Blom HJ, Verbeek MM, Rieckmann P, De Bruijn C, Steinbusch HW, de Vente J.

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Source: Neurobiology of Aging. 2003 November; 24(7): 893-902. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12928047&dopt=Abstract •

Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer's disease. Author(s): Roher AE, Kuo YM, Esh C, Knebel C, Weiss N, Kalback W, Luehrs DC, Childress JL, Beach TG, Weller RO, Kokjohn TA. Source: Molecular Medicine (Cambridge, Mass.). 2003 March-April; 9(34): 112-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12865947&dopt=Abstract

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Cranial electrostimulation (CES) in patients with probable Alzheimer's disease. Author(s): Scherder EJ, Deijen JB, Vreeswijk SH, Sergeant JA, Swaab DF. Source: Behavioural Brain Research. 2002 January 22; 128(2): 215-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11796166&dopt=Abstract

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Current status of metals as therapeutic targets in Alzheimer's disease. Author(s): Finefrock AE, Bush AI, Doraiswamy PM. Source: Journal of the American Geriatrics Society. 2003 August; 51(8): 1143-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12890080&dopt=Abstract

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Deficit in sensory motor processing in depression and Alzheimer's disease: a study with EMG and event related potentials. Author(s): Ortiz Alonso T, Lopez-Ibor MI, Martinez Castillo E, Fernandez Lucas A, Maestu Unturbe F, Lopez-Ibor JJ. Source: Electromyogr Clin Neurophysiol. 2000 September; 40(6): 357-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11039120&dopt=Abstract

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Diagnosis and management of Alzheimer's disease. Author(s): Coll PP, Fortinsky RH, Kaplan R, Song C. Source: Conn Med. 2003 September; 67(8): 505-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14587132&dopt=Abstract

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Dietary lipids in the aetiology of Alzheimer's disease: implications for therapy. Author(s): Cooper JL. Source: Drugs & Aging. 2003; 20(6): 399-418. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12710861&dopt=Abstract

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Differentiating frontal and temporal variant frontotemporal dementia from Alzheimer's disease. Author(s): Perry RJ, Hodges JR. Source: Neurology. 2000 June 27; 54(12): 2277-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10881252&dopt=Abstract

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Discovery of natural products from Curcuma longa that protect cells from beta-amyloid insult: a drug discovery effort against Alzheimer's disease. Author(s): Park SY, Kim DS. Source: Journal of Natural Products. 2002 September; 65(9): 1227-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12350137&dopt=Abstract

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Discussion of the role of the extracellular signal-regulated kinasephospholipase A2 pathway in production of reactive oxygen species in Alzheimer's disease. Author(s): Andersen JM, Myhre O, Fonnum F. Source: Neurochemical Research. 2003 February; 28(2): 319-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12608704&dopt=Abstract

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Docosahexaenoic acid provides protection from impairment of learning ability in Alzheimer's disease model rats. Author(s): Hashimoto M, Hossain S, Shimada T, Sugioka K, Yamasaki H, Fujii Y, Ishibashi Y, Oka J, Shido O. Source: Journal of Neurochemistry. 2002 June; 81(5): 1084-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12065621&dopt=Abstract

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Early Vitamin E supplementation in young but not aged mice reduces Abeta levels and amyloid deposition in a transgenic model of Alzheimer's disease.

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Author(s): Sung S, Yao Y, Uryu K, Yang H, Lee VM, Trojanowski JQ, Pratico D. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2003 December 4 [epub Ahead of Print] http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14656990&dopt=Abstract •

Effects of individualized versus classical “relaxation” music on the frequency of agitation in elderly persons with Alzheimer's disease and related disorders. Author(s): Gerdner LA. Source: Int Psychogeriatr. 2000 March; 12(1): 49-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10798453&dopt=Abstract

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Effects of low-frequency cranial electrostimulation on the rest-activity rhythm and salivary cortisol in Alzheimer's disease. Author(s): Scherder E, Knol D, van Someren E, Deijen JB, Binnekade R, Tilders F, Sergeant J. Source: Neurorehabilitation and Neural Repair. 2003 June; 17(2): 101-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12814055&dopt=Abstract

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Effects of low-level lead on glycolytic enzymes and pyruvate dehydrogenase of rat brain in vitro: relevance to sporadic Alzheimer's disease? Author(s): Yun SW, Hoyer S. Source: Journal of Neural Transmission (Vienna, Austria : 1996). 2000; 107(3): 355-68. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10821444&dopt=Abstract

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Effects of stimulus sequence on event-related potentials and reaction time during target detection in Alzheimer's disease. Author(s): Golob EJ, Starr A. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2000 August; 111(8): 1438-49. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10904226&dopt=Abstract

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Elevation of oxidative free radicals in Alzheimer's disease models can be attenuated by Ginkgo biloba extract EGb 761. Author(s): Smith JV, Luo Y. Source: Journal of Alzheimer's Disease : Jad. 2003 August; 5(4): 287-300. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14624024&dopt=Abstract

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Emerging neuroprotective strategies for Alzheimer's disease: dietary restriction, telomerase activation, and stem cell therapy. Author(s): Mattson MP. Source: Experimental Gerontology. 2000 July; 35(4): 489-502. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10959037&dopt=Abstract

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Estrogen and cerebral blood flow: a mechanism to explain the impact of estrogen on the incidence and treatment of Alzheimer's disease. Author(s): Greene RA. Source: Int J Fertil Womens Med. 2000 July-August; 45(4): 253-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10997480&dopt=Abstract

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Ethical, and practical issues in applying functional imaging to the clinical management of Alzheimer's disease. Author(s): Rosen AC, Bokde AL, Pearl A, Yesavage JA. Source: Brain and Cognition. 2002 December; 50(3): 498-519. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12480493&dopt=Abstract

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Expression of melanotransferrin isoforms in human serum: relevance to Alzheimer's disease. Author(s): Desrosiers RR, Bertrand Y, Nguyen QT, Demeule M, Gabathuler R, Kennard ML, Gauthier S, Beliveau R. Source: The Biochemical Journal. 2003 September 1; 374(Pt 2): 463-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12809550&dopt=Abstract

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Fatty acid analysis of blood plasma of patients with Alzheimer's disease, other types of dementia, and cognitive impairment. Author(s): Conquer JA, Tierney MC, Zecevic J, Bettger WJ, Fisher RH.

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Source: Lipids. 2000 December; 35(12): 1305-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11201991&dopt=Abstract •

Ginkgo biloba neuroprotection: Therapeutic implications in Alzheimer's disease. Author(s): Luo Y. Source: Journal of Alzheimer's Disease : Jad. 2001 August; 3(4): 401-407. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12214044&dopt=Abstract

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Health professionals' views on standards for decision-making capacity regarding refusal of medical treatment in mild Alzheimer's disease. Author(s): Volicer L, Ganzini L. Source: Journal of the American Geriatrics Society. 2003 September; 51(9): 1270-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12919240&dopt=Abstract

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Homocysteine and Alzheimer's disease. Author(s): Leboeuf R. Source: Journal of the American Dietetic Association. 2003 March; 103(3): 304-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12616250&dopt=Abstract

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How physicians approach advance care planning in patients with mild to moderate Alzheimer's disease. Author(s): Cavalieri TA, Latif W, Ciesielski J, Ciervo CA Jr, Forman LJ. Source: J Am Osteopath Assoc. 2002 October; 102(10): 541-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12401040&dopt=Abstract

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In vivo imaging of region and cell type specific neocortical neurodegeneration in Alzheimer's disease. Perspectives of MRI derived corpus callosum measurement for mapping disease progression and effects of therapy. Evidence from studies with MRI, EEG and PET. Author(s): Hampel H, Teipel SJ, Alexander GE, Pogarell O, Rapoport SI, Moller HJ.

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Source: Journal of Neural Transmission (Vienna, Austria : 1996). 2002 May; 109(5-6): 837-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12111472&dopt=Abstract •

Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors? Author(s): Leclerc S, Garnier M, Hoessel R, Marko D, Bibb JA, Snyder GL, Greengard P, Biernat J, Wu YZ, Mandelkow EM, Eisenbrand G, Meijer L. Source: The Journal of Biological Chemistry. 2001 January 5; 276(1): 25160. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11013232&dopt=Abstract

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Inflammation and cerebral amyloidosis are disconnected in an animal model of Alzheimer's disease. Author(s): Quinn J, Montine T, Morrow J, Woodward WR, Kulhanek D, Eckenstein F. Source: Journal of Neuroimmunology. 2003 April; 137(1-2): 32-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12667645&dopt=Abstract

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Influence of the severity of cognitive impairment on the effect of the Gnkgo biloba extract EGb 761 in Alzheimer's disease. Author(s): Le Bars PL, Velasco FM, Ferguson JM, Dessain EC, Kieser M, Hoerr R. Source: Neuropsychobiology. 2002; 45(1): 19-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11803237&dopt=Abstract

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Influence of vitamin E and C supplementation on lipoprotein oxidation in patients with Alzheimer's disease. Author(s): Kontush A, Mann U, Arlt S, Ujeyl A, Luhrs C, MullerThomsen T, Beisiegel U. Source: Free Radical Biology & Medicine. 2001 August 1; 31(3): 345-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11461772&dopt=Abstract

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In-vitro activity of S. lavandulaefolia (Spanish sage) relevant to treatment of Alzheimer's disease.

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Author(s): Perry NS, Houghton PJ, Sampson J, Theobald AE, Hart S, LisBalchin M, Hoult JR, Evans P, Jenner P, Milligan S, Perry EK. Source: The Journal of Pharmacy and Pharmacology. 2001 October; 53(10): 1347-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11697542&dopt=Abstract •

Is vitamin E the magic bullet for the treatment of Alzheimer's disease (AD)? Author(s): Woo K. Source: Perspectives. 2000 Spring; 24(1): 7-10. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12026332&dopt=Abstract

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Lateralized cortical perfusion in women with Alzheimer's disease. Author(s): Ott BR, Heindel WC, Tan Z, Noto RB. Source: J Gend Specif Med. 2000 September-October; 3(6): 29-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11253380&dopt=Abstract

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Longitudinal PET Evaluation of Cerebral Metabolic Decline in Dementia: A Potential Outcome Measure in Alzheimer's Disease Treatment Studies. Author(s): Alexander GE, Chen K, Pietrini P, Rapoport SI, Reiman EM. Source: The American Journal of Psychiatry. 2002 May; 159(5): 738-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11986126&dopt=Abstract

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Low serum cholesteryl ester-docosahexaenoic acid levels in Alzheimer's disease: a case-control study. Author(s): Tully AM, Roche HM, Doyle R, Fallon C, Bruce I, Lawlor B, Coakley D, Gibney MJ. Source: The British Journal of Nutrition. 2003 April; 89(4): 483-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12654166&dopt=Abstract

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Management of Alzheimer's disease. Author(s): Grossberg GT, Desai AK.

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Source: The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2003 April; 58(4): 331-53. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12663697&dopt=Abstract •

Melissa officinalis extract in the treatment of patients with mild to moderate Alzheimer's disease: a double blind, randomised, placebo controlled trial. Author(s): Akhondzadeh S, Noroozian M, Mohammadi M, Ohadinia S, Jamshidi AH, Khani M. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 July; 74(7): 863-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12810768&dopt=Abstract

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More than memory. The ancient art of storytelling can liberate the voices and imaginations of those with Alzheimer's disease. Author(s): Maher L. Source: Contemporary Longterm Care. 2002 July; 25(7): 16-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12154617&dopt=Abstract

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Neuroimaging in Alzheimer's disease: relevance for treatment. Author(s): van Dyck CH. Source: Current Psychiatry Reports. 2001 February; 3(1): 13-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11177754&dopt=Abstract

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Nicotinic receptor abnormalities of Alzheimer's disease: therapeutic implications. Author(s): Nordberg A. Source: Biological Psychiatry. 2001 February 1; 49(3): 200-10. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11230871&dopt=Abstract

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Non-cholinergic strategies for treating and preventing Alzheimer's disease. Author(s): Doraiswamy PM. Source: Cns Drugs. 2002; 16(12): 811-24. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12421115&dopt=Abstract

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Omental transposition to the brain as a surgical method for treating Alzheimer's disease. Author(s): Goldsmith HS, Wu W, Zhong J, Edgar M. Source: Neurological Research. 2003 September; 25(6): 625-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14503017&dopt=Abstract

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Oxidative injury in diseases of the central nervous system: focus on Alzheimer's disease. Author(s): Pratico D, Delanty N. Source: The American Journal of Medicine. 2000 November; 109(7): 57785. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11063960&dopt=Abstract

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Part VI. Primary drug therapies for Alzheimer's disease. Author(s): Knopman DS. Source: Disease-A-Month : Dm. 2000 November; 46(11): 745-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11130325&dopt=Abstract

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Pharmacologic treatment of Alzheimer's disease: an update. Author(s): DeLaGarza VW. Source: American Family Physician. 2003 October 1; 68(7): 1365-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14567491&dopt=Abstract

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Pharmacological studies supporting the therapeutic use of Ginkgo biloba extract for Alzheimer's disease. Author(s): Ahlemeyer B, Krieglstein J. Source: Pharmacopsychiatry. 2003 June; 36 Suppl 1: S8-14. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=13130383&dopt=Abstract

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Plants with traditional uses and activities, relevant to the management of Alzheimer's disease and other cognitive disorders. Author(s): Howes MJ, Perry NS, Houghton PJ. Source: Phytotherapy Research : Ptr. 2003 January; 17(1): 1-18. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12557240&dopt=Abstract

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Potent anti-amyloidogenic and fibril-destabilizing effects of polyphenols in vitro: implications for the prevention and therapeutics of Alzheimer's disease. Author(s): Ono K, Yoshiike Y, Takashima A, Hasegawa K, Naiki H, Yamada M. Source: Journal of Neurochemistry. 2003 October; 87(1): 172-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12969264&dopt=Abstract

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Practice guidelines for the diagnosis and treatment of Alzheimer's disease in a managed care setting: Part II--Pharmacologic therapy. Alzheimer's Disease (AD) Managed Care Advisory Council. Author(s): Fillit H, Cummings J. Source: Manag Care Interface. 2000 January; 13(1): 51-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10747691&dopt=Abstract

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Preserved stimulus deviance detection in Alzheimer's disease. Author(s): Pekkonen E, Jaaskelainen LP, Erkinjuntti T, Hietanen M, Huotilainen M, Ilmoniemi RJ, Naatanen R. Source: Neuroreport. 2001 June 13; 12(8): 1649-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11409733&dopt=Abstract

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Prevention of age-related spatial memory deficits in a transgenic mouse model of Alzheimer's disease by chronic Ginkgo biloba treatment. Author(s): Stackman RW, Eckenstein F, Frei B, Kulhanek D, Nowlin J, Quinn JF. Source: Experimental Neurology. 2003 November; 184(1): 510-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14637120&dopt=Abstract

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Prevention of Alzheimer's disease: where we stand. Author(s): Sano M. Source: Curr Neurol Neurosci Rep. 2002 September; 2(5): 392-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12169218&dopt=Abstract

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Progress in clinical, pharmacological, chemical and structural biological studies of huperzine A: a drug of traditional chinese medicine origin for the treatment of Alzheimer's disease. Author(s): Jiang H, Luo X, Bai D.

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Source: Current Medicinal Chemistry. 2003 November; 10(21): 2231-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14529340&dopt=Abstract •

Quantification of F-ring and D-/E-ring isoprostanes and neuroprostanes in Alzheimer's disease. Author(s): Reich EE, Markesbery WR, Roberts LJ 2nd, Swift LL, Morrow JD, Montine TJ. Source: Advances in Experimental Medicine and Biology. 2001; 500: 2536. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11764949&dopt=Abstract

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Regional cerebral blood flow and prognostic evaluation in Alzheimer's disease. Author(s): Nobili F, Copello F, Buffoni F, Vitali P, Girtler N, Bordoni C, Safaie-Semnani E, Mariani G, Rodriguez G. Source: Dementia and Geriatric Cognitive Disorders. 2001 March-April; 12(2): 89-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11173880&dopt=Abstract

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Regional cerebral blood flow patterns and response to donepezil treatment in patients with Alzheimer's disease. Author(s): Hanyu H, Shimizu T, Tanaka Y, Takasaki M, Koizumi K, Abe K. Source: Dementia and Geriatric Cognitive Disorders. 2003; 15(4): 177-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12626849&dopt=Abstract

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Regional effects of donepezil and rivastigmine on cortical acetylcholinesterase activity in Alzheimer's disease. Author(s): Kaasinen V, Nagren K, Jarvenpaa T, Roivainen A, Yu M, Oikonen V, Kurki T, Rinne JO. Source: Journal of Clinical Psychopharmacology. 2002 December; 22(6): 615-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12454562&dopt=Abstract

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Reminiscence group activities and discourse interaction in Alzheimer's disease.

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Author(s): Moss SE, Polignano E, White CL, Minichiello MD, Sunderland T. Source: Journal of Gerontological Nursing. 2002 August; 28(8): 36-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12219552&dopt=Abstract •

Response patterns of EGb 761 in Alzheimer's disease: influence of neuropsychological profiles. Author(s): Le Bars PL. Source: Pharmacopsychiatry. 2003 June; 36 Suppl 1: S50-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=13130389&dopt=Abstract

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Responses to donepezil in Alzheimer's disease and Parkinson's disease. Author(s): Mori S. Source: Annals of the New York Academy of Sciences. 2002 November; 977: 493-500. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12480791&dopt=Abstract

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Review of the next generation of Alzheimer's disease therapeutics: challenges for drug development. Author(s): Cutler NR, Sramek JJ. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2001 January; 25(1): 27-57. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11263756&dopt=Abstract

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Salvia officinalis extract in the treatment of patients with mild to moderate Alzheimer's disease: a double blind, randomized and placebo-controlled trial. Author(s): Akhondzadeh S, Noroozian M, Mohammadi M, Ohadinia S, Jamshidi AH, Khani M. Source: Journal of Clinical Pharmacy and Therapeutics. 2003 February; 28(1): 53-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12605619&dopt=Abstract

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Sensory cortical interactions in aging, mild cognitive impairment, and Alzheimer's disease. Author(s): Golob EJ, Miranda GG, Johnson JK, Starr A.

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Source: Neurobiology of Aging. 2001 September-October; 22(5): 755-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11705635&dopt=Abstract •

Sensory gating deficit expressed by a disturbed suppression of the P50 event-related potential in patients with Alzheimer's disease. Author(s): Jessen F, Kucharski C, Fries T, Papassotiropoulos A, Hoenig K, Maier W, Heun R. Source: The American Journal of Psychiatry. 2001 August; 158(8): 1319-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11481170&dopt=Abstract

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Should we encourage the use of high-dose vitamin E in persons with memory complaints as a preventive strategy against Alzheimer's disease? Author(s): Gauthier S. Source: Journal of Psychiatry & Neuroscience : Jpn. 2000 September; 25(4): 394. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11022404&dopt=Abstract

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Skill learning in patients with moderate Alzheimer's disease: a prospective pilot-study of waltz-lessons. Author(s): Rosler A, Seifritz E, Krauchi K, Spoerl D, Brokuslaus I, Proserpi SM, Gendre A, Savaskan E, Hofmann M. Source: International Journal of Geriatric Psychiatry. 2002 December; 17(12): 1155-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12461765&dopt=Abstract

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Spelling via semantics and phonology: exploring the effects of age, Alzheimer's disease, and primary semantic impairment. Author(s): Cortese MJ, Balota DA, Sergent-Marshall SD, Buckner RL. Source: Neuropsychologia. 2003; 41(8): 952-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12667531&dopt=Abstract

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The brain alpha7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease: studies with DMXBA (GTS-21). Author(s): Kem WR.

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Source: Behavioural Brain Research. 2000 August; 113(1-2): 169-81. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10942043&dopt=Abstract •

The dentate gyrus neurogenesis: a therapeutic target for Alzheimer's disease. Author(s): Tatebayashi Y, Lee MH, Li L, Iqbal K, Grundke-Iqbal I. Source: Acta Neuropathologica. 2003 March; 105(3): 225-32. Epub 2002 November 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12557008&dopt=Abstract

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The development of an Alzheimer's disease channel for the Michigan Interactive Health Kiosk Project. Author(s): Connell CM, Shaw BA, Holmes SB, Hudson ML, Derry HA, Strecher VJ. Source: Journal of Health Communication. 2003 January-February; 8(1): 11-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12635808&dopt=Abstract

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The effect of therapeutic touch on agitated behavior and cortisol in persons with Alzheimer's disease. Author(s): Woods DL, Dimond M. Source: Biological Research for Nursing. 2002 October; 4(2): 104-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12408216&dopt=Abstract

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The 'hidden' victims of Alzheimer's disease. Author(s): Ullman T. Source: Fda Consumer. 2003 July-August; 37(4): 40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12971350&dopt=Abstract

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The importance of awareness: An experience of small support groups for the caregivers of Alzheimer's disease patients. Author(s): Monini P, Tognetti A, Cinque R, Di Franco F, Bartorelli L.

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Source: Archives of Gerontology and Geriatrics. 2001 January; 33 Suppl 1: 267-271. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11431073&dopt=Abstract •

The role of religion and ethnicity in the help seeking of family caregivers of elders with Alzheimer's disease and related disorders. Author(s): Levkoff S, Levy B, Weitzman PF. Source: Journal of Cross-Cultural Gerontology. 1999 December; 14(4): 335-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=14618013&dopt=Abstract

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Theory of mind in patients with frontal variant frontotemporal dementia and Alzheimer's disease: theoretical and practical implications. Author(s): Gregory C, Lough S, Stone V, Erzinclioglu S, Martin L, BaronCohen S, Hodges JR. Source: Brain; a Journal of Neurology. 2002 April; 125(Pt 4): 752-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11912109&dopt=Abstract

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Thiamine for Alzheimer's disease. Author(s): Rodriguez-Martin JL, Qizilbash N, Lopez-Arrieta JM. Source: Cochrane Database Syst Rev. 2001; (2): Cd001498. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11405995&dopt=Abstract

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Thiamine for Alzheimer's disease. Author(s): Rodriguez-Martin JL, Lopez-Arrieta JM, Qizilbash N. Source: Cochrane Database Syst Rev. 2000; (2): Cd001498. Review. Update In: http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10796655&dopt=Abstract

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Treatment of Alzheimer's disease by transposition of the omentum. Author(s): Goldsmith HS. Source: Annals of the New York Academy of Sciences. 2002 November; 977: 454-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12480786&dopt=Abstract

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Treatment of Alzheimer's disease with clioquinol. Author(s): Regland B, Lehmann W, Abedini I, Blennow K, Jonsson M, Karlsson I, Sjogren M, Wallin A, Xilinas M, Gottfries CG. Source: Dementia and Geriatric Cognitive Disorders. 2001 NovemberDecember; 12(6): 408-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11598313&dopt=Abstract

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Treatment of Alzheimer's disease: current status and new perspectives. Author(s): Scarpini E, Scheltens P, Feldman H. Source: Lancet. Neurology. 2003 September; 2(9): 539-47. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12941576&dopt=Abstract

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Use of neuroimaging to detect early brain changes in people at genetic risk for Alzheimer's disease. Author(s): Small GW. Source: Advanced Drug Delivery Reviews. 2002 December 7; 54(12): 1561-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12453673&dopt=Abstract

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Using complementary and alternative approaches for residents with Alzheimer's disease. Author(s): Eliopoulos C. Source: Director. 2000 Winter; 8(1): 16. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11081017&dopt=Abstract

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Using music therapy to help a client with Alzheimer's disease adapt to long-term care. Author(s): Kydd P. Source: Am J Alzheimers Dis Other Demen. 2001 March-April; 16(2): 1038. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11302070&dopt=Abstract

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Utilization of Alzheimer's disease community resources by AsianAmericans in California. Author(s): Chow TW, Ross L, Fox P, Cummings JL, Lin KM.

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Source: International Journal of Geriatric Psychiatry. 2000 September; 15(9): 838-47. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10984731&dopt=Abstract •

Validity of direct assessment of functional status as a tool for measuring Alzheimer's disease severity. Author(s): Zanetti O, Frisoni GB, Rozzini L, Bianchetti A, Trabucchi M. Source: Age and Ageing. 1998 September; 27(5): 615-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12675100&dopt=Abstract

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Visual object and face processing in mild-to-moderate Alzheimer's disease: from segmentation to imagination. Author(s): Tippett LJ, Blackwood K, Farah MJ. Source: Neuropsychologia. 2003; 41(4): 453-68. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12559162&dopt=Abstract

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What's new in Alzheimer's disease? Author(s): Long CO, Dougherty J. Source: Home Healthcare Nurse. 2003 January; 21(1): 8-14; Quiz 15. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12544456&dopt=Abstract

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Yellow glasses improve contrast sensitivity of a patient with a visual variant of Alzheimer's disease. Author(s): Sakai S, Hirayama K, Iwasaki S, Fujii T, Hashimoto R, Yamadori A. Source: European Neurology. 2002; 48(4): 224-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12422073&dopt=Abstract

Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •

Alternative Medicine Foundation, Inc.: http://www.herbmed.org/

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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats

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Chinese Medicine: http://www.newcenturynutrition.com/

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

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

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

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TPN.com: http://www.tnp.com/

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

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

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,,00.html

General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at: www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources. The following additional references describe, in broad terms, alternative and complementary medicine (sorted alphabetically by title; hyperlinks provide rankings, information, and reviews at Amazon.com): •

Alternative and Complementary Treatment in Neurologic Illness by Michael I. Weintraub (Editor); Paperback - 288 pages (March 23, 2001), Churchill Livingstone; ISBN: 0443065586; http://www.amazon.com/exec/obidos/ASIN/0443065586/icongroupinter na

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Radical Healing: Integrating the World’s Great Therapeutic Traditions to Create a New Transformative Medicine by Rudolph Ballentine, M.D., Linda Funk (Illustrator); Paperback - 612 pages; Reprint edition (March 14, 2000), Three Rivers Press; ISBN: 0609804847; http://www.amazon.com/exec/obidos/ASIN/0609804847/icongroupinter na

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The Review of Natural Products by Facts and Comparisons (Editor); CdRom edition (January 2002), Facts & Comparisons; ISBN: 1574391453; http://www.amazon.com/exec/obidos/ASIN/1574391453/icongroupinter na

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For additional information on complementary and alternative medicine, ask your doctor or write to: National Center for Complementary and Alternative Medicine Clearinghouse National Institutes of Health P. O. Box 8218 Silver Spring, MD 20907-8218

Vocabulary Builder The following vocabulary builder gives definitions of words used in this chapter that have not been defined in previous chapters: Attenuated: Strain with weakened or reduced virulence. [NIH] EMG: Recording of electrical activity or currents in a muscle. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH]

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APPENDIX C. RESEARCHING NUTRITION Overview Since the time of Hippocrates, doctors have understood the importance of diet and nutrition to patients’ health and well-being. Since then, they have accumulated an impressive archive of studies and knowledge dedicated to this subject. Based on their experience, doctors and healthcare providers may recommend particular dietary supplements to patients with Alzheimer’s disease. Any dietary recommendation is based on a patient’s age, body mass, gender, lifestyle, eating habits, food preferences, and health condition. It is therefore likely that different patients with Alzheimer’s disease may be given different recommendations. Some recommendations may be directly related to Alzheimer’s disease, while others may be more related to the patient’s general health. These recommendations, themselves, may differ from what official sources recommend for the average person. In this chapter we will begin by briefly reviewing the essentials of diet and nutrition that will broadly frame more detailed discussions of Alzheimer’s disease. We will then show you how to find studies dedicated specifically to nutrition and Alzheimer’s disease.

Food and Nutrition: General Principles What Are Essential Foods? Food is generally viewed by official sources as consisting of six basic elements: (1) fluids, (2) carbohydrates, (3) protein, (4) fats, (5) vitamins, and (6) minerals. Consuming a combination of these elements is considered to be a healthy diet:

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Fluids are essential to human life as 80-percent of the body is composed of water. Water is lost via urination, sweating, diarrhea, vomiting, diuretics (drugs that increase urination), caffeine, and physical exertion.

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Carbohydrates are the main source for human energy (thermoregulation) and the bulk of typical diets. They are mostly classified as being either simple or complex. Simple carbohydrates include sugars which are often consumed in the form of cookies, candies, or cakes. Complex carbohydrates consist of starches and dietary fibers. Starches are consumed in the form of pastas, breads, potatoes, rice, and other foods. Soluble fibers can be eaten in the form of certain vegetables, fruits, oats, and legumes. Insoluble fibers include brown rice, whole grains, certain fruits, wheat bran and legumes.

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Proteins are eaten to build and repair human tissues. Some foods that are high in protein are also high in fat and calories. Food sources for protein include nuts, meat, fish, cheese, and other dairy products.

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Fats are consumed for both energy and the absorption of certain vitamins. There are many types of fats, with many general publications recommending the intake of unsaturated fats or those low in cholesterol.

Vitamins and minerals are fundamental to human health, growth, and, in some cases, disease prevention. Most are consumed in your diet (exceptions being vitamins K and D which are produced by intestinal bacteria and sunlight on the skin, respectively). Each vitamin and mineral plays a different role in health. The following outlines essential vitamins: •

Vitamin A is important to the health of your eyes, hair, bones, and skin; sources of vitamin A include foods such as eggs, carrots, and cantaloupe.

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Vitamin B1, also known as thiamine, is important for your nervous system and energy production; food sources for thiamine include meat, peas, fortified cereals, bread, and whole grains.

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Vitamin B2, also known as riboflavin, is important for your nervous system and muscles, but is also involved in the release of proteins from nutrients; food sources for riboflavin include dairy products, leafy vegetables, meat, and eggs.

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Vitamin B3, also known as niacin, is important for healthy skin and helps the body use energy; food sources for niacin include peas, peanuts, fish, and whole grains

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Vitamin B6, also known as pyridoxine, is important for the regulation of cells in the nervous system and is vital for blood formation; food sources for pyridoxine include bananas, whole grains, meat, and fish.

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Vitamin B12 is vital for a healthy nervous system and for the growth of red blood cells in bone marrow; food sources for vitamin B12 include yeast, milk, fish, eggs, and meat.

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Vitamin C allows the body’s immune system to fight various diseases, strengthens body tissue, and improves the body’s use of iron; food sources for vitamin C include a wide variety of fruits and vegetables.

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Vitamin D helps the body absorb calcium which strengthens bones and teeth; food sources for vitamin D include oily fish and dairy products.

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Vitamin E can help protect certain organs and tissues from various degenerative diseases; food sources for vitamin E include margarine, vegetables, eggs, and fish.

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Vitamin K is essential for bone formation and blood clotting; common food sources for vitamin K include leafy green vegetables.

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Folic Acid maintains healthy cells and blood and, when taken by a pregnant woman, can prevent her fetus from developing neural tube defects; food sources for folic acid include nuts, fortified breads, leafy green vegetables, and whole grains.

It should be noted that it is possible to overdose on certain vitamins which become toxic if consumed in excess (e.g. vitamin A, D, E and K). Like vitamins, minerals are chemicals that are required by the body to remain in good health. Because the human body does not manufacture these chemicals internally, we obtain them from food and other dietary sources. The more important minerals include: •

Calcium is needed for healthy bones, teeth, and muscles, but also helps the nervous system function; food sources for calcium include dry beans, peas, eggs, and dairy products.

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Chromium is helpful in regulating sugar levels in blood; food sources for chromium include egg yolks, raw sugar, cheese, nuts, beets, whole grains, and meat.

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Fluoride is used by the body to help prevent tooth decay and to reinforce bone strength; sources of fluoride include drinking water and certain brands of toothpaste.

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Iodine helps regulate the body’s use of energy by synthesizing into the hormone thyroxine; food sources include leafy green vegetables, nuts, egg yolks, and red meat.

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Iron helps maintain muscles and the formation of red blood cells and certain proteins; food sources for iron include meat, dairy products, eggs, and leafy green vegetables.

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Magnesium is important for the production of DNA, as well as for healthy teeth, bones, muscles, and nerves; food sources for magnesium include dried fruit, dark green vegetables, nuts, and seafood.

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Phosphorous is used by the body to work with calcium to form bones and teeth; food sources for phosphorous include eggs, meat, cereals, and dairy products.

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Selenium primarily helps maintain normal heart and liver functions; food sources for selenium include wholegrain cereals, fish, meat, and dairy products.

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Zinc helps wounds heal, the formation of sperm, and encourage rapid growth and energy; food sources include dried beans, shellfish, eggs, and nuts.

The United States government periodically publishes recommended diets and consumption levels of the various elements of food. Again, your doctor may encourage deviations from the average official recommendation based on your specific condition. To learn more about basic dietary guidelines, visit the Web site: http://www.health.gov/dietaryguidelines/. Based on these guidelines, many foods are required to list the nutrition levels on the food’s packaging. Labeling Requirements are listed at the following site maintained by the Food and Drug Administration: http://www.cfsan.fda.gov/~dms/labcons.html. When interpreting these requirements, the government recommends that consumers become familiar with the following abbreviations before reading FDA literature:47 •

DVs (Daily Values): A new dietary reference term that will appear on the food label. It is made up of two sets of references, DRVs and RDIs.

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DRVs (Daily Reference Values): A set of dietary references that applies to fat, saturated fat, cholesterol, carbohydrate, protein, fiber, sodium, and potassium.

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RDIs (Reference Daily Intakes): A set of dietary references based on the Recommended Dietary Allowances for essential vitamins and minerals and, in selected groups, protein. The name “RDI” replaces the term “U.S. RDA.”

47

Adapted from the FDA: http://www.fda.gov/fdac/special/foodlabel/dvs.html.

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•

RDAs (Recommended Dietary Allowances): A set of estimated nutrient allowances established by the National Academy of Sciences. It is updated periodically to reflect current scientific knowledge.

What Are Dietary Supplements?48 Dietary supplements are widely available through many commercial sources, including health food stores, grocery stores, pharmacies, and by mail. Dietary supplements are provided in many forms including tablets, capsules, powders, gel-tabs, extracts, and liquids. Historically in the United States, the most prevalent type of dietary supplement was a multivitamin/mineral tablet or capsule that was available in pharmacies, either by prescription or “over the counter.” Supplements containing strictly herbal preparations were less widely available. Currently in the United States, a wide array of supplement products are available, including vitamin, mineral, other nutrients, and botanical supplements as well as ingredients and extracts of animal and plant origin. The Office of Dietary Supplements (ODS) of the National Institutes of Health is the official agency of the United States which has the expressed goal of acquiring “new knowledge to help prevent, detect, diagnose, and treat disease and disability, from the rarest genetic disorder to the common cold.”49 According to the ODS, dietary supplements can have an important impact on the prevention and management of disease and on the maintenance of health.50 The ODS notes that considerable research on the effects of dietary supplements has been conducted in Asia and Europe where the use of plant products, in particular, has a long tradition. However, the overwhelming majority of supplements have not been studied scientifically. To explore the role of dietary supplements in the improvement of health care, the ODS plans, organizes, and supports conferences, workshops, and This discussion has been adapted from the NIH: http://ods.od.nih.gov/showpage.aspx?pageid=46. 49 Contact: The Office of Dietary Supplements, National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: (301) 435-2920, Fax: (301) 480-1845, E-mail: [email protected]. 50 Adapted from http://ods.od.nih.gov/showpage.aspx?pageid=2. The Dietary Supplement Health and Education Act defines dietary supplements as “a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients: a vitamin, mineral, amino acid, herb or other botanical; or a dietary substance for use to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of any ingredient described above; and intended for ingestion in the form of a capsule, powder, softgel, or gelcap, and not represented as a conventional food or as a sole item of a meal or the diet.” 48

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symposia on scientific topics related to dietary supplements. The ODS often works in conjunction with other NIH Institutes and Centers, other government agencies, professional organizations, and public advocacy groups. To learn more about official information on dietary supplements, visit the ODS site at http://ods.od.nih.gov/whatare/whatare.html. Or contact: The Office of Dietary Supplements National Institutes of Health Building 31, Room 1B29 31 Center Drive, MSC 2086 Bethesda, Maryland 20892-2086 Tel: (301) 435-2920 Fax: (301) 480-1845 E-mail: [email protected]

Finding Studies on Alzheimer’s Disease The NIH maintains an office dedicated to patient nutrition and diet. The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.51 IBIDS is available to the public free of charge through the ODS Internet page: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. We recommend that you start with the Consumer Database. While you may not find references for the topics that are of most interest to you, check back periodically as this database is frequently updated. More studies can be found by searching the Full IBIDS Database. Healthcare professionals and researchers generally use the third option, which lists peer-reviewed citations. In all cases, we suggest that you take advantage of the “Advanced Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.

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Search” option that allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “Alzheimer’s disease” (or synonyms) into the search box. To narrow the search, you can also select the “Title” field. The following is a typical result when searching for recently indexed consumer information on Alzheimer’s disease: •

Acetyl-carnitine and Alzheimer's disease. Author(s): Department of Nutrition and Dietetics, Georgia State University, Atlanta 30303-3083. Source: Bowman, B A Nutr-Revolume 1992 May; 50(5): 142-4 0029-6643

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Ask the doctor. In your article on Alzheimer's disease (March, 1999), you mention “high doses of vitamin E” as helpful in slowing the progression of the condition. Specifically, what dose is recommended? Source: Nicholson, C R Harv-Womens-Health-Watch. 1999 May; 6(9): 8 1070-910X

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Homocysteine and Alzheimer's disease. Author(s): University of California-Davis Medical Center, Department of Medical Pathology, Sacramento 95817, USA. Source: Miller, J W Nutr-Revolume 1999 April; 57(4): 126-9 0029-6643

The following information is typical of that found when using the “Full IBIDS Database” when searching using “Alzheimer’s disease” (or a synonym): •

A 28-week, double-blind, placebo-controlled study with Cerebrolysin in patients with mild to moderate Alzheimer's disease. Author(s): Goettingen University Clinic for Psychiatry, Germany. Source: Ruether, E Husmann, R Kinzler, E Diabl, E Klingler, D Spatt, J Ritter, R Schmidt, R Taneri, Z Winterer, W Koper, D Kasper, S Rainer, M Moessler, H Int-Clin-Psychopharmacol. 2001 September; 16(5): 253-63 0268-1315

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A review of epidemiologic studies on aluminum and silica in relation to Alzheimer's disease and associated disorders. Author(s): INSERM U330, Bordeaux. [email protected] Source: Rondeau, V Rev-Environ-Health. 2002 Apr-June; 17(2): 107-21 0048-7554

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A role for estrogen in the primary prevention of Alzheimer's disease. Source: Thomas, T Climacteric. 2001 June; 4(2): 102-9 1369-7137

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Accumulation of calbindin in cortical pyramidal cells with ageing; a putative protective mechanism which fails in Alzheimer's disease. Author(s): Department of Biomedical Science, University of Sheffield, Sheffield, UK. [email protected]

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Source: Greene, J R Radenahmad, N Wilcock, G K Neal, J W Pearson, R C Neuropathol-Appl-Neurobiol. 2001 October; 27(5): 339-42 0305-1846 •

Acetylcholinesterase inhibitors for vascular dementia and Alzheimer's disease combined with cerebrovascular disease. Author(s): Department of Neurology, Royal Free Hospital, London, UK. [email protected] Source: Bowler, J V Stroke. 2003 February; 34(2): 584-6 1524-4628

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Actigraphic sleep-wake patterns and urinary 6-sulfatoxymelatonin excretion in patients with Alzheimer's disease. Author(s): Endocrine Institute, Haemek Medical Center, Afula, Israel. Source: Luboshitzky, R Shen Orr, Z Tzischichinsky, O Maldonado, M Herer, P Lavie, P Chronobiol-Int. 2001 May; 18(3): 513-24 0742-0528

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Action-based memory in Alzheimer's disease: a longitudinal look at tea making. Author(s): Laboratory of Experimental Psychology, University of Sussex, Brighton BN1 9QG, UK. [email protected] Source: Rusted, Jennifer Sheppard, Linda Neurocase. 2002; 8(1-2): 111-26 1355-4794

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Activated microglia in Alzheimer's disease and stroke. Author(s): Cell Signalling Laboratory, Institute of Neurology, University College, 1 Wakefield Street, London WC1NPJ, UK. [email protected] Source: Pocock, J M Liddle, A C Hooper, C Taylor, D L Davenport, C M Morgan, S C Ernst-Schering-Res-Found-Workshopage 2002; (39): 105-32 0947-6075

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Advances in Alzheimer's disease. Author(s): Florida Gulf Coast University, Fort Myers, USA. Source: Gray Vickrey, P Nursing. 2002 November; 32(11 Pt 1): 64 03604039

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Alzheimer's disease is not associated with altered concentrations of the nitric oxide synthase inhibitor asymmetric dimethylarginine in cerebrospinal fluid. Author(s): Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands, Sweden. Source: Mulder, C Wahlund, L O Blomberg, M de Jong, S van Kamp, G J Scheltens, P Teerlink, T J-Neural-Transm. 2002 September; 109(9): 1203-8 0300-9564

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Cerebrolysin in Alzheimer's disease: a randomized, double-blind, placebo-controlled trial with a neurotrophic agent. Author(s): McGill Centre for Studies in Ageing, Montreal, Quebec, Canada.

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Source: Panisset, M Gauthier, S Moessler, H Windisch, M J-NeuralTransm. 2002 July; 109(7-8): 1089-104 0300-9564 •

Cerebrospinal fluid levels of thiamine in patients with Alzheimer's disease. Author(s): Department of Neurology, Hospital Universitario Doce de Octubre, E-28030 Madrid, Spain. Source: Molina, J A Jimenez Jimenez, F J Hernanz, A Fernandez Vivancos, E Medina, S de Bustos, F Gomez Escalonilla, C Sayed, Y J-Neural-Transm. 2002 July; 109(7-8): 1035-44 0300-9564

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Clinical and cost-effectiveness of donepezil, rivastigmine, and galantamine for Alzheimer's disease. A systematic review. Author(s): University of Southampton. Source: Clegg, A Bryant, J Nicholson, T McIntyre, L De Broe, S Gerard, K Waugh, N Int-J-Technol-Assess-Health-Care. 2002 Summer; 18(3): 497-507 0266-4623

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Contrasting, species-dependent modulation of copper-mediated neurotoxicity by the Alzheimer's disease amyloid precursor protein. Author(s): Department of Pathology, The University of Melbourne, Victoria 3010, Australia. Source: White, Anthony R Multhaup, Gerd Galatis, Denise McKinstry, William J Parker, Michael W Pipkorn, Rudiger Beyreuther, Konrad Masters, Colin L Cappai, Roberto J-Neurosci. 2002 January 15; 22(2): 36576 1529-2401

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Contributions of mitochondrial alterations, resulting from bad genes and a hostile environment, to the pathogenesis of Alzheimer's disease. Author(s): Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [email protected]/gov Source: Mattson, M P Int-Rev-Neurobiol. 2002; 53: 387-409 0074-7742

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Current status and new developments with galantamine in the treatment of Alzheimer's disease. Author(s): Univeristy of Rochester Medical Center, Rochester, NY, USA. Source: Tariot, P Expert-Opin-Pharmacother. 2001 December; 2(12): 202749 1465-6566

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D-cycloserine for Alzheimer's disease. Author(s): Department of Geriatric Medicine, Ullevaal Hospital, Kirkevn. 166, Oslo, Norway. [email protected] Source: Laake, K Oeksengaard, A R Cochrane-Database-Syst-Revolume 2002; (2): CD003153 1469-493X

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Development of indole-3-propionic acid (OXIGON) for Alzheimer's disease. Author(s): Minden BioPharmaceuticals, Ltd, Jerusalem, Israel. [email protected] Source: Bendheim, P E Poeggeler, B Neria, E Ziv, V Pappolla, M A Chain, D G J-Mol-Neurosci. 2002 Aug-October; 19(1-2): 213-7 0895-8696

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Diet-related prevention of Alzheimer's disease: different hypotheses. Source: Nicolas, A S Vellas, B Nestle-Nutr-Workshop-Ser-Clin-PerformProgramme. 2001; (5): 219-27; discussion 228-30 1422-7584

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Differences in the fatty acid composition of the grey and white matter of different regions of the brains of patients with Alzheimer's disease and control subjects. Author(s): Department of Molecular and Cell Biology, University of Aberdeen, Scotland. Source: Skinner, E R Watt, C Besson, J A Best, P V Brain. 1993 June; 116 ( Pt 3): 717-25 0006-8950

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Do cholinesterase inhibitors have disease-modifying effects in Alzheimer's disease? Author(s): University Hospitals of Geneva, Department of Geriatrics, University of Geneva Medical School, Thonex, Switzerland. [email protected] Source: Giacobini, E CNS-Drugs. 2001; 15(2): 85-91 1172-7047

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Does caffeine intake protect from Alzheimer's disease? Author(s): Dementia Clinics, Hospital of Santa Maria and Laboratory of Neurosciences, Faculty of Medicine of Lisbon, Portugal. Source: Maia, L de Mendonca, A Eur-J-Neurol. 2002 July; 9(4): 377-82 1351-5101

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Dysregulation of cellular calcium homeostasis in Alzheimer's disease: bad genes and bad habits. Author(s): Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, MD 21224, USA. [email protected] Source: Mattson, M P Chan, S L J-Mol-Neurosci. 2001 October; 17(2): 20524 0895-8696

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Effects of Cerebrolysin on amyloid-beta deposition in a transgenic model of Alzheimer's disease. Author(s): Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA 92093-0624, USA. Source: Rockenstein, E Mallory, M Mante, M Alford, M Windisch, M Moessler, H Masliah, E J-Neural-Transm-Suppl. 2002; (62): 327-36 03036995

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Effects of rapid tryptophan depletion on salivary and plasma cortisol in Alzheimer's disease and the healthy elderly. Author(s): Department of Psychological Medicine, Christchurch School of Medicine, University of Otago, New Zealand. Source: Porter, R J Marshall, E F O'Brien, J T J-Psychopharmacol. 2002 Mar; 16(1): 73-8 0269-8811

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Efficacy and safety of nicotine on Alzheimer's disease patients. Author(s): Hospital de Cantoblanco, Consejeria de Sanidad, Carretera de Colmenar km 14.500, Madrid, Madrid, Spain, 28049. [email protected] Source: Lopez Arrieta, J M Rodriguez, J L Sanz, F Cochrane-DatabaseSyst-Revolume 2001; (2): CD001749 1469-493X

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Efficacy of metrifonate in improving the psychiatric and behavioral disturbances of patients with Alzheimer's disease. Author(s): Reed Neurological Research Center, University of California at Los Angeles, 90095-1769, USA. Source: Cummings, J L Nadel, A Masterman, D Cyrus, P A J-GeriatrPsychiatry-Neurol. 2001 Summer; 14(2): 101-8 0891-9887

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Estrogen and Alzheimer's disease. Author(s): The Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B Davis Jewish General Hospital, Montreal, Quebec, Canada. [email protected] Source: LeBlanc, A Curr-Opin-Investig-Drugs. 2002 May; 3(5): 768-73 1472-4472

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Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease. Author(s): Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland 21224, USA. Source: Kruman, Inna I Kumaravel, T S Lohani, Althaf Pedersen, Ward A Cutler, Roy G Kruman, Yuri Haughey, Norman Lee, Jaewon Evans, Michele Mattson, Mark P J-Neurosci. 2002 Mar 1; 22(5): 1752-62 1529-2401

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Galantamine for Alzheimer's disease. Author(s): Adult and Geriatric Treatment and Preventative Interventions Branch, National Institute of Mental Health, NIMH, Room 7160, MSC 9635, 6001 Executive Blvd., Bethesda, Maryland 20892-9635, USA. [email protected] Source: Olin, J Schneider, L Cochrane-Database-Syst-Revolume 2001; 1: CD001747 1469-493X

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Galantamine--a novel cholinergic drug with a unique dual mode of action for the treatment of patients with Alzheimer's disease. Author(s): Janssen Pharmaceutical Inc., Janssen Research Foundation, Division of Janssen Pharmaceutica Ltd., 1125 Trenton Harbourton Road, Titusville, NJ 08560, USA. [email protected]. Source: Lilienfeld, S CNS-Drug-Revolume 2002 Summer; 8(2): 159-76 1080-563X

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Genetic and environmental risk factors for Alzheimer's disease in Israeli Arabs. Author(s): Department of Neurology, Case Western Reserve University School of Medicine, Cleveland OH 44106, USA. Source: Bowirrat, A Friedland, R P Farrer, L Baldwin, C Korczyn, A JMol-Neurosci. 2002 Aug-October; 19(1-2): 239-45 0895-8696

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Implications of the kynurenine pathway and quinolinic acid in Alzheimer's disease. Author(s): Centre for Immunology and Department of Neurology, St Vincent's Hospital and University of New South Wales, Sydney, Australia. [email protected] Source: Guillemin, G J Brew, B J Redox-Repage 2002; 7(4): 199-206 13510002

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Increased oxidative stress in Alzheimer's disease as assessed with 4hydroxynonenal but not malondialdehyde. Author(s): Department of Geriatric Medicine, Queens University of Belfast, Belfast, UK. Source: McGrath, L T McGleenon, B M Brennan, S McColl, D McILroy, S Passmore, A P QJM. 2001 September; 94(9): 485-90 1460-2725

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In-vitro activity of S. lavandulaefolia (Spanish sage) relevant to treatment of Alzheimer's disease. Author(s): Pharmacognosy Research Laboratories, Department of Pharmacy, King's College London, UK. Source: Perry, N S Houghton, P J Sampson, J Theobald, A E Hart, S Lis Balchin, M Hoult, J R Evans, P Jenner, P Milligan, S Perry, E K J-PharmPharmacol. 2001 October; 53(10): 1347-56 0022-3573

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Is vitamin E the magic bullet for the treatment of Alzheimer's disease (AD)? Author(s): Mount Sinai Hospital, Toronto. Source: Woo, K Perspectives. 2000 Spring; 24(1): 7-10 0831-7445

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Lipid peroxidation and advanced glycation end products in the brain in normal aging and in Alzheimer's disease. Author(s): Department of Neurology, Nagoya University School of Medicine, Tsurumai 65, Showa, Nagoya 466-8550, Japan.

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Source: Dei, R Takeda, A Niwa, H Li, M Nakagomi, Y Watanabe, M Inagaki, T Washimi, Y Yasuda, Y Horie, K Miyata, T Sobue, G ActaNeuropathol-(Berl). 2002 August; 104(2): 113-22 0001-6322 •

Lipid peroxidation in neurodegeneration: new insights into Alzheimer's disease. Author(s): Department of Molecular Cell Biology, Institute for Medical Biochemistry and Molecular Biology, University Hospital HamburgEppendorf, Germany. [email protected] Source: Arlt, S Beisiegel, U Kontush, A Curr-Opin-Lipidol. 2002 June; 13(3): 289-94 0957-9672

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Locally reduced levels of acidic FGF lead to decreased expression of 28kda calbindin and contribute to the selective vulnerability of the neurons in the entorhinal cortex in Alzheimer's disease. Author(s): Institute of Neuropathology, Medical School of Hannover, Germany. [email protected] Source: Thorns, V Licastro, F Masliah, E Neuropathology. 2001 September; 21(3): 203-11 0919-6544

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Medical treatment of Alzheimer's disease: past, present, and future. Author(s): Memorial Hospital Alzheimer's Disease and Memory Disorders Center, Pawtucket, RI, USA. [email protected] Source: Ott, B R Med-Health-R-I. 2002 July; 85(7): 210-2 1086-5462

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Medications for the treatment of Alzheimer's disease. Author(s): Donald W. Reynolds Department of Geriatric Medicine, 921 NE 13th Street, VA Medical Center, #11G-Geriatrics, Oklahoma City, OK 73104-5028, USA. Source: Lampley Dallas, V T J-Okla-State-Med-Assoc. 2001 August; 94(8): 347-9 0030-1876

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Melatonin acts as antioxidant and pro-oxidant in an organotypic slice culture model of Alzheimer's disease. Author(s): Institute of Arctic Biology and Department of Chemistry, University of Alaska Fairbanks, Fairbanks, AK 99775, USA. Source: Clapp Lilly, K L Smith, M A Perry, G Harris, P L Zhu, X Duffy, L K Neuroreport. 2001 May 8; 12(6): 1277-80 0959-4965

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Mitochondrial abnormalities in Alzheimer's disease. Author(s): Institute of Pathology, Department of Neurology, Case Western Reserve University, Cleveland, Ohio 44106, USA. Source: Hirai, K Aliev, G Nunomura, A Fujioka, H Russell, R L Atwood, C S Johnson, A B Kress, Y Vinters, H V Tabaton, M Shimohama, S Cash, A D Siedlak, S L Harris, P L Jones, P K Petersen, R B Perry, G Smith, M A J-Neurosci. 2001 May 1; 21(9): 3017-23 1529-2401

396 Alzheimer’s Disease

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Nicotinic receptor modulation: advantages for successful Alzheimer's disease therapy. Source:

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No long-term effect of behavioral treatment on psychotropic drug use for agitation in Alzheimer's disease patients. Author(s): Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, USA. Source: Weiner, M F Tractenberg, R E Sano, M Logsdon, R Teri, L Galasko, D Gamst, A Thomas, R Thal, L J J-Geriatr-Psychiatry-Neurol. 2002 Summer; 15(2): 95-8 0891-9887

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Novel excitatory actions of galanin on rat cholinergic basal forebrain neurons: implications for its role in Alzheimer's disease. Author(s): Division of Neurology, Department of Medicine, University of Alberta, 530 Heritage Medical Research Centre, Edmonton, Alberta T6G 2S2, Canada. [email protected] Source: Jhamandas, Jack H Harris, Kim H MacTavish, David Jassar, Balvinder S J-Neurophysiol. 2002 February; 87(2): 696-704 0022-3077

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Nutritional factors and Alzheimer's disease. Author(s): Department of Clinical Gerontology and Internal Medicine, University Hospital of Toulouse, France. Source: Reynish, W Andrieu, S Nourhashemi, F Vellas, B J-Gerontol-ABiol-Sci-Med-Sci. 2001 November; 56(11): M675-80 1079-5006

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Oxidative nerve cell death in Alzheimer's disease and stroke: antioxidants as neuroprotective compounds. Source: Behl, C. Moosmann, B. Biol-Chem. Berlin; New York : W. de Gruyter, c1996-. Mar/April 2002. volume 383 (3/4) page 521-536. 14316730

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Pharmacodynamic-tolerability relationships of cholinesterase inhibitors for Alzheimer's disease. Author(s): Research & Development Department, Chiesi Farmaceutici, Parma, Italy. [email protected] Source: Imbimbo, B P CNS-Drugs. 2001; 15(5): 375-90 1172-7047

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Physostigmine for Alzheimer's disease. Author(s): Departamento de Medicina Clinica, Universidade Federal do Ceara, Fortaleza, Ceara, Brazil. [email protected] Source: Coelho, F Birks, J Cochrane-Database-Syst-Revolume 2001; (2): CD001499 1469-493X

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Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. Author(s): Department of Neurology, Boston University School of Medicine, MA 02118-2526, USA.

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Source: Seshadri, Sudha Beiser, Alexa Selhub, Jacob Jacques, Paul F Rosenberg, Irwin H D'Agostino, Ralph B Wilson, Peter W F Wolf, Philip A N-Engl-J-Med. 2002 February 14; 346(7): 476-83 1533-4406 •

Plasma membrane cholesterol controls the cytotoxicity of Alzheimer's disease AbetaP (1-40) and (1-42) peptides. Author(s): Department of Anatomy, Physiology and Genetics, and Institute for Molecular Medicine, Uniformed Services University School of Medicine, USUHS, Bethesda, Maryland 20814, USA. [email protected] Source: Arispe, N Doh, M FASEB-J. 2002 October; 16(12): 1526-36 15306860

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Prevention of Alzheimer's disease. Author(s): McGill Centre for Studies in Aging, 6825 Boul. LaSalle, Verdun, Quebec, Canada H4H 1R3. Source: Gauthier, S Ann-Med-Interne-(Paris). 1998 June; 149(4): 228-30 0003-410X

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Protein phosphatase 2A methylation: a link between elevated plasma homocysteine and Alzheimer's Disease. Author(s): Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. [email protected] Source: Vafai, Scott B Stock, Jeffry B FEBS-Lett. 2002 May 8; 518(1-3): 1-4 0014-5793

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Proton MR spectroscopic study at 3 Tesla on glutamate/glutamine in Alzheimer's disease. Author(s): BF Research Institute, Inc, National Cardiovascular Center, Suita, Osaka, Japan. Source: Hattori, Noriaki Abe, Kazuo Sakoda, Saburo Sawada, Tohru Neuroreport. 2002 January 21; 13(1): 183-6 0959-4965

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Regulation of the frontocortical sodium pump by Na+ in Alzheimer's disease: difference from the age-matched control but similarity to the rat model. Author(s): Department of Biochemistry, Tartu University, Ravila 19, Tartu, Estonia. Source: Kairane, C Roots, K Uusma, T Bogdanovic, N Karelson, E Koks, S Zilmer, M FEBS-Lett. 2002 Nov 6; 531(2): 241-4 0014-5793

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Relationship of calbindin D28K-immunoreactive cells and neuropathological changes in the hippocampal formation of Alzheimer's disease. Author(s): Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital, Setagaya, Japan. [email protected]

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Source: Iritani, S Niizato, K Emson, P C Neuropathology. 2001 September; 21(3): 162-7 0919-6544 •

Safety and efficacy of idebenone versus tacrine in patients with Alzheimer's disease: results of a randomized, double-blind, parallelgroup multicenter study. Author(s): Wilhelm Griesinger Hospital, Department of Gerontopsychiatry, Retzdorffpromenade 3, 12161 Berlin, Germany. [email protected] Source: Gutzmann, H Kuhl, K P Hadler, D Rapp, M A Pharmacopsychiatry. 2002 January; 35(1): 12-8 0176-3679

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Serum pentosidine as an indicator of Alzheimer's disease. Author(s): Service de Biochimie, Hopital Nord, CHU Saint-Etienne, SaintEtienne, France. Source: Meli, M Perier, C Ferron, C Parssegny, F Denis, C Gonthier, R Laurent, B Reynaud, E Frey, J Chamson, A J-Alzheimers-Dis. 2002 April; 4(2): 93-6 1387-2877

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Sustained improvement of cognition and global function in patients with moderately severe Alzheimer's disease: a double-blind, placebocontrolled study with the neurotrophic agent Cerebrolysin. Author(s): Gottingen University Clinic for Psychiatry, Gottingen, Federal Republic of Germany. Source: Ruether, E Alvarez, X A Rainer, M Moessler, H J-Neural-TransmSuppl. 2002; (62): 265-75 0303-6995

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Tacrine-huperzine A hybrids (huprines): a new class of highly potent and selective acetylcholinesterase inhibitors of interest for the treatment of Alzheimer's disease. Author(s): Laboratori de Quimica Farmaceutica, Facultat de Farmacia, Universitat de Barcelona, Av Diagonal 643, E-08028, Barcelona, Spain. [email protected] Source: Camps, P Munoz Torrero, D Mini-Rev-Med-Chem. 2001 July; 1(2): 163-74 1389-5575

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Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer's disease. Author(s): Department of Neurobiology, University of Osnabruck, 49076 Osnabruck, Germany. Source: Fath, T Eidenmuller, J Brandt, R J-Neurosci. 2002 November 15; 22(22): 9733-41 1529-2401

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The interaction of serum folate and estradiol levels in Alzheimer's disease. Author(s): Oxford Project To Investigate Memory and Ageing, University Department of Pharmacology, Radcliffe Infirmary, Oxford, United Kingdom. [email protected] Source: Hogervorst, E Smith, A D Neuroendocrinol-Lett. 2002 April; 23(2): 155-60 0172-780X

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The neuronal calcium sensor protein VILIP-1 is associated with amyloid plaques and extracellular tangles in Alzheimer's disease and promotes cell death and tau phosphorylation in vitro: a link between calcium sensors and Alzheimer's disease? Author(s): Research Institute for Applied Neuroscience, FAN GmbH, Magdeburg, Germany. Source: Schnurra, I Bernstein, H G Riederer, P Braunewell, K H Neurobiol-Dis. 2001 October; 8(5): 900-9 0969-9961

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The role of tau in Alzheimer's disease. Author(s): Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Maloney Building, 3rd Floor, HUP, Philadelphia, PA 19104, USA. [email protected] Source: Trojanowski, John Q Lee, Virginia M Y Med-Clin-North-Am. 2002 May; 86(3): 615-27 0025-7125

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The significance of environmental factors in the etiology of Alzheimer's disease. Author(s): 12 Sir Francis Wyatt Place, Newport News, VA 23606-3660, USA. [email protected] Source: Grant, W B Campbell, A Itzhaki, R F Savory, J J-Alzheimers-Dis. 2002 June; 4(3): 179-89 1387-2877

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The treatment of Alzheimer's disease: the approach from a clinical specialist in the trenches. Author(s): Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA. Source: Hake, A M Semin-Neurol. 2002 March; 22(1): 71-4 0271-8235

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The use of melatonin in Alzheimer's disease. Author(s): Departament of Physiology, Faculty of Medicine, University of Buenos Aires, Argentina. [email protected] Source: Cardinali, D P Brusco, L I Liberczuk, C Furio, A M Neuroendocrinol-Lett. 2002 April; 23 Suppl 1: 20-3 0172-780X

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The utility of muscarinic agonists in the treatment of Alzheimer's disease. Author(s): Department of Pharmacology, College of Pharmacy, The University of Toledo, OH 43606, USA. [email protected] Source: Messer, W S Jr J-Mol-Neurosci. 2002 Aug-October; 19(1-2): 187-93 0895-8696

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Treatment of Alzheimer's disease. New developments. Author(s): Department of Geriatrics, University Hospitals of Geneva, Geneva Medical School, Route de Mon-Idee, CH-1226 Thonex, Geneva. Source: Giacobini, E Michel, J P Ann-Med-Interne-(Paris). 1998 June; 149(4): 231-7 0003-410X

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What evidence would prove the amyloid hypothesis? Towards rational drug treatments for Alzheimer's disease. Author(s): Department of Pharmacology and Biochemistry, University of South Florida College of Medicine, Tampa FL 33612-4799, USA. [email protected] Source: Morgan, D Keller, R K J-Alzheimers-Dis. 2002 June; 4(3): 257-60 1387-2877

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What's new in Alzheimer's disease? Author(s): The Capstone Group, 3416 E. Winona Street, Phoenix, AZ 85044, USA. [email protected] Source: Long, C O Dougherty, J Home-Healthc-Nurse. 2003 January; 21(1): 8-14; quiz 15 0884-741X

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Your best bets for preventing Alzheimer's disease. Source: Anonymous Harv-Health-Lett. 2002 August; 27(10): 6 1052-1577

Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •

healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&pag e=0

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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov

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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov

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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/

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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/

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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/

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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/

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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/

Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats

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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html

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

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

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

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

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,,00.html

Vocabulary Builder The following vocabulary builder defines words used in the references in this chapter that have not been defined in previous chapters: Bernstein: A sensitive means of determining whether acid reflux is the

402 Alzheimer’s Disease

cause of pain, but may be falsely negative in the patient receiving treatment. [NIH]

Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH] Quinolinic: It is produced by immune cells and slowly infiltrates the brain tissues after an injury. [NIH] Spectroscopic: The recognition of elements through their emission spectra. [NIH]

Wound: Any interruption, by violence or by surgery, in the continuity of the external surface of the body or of the surface of any internal organ. [NIH]

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APPENDIX D. FINDING MEDICAL LIBRARIES Overview At a medical library you can find medical texts and reference books, consumer health publications, specialty newspapers and magazines, as well as medical journals. In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Before going to the library, highlight the references mentioned in this sourcebook that you find interesting. Focus on those items that are not available via the Internet, and ask the reference librarian for help with your search. He or she may know of additional resources that could be helpful to you. Most importantly, your local public library and medical libraries have Interlibrary Loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. NLM’s interlibrary loan services are only available to libraries. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.52

52

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

404 Alzheimer’s Disease

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)53: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

•

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

•

Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

•

California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

•

California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

•

California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

California: Health Library (Stanford University Medical Center), http://www-med.stanford.edu/healthlibrary/

53

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

Finding Medical Libraries 405

•

California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

•

California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

•

California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

•

California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

•

California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

•

California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

•

California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

•

Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

•

Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

•

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

•

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

•

Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health _info.cfm

•

Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

•

Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

•

Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

406 Alzheimer’s Disease

•

Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

•

Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

•

Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

•

Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

•

Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

•

Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

•

Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

•

Louisiana: Louisiana State University Health Sciences Center Medical Library-Shreveport, http://lib-sh.lsuhsc.edu/

•

Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

•

Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

•

Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

•

Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

•

Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

•

Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

•

Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

•

Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

Finding Medical Libraries 407

•

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

•

Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

•

Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

•

Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://medlibwww.bu.edu/library/lib.html

•

Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

•

Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

•

Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

•

Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

•

Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

•

Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

•

Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

•

Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

•

Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

•

Michigan: Sladen Library & Center for Health Information Resources Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

408 Alzheimer’s Disease

•

Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

•

National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

•

National: National Network of Libraries of Medicine (National Library of Medicine) - provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

•

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

•

Nevada: Health Science Library, West Charleston Library (Las VegasClark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

•

New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld

•

New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

•

New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

•

New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

•

New York: Choices in Health Information (New York Public Library) NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

•

New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

•

New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

•

New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

•

Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

Finding Medical Libraries 409

•

Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfhtulsa.com/services/healthinfo.asp

•

Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

•

Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

•

Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

•

Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

•

Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

•

Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

•

Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

•

Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

•

Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

•

South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

•

Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

•

Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

•

Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

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APPENDIX E. ALZHEIMER’S DISEASE: UNRAVELING THE MYSTERY Overview54 Over the past few decades, Alzheimer's disease has emerged from obscurity. Once considered a rare disorder, it is now seen as a major public health problem that has a severe impact on millions of older Americans and their families. Research on Alzheimer's disease has grown accordingly. The small group of pioneers who conducted research on the disease in the 1970s has expanded to thousands of scientists in laboratories and institutions all over the world. The lead agency for Alzheimer's research at the National Institutes of Health (NIH) is the National Institute on Aging (NIA), which launched its Alzheimer's disease program in 1978. Since then, the study of this disease has become one of NIA's top priorities. Several other NIH institutes also conduct and sponsor studies on Alzheimer's disease, including the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, and the National Institute of Nursing Research. In the private sector, the Alzheimer's Association, other voluntary organizations, and private industry are also working to combat this disease. They fund research, contribute to public policy decisions, inform and educate the public, and provide critical services to people with Alzheimer's disease and their families. Their support for research is critical in the effort to understand and defeat this disorder.

Adapted from the National Institute on Aging: http://www.niapublications.org/pubs/unraveling/index.asp.

54

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Thanks to these many groups, the study of Alzheimer's disease is moving ahead rapidly. This appendix explains what Alzheimer's disease is, describes what we have learned to date, and provides a glimpse into future directions for research.

Introduction Often, Mary was afraid, a nameless, shapeless fear. Her impaired mind could not put a name or an explanation to her fear. People came, memories came, and then they slipped away. She could not tell what was reality and what was memory of people past. The bathroom was not where it was yesterday. Dressing became an insurmountable ordeal....Mary gradually lost the ability to make sense out of what her eyes and ears told her....She worried about her things: a chair, and the china that had belonged to her mother. They said they had told her over and over, but she could not remember where her things had gone. Perhapssomeone had stolen them. She had lost so much.... Mary was glad when her family came to visit. Sometimes she remembered their names; more often she did not. She never remembered that they had come last week, so she regularly scolded them for abandoning her....She was glad when they didn't try to remind her of what she had just said or that they had come last week, or ask her if she remembered this person or that one. She liked it best when they just held her and loved her. This excerpt from The 36-Hour Day, a book for families and caregivers of people with Alzheimer's disease (AD) and other similar diseases, gives a glimpse into what an Alzheimer's patient might be thinking and feeling. The gradual slipping away of mind and memory is frightening and frustrating, both for the person with the disease and for family and friends. Not so long ago, we couldn't do much for Mary or others like her. Happily, that situation is changing. Thousands of scientists, voluntary organizations, health care professionals, and families are working hard to learn more about Alzheimer's. They are also finding ways to manage, treat, and eventually perhaps, prevent this terrible disease. Alzheimer's is an irreversible, progressive brain disease that slowly destroys memory and thinking skills, eventually even the ability to carry out the simplest tasks. Although the risk of developing AD increases with age — in most people with AD, symptoms first appear after age 60 — AD is not a part of normal aging. It is caused by a disease that affects the brain. In the absence of disease, the human brain often can function well into the tenth decade of life.

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The Impact of Alzheimer's Disease AD is the most common cause of dementia among people age 65 and older. Dementia is the loss of memory, reason, judgment, and language to such an extent that it interferes with a person's daily life and activities. It is not a disease itself, but a group of symptoms that often accompanies a disease or condition. AD is a major public health problem for the United States because it has such a huge impact on individuals, families, the health care system, and society. Scientists estimate that up to 4 million people now have AD. For every 5year age group beyond 65, the percentage of people with AD doubles. More than 34 million people are now age 65 or older. This number is 13 percent of the total population of the U.S. The percentage of people over age 65 will increase rapidly over the next few years as the "baby boom" generation reaches 65. In addition, the group of people over 85 - the group with the highest risk of Alzheimer's disease - is the fastest growing segment of the population. By 2050, 14 million older Americans are expected to have Alzheimer's disease if the current numbers hold and no preventive treatments become available. Slightly more than half of those with AD are cared for at home, while the rest are in different kinds of care facilities. A recent study estimated that the annual cost of caring for one person with AD in 1996 was between $18,400 and $36,100, depending on how advanced the disease was and whether or not the person wasat home. The cost of care has been steadily rising since then. The national cost of caring for people with AD is now thought to be about $100 billion every year. The cost of care is not only financial. Families, friends, and caregivers strugglewith great emotional and physical stress as they cope with the physical and mental changes in their loved ones. Caregivers must juggle many responsibilities and adjust to new and changing roles. As the disease gets worse and caring at home becomes increasingly difficult, family members face difficult decisions about longterm care. The number of caregivers - and their needs - will steadily grow as our population ages and the number of people with AD increases.

How Many New Cases of AD Were There in 1995? How Many New Cases May Occur in the Future? Researchers recently projected the number of new cases of AD that could occur every year over the next 50 years if current population trends continue

414 Alzheimer’s Disease

and no preventive treatments emerge. They estimate that the number of new cases every year will double between 1995 and 2050 - from 377,000 to 959,000. Two factors will combine to cause this large increase: •

The fact that the risk of AD increases as people get older.

•

The growing numbers of older people, especially those over 85.

•

The annual number of new cases will begin to climb sharply around the year 2040, when all the baby boomers will be over 65.

Where Are People with Alzheimer's Disease Cared For? •

Home

•

Assisted living facilities (those in the early stages)

•

Nursing homes

•

Special care units

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A Walking Tour Through the Brain The brain is a remarkable organ. Seemingly without any effort, it allows us to carry out every element of our daily lives. It manages many of the body functions that happen without our knowledge or direction, such as breathing, blood circulation, and digestion. It also directs all the functions we carry out consciously. We can speak, move, see, remember, feel emotions, and make decisions because of the complicated mix of chemical and electrical processes that take place in our brains. Our brains are made of nerve cells and lots of other cell types. Nerve cells are also called neurons. The neurons of all animals function in basically the same way, even though animals can be very different from each other. What sets people apart from other animals is the huge number of nerve cells we have in the cerebral cortex, regions of which are proportionally much larger in humans than in any other animals. These regions are the parts of the brain where cognitive functions, like thinking, learning, speaking, remembering, and making decisions, take place. The many interconnections among the nerve cells in these regions also make us different from other animals. To understand Alzheimer's disease, it's important to know a bit about the brain. Part 1 of Unraveling the Mystery first gives an inside view of the normal brain, how it works, and what happens during aging. Then, it shows what happens to the brain in Alzheimer's and how the disease slowly destroys a person's mental and physical capacities.

The Brain's Vital Statistics •

Adult weight: about 3 pounds

•

Adult size: a medium cauliflower

•

Number of neurons: 100,000,000,000 (1 billion)

•

Number of synapses (the gap between neurons): 100,000,000,000,000 (100 trillion)

416 Alzheimer’s Disease

Inside the Human Brain

The Three Main Players •

The cerebral hemispheres accounts for 85 percent of the brain's weight. The billions of neurons in the two hemispheres are connected by a thick bundle of nerves called the corpus callosum. Scientists now think that the two hemispheres differ not so much in what they focus on (the "logical versus artistic" notion), but how they process information. The left hemisphere appears to focus on the details (such as recognizing a particular face in a crowd). The right hemisphere focuses on the broad background (such as understanding the relative position of objects in a

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space). The cerebral hemispheres have an outer layer called the cerebral cortex. This is where the brain processes sensory information received from the outside world, controls voluntary movement, and regulates conscious thought and mental activity. •

The cerebellum takes up a little more than 10 percent of the brain. It's in charge of balance and coordination. The cerebellum also has two hemispheres. They are always receiving information from the eyes, ears, and muscles and joints about the body's movements and position. Once the cerebellum processes the information, it works through the rest of the brain and spinal cord to send out instructions to the body. The cerebellum's work allows us to walk smoothly, maintain our balance, and turn around without even thinking about it.

•

The brain stem sits at the base of the brain. It connects the spinal cord with the rest of the brain. Even though it's the smallest of the three main players, its functions are crucial to survival. The brain stem controls the functions that happen automatically to keep us alive - our heart rate, blood pressure, and breathing. It also relays information between the brain and the spinal cord, which then sends out messages to the muscles, skin, and other organs. Sleep and dreaming are also controlled by the brain stem.

Other Crucial Parts Several other essential parts of the brain lie deep inside the cerebral hemispheres: •

The limbic system links the brain stem with the higher reasoning elements of the cerebral cortex. It controls emotions and instinctive behavior. This is also where the sense of smell is located.

•

The hippocampus is important for learning and short-term memory. This part of the brain is considered to be the site where short-term memories are converted into long-term memories for storage in other brain areas.

•

The thalamus receives sensory and limbic information, processes it, and then sends it to the cerebral cortex.

•

The hypothalamus is a structure under the thalamus that monitors activities like body temperature and food intake. It issues instructions to correct any imbalances. The hypothalamus also controls the body's internal clock.

418 Alzheimer’s Disease

The Brain in Action New imaging techniques allow scientists to monitor brain function in living people. This is opening up worlds of knowledge about normal brain function and how it changes with age or disease. One of these techniques is called positron emission tomography, or PET scanning. PET scans measure blood flow and glucose metabolism throughout the brain. When nerve cells in a region of the brain become active, blood flow and metabolism in that region increase. These increases are usually shown as red and yellow colors on a PET scan. Shades of blue and black indicate decreased or no activity within a brain region. In essence, a PET scan produces a "map" of the active brain. Scientists use PET scans to see what happens in the brain when a person is engaged in a physical or mental activity, at rest, or even sleeping or dreaming. Scientists can also inject chemicals tagged with a tracer that will "light up" on PET scans. These tracers can track the activity of brain chemicals, for example neurotransmitters such as dopamine and serotonin. Some of these neurotransmitters are altered with age, disease, and drug treatment.

The Aging Brain As a person gets older, changes occur in all parts of the body, including the brain: Some neurons shrink, especially large ones in areas important to learning, memory, planning, and other complex mental activities. Tangles and plaques develop in neurons and surrounding areas, though in much smaller amounts than in AD. Damage by free radicals increases (free radicals are a kind of molecule that reacts easily with other molecules; see the section Oxidative Damage from Free Radicals for more on these molecules).

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What is the impact of these changes? Healthy older people may notice a modest decline in their ability to learn new things and retrieve information, such as remembering names. They may perform worse on complex tasks of attention, learning, and memory. However, if given enough time to perform the task, the scores of healthy people in their 70s and 80s are often the same as those of young adults. As they age, adults often improve their vocabulary and other forms of verbal knowledge.

Neurons and Their Jobs The human brain is made up of billions of neurons. Each has a cell body, an axon, and many dendrites. The cell body contains a nucleus, which controls all of the cell's activities, and several other structures that perform specific functions. The axon, which is much, much narrower than the width of a human hair, extends out from the cell body and transmits messages to other neurons. Sometimes, the messages have to travel over very long distances (even up to 5 feet!). Dendrites also branch out from the cell body. They receive messages from the axons of other nerve cells. Each nerve cell is connected to thousands of other nerve cells through its axon and dendrites. Neurons are surrounded by glial cells, which support, protect, and nourish them. Groups of neurons in the brain have special jobs. For example, some are involved with thinking, learning, and memory. Others are responsible for receiving sensory information. Still others communicate with muscles, stimulating them into action.

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Several processes all have to work smoothly together for neurons to survive and stay healthy. These processes are communication, metabolism, and repair.

Communication: Sending Millions of Messages a Second Imagine the telecommunication cables that run under our streets. All day and night, millions of telephone calls are flashing down fiber optic cables at incredible speeds, letting people strike deals, give instructions, share a laugh, or learn some news. Multiply that many-fold and that's the brain. Neurons are the great communicators, always in touch with their neighbors. As a neuron receives messages from surrounding cells, an electrical charge, or nerve impulse, builds up. This charge travels down the axon until it reaches the end. Here, it triggers the release of chemical messengers called neurotransmitters, which move from the axon across a tiny gap to the dendrites or cell bodies of other neurons. The typical neuron has up to 15,000 of these tiny gaps, or synapses. After they move across the synapse, neurotransmitters bind to specific receptor sites on the receiving end of dendrites of the nearby neurons. They can also bind directly to cell bodies. Once the receptors are activated, they open channels through the cell membrane into the receiving nerve cell's interior or start other processes that determine what the receiving nerve cell will do. Some neurotransmitters inhibit nerve cell function (that is, they make it less likely that the nerve cell will send an electrical signal down its axon). Other neurotransmitters stimulate nerve cells; they prime the receiving cell to become active or send an electrical signal down the axon to more neurons in the pathway.

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Repair: Keeping Long-lived Neurons in Good Working Order Unlike most cells, which have a fairly short lifespan, nerve cells, which are generated in the fetus or a short time after birth, live a long time. Brain neurons can live for up to 100 years or longer. In an adult, when neurons die because of disease or injury, theyare not usually replaced. Recent research, however, shows that in a few brain regions, new neurons can be born, even in the old brain. To prevent their own death, living neurons must constantly maintain and remodel themselves. If cell cleanup and repair slows down or stops for any reason, the nerve cell cannot function well. Eventually, it dies.

422 Alzheimer’s Disease

This figure shows the effects of exercise on levels of brain-derived neurotrophic factor (BDNF) in the hippocampus of rats. Growth factors like BDNF help many neurons survive. Levels of the message that makes BDNF are much higher in exercising rats (a) than in sedentary animals (b). Exercise may promote healthy neurons in rats by causing their neurons to make more protective BDNF. Red and yellow denote the highest levels of BDNF, while green and blue denote the lowest.

Plaques and Tangles: The Hallmarks of AD Alzheimer's disease disrupts each of the three processes that keep neurons healthy: communication, metabolism, and repair. This disruption causes certain nerve cells in the brain to stop working, lose connections with other nerve cells, and finally, die. The destruction and death of nerve cells causes the memory failure, personality changes, problems in carrying out daily activities, and other features of the disease. The brains of AD patients have an abundance of two abnormal structures beta amyloid plaques and neurofibrillary tangles. This is especially true in

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certain regions of the brain that are important in memory. Plaques are dense, mostly insoluble (cannot be dissolved) deposits of protein and cellular material outside and around the neurons. Tangles are insoluble twisted fibers that build up inside the nerve cell. Though many older people develop some plaques and tangles, the brains of AD patients have them to a much greater extent. Scientists have known about plaques and tangles for many years, but recent research has shown much about what they are made of, how they form, and their possible roles in AD.

Amyoloid Plaques Plaques are made of beta-amyloid, a protein fragment snipped from a larger protein called amyloid precursor protein (APP). These fragments clump together and are mixed with other molecules, neurons, and non-nerve cells. In AD, plaques develop in the hippocampus, a structure deep in the brain that helps to encode memories, and in other areas of the cerebral cortex that are used in thinking and making decisions. We still don't know whether beta-amyloid plaques themselves cause AD or whether they are a by-product of the AD process. We do know that changes in APP structure can cause a rare, inherited form of AD (see the section Genes and Early-Onset Alzheimer's Disease for more on inherited AD).

From APP to Beta-Amyloid APP is a protein that appears to be important in helping neurons grow and survive. APP may help damaged neurons repair themselves and may help parts of neurons grow after brain injury. In AD, something causes APP to be snipped into fragments, one of which is called beta-amyloid; the betaamyloid fragments eventually clump together into plaques. APP is associated with the cell membrane, the thin barrier that encloses the cell. After it is made, APP sticks through the neuron's membrane, partly inside and partly outside the cell. Enzymes (substances that cause or speed up a chemical reaction) act on the APP and cut it into fragments of protein, one of which is called beta-amyloid. The beta-amyloid fragments begin coming together into clumps outside the cell, then join other molecules and non-nerve cells to form insoluble plaques.

424 Alzheimer’s Disease

APP is associated with the cell membrane, the thin barrier that encloses the cell. After it is made, APP sticks through the neuron's membrane, partly inside and partly outside the cell.

Enzymes (substances that cause or speed up a chemical reaction) act on the APP and cut it into fragments of protein, one of which is called beta-amyloid.

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The beta amyloid fragments begin coming together into clumps outside the cell, then join other molecules and non-nerve cells to form insoluable plaques.

Neurofibrillary Tangles Healthy neurons have an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell down to the ends of the axon and back. A special kind of protein, tau, makes the microtubules stable. In AD, tau is changed chemically. It begins to pair with other threads of tau and they become tangled up together. When this happens, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in communication between neurons and later in the death of the cells.

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The Changing Brain in Alzheimer's Disease No one knows exactly what causes the Alzheimer's disease process to begin or why some of the normal changes associated with aging become so much more extreme and destructive in patients with the disease. We do know a lot, however, about what happens in the brain once AD takes hold and about the physical and mental changes that occur over time. The time from diagnosis to death varies - as little as 3 years if the patient is over 80 when diagnosed, as long as 10 or more years if the patient is younger. Although the course of AD is not the same in every patient, symptoms seem to develop over the same general stages.

PET Scan of Normal Brain

Preclinical AD

PET Scan of Alzheimer's Disease Brain

Mild to Moderate AD

Severe AD

Preclinical AD AD begins in the entorhinal cortex, which is near the hippocampus and has direct connections to it. It then proceeds to the hippocampus, the structure that is essential to the formation of short-term and long-term memories. Affected regions begin to atrophy (shrink). These brain changes probably start 10 to 20 years before any visible signs and symptoms appear. Memory loss, the first visible sign, is the main feature of mild cognitive impairment (MCI) (see the section Criteria for "Probable" Alzheimer's Disease for more

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on MCI). Many scientists think MCI is often an initial, transitional phase between normal brain aging and AD.

Mild AD As the disease begins to affect the cerebral cortex, memory loss continues and changes in other cognitive abilities emerge. The clinical diagnosis of AD is usually made during this stage. Signs of mild AD can include: •

Memory loss

•

Confusion about the location of familiar places (getting lost begins to occur)

•

Taking longer to accomplish normal daily tasks

•

Trouble handling money and paying bills

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Poor judgment leading to bad decisions

•

Loss of spontaneity and sense of initiative

•

Mood and personality changes, increased anxiety

The growing number of plaques and tangles first damage areas of brain that control memory, language, and reasoning. It is not until later in the disease that physical abilities decline. This leads to a situation in mild AD in which a person seems to be healthy, but is actually having more and more trouble making sense of the world around him or her. The realization that something

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is wrong often comes gradually because the early signs can be confused with changes that can happen normally with aging. Accepting these signs and deciding to go for diagnostic tests can be a big hurdle for patients and families to cross.

Moderate AD By this stage, AD damage has spread further to the areas of the cerebral cortex that control language, reasoning, sensory processing, and conscious thought. Affected regions continue to atrophy and signs and symptoms of the disease become more pronounced and widespread. Behavior problems, such as wandering and agitation, can occur. More intensive supervision and care become necessary, and this can be difficult for many spouses and families. The symptoms of this stage can include: •

Increasing memory loss and confusion

•

Shortened attention span

•

Problems recognizing friends and family members

•

Difficulty with language; problems with reading, writing, working with numbers

•

Difficulty organizing thoughts and thinking logically

•

Inability to learn new things or to cope with new or unexpected situations

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•

Restlessness, agitation, anxiety, tearfulness, wandering - especially in the late afternoon or at night

•

Repetitive statements or movement, occasional muscle twitches

•

Hallucinations, delusions, suspiciousness or paranoia, irritability

•

Loss of impulse control (shown through sloppy table manners, undressing at inappropriate times or places, or vulgar language)

•

Perceptual-motor problems (such as trouble getting out of a chair or setting the table)

Behavior is the result of complex brain processes, all of which take place in a fraction of a second in the healthy brain. In AD, many of these processes are disturbed, and this is the basis for many distressing or inappropriate behaviors. For example, a person may angrily refuse to take a bath or get dressed because he does not understand what his caregiver has asked him to do. If he does understand, he may not remember how to do it. The anger is a mask for his confusion and anxiety. Or, a person with AD may constantly follow her husband or caregiver and fret when the person is out of sight. To a person who cannot remember the past or anticipate the future, the world around her can be strange and frightening. Sticking close to a trusted and familiar caregiver may be the only thing that makes sense and provides security. Taking off clothes may seem reasonable to a person with AD who feels hot and doesn't understand or remember that undressing in public is not acceptable.

Severe AD In the last stage of AD, plaques and tangles are widespread throughout the brain, and areas of the brain have atrophied further. Patients cannot recognize family and loved ones or communicate in any way. They are completely dependent on others for care. All sense of self seems to vanish. Other symptoms can include: •

Weight loss

•

Seizures, skin infections, difficulty swallowing

•

Groaning, moaning, or grunting

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Increased sleeping

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Lack of bladder and bowel control

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At the end, patients may be in bed much or all of the time. Most people with AD die from other illnesses, frequently aspiration pneumonia. This type of pneumonia happens when a person is not able to swallow properly and breathes food or liquids into the lungs.

Then and Now: the Fast Pace of Development in AD Research What We Didn't Know Then 15 years ago •

We didn't know any of the genes that could cause AD.

•

We had no idea of the biological pathways that were involved in the development of damage to the brain in AD.

10 years ago •

We couldn't model the disease in animals

5 years ago •

NIH did not fund any prevention clincial trials.

•

We had no way to identify people at high risk of developing AD.

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1 year ago •

We didn't understand anything about how plaques and tangles relate to each other.

What We Know Now (2002) •

We know the 3 major genes for early-onset AD adn 1 of the major risk factor genes for late-onset AD.

•

We know a lot about the pathways that lead to the development of betaamyloid plaques in the brain — one of the main features of AD.

•

Scientists have developed special kinds of mice that produce betaamyloid plaques.

•

NIH is funding clinical trials that are looking at possible ways to prevent AD.

•

We can identify individuals at high risk through neuropsychological tests, and structured interviews.

•

By developing another kind of mice that have both plaques and tangles, we now know that plaques can influence the development of tangles.

imaging,

The Search for Causes One of the most important parts of unraveling the AD mystery is finding out what causes the disease. What makes the disease process begin in the first place? What makes it worse over time? Why does the number of people with the disease increase with age? Why does one person develop it and another remain healthy? Some diseases, like measles or pneumonia, have clear-cut causes. They can be prevented with vaccines or cured with antibiotics. Others, such as diabetes or arthritis, develop when genetic, lifestyle, and environmental factors work together to cause a disease process to start. The importance of each one of these factors may be different for each individual. AD fits into this second group of diseases. We don't yet fully understand what causes AD, but we know it develops because of a complex series of events that take place in the brain over a long period of time. Many studies are exploring the factors involved in the cause and development of AD.

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Genetic Factors at Work in AD In the last few years, painstaking detective work by scientists has paid off in discoveries of genetic links to the two main types of AD. One type is the more rare, early-onset Alzheimer's disease. It usually affects people aged 30 to 60. Some cases of early-onset disease are inherited and are called familial AD (FAD). The other is late-onset Alzheimer's disease. It is the most common form and occurs in those 65 and older

DNA, Chromosomes, and Genes: The Body's Amazing Control Center The nucleus of almost every human cell contains a vast chemical information database. This database carries all the instructions the cell needs to do its job. This database is DNA. DNA exists as two long, intertwined, thread-like strands packaged in units called chromosomes. Each cell has 46 chromosomes in 23 pairs. Chromosomes are made up of four chemicals, or bases, arranged in various sequence patterns. People inherit material in each chromosome from each parent. Each chromosome has many thousands of segments, called genes. The sequence of bases in a gene tells the cell how to make specific proteins. Proteins determine the physical characteristics of living organisms. They also direct almost every aspect of the organism's construction, operation, and repair. Even slight alterations in a gene can produce an abnormal protein, which, in turn, can lead to cell malfunction, and eventually, to disease. Any rare change in a gene's DNA that causes a disease is called a mutation. Other more common (or frequent) changes in a gene's DNA don't automatically cause disease, but they can increase the chances that a person will develop a particular disease. When this happens, the changed gene is called a genetic risk factor.

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Genes and Early-Onset Alzheimer's Disease Over the past several decades, researchers working on AD realized that some cases, particularly of early-onset AD, ran in families. This led them to examine DNA samples from such families to see whether they had some genetic trait in common. Chromosomes 21, 14, and 1 became the focus of attention. The scientists found that some families have a mutation in selected genes on these chromosomes. On chromosome 21, the mutation causes an abnormal amyloid precursor protein (APP) to be produced. On chromosome 14, the mutation causes an abnormal protein called presenilin 1 to be produced. On chromosome 1, the mutation causes yet another abnormal protein to be produced. This protein, called presenilin 2, is very similar to presenilin 1. Even if only one of these genes inherited from a parent contains a mutation, the person will almost inevitably develop early-onset AD. This means that in these families, children have about a 50-50 chance of developing the disease if one of their parents has it. Even though early-onset AD is very rare and mutations in these three genes do not play a role in the more common late-onset AD, these findings were crucial because they showed that genetics was indeed a factor in AD, and they helped to identify some key players in the AD disease process. Importantly, they showed that mutations in APP can cause AD, highlighting the key role of beta-amyloid in the disease. Many scientists believe that

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mutations in each of these genes cause an increased amount of the damaging beta-amyloid to be made in the brain. The findings also laid the foundation for many other studies that have pushed back the boundaries of our knowledge and created new possibilities for future treatment. For example, in the last several years, a series of highly sophisticated experiments have shown that presenilin may actually be one of the enzymes (substances that cause or speed up a chemical reaction) that clips APP to form beta-amyloid (the protein fragment that is the main component of AD plaques). This discovery has helped clarify how presenilins might be involved in the early stages of AD. It has also given scientists crucial new targets for drug therapy and has spurred many new studies in the test tube, in animals, and even in people.

A Different Genetic Story in Late-Onset Alzheimer's Disease While some scientists were focused on the role of chromosomes 21, 14, and 1 in early-onset AD, others were looking elsewhere to see if they could find genetic clues for the late-onset form. By 1992, these investigators had narrowed their search to a region of chromosome 19. At the same time, other colleagues were looking for proteins that bind to beta-amyloid. They were hoping to clarify some of the steps in the very early stages of the disease process. They found that one form of a protein called apolipoprotein E (ApoE) did bind quickly and tightly to beta-amyloid. They also found that the gene that produces ApoE was located in the same region of chromosome 19 pinpointed by the geneticists. This finding led them to suggest that one form of this gene was a risk factor for late-onset Alzheimer's disease. Other studies since then have shown that the gene that produces ApoE comes in several forms, or alleles - e2, e3, and e4. The APOE e2 allele is relatively rare and may provide some protection against the disease. If AD does occur in a person with this allele, it develops later in life. APOE e3 is the most common allele. Researchers think it plays a neutral role in AD. APOE e4 occurs in about 40 percent of all AD patients who develop the disease in later life. It is not limited to people whose families have a history of AD, though. AD patients with no known family history of the disease are also more likely to have an APOE e4 allele than persons who do not have AD. Dozens of studies have confirmed that the APOE e4 allele increases the risk of developing AD. These studies have also helped to explain some of the variation in the age at which AD develops. However, inheriting an APOE e4 allele doesn't mean that a person will definitely develop AD. Some people

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with one or two APOE e4 alleles never get the disease and others who do develop AD do not have any APOE e4 alleles. Although we still don't exactly know how APOE e4 increases AD risk, one theory is that when its protein product binds quickly and tightly to betaamyloid, the normally soluble amyloid becomes insoluble. This may mean that it is more likely to be deposited in plaques. While scientists are working to understand more fully the APOE gene and its role in AD, they have also identified regions on other chromosomes that might contain genetic risk factors. For example, in 2000, three teams of scientists, using three different strategies, published studies showing that chromosome 10 has a region that may contain several genes that might increase a person's risk of AD. Identifying these genes is one important step in the research process that will lead to new understanding about the ways in which changes in protein structures cause the disease process to begin and the sequence of events that occurs as the disease develops. Once they understand these processes, scientists can search for new ways to diagnose, treat, or even prevent AD.

Other Factors at Work in AD Even if genetics explains some of what might cause AD, it doesn't explain everything. So, researchers have looked at other possibilities that may reveal how the Alzheimer's disease process starts and develops.

Beta-Amyloid We still don't know whether beta-amyloid plaques cause AD or whether they are a by-product of the disease process. We do know, however, that forming beta-amyloid from APP is a key process in AD. That's why finding out more about beta-amyloid is an important avenue of ongoing AD research. Investigators are studying: •

The nature of beta-amyloid

•

Ways in which it is toxic to neurons

•

Ways in which plaques form and are deposited

•

Ways in which beta-amyloid and plaques might be reduced in the brain

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Tau In the last few years, scientists have been giving an increasing amount of attention to tau, the other hallmark of Alzheimer's disease. This protein is commonly found in nerve cells throughout the brain. In AD, tau undergoes changes that cause it to gather together abnormally in tangled filaments in neurons (for more on this, see the section A Walking Tour Through the Brain). In studying tau and what can go wrong, investigators have found that tau abnormalities are also central to other rare neurodegenerative diseases. These diseases, called tauopathies, include frontotemporal dementia, Pick's disease, supranuclear palsy, and corticobasal degeneration. They share a number of characteristics, but also each have distinct features that set them apart from each other and from AD. Characteristic signs and symptoms include changes in personality, social behavior, and language ability; difficulties in thinking and making decisions; poor coordination and balance; psychiatric symptoms; and dementia. Recent advances include the discovery of mutations in the tau gene that cause one tauopathy called frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). The development of several mouse models that produce tau tangles, will allow researchers to address the many questions that remain about these diseases. The development of a "double transgenic" mouse that has both tau tangles and beta-amyloid plaques will also lead to further insights about AD.

Cardiovascular Risk Factors Several recent studies in populations have found a possible link between factors related to cardiovascular disease and AD. One of these studies found that elevated levels of an amino acid called homocysteine, a risk factor for heart disease, are associated with an increased risk of developing AD. The relationship between AD and homocysteine is particularly interesting because blood levels of homocysteine can be reduced by increasing intake of folic acid and vitamins B6 and B12. In fact, in other studies, scientists have shown that folic acid may protect against nerve cell loss in brain regions affected by AD. Investigators have also found that the use of statins, the most common type of cholesterol-lowering drugs, is associated with a lower risk of developing AD.

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Oxidative Damage from Free Radicals Another promising area of investigation relates to a longstanding theory of aging. This theory suggests that over time, damage from a kind of molecule called a free radical can build up in neurons, causing a loss in function. Free radicals can help cells in certain ways, such as fighting infection. However, too many can injure cells because they are very active and can readily change other nearby molecules, such as those in the neuron's cell membrane or in DNA. The resulting molecules can set off a chain reaction, releasing even more free radicals that can further damage neurons. This kind of damage is called oxidative damage. It may contribute to AD by upsetting the delicate machinery that controls the flow of substances in and out of the cell. The brain's unique characteristics, including its high rate of metabolism and its long-lived cells, may make it especially vulnerable to oxidative damage over the lifespan. Some epidemiological and laboratory studies suggest that antioxidants from dietary supplements or food may provide some protection against developing AD. Other studies suggest that low calorie diets may protect against the development of AD by slowing down metabolic rates.

Inflammation Another set of hints about the causes of AD points to inflammation in the brain. This process is part of the immune system and helps the body react to injury or disease. Fever, swelling, pain, or redness in other parts of the body are often signs of inflammation. Because cells and compounds that are known to be involved in inflammation are found in AD plaques, some researchers think it may play a role in AD. They disagree, though, on whether inflammation is a good or a bad thing. Some think it is harmful - that it sets off a vicious cycle of events that ultimately causes neurons to die. Evidence from many studies supports this idea. Other scientists believe that some aspects of the inflammatory process may be helpful - that they are part of a healing process in the brain. For example, certain inflammatory processes may play a role in combating the accumulation of plaques. Many studies are now underway to examine the different parts of the inflammatory process more fully and their effects on AD.

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Brain Infarction We've all heard the sensible advice about ways to live a long and healthy life: eat right, exercise, don't smoke, wear a seat belt. All of these habits can help prevent heart attacks, stroke, and injuries. This advice may even have some relevance for AD as well. Results from one long-term study of aging and AD show that participants who had evidence of stroke in certain brain regions had more symptoms of dementia than could be explained by the number of plaques and tangles in their brain tissue. These findings suggest that damage to blood vessels in the brain may not be enough to cause AD, but that it could make AD clinical symptoms worse.

New Techniques Help in Diagnosing AD A healthy man in his early 60s begins to notice that his memory isn't as good as it used to be. More and more often, a word will be on the tip of his tongue but he just can't remember it. He forgets appointments, makes mistakes when paying his bills, and finds that he's often confused or anxious about the normal hustle and bustle of life around him. One evening, he suddenly finds himself walking in a neighborhood a couple of miles from his house. He has no idea how he got there. Not so long ago, this man's condition would have been swept into a broad catch-all category called "senile dementia" or "senility." Today, the picture is very different. We now know that Alzheimer's and other illnesses with dementia are distinct diseases. Armed with this knowledge, we have rapidly improved our ability to accurately diagnose AD. We are still some distance from the ultimate goal - a reliable, valid, inexpensive, and early diagnostic marker - but experienced physicians now can diagnose AD with up to 90 percent accuracy. Early diagnosis has several advantages. For example, many conditions cause symptoms that mimic those of Alzheimer's disease. Finding out early that the problem isn't AD but is something else can spur people into getting treatment for the real condition. For the small percentage of dementias that are treatable or even reversible, early diagnosis increases the chances of successful treatment. Even when the cause of the dementia turns out to be Alzheimer's disease, it's good to find out sooner rather than later. One benefit is medical. The drugs now available to treat AD can help some people maintain their mental abilities for months to years, though they do not change the underlying

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course of the disease (see the section Helping People with AD Maintain their Mental Functioning for more on these drugs). Other benefits are practical. The sooner the person with AD and family know, the more time they have to make future living arrangements, handle financial matters, establish a durable power of attorney, deal with other legal issues, create a support network, or even make plans to join a research study. Being able to participate for as long as possible in making decisions about the present and future is important to many people with AD. Finally, scientists also see advantages to early diagnosis. Developing tests that can reveal what is happening in the brain in the early stages of Alzheimer's disease will help them understand more about the cause and development of the disease. It will also help scientists learn when and how to start drugs and other treatments so that they can be most effective. Scientists are now exploring ways to help physicians diagnose AD earlier and more accurately. For example, some studies are focusing on changes in personality and mental functioning. These changes can be measured through memory and recall tests. Tests that measure a person's abilities in areas such as abstract thinking, planning, and language can also help pinpoint changes in function. Researchers are working hard to improve these standardized tests so that they can better track the changes that might point to early AD or predict which individuals are at higher risk of developing AD in the future. Other studies are examining the relationship between early damage to brain tissue and outward clinical signs. Still others are looking for changes in blood chemistry that might indicate the progression of Alzheimer's disease. One of the most exciting areas of ongoing research in this area is neuroimaging. Over the last decade, scientists have developed several highly sophisticated imaging systems that have been used in many areas of medicine, including Alzheimer's disease. Positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) are all examples. These "windows" on the living brain can help scientists measure the earliest changes in brain function or structure in order to identify those people who are at the very first stages of the disease - even before they develop signs and symptoms. These types of scans are still primarily research tools, but one day, neuroimaging might be used more commonly to help physicians diagnose AD early. These tools may even be used someday to monitor the progress of the disease and assess patient responses to drug treatment.

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Current Tools for Diagnosing AD A definitive diagnosis of Alzheimer's disease is still only possible after death, during an autopsy, when the plaques and tangles can actually be seen. But with the tools now available, experienced physicians can be pretty confident about making an accurate diagnosis in a living person. Here's how they do it. They take a detailed patient history, including: •

A description of how and when symptoms developed

•

A description of the patient's and his or her family's overall medical condition and history

•

An assessment of the patient's emotional state and living environment

They get information from family members or close friends: •

People close to the patient can provide valuable insights into how behavior and personality have changed; many times, family and friends know something is wrong even before changes are evident on tests.

They conduct physical and neurological examinations and laboratory tests: •

Blood and other medical tests help determine neurological functioning and identify possible non-AD causes of dementia.

They do a computerized tomography (CT) scan or a magnetic resonance imaging (MRI) test: •

Brain scans like these can detect strokes or tumors or can reveal changes in the brain's structure and function that indicate early AD.

They conduct neuropsychological testing: •

Q&A tests or other tasks that measure memory, language skills, ability to do arithmetic, and other abilities related to brain functioning help indicate what kind of cognitive changes are occurring.

Criteria for "Probable" Alzheimer's Disease Because no simple and reliable biological test for AD is available, the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Association together established criteria to help

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physicians diagnose AD. These criteria also help physicians distinguish between AD and other forms of dementia. "Probable" Alzheimer's disease is determined when a person has: •

Dementia confirmed by clinical and neuropsychological examination

•

Progressive worsening of memory and other mental functioning

•

No disturbances of consciousness (no "blacking out")

•

Symptoms beginning between ages 40 and 90

•

No other disorders that might account for the dementia

As they get older, some people develop a memory deficit greater than that expected for their age. However, other aspects of cognition are not affected, so these people do not meet all the accepted criteria for AD. Thus, they are said to have "mild cognitive impairment" (MCI). About 40 percent of these individuals will develop AD within 3 years. Others, however, do not seem to progress to AD, at least in the time frame studied thus far (up to approximately 6 years). Understanding more about the characteristics and development of MCI is essential in helping clinicians diagnose early stages of AD.

The Search for New Treatments Research over the last two decades has revealed many pieces of the Alzheimer's disease puzzle. Using recent advances in genetics and molecular biology, scientists have begun to put these pieces into place. In doing so, they've vastly increased our understanding of AD and opene many avenues that could lead to effective treatments. It has become clear that there probably isn't a "magic bullet" that will, by itself, prevent or cure AD. However, scientists may be able to identify a number of interventions that can be used to reduce risk and treat the disease. Today, it is estimated that the National Institute on Aging, other NIH Institutes, and private industry are conducting clinical trials (studies involving humans that rigorously test how well an intervention works) on around 30 compounds that may be active against AD. These studies focus on three main areas: •

Helping people with AD maintain their mental functioning

•

Slowing the progress of AD, delaying its onset, or preventing it

•

Managing symptoms

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Helping People with AD Maintain Their Mental Functioning In the mid-1970s, scientists discovered that levels of a neurotransmitter called acetylcholine fell sharply in people with Alzheimer's disease (see the section A Walking Tour Through the Brain for more on neurotransmitters). This discovery was one of the first that linked AD with biochemical changes in the brain. Since then, scientists have conducted hundreds of studies on acetylcholine. They have found that acetylcholine is important for several reasons. It is a critical player in the process of forming memories. It is also commonly used by neurons in the hippocampus and cerebral cortex - two regions devastated by AD. These findings led naturally to the idea that increasing levels of acetylcholine, replacing it, or slowing its breakdown could stop the disease. The Food and Drug Administration (FDA) has approved four medications for the treatment of mild to moderate AD symptoms. The first, tacrine (Cognex), has been replaced by three newer drugs - donepezil (Aricept), rivastigmine (Exelon), and galantamine (Reminyl). All act by stopping or slowing the action of acetylcholinesterase, an enzyme that normally breaks down acetylcholine. These drugs improve some patients' ability to carry out activities of daily living, such as eating and dressing. The drugs also help with behavioral symptoms, such as delusions and agitation, and can also improve thinking, memory, and speaking skills. However, these medications will not stop or reverse AD and appear to help patients only for months to a few years. Helping people with AD carry out their daily lives and maintain their mental abilities is one of the most important goals of AD treatment research. Many investigators are working to develop new and better drugs that can preserve this critical function for as long as possible.

Slowing, Delaying, or Preventing Alzheimer's Disease Understanding all the steps involved in the development of AD - from beginning to end - is important in and of itself. It also can have a big payoff down the road, for if we have this knowledge we might be able to develop drugs that slow, delay, or even prevent the disease process. That's the thinking behind this area of AD treatment research.

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For example, estrogen is a hormone produced by a woman's ovaries during her childbearing years. Over the past 25 years, animal studies have suggested that estrogen has some positive effects on memory function. Some human studies have supported this notion. Estrogen also has other effects that may be important in AD. These findings have created scientific interest in the relationship among estrogen, memory, and cognitive function. Several recent studies have examined the effects of estrogen in post-menopausal women with mild to moderate AD. None of them found that estrogen had a helpful effect on women who already have AD. We still don't know whether normally aging women who take estrogen or combined estrogen/progestin after menopause will be protected from developing AD or age-related cognitive decline. The NIA is supporting a clinical trial on cognitively normal older women with a family history of dementia to see whether taking estrogen can prevent or delay the development of AD. A recent clinical trial showed that combined estrogen/progestin therapy taken over a certain period of time has negative effects on heart disease and some cancers. However, the risk of the women in the estrogen AD prevention trial developing AD is much higher than their risk of other illnesses resulting from their taking estrogen. Therefore, it may be that the benefits of hormone replacement therapy in preventing memory loss may outweigh potential risks in other areas. Clearly, more research is needed on this complex issue. Investigators are looking at other possibilities as well. For example, inflammation of tissue in the brain and overproduction of free radicals are two processes that are thought to be a feature of AD. The NIA is now supporting clinical trials in both of these areas to see whether specific antiinflammatory agents and agents that protect against oxidative damage can slow or prevent the development of AD. Scientists are also conducting clinical trials to see whether substances already used to reduce cardiovascular risk factors also help reduce AD risk. The NIA has several ongoing and planned clinical trials to test whether supplementation with folic acid and vitamins B6 and B12 can slow the rate of cognitive decline in cognitively normal men and women, women at increased risk of developing dementia, and in people diagnosed with AD. The Institute will also conduct a study of statins, the most common type of cholesterol-lowering drug, to see whether these drugs can slow the rate of disease progression in AD patients. Another area of work involves nerve growth factor (NGF). NGF is one of several growth factors in the body that maintain the health of neurons. NGF

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also promotes the growth of axons and dendrites, the neuron branches that connect with other neurons and that are essential in nerve cells' ability to communicate (see the section A Walking Tour Through the Brain for more on the structure and function of neurons). Studies have turned up a number of clues that link NGF to the neurons that use acetylcholine as a neurotransmitter, so researchers have been eager to see what happens when NGF is added to aging brain tissue. In animal studies, researchers have been able to reverse most of the age-related neuronal shrinkage and loss of ability to make acetylcholine. This success has led to a small-scale, privately funded gene therapy trial that is testing whether this procedure can be done safely in humans and whether it might lessen symptoms of AD. Finally, a number of clinical trials are focusing on the earliest stages of the disease process. For example, scientists are developing drugs that prevent enzymes from clipping beta-amyloid out from APP. Others are working on ways to stop beta-amyloid from clumping together into plaques. Teams of investigators are also studying certain enzymes that seem to be able to break beta-amyloid into pieces after it is released from cells but before it has a chance to form into plaques. Still other scientists are exploring the role of neurotransmitter systems other than acetylcholine, such as glutamate. One especially active area of research involves the possibility that a vaccine might be able to stimulate the immune system into getting rid of plaques once they have formed, stopping beta-amyloid and plaque buildup, or even getting rid of plaques once they have formed.

Immunizing Against AD: Just a Neat Idea or a Real Possibility? Getting vaccinated against measles, tetanus, polio, and other diseases is common practice these days. A person is injected with a weakened form of a disease-causing bacterium or virus. His or her immune system mobilizes to fight against it, and this protects the person against getting the disease. One scientist wondered whether this approach could work for Alzheimer's disease as well. Researchers have developed special kinds of mice (called transgenic mice) that gradually develop AD beta-amyloid plaques in the brain. These mice are invaluable tools to test how plaques can be stopped from forming. Over the course of several studies, scientists tested the effects of injections of a vaccine composed of beta-amyloid and a substance known to stimulate the immune system. They found that long-term immunization resulted in much less betaamyloid being deposited in the brains of the mice. Similar transgenic mice

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that had been immunized also performed far better on memory tests than did a group of these mice that had not been immunized. These exciting developments led to preliminary studies in humans to test the safety and effectiveness of the vaccine. Based on positive results, a further study was designed to measure the immune response in participants with AD who received immunizations with the beta-amyloid vaccine. In this study, which began in the fall of 2001, inflammation unexpectedly developed in the brains of some of the participants. As a result of this complication, the pharmaceutical companies that were conducting the research stopped the trial and are continuing to closely monitor the health of the participants. Despite their disappointment with this development, the scientists and funders involved in this research emphasize that a tremendous amount of valuable information has been gained from this work so far. It is not unusual for such a revolutionary concept to have setbacks, and they are moving forward with other possible strategies.

Improving Support for Families and Other Caregivers Perhaps one of the greatest costs of Alzheimer's disease is the physical and emotional toll on family, caregivers, and friends. The changes in a loved one's personality and mental abilities; the need to provide constant, loving attention for years on end; and the demands of bathing, dressing, and other caregiving duties can be hard to bear. Many caregivers must assume new and unfamiliar roles in the family and these changes can be both difficult and sad. Not surprisingly, caregivers of people with dementia spend significantly more time on caregiving tasks than do caregivers of people with other types of illnesses. Although research on caregiver support is still in its early days, we've already learned a lot about the unique aspects of caregivers' personalities and situations. For example, one study of the psychological and physical responses of AD caregivers showed that they don't all have the same response to caregiving. Certain characteristics seem to make some caregivers more vulnerable to the physical and emotional stresses associated with dementia care. These characteristics include being a male spouse, having few breaks from caregiving responsibilities, and having preexisting illnesses. Caregiver research is also beginning to tease out characteristics of support programs that might be most useful for particular groups of caregivers. For example, peer support programs that link caregivers with trained volunteers

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who also have been dementia caregivers appear to help. These programs are especially good for caregivers whose social support networks are weak or who are in very stressful situations. Other research has confirmed that the information and problem-solving needs of caregivers evolve over time as the person with AD changes. Support programs can respond by offering services and information geared to different stages of the disease. One of the most difficult decisions that many families face is whether and when to place a loved one with Alzheimer's disease in a nursing home or other type of care facility. Once this decision is made, families must decide what type of care is best for the person and the family. Many investigators are working to identify strategies that can lead to improved quality of care in various facilities, including assisted living facilities, continuing care retirement communities, nursing homes, and special care units (a separate area within a nursing home or assisted living facility designed especially for patients with dementia).

Who are the AD Caregivers Caregivers vary depending on the culture and ethnic group involved. Most primary caregivers are family members: •

Spouses: This is the largest group of caregivers. Most are older, too, and many have their own health problems to deal with.

•

Daughters: The second largest group of primary caregivers are daughters. Many are married and raising children of their own. Juggling two sets of responsibilities is often tough for these members of the "sandwich generation."

•

Daughters-in-law: Many women in this group help take care of an older person with AD. They are the third largest group of family caregivers.

•

Sons: Though many are involved in the daily care of a parent with AD, sons often focus on the financial, legal, and business aspects of caregiving.

•

Brothers and sisters: Siblings may assume primary responsibility for care if they live close by, but many are older and are coping with their own frailties or health problems.

•

Grandchildren: Older children may become major helpers in caring for a person with AD. Adolescent or young grandchildren may need extra help and support if their parents' attention is heavily focused on the ill grandparent, or if the grandparent with AD lives in the family's home.

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•

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Other: Friends, neighbors, and fellow faith community members also often help care for a person with AD.

The Realities, the Positives, and the Negatives of Caring for a Person with AD A reality check for an AD caregiver might look something like this: •

Physical effort and time commitment: Help with bathing, eating, dressing, and other activities of daily living take a lot of time. As the disease progresses, the need for this kind of help increases. Behavior problems and safety concerns mean that the caregiver is always "on duty," even when not actively helping the person.

•

Financial costs: The costs of care vary, but can be high depending on whether the person is cared for at home or in a residential care setting and how much help the caregiver has. Many caregivers give up their jobs or cut back on their work hours and this also has financial implications.

•

Psychological loss: Caregivers often experience a profound sense of loss as the disease slowly takes their husband, wife, parent, or friend. The relationship as it once was gradually ends and plans for the future must be radically changed. Caregivers must come to terms with "the long goodbye."

Many research studies have shown that caring for a person with AD can have some negative effects on the caregiver... •

Employment complications

•

Emotional distress

•

Fatigue and poor physical health

•

Social isolation

•

Family conflict

•

Less time for leisure, self, and other family members

...but research has shown that caregiving also has important positive effects: •

A new sense of purpose or meaning in life

•

Fulfillment of a lifelong commitment to a spouse

•

An opportunity to give back to a parent some of what the parent has given to them

448 Alzheimer’s Disease

•

Renewal of religious faith

•

Closer ties with people through new relationships or stronger existing relationships

Studying New Ways to Help Caregivers It was midnight, the end of a long day of taking care of her husband. She was exhausted but she couldn't sleep. A year ago she would have felt totally alone, unable to share the hardships of caregiving, and desperate for ideas for how to cope better with his changeable moods and withdrawal from the world. Tonight was different. She went to the living room, switched on her computer, and plugged into a computer-based support group for family caregivers. She sent out a message and soon received replies from several fellow caregivers. They knew just what she was feeling. Their words of understanding and support eased her mind and helped give her the strength she needed for the days ahead. Caring for a person with Alzheimer's disease has special stresses and difficulties. As a result, support groups have always been an important feature of AD caregiver programs. Conventional support groups have been enormously helpful for many caregivers, but they have a few drawbacks. Attending a group involves finding transportation and arranging for care for the person with AD. The group's meeting time may not coincide with the time that a caregiver wants advice or needs to express feelings. Some caregivers do not feel comfortable discussing their experiences publicly in a group. Members of some ethnic or cultural groups may be particularly reluctant to join a traditional support group. In 1989, a researcher had an idea for a radically different, new kind of support system for family caregivers. She envisioned a computer-based system that would operate 24 hours a day, 7 days a week. It would provide expert medical advice and information about the latest developments in AD research. It would also include a "bulletin board" component that would allow caregivers to share ideas and give and get support by posting messages on-line. The project would provide a computer if needed, and would train caregivers in how to use the equipment. From the start, she invited the local Alzheimer's Association to join her in carrying out the idea. This partnership is still flourishing today. Although many people doubted that adult and elderly caregivers with little or no computer experience would want to go online, the project, called the Alzheimer's Disease Support Center, was a hit from the start. In fact, the

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449

bulletin board component, called the Caregiver Forum, soon became the most popular element. Users were eager to communicate, share experiences and feelings, and learn from each other. They soon became, as they called it, a "computer family." Scientists who have been conducting research with computer-based support systems have found they have two qualities that make them especially useful: •

They reach lots of people simultaneously. Many users can log on to get information that is posted on the system. In addition to providing lists of useful publications and materials, the systems post information on traditional support groups, daycare centers, and other services. They also provide a "Q&A" module where users can get answers to their specific caregiving questions from a team of physicians, nurses, social workers, psychologists, and staff of the Alzheimer's Association. In addition, users can browse an archive of previously asked questions and answers organized by topic. Users can also interact with each other through the bulletin board component.

•

Computer-based systems address some of the drawbacks of traditional support groups. They put control of the support process in the hands of the user. Users can talk with others and get help whenever they need it, day or night. Some users log on daily; others log on only when they have a specific question or need. Because the computer is at home, they don't need to make special arrangements to get to a support group meeting. Users can express themselves publicly if they want to or they can be anonymous if that is better for them. For every user who posts messages on the system, researchers have documented that several just read what others have posted. These users seem to benefit from the sense of kinship with others facing similar situations and may in time begin to participate more actively.

One of the most fascinating findings from this project was how quickly users overcame the potential barriers posed by an electronic communication system. Here are just a few of the techniques users have adopted to "humanize" the system, especially the Caregiver Forum: •

Using punctuation keys, users have incorporated an array of icons into their messages to represent faces and gestures. They also intentionally misspell words and manipulate the placement of letters. All of these devices help users convey their feelings.

•

Users talk about all sorts of things, not just caregiving issues. Sharing details of everyday life - weddings, children's activities, hobbies, even the

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weather - seems to help users reduce their feelings of isolation and brings a sense of normality and balance to their relationships with others. •

Friendships begun over the computer have blossomed into regular meetings for meals and get-togethers.

In 2000, the NIA funded a follow-up study to the original project. Called Computer Mediated Support for Family Caregivers, or CO-MES, the study is exploring how best to use computers to provide information and support to family caregivers. The study team is trying to learn more about who uses this type of support and whether computer-based groups help to lessen the negative effects of caregiving. Two types of computer-based groups are being studied - a group led by a family caregiver and a group led by a nurse. Many of the system's features are the same as before, though users now access the system through the Internet. The system also now has a chat room, which allows users to have "real-time" conversations. At the same time, the original computer-based support group continues to operate.

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APPENDIX F. ALZHEIMER’S DISEASE AND RELATED DEMENTIAS: ACUTE AND LONG-TERM CARE SERVICES Overview55 The United States is undergoing a major shift in its approach to delivering health and social service programs. People with Alzheimer’s disease and related disorders (ADRD) are likely to be affected by these developments. In addition to a re-evaluation of the role of government, at all levels, in delivering (or being responsible for the delivery of) services, at least two other shifts in strategy are occurring to reform the targets of economics, access, and quality. Managed care has been seized as the solution to a series of yet poorly defined problems. Chief among these is the rapidly escalating cost of care. The general belief exists that by combining all costs into a single capitated payment, sufficient management pressure can be brought to bear to contain the growth. Those opposed to managed care raise concerns about the restricted choices imposed and the potential for selective enrollment of participants. At a minimum, there is a strong need to adopt some method of payment that accurately reflects the actual risks of those enrolled. People with ADRD are especially vulnerable because popular belief holds that they are expensive to care for. The enthusiasm for managed care seems to extend to both acute and chronic care. States are turning to such programs as a way to control the rapidly rising costs of their Medicaid programs. If the Federal Government turns over full responsibility for Medicaid to the States, the pressure will increase still further.

Adapted from the National Institute on Aging: http://www.alzheimers.org/pubs/acute96.html.

55

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In the sphere of long-term care (LTC), there is growing interest in shifting the balance of effort away from the present institutionally-dominated model to include more home and community-based care (HCBC). Such a transition would include the emergence of new hybrid forms of institutional and community care, such as assisted living, which permit better (less institutional) living situations and individually packaged services that respond to client needs. Although no specific programs have been proposed exclusively for people with ADRD, their special needs must be addressed in any potential solutions. In addition to these newer trends, several issues persist. Demographic changes are leading to a growing number of older women who live alone, who fall near or below the poverty line, and who have little or no access to informal support or care. These women will place increasing demands on formal, publicly funded services. In addition, LTC continues to rely heavily on informal care. The care from spouses, relatives, and friends and neighbors still represents the bulk of services provided. There is no indication that the 80-85 percent of care usually attributed to this source has diminished, but sociological forecasts regularly warn that changes in this country’s social and economic situation threaten the stability of this arrangement. As the large majority of women (the traditional source of informal care) enter the workforce, as marital arrangements become more diverse and less stable, and as the birthrate falls (producing fewer children to provide both economic support and direct care), the prospects of continuing to rely heavily on informal care darken. People with ADRD have historically been cared for by just such sources, to the point where caregiver burden and equity issues have become a regular source of concern. As the pressures for more service grow and the enthusiasm for providing it declines, the nagging questions about effectiveness of care will intensify. There is a great need to establish just what kinds of care make a difference. As reflected in an earlier report from this Panel, much thought and effort must be directed to the basic question of what is meant by “a difference” (Advisory Panel on Alzheimer’s Disease, 1992). The effect of care can be assessed along various individual dimensions, including such factors as cognition, functional status, affect, quality of life, burden of care, and satisfaction. At a minimum, it is important to distinguish compensatory services (designed to assist with those activities the person with ADRD can no longer do for him/herself) from those aimed at restoring function. Historical problems of access to care are likely to be exacerbated. Under the present system of a federally administered Medicare program to provide acute care health insurance benefits for virtually all people aged 65 and

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older, and a State administered, but federally overseen, welfare-based Medicaid program that addresses more LTC issues, there already is substantial variation in the types and amount of services provided. Some of this variation is geographic. Rural areas usually have a more restricted supply of services than do more urban areas. Some is based on wealth; affluent areas usually offer more than areas of poverty. But much of the difference seems to be based on other factors. For example, Medicare expenditures per enrollee vary by more than a factor of 100 percent across States for a mandated equivalent package of benefits. The spread in Medicaid payments and covered services is even greater. As Federal participation is capped, the variation can be expected to widen dramatically. People with ADRD may be adversely affected as services designed specifically to meet their needs, especially those intended to support the informal care system, are assigned low priority. To the extent that organizations seek to enroll participants, people with ADRD may be shunned under the belief that they will present too great a burden for the reimbursement available, although this assumption is not supported by research.

Providing Care to People with ADRD Beyond the care burdens associated with ADRD, these patients present special problems in developing a rational approach to care. Caregiving burdens are exacerbated by the nature of the disease, especially for informal caregivers, who often must contend with intimate relations with people who are cognitively deteriorating with no obvious concomitant physical signs. These patients also may be shunned by the traditional care system, which sees them as simply too difficult to manage easily. From a medical perspective, many ADRD patients are physically well except for their cognitive problems. They may be ignored by the medical community because of a sense of impotence about how to manage them and a misperceived threat of high costs. The care needs of ADRD patients are not a part of the repertoire of most primary care providers. In a social environment that places increasing emphasis on the importance of consumer choice, diseases like ADRD, which attack cognitive function, make it much more difficult to assess patient preferences or even to determine when a treatment is having a positive effect. Much of the response burden is necessarily transferred to proxies, who may or may not be in a position to accurately reflect the preferences of the patients themselves. Moreover, studies of the utility weights (the relative importance) assigned by others to

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the potential outcomes of care for people with ADRD suggest that the general population has a lower level of concern for the success of interventions directed toward such individuals compared to services for those deemed cognitively competent (Kane et al., 1986). In large measure, ADRD remains a family affair. The care and the burdens of the disease mean that families are virtually as much the victims of the disease as the patients themselves. Hence, treatment programs need to address these families, at the same time that such strategies may not be highly valued because of budgetary cuts. The Alzheimer’s Association continues to play a major advocacy role for families, and may expand their role in the development of clinical care programs and service provision in response to managed care initiatives. Family caregivers at four recent forums sponsored by the California Caregiver Resource Centers, for example, consistently reported that what they wanted from LTC services was flexibility to meet individual and family needs, consumer choice, accessibility to affordable care, and assurances that there will be continuity of care. Other issues highlighted were caregiver support services, legal/financial concerns, and meeting the needs of an ethnically diverse caregiving population.

Current Themes Affecting ADRD Care Managed Care Managed care has been seized as a potential solution to the escalating cost of health care. Managed care combines the familiar insurance function with more direct responsibility for providing the needed care through a defined health care delivery system. Managed care offers some potential advantages for older consumers. It simplifies the current Medicare arrangements by eliminating much of the bookkeeping. It holds out the potential for providing an organized approach to care with the capacity to invest in expertise, structured programs, and a management information system that could minimize iatrogenic complications (such as medication interactions). Such systems also could be used to track patients in order to intervene early in deteriorating conditions or even to screen for potentially correctable problems. Case managers could intervene to prevent the development of major disability and mobilize community resources to provide timely assistance to prevent or delay institutional care. The incentives created by capitated prepayment should encourage the development of alternatives to reduce the use of more expensive services.

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Hence, ambulatory services and case-finding would be encouraged where there was evidence that interventions reduced subsequent resource utilization. At the same time, managed care for older people may respond to some undesired incentives. There is reason to believe that the current Medicare health maintenance organizations (HMO’s) have benefited from favorable selection, attracting less ill people (Brown et al., 1993). For example, managed care programs are not anxious to enroll older people whom they expect will require more care, such as people with multiple chronic illnesses or those who need special care. They may include people with dementia in that category. It is less clear how much of this selection occurred by design and how much by chance. Certainly, marketing strategies have some effect, and benefit policies will encourage different types of people to apply. For example, offering a drug benefit would encourage those with multiple chronic diseases to join, whereas a broad range of preventive services might be more attractive to healthier people. Overall, managed care operations anxious to maximize profits will opt not to provide services as long as the omission does not produce a problem. For older people, this strategy may mean foregoing services that have as yet unproved value. Those services not tested may be assumed to be ineffective. Growth in managed care among both privately and publicly insured groups also produces a number of inconveniences. Choice of care provider is restricted. Some people may have to give up the physician or hospital with which they are familiar. Some programs may introduce various procedures to reduce the use of specialists, such as waiting lists for a restricted panel of specialists, requiring a formal referral from the patient’s primary care physician, or having some form of case manager authorize the visit. To date, the track record of managed care serving older people has not been exemplary. Although some Medicare HMO’s have developed innovative geriatric programs (Fox et al., 1991), most essentially have done business as usual, with little adaptation to respond to a geriatric clientele (Friedman and Kane, 1993). Indeed, there is some reason to suspect that Medicare HMO’s may be reluctant to establish active, visible geriatric programs for fear of attracting too many frail older people. Anecdotal information suggests that managed care organizations may be using more registry nurses for home care and hence reducing continuity of care. A study of Medicare home health care indicated that managed care was associated with fewer visits and poorer outcomes (Shaughnessy et al., 1994).

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A few geriatrically-oriented models of managed care have been developed that include at least some efforts to bridge the service gap between acute care and LTC. The two most prominent models are the Program for All-Inclusive Care for the Elderly (PACE), which is a series of replications of a model originally developed by On Lok in San Francisco’s Chinatown. The PACE programs serve frail older people, most of whom are covered by both Medicare and Medicaid. They use an integrated approach to care built around a day health care center to emphasize active primary care and creative service packages as a means to reduce the use of acute and longterm institutional care (Kane et al., 1992; Branch et al., 1995). Many of their clients suffer from dementia, to the point where some PACE programs were concerned about enrolling too many clients with dementia. The second model is the social health maintenance organization (S/HMO). This approach combines the Medicare HMO with a limited LTC benefit. It features active case management and varying degrees of geriatric programming. The first series of four S/HMO’s originally was designed by Brandeis (Leutz et al., 1991). The evaluation of these programs suggests that they had, at best, modest effects on changing the health status of their enrollees (Manton et al., 1994). A second set of S/HMO’s has been chartered by the Health Care Financing Administration. These programs will utilize a more intense geriatric approach. They will not be able to control the proportion of enrollees who are severely disabled, but will receive different levels of capitated payment based on the risk of greater utilization of services. The S/HMO’s receive 100 percent of the Medicare Average Adjusted Per Capita Cost (compared to the 95 percent other Medicare HMO’s receive) and use a special rate cell risk adjustment that pays them more for people who are more disabled (and correspondingly less for enrollees who are healthy). Although there is no specific prohibition against enrollees with dementia, there are no specific S/HMO programs to address their needs. People with dementia are not likely to be attractive to managed care organizations. They are expected to cost more. They are more difficult to manage. They may require special programs. It is, therefore, unlikely that HMO’s will develop programs to recruit such members unless special incentives are created. However, managed care could serve as a useful vehicle to develop coordinated care for people with dementia. The data available do not support concerns about extra costs. The studies by Hay and Ernst (Hay and Ernst, 1987; Ernst and Hay, 1994) suggest that the added costs involve some one-time diagnostic costs (not applicable to most

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people already diagnosed) and nursing home care (not covered by Medicare HMO’s). There was some modest additional cost ($375-$1,200) associated with hospital care, but most of this cost seems to be attributable to delays in discharge associated with placement problems. These issues should be more effectively dealt with in a managed care setting, which has access to case management and the potential for making more efficient arrangements for post-hospital care. Rice and colleagues also found additional hospital costs in about the same range (Rice et al., 1993). They noted substantially increased costs related to institutional care and social services (both not covered by Medicare, although the working definition of home health care under Medicare is broadening). A Canadian study found no increased cost for hospital care. Most of the increased costs were attributable to LTC services in institutions or in the community (Ostbye and Crosse, 1994). Other older, more confined studies also have shown increases in hospital lengths of stay (LOS), usually associated with care planning difficulties (Fields et al., 1986; Levenson et al., 1990; Saravay et al., 1991). Other studies have found no difference in the rate of hospitalization or LOS for patients with dementia (Ganguli et al., 1993; Welch et al., 1992). At the very least, better studies and experimentation around this issue should be encouraged and efforts should be made to establish actuarially sound capitation rates for government (and perhaps private) programs based on the real financial risks presented by clients with dementia.

Integrating Acute and Chronic Care As noted, several managed care programs have made at least partial efforts to integrate, or coordinate, acute care and LTC. The two efforts certainly are linked. People receiving LTC need good primary care; and acute care, especially the hospital, often is the entry point for LTC. LTC is the component of comprehensive health care in which services are provided to frail elderly and disabled people of all ages and their families to promote or restore health or minimize the effects of illness and disability. Techniques such as case management, which devote extra efforts to coordinating care, can prove effective in controlling the costs of such care by avoiding iatrogenic complications and addressing incipient problems early. In this sense, case management serves not simply a gatekeeping, or resource control role, but becomes an extension of primary care. In the case of ADRD, special planning to be sure that medical problems are addressed promptly can avoid later complications. For example, special attention to medication management to be sure that the right drugs are taken as prescribed and that early signs of adverse side effects are detected can prevent hospital

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admissions. Prompt attention to issues around discharge planning can prevent extended hospital stays while waiting for resolution of caregiving crises. Conversely, better coordinated LTC, including attention to caregivers, can reduce the need for acute interventions around crises. More individualized care plans, which are based on a better understanding of individual client preferences, may avoid the use of psychoactive drugs that invite iatrogenic complications. A systematic approach to dementia care for nursing home residents, which included activities, guidelines for the use of psychotropic drugs, and educational rounds, was shown in a randomized controlled trial to be associated with a reduction in behavior disorders and less use of antipsychotic drugs or physical restraints (Rovner et al., 1996). Housing arrangements that provide greater levels of independence and privacy likewise may alleviate the need for such medications to control disruptive behaviors. More effective information systems are needed for patients with dementia and their families, as they move between levels of care. For example, a Cleveland project provides information about ADRD, services, and research, as well as an electronic support group on the Cleveland Freenet. Cognitive problems can interfere with people’s ability to make choices. For example, Joanne Lynn found that some impaired individuals could not understand complex changes in the Medicare benefit she was proposing as part of a tradeoff of acute care for more LTC (Building Health Systems for People with Chronic Illness newsletter, Vol. 1, No. 1, October 1994, Robert Wood Johnson Foundation).

Balance between Community and Institutional Care For many Americans, access to LTC services is problematic. Issues of equity of access to LTC for the dependent elderly focus on the shortage of in-home and community services to support family caregivers. There are wide disparities in the availability and access to community services by geographic region, ethnicity and race, class, and gender (Estes, 1993). Public expenditures for community-based services are relatively small compared to those for nursing home care (O’Shaunessy and Price, 1987). Medicaid, which is the principal source of funding of health care services for low income people, finances mostly nursing home care and was not designed to support a full array of social and other long-term community-based care services. Expenditures for LTC in 1993 were estimated to be $74.9 billion for institutional care ($36.9 billion Medicaid/$4.8 billion Medicare) and $32.9

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billion for home care ($7.1 billion Medicaid/$10.7 billion Medicare). The Administration on Aging (AoA) also provides some funding for HCBC to support some portion of personal care at home. Although public costs for LTC are growing, a substantial proportion of the direct costs for this care still are paid “out of pocket,” and by far the largest share of the indirect costs of ADRD are borne by families. There is concern that limited access to services or overly burdensome out-of-pocket expenses, such as costs of remodeling to accommodate assistive equipment for the functionally dependent, cause many elderly and their informal caregivers to choose institutional placement (Kovar and Harris, 1990). Others, most often widowed and childless older adults with severe dependencies, cannot get the care they need unless they enter a nursing home. A substantial share of community dwelling elderly in need of assistance with one or two activities of daily living (ADL’s) or instrumental ADL’s need more help than they actually receive (Scanlon, 1988). While there is consensus that health care reform should include services in and among multiple settings and the plan proposed by President Clinton (the Health Security Act of 1993) included LTC provisions (Kane and Kane, 1994), no specific plan has yet evolved to meet the diverse and complex needs of all people who require LTC (Rantz, 1993). People with ADRD, the functionally dependent elderly, and the chronically ill of all age groups are among the most disadvantaged for access to LTC, especially HCBC. This is especially true for those who live in rural areas of the United States; are members of ethnic and racial minorities; or are poor, uninsured, or underinsured. The National Chronic Care Consortium, a vanguard group of organizations concerned about bridging the gap between acute and chronic care, should be encouraged to direct some of its attention specifically to issues of caring for patients with ADRD. Several issues deserve special attention.

Home and Community-Based Long-Term Care Home and community-based services usually are planned and coordinated by an agency using employed staff or contractual arrangements. HCBC is different from nursing home care in that services are provided to people living at home or in a homelike environment rather than requiring recipients to be residents of institutions (Miller, 1991).

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The objectives of the services are to assist disabled individuals with basic tasks of living and/or to provide relief to their caregivers. HCBC covers a broad range of services that extend from skilled-level, medically related services with professional staff to social support services provided by nonprofessionals or informal caregivers (family and friends). Ideally, the formal (paid) community-based services should complement rather than impede services provided by informal caregivers. About 75 percent of the impaired/disabled elderly living outside institutions rely solely on informal care (U.S. Senate, 1988). For every person currently receiving institutional care, there are an estimated four more people in the community who require some form of LTC (U.S. Senate, 1988). By the year 2000, 18 percent of the elderly (over 5 million) are projected to have some impairment that requires the help of others. About 5 percent (1.75 million) of these people will be in nursing homes or other institutions, but a staggering 3.5 million needing substantial LTC will not be institutionalized. Approaches to this looming problem include: (1) reducing the need for home care by improving the health of older people; (2) providing home care when disability and frailty preclude continued independence and self-care; and (3) improving integration across the total continuum of care, and coordinating different care providers who subscribe to a broad view of health care that includes both medical and social components. Unfortunately, HCBC often is “piecework and patchwork” (Kane and Kane, 1987) and characterized by inaccessibility, poor care, unskilled personnel, high out-of-pocket costs, and inadequate linkages to other services, rather than a comprehensive array of services. Miller (1991) provides a taxonomy of services and caregivers in the HCBC domain including five main categories of services: •

Assessment, information, and referral services that include services to help people find and coordinate home care.

•

Health and support services that include medically related home care and personal and custodial in-home care.

•

Community-based out-of-home services.

•

Living arrangements representing a continuum of living options that provide assistance services short of institutionalization.

•

Integrated systems illustrating an array of services that combine financing and care delivery, including medical and social support services that promote independence and quality of life.

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Rural Health Care Several special groups do not receive adequate LTC services. For example, minority women, impoverished elders, and those without families are especially disadvantaged. Earlier reports have highlighted the gaps in our knowledge about how ethnic and cultural issues may affect care for ADRD (Advisory Panel on Alzheimer’s Disease, 1993). Another large group that faces special problems in responding to the challenges of ADRD is the part of the population living in rural areas. In many rural areas the health care service delivery system is impoverished and fragmented; the health, mental health, and social services cannot support people with ADRD and their caregivers. Many services, such as nutrition, adult day care, case management, and transportation, simply do not exist outside the county seat. Improving accessibility to diagnostic services in rural areas, such as through the development of mobile diagnostic clinics or telemedicine, also is essential to rule out reversible dementias and to establish standardized diagnostic criteria for clinical and research purposes. Follow-up networks (coordinated by the Area Agencies on Aging) linked to diagnostic evaluation could facilitate the development of statewide ADRD registries, which could enhance epidemiological research efforts and facilitate efficient and standardized collection of data to aid State Governments in planning for future care needs. Even where chore and companion services are available, rural caregivers have limited access to them because there are few mechanisms for communication and articulation of available services. The cost of long distance telephone calls prohibits some caregivers from inquiring about available services, and there is no central repository for current and accurate information on resources, regulations, etc. Better information/dissemination mechanisms in rural areas could help address the isolation of both patients and caregivers. A diverse array of health care professionals are in short supply in rural areas; most rural nursing homes do not offer the full complement of health care services (e.g., social services, physical therapy). Many home care programs are based in struggling rural hospitals and lack the full range of services needed by people with dementia. Counseling and mental health services are needed to assist caregivers in dealing with issues of burden, anger, and depression, and in coping with behavioral and emotional manifestations of ADRD. There is some evidence that providing support to caregivers can reduce the incidence of depression and the consequences of such (Mittleman et al., 1995). Outreach programs,

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based in community mental health centers (CMHC’s) serving rural catchment areas, also are needed to provide case-finding and in-home treatment, and sponsor support groups for caregivers and people with dementia. In a recent survey of 107 rural Iowa caregivers, only 51 percent reported using any community-based services. The average cost to them was $73 per month, borne largely out of pocket. Caregivers reported being motivated by a religious ethic in their caregiving responsibilities and felt a deep sense of personal satisfaction and growth from the experience. Respondents indicated that they were not interested in resources outside of family and friends, in part because they were concerned that confidentiality would be a problem in their rural communities and that help from agencies would be “too close to charity” (Buckwalter et al., 1995). These values, beliefs, and the stigma associated with the use of counseling/mental health services may account in part for the low use of formal services reported, and deserve further investigation. As part of a study of Ohio’s PASSPORT program, a Medicaid waiver program for community-based care, investigators found that more than half the cases they investigated affected a client who was cognitively impaired. Rural clients were enthusiastic about the program and felt that the funding was creating services that reached them (Applebaum, 1995). A current demonstration project sponsored by the Health Resources and Services Administration (HRSA) is testing different types of support and services for ADRD patients and their families.

“New” Forms of Care for People with ADRD Special Care Units (SCU’s) SCU’s were developed in the 1980’s as LTC settings attempted to better meet the needs of people with dementia and to protect residents without dementia in nursing homes. In addition to the growing number of elders, the recognition that people with dementia have different care needs from those who are physically frail, and concern that traditional nursing home care has not been responsive to those needs, families and caregivers have created strong interest in establishing specially tailored care for this group (Ory, 1995). At present about 15 percent of nursing homes, representing approximately 2,500 units and more than 50,000 beds, have a SCU or specialized program for people with dementia. Although there has been a clear pattern of growth in SCU’s for the past decade, it is less evident whether that trend now has leveled out. The great diversity among SCU’s, together with other conceptual, methodological, and measurement issues

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(e.g., insufficient sample size, high attrition, lack of rigorously controlled studies, ambiguities in definition and selection of units, difficulties in measuring outcomes in a communication-impaired population, and problems related to assessing change and effect over time), have hindered examination of the influence of SCU’s on patients (Ory, 1995). Moreover, these studies may reflect potential sources of bias (Sloane et al., 1995). The NIA Collaborative Studies Initiative was established to address SCU research from a variety of perspectives. Currently, 10 funded studies are included in this 5-year research consortium with goals of identifying key elements of care and appropriate outcomes, evaluating their effects, facilitating standardization in the definition of SCU’s, developing consensus on common data elements, and encouraging cross-site analyses to enhance sample size. Because of setting limitations, most of the collaborative studies use epidemiological methodologies to compare care and outcomes in SCU’s versus traditional nursing home units, rather than randomized controlled clinical trials (RCT’s). However, RCT’s may not always be the best design for evaluating interventions related to the milieu. Many of the studies also examine outcomes related to staff, family, other residents without dementia, and case mix/reimbursement issues. Family members, providers, and policymakers need to know if SCU’s are effective, for whom, and at what cost, if they are to avoid paying more for care that is not truly more “special” or beneficial. Moreover, restrictive regulations could stifle innovation that may enhance functioning and quality of life for residents with ADRD, their families, and staff caregivers (Ory, 1995). As the concept of specialized care moves into other community-based settings such as adult daycare centers and assisted living, it becomes increasingly important to be able to define what makes special care “special,” and to articulate the effect associated with different types of specialized dementia care across the entire continuum of care settings. Finally, the “outfall” from the NIA collaborative studies also is expected to increase understanding of related issues in this population such as functional assessment, and to refine methods for assessing small changes over time, standardizing environmental measures, and developing typologies for use in evaluating different care settings (Ory, 1995). The results of the collaborative SCU studies will need to be reviewed carefully. Likely they will reveal a mixed picture, with some outcomes showing favorable differences and others not. It will be important to identify the components of care that seem to account for observed benefits and to recognize the areas where SCU’s are not effective. A critical question will be whether such care can be cost effective (i.e., can the resources currently invested be better used). At a time of tight fiscal pressures, proposals for

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increased spending are not likely to find enthusiastic reception, especially if the gains are modest. Despite these good beginnings, more rigorously controlled research is needed on the effects of various interventions in SCU’s and community settings and with families. For example, the value of intergenerational programs and opportunities for young people or intellectually intact elders to provide care for patients with ADRD needs to be examined. More work also is needed to enhance conceptual and methodological efforts to evaluate program effectiveness. Promising directions for future research related to special care for people with dementia fall into three major themes: (1) What individual elements of SCU’s make a difference? (2) What interventions work? and (3) Expansion of the settings for care.

Home and Community-Based Care A perceptible shift is occurring in the preferences for the site of LTC. For several reasons, we are witnessing expanded interest in HCBC. Although it is by no means always the case, some see it as less expensive. Others view it as a response to the need to develop alternatives to the medical model emphasis in most LTC facilities, and still others believe it improves quality of care and quality of life. A review of the effectiveness of community-based LTC, a substantial portion of which affects people with dementia, finds a mixed bag of results. Other than meeting unmet needs, the majority of studies failed to show significant positive results (Weissert and Hedrick, 1994). Nonetheless, enthusiasm for community-based care remains high. More research is needed to document these perceived improvements over traditional forms of LTC (e.g., nursing homes). New forms of HCBC are being created. These include a range of State licensed and unlicensed residential living environments such as small group homes for the aged, adult foster care, residential care facilities, and assisted living arrangements (Wilson, 1994). At present we have little basic descriptive information about these types of residential care facilities or about the characteristics and needs of the growing number of residents who inhabit them. Adult Foster Care Homes (AFC’s), also known as board and care homes or family care homes, are State regulated, generally small (usually not more than five clients per home) residential sites that provide housing and protective oversight. It is estimated that over 60,000 State licensed AFC’s exist nationwide, a high percentage of which provide care to frail elderly

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clients. AFC’s probably provide care to large numbers of older adults with early and middle stages of dementia as well, although the precise number is unknown. Yet, extremely limited information is available about care processes and outcomes for residents with dementia in these settings (Collins, 1994). One recent secondary analysis of survey data from families of people with dementia begins to provide an indication of perceived quality of care from the perspective of family members (Collins 1994). However, these data are limited by lack of information on the person with dementia (e.g., stage of disease), as well as knowledge of whether or not the AFC’s represented in the survey were dementia specific. Overall, family members of people with dementia residing in AFC’s reported a high level of satisfaction; 90 percent of family respondents indicated that the care met their expectations; and 66 percent said their loved ones adjusted well, while 7 percent reported poor adjustment. Families reported a higher level of overall care in smaller homes (less than 15 beds) compared to larger ones. Based on the findings from this preliminary survey, from the families’ perspective, it appears that AFC’s are a viable residential care alternative for people with dementia, certainly worthy of closer scrutiny for the potential of these settings to provide high quality care in a smaller, more homelike environment. Of course, family satisfaction is only one of many outcome measures that need to be examined. The answers to the questions of for WHOM (in terms of older adults with dementia) these settings are best suited, WHEN in the dementia continuum they work best, and HOW dementia care is and should be provided await further research (Collins, 1994). An analysis of the regulation of board and care homes suggests that much of this care (including assisted living) is unlicensed (Hawes et al., 1995), although there are approximately 34,000 licensed board and care homes with more than 613,000 beds. The report calls for improvements in quality through licensure with or without heavy regulation, and indicates that broad State regulation and licensure of board and care homes may be necessary to improve the safety, quality of life, and quality of care. For example, the report indicates that 40 percent of board and care residents are cognitively impaired and 41 percent are on major psychotropic medications without adequate medical or nursing monitoring. Licensed homes were found to provide more supportive services, operator training in care of the elderly, and less use of psychotropic drugs and medications contraindicated for use in the elderly than unlicensed board and care homes. Extensive regulation and licensure did not appear to affect the proportion of professional nursing

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staff, knowledge of care procedures and appropriate monitoring of health conditions, or more “cosmetic” features such as availability of physical amenities and attractiveness of the homes. A recent report on State statutes and regulations for Assisted Living (Mathews and Mathews, 1995) noted that at least 86 different titles were used to classify these facilities nationwide, including “residential,” “adult,” “foster,” “family,” “boarding,” “domiciliary,” “home,” and “assisted living.” In addition, great variation was noted in inspection mandates, the nature of licensure, minimum/maximum number of beds, penalties for violations, and staffing. Only 3 percent of the facilities reviewed in this survey of statutes and regulations described themselves as “dementia-specific.” There also is a lack of Federal guidelines to standardize residential care. State regulations vary widely regarding environmental, programming, and nursing care standards, with minimum staffing ratios ordinarily quite low. Although residential care settings vary in size from small private homes for up to 4 residents to large congregate care facilities for more than 100 residents, all offer assistance/care and share with residents the responsibilities for ADL’s. Ideally, the care provided is flexible, resident and family oriented, and intended to optimize individual dignity and enhance health status, functioning, and well-being. The physical environment and design features of the facility should support the functioning of the impaired older adult and accommodate behaviors and diminished abilities (Alzheimer’s Association, 1994). It has been suggested (Tanner, 1994) that a residential Alzheimer’s disease care facility with an aide to resident ratio of 1:5 can care for even severely cognitively impaired residents, and that desirable program and care planning characteristics include the following: •

A supportive and low stress environment

•

Services that match the stage of the disease process

•

Resident care without unnecessary chemical and/or physical restraint

•

Good support systems for families and staff

The Alzheimer’s Association monograph, Residential Settings: An Examination of Alzheimer Issues, reviews the range of residential settings. It presents a conceptual model illustrating the many issues that need to be addressed, including: philosophy; practice issues such as admissions, staffing patterns, and training; environmental factors such as a supportive physical environment; macro influences and factors (e.g., regulatory process,

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public funding, market forces) and micro influences and factors (e.g., regional influences, operator specialization); and outcomes/success indicators. Notable from the health services research perspective is the paucity of information beyond anecdotal provider reports of what is needed for “Alzheimer’s-friendly” care to be accessible, affordable, and appropriate in residential facilities.

Assisted Living Over the last decade, research on LTC services for people with ADRD has focused heavily on two ends of the LTC continuum--nursing homes and community-based services. While researchers and policymakers have been investigating these care systems, another segment of LTC--assisted living-has emerged that is neither nursing home nor community care as it has been previously defined. Defined broadly, assisted living is any group residential program not licensed as a nursing home that can respond to unscheduled needs for assistance. The spectrum of assisted living services includes such diverse options as congregate housing, residential care facilities, and adult foster care homes (Collins, 1994); and the package of services can be tailored according to consumer needs and perferences. Recently, assisted living has been defined more specifically as a service that combines the nursing home’s institutional efficiencies of co-locating many clients with a greater emphasis on preserving the homelike qualities of control over one’s personal space. Indeed, many nursing homes violate the elements traditionally associated with culturally and socially relevant definitions of “home,” in that residents have little control over whom they live with, who comes and goes in their personal space, and other aspects of the environment such as furnishings and appointments. Assisted living is a model of supportive housing that is growing rapidly because of consumer preferences and costs associated with traditional models of LTC (Wilson, 1994). In assisted living settings, clients are viewed primarily as dwellers in apartment-like settings, where they can exercise all the autonomy that accompanies such a situation. Hence, they can decide whom to admit and when to do things. Families of patients with ADRD often prefer the ability to purchase only those services they need and thus conserve resources. In many cases, essential services tailored to the client’s needs can be delivered to the client in his/her dwelling without the heavy travel costs usually associated with home care. In essence, assisted living has the potential to combine the

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features of home care and nursing home, without some of the liabilities of each (Kane and Wilson, 1993). At the same time, assisted living is viewed by some as a return to an earlier time when nursing homes provided less sophisticated care and were less intensively regulated. The standards for assisted living should not allow substandard care, but neither can the regulatory mechanisms so restrict care as to recreate nursing home conditions. Accountability must be based on some type of outcomes system that permits innovation while maintaining quality. The State of Oregon has been a leader in developing standards of assisted living for licensure and evaluation of resident outcomes. In Oregon’s model program, residents are entitled to a private apartment, shared only by choice, that includes a kitchen, bath with roll-in shower, locking doors, and temperature control capability. The overall shelter costs are not substantially higher in assisted living than in nursing facilities (Wilson, 1994). Routine nursing services and case management for ancillary services are provided. Most importantly, the orientation of staff toward the residents is to empower them by sharing responsibilities, enhancing choices, and managing risks (Wilson, 1994). A variety of other approaches to assisted living, including statutory changes, demonstration projects, and rule amendments, have been tried in other States with varying degrees of success. Part of the problem is that there is no agreed-upon definition of what constitutes assisted living, except that it is a form of supportive housing. Although some claims have been made that people with ADRD, even in advanced stages, can at the very least be as effectively managed in assisted living settings as in nursing homes (Brown et al., 1993), there is as yet no empirical evidence to assess the effectiveness of such care for people with ADRD. A strong case can be made that by providing separate accommodations for clients, assisted living provides a prima facie argument for improving the quality of life for cognitively intact people who may share the same facility with people with ADRD and may offer an environment to allow people with ADRD to function without the need for as many external controls. However, this assumption needs to be tested. Although data show that residents in assisted living facilities in Oregon have a substantial level of disability--84 percent with some mobility impairment, 75 percent requiring assistance with medications, and 63 percent requiring assistance with bathing (Wilson, 1994)--more widespread and systematic evidence is needed of the capability of assisted living settings for managing patients with

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dementia (and at what stage of the disease process they are most suitable). Wilson (1994) has identified four general issues that have arisen around the assisted living movement, which also should be addressed in the context of people with dementia: •

Who should be served by assisted living?

•

What services should be provided?

•

How will services be delivered?

•

What setting works best for assisted living?

Moreover, the distinction between assisted living facilities and other types of residential care facilities often is unclear. To date, little evaluative research has been conducted on assisted living facilities. There remains a need to develop research-based typologies for assisted living facilities as well as other types of residential care facilities (e.g., board and care, homes for the aged, adult foster care homes) to be able to design and implement credible evaluative studies and to address other concerns, as noted below. Some observers of assisted living express strong concerns that the lower levels of staffing represent a throwback to the nursing home care when Medicaid was first introduced. They worry about the lack of professional oversight and the concomitant potential for resident problems.

Adult Day Centers (ADC’s) The numbers of ADC’s have grown from about 15 in the 1970’s to more than 3,000, with a projected need for 10,000 centers nationally. Adult day services, which provide daytime care and activities in congregate community settings, are being touted as the “un-nursing home” (Partners in Caregiving: The Dementia Services Program, 1995) and are defining themselves as the “cornerstone of community-based LTC.” Two projects funded by the Robert Wood Johnson Foundation, the Dementia Care and Respite Services Program (1988-1992) and the Partners in Caregiving: The Dementia Services Program, still underway, were designed to demonstrate the effectiveness of ADC’s in serving people with dementia, while at the same time achieving financial self-sufficiency. Proponents view adult day programs as a major solution to the need for LTC alternatives, and bemoan their lack of public awareness (Reifler, 1995). They urge that adult day services become part of any mandated comprehensive service “package” for both custodial LTC and post-hospital care. Currently,

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Medicare does not reimburse for ADC, and Medicaid dollars for adult day programs vary from State to State, with some providing adequate reimbursement, while others suffer from insufficient funding, or none at all (Partners in Caregiving: The Dementia Services Program, 1995). More rigorous evaluation research is needed if adult day programs are to convince policymakers and consumers that they are an essential component of the LTC continuum. Studies must determine the true costs associated with adult day services, and compare cost and patient clinical outcomes with 24hour institutional or home care with options such as ADC’s as part of an integrated service network. ADC’s will have to be able to demonstrate their cost-effectiveness; however, to do so, they must first determine what constitutes “effectiveness” and “good care” for this population, and what appropriate outcome measures, from a lifetime perspective, would be—i.e. survival time, quality of life, patient and family satisfaction, family burden. (Partners in Caregiving: The Dementia Services Program, 1995). Recommendations were set forth from a mini White House Conference on Aging, related to adult day services in the areas of financing/funding; education/public awareness; tax credits/deductions; private sector initiatives; regulations; and research.

Health Services Questions Several important health services research questions, including descriptive/epidemiological and outcomes issues, have emerged from examination of the balance between community and institutional care and the development of new forms of care for people with ADRD. These questions build on the crosscutting research needs identified by Ory and Duncker (1992). Examples of questions that should be addressed include the following: •

How many people with ADRD currently use various care modalities?

•

What is the geographic distribution of each modality of care?

•

Does use of one type of care displace use of another?

•

Do people with ADRD fare better when they are treated separately (segregated) or integrated with cognitively intact individuals? Do cognitively intact patients enjoy a better quality of life when housed separately from people with ADRD? Is this effect equivalent in all LTC settings?

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•

Which modalities can safely manage people with ADRD at different stages of their illness? Which types of care are most effective in caring for people with ADRD over the course of the disease (increasing cognitive and functional impairments)?

•

What are optimal staff:patient ratios in each of these care modalities? Are these ratios different for people with ADRD?

•

What would be the economic effect on hospice of treating people with ADRD in the advanced stages of the disease as terminally ill?

•

What are the effects (risks and benefits) of leaving people with ADRD at home without informal care?

•

Can outcomes of care be compared across modalities with appropriate adjustments for case mix? Should these outcomes then be used as the basis for regulations? To create more appropriate incentives, can outcomes be used as a basis for reimbursement?

•

What type and amount of staff training leads to improved patient outcomes

Changing Government Policies Cutbacks in Medicaid Government at all levels is looking for methods to reduce its obligations for supporting care. If responsibility for LTC under Medicaid becomes primarily a State-directed program, the disparities that already exist among States will likely increase. At the same time, States will have greater opportunities to pursue innovative programs. For example, only a handful of States have actively undertaken programs to shift the primary site of LTC from institutions to the community. Federal waiver requirements have held States to a tight substitution standard designed to prevent the overall growth in program expenditures. Most States face serious problems with regard to LTC. Medicaid expenditures have become a major component of their budgets and LTC usually receives the largest share of these funds. They are thus not anxious to increase spending in this area, although demographic forecasts suggest that such a shift is inevitable. Most of the Medicaid LTC dollars currently flow to nursing homes, which nonetheless regularly complain of being underfunded, especially in light of the ever greater demands made on them by regulatory efforts for better quality. In most States, nursing homes have developed formidable lobbying efforts to argue their case. Hence, any efforts

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to redirect the balance of care between the nursing home and HCBC are likely to encounter substantial political resistance unless it is done as part of a package to add new resources, which does not seem a likely scenario in an era of budget tightening. Moreover, as responsibility devolves to the individual States, the planning and political process is diffused. No central policies are feasible. The shift to greater State control inevitably will exacerbate the already large variation in the types and intensity of LTC services. Today, the level of investment in Medicaid-supported LTC varies widely. For example, 1992 total annual State expenditures on LTC per person aged 65 and older ranged from $2,720 in New York to $349 in Arizona. State annual expenditures on nursing home care per person aged 65 and older in that same year ranged from $1,555 in Alaska to $294 in Arizona.

Training Primary Care Providers Currently, the modest Federal support specifically targeted at increasing geriatric content in health workforce curricula is being threatened with discontinuation as part of general budgetary reductions. The need for better trained personnel to work with ADRD clients already has been addressed in an earlier Panel report (Advisory Panel on Alzheimer’s Disease, 1991). Despite the calls for more and better prepared primary care providers to meet the needs of a growing population of older people (Kane et al., 1980; Institute of Medicine, 1993; Reuben and Beck, 1994), substantial gaps still remain (Reuben and Beck, 1994). In addition to physicians, geriatric nurse practitioners have been shown to be an effective source of care for frail older people (Mezey et al., 1989; Kane et al., 1991; Mundinger, 1994; Shaughnessy et al., 1995). However, little specific training in the diagnosis and management of Alzheimer’s disease is offered in general training programs for either medicine or nursing (National Forum on Geriatric Education and Training White Papers, 1995; Stolley et al., 1991).

Boundary Issues The role of Medicare in providing long-term services has begun to increase as the result of broader interpretations of regulations governing home health care. Medicare-supported home health has come to cover longer stays and hence more visits per recipient (Vladeck and Miller, 1994). But these changes have not had a substantial direct benefit on ADRD clients because the initial

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reason for covering home health care still must relate to an acute problem that is expected to either improve or worsen. At least one Medicare program, the S/HMO’s, is providing some, albeit modest, coverage for LTC. Such a step represents a cross-subsidy for Medicaid because at least some of the care provided under this aegis otherwise might have to be covered by the Medicaid program. As pressures on Medicaid programs increase, they can be expected to look for other opportunities to exploit Medicare services. At present, Medicaid is more likely to subsidize Medicare than the reverse. Programs designed to provide better or more intensive care to patients in nursing homes, for example, prevent hospitalizations, which are paid for by Medicare. Although one currently operating program, Evercare, uses a Medicare capitated contract to cover both hospital care and medical services for nursing home patients in an effort to reduce hospitalizations, it must rely on either the willingness of nursing homes to provide more intensive care or find some incentive for them to do so (Malone et al., 1993). Better integration of Medicaid and Medicare payments would encourage more creative approaches to integrating the care being supported and may lead to overall savings, as well as addressing current concerns about people with dementia being relegated to the “no care” zone, that is bounced back and forth between services in response to increasing restrictions in Medicare and Medicaid spending (Estes and Swan, 1993).

Client Preferences and Ethical Concerns Client Preferences Although there is increasing rhetoric about the need for more client-directed care, the likelihood of providing such opportunities in an era of constrained resources seems small. Some have used client-directed care as a code phrase for some form of voucher, which would limit the government’s responsibility for paying for care. However, even proponents have not made clear just how the government could limit its responsibility short of contracting all care to private providers who would assume full risk. Many fear the consequences of such action, worrying that substantial underservice would result. Because dementia patients, by definition, have lost their capacity for judgment, they cannot be expected to express strong preferences or to be in a position to assume control of their own care. This may be a particular

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problem for people without families and those who develop dementia after placement in an institution. Some sort of agents will be needed. Putting money into the hands of family members raises concerns about the so-called “woodwork effect” (i.e., inducing demand). However, many of the fears about creating excessive demand by offering community services have not been borne out by experience (Lawton et al., 1989). Indeed, an important question to be explored is why many supportive services for ADRD patients and their families, which some champion as sorely needed, often go underutilized. Issues related to the effectiveness, accessibility, and other barriers to use of available services deserve further attention. On the other hand, it is likely that offering payment for informal care might induce a demand for service, simply because such a policy offers to pay for what already is being done. Perhaps a demonstration project is most suitable to test the effects of such a strategy.

Ethical Concerns A question that haunts all discussions of LTC is the extent to which clients should be empowered to make choices about their care. Although much is said about the need for more client-centeredness and even client control, serious concerns are expressed about the dangers involved in clients (or their agents) making bad decisions. The right to folly is not guaranteed, especially if society retains a residual obligation to deal with the results of a poor choice. Our society has not reached the point where it can act like a private insurance agency, monetizing its obligations to a client and negotiating a fixed payment that absolves it of further responsibility. As a result, we feel a need to protect people from themselves, relying on professional guidance to direct, or limit, choices among those deemed appropriate. The tension between assuring responsible action and offering clients real options persists (Kane, 1994). It would be easier to advocate for freer decision-making if the conditions for making good decisions could be met. These conditions include good information about the risks and benefits of each of various options and a clear expression of the values the client places on alternative outcomes as a basis for calculating the options that maximize the most desired events. With most LTC, and especially with regard to ADRD, these conditions cannot be met. An earlier Panel report addressed the problems of assessing the values placed on possible outcomes associated with ADRD (Advisory Panel on Alzheimer’s Disease, 1992). The current state of the art does not yield the requisite information base to assess the effects of alternative modalities of care.

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The past several years have witnessed growing interest in achieving some form of client control through use of advance directives to guide care when the client can no longer speak for him/herself. These directives usually address the avoidance or discontinuance of life support equipment. Closely related to this topic is the whole role of assisted suicide for people who fear living without their cognitive abilities and the potential for developing programs more akin to hospices, which focus exclusively on improving the quality of life of people with terminal conditions. Here too, because dementia robs individuals of their cognitive faculties, it is difficult to talk about quality of life, or at least to know how to assess success in improving it. A more generic question involves redistribution of resources. As society perceives a shrinking pool of resources for frail older people, questions can be raised about how best to distribute them. At present, a guiding principle has been to try to match resources to needs; those who need more care should get it. An alternative formulation uses more of a triage approach, which takes into account the likelihood of benefit. Resources are allocated to those who have both a need for them and a strong likelihood of benefiting from them. Under such a plan, those who are severely cognitively impaired and hence have little ability to express their quality of life might receive fewer services to make these resources more available to those who can better appreciate them. Because such a utilitarian doctrine raises major ethical dilemmas, careful analysis and much discussion are needed to examine the pros and cons of such a principle of resource distribution. Earlier reports from this Panel have addressed the need to find better ways to measure the success of different types of treatment for ADRD, both therapeutic and compensatory (Advisory Panel on Alzheimer’s Disease, 1992). The Panel’s interest in conducting outcomes research in ADRD and broadening our conceptions of outcome assessment is ongoing, including the planning and coordination of a 1996 conference devoted to outcomes and jointly sponsored by the Alzheimer’s Association, Agency for Health Care Policy and Research, and the Panel. The conference is viewed as a forum for identification and exploration of conceptual and methodological issues that must be addressed in evaluating the effectiveness of interventions designed to improve the lives of people affected by dementia. Resource allocation questions extend to distributional issues within ADRD as well. At present, most ADRD care is compensatory rather than therapeutic. That is, the clinical goals are directed at making patients comfortable and reducing stressors associated with the disease rather than seeking some demonstrative improvement in functional state. If services

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should be allocated on the basis of potential benefit, then those ADRD clients who have the least interaction with their environment should receive only minimal care, freeing resources for those who can appreciate the care more. Such a step would mean pursuing a policy that no longer devotes heavy nursing care to people in a vegetative state, for example, but instead looks for less intensive ways to mange these people humanely. More attention would be redirected to those who were more responsive to their environments in an effort to make those environments more satisfying and less disruptive.

End of Life Concerns Because ADRD are terminal illnesses, concern should be directed toward ways of best managing the end of life. For those patients who have reached a terminal stage, some form of hospice care may be appropriate. There is some evidence to suggest that levels of patient discomfort and the costs of care may be reduced (Volicer et al., 1994) and quality of life improved (Collins and Ogle, 1994). Further research is warranted on palliative care approaches in ADRD and on the needs of families who provide terminal care in the home.

Measuring Therapeutic Effectiveness More work is generally needed to assess the outcomes of care for ADRD patients. The Panel is participating in this effort by preparing a companion document devoted to an exploration of the goals of therapy in ADRD, and the general principles underlying the analysis of therapeutic goals. While work is ongoing to seek specific therapies designed to improve cognitive performance for people with ADRD, most of the current treatment efforts are designed to prevent untoward behavior or to reduce the stresses associated with the disease. Fogel has identified five patient-related factors that interact to produce behavior problems, given a specific physical and social environment: perception of current situation, level of arousal, awareness of social context and likely consequences of action, capacity for impulse control, and alternative outlets for self-expression (Fogel, 1994). Several categories of endpoints have been identified as outcomes to be considered and measured in therapeutic trials and interventions. These include cognition, physical function, social function, pain and discomfort, adverse behaviors, caregiver stress, and quality of life. Additional factors to be considered include

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management of co-existing medical conditions, avoidance of iatrogenic consequences, satisfaction with services, and involvement of caregivers in care planning.

Recommendations The Panel continues to support recommendations originally made in 1992: •

Specific research should be directed toward exploring a wider variety of living situations for people with ADRD and the effects on function and quality of life associated with these varied situations.

•

Research on support services for people with ADRD and their families (e.g., respite care) needs to address the issue of “dose-response,” including better quantification of both elements, the services provided, and the effects achieved.

•

In addition, several new recommendations have emerged that would facilitate research, policy development, and public understanding of alternatives to nursing home care:

•

State and Federal Governments should adopt uniform language to clearly describe for the public the residential care levels of LTC services and definitions of residential care based on the type of LTC services provided.

•

Appropriate assessment of the individual resident’s needs (which does not place an unreasonable burden on staff and facilities) should be required before entry into all levels of care in the LTC system, whether publicly or privately financed.

•

Create a centralized national database on home and community-based care capable of generating outcomes information to be used in comparing the quality and cost-effectiveness across all types of LTC.

•

The LTC system should allow and encourage older individuals, including those with ADRD, to choose to live in the settings they desire.

•

More work is needed to establish actuarially sound reimbursement rates based on the real financial risks presented by clients with dementia.

•

Work is needed to assess the relative effectiveness of alternative approaches to LTC (e.g., assisted living) for ADRD clients.

•

To improve rural care, the following recommendations should be considered:

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-

More training grants to increase the knowledge base and supply of rural practitioners working with people with ADRD and their caregivers.

-

More demonstration services grants with rigorous evaluation components to CMHC’s, community health centers, and county aging services reaching rural areas to develop, implement, and evaluate multidisciplinary outreach programs for people with dementia and their caregivers.

-

Establish and evaluate information/dissemination related to ADRD in rural settings.

-

Establish and evaluate mobile diagnostic and followup services coordinated by local health care providers with referral to “experts” in remote academic medical centers using innovative technology such as fiber optic networks.

mechanisms

•

Research on dementia care should address how value differences based on ethnicity, immigration status, race, and religion influence caregivers. Do these factors operate differently in rural compared to urban settings? Do these values change over the course of the illness, and are they different among caregivers in various geographic regions? What outcomes are desired by family caregivers in rural settings? What interventions enhance or maintain positive caregiving experiences in rural caregivers? Are they different than for their urban counterparts?

•

More research is needed on SCU’s with regard to staff and administrative issues: -

Determining which individual elements of programs for caring for people with dementia are most beneficial and cost effective

-

Number and type of SCU’s on a national basis

-

Separating patients with dementia versus integrated care along the continuum of care settings

-

Role of SCU’s within the LTC delivery system

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Organization of dementia-oriented practices in other LTC settings

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Controlled trials of specialized care

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Innovative use of technology for care and training

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Formal staff augmentation through training of volunteers and family

-

Abuse/exploitation and poor care of residents with dementia in SCU’s versus traditional nursing homes

Alzheimer’s and Related Dementias: Acute and Long-Term Care Services 479

-

Treatment/residential standards, focused differentially on caregiver groups

-

Detection and amelioration of depression, pain, anxiety, etc.

-

Appropriate levels of care to correspond with disease stage

-

Environmental design

•

More research is needed on dementia care in ADC’s with regard to the cost-effectiveness of adult day services, including quality of life for both caregiver/family and client/participant.

•

More research is needed on dementia care in assisted living with regard to:

•

-

Outcomes of assisted living compared to nursing home care

-

Outcomes and costs of aging in place in assisted living (with additional services provided as needed) compared to transfer to nursing homes

-

For which residents with dementia is assisted living more appropriate than nursing homes

-

Cost-effectiveness of small facilities versus larger ones

-

Effect of regulation on assisted living

Alzheimer’s Disease Research Centers should incorporate health services research. Specifically, more information is needed about the patterns of use and related costs for ADRD patients. A longitudinal database combining detailed clinical information with equally precise information about utilization of services would provide a useful basis for many estimations of the fiscal benefits of treatments.

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APPENDIX G. GENETICS OF ALZHEIMER’S DISEASE Overview56 Genes play a complex and not yet fully understood role in all living things. Their part in Alzheimer’s disease (AD) is no exception. The more researchers learn about AD, the more they become aware of the important function genes play in the development of AD. Recent excitement has centered around the discovery of the relationship between the apolipoprotein E (apoE) gene and AD.

Genes Like recipes, genes provide instructions about how to make something, indicating what ingredients go in and in what order. But, the environment (things outside the body like food, the air we breathe, or chemicals we are exposed to) and processes inside the body determine which ingredients are available and in what forms and quantities. Along with environmental influences, genes and processes inside the body combine to do more than just determine eye and hair color and other traits inherited from our parents. For example, genes ensure that we have two hands and can use them to do things, like play the piano. In almost every case, nature (genes) and nurture (including the physical and chemical environment) work together to shape all living things. Genes alone are not all-powerful. Most genes can do little until spurred on by other substances. Although they are necessary in their own right, genes Adapted from the National Institute on Aging: http://www.alzheimers.org/pubs/genefact.html.

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basically wait inside the cell’s nucleus (control center) for other molecules to come along and read their messages. Each of these messages is used to build a certain protein. Genes may build a protein correctly or incorrectly, depending on the content of the DNA (deoxyribonucleic acid) message. A gene can produce a faulty protein if it has one or more mutations (defects) in its DNA. Faulty proteins can lead to cell malfunction, disease, and death.

Anatomy of Genes57 The following illustration shows a cell, mitochondria, the cell membrane, a chromosome, the DNA double helix, DNA chains, linked sequence pairs of bases, paired bases, and the four bases (cytosine, adenine, quanine, and thymine). Within the nucleus of every human cell, two long, thread-like DNA strands encode the instructions for making all proteins needed for life. Each cell holds more than 50,000 different genes found on 46 chromosomes of tightly coiled DNA. Each DNA strand bears four types of coding molecules or bases. The sequence of bases in a gene is the code for making a protein.

57

http://www.alzheimers.org/pubs/dnagene.html

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Alzheimer’s Disease: Not a Single-Gene Disorder Diseases such as cystic fibrosis, muscular dystrophy, and Huntington’s disease are single-gene disorders. If a person inherits the gene that causes one of these disorders, he or she surely will get the disease, unless it is prevented by other means. AD, on the other hand, is not a single-gene disorder. More than one gene mutation can cause AD, and genes on multiple chromosomes are involved. Sometimes, two genes--one from each parent-are needed for a person to get the disorder. The two basic types of AD are familial and sporadic. Familial AD (FAD) is a rare form of AD, affecting less than 10 percent of AD patients. It is associated with gene mutations on chromosomes 1, 14, and 21. FAD is the result of a certain inheritance pattern called autosomal dominant. In this pattern, all offspring in the same generation have a 50/50 chance of developing AD if 1 of their parents had it. FAD occurs in younger people (usually before age 60) than sporadic AD does.

ApoE in Sporadic Alzheimer’s Disease Sporadic AD usually occurs later in life, is far more common than FAD, and appears to be related to the apoE gene found on chromosome 19. ApoE comes in several different forms or alleles, but three occur most frequently. People inherit one allele (apoE2, apoE3, or apoE4) of the apoE gene from each parent. People with both apoE3 and apoE4 alleles (E3/E4) are affected by both alleles. Having one or two copies of the E4 allele increases a person’s risk of getting AD. That is, having the E4 allele is a risk factor for AD. But, it does not mean that AD is certain. Having one or two E4 alleles of the apoE gene increases a person’s risk of AD, but not to 100 percent. Some people with two copies of the E4 allele (the highest risk group) have not developed the disease, and others with no E4s have. Scientists have yet to determine the exact degree of risk of AD for any given person based on apoE status.

Medical Tests Medical tests are designed for various purposes. Some tests can indicate susceptibility (the risk or likelihood of getting a disease); some help confirm diagnoses, and others assist in planning or monitoring treatment. In an effort to prevent disease, physicians test some people without symptoms to predict

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who might develop a given medical problem. For people with AD symptoms, doctors try to rule out other disorders and determine, as accurately as possible, what is causing the symptoms. If no other cause is found, AD is diagnosed.

ApoE Testing A blood test is available to identify which apoE alleles a person has, because apolipoprotein also is associated with an already well-studied condition, heart disease. However, this blood test cannot tell people whether they will develop AD, or when. Instead of a yes or no answer, the best information a person can get from this genetic assessment for apoE is maybe or maybe not. Although some people want to know whether they will get AD later in life, this type of prediction is not yet possible. In fact, some researchers believe that apoE tests or other screening measures may never be able to predict AD with 100 percent accuracy. In the research setting, apoE testing is a tool that can identify study volunteers who may be at risk of getting AD. In this way, researchers can look for early brain changes. This test also helps researchers compare the effectiveness of treatments for patients with different apoE statuses. Several researchers believe that the apoE test is most useful for studying AD risk in large groups of people and not for determining one person’s individual risk. Predictive screening in otherwise healthy people will be useful when effective ways to treat or prevent AD are available.

Concerns about Confidentiality ApoE testing, and indeed all genetic testing, raises ethical, legal, and social questions for which we have few answers. ApoE information gathered for research purposes generally can be protected by confidentiality laws. On the other hand, information obtained in apoE testing may not be protected as confidential once it is part of a person’s medical records. Thereafter, employers, insurance companies, and other health care organizations could gain access to this information; and discrimination could result. For example, employment opportunities or insurance premiums could be affected. Little is known about how stigma associated with an increased risk for AD may affect people’s families and their lives.

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Public Policy on ApoE Testing Scientists, ethicists, and other health professionals joined together in October of 1995 to write a public policy statement about the appropriateness of apoE testing and the role of genetic counseling for AD. Discussions leading to the statement took place at a conference in Chicago, Illinois, sponsored by the National Institute on Aging (NIA) and the Alzheimer’s Association. The public policy statement supports the use of apoE testing for diagnostic purposes only in conjunction with other tests during medical evaluations of patients who show AD symptoms. It recommends not using apoE testing as a patient screening (predictive) method. Conference participants said that further research and agreement about confidentiality are needed before they will recommend routine apoE testing.

Genetic Counseling Depending on the study, research volunteers may have the opportunity, during genetic counseling, to learn the results of their apoE testing. The meaning of these results is complex. Since the results of apoE testing can be hard to understand, and more importantly, devastating to those tested, the NIA and the Alzheimer’s Association recommend that research volunteers and their families receive genetic counseling before and after testing. People who learn through testing that they have an increased risk of getting AD may experience emotional distress and depression about the future because there is no effective way to prevent or cure the disease. Through counseling, families can learn about the genetics of AD, the tests themselves, and possible meanings of the results. Due to privacy, emotional, and health care issues, the primary goal of genetic counseling is to help people with AD and their families explore and cope with the consequences of such knowledge.

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For the free fact sheet, Genetic Counseling: Valuable Information for You and Your Family, you may write, fax, or e-mail the National Society for Genetic Counselors (NSGC). Their address is: NSGC, Executive Office 233 Canterbury Drive Wallingford, PA 19086-6617 610-872-1192 (fax) [email protected] (e-mail) The NSGC does not provide information about specific genetic disorders.

Research Questions Many questions remain about the usefulness of apoE testing in non-research settings. Some researchers believe that the best use of apoE testing will be as one in a combination of methods for assessing patients (including family history, neurological tests, needs assessments, etc.) to help doctors make informed treatment recommendations. Experts still do not know how limited information about AD risk can benefit people. Among the issues are privacy and confidentiality policies related to genetic information and AD, and the small number of genetic counselors now trained in neurodegenerative disorders. Learning more about the role of apoE in the development of AD may help scientists identify who would benefit from prevention and treatment efforts. Age, still the most important known risk factor for AD, continues to be associated with the disease even when no known genetic factors are present. Research focusing on advancing age may help explain the role that other genes play in most AD cases. For example, recent research suggests that certain alleles of other as yet unidentified genes also may increase risk in late-onset cases. Scores of AD researchers are studying the genetics of AD. In addition, researchers, ethicists, and health care providers are developing policies about the appropriate use of genetic testing and counseling for AD.

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For More Information Accurate, current information about AD and its risk factors is important to patients and their families, health professionals, and the public. The Alzheimer’s Disease Education and Referral (ADEAR) Center is a service of the NIA and is funded by the Federal Government. The ADEAR Center offers information and publications about diagnosis, treatment, patient care, caregiver needs, long-term care, education and training, and research related to AD. Staff respond to telephone and written requests and make referrals to national- and State-level resources. The ADEAR Center distributes two other free fact sheets about apoE and heredity: •

Alzheimer’s Disease and Apolipoprotein E From the University of California, San Diego Alzheimer’s Disease Research Center. Describes the relationship between AD and apoE.

•

Alzheimer’s Disease and Heredity From the Alzheimer Society of Canada. Discusses current knowledge about family history and AD, FAD, sporadic AD, and apoE4; and what scientists are doing to learn more about each.

For more information about genetics and AD, contact: ADEAR Center PO Box 8250 Silver Spring, MD 20907-8250 800-438-4380 (toll-free) 301-495-3334 (fax) [email protected] (e-mail) http://www.alzheimers.org/adear

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APPENDIX H. 2000 PROGRESS REPORT ON ALZHEIMER’S DISEASE Overview58 Alzheimer’s disease (AD) is an age-related and irreversible brain disorder that occurs gradually and results in memory loss, behavior and personality changes, and a decline in thinking abilities. These losses are related to the breakdown of the connections between nerve cells in the brain and the eventual death of many of these cells. The course of this disease varies from person to person, as does the rate of decline. On average, patients with AD live for 8 to 10 years after they are diagnosed, though the disease can last for up to 20 years. AD is part of a group of disorders, termed dementias, that are characterized by cognitive and behavioral problems. AD advances progressively, from mild forgetfulness to a severe loss of mental function. In most people with AD, symptoms first appear after age 60. The earliest symptoms characteristically include loss of recent memory, later compounded by faulty judgment, and changes in personality. Often, people in the initial stages of AD think less clearly and tend to be easily confused. Later in the disease, they may forget how to do simple tasks, such as how to dress themselves or eat with proper utensils. Eventually, people with AD lose the capacity to function on their own and become completely dependent on other people for their everyday care. Finally, the disease becomes so debilitating that patients are bedridden and likely to develop other illnesses and infections. Most commonly, people with AD die of pneumonia.

Adapted from the National Institute on Aging: http://www.alzheimers.org/pubs/prog00.htm.

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Although the risk of developing AD increases with age, AD and dementia symptoms are not a part of normal aging. AD and other dementing disorders are caused by diseases that affect the brain. In the absence of disease, the human brain often can function well into the tenth decade of life.

The Impact of Alzheimer’s Disease AD is the most common cause of dementia among people age 65 and older. It presents a major health problem for the United States because of its enormous impact on individuals, families, the health care system, and society as a whole. Scientists estimate that up to 4 million people currently suffer with the disease, and the prevalence (the number of people with the disease at any one time) doubles every 5 years beyond age 65. It is also estimated that approximately 360,000 new cases (incidence) will occur each year and that this number will increase as the population ages (Brookmeyer et al., 1998). These numbers are significant now and will become even more so in the future. Since the turn of the century, life expectancies have increased dramatically. An estimated 35 million people – 13 percent of the total population of the United States – are now aged 65 and older. According to the U.S. Bureau of the Census, this percentage will accelerate rapidly beginning in 2011, when the first baby boomers reach age 65. By 2050 the number of Americans aged 65 and older will have doubled, to 70 million people. Approximately 4 million Americans are 85 years old or older, and in most industrialized countries, this age group is one of the fastest growing segments of the population. The Bureau of the Census estimates that this group will number nearly 19 million by the year 2050; some experts who study population trends suggest that the number could be even greater. This trend is not only apparent in the U.S. but also worldwide. As more and more people live longer, the number of people affected by diseases of aging, including AD, will continue to grow. For example, one study shows that nearly half of all people age 85 and older have some form of dementia (Evans et al., 1989). One of the most pressing current issues is determining possible differences in AD risk, incidence, and prevalence among various racial and ethnic groups. These differences are important to study for several reasons. One is that the percentage of non-Caucasians in the older U.S. population is growing rapidly (by the year 2050, the percentage of the population over the

2000 Progress Report on Alzheimer’s Disease 491

age of 65 that is non-Caucasian will have increased from 16 percent to 34 percent). Another is that the variations in prevalence may give us important future insights into the different roles that particular genetic and environmental factors play in the development of AD. Recent research has shown that African Americans and Hispanic Americans may have a higher overall risk of AD than do Caucasians (Tang et al., 1998), although other studies have found conflicting results (Fillenbaum et al., 1998). It is important to note that many factors may be responsible for these differing estimates, for these populations vary in many respects besides their racial or ethnic diversity. Differences in socioeconomic status, health care, education, events occurring before birth (prenatally) or right around birth (perinatally), and life history may all influence a person’s eventual risk of AD. Even the ways in which diagnostic tests that measure language, memory, and cognitive function are constructed and applied may cause people to be diagnosed with AD if their level of education or cultural assimilation makes them score lower on the test than do people with a higher level of education who are more culturally assimilated. Clearly, further careful investigation is needed to examine the role that ethnic and racial differences may play in determining the risk of AD, and studies now ongoing should begin to provide some answers. AD puts a heavy economic burden on society. A recent study estimated that the annual cost of caring for one AD patient is $18,408 for a patient with mild AD, $30,096 for a patient with moderate AD, and $36,132 for a patient with severe AD (Leon et al., 1998). The annual national direct and indirect costs of caring for AD patients are estimated to be as much as $100 billion (Ernst and Hay, 1994; Ernst et al., 1997; Huang et al., 1988). Slightly more than half of AD patients receive care at home, while the remainder are cared for in a variety of health care institutions. Many spouses, relatives, and friends take care of people with AD. During their years of caregiving, these families and friends experience emotional, physical, and financial stresses. They watch their loved ones become more and more forgetful, frustrated, and confused. Eventually, the person with AD may not even recognize his or her nearest and dearest relatives and friends. Caregivers – most of whom are women – must juggle child care, jobs, and other responsibilities with caring for relatives with AD who cannot function on their own. As the disease runs its course and the abilities of people with AD steadily decline, family members face difficult decisions about the long-term care of their loved ones. Frequently, they have no choice but to place their relative in a nursing home. The numbers of caregivers – and their needs – can be expected to grow significantly as the population ages and as the number of people with AD increases.

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Alzheimer’s Disease: An Urgent National Health and Research Priority Given our aging population, the magnitude of AD as a national health problem is steadily increasing. This makes the disease an urgent research priority. Interventions that could delay the onset of AD would have an enormous positive public health impact because they would reduce the number of people with the disease. This in turn would reduce the personal and financial costs associated with caring for them. A recent analysis provides a vivid illustration of the impact of delaying AD by even a few years. In this paper, the authors report that an intervention that could delay the mean onset of Alzheimer’s disease by approximately 5 years, would reduce the numbers of persons with AD by 50 percent by the year 2050 (Brookmeyer et al., 1998).

The AD Research Effort AD research supported by the Federal Government is divided into three broad, overlapping areas: causes/risk factors, diagnosis, and treatment/caregiving. Research into the basic biology of the aging nervous system is critical to understanding what goes wrong in the brain of a person with AD. Understanding how nerve cells lose their ability to communicate with each other and the reasons why some nerve cells die and others do not is at the heart of scientific efforts to discover what causes AD. Many researchers also are looking for better ways to diagnose AD in the early stages and to identify the earliest brain changes that eventually result in AD. Investigators are striving to identify markers (indicators) of dementia, develop and improve ways to test patient function, determine causes and assess risk factors, and improve case-finding and sampling methods for population studies. Other researchers are working hard to discover and develop drugs that may help to treat symptoms or slow the progress of the disease, and eventually delay the onset of and prevent AD. Many of these drugs are now being tested in clinical trials. Finally, scientists and many health care professionals are seeking better ways to help patients and caregivers cope with the decline in mental and physical abilities and the problem behaviors that accompany the disease and to support those who care for people with AD. The National Institute on Aging (NIA), part of the Federal Government’s National

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Institutes of Health (NIH), has primary responsibility for research aimed at finding ways to prevent, treat, and cure AD. The Institute’s AD research program is integral to one of its main goals, which is to enhance the quality of life of older people by expanding knowledge about the aging brain and nervous system. The 2000 Progress Report on Alzheimer’s Disease summarizes AD research conducted or supported by NIA and other components of NIH, including: •

National Institute of Neurological Disorders and Stroke

•

National Institute of Mental Health

•

National Institute of Nursing Research

•

National Institute on Alcohol Abuse and Alcoholism

•

National Institute of Environmental Health Sciences

•

National Institute of Child Health and Human Development

•

Human Genome Research Institute

•

National Center for Complementary and Alternative Medicine

Other more modest AD research efforts not summarized in this report are supported by the National Institute on Deafness and Other Communication Disorders, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Fogarty International Center. The manifestations of Alzheimer’s disease have been recognized since ancient times. Greek and Roman writers described symptoms similar to those that we know as AD. In the 16th century, Shakespeare wrote about very old age as a time of “second childishness and mere oblivion,” suggesting that the symptoms of AD, or something quite like it, were known and recognized then. Despite this long familiarity, relatively little was known until recently about the processes in the brain that lead to Alzheimer’s disease. Most physicians assumed that AD dementia was merely an inevitable consequence of aging. Scientists have made enormous progress in the last 25 years. Today, we know much more about Alzheimer’s disease – what it is, who gets it, how it develops, and what course it follows. We have also made significant progress in the critical area of early diagnosis and have some promising leads on possible treatments. All of this research has deepened our understanding of this devastating disease. It also has expanded our knowledge about other late-life neurodegenerative diseases, brain function in healthy older people, and ways in which to minimize normal age-related cognitive decline.

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The 2000 Progress Report on Alzheimer’s Disease describes this important research effort. It begins with a description of our current knowledge about AD. This provides the backdrop for the next two sections, which present highlights of recent research conducted by NIA and by other NIH Institutes. The report closes with a section called “Outlook for the Future,” which summarizes progress in the ongoing NIH Alzheimer’s Disease Prevention Initiative as well as the new President’s Initiative on Alzheimer’s Disease. These initiatives are designed to accelerate laboratory and clinical research and collaboration across the Federal Government and the private sector and to turn research results into real advances for patients, families, and caregivers.

Alzheimer’s Disease: More Pieces of the Puzzle Fall into Place In normal aging, nerve cells in the brain are not lost in large numbers. In contrast, AD causes many nerve cells to stop functioning, lose connections with other nerve cells, and die. At first, AD destroys neurons in parts of the brain that control memory, including the hippocampus (a structure deep in the brain that helps to encode short-term memories) and related structures. As nerve cells in the hippocampus stop working properly, short-term memory fails, and often, a person’s ability to do easy and familiar tasks begins to decline. AD later attacks the cerebral cortex, particularly the areas responsible for language and reasoning. At this point, AD begins to take away language skills and changes a person’s ability to make judgments. Personality changes also may occur. Emotional outbursts and disturbing behaviors, such as wandering and agitation, begin to occur and become more and more frequent as the disease continues its course. Eventually, many other areas of the brain are involved, all these brain regions atrophy (shrink and lose function), and the person with AD becomes bedridden, incontinent, totally helpless, and unresponsive to the outside world.

What Are the Main Characteristics of AD? Two abnormal structures in the brain are the hallmarks of AD: amyloid plaques and neurofibrillary tangles. Though scientists have known about plaques and tangles for many years, more recent research has revealed much about their composition, how they form, and their possible roles in the development of AD.

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Amyloid Plaques In AD, plaques develop first in areas of the brain used for memory and other cognitive functions. They consist of largely insoluble (cannot be dissolved) deposits of beta-amyloid – a protein fragment snipped from a larger protein called amyloid precursor protein (APP) – intermingled with portions of neurons and with non-nerve cells such as microglia (cells that surround and digest damaged cells or foreign substances that cause inflammation) and astrocytes (glial cells that serve to support and nourish neurons). Plaques are found in the spaces between the brain’s nerve cells. Although researchers still do not know whether amyloid plaques themselves cause AD or whether they are a by-product of the AD process, there is evidence that amyloid deposition may be a central process in the disease. Certainly, changes in the structure of the APP protein can cause AD, as shown in one inherited form of AD, which is caused by mutations in the gene that contains instructions for making the APP protein. Recent work has revealed much about the nature of beta-amyloid and the ways in which it may be toxic to neurons, the processes by which plaques form and are deposited in the brain, and ways in which the numbers of plaques can be reduced.

Neurofibrillary Tangles The second hallmark of AD consists of abnormal collections of twisted threads found inside nerve cells. The chief component of these tangles is one form of a protein called tau. In the central nervous system, tau proteins are best known for their ability to bind and help stabilize microtubules, which are one constituent of the cell’s internal support structure, or skeleton. In healthy neurons, microtubules form structures like train tracks, which guide nutrients and molecules from the bodies of the cells down to the ends of the axon. Tau normally holds together the “railroad ties” or connector pieces of the microtubule tracks. However, in AD tau is changed chemically, and this altered tau twists into paired helical filaments – two threads of tau wound around each other. These filaments aggregate to form neurofibrillary tangles. When this happens, the tau no longer holds the railroad tracks together and the microtubules fall apart. This collapse of the transport system first may result in malfunctions in communication between nerve cells and later may lead to neuronal death that contributes to the development of dementia. Recent research has shed much light on this abnormal aggregation of tau protein and on the role that certain genetic

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mutations play in neurodegeneration.

changing

tau’s

structure

and

contributing

to

Structure and Function of the Brain The brain (the central nervous system) is essential to our survival. With the help of motor and sensory nerves outside of the brain and spinal cord (the peripheral nervous system), it integrates, regulates, initiates, and controls functions in the whole body. The brain governs thinking, personality, mood, the senses, and physical action. We can speak, move, remember, and feel emotions and physical sensations because of the complex interplay of chemical and electrical processes that take place in our brains. The brain also regulates body functions that happen without our knowledge or direction, such as breathing and digesting food. The human brain is made up of billions of nerve cells, called neurons, that share information with one another through a large array of biological and chemical signals. Each neuron has a cell body, an axon, and many dendrites, all surrounded by a cell membrane.The nucleus, which contains genes composed of deoxyribonucleic acid (DNA), controls the cell’s activities. The axon, which extends from the cell body, transmits messages to other neurons, sometimes over very long distances. Dendrites, which also branch out from the cell body, receive messages from axons of other nerve cells or from specialized sense organs. Axons and dendrites collectively are called neurites. Even more numerous are the glial cells (such as astrocytes), which surround, support, and nourish neurons. Neurons communicate with each other and with sense organs by producing and releasing special chemicals called neurotransmitters. As a neuron receives messages from surrounding cells, an electrical charge (nerve impulse) builds up within the cell. This charge travels down the axon until it reaches the end. Here, it triggers the release of the neurotransmitters that move from the axon across a gap between it and the dendrites or cell bodies of other neurons. Scientists estimate that the typical neuron has up to 15,000 of these gaps, called syn-apses. The neurotransmitters bind to specific receptor sites on the receiving end of dendrites or cell bodies of adjacent nerve cells. In this way, signals travel back and forth across the neurons or connections in the brain in a fraction of a second. Millions of signals are flashing through the brain at any one time.

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Groups of neurons in the brain have specific jobs. For example, some neurons are involved in thinking, learning, remembering, and planning. Others are responsible for processing visual or auditory stimuli, regulating the body’s biological clock, or managing the myriad of other jobs that keep the human body functioning. The survival of neurons in the brain depends on the healthy functioning of several processes all working in harmony. These processes involve neuronal activities related to intercellular com-munication, cellular metabolism, and cell and tissue repair. The first process, communication between neurons, depends on the integrity of the neuron and its connections, as well as the production of neurotransmitters. The loss or absence of any one of the parts in this process disrupts cell-to-cell communication and interferes with normal brain function. The second process is metabolism, the pathway(s) by which cells and molecules break down chemicals and nutrients to generate energy. This energy is then used to replenish the building blocks necessary for optimal neuronal function. Efficient metabolism requires adequate blood circulation to supply the cells with oxygen and important nutrients, such as glucose (a sugar). Sometimes, metabolic processes go awry and by-products such as tangles and plaques build up inside and outside of cells and prevent them from working efficiently. The third process is the repair of injured neurons. Unlike most other body cells, neurons must live a long time. Brain neurons have the capacity to last more than 100 years. In an adult, when neurons die because of disease or injury, they are usually not replaced (the exceptions are neurons in particular locations and of a particular type). To prevent their own death, living neurons must constantly maintain and remodel themselves. If cell cleanup and repair slows down or stops for any reason, the nerve cell cannot function properly. It is not clear when and why some neurons start to die and some synapses stop working. Research shows that the damage seen in Alzheimer’s disease involves changes in all three of these processes: nerve cell communication, metabolism, and repair.

What Causes AD? One important part of solving the AD puzzle is knowing what causes it: What makes the disease process begin in the first place and what contributes

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to its development? Why are some neurons more vulnerable and likely to die than are others? Why does the prevalence of AD increase with age? Some diseases, like tuberculosis, have clear-cut causes. Others, such as diabetes or arthritis, result from many interrelated factors, including genetic, environmental, and other factors. AD fits into this latter group of diseases. Scientists do not yet fully understand what causes AD, but it is clear that AD develops as a result of a complex cascade of events that take place over many years inside the brain. The disease may be triggered by any number of small changes in this cascade, probably as a result of the interaction of different genetic and non-genetic factors in different individuals. Scientists have come a long way toward elucidating the genetic and non-genetic factors that contribute to the development of AD.

Genetic Factors in AD Development Two types of Alzheimer’s disease exist: familial AD (FAD), which follows a certain inheritance pattern, and sporadic AD, where no obvious inheritance pattern is seen. Because of differences in the age at onset, AD is further described as early-onset (occurring in people younger than 65) or late-onset (occurring in those 65 and older). Early-onset AD is rare (about 5 to 10 percent of cases) and generally affects people aged 30 to 60. Some forms of early-onset AD are inherited and run in families. Early-onset AD also often progresses faster than the more common, late-onset form. All FAD known so far has an early onset, and as many as 50 percent of FAD cases are now known to be caused by defects in three genes located on three different chromosomes. Some families have mutations in the APP gene located on chromosome 21, which causes an abnormal APP protein to be produced; others have mutations in a gene called presenilin 1 located on chromosome 14, which causes an abnormal presenilin 1 protein to be produced; and still others have mutations in a very similar gene called presenilin 2 located on chromosome 1, which causes an abnormal presenilin 2 protein to be produced. Even if one of these mutations is present in only one of the two copies of a gene inherited from the parents, the person will inevitably develop that form of early-onset AD (this is called autosomal dominant inheritance). However, the total known number of these cases is small (between 100 and 200 worldwide), and there is as yet no evidence that any of these mutations play a major role in the more common, sporadic or non-familial form of late-onset AD. Scientists are now working to reveal the normal function of APP and presenilins and to determine how mutations of these genes cause the onset of FAD.

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Although there is no evidence that autosomal dominant inheritance of mutated genes causes late-onset AD, genetics does appear to play a role in the development of this more common form of AD. In the early 1990s, researchers at the NIA-supported Alzheimer’s Disease Center at Duke University in Durham, North Carolina, found an increased risk for late-onset AD with inheritance of one or two copies of the apolipoprotein E epsilon4 (APOE e4) allele on chromosome 19 (Strittmatter et al., 1993). Different alleles of particular genes produce variations in inherited characteristics, such as eye color or blood type. In this case, the variations are in the APOE gene that directs the manufacture of the ApoE protein. This protein helps carry blood cholesterol throughout the body, among other functions. It is found in glial cells and neurons of healthy brains, but it is also associated in excess amounts with the plaques found in the brains of people with AD. Researchers are particularly interested in three common alleles of the APOE gene: e2, e3, and e4. The finding that increased risk is linked with inheritance of the APOE e4 allele has helped explain some of the variations in age of onset of AD based on whether people have inherited zero, one, or two copies of the APOE e4 allele from their parents. The more APOE e4 alleles inherited, the lower the age of onset. The relatively rare APOE e2 allele may protect some people against the disease; it seems to be associated with a lower risk for AD and a later age of onset if AD does develop. APOE e3 is the most common version found in the general population and may play a neutral role in AD. The inheritance of one or two APOE e4 alleles does not predict AD with certainty. That is, unlike early-onset FAD, which is caused by specific genetic mutations, a person can have one or two APOE e4 alleles and still not get the disease, and a person who develops AD may not have any APOE e4 alleles. APOE e4 increases the risk of developing AD; it does not cause the disease. The ways in which APOE e4 increases the likelihood of developing AD are not known with certainty, but one possible mechanism is that it facilitates beta-amyloid buildup in plaques and this contributes to lowering the age of onset of AD. Other theories involve interactions with cholesterol levels and effects on nerve cell death that are independent of its effects on plaque buildup. Studies over the last several years strongly suggest that there are additional risk factor genes for late-onset AD, and candidates continue to be identified in this exciting new area of research. Building on the improving understanding of AD genetics, scientists will continue to look for clues as to which protein structures hasten the initiation of the disease process, what mechanisms cause AD, and what the sequence of events is. Once they

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understand these, they can then look for new ways to diagnose, treat, or even prevent AD.

Aging and AD Development Getting older, in and of itself, is the major risk factor for AD. During the course of normal aging, the brain undergoes a number of changes: •

Some neurons in some brain regions die, although most neurons important to learning do not die;

•

Some neurons and their processes shrink and function less well, especially neurons in areas important to learning, memory, planning, and other complex mental activities;

•

Tangles develop in neurons and plaques develop in surrounding areas in particular brain regions;

•

The mitochondria in cells become more susceptible to damage (mitochondria are tiny organelles within the cell that break down glucose to release energy, which is then used by the cell to carry out its functions);

•

Inflammation increases; and

•

Oxidative stress increases.

In healthy older people, the impact of these changes may be modest, resulting in various degrees of age-related memory decline. In people who develop AD, on the other hand, some of these changes are much more extreme and have devastating consequences. Many scientists are studying the processes involved in normal aging of the brain in hopes of learning more about them and the differences between normal brain aging and AD. For example, scientists are intensively studying the increase in oxidative stress that occurs in the aging brain when mitochondria in cells become more susceptible to damage. During normal metabolism, the body produces a kind of molecule called a free radical. Free radicals may help cells in certain ways, such as in fighting infection. However, free radicals are highly reactive, and the production of too many is called oxidative stress. Oxidative stress, which can injure cells, resulting in nerve cell damage and death, is now believed to be a major contributor to the aging process. Because AD almost always develops in older people, who often have other conditions, such as heart disease or high blood pressure, scientists are also interested in exploring whether these conditions play any role in the development of AD. For example, cerebrovascular disease is the second most

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common cause of dementia and there is some evidence that brain infarctions (strokes) and AD may possibly be linked. A brain infarction is an area of injury in brain tissue that usually occurs when the blood supply to that area is interrupted, depriving neurons of essential oxygen and glucose and causing vital circuits to die. Although major strokes have obvious consequences, small ones may go undetected clinically. Another lifestyle factor that may be important is blood cholesterol levels. Scientists are showing that high blood cholesterol levels may increase the rate of plaque deposition in special breeds of genetically engineered, or transgenic, mice. Finally, it is becoming clear that there are parallels between AD and other progressive neurodegenerative disorders that cause dementia, including prion diseases, Parkinson’s disease (PD), and Huntington’s disease. All involve deposits of abnormal proteins in the brain, and new research is showing that these diseases have a number of important overlapping characteristics.

What Do We Know about Diagnosing AD? Currently, clinicians use a range of tools to diagnose “possible AD” (dementia could also be due to another condition such as stroke) or “probable AD” (no other cause of dementia can be found) in a patient who is having difficulties with memory or other mental functions. These tools include a patient history, physical exam, and tests that measure memory, language skills, and other abilities related to brain functioning. Much is known about the clinical and behavioral characteristics of the disease and this also helps in diagnosing AD. Sometimes, brain scans are used to rule out the presence of strokes or tumors. The diagnostic process is crucial not only to accurately identify AD but to rule out other conditions that might be causing cognitive problems or dementia, such as stroke, PD, or inappropriate doses of medications. However, at the present time, AD can be diagnosed conclusively only by examining the brain after death in an autopsy to determine whether the levels of plaques and tangles in certain brain regions are characteristic of AD. The earlier an accurate diagnosis of AD is made clinically, the greater the gain in managing symptoms. An early, accurate diagnosis of AD is especially important to patients and their families because it helps them plan for the future and pursue care options while the patient can still take part in making decisions. Researchers have made major progress in developing accurate diagnostic tests and techniques. In specialized research facilities, trained clinicians can now diagnose AD with up to 90 percent accuracy. Scientists are now

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working in several areas that may improve the ability of clinicians to make accurate diagnoses of AD even earlier and that are providing important insights into the earliest changes that occur in the brain of an AD patient even before a clinical diagnosis is made. These insights will help scientists determine the natural history of AD and understand the ways in which the changes in memory and other cognitive functions that occur in AD differ from those of normal aging and of other dementias. They will also help researchers pinpoint early changes that could be targets for drug therapy. One area of very active research is mild cognitive impairment (MCI). Individuals who have a memory problem but who do not meet the generally accepted clinical criteria for AD are considered to have MCI with memory loss. They are becoming an increasingly important group for AD researchers to study because it is now known that about 40 percent of them will develop AD within 3 years. Some, however, whose memory loss is due to other causes, never develop AD. Understanding the different characteristics and clinical courses of MCI and AD will be essential in helping clinicians diagnose AD early and accurately. One of the most important developments in neuroscience research during the past 10 years has been the refinement of techniques that allow scientists to look at changes in structure and function in the living brain. One of these techniques is magnetic resonance imaging (MRI), which can be used to measure the size of various structures in the brain. Many studies have shown that AD causes some brain structures, particularly the hippocampus, to shrink early on in the disease, and scientists are exploring exactly how early this shrinkage can be detected. Several teams of NIA-funded scientists have established the usefulness of MRI as a research tool to help determine which people with memory problems are in the earliest stages of AD; to identify people who later will be diagnosed with AD; and to distinguish between people with MCI and those with no memory or learning problems, and between people without AD and those with very mild AD. Another set of imaging techniques allows scientists to visualize the activity and interactions of particular brain regions as they are used during cognitive operations such as memorizing, recalling, speaking, reading, learning, and other sorts of information processing. This window on the living brain can help scientists measure early changes in brain function or structure to identify those individuals who are at risk of Alzheimer’s disease even before they develop the symptoms of the disease. These imaging techniques include positron emission tomography (PET) scans and single photon emission computed tomography (SPECT) scans. Although these various imaging techniques are still used primarily as research tools, they hold great promise,

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along with other diagnostic measures, for earlier identification of persons at risk of developing AD.

Chromosomes and Genes: The Database of Life The nucleus of every human cell in a healthy person’s body contains a vast chemical information database that carries all the instructions the cell needs to carry on all its functions (the only exception is mature red blood cells, which have no nucleus). This database is DNA, which exists as two long, intertwined, thread-like strands – the double helix. These tightly coiled strands are packaged in units called chromosomes. Each human cell has 46 chromosomes in 23 pairs. An equal amount of the genetic material in these chromosomes is inherited from each parent. The chromosomes are made up of linear arrays of four chemicals, called bases, arranged in various sequence patterns. These sequence patterns make up many thousands of segments, called genes. In each gene, the bases are lined up in a unique and specific order, and these different sequences of bases direct the production of specific proteins. The proteins that are produced as a result of these genetic instructions determine the physical characteristics of living organisms and direct almost every aspect of the organism’s construction, operation, and repair. Even one base change in a gene’s DNA code can result in the production of an abnormal protein, and such a protein can lead to cell malfunction and possible disease. Rare changes in a gene’s DNA code are called mutations. Some mutations can cause disease. Variations in DNA sequence that do not automatically cause disease and that occur relatively frequently in particular human populations are called polymorphisms. Everyone inherits a large number of these polymorphisms all along their DNA. Particular sets of polymorphisms vary in frequency among different ethnic groups. Some can affect protein structure, altering the efficiency with which metabolic reactions take place, but not so much as to cause disease on their own. Versions of a gene that contain different polymorphisms are called alleles. When one of these alterations in a gene increases the likelihood that a person will develop a particular disease, it is called a genetic risk factor. The APOE e4 allele is one example of a genetic risk factor for AD.

How Can Alzheimer’s Disease Be Treated? For those who are already suffering from the effects of AD, the most immediate need is for treatments to control their symptoms, including

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cognitive loss as well as problem behaviors such as verbal and physical aggression, agitation, wandering, depression, sleep disturbances, and delusions. Treatments are needed that work on many patients, remain effective for a long time, ease a broad range of symptoms, improve patients’ cognitive function and ability to carry out activities of daily living, and have no serious side effects. Eventually, scientists also hope to develop drugs that attack fundamental AD processes, preventing them from progressing to the state where they damage cognitive function and quality of life. The Food and Drug Administration (FDA) has approved three medications for AD. All act by inhibiting acetylcholinesterase, an enzyme that normally breaks down acetylcholine, a key neurotransmitter involved in cognitive functioning. This neurotransmitter is produced by one set of neurons whose function is gradually lost in AD. The first of these medications, approved in 1993, was tacrine (Cognex). The second, approved in 1996, was donepezil hydrochloride (Aricept). Aricept is the drug most commonly used now to treat mild to moderate symptoms of AD. However, like Cognex, Aricept does not stop or reverse the progression of AD, and it appears to help only some AD patients for a period of time ranging from months to about 2 years, so its usefulness is limited. In April 2000, the FDA approved rivastigmine (Exelon) for the treatment of mild to moderate AD symptoms. In clinical trials involving more than 3,900 patients worldwide, the drug improved patients’ ability to carry out activities of daily living, such as eating and dressing. Patients also had fewer or less severe behavioral symptoms, such as delusions and agitation, and showed improvement in cognitive functions such as thinking, memory, and speaking. However, like the other two drugs, Exelon will not stop or reverse AD. Many other investigators are working to improve the quality of life for both patients and caregivers through research to develop better behavioral management techniques and caregiver skills. One of the primary characteristics of the NIH AD research effort over the last 25 years has been support for a wide range of studies by a large and multidisciplinary cadre of researchers. Some of these investigations have developed to the point of suggesting new ways of treating AD. All have contributed to building the solid base of knowledge that exists today. The continuing expansion of this base is pointing scientists in new and productive research directions. It is also helping investigators ask better questions about the issues that still remain unclear. The remaining sections of the 2000 Progress Report on Alzheimer’s Disease describe some of these exciting areas of research and the results that have emerged in the last year.

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2000 AD: Research Advances: Taking the Next Steps During the last year, researchers supported by NIA and other NIH Institutes made advances in a number of areas important to Alzheimer’s disease, including: •

Understanding the etiology of AD – the biological events that cause the changes in brain cells and tissues that lead to AD;

•

Improving early diagnosis;

•

Developing drug treatments;

•

Improving support for caregivers; and

•

Building the research infrastructure.

Understanding the Etiology of AD In the last year, scientists continued to improve their understanding of how different forms of AD develop, how mutations in the AD early-onset genes initiate the cascade of biological events that eventually lead to the death of a person with AD, in what order events in the cascade take place, what brain regions are affected earliest and why, and how genetic and environmental factors may interplay to determine the overall likelihood of AD developing. Answers to questions about the fundamental nature of the disease and the way in which it evolves will help investigators create improved methods for diagnosing AD before a patient has any behavioral symptoms, develop effective treatments, or perhaps someday, even prevent this devastating disease.

Amyloid Scientists have known for many years that amyloid plaques in the brain, formed by the aggregation of individual fragments derived from a larger protein, APP, are a prominent and diagnostic feature of AD. It has been hypothesized that an approach to preventing AD is to block the production of amyloid in the brain, though there is as yet no formal proof that this would prevent the development of the clinical symptoms of AD. An important focus of scientific research, therefore, is finding out how to block the formation of beta-amyloid. Another is finding ways to inhibit amyloid’s deposition into insoluble plaques once it is formed. NIA-supported investigators in a number of laboratories made significant progress in these

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areas, including headway on a possible anti-amyloid vaccine. In addition, in one of the most important stories of the year, several teams of industry-, foundation-, and NIH-supported researchers identified two of the longelusive enzymes that clip APP and create the beta-amyloid fragments.

Pursuing an Anti-Amyloid Vaccine The 1999 Progress Report on Alzheimer’s Disease described recent breakthrough studies that took the first steps toward a possible AD vaccine. Using transgenic mice that carry mutant human forms of APP and show extensive amyloid plaque formation with advancing age, researchers at Elan Pharmaceuticals showed that repeated administration of an amyloid vaccine to generate an immune response can almost eliminate formation of amyloid plaques in these mice (Schenk et al., 1999). Research this year by these same scientists has shown encouraging results in the further development and testing of the amyloid vaccine approach. For example, they found that the vaccine is not toxic in a variety of animals studied, including non-human primates. Preliminary safety studies in humans have shown that one vaccination is well tolerated, and safety testing of multiple injections has begun. If additional testing of the vaccine approach reveals that it is safe in humans, the company plans to start efficacy trials in 2001 (Helmuth, 2000). Two major hurdles remain: Will the vaccine effectively clear amyloid in humans? Will clearing amyloid improve the clinical symptoms of AD? Promising results presented by NIH researchers at the World Congress on Alzheimer’s Disease in July 2000 replicated Elan’s findings in other APP transgenic mice. One finding indicated that the vaccination prevented memory loss in another transgenic mouse model of AD. Additional research is clearly needed to determine whether these findings in mice will hold true for humans. A recent study by NIA-funded researchers at Harvard Medical School provided a second approach to using the immune response to remove amyloid plaques. These researchers used the same amyloid as that used in the vaccine but administered it nasally rather than through injections (Weiner et al., 2000). They found that the nasal administration induced an immune response in the transgenic mice that develop extensive amyloid plaques at later ages. When young transgenic mice were given the human beta-amyloid by this route, they had a much lower amyloid burden at middle age than did animals that did not receive the vaccine. Although the nasal administration was not as effective as the original vaccination method, these results open the door to an alternative approach that may be better tolerated long-term than the injected amyloid vaccine.

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Removing Amyloid Other researchers are exploring ways in which brain microglia may destroy amyloid naturally. Certain kinds of scavenging microglia can engulf betaamyloid, which suggests that they have the potential for clearing amyloid from the AD brain even without being activated by an immune response against amyloid. Scientists at the University of California, Irvine, showed that microglial uptake of beta-amyloid can be reduced by some forms of complement, a component of the inflammation cascade that occurs in the AD brain (Webster et al., 2000). Fibrillar (more damaging) complementcontaining plaques may develop as AD progresses. These results suggest that mechanisms that inhibit the inflammatory process may increase the capacity of certain types of microglia to engulf amyloid and may be of therapeutic value.

Preventing Beta-Amyloid from Forming One way to prevent amyloid plaque formation is to stop beta-amyloid production. There are many ways of doing this. In one example, scientists at Rockefeller University in New York City built on previous test tube studies indicating that estrogen might reduce the risk of developing AD by lowering beta-amyloid secretion. They showed that treating cultured neurons with estrogen reduced the secretion of beta-amyloid peptides. In other studies, testosterone also decreased secretion of beta-amyloid (Gouras et al., 2000). It is not known whether these sex hormones have this effect in the body or whether the effect would be large enough to reduce amyloid accumulation and make a difference in the rate at which AD develops. Scientists are pursuing studies to try and answer these questions as well as exploring a number of other approaches to preventing formation of beta-amyloid.

At Long Last: The Elusive APP-Clipping Enzymes Are Identified Amyloid precursor protein (APP) is one of many proteins that are associated with cell membranes. The membrane surrounds the cell and acts as a barrier that selects which substances can go in and out of it. After it is made, APP becomes embedded in the nerve cell’s membrane, partly inside and partly outside, like a toothpick stuck in an orange. While APP is embedded in the cell membrane, proteases (a kind of enzyme, which are proteins that cause or speed up chemical reactions in the body) act on particular sites, cleaving the APP into protein fragments. Over the years, experiments from many laboratories have given investigators a detailed picture of the steps between

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synthesis of APP and its snipping into fragments, but they have never been able to physically identify the elusive enzymes that actually did the clipping. The scientists knew, however, that these enzymes existed and gave them names: beta secretase and gamma secretase. They also knew that another enzyme, alpha secretase, clipped APP in the middle of the amyloid region, preventing beta-amyloid from being formed. Many candidates for these enzymes have been suggested, but none has stood up to rigorous examination. During the past year, teams of researchers working at several pharmaceutical companies and one research foundation published papers describing a series of elegant experiments that finally isolated one of these three enzymes and proved that it had the beta secretase activity (Hussain et al., 1999; Lin et al., 2000; Sinha et al., 1999; Vassar et al., 1999; Yan et al., 1999). What makes this research particularly impressive is that the teams, building on recent advances in gene and protein techniques, all used different approaches to achieve the same end. Because of this work, beta secretase now has been identified as a member of a family of protein-clipping enzymes called aspartic proteases. Establishing the enzyme’s structure will lead to a whole new avenue of research into its mode of action and its activity in different cell types. Even more recently, other teams of researchers conducted studies that are believed to have identified the second APP-clipping enzyme – gamma secretase. For some time, investigators have been exploring the possibility of a connection between gamma secretase and presenilin 1, the protein product of a gene whose mutation is responsible for much of inherited early-onset AD (Wolfe et al., 1999). For one thing, changes in presenilin 1 activity always seem to correlate with the amount of amyloid produced by gamma secretase cleavage. Building on this finding, researchers at Harvard Medical School showed that changing the structure of presenilin 1 at its active site dramatically altered a cell’s ability to make the gamma secretase cut in APP (Kimberly et al., 2000). This correlation was also shown to be true for presenilin 2, the protein product of a gene very similar to presenilin 1 that, when mutated, can cause familial early-onset AD. These results strongly suggested, but did not prove, that gamma secretase and the presenilins were one and the same. Further evidence supporting this possibility came from a pharmaceutical company-supported team, closely followed by the Harvard Medical School group. Both teams independently showed that inhibitors designed to bind and curb the active site of gamma secretase actually bind to presenilin 1 (Esler et al., 2000; Li et al., 2000).

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To have formal proof that presenilin 1 is actually gamma secretase, researchers would have to show in test tube studies that the purified presenilin 1 actually cleaves APP at the correct place, and this has not yet been accomplished, possibly because it is very difficult to maintain the activity of a membrane protein such as presenilin 1 once it is isolated. Nevertheless, these studies certainly suggest that gamma secretase’s identity also has been revealed this year. Identifying these two enzymes has given scientists crucial targets for novel drug therapies that are designed to inhibit their actions, and thus, to inhibit the formation of beta-amyloid. At the same time, researchers caution that many issues need to be resolved before such a drug could be ready for use by patients. For example, if these inhibitors were to work to prevent AD, they would need to be started many years before AD clinical symptoms develop, in the early preclinical stages of plaque deposition. Treatment also would have to be continued for a lifetime. However, the secretase enzymes probably have many body functions besides clipping APP, so an inhibitor drug might well have side effects that could not easily be tolerated, especially if taken for many years. Several companies have already identified drugs that inhibit gamma secretase or that increase the activity of the beta amyloid-destroying alpha secretase. Ongoing safety or efficacy trials on these compounds are showing results in the test tube and in animal studies and are rapidly being pushed forward to human studies.

Breaking Down Beta-Amyloid Another way to prevent amyloid plaque formation is to break beta-amyloid into pieces once it is released from cells and before it has a chance to aggregate into insoluble plaques. Researchers from Harvard Medical School found that an enzyme called “insulin degrading enzyme” can do this in tissue culture (Vekrellis et al., 2000). The enzyme regulated extracellular amyloid levels, suggesting that it might do the same in the brain. Finding ways to increase the activity of this enzyme could conceivably be a therapy for AD. Another approach that scientists have taken to prevent plaque formation is to develop short peptides called “beta peptide sheet breakers,” which inhibit beta-amyloid from forming plaques. A research team at New York University showed that beta peptide sheet breakers also reduce plaque formation when injected into the amyloid plaque-containing brains of rats. The peptide breakers reduced plaque size, neuronal shrinkage, and

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microglial activity around plaques and broke up amyloid deposits even after they were formed (Sigurdsson et al., 2000). All of these findings raise a fundamental question: If plaque deposits could be removed from the brain of a person with AD, would that stop the progression of the disease or even allow the brain to regain some of its lost function? Current and future studies should shed light on these critically important questions.

Presenilins Scientific interest in the presenilin proteins heightened dramatically when scientists discovered that mutations in the genes that code for presenilin 1 and presenilin 2 account for approximately 40 percent of cases of familial Alzheimer’s disease. The recent discovery that presenilin 1, in fact, may be one of the enzymes that clip APP into beta-amyloid generated much excitement in the scientific world and provides a perfect example of how a genetic finding can lead to other, non-genetic insights into particular cellular pathways that may be important in the early preclinical stages of AD development. Investigators have found that presenilins have a number of other possible functions besides clipping APP. Understanding more about these functions will shed further light on the nature and development of AD, possibly leading to new targets for prevention or treatment strategies. One of the other ways presenilins may be important is their involvement in cell death pathways. Studies conducted by a number of research teams, including intramural investigators at the NIA, indicate that in a transgenic mouse model, neurons expressing presenilin 1 mutations causing AD in humans are more vulnerable to stress-related cell death. Neurons in these mice can be rescued by treating them with inhibitors of programmed cell death (apoptosis) that work through channels in the cell that transport calcium (Mattson et al., 2000). Normal changes in cellular calcium levels are involved in regulating the activity of many cellular pathways and proper regulation of these levels is essential because abnormal increases in calcium can lead to cell death. Yet another function suggested for the presenilins is that they are involved in cell-cell communication through maintaining synapses (the tiny gaps between neurons across which neurotransmitters travel). A study conducted by scientists at Mt. Sinai Medical Center in New York showed that presenilin 1 is located at the synapse and that it may be necessary for proper connections between neurons (Georgakopoulos et al., 1999). Thus, presenilin

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1 may be important in the way neurons connect with one another and how they maintain their contacts. Presenilin mutations that cause AD could possibly affect presenilin function at the synaptic connections between brain cells. These studies have brought us a lot closer to understanding presenilins, but there is a great deal still to be learned. How can these molecules have so many functions? Which function(s) is the one that, when disrupted in persons carrying a presenilin mutation, initiates AD pathology? Knowing the answers to these questions will help investigators better understand the early stages of AD and then find effective therapeutic approaches for its prevention and treatment.

Programmed Cell Death (Apoptosis) AD is characterized by abnormal cell death of vulnerable neurons in regions of the brain that are essential to learning, memory, attention, and judgment. Understanding the mechanisms of cell death in response to different signals will give scientists clues about how to prevent it in AD. An important area of research into the etiology of AD, therefore, is the process of programmed cell death, called apoptosis. Apoptosis is a kind of cell suicide that is important for weeding out unnecessary cells in normal development, maintaining tissues in a continuously healthy state, and targeting cancerous cells in the adult. However, a high level of apoptosis in the adult brain results in irreversible loss of brain function because most neurons are irreplaceable. A family of enzymes called caspases is important in the apoptosis process, and in the past year, several teams of NIA-supported scientists made important advances in the understanding of the possible role that caspases play in AD. In one series of studies, researchers at Columbia University College of Physicians and Surgeons sought to discover whether the activation of caspases could explain any of the features of AD’s progression (Troy et al., 2000). They found that beta-amyloid induced one particular caspase not only to initiate the cell death pathway – to start apoptosis – but also to act as an effector of cell death, in essence becoming the “cell terminator.” This study suggests that gene or drug therapies that target this specific caspase might prevent the cell death that is associated with beta-amyloid and might be a therapeutic approach for AD. There are several other potential targets for therapies that prevent apoptosis. One of them involves telomerase, an enzyme that maintains chromosome structure. Intramural scientists at the NIA have shown that under certain

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circumstances, telomerase can block specific apoptotic pathways and in tissue culture can decrease vulnerability to cell death induced by betaamyloid (Zhu et al., 2000). It remains to be seen whether this also works in the brain. Another possible avenue for preventing cell death may be to mimic the changes in biology that accompany reduced food intake in animal models. NIA intramural researchers have shown that both normal mice and transgenic mice carrying the presenilin 1 mutation were less vulnerable to toxin-induced neuronal cell death when they ate 30-40 percent less food over time. This may occur because oxidative stress is reduced by consuming less food (Zhu et al., 1999).

ApoE Understanding the genetic factors associated with AD is important because through this work scientists will be able to better understand how the disease starts and progresses. Researchers are working to discover not only what gene mutations cause the disease and how they initiate the disease process, but also what risk factor genes might work together to make individuals more susceptible to late-onset disease. As noted earlier, mutations in three genes – APP, presenilin 1, and presenilin 2 – have been identified as causing early-onset disease, and the APOE e4 allele of the APOE gene has been identified as a major risk factor for the more common late-onset disease. For example, in a recent follow-up study of the APOE risk factor alleles in late-onset AD, a University of Washington at Seattle research team showed that having the e4 allele can make a difference of as much as 17 years in the age of onset of the disease (Warwick Daw et al., 2000). This past year, exciting new data on why APOE e4 is a genetic risk factor for late-onset AD were provided by scientists at the Washington University School of Medicine in St. Louis (Holtzman et al., 2000). These studies, using transgenic mice, focused on the cellular mechanism involved in APOE e4 function. Previous studies in transgenic mice with a mutated human APP gene suggested that an interaction between APOE and beta-amyloid is somehow linked to beta-amyloid deposition and amyloid plaque formation. In this new study, transgenic mice with the mutated APP were used to create mice in which both of their mouse APOE genes had been removed and replaced either with the human APOE e3 or APOE e4 allele. Mice with the APP mutation and no mouse APOE genes had fewer amyloid deposits and no neuritic plaques. When either of the human APOE genes was present, the pattern of beta-amyloid deposition changed. There was amyloid deposition

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in the hippocampus but few neuritic plaques until later ages. In mice with the human APOE e4 risk factor gene, there was more amyloid deposited as well as a large increase in the amount of fibrillar beta-amyloid compared to mice with the human APOE e3 gene. Thus, APOE e4 may be critical for the formation of plaques and consequent nerve cell damage and death. These findings could help in developing drugs that could alter the levels of the ApoE protein in the brain and consequently prevent the formation of fibrils, inhibit beta-amyloid deposition, and promote the removal of amyloid. This could ultimately slow or prevent the development of AD. Studies in similar transgenic mouse models by researchers at the University of California at San Francisco showed that different APOE genes had different effects on memory in mice (Raber et al., 2000). A spatial memory test was used to see how well the animals remembered cues from the environment in order to find a hidden platform placed in a water maze. (An example of “spatial memory” in people is remembering where things are around the home, like the bathroom, kitchen, or telephone. AD patients eventually lose this type of memory completely and this is a likely reason why they easily become disoriented.) APOE e3-bearing mice remembered better than the APOE e4 ones. This may help explain why human APOE e4 carriers are at greater risk of developing AD than are APOE e3 carriers. By combining several powerful tools – molecular biology, genetics, and mathematical modeling – the University of Washington at Seattle researchers identified four new AD-related regions in the human genome where one out of the several hundred genes in each of these regions may be a risk factor gene for the disease (Warwick Daw et al., 2000). Their calculations showed that these as yet unidentified genes seem to make a contribution to the risk of developing late-onset AD that is at least as important as the contribution of APOE e4. In fact, one of these genes is calculated to make a contribution that is several times greater than the impact of the APOE e4 gene. There is much work still to be done here, for not only do the identities of the four new genes associated with AD need to be established, but scientists must then determine why certain alleles of these genes contribute to the likelihood of a person developing AD.

Additional Genetic Links to AD Other investigators, working at Harvard and the Massachusetts General Hospital, have continued previous work that identified chromosome 12 as having a region that predisposes toward developing late-onset AD. The precise identity of the gene in the predisposing region is not yet known, but

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the alpha-2 macroglobulin gene has been identified as one that may confer risk (Tanzi et al., 1999). Other possible nearby sites on chromosome 12 also could contribute to the risk of developing the disease. Research on one of these, identified by a research team at Duke University, indicates that the new site acts independently of APOE to increase the risk of late-onset familial AD and that it may be associated with Lewy body disease, a neurodegenerative disease that has features of both AD and Parkinson’s disease (Scott et al., 2000). Other genetic associations with AD, suggesting new risk factors, have been found in population-based studies. One possibility that has emerged is that specific polymorphisms in genes for pro-inflammatory agents increase the risk of developing AD. For example, researchers at McClellan Memorial Veterans Affairs Medical Center, Little Rock, Arkansas, and Glasgow University, Glasgow, Scotland, found that one type of polymorphism in the interleukin 1 (IL-1) gene doubles the risk for AD in two separate populations (Nicoll et al., 2000). Investigators caution, however, that many of the genetic associations that have been identified may be spurious, caused by differences in genetic backgrounds and in environment between the control and AD groups rather than being associated with risk of AD. The fact that families share the same genetic background reduces the possibility that associations of genes with the disease may be related to the genetic differences that exist between unrelated persons. Because of this, scientists have also analyzed data from families, though the statistical methods for detecting risk factor genes in genetically complex diseases such as AD are still evolving. Only as additional populations and families are studied with refined methodologies and as the various research groups share their data will it become clear exactly what genes are risk factor genes for AD. In a related research area on genetic links to AD and aging, scientists have long been intrigued by the fact that some people retain healthy and vigorous cognitive function into very old age, while others become cognitively impaired. Currently, some controversy exists as to whether the risk of developing AD increases even in very old age (in persons over 90 years of age). Data from another study done this year by investigators at the Mt. Sinai School of Medicine have fueled this debate by suggesting that people 90-102 years of age were actually less likely to develop late-onset AD than were younger individuals (60-89 years old) (Silverman et al., 1999). While the possibility of non-genetic protective factors cannot be ruled out, this study suggests the existence of genetic factors that protect specific longlived individuals from becoming cognitively impaired. The hunt for genes that may protect against late-onset AD might specifically target nonagenarians and centarians who have experienced healthy aging.

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Protein Aggregation in Other Neurodegenerative Diseases A common thread in neurodegenerative disorders is the abnormal aggregation of proteins in the brain. Examples of these proteins include amyloid in AD; synuclein in Parkinson’s disease; prions in prion diseases; huntington in Huntington’s disease; BRI in familial British dementia; and tau in tauopathies, such as frontotemporal dementia with Parkinson’s disease (FTDP-17), progressive supranuclear palsy, and Pick’s disease. Most researchers believe that the protein aggregates formed are toxic and give rise to the multiple brain changes that characterize the different neurodegenerative diseases. If one relationship between these diseases really is abnormal protein aggregation, then discovering ways to prevent aggregation, or the processes set in motion by the aggregation, may halt the disease process. In the last year, researchers made significant advances in understanding abnormal protein aggregation in a number of these diseases.

Tau One major diagnostic feature of AD is the formation of neurofibrillary tangles in susceptible nerve cells in the brains of persons with AD. Tangles are composed of tau-containing paired helical filaments. Since the discovery in 1998 that mutations in the tau gene cause FTDP-17, scientists have rapidly initiated experiments to try to understand how changes in the structure of tau or how altered levels of specific forms of tau could result in the abnormal production of paired helical filaments and death of neurons in this disease. Finding out how changes in tau structure cause paired helical filaments and neuron death in FTDP-17 will help scientists to understand the similar process in AD brains. Two types of transgenic mice have been used to examine how tau is involved in this process. One type of mouse, created by scientists at the University of Pennsylvania School of Medicine, overproduced one of the six forms of human tau (Ishihara et al., 1999). The mice showed aggregation of tau resulting in loss of microtubules in the neurons as well as degeneration of axons. The mice had pathology similar to that seen in FTDP-17 and the amyotrophic lateral sclerosis/Parkinsonism-dementia complex of Guam. These findings suggest that these neurodegenerative diseases can result from altered expression of normal forms of tau.

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A second type of transgenic mouse was created with one form of the human tau gene containing the most common human mutation causing FTDP-17 (Lewis et al., 2000). Investigators at the Mayo Clinic, Jacksonville, Florida, found that this mouse had problems with walking and other movements and had behavioral deficits. The investigators found a direct relationship between the level of expression of the mutated gene, the number of neurofibrillary tangles, and the age of the mouse. This mouse model confirms the hypothesis that neuron loss can and does result from a mutation of the tau gene.

Synuclein A protein called alpha-synuclein is known to accumulate abnormally in plaques in AD, in Lewy bodies in Lewy body disease and Parkinson’s disease, and in a number of other diseases that are collectively called synucleinopathies. A rare form of inherited PD is caused by a mutation in the gene that directs the production of alpha-synuclein, and the mutated alpha-synuclein forms insoluble deposits. This strengthens the hypothesis that abnormal protein deposition is one common thread that links dementing diseases. When abnormal proteins, such as alpha-synuclein, accumulate on the pre-synaptic side of synapses, the chemical information between cells might not be transmitted properly and the circuit might be interrupted. This year, three model systems have been used to study alpha-synuclein function. Using immature brain cells in a test tube, scientists at the University of Pennsylvania examined the way in which alpha-synuclein is expressed in development and its functions (Murphy et al., 1999). Alphasynuclein was seen only after interneuronal connections were formed and then only in the pre-synaptic part of the synapse. Alpha-synuclein may, therefore, help regulate function at the synapse, but it is not yet known whether altering the amount of alpha-synuclein or mutating it will change how much neurotransmitter gets from one neuron to the next. Researchers at the University of California at San Diego worked with a second model for alpha-synuclein. Transgenic mice overexpressing the protein had problems with motor function similar to those found in Parkinson’s disease (Masliah et al., 2000). These findings suggested that increased amounts or accumulation of alpha-synuclein within neurons may play an important role in the development of pathology seen in Parkinson’s disease and related disorders such as Lewy body disease.

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A third transgenic mouse that overexpresses abnormal forms of one kind of APP was created at the University of California at Los Angeles and researchers looked at altered alpha-synuclein expression in this mouse model of AD. Unlike control mice, these mice had large numbers of nerve processes containing alpha-synuclein, very similar in location to those found in Lewy body disease. This again suggests that there is likely to be a connection between AD, Lewy body disease, and Parkinson’s disease (Yang et al., 2000).

Alzheimer’s Disease and Parkinson’s Disease: Two Diseases or One? While Alzheimer’s disease and Parkinson’s disease are always classified as different diseases, a growing body of evidence demonstrates a number of common physical signs and neuroanatomy (Perl et al., 1998). For example, some AD patients have problems with movement, the most obvious symptom of PD. AD patients can also show changes in the substantia nigra— a place in the brain controlling certain types of movements—whose neurons are severely depleted in PD. Some AD patients demonstrate Lewy bodies, a typical marker for neuron pathology that is found in PD but in different brain regions than in AD. Similarly, many PD patients develop dementia and have neurofibrillary tangles and senile plaques like those found in AD. A further indication of overlap is Lewy body disease, a neurodegenerative disorder whose clinical signs occupy a middle ground between AD on the one hand and PD on the other. Furthermore, one population on the island of Guam also shows a constellation of signs that are common to both types of disease. Often, it is not possible, on either clinical or neuropathologic examination, to make a clear diagnostic distinction between the two diseases. On a statistical basis, the numbers of individuals showing signs of both diseases is surprisingly high. Because of this crossover of anatomical and physical signs, some clinicians have suggested that AD and PD are the same disease occurring over a broad spectrum. An alternative notion is that the two diseases simply co-exist in the same brain. As scientists conduct more research into these two diseases and the possible overlaps in their etiologies, the growing knowledge base may help to explain the development of many neurological diseases and point the way to common therapeutic approaches. This also applies to research on other dementias, for example, those caused by tau mutations and by other forms of amyloid such as prions.

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Prion Diseases The family of prion diseases, including Creutzfeldt-Jakob Disease in humans, bovine spongiform encephalopathy (“mad cow disease”), and sheep scrapie, are caused by abnormal folding of a prion protein, which then can infect another animal with the disease. Although AD is not infectious, many parallels exist between the prion diseases and AD, including the fact that both prions and beta-amyloid form amyloid structures in the brain. In a series of experiments, similar to those that inhibited beta-amyloid formation (see the section Preventing Beta-amyloid From Forming), researchers at New York University Medical Center showed that, as in AD, an amyloid peptide breaker custom-designed for the prion amyloid fibril reversed prion protein aggregation in the test tube, in living cells, and in a mouse infected with sheep scrapie (Soto et al., 2000). These results give investigators possible avenues for future treatments of these invariably fatal dementing diseases.

Familial British Dementia and Associated Disorders Recent studies have shown that a number of dementias besides AD are associated with genetic defects that result in other kinds of amyloid deposits in the brain. For example, in 1999, scientists at the New York University School of Medicine and the National Hospital for Neurology and Neurosurgery and the Institute of Neurology, both in London, identified a defect in the gene called BRI, which is located on chromosome 13 (Vidal et al., 1999). This gene is associated with the development of familial British dementia (FBD), a disease characterized by progressive dementia, paralysis, and loss of balance. It usually occurs around age 40-50. Similar to AD, FBD patients have amyloid deposition associated with blood vessels and neurofibrillary tangles. The mutation in the BRI gene causes longer than usual forms of the protein to be made. Part of the new protein is clipped off and deposited in the brain as amyloid plaques, which leads to neuronal dysfunction and dementia. Several teams of scientists are intensively studying the BRI gene. One team, located at the University of Chicago and Rockefeller University, showed that an enzyme called furin and specific processing pathways are involved in the formation of fibrils in FBD (Kim et al., 1999). This year, the New York University School of Medicine research team identified a close variant of FBD in a small Danish population (Vidal et al., 2000). Severe accumulations of amyloid around blood vessels, cataracts, deafness, loss of balance, and dementia characterize this variant. The genetic

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defect is a single base mutation in the same gene as FBD. Its presence, too, results in the formation of a longer than usual protein that is clipped to form amyloid. Future studies of animal models that have this specific mutation may be helpful in understanding why the Danish form of the variant has abnormal amyloid deposition that is closely associated with specific blood vessels in the brain. By studying the different amyloid types, the product of distinctly different genes and processing pathways, scientists hope to gain a better understanding of the effects of amyloid in the AD brain.

Possible Therapeutic Deposition

Approaches

for

Abnormal

Protein

One approach to therapeutic targets for preventing protein aggregation might be to use members of a large family of proteins that are collectively called chaperones. Members of this family help proteins fold properly and discourage improper folding and abnormal aggregation. By assisting in proper protein folding, chaperones help cells survive in the face of stress insults that might otherwise kill them. One member of the chaperone family, which so far has only been found in lower organisms, dramatically affects abnormal folding of a prion-like protein in yeast (Lindquist et al., 2000). Researchers at the University of Chicago supported by NIH’s National Institute for General Medical Sciences (NIGMS) introduced a chaperone family member called Hsp 104, along with the abnormal protein segment that gives rise to Huntington’s disease, into C. elegans, a kind of worm that is commonly used in biology research. When expressed alone, the abnormal protein segment aggregated and was toxic to the worm. When it was expressed along with Hsp 104, however, both the aggregation and the toxicity were reduced (Satyal et al., 2000). These observations show that chaperones can affect the abnormal folding of a protein fragment that causes Huntington’s disease. Perhaps ways of increasing the production of certain chaperone family members could be another way of limiting deposition of the toxic protein aggregates that are found in many neurodegenerative diseases.

Aging and AD Development A certain number of changes in the way the brain functions can be expected during normal aging, and investigators are looking at how these processes differ from what occurs during AD. A recent study by intramural scientists at the NIA, for example, showed that in normal healthy aging, there was a loss of cell markers for neuron remodeling (or plasticity). On the other hand,

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in AD brains there were much more dramatic changes in these markers (Hatanpää et al., 1999). Determining how the brain changes in normal aging and what relevance this has to development of AD is an important area of research. Another area of active investigation is how to limit the production of free radicals, those highly reactive molecules whose overproduction can injure cells. Brain metabolism requires large amounts of oxygen, which can be converted into damaging free radical molecules. It is now believed that oxidative stress, which occurs when too many free radicals are produced, is a major contributor to the aging process. Brain aging is an added risk factor for the accumulation of free radicals. With age, the compensatory mechanisms that have evolved to cope with and eliminate free radicals become less efficient. Neurons are particularly vulnerable to attack by free radicals because they have a high metabolism and are low in natural antioxidants. DNA and RNA are prime targets of free radical attack, as are brain lipids and proteins. Part of the heterogeneity of brain aging in different individuals may, in fact, be due to the generalized effect of free radicals on the brain as people age. Several ongoing clinical trials have been designed to determine whether treatment with antioxidants can slow age-related cognitive decline or development of AD.

Early Life Events and Other Factors Another way to look at the cause and development of a disease is to examine it from a population-based perspective. Does the disease occur more or less often in certain racial or ethnic groups? Does it occur more or less often in groups who live in particular environments, follow certain lifestyle patterns, or have particular experiences during their lives? A number of investigators have conducted these types of epidemiologic studies to learn more about whether and to what extent early life events and other factors have an impact on the development of AD. For example, studies have examined the relationship between level of education and childhood rural residence as possible risk factors for AD in older African Americans (Hall et al., 2000); the association of AD with mother’s age at the patient’s birth, birth order, number of siblings, and area of residence before age 18 (Moceri et al., 2000); the potential interactions among total serum cholesterol, APOE genotype, and risk of AD in older African Americans (Evans et al., 2000); and head injury as a risk factor for AD (Guo et al., 2000; Plassman et al., 2000). Other studies have examined cognitive function and risk of dementia in a group of several thousand Japanese-American men who have been followed for a period of 36 years (Launer et al., 2000;

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Petrovitch et al., 2000) and have analyzed data pooled from several largescale existing studies to determine the association of AD risk with family history of dementia, female gender, low levels of education, smoking, and head trauma (Launer et al., 1999). Several intriguing possibilities have emerged from these studies. For example, investigators in the cholesterol study found that high blood cholesterol was a risk factor for AD in those with no APOE e4 alleles, but not in those with one or two e4 alleles. Blood cholesterol, therefore, may be a potentially modifiable risk factor for AD in some people (Evans et al., 2000). Results from one of the other studies indicated that rural residence in childhood, together with fewer than 6 years of school, was associated with increased AD risk (Hall et al., 2000). Though epidemiologic findings such as these can be suggestive and interesting, they can be conflicting or incomplete as well, partly because investigators looking at the same issues may use different study methods, but also because of the complexity of the issues and the large number of variables involved. For example, the low educational attainment that emerged as a risk factor in the study mentioned above may actually be a surrogate or marker for other deleterious socioeconomic or environmental influences in childhood. Nevertheless, epidemiologic research is a valuable complement to basic research on AD, and ongoing and future studies show promise for shedding further light on the relationship among AD risk, early life events, and other factors.

Improving Early Diagnosis The clinical diagnosis of AD has improved significantly in recent years. However, important gaps in knowledge remain, and work continues on the search for reliable, valid, and easily attained ways to identify AD very early in the course of the disease. Early diagnosis is important for a number of reasons. First, to understand the cause(s) of the diseases and how best to intervene at early stages, scientists need to know what is happening in the brain during that time. Tests are also needed that can reliably separate people with Alzheimer’s disease from those with cognitive problems that stem from other causes. Finally, when more effective treatments become available, it will be important to identify people at the very earliest stages of AD so that treatment can be started before brain changes result in cognitive deficits.

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The 1999 Progress Report on Alzheimer’s Disease described advances in our understanding of the early changes in AD that researchers made as a result of examining the brains of people who had died while still in the very early, preclinical stage of AD. In the last year, researchers continued to make significant progress in several areas related to early diagnosis, including improving neuroimaging techniques, improving the predictive ability of neuropsychological tests, focusing on correlations between clinical signs of possible AD and pathological changes in the brain, and understanding the biological markers of early disease.

Neuroimaging Researchers at Brigham and Women’s Hospital in Boston used magnetic resonance imaging (MRI) measurements to determine whether healthy older persons and persons in the presymptomatic phase of AD could be identified before they developed clinically diagnosed AD (Killiany et al., 2000). MRI scans can image a living person’s brain and are used to measure the size of different structures in it. In this study, which was jointly supported by NIA and the National Center for Research Resources, healthy people and those with mild memory difficulty received an MRI scan at the beginning of the study (“at baseline”). Over the next 3 years, the researchers determined which of the participants later met clinical criteria for AD. The investigators looked at differences in brain tissue volume in a number of areas, focusing on the regions involved in memory and executive functions, such as organizing, planning, and switching back and forth among tasks and ideas. The researchers found that they could identify people who would develop AD over time based on measurements of these brain regions. The MRIs were 100 percent accurate in discriminating between the participants who were healthy and those from a third group who already had mild AD. They were 93 percent accurate in discriminating between participants who were healthy and those who initially had memory impairments and ultimately developed AD. In the case of the people “converting” to AD, one of the regions involved with memory had about 37 percent less volume than that of the individuals who remained healthy, probably reflecting a loss of brain cells. Other comparisons showed a relatively high accuracy rate as well, although it was more difficult to distinguish the people who continued to have memory problems but did not progress to AD from those who eventually converted to AD. In a second, similar study, conducted at New York University Medical Center, healthy older people and those with mild cognitive impairment received an MRI and a clinical and cognitive evaluation at baseline and

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follow-up (3.2 years) (Convit et al., 2000). Again, results indicated several specific sites in the brain that may be affected in preclinical AD, and that atrophy in these areas may indicate future AD in these individuals. Another neuroimaging study, carried out by investigators at the Mayo Clinic Alzheimer’s Disease Center/Alzheimer’s Disease Patient Registry in Rochester, Minnesota, focused on demonstrating relationships between certain brain structures, especially the hippocampus, and cognitive function in AD patients and healthy people (Petersen et al., 2000). The scientists found that the volume of the hippocampus (as measured by MRI) predicted performance on most acquisition and recall measures across the spectrum of normal aging and AD. An additional MRI study, not funded by NIH, contributed important insights into the potential use of imaging to assess disease progression and response to drugs. In this study, conducted by researchers at the National Hospital for Neurology and Neurosurgery in London, England, the rate of brain atrophy was assessed from two MRI scans separated by 12 months in AD patients and healthy individuals (Fox et al., 2000). The second scan was compared with each individual’s first scan, and the volume of cerebral tissue loss was calculated based on the difference between the two scans. Results indicated that the mean rate of brain atrophy was 2.4 percent per year for the AD patients and 0.4 percent per year for the controls. This method can be used to quantify brain atrophy over time and might be a tool to monitor progression of AD in clinical trials over a shorter time course than possible using neuropsychological tests. Two other studies focused on trying to develop methods for imaging plaques in the living brain. One, conducted by scientists at Duke University Medical Center and involving brain tissue from individuals who had died, used magnetic resonance microscopy to try to distinguish plaque-specific signal from noise (Benveniste et al., 1999). The other, conducted by University of Pennsylvania School of Medicine researchers, used mouse tissue and transgenic mice to explore the potential usefulness of a special type of probe (a radioligand probe) to image plaques (Skovronsky et al., 2000). Both of these studies are early developmental studies that may eventually lead to imaging studies in humans and ways to monitor plaque levels in the brain in response to vaccine or other treatment. Brain activity may decline before brain atrophy becomes noticeable and both may predict later cognitive decline and dementia. A number of research teams supported by NIA and NIMH have measured brain activity as a predictor of cognitive change.

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Neuropsychological Testing In the past year, NIA-supported investigators also have looked at ways to improve standardized tests of memory, language, and other neuropsychological components in hopes of being able to better predict future development of AD. In one study, scientists at Harvard and the Massachusetts General Hospital examined whether it was possible to identify aspects of the Clinical Dementia Rating (CDR) scale to predict which people with “questionable” AD have a high likelihood of converting to a diagnosis of AD over time (Daly et al., 2000). The CDR is a semi-structured clinical interview that stages AD from 0 (normal) to 0.5 (questionable), 1.0 (mild), 2.0 (moderate), and 3.0 (severe), based on an assessment of six categories of function (memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care). Results of this study indicated that the likelihood of progressing to AD was strongly related to the sum of the individual scores in each category. For example, more than 50 percent of individuals with a total CDR score of 2.0 or higher at baseline developed AD during the 3-year follow-up, whereas only about 10 percent of individuals with a score of 1.0 or lower developed AD during this interval. A second study also examined whether initial performance on a variety of neuropsychological tests in healthy older people could accurately predict subsequent decline to dementia over a period of nearly 4 years (Kluger et al., 1999). This research team from the New York University School of Medicine found that a small set of neuropsychological measures, especially a paragraph delayed recall test, significantly differentiated those who later developed AD from those who did not. This assessment may be particularly useful in predicting the future cognitive status of older people with mild cognitive impairment.

Clinical-Pathological Correlations Another important focus for scientists working on the early diagnosis of AD is improving the understanding of the relationship between early pathological damage to the brain and outward clinical signs. For example, the Oregon Brain Aging Study follows healthy individuals without cardiovascular or other diseases of aging who are 85 years or older. Investigators made measurements of senile plaques and neurofibrillary tangles in certain regions of the brain after participants had died and compared these measurements to the individuals’ previous clinical status, cognitive measures, and rate of cognitive change (Green et al., 2000). Results

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indicated that there was an increased burden of these neuropathological markers even in those individuals who had cognitive decline but were not functionally impaired and did not meet diagnostic criteria for dementia. The strong relationship between the cumulative pathological changes and the rate of decline suggests that these markers have clinical consequences and are not just benign indications of aging. Another study, conducted by scientists at the Rockefeller University and Mt. Sinai School of Medicine, New York, assessed levels of beta-amyloid variants and tau in the cortex of subjects with no, questionable, mild, moderate, and severe dementia (Naslund et al., 2000). Results indicated that total levels of two types of amyloid peptides were elevated early in dementia and that these levels were strongly correlated with cognitive decline. Additionally, in the frontal cortex, beta-amyloid was elevated before the occurrence of significant tau pathology. These findings support an important role for betaamyloid in the initial pathological events in AD dementia. Researchers at the Washington University School of Medicine, St. Louis, Missouri, looked at tangle formation in various stages of aging and AD (Uboga et al., 2000). Results indicated that fibrillar tangles, corresponding to what are generally understood to be classical tangles, increased exponentially with age and severity of AD, whereas diffuse tangles seemed to represent an earlier form of tangles. The density of diffuse tangles peaked around preclinical AD and then decreased in more severe stages of AD.

Markers Scientists are also trying to establish whether there are biological markers for AD. If so, clinicians could eventually use them to determine whether a person is entering an early, preclinical stage of AD. Thus, treatments could be started earlier, perhaps when they might be more effective. In one such study, researchers at the University of Washington School of Medicine determined whether changes in a person’s sense of smell (using the Cross-Cultural Smell Identification Test) were able to predict cognitive decline over a 2-year period in older Japanese-Americans enrolled in a community-based longitudinal study of memory and aging (Graves et al., 1999). Results indicated that unexplained loss in the sense of smell in the presence of one or more APOE e4 alleles was associated with a high risk of cognitive decline. In another longitudinal study of older individuals, Columbia University investigators found that plasma levels of beta-amyloid were higher at the

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beginning of their study in those who subsequently developed AD than in those who did not (Mayeux et al., 1999). Thus, plasma levels of beta-amyloid may be detected several years before the onset of symptoms.

Developing Drug Treatments Improvement in the understanding of AD is making it possible for scientists to design new therapeutic strategies to intervene at multiple stages of the disease process. Insights into the neurochemistry and neurobiology of the disease and epidemiologic studies pinpointing risk factors have resulted in a marked expansion of the types and numbers of drugs that are being developed and are now being tested or may be tested in the future. Today, it is estimated that NIA, other NIH Institutes, and a number of pharmaceutical companies are or will be testing 50 to 60 compounds in human trials. They focus on three major aspects of AD: treatments for short-term maintenance of cognitive function in patients with AD; treatments to slow the progress of the disease, delay its onset, or prevent it; and treatments for AD-associated behavioral problems.

Short-Term Maintenance of Cognitive Function One of the most prominent features of AD is that levels of a neurotransmitter called acetylcholine fall sharply in patients. This is important because acetylcholine is crucial in the formation of memories and is used commonly by neurons in the hippocampus and cerebral cortex – regions devastated by AD. This discovery about acetylcholine, which occurred in the mid-1970s, led to many studies on the cells that use acetylcholine and the enzymes and other proteins that take part in its manufacture or activity – a network known as the cholinergic system. This system was the first major system to be targeted for drug intervention. A number of drugs that temporarily maintain the cholinergic system have been developed or are now being tested to treat the cognitive decline experienced by patients with AD. For example, all three of the drugs that have been approved by the FDA – tacrine (Cognex), donepezil hydrochloride (Aricept), and rivastigmine (Exelon) – act by slowing down the metabolic breakdown of acetylcholine. These agents do not, however, alter the underlying course of the disease.

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Slowing, Delaying, or Preventing the Disease Scientists are working at a stepped-up pace to examine a number of compounds that might delay the onset of AD, slow its progress, or prevent it altogether. These compounds include estrogen, anti-inflammatory agents, antioxidants, and nerve growth factors.

Estrogen Estrogen, a hormone that is produced by the ovaries during a woman’s reproductive years, affects brain regions relevant to memory, such as the hippocampus. A large body of data gathered over the past 25 years in animal studies supports the notion that estrogen has some positive effects on memory function. In epidemiologic studies, estrogen use has been associated with a decreased risk of AD and with enhanced cognitive function. It also has both antioxidant and anti-inflammatory effects and enhances the growth of processes from particular neurons important for memory function. These data have created intense scientific interest in the relationship between estrogen, memory, and cognitive function in humans. In recent years, NIA has supported one AD clinical trial on estrogen in the hope that it might be able to provide evidence on whether estrogen actually affects the progression of AD. This trial, which was conducted through the Alzheimer’s Disease Cooperative Study (ADCS) (follow the link for a description of the ADCS), was a pilot study of estrogen replacement therapy (ERT), using a commonly prescribed form of estrogen, in post-menopausal women who had had a hysterectomy and who had mild to moderate AD. Results of this study indicated that ERT did not slow progression of AD or improve cognitive or functional outcomes (Mulnard et al., 2000). Even if given for a full year, estrogen was not helpful for these women. It should be noted that the findings apply only to a very specific population of older patients who had had AD for some time. A closely associated study by researchers at the University of Southern California that was not funded by NIA provided similar results (Henderson et al., 2000). In this study, postmenopausal women with mild to moderate AD were treated for 16 weeks with 1.25 mg/day of estrogen. At both 4 and 16 weeks there were no significant differences between treatment and placebo groups on measures of cognition or caregiver-rated functional status. Estrogen did not slow the functional decline associated with AD, and did not improve mood or other symptoms of AD.

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Another clinical trial, not funded by NIA, examined the effects of estrogen on cognition, mood, and blood flow to the brain in women with mild to moderate AD (Wang et al., 2000). Blood flow is important because nutrients such as glucose and oxygen reach the brain through the blood stream. The better the blood flow, the more likely a person is to have good cognitive function. This study tested the effect of 1.25 mg of estrogen given without any progesterone to women in Taipei, Taiwan, who had a diagnosis of mild to moderate AD. Women were given the hormone for 3 months. Again, there was no beneficial effect, either on blood flow or cognitive decline in these women. When taken with data from clinical trials done in the U.S., the data suggest that the negative estrogen findings might be generalizable to older women with AD who are of different races. Though these three studies have found that estrogen does not have a beneficial effect on women who already have AD, they do not answer the question of whether normally aging women who take estrogen after menopause will be protected from developing AD or age-related cognitive decline. Separate studies are underway to examine this question. For example, an ongoing study, the Women’s Health Initiative Memory Study, is a component added to the NIH’s Women’s Health Initiative. This component, which is being supported by Wyeth-Ayerst Laboratories, will determine whether hormone replacement therapy decreases the incidence of cognitive decline and dementia in cognitively normal women aged 65 and older (Shumaker et al., 1998). Another element of this study, called the Women’s Health Initiative Study of Cognitive Aging, is investigating whether hormone replacement therapy protects against age-associated memory and cognitive decline. A similar study on possible preventive measures during normal aging is now in the patient recruitment phase. This multi-site, NIA-supported clinical trial will determine whether the use of estrogen in cognitively normal older women with a family history of AD (and therefore a twofold to threefold increased risk of developing the disease) may prevent the development of AD. Scientists at Columbia University are coordinating this study. Other clinical studies involving estrogen include a study by intramural NIA researchers who examined the effects of estrogen and progesterone on memory and other cognitive functions in normally aging women as part of the Baltimore Longitudinal Study of Aging. Women taking hormones did better on tests involving verbal learning and memory than women who had never taken them (Maki et al., 2000). NIA intramural researchers also have conducted studies on the effects of estrogen replacement therapy in which PET measurements of cerebral blood flow in brain regions important to

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learning and memory showed significant improvement after one year of estrogen treatment. This study further supports the beneficial effects of the hormone in normally aging women (Maki et al., 2001).

Anti-Inflammatory Agents One of the hallmarks of AD is inflammation in the brain, but whether it is a cause or an effect of the disease is not yet known. As the new vaccine work indicates, in some circumstances, inflammation – stepping up the activity of brain microglial cells – might actually help curb amyloid accumulation. However, epidemiologic evidence strongly suggests that anti-inflammatory agents, such as prednisone (a steroid) and NSAIDs, including ibuprofen and indomethacin, are associated with a decreased risk of AD. Recent studies in transgenic mice suggest that an NSAID can limit plaque production in the mouse brain (Lim et al., 2000). The NIA has supported a study to compare the effects of prednisone versus a placebo (inactive pill) on patients with diagnosed AD to see whether progression of the disease can be slowed. Results of this study, which was conducted through the ADCS, indicated that there was no difference in cognitive decline between the prednisone and placebo treatment groups (Aisen et al., 2000). Thus, a low-dose regimen of prednisone does not seem to be useful in treating AD. While results of this study were negative, they point the way to additional research. For example, one trial is testing NSAIDs, as opposed to steroids like prednisone, in clinical trials. An ADCS study with AD patients, which began at the end of 1999, will compare treatment with a traditional NSAID (naproxen), which blocks the activities of both COX-1 and COX-2 enzymes, to treatment with a COX-2 inhibitor (rofecoxib), which is a more specific type of NSAID with pain relieving qualities but without some of NSAIDs’ side effects on the gastrointestinal system. A second trial will determine whether NSAIDs might act earlier in the disease process to block the development of AD, as suggested by the epidemiologic studies. The NIA has just funded such a trial to determine if naproxen or another COX-2 inhibitor (celecoxib), can slow or prevent development of AD in cognitively normal elderly persons with a family history of AD.

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Inflammation Inflammation is a dynamic and complex biological process that involves several pathways and a very large number of subsystems and feedback loops that affect cells and tissues in all parts of the body. Inflammation occurs in response to an injury or abnormal situation. It can be as simple as the reaction to a cut or scrape, when the body moves quickly to heal the wound and counteract any bacteria or foreign matter. Inflammation can also be a chronic situation that involves body systems more generally. Rheumatoid arthritis is an example of a disease in which inflammation occurs in a more widespread way. In recent years, there has been a significant increase of interest in the role that inflammation plays in the development and progress of AD. Two schools of thought currently exist on how the inflammatory process may work in the AD brain. The following studies show just how complicated and difficult it can be to get to the bottom of certain scientific issues.

On the One Hand...Inflammation Is Detrimental •

Many scientists think that when the inflammatory process begins in the brain, it sets off a vicious cycle that includes the activation of microglia, interleukins (IL), cyclooxygenase (COX), complement, cytokines, and amyloid deposition. They hypothesize that one or all of these elements ultimately lead to neuron death. Certainly, when it occurs over a long period of time, neuro- inflammation has the potential to underlie the genesis of some of the cellular damage seen in AD as well as in normal aging.

•

Research has shown that overproduction of a protein called IL-1 by microglia is an integral part of the inflammatory response that has been reported in AD. Over-expression of IL-1 induces astrocyte activation that is associated with the conversion of beta-amyloid deposits into neuritic plaques and may have a role in increased synthesis and processing of APP. This self-perpetuating cycle may explain, in part, the progressive nature of AD, but these complex pathways need to be confirmed in other types of studies.

•

Epidemiologic evidence strongly suggests that persons who take antiinflammatory agents that inhibit prostaglandin synthesis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen and indomethacin, have a decreased risk of AD. These drugs inhibit COX, a type of enzyme that plays a major role in the series of events

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leading to the production of prostaglandins. Two forms of COX exist: COX-1 and COX-2. COX-2 levels rise sharply in the brains of patients in the early stages of AD. Inhibiting the COX enzymes, and therefore inhibiting the synthesis of prostaglandins, may be an important key to anti-inflammation therapy for AD. •

Complement is another key player in the inflammatory response. Its involvement triggers the recruitment of still more inflammatory components to the site of injury and causes a domino effect whose end point is the disruption of normal cellular activities and cell death. Researchers have found that beta-amyloid is a potent complement activator. Activation of the complement pathway marks cells for attack by white blood cells activated in the body and microglia in the brain and causes the release of proteins that further stimulate the cell death response.

But on the Other Hand...Inflammation Is Beneficial •

Another group of scientists believes that some aspects of the inflammatory process may be valuable to the brain. They suggest that activated microglia can “home in” on amyloid and clear it away and that the inflammatory process is part of a healing event that can be used to advantage. One research team has recently reported that activated microglia could be involved in this natural process as well as being involved in clearing amyloid in the amyloid vaccine-induced immune response (Bard et al., 2000).

•

It is clear from all these studies that inflammation is important to the pathophysiology of AD in several ways. The results demonstrate just how complex the question is. Research on both sides of the question continues in an effort to determine what aspects of the immune response play detrimental or beneficial roles in the development of AD, and clinical trials to test both possibilities have been started.

Antioxidants Over-production of free radicals can result in oxidative damage to cells. Because free radicals may play a key role in both normal aging and AD, researchers are studying agents that inhibit and protect against oxidative damage. Several experimental studies have shown that these agents, called free radical scavengers or antioxidants, can inhibit the toxic effects of betaamyloid in tissue culture. Investigators are now exploring whether the scavengers may indeed delay or prevent the disease. Many free radical

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scavengers are known. These include vitamins E and C, ginkgo biloba, melatonin, flavonoids (chemicals found in many plants, including tomatoes), and carotenoids (chemicals found in plants such as carrots). One free radical scavenger, vitamin E, is now used therapeutically as it staved off progression to certain important endpoints in AD patients by 6 months in an NIA-funded clinical trial. The beneficial effects of estrogen on AD and on the aging process in healthy women may be partly due to its antioxidant activity. An NIA-supported clinical trial, the Memory Impairment Study, is testing the ability of two agents – vitamin E and donepezil – to intervene earlier, before signs of memory impairment have developed into clinically diagnosed AD. Investigators want to see whether these agents can delay or prevent the onset of AD. The study is being carried out over a 3-year period in more than 700 people with MCI. People with MCI have memory problems but do not meet the accepted clinical criteria for AD. Another compound being tested is ginkgo biloba, an extract derived from the leaves of the ginkgo tree. It appears to have antioxidant properties as well as anti-inflammatory and anticoagulant properties. The NIH’s National Center for Complementary and Alternative Medicine (NCCAM), along with several other Institutes, is supporting a new clinical trial of this compound to determine whether it can delay or prevent dementia in older individuals.

Nerve Growth Factor (NGF) and Other Neurotrophic Factors NGF is the best known of a class of compounds known as neurotrophic factors and has been well studied in animal models for its ability to maintain viability in specific neuronal classes. In one study with aged rhesus monkeys (the best animal model of human aging) researchers at the Salk Institute, La Jolla, California, found that cholinergic neurons in a particular region of the brain exhibited age-related shrinking and loss of the ability to make acetylcholine (Smith et al., 1999). The investigators were able to reverse most of the shrinkage and loss of cholinergic properties in the monkeys by using specialized cells called fibroblasts that were genetically modified to secrete NGF. The fibroblasts were grafted directly into the affected regions in the brain. Based on the results of this study, researchers have now initiated privately-funded human phase I gene therapy clinical trials to test the safety of this grafting procedure.

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Alzheimer’s Disease Clinical Trials Database As one element of its effort to make information about Alzheimer’s disease and clinical trials research more widely available to the general public and other audiences and to assist with recruitment to AD clinical trials, the NIA, in collaboration with the FDA, maintains a database of ongoing AD clinical trials supported by both the Federal Government and private industry. This database, which is part of an NIH-wide initiative, is maintained by the NIA’s Alzheimer’s Disease Education and Referral (ADEAR) Center. As of December 2000, 13 trials were listed in the database, and it is continually updated. Each listing includes information about the sponsoring organization, a description of the purpose and design of the trial, a list of the sites where the research will be conducted, and recruitment procedures. Physicians, patients, family members, and others can learn more about these trials and other AD research by visiting the ADEAR Center website at: http://www.alzheimers.org or by calling the Center’s toll-free telephone number at: 800-438-4380.

Treating Behavioral Symptoms Behavioral symptoms – agitation, aggression, wandering, and sleep disorders – are common in AD patients and can be serious. Physicians now have several treatments for these symptoms, such as antidepressants, antipsychotic drugs, and sedatives, but researchers continue to search for better treatments, including non-drug approaches for AD patients. One ADCS clinical trial is focusing on alleviating sleep disturbances, a common problem for AD patients. Nighttime wandering and agitation can result in injury for patients and disrupted sleep for caregivers. In this study, groups of patients were given either a slow-release preparation of melatonin (a naturally occurring hormone that can induce sleepiness), an immediaterelease preparation of melatonin, or a placebo. This trial has finished and data are being analyzed. Another ADCS study focused on agitation, a problem affecting 70 to 90 percent of AD patients and one that can make caring for a patient at home very difficult. Drugs are commonly used to control signs of agitation, but they can have distressing side effects. This study involved people with AD who were living in the community (not in a nursing home or other care facility). Participants were randomly assigned to four groups, receiving either non-drug behavior management techniques, medication (haloperidol, an antipsychotic, or trazodone, an antidepressant), or a placebo (Teri et al.,

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2000). Over a 4-month period, study investigators followed the participants to see which intervention was most effective in reducing irritability, restlessness, pacing, wandering, and physical and verbal abuse of caregivers. The investigators found that about one-third of the study participants in each of the two medication groups and in the behavior modification group showed improvement by the end of the study. However, about one-third of the group that received the placebo also improved over the course of the study, meaning that a portion of the study participants got better regardless of the treatment they received. These results underscore the need for additional research into new treatments that might more effectively relieve this difficult problem for people with AD and their caregivers.

Clues to Healthy Aging Found in Lifestyles It is clear that genes, environment, and lifestyle all affect the way our brains age. One of the major reasons for studying aging is to find factors that will help us to grow older in a healthy way and to retain normal and active cognitive function for as long as possible. Evidence from studies in mice and humans is accumulating that early life events and our lifestyles may play an important role in the aging of our brains, the degree to which we retain normal cognitive function, and perhaps also our chances of developing AD.

Physical Activity Recent studies have shown that light to moderate physical activity, such as walking, results in a gain, or perhaps less loss, in some aspects of cognitive function in humans. The mechanisms that may help with cognitive function are difficult to study in the human, so researchers have turned to animal models to understand what is happening in the brain in the older individual. They are beginning to be able to link changes in the brains of animals to changes in cognitive function. Scientists have only recently learned that in certain brain regions, new neurons are born, even in older age. This was a surprising finding because for more than 100 years it was believed that all of the neurons a person will ever have are produced by the time infancy ends. Studies done 2 years ago demonstrated that new neurons are added continuously in the hippocampus of the adult brain in rodents, non-human primates, and humans. In rodents, the number of new cells varies, with numbers increasing with exercise and environmental enrichment and decreasing with old age and some forms of

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stress. Voluntary physical activity in mice, such as running in an exercise wheel, increases the number of new neurons in the hippocampus. New data in a mouse model have shown that running not only increased the numbers of neurons in the hippocampus, but also helped with spatial memory (that is, how the animals oriented themselves to their environment). Brains were studied both for changes in neuron number and for long-term potentiation (LTP). LTP is a complex form of electrical activity believed to be one of the factors important in the formation of memory in the hippocampus. Running helped the mice perform better in a maze, increased the numbers of neurons in the hippocampus, and selectively enhanced LTP, all of which may in turn have had a positive impact on memory function (Van Praag et al., 1999). Although at present the studies are only correlative, they suggest that physical activity can regulate nerve cell division in the hippocampus in the adult animal and improve learning. It may even be possible to stimulate brain repair mechanisms by exercising. Thus, physical activity may be one way to maintain or even improve cognitive performance as we age. Whether or not it would influence the risk of developing AD pathology is another question.

Healthful Eating throughout Life For generations, mothers have exhorted their children to eat their fruits and vegetables. Folklore has taught us that fruits and vegetables are good for us, but evidence on why this is so is only now emerging. Much of the data in the scientific literature on the effects of fruits and vegetables have come from studies on aging animals. An animal study by researchers at the University of Colorado Health Sciences Center and the USDA Human Nutrition Research Center on Aging, Tufts University, Boston, this year reported that a diet rich in spinach, strawberries, or blueberries can reduce age-related deficits in specific neurotransmitter systems in the brain (Bickford et al., 2000). In addition, the spinach diet improved learning in a test of motor function. Motor learning is important for adaptation to changes in the environment as well as being key to recovery from stroke and spinal cord injury.

Future Considerations for AD Clinical Research Scientists engaged in designing and developing clinical trials to test potential treatments for AD face a number of challenges. One is the need to recruit

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large numbers of participants – those with diagnosed AD, those earlier in the course of the disease (before clinical diagnosis), and healthy older people – so that the effects of the treatment and its safety and effectiveness at different stages of the disease can be measured with confidence. Close collaboration with existing research and treatment facilities, such as the Alzheimer’s Disease Centers and Alzheimer’s Disease Cooperative Study sites, helps to ensure a sufficient pool of potential study participants. Recruitment strategies being developed for trials such as the Memory Impairment Study will also help to ensure strong participation. A second challenge is the need to incorporate into study designs the special characteristics of people with AD. In many respects – cognitively, behaviorally, psychologically, and medically – this patient population is different from patients who participate in clinical trials for other diseases, and a number of research programs are now looking at issues relating to the ethical aspects of research on dementia patients (Earnst et al., 2000; Marson et al., 1999). Because of their dementia, many AD patients at later stages of the disease may not even be fully aware that they are participating in clinical research. Their disease means that family members and other caregivers need to be included as full partners in the research effort, and extra care must be taken to accommodate AD patients and protect their interests and rights. Institutional Review Boards, which judge the risks and benefits to patients and approve research involving human participants, are an important player in this process for they ensure that adequate protections for the rights of the research participants have been incorporated into the research plan, and they ensure that Federal and State regulations for the protection of human research subjects are being followed. The discovery of genetic mutations that increase the risk of developing AD has raised an important new ethical issue for clinical research in AD. Although this discovery has brought new promise of predictive testing for the disease, the information yielded by genetic testing for AD and the implications it has for the person tested and for other family members raises important questions about the use of such tests. Access to genetic information could affect a patient’s insurability if disclosed and could affect employment status and legal rights. The National Bioethics Advisory Commission (NBAC) is currently reexamining the Federal regulations to see whether AD patients participating in clinical research need any further protections and to ensure that protection of sensitive information is part of every research plan.

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Improving Support for Caregivers Perhaps one of the greatest costs of Alzheimer’s disease is the physical and emotional toll on family, caregivers, and friends. As Alzheimer’s disease makes inroads into a person’s memory and mental skills, it also begins to alter his or her emotions and behaviors. Patients can experience extreme agitation and feelings of anger, frustration, and depression. They can begin to exhibit bizarre behaviors such as pacing, wandering, screaming, and physical or verbal aggression. These changes in a loved one’s personality, the need to provide constant, loving attention for years on end, and the physical demands of bathing, dressing, and other caregiving duties are major reasons for caregiver exhaustion and depression and for placing AD patients in nursing homes. A recent study analyzing data from more than 1,500 caregivers who participated in the 1996 National Caregiver Survey provides details on the physical and other costs of caregiving (Ory et al., 1999). These data show that dementia caregivers spend significantly more time on caregiving tasks than do people caring for those with other types of illnesses. In addition, they report that this type of caregiving has a greater impact in terms of employment complications, caregiver strain, mental and physical health problems, time for leisure and other family members, and family conflict than do other types of caregiving. Other research shows that the information and problem-solving needs of caregivers evolve over time as the disease progresses and caregiving issues shift. These findings point to a need for programs and support services tailored to the unique and evolving challenges faced by AD caregivers. This suggestion is supported by a recent study conducted by researchers at Thomas Jefferson University, in Philadelphia. These investigators examined particular characteristics of caregivers that might predict whether they would start and stick with an intervention designed to help them with caregiving (Gitlin et al., 1999). Knowing these characteristics may help in the future to create better ways of assisting family members and other caregivers to care for persons with AD. The researchers found that being older and female predicted participation in the intervention. Those who found it easier to adhere to the intervention were older, were less depressed, and had a less dependent person to care for. Caregivers who reported depressive symptoms were unable to adhere to strategies that involved behavioral change or manipulations to the physical environment, and the authors suggest that these caregivers should be treated for their depression before they are asked to learn environmental modification techniques.

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Research focusing on the safety of the home environment as an important component of caring for persons with dementia has recently been reported by this same team from Thomas Jefferson University (Gitlin et al., 2000). Persons with dementia living alone or with a family caregiver must deal with six basic safety concerns: injury from falls, injury from ingesting dangerous substances, leaving the home and getting lost, injury to self or others from sharp objects, fire or burns, and inability to respond rapidly to crisis situations. A wide range of environmental strategies can be introduced to maximize home safety. As everyday competencies decline with memory loss, persons with dementia may have increasing difficulty navigating physical spaces and processing and interpreting environmental cues and stimuli. As a result, caregivers may need periodically to reevaluate the physical safety of the home and introduce new strategies for keeping the home safe.

REACH In 1995, the NIH established a major 5-year initiative to carry out social and behavioral research on interventions designed to help caregivers of patients with AD and related disorders. Resources for Enhancing Alzheimer’s Caregiver Health (REACH) is co-sponsored by NIA and the National Institute of Nursing Research (NINR). Participating researchers are from universities and medical centers around the country: •

University of Alabama and University of Alabama at Birmingham;

•

Veterans Affairs Medical Center and University of Tennessee at Memphis;

•

Center on Adult Development and Aging at the University of Miami, Florida;

•

Veterans Affairs Palo Alto Health Care System and Stanford University, California;

•

Center for Collaborative Research at Thomas Jefferson University in Philadelphia, Pennsylvania;

•

Hebrew Rehabilitation Center for the Aged and Boston University; and

•

University Center for Social and Urban Research at the University of Pittsburgh, Pennsylvania.

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REACH projects focus on characterizing and testing the most promising home- and community-based interventions for helping caregivers, particularly in minority families. The interventions include support groups, behavioral skills training programs, family-based interventions, environmental modifications, and computer-based information and communication services. Information about the project is available on the REACH website (www.edc.gsph.pitt.edu/reach/). A recent study supported by REACH concerns clinical trials recruitment, an issue vital to the continuing success of AD research. Researchers often experience difficulty in recruiting adequate numbers of participants, and this can add to the cost of the study, the time necessary to complete it, and the usefulness of the results. Recruiting older participants and their caregivers, particularly those in minority communities, presents a special set of challenges for AD researchers. Unfortunately, recruitment outcomes are not routinely reported in the literature and the documentation of recruitment costs is rare. This REACH study compared the cost-effectiveness of methods used by the project’s Boston site at the Hebrew Rehabilitation Center for the Aged to recruit participants for a study of AD caregivers (Tarlow et al., 2000). The results of this study indicate that a well-planned, multi-pronged, and flexible recruitment plan is the most productive for recruiting AD caregivers. Effective planning includes budgeting for enough personnel, materials, and time to conduct the recruitment process; using realistic estimates of the potential pools; and establishing contingency plans for under-enrollment.

Building a Research Infrastructure An important component of the success of NIH’s AD research effort is its vibrant network of research institutions and investigators who work together, as well as independently, to continue the process of discovery in AD. Building this research infrastructure is an ongoing effort and it ranges from developing a variety of innovative mechanisms for funding research, to sponsoring research conferences on cutting-edge issues, to enhancing the effectiveness with which research is conducted and data gathered, to ensuring that AD research has a broad and comprehensive focus.

Pursuing Innovative Mechanisms for Funding AD Research Because of the cost, time, and effort involved, relatively few medications or treatment strategies are tested in full-scale clinical trials. However, it is

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important to provide as many opportunities as possible to explore the potential of multiple compounds and strategies. NIA has therefore developed a number of mechanisms for funding research aimed at each stage of drug development, from efforts to identify useful drugs, through testing in animals and pilot clinical trials, to full-scale clinical trials. At each step, the NIA is fostering industry participation.

Small Business Innovation Research Grants (Sbirs) SBIRs are grant mechanisms designed to establish the merit and feasibility of ideas that may eventually lead to commercial products or services, and to support in-depth development of those whose feasibility have been established. A number of these grants have been funded in the area of AD research and they provide an important way for small businesses to participate in the research process. They also serve as a bridge between laboratory work and commercial development.

Drug Development Contract NIA maintains a contract mechanism for funding investigators or small companies who have a potentially interesting candidate AD treatment drug but who lack the means to begin the formal drug testing process. This contract, Investigational New Drug Toxicology for Drugs to Treat Alzheimer’s Disease and Other Diseases of Aging, funds a contractor to conduct animal studies to evaluate drugs for toxicity. If the toxicology screening is successful, the data generated are used to file a request to the Food and Drug Administration for approval to carry out initial tests for safety and efficacy in humans. This contract mechanism has already yielded several potentially promising compounds, and applications to test several more drugs are in process.

Pilot Trial and Trial Planning Grants These grant mechanisms give investigators funding to plan future large multi-site clinical trials and conduct smaller-scale clinical trials aimed at treating AD’s cognitive and behavioral symptoms as well as slowing the progression of and ultimately preventing AD. The trials allow investigators to develop recruitment strategies and diagnostic procedures, test drug responses, and generate data necessary to apply for funding of a full-scale clinical trial.

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“Add-On” Components to Ongoing Clinical Trials One efficient way to conduct AD clinical trials is to add a cognitive or dementia component to an ongoing trial. For example, an NIA-funded cognitive component has been added to the Women’s Health Study, which is a clinical trial funded by the National Heart, Lung, and Blood Institute (NHLBI) in which healthy older women are taking aspirin or the antioxidant vitamin E to measure possible effects on cardiovascular disease. A cognitive component has also been added to a second NHLBI trial, the Women’s Antioxidant Cardiovascular Study, in which older women at high risk of cardiovascular disease are taking either antioxidants or a combination of folate and vitamins B6 and B12. In both of these trials, the add-on studies are testing the effect of these compounds on age-related cognitive decline. In an add-on to a third NHLBI-funded study, the Physician’s Health Study II, researchers will examine whether the antioxidant supplement or multivitamin the participants are taking to measure effects on cardiovascular function have an influence on their age-related cognitive changes.

Enhancing the Efficiency and Effectiveness with which Research Is Conducted Alzheimer’s Disease Centers (ADC’s) The ADCs Program promotes research, training and education, technology transfer, and multicenter and cooperative studies in AD and other dementias and normal brain aging. Each of these centers enrolls and performs longitudinal studies on AD patients and healthy older people. Autopsy is an important part of this research effort. Many NIH-supported research projects depend on the ADC Program to provide access to patients and biological fluid and tissue samples. In addition to individual research grants, several other major initiatives depend on the ADCs, including the Alzheimer’s Disease Cooperative Study, CHORD (Caregiving, Health Services, and Outcomes Research in Dementia) and the National Alzheimer’s Coordinating Center. Many of the Centers have satellite clinics that target minority, rural, or other underserved populations in order to expand the numbers of persons from diverse population groups who participate in research protocols and clinical drug trials associated with the parent Center.

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National Alzheimer’s Coordinating Center The National Alzheimer’s Coordinating Center (NACC), established in 1999, is designed to facilitate research on Alzheimer’s disease by providing a facility for the analysis of combined data collected systematically from all of the existing ADCs as well as other sources. Until NIA established the NACC, each ADC collected and stored its own information separately. Now that there is a central data coordinating center, data from all ADCs are being combined, analyzed, and made available to researchers in the ADCs and soon to other qualified scientists in the wider research community. The NACC assembles, maintains, analyzes, and disseminates data; catalogs brain tissue and other biological samples stored at the ADCs; serves as a study design and statistical consulting resource for ADCs; and coordinates semiannual meetings of the ADCs to discuss progress and planning for shared initiatives. Research activities that use NACC resources are supported by the NACC itself and by the NIH and other Federal and non-Federal sources. Ongoing NACC initiatives include: •

A collaborative study by 16 adcs that is exploring the possibility of defining neuropsychological characteristics that might predict which of the healthy participants in a study will get AD. Such predictions could dramatically shorten the time needed to conduct prevention trials, decrease the number of study participants needed, and decrease trial costs.

•

A study by five adcs that will enroll up to 500 sibling pairs, one member of whom has AD and the other does not. This will permit the investigators to identify gene differences between the affected and the unaffected siblings as part of a larger effort to find risk factor genes for late-onset AD.

•

A study by five adcs that is collecting data on the clinical expression of Alzheimer’s disease in Hispanics of Mexican and Caribbean origin. Hispanics are the fastest growing minority group in the United States and estimates are that they will be the largest minority group by the middle of this century. Data suggest that the onset of AD may be earlier in this population than in others. Better and more complete information on cognitive and behavioral function as well as on demographic, acculturation, and medical variables that might affect the age at which symptoms begin are needed to determine if disease onset is actually earlier in this population and, if so, what factors may contribute to the earlier onset.

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Alzheimer’s Disease Cooperative Study (ADC’s) NIA first funded the ADCS in 1991 to build an organizational structure so that many Centers could cooperate in investigating promising drugs for AD and develop and improve tests for evaluating AD patients in clinical trials. The studies funded by the ADCS are carried out largely through the ADC clinical cores. During the first 5-year grant period, the ADCS began four drug studies and two studies of cognitive impairment assessment tests for Alzheimer’s disease clinical trials (one each in English and Spanish). In 1996, NIA funded the ADCS for another 5 years. The new studies include the Memory Impairment Study; the study of two different kinds of antiinflammatory compounds; the study of melatonin and sleep disorders in AD; and research on divalproex sodium (Depakote), an antiseizure drug, as a possible therapy for agitation and dementia in nursing home residents.

Broadening the Focus of AD Research NIA also supports some AD research at ten Exploratory Centers on the Demography of Aging. The goal of the Centers is to stimulate innovative and policy-relevant research on the health and economic circumstances of individuals as they age, and on the growing population of older persons in the United States and worldwide. The Centers have helped to identify and describe some of the most important aging-related trends in the population in the areas of health, longevity, disability, retirement, economic circumstances, and family support. Several of the Centers have projects on the demography or biodemography of AD. For example, two centers – one at Duke University and one at the University of Michigan – are exploring the potential for integrating survey and biological data to create a substantial new resource for relating individual physiology and genetics on the one hand, with cognition, functional ability, and the progression of illness on the other. At the Duke Center, NIA is supporting a supplement to the National Long-Term Care Survey (NLTCS) to collect biological data (blood and/or saliva) from about 7,500 of the NLTCS participants. These data will help to identify the genotypes that are associated with chronic illness and dementia in a population sample. They will also help to compare the onset and progression of AD among those with different APOE genotypes. Researchers at the Demography Center at the University of Pennsylvania are exploring the relationships between APOE genotype, AD, and heart disease as they differ across population subgroups through integrating a diversity of data sources. Researchers at the USC-UCLA Demography Center are also

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exploring the interactive influences of the APOE genotype with social, demographic, biological, and health behavior factors, using new data from the MacArthur Study of Successful Aging. They are comparing the increased risk of cognitive and physical decline from the APOE e4 genotype across populations with different characteristics, including gender, education, exercise, and social environment. In a closely related project, the UCLA researchers are estimating the incidence of cognitive change and cognitive impairment in the United States population as a whole. This analysis will serve as a baseline for understanding future population trends, and the effects on cognition of various interventions, such as drugs for AD, or behavioral change interventions.

Support for AD Research by Other NIH Institutes National Institute of Neurological Disorders and Stroke (NINDS) Scientists supported by NINDS conduct studies aimed at increasing our knowledge of the brain processes responsible for a variety of neurodegenerative disorders, including AD. It is well known that cells in the brain die in chronic neurodegenerative diseases. Because the mature brain cannot normally replace lost nerve cells, an important goal of treatment and prevention is to minimize nerve cell death. To do this, we must understand the molecular mechanisms involved in cell death, also called apoptosis. NINDS-supported scientists are seeking a more complete understanding of the molecular mechanisms that damage cells and trigger apoptosis as well as the metabolic steps that carry out the processes. Such knowledge will provide the foundation upon which to base new therapeutic strategies. In one study, NINDS-supported investigators at Harvard Medical School reported that the interaction of APP with beta-amyloid can result in neurotoxicity (Lorenzo et al., 2000). Beta-amyloid is found in two forms: fibrillar, which is neurotoxic, and soluble, which is not. The investigators sought to determine the mechanism by which fibrillar beta-amyloid becomes neurotoxic. They found that when soluble beta-amyloid is converted into a fibrillar form, it is much more likely to bind to certain protein receptors on the surface of neurons, including one for APP. Neurons without APP were less vulnerable to beta-amyloid’s neurotoxicity than neurons with APP, indicating that the interaction of beta-amyloid with APP (and certain other surface proteins) may mediate beta-amyloid’s toxicity. The researchers theorized that this binding may either abnormally inhibit or activate cell systems, leading to toxicity. Beta-amyloid did not interact as readily with a

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secreted form of APP that is known to protect the brain against a variety of toxic events, as it did with another form called holo-APP. These studies indicate fibril formation significantly increases the likelihood that betaamyloid will bind with APP. The study showed that APP may be implicated in neurodegeneration and that beta-amyloid toxicity is at least partially linked to its interaction with APP. Determining the mechanism(s) by which beta-amyloid becomes toxic may one day allow researchers to block its lethal effects and prevent the death of nerve cells. In a second study, NINDS-supported investigators at the University of Cincinnati reported that neurotoxicity associated with the ApoE peptide may be tied to its fragmentation (Tolar et al., 1999). They placed full-length ApoE, a fragmented form of ApoE, and a synthetic ApoE-related peptide into cultures of chick and rat neurons; all three forms were toxic to the neurons, and the full length ApoE became fragmented. When the scientists added a mixture of protease inhibitors to block the action of enzymes that cut ApoE into fragments, both the neurotoxicity and fragmentation of full-length ApoE were blocked, but the protease inhibitors had little or no effect on the other two forms of ApoE. This suggests that the neurotoxicity seen with the fulllength ApoE is related to fragmentation. The investigators also found that exposure to the ApoE peptide caused a significant influx of calcium into the neurons, causing the cell bodies to swell and their neurites to fragment. Eliminating calcium found outside the cells reduced, but did not eliminate, this effect. Several calcium channel blockers, each of which works using different cell surface receptors, were then tested for their effect on the cells’ calcium response. Only MK-801, which works by way of specific neurotransmitter receptors, was able to significantly decrease the cellular influx of calcium and prevent cell death in rat neurons exposed to the ApoE peptide. However, MK-801 did not protect chick neurons against the toxic effects even though it did affect the influx of calcium, indicating that something other than the calcium load itself may be involved in the toxic effects of ApoE. These experiments substantiate the hypothesis that ApoE is involved in neuronal degeneration in AD. Characterizing the neurotoxic effects of ApoE and determining the cellular receptors and systems involved may some day lead to a way to prevent AD. In a third NINDS-supported study, investigators at McGill University in Canada focused on a group of enzymes, called caspases, that are known to be involved in apoptosis and APP processing (LeBlanc et al., 1999). Their preliminary findings indicate a possible role for caspase-6 in APP metabolism and beta-amyloid production in AD. Using cultures of human neuronal cells, the researchers showed that serum deprivation, which is

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known to induce apoptosis and consequent changes in APP metabolism, causes caspase-6 to become activated and that, some hours after this activation, the production of beta-amyloid is increased and cells die. Inhibition of caspase-6 prevents an increase of beta-amyloid in serumdeprived neurons. They also determined the process whereby caspase-6 increases production of beta-amyloid. Caspase-6 generates beta-amyloid indirectly by cutting APP into beta-amyloid-forming fragments. This is believed to be the first study to link caspase-6 to neuronal cell death. While additional studies are needed to fully understand the molecular mechanisms by which neurons die, the McGill research suggests that caspase inhibitors may one day be adapted to interrupt or prevent a cascade of processes that lead to neuronal cell death. The McGill team hypothesizes that caspases may cause APP/beta-amyloid processing changes that sicken, but do not kill, neurons. Over time, these damaged neurons would increase the production of beta-amyloid in the brains of people with AD.

National Institute of Mental Health (NIMH) NIMH supports research on the causes of AD, its clinical course, and treatment and services for patients with AD. In the last year, researchers supported by NIMH have made advances in a number of areas, including the use of advanced imaging techniques, improvements in understanding mental illnesses in both caregivers and patients, and the basic molecular and genetic underpinnings of the disease. For example, in a study conducted by a team from Massachusetts General Hospital and Harvard Medical School, researchers showed that the genes for the protease known as beta-secretase map to chromosome 11 (BACE1) and the Down’s region of chromosome 21 (BACE2) (Saunders et al., 1999). The beta-secretases cleave the amyloid precursor protein to produce betaamyloid in the brains of patients with AD and Down’s syndrome, and they represent powerful new targets for drugs to treat these disorders. The mapping of their genes has now allowed NIMH-supported scientists to continue to search for Alzheimer gene mutations in these genes using the NIMH Alzheimer family sample, a national resource of clinical data and biomaterials (tissue and DNA samples) collected from individuals with AD, schizophrenia, or bipolar I disorder. This database was established to aid researchers in understanding the genetic bases of these disorders and is known as the NIMH Human Genetics Initiative. This study is important because the BACE genes are candidates for genes whose mutations could cause AD. Inhibiting the proteases that are made by these genes could represent a novel treatment for Alzheimer’s disease.

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Tau and neuronal thread protein (AD7C-NTP) are two proteins that are found at elevated levels in the cerebrospinal fluid of patients with AD. Assays for AD7C-NTP and tau are marketed commercially by two separate firms to aid in the diagnosis of AD. However, the relative utility of these two tests in diagnosing AD has never been compared. NIMH-supported scientists at Stanford University compared the ability of AD7C-NTP and tau tests to correctly differentiate patients with AD from healthy individuals and from patients with other neurologic disorders such as Parkinson’s disease (Kahle et al., 2000). When used together, the tests resulted in an overall diagnostic accuracy for AD of 81 percent. However, this combined diagnostic accuracy was only slightly better than that achieved with either test alone. These results demonstrate that AD7C-NTP and tau are both potentially useful markers for AD. In 1998, in a highly publicized report, a team at Harvard University asserted that a polymorphism in the gene for alpha-2 macroglobulin (A2M) was a major risk factor for AD. This finding generated a great deal of interest because the A2M protein had been linked in other reports to the basic biological process thought to give rise to AD pathology in the brain. Two studies have carried these findings to the next stage. The first, conducted by scientists at Massachusetts General Hospital and Harvard Medical School, confirmed the previously published association of the A2M gene with lateonset AD (Blacker et al., 1999). The original association and the confirmation were observed using the NIMH Alzheimer sample families. A2M can enhance the clearance of amyloid from the brains of AD patients, and the association of this gene with AD can provide clues about this process as well as ideas for new therapies for treating the disease. In the second study, investigators at Indiana University working with other researchers from Munich University, Stanford University, and the Eli Lilly Company, tested the association between the A2M mutation and Alzheimer’s disease in a sample of almost 600 patients with AD and healthy older people (Dodel et al., 2000). While the A2M mutation was indeed a risk factor in the patient sample, individuals with the A2M mutation had about 1.5 times the risk of AD as did those without the mutation, suggesting that the risk of developing AD is not as great as previously reported. In comparison, APOE e4 increases the risk for AD by about 5 times. These results show that A2M mutations result in a small but significant increase in the risk for AD. NIMH-supported researchers at UCLA have combined genetic testing with PET scanning to determine brain function in people at risk for AD who still

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have normal memory function. The researchers found that adults carrying the AD risk factor allele APOE e4 show significant decline in brain function over a 2-year period – without symptoms of the disease (Small et al., 2000). The genetic testing was performed on 54 adults, aged 50-84, with very mild and common age-related memory complaints. Half of the participants carried the APOE e4 allele. Initial PET scans revealed that the group carrying this allele had significantly lower function in the regions of the brain important to memory and learning, compared with the group without the APOE e4 allele. The researchers then conducted a 2-year follow-up on 20 study participants. The group carrying the APOE e4 allele demonstrated a 5 percent function decline in these same regions of the brain compared with their initial PET scans. Consistent with normal aging, the group without the APOE e4 gene demonstrated decline only in the frontal cortex, where executive functions reside. Results of memory testing, when researchers ask questions to measure forgetfulness and changes in memory, appeared normal for both groups at the beginning of the study and at the 2-year follow-up. The investigators found on follow-up examination that a single copy of the APOE e4 gene was associated with lowered brain function in people with normal memory performance. The UCLA study is the first to report long-term PET results for individuals with the genetic risk for AD who have no disease symptoms. The research team has just announced a new UCLA Memory Clinic for testing treatments to prevent age-related memory loss. Studies will continue research into exploring the use of PET scanning and genetic testing for identifying persons who may be at high risk of developing AD. Scientists at Good Samaritan Regional Medical Center and Mayo Clinic, Scottsdale, Arizona, the University of Arizona, and Arizona State University used PET to characterize AD-related reductions in brain activity before the onset of symptoms in persons who carry the APOE e4 gene (Reiman et al., 2000). The study focused on determining the power of PET to rapidly test treatments to prevent this disorder. After only 2 years, cognitively healthy, late middle-aged APOE e4 carriers had significant reductions in regional brain activity, and these reductions were significantly greater than those in people who did not have this gene. The scientists estimated that fewer than 30 cognitively healthy APOE e4 carriers would be needed per active and placebo treatment group to test a candidate prevention therapy after only one year and that fewer than 100 cognitively normal APOE e4 carriers would be needed per treatment group to test a candidate prevention therapy after only 2 years. This study leads the way to potential testing of treatments to prevent AD without having to study thousands of individuals or wait many years to determine whether or when treated individuals develop symptoms.

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Behavioral disturbances are very common among patients with Alzheimer’s disease and contribute substantially to the morbidity of the illness. These symptoms include delusions (the false beliefs that patients may have), hallucinations, and agitated or aggressive behavior. Scientists supported by NIMH are conducting many studies on aspects of depression and other mental illnesses in AD patients and caregivers. For example, approximately one-half of the AD patients who were participating in a study conducted by researchers from the University of California, San Diego, and University of Iowa developed psychotic symptoms of delusions and hallucinations over a period of 3 years (Paulsen et al., 2000). Such symptoms cause considerable distress for the patients and their caregivers, and frequently result in the decision to place the patients into a nursing home or other care facility. Patients with signs of parkinsonism and more rapid decline in cognitive function were at the highest risk of developing psychotic symptoms. From practical and theoretical viewpoints, understanding the pathophysiology and risk factors of psychotic symptoms is important because of their common association with severe behavioral problems, such as agitation and aggression, that lead to expensive institutionalization. These findings suggest a very high incidence of such symptoms, and possible identification of a subtype of AD characterized by parkinsonism and rapid cognitive decline. In a study among 307 middle-aged and elderly psychiatric outpatients (a third of whom had AD dementia with psychosis or severe agitation that was being treated with relatively low doses of medications), scientists at the University of California, San Diego (UCSD), and the VA San Diego Healthcare System (Jeste et al., 1999a) found that 22 to 37 percent developed tardive dyskinesia. Tardive dyskinesia is a serious movement disorder that tends to persist and may even be irreversible in some patients. This incidence is much higher than that reported for younger adults with schizophrenia (4 to 5 percent per year). The high risk of tardive dyskinesia in AD patients treated with rather low doses of typical medications has clinical implications for the use of these drugs, which are among the most commonly prescribed agents for this problem in this population. In a second study, the UCSD/VA research team found that the risk of tardive dyskinesia was significantly (about sixfold) lower with the atypical antipsychotic drug, risperidone, compared to the typical drug, haloperidol, in 122 middle-aged and elderly outpatients (21 percent of whom had AD dementia, with psychosis or severe agitation treated for 9 months) (Jeste et al., 1999b). The marked difference in the risk of tardive dyskinesia with typical versus atypical antipsychotics suggests that the latter may be

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preferred in the treatment of elderly AD patients with psychosis or severe agitation who are at a high risk of tardive dyskinesia. Neuropsychiatric symptoms are known to play an important role in patient distress, caregiver burden, nursing home placement decisions, and health care costs of patients with AD. Unfortunately, the factors that contribute to the expression of these symptoms are not well understood. Why some patients develop certain symptoms and others do not is not clear. A group of investigators at the UCLA School of Medicine used 18F fluoro-deoxyglucose (FDG) PET to examine the metabolic activity in critical brain regions in patients with AD (Sultzer, 1999; Sultzer, 1996). This noninvasive technique can reveal specific areas of brain dysfunction in living patients. Recent results from this UCLA laboratory demonstrate that delusions are associated with dysfunction in specific brain regions: the anterior cingulate and areas of the prefrontal cortex. These parts of the brain are important in the ability to compare internal ideas with previous experience and external reality. Additional results indicate that dysfunction in other specific areas of the brain are associated with depression and agitated behavior in AD. These findings demonstrate that behavioral symptoms of AD are a fundamental expression of specific changes in brain region function, rather than random consequences of global brain disease. Current activities by this research group include examining how dysfunction in specific regions of the brain may predict whether patients with AD respond to treatment for cognitive deficits or behavioral symptoms. They are also examining whether regional brain function improves in association with successful treatment. Recent advances in basic science research have provided clues to mechanisms by which genetic vulnerability, aging, and other factors lead to the neuropathologic changes of AD. At the other end of the AD research spectrum, clinical trials have shown that pharmacologic interventions can help treat the symptoms of the disorder. Unfortunately, treatment may not always be helpful, and psychotropic medications used to treat behavioral disturbances in the elderly often have adverse effects. These investigators are continuing research on ways to clarify why specific symptoms occur, which can facilitate development of more targeted and effective treatments. By examining critical brain mechanisms involved in the expression of clinical symptoms, these investigators are conducting “intermediary” work that provides a bridge between basic science and clinical research. This work has the potential for identifying neurobiologic markers that predict response to treatment. Such work allows researchers an opportunity to translate and apply our new understanding of basic mechanisms in AD to the clinical care of patients and development of more effective treatments.

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Finally, as part of a project entitled the Sources and Mediators of Alzheimer’s Caregiver Stress, NIMH-supported researchers at the University of Maryland are examining the impact of caregiving on the lives of adult children who provide assistance to a parent impaired by AD. These scientists are exploring the effects of caregiving on health by observing its disruptive and stressful consequences for roles, relationships, and activities outside of actual caregiving, such as social and leisure life, relationships with children or spouses, or conflicts between the simultaneous fulfillment of job and caregiving responsibilities. Because of the progressive character of AD, it often happens that increasing caregiving involvement eventually comes to exert these kinds of consequences. The resultant negative health effects, in turn, may lead to an increased use of the medical care system.

National Institute of Nursing Research (NINR) NINR supports research on biobehavioral aspects of AD and related dementias. The primary focus of current studies is on behavioral, physical, and functional problems such as wandering, agitation and aggression, and maintaining activities of daily living. Family members are usually the primary caregivers for people with dementia. An NINR-supported study conducted by researchers at the University of Texas, Houston, involved a controlled trial of an intervention to ease the burdens of family caregivers who are living with relatives with dementia (Ostwald et al., 1999). Although many family members willingly assume the caregiving role, they often discover that it imposes particular burdens. For example, caregiving has been linked to substance abuse, isolation, family stress, and depression. This study randomly assigned pairs of caregivers and relatives with dementia to either a treatment or a control group. Caregivers in the treatment group participated in seven weekly 2hour sessions that taught them about dementia, developed their practical skills, increased their confidence and coping abilities, and improved communication with their affected family members. Meanwhile, the relatives with dementia participated in daycare activities that gave clinicians opportunities to assess their disruptive behaviors. At 5 months, researchers collected data from this group of caregivers and relatives as well as from the control group, all of whose members were awaiting treatment. Even though approximately 3 months had elapsed since the first group had completed treatment, these caregivers reported fewer burdens and negative reactions to disruptive behaviors than did caregivers in the untreated control group. This difference was particularly striking in light of the fact that the two groups of relatives with dementia showed no difference in numbers of disruptive

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behaviors and had suffered similar declines in cognitive functioning over the course of the study. This study demonstrates that a short-term intervention can reduce caregivers’ burdens and negative reactions to disruptive behaviors displayed by family members with dementia. These findings suggest that reducing the burdens of caregiving can delay the institutionalization of patients with dementia. Ongoing studies will investigate this possibility. In a second NINR-supported study, researchers from the University of Michigan examined a training program to assist nurse aides in detecting agitation and aggression in patients with dementia. Episodes of agitation become increasingly frequent as dementia progresses (Whall et al., 1999). Agitation that goes unnoticed and untreated can lead to acute episodes of aggression during which patients may injure themselves or others. Aggression in dementia is a major problem, causing individuals to be placed in nursing homes, nursing staff members to burn out, and nursing homes to use physical and pharmaceutical restraints. Estimates suggest that as many as one-half of demented patients exhibit aggression. Nurses’ aides provide the majority of care in nursing homes, and consequently, they are usually in the best position to detect early signs of agitation in demented patients. However, nurses’ aides are sometimes unable to provide accurate observations of patients’ behavior. In this study, nurses’ aides were taught in two sessions that totaled just 50 minutes how to recognize and rate degrees of agitation. Because patients’ shower baths often elicit agitation, the study focused on this routine event. Nurses’ aides and nurse experts rated patients’ agitation during their shower baths. After the training, the nurses’ aides agreed with the nurse experts more than 90 percent of the time about the signs of agitation that they were seeing. This kind of assessment and early detection can be crucial in preventing agitation from escalating to physical aggression. With relatively little training, nurses’ aides can recognize the first signs of agitation in nursing home patients with dementia.

National Institute On Alcohol Abuse and Alcoholism (NIAAA) Dementia in older adults can be caused by a number of factors, including AD, vascular disease, or alcohol. In fact, alcohol-related dementia is frequently misdiagnosed as AD and is a significant cause of dementia in the United States. Because alcohol-related dementia is thought to be at least partly reversible with abstinence, its prognosis is very different from that for AD. Establishing criteria for differential diagnoses of these two dementias thus has major practical and public health implications. NIAAA-supported

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researchers are concerned with establishing criteria for differential diagnoses. NIAAA-funded investigators at the University of Pittsburgh School of Medicine compared elderly alcoholics with dementia with AD patients in an effort to distinguish the two conditions from the standpoint of types of cognitive impairment and long-term outcome (Saxton et al., 1999). The investigators found evidence that these are two quite distinct conditions. For example, disorientation in space and time is an early problem encountered by all patients with AD, whereas it was observed in a milder form in only 3 out of 10 patients with alcohol-related dementia. In contrast with AD, where memory impairment typically is profound, memory impairment in alcoholics with dementia appears to be mild and slowly progressive and verbal intelligence and language skills are preserved. Common deficits in alcoholics with dementia include impaired abstraction, poor short-term memory, and visuospatial difficulties, whereas patients with AD do not manifest the same degree of visuospatial impairment but do manifest profound memory loss that involves loss of both recognition and recall as well as word-finding deficits. The investigators caution that these findings are based on a study of only 10 alcoholics with dementia and 10 AD patients. A much larger study is needed to establish and validate diagnostic criteria to distinguish the two types of dementia. The ultimate outcome of this project will be to provide diagnostic criteria for distinguishing AD from alcoholrelated dementia. This will have both practical and medical significance for the development of treatment plans and interventions that target the two different groups.

National Institute of Environmental Health Sciences (NIEHS) Scientists supported by NIEHS are examining the ways in which metals and other compounds found in the environment may affect brain tissues and possibly contribute to the development of AD. Inflammatory processes are considered to be a critical factor at various stages in the development of AD, and the microglial cells involved may play both positive and negative roles in the process (see Background Information: Inflammation for more detail on inflammation). The research of one NIEHS intramural laboratory is directed toward understanding the role that microglia play in neurodegeneration and the mechanisms involved in microglia regulation. Such understanding may lead to the development of a treatment to minimize progression of the disease following acute trauma to the brain. In one series of studies, the investigators found that early

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activation of microglial cells may not be associated with an injury response. However, the presence of microglia appears to be required in the cascade of events, and the lack of a prominent microglial response can lead to an exacerbation of the neuronal damage (Bruccoleri et al., 2000; Bruccoleri et al, 1999; Harry et al., 2000). The microglial response was altered in the APOE transgenic mouse model for AD. However, the response was dependent upon the age of the animals. The importance of these observations in AD research is that previous efforts toward a therapeutic intervention have been focused on minimizing the microglial response. This work demonstrates that always reducing the microglial response does not necessarily lead to a positive outcome and that the basal level of the pro-inflammatory cytokines needs to be taken into consideration before such intervention is attempted. Another area of investigation by NIEHS-supported researchers has been the role of substances called growth factors and inhibitors. Scientists at the University of Utah are studying the structural properties of a protein known as human neuronal growth inhibitory factor (GIF) (Faller et al., 1999). GIF inhibits survival and growth of cultured neurons and has been reported to be decreased in the postmortem brains of patients with AD. GIF is a member of a class of metallothionein proteins that bind and regulate metal ions within cells. In comparing the structural features of GIF with other metalloproteins, the research team found evidence for increased conformational flexibility of both domains of the GIF protein, a property desirable for receptor-ligand interactions and metal exchange. The increased conformational flexibility of GIF may underlie its function as an inhibitory growth factor, as less flexible metallothionein proteins do not share this biological activity. Because AD is a neurodegenerative disease characterized by the buildup of plaques, there has been great interest in understanding how these plaques are formed. Knowing more about the GIF protein may help investigators to understand the details of plaque formation. In recent publications, scientists at the University of California, Irvine, have described alterations in key neural proteins following treatment with aluminum compounds. In one study, levels of beta-amyloid and ubiquitin were increased in mouse neural cell cultures after aluminum administration (Campbell et al., 2000). These two proteins have been found in increased amounts in the pathological lesions of AD. The data suggest that aluminum might play a role in AD by promoting the formation of neuronal betaamyloid and ubiquitin. Aluminum has long been suspected to play a role in several neurological diseases associated with aging including AD, but the link has never been unequivocally identified. Possible mechanisms include enhancement of iron-induced free radical formation by aluminum and changes in protein structure and function.

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In another report from the University of California, Irvine, researchers describe depressions of glial fibrillary acidic protein (GFAP) after injections of aluminum lactate were given to laboratory rats (Guo-Ross et al., 1999). GFAP is a component of the protein structure or cytoskeleton of astrocytes that are found in the brain. Normally, astrocytes mount a vigorous inflammatory response to brain injuries, which includes increased levels of GFAP. The reported depression of GFAP levels may reflect impairment of astrocyte function and suggests that these cells may be the primary targets for aluminum neurotoxicity. The results of this study may help to elucidate the role of aluminum in neurodegenerative diseases like AD.

National Institute of Child Health and Human Development (NICHD) NICHD supports research related to AD primarily through its programs involving neurobiology and mental retardation and developmental disabilities. NICHD-supported advances in basic neurobiology stem from the Institute’s efforts to understand the processes underlying both normal and abnormal human development. These advances are helping researchers understand how brain functions, such as memory and thought processing, are established in early embryonic development. They hope this knowledge will ultimately lead to drugs that can address the gradual loss of memory in patients with AD. For example, scientists have traditionally believed that the number of brain cells was established at birth and unresponsive to signals outside the cell later in life, leaving little hope for efforts to replace old or damaged brain cells. However, the recent identification of neural “precursor” cells and persistent cell development in the mature brain raises the possibility that the number of neurons in certain regions of an individual’s brain is actively maintained throughout life, rather than being diminished over time. Scientists sponsored by NICHD have found that a protein in the body, basic fibroblast growth factor (bFGF), regulates nerve cell growth in the brain of newborn rats by crossing the blood-brain barrier to stimulate nerve cell division (Wagner et al., 1999). These researchers also discovered that the effects of bFGF were not restricted to the perinatal period, but also stimulated brain cell growth in older animals, indicating that cells continue to be responsive to bFGF later in life. In adult animals, peripheral bFGF increased cell division threefold in the forebrain and areas related to the sense of smell, indicating that bFGF regulates ongoing generation of nerve cells by a unique pathway, potentially providing new approaches for

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treating damaged brain cells during development and into adulthood. Researchers also found that the peripheral injection of small doses of bFGF increased the proportion of early nerve cells and stimulated the growth of new nerve cells in the neonatal rat brain. The existence of a biological pathway transporting growth factors to the nervous system has potential implications for developing treatments for brain damage associated with neurodegenerative conditions, such as AD, in addition to congenital conditions and acquired brain disease.

National Human Genome Research Institute (NHGRI) The NHGRI supports research aimed at carrying out the Human Genome Project, an international research program designed to construct detailed genetic and physical maps of the human genome and develop a resource of detailed information about the structure, organization, and function of human DNA. Another major component of NHGRI’s mission is to analyze the ethical, legal, and social implications of the genetic information uncovered through research and to develop policy options for public consideration. Now that it is known that an allele of a risk factor gene (APOE) is linked to late-onset AD, controversy has surrounded the issue of presymptomatic testing for this disorder. NHGRI-supported investigators at Johns Hopkins University are developing a survey to determine how the public, particularly those at increased risk, understand the current information regarding inheritance of AD risk and the role of other risk factors. In addition, they will study physician understanding and interest in genetic testing for AD. Expectations of the genetic testing process will be compared between the public and physicians. Participants will include adult offspring of previously studied AD patients and physicians who treat these patients. The study focuses on knowledge of AD genetic risk and attitudes toward presymptomatic genetic testing, where false negatives and false positives are a well-known feature. Focus groups of physicians and high-risk offspring will be conducted to explore the educational needs of these populations. This research will help in the development of effective methods to integrate genetic testing for AD into health care. In a second NHGRI-supported project, Boston University Memory Assessment researchers will examine the factors that influence an individual’s choice to obtain susceptibility genotyping for AD and what the consequences of that information would be. Clinicians will assess the benefits and risks of providing this information to adult children of people

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with AD. Determination of APOE status will be used in a format that parallels likely clinical usage and will permit the development of guidelines for clinicians for genetic testing, risk assessment, and appropriate counseling scenarios. Because of its inherent uncertainties, APOE determination and counseling is an ideal model to develop new guidelines for whether and how best to use susceptibility gene markers in this and other diseases where such markers are or will be available in the future. This research will examine how genetic testing for AD is perceived by physicians and patients at high risk. It will also aid in the development of guidelines for the effective integration of genetic testing for AD. A third NHGRI project, conducted by researchers at Massachusetts General Hospital and the University of Alabama, addresses the ethical, legal, and social implications of AD genetics from the critical perspective of a group at high risk for the disease: currently unaffected relatives of individuals with AD. The investigators have been working together since 1990 as part of the NIMH Human Genetics Initiative to identify families with AD. Nearly 350 such families, predominantly affected sibling pairs and over 300 of their unaffected siblings, will be included in the study, which will examine knowledge, attitudes, and behavior related to genetic testing in the unaffected individuals in these AD families and their primary care physicians. Researchers will develop educational materials for genetic testing for AD for individuals at high risk and examine attitudes toward such testing on the part of physicians and these high-risk individuals.

National Center for Complementary and Alternative Medicine (NCCAM) NCCAM conducts and supports basic and clinical research and research training on complementary and alternative medicine (CAM) and develops other programs to further the investigation and application of CAM treatments that show promise. The Center is currently pursuing several projects related to AD. In one, conducted at Oregon State University, Corvallis, researchers will use a recently developed transgenic mouse model of AD to investigate whether oxidative stress plays a role in the deposition within the brain of beta-amyloid plaques and the brain’s reaction to deposited beta-amyloid. Oxidative stress is known to be a feature of aging, the major risk factor for AD. Matched transgenic and wild-type mice will be studied at various ages that are relevant to plaque deposition. Treatment with antioxidants, vitamin E, and ginkgo biloba extract (GBE) will be compared to treatment with an oxidative stressor and with no treatment to

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assess the degree of plaque deposition. This project may elucidate possible causes of AD as well as suggest therapeutic interventions. A second project conducted by NCCAM-supported researchers at the Oregon Health Sciences University, Portland, is a randomized, placebocontrolled, double-blind study of the effect of standardized GBE on preventing or delaying cognitive decline in people age 85 years or older (the oldest old). The study focuses on this population because of their high risk for developing MCI, which can be a precursor to dementia. Approximately 200 elderly cognitively healthy people will be enrolled and followed to see whether researchers can detect conversion to MCI. The study will ascertain whether GBE has a disease-modifying effect on the brain and will assess the antioxidant effects of GBE and the magnitude of the biological effect of the treatment using volumetric quantitative MRI. Older individuals who exhibit general cognitive decline are at a higher risk of developing AD. Preventing this cognitive decline may slow conversion to AD. Another study of the effects of ginkgo biloba is now underway, jointly supported by NCCAM, NIA, NHLBI, and NINDS. This is a multi-center, randomized, double-blind, placebo-controlled trial to determine the effect of 240mg/day of ginkgo biloba in decreasing the incidence of dementia in general and AD specifically. The participants will be aged 75 years and older. Secondary outcomes will be changes in cognitive function, incidence of cardiovascular disease, and total mortality. Because there is no approved therapy for preventing AD, if ginkgo biloba extract is found effective, individuals at high risk of developing dementia will have an inexpensive and safe prevention option. However, if the extract is ineffective as a prevention agent, these data will provide important information to consumers and allow for informed decision making concerning continued use of this botanical. The study is also one of the largest primary prevention trials of AD. As such, valuable information will be obtained on the progression of AD in a healthy population.

Outlook for the Future In the last 25 years, scientists have produced an extraordinary body of research findings on AD. Many of these findings have defined the genetic and biologic changes that underlie AD and offer possible targets for treatment. Researchers have identified drugs and other agents that could potentially counteract the pathologic changes that occur in AD and are testing many in clinical trials. They have made gains in defining people at high risk of developing AD. As methodologies are refined, scientists and

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clinicians will be able to investigate and understand the very earliest pathological and clinical signs of AD – perhaps 10 to 20 years before an actual clinical diagnosis is made. A variety of approaches also have been applied to improve methods of providing quality care for AD patients, reduce caregiver burden, and decrease the need for institutionalization. In seeking to understand AD, investigators are also defining normal aging. Research is beginning to shed light on healthy cognition and how to minimize normal, age-related cognitive decline. Federal support of AD research has been the foundation of many of these breakthroughs in our understanding of the disease. This funding also has helped establish an infrastructure that will continue to facilitate research advances. Novel grant award mechanisms, such as the Alzheimer’s Disease Centers Program, the Leadership and Excellence in Alzheimer’s Disease award, and the National Alzheimer’s Coordinating Center, have attracted distinguished scientists to AD research, promoted interdisciplinary research collaborations, enhanced coordination of research data from multiple studies, developed patient examination facilities and biologic resources that are necessary for research on the disease, and enabled patient outreach efforts. These advances have made it possible for the NIH to launch two new initiatives that build on current activities and give a new focus to future work. The first initiative, the NIH Alzheimer’s Disease Prevention Initiative, is designed to expedite the progress toward finding effective medications and other approaches to delaying or preventing the onset of Alzheimer’s disease. In collaboration with other Federal agencies and the private sector, this initiative is moving forward on several fronts simultaneously: •

Fostering new approaches to basic biologic and epidemiologic research

•

Increasing the focus on drug discovery and development

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Improving methods to identify early those people who are at increased risk of developing ad

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Facilitating movement of possible new treatments into the clinic for testing in clinical trials

•

Actively pursuing research into drug and non-drug strategies for treating behavioral disturbances in ad patients

Candidate interventions for AD prevention have been identified. These include estrogen-like compounds, anti-inflammatory agents, and antioxidants, as well as drugs that target cell death, the accumulation of abnormal insoluble molecules like plaques and tangles, and other harmful

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processes involved in AD. The evidence upon which these interventions are based was largely unknown only a few years ago, and the pace of discovery is accelerating. The AD Prevention Initiative will stimulate laboratory and clinical research in these areas. Some of the clinical trials that are part of the AD Prevention Initiative are already underway, and many more are planned. For example, the first NIH clinical trial aimed at preventing or delaying the onset of clinically diagnosed AD in persons at risk – the Memory Impairment Study – was launched in March 1999, and a major prevention trial of two anti-inflammatory drugs has been started. Other trials will be added to already ongoing trials that are investigating treatments or prevention strategies for other conditions. This “piggy-backing” approach will produce results much more swiftly and costeffectively than will newly initiated, freestanding studies. The second initiative, called the President’s Initiative on Alzheimer’s Disease, was announced by President Clinton on July 16, 2000. In this effort, the NIH will set aside $50 million over the next 5 years to support new research on AD. The NIH will be soliciting applications to support meritorious research, including both basic research as a part of pre-clinical studies and clinical interventions to treat or prevent AD by targeting the production of disease-associated processes, such as formation of amyloid plaques and neurofibrillary tangles. A major component of the President’s Initiative will be efforts to address promising immunological strategies to prevent amyloid deposition. Importantly for those who now have the disease, NIH also is intensifying its AD research and information efforts on issues related to supporting patients and the family members, friends, and providers who care for them. These efforts will include a special emphasis on the needs of a diverse patient population. A defining aspect of these AD initiatives is collaboration among NIH Institutes and with other Federal agencies, private pharmaceutical companies, and other entities in the private sector, such as foundations. The major funders of AD research – the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, and the National Institute of Nursing Research – make up the NIH AD Working Group that will coordinate and direct these efforts. Other NIH institutes that fund AD research also will be closely involved. For several years, NIA staff have worked with other Federal agencies, including the Health Care Financing Administration, the Department of

2000 Progress Report on Alzheimer’s Disease 561

Veterans Affairs, the Food and Drug Administration, and the Centers for Disease Control and Prevention on various areas related to AD. These areas include developing data sets for research purposes, collaborating in research, developing appropriate standards for testing drug efficacy, and pursuing outreach and education efforts. NIH will continue this collaboration, as well as efforts to develop relationships with State and local agencies, so that effective AD prevention and treatment strategies can be successfully carried out in the community. The NIH also will continue to cooperate with pharmaceutical companies in basic research, drug development, and testing and, in particular, will continue to encourage small companies to apply for drug development grants. As part of this effort, NIH will continue to identify partners for collaboration and to encourage its grantees to build collaborative research relationships with the private sector. Last, but by no means least, the NIH will continue to work closely with voluntary organizations such as the Alzheimer’s Association. One example of this partnership is NIH/Alzheimer’s Association co-sponsorship of conferences on different aspects of AD research. The Alzheimer’s Association also collaborates in research, education, and outreach at the local and national levels with Alzheimer’s Disease Centers, NIH-supported AD investigators, and the NIA’s ADEAR Center. The Institute for the Study of Aging, Inc., (ISOA) a non-profit organization recently established primarily to facilitate development and testing of effective drugs for AD, co-sponsored with NIA a workshop on maintaining cognitive vitality, and future joint initiatives are being discussed. These multifaceted collaborative initiatives, which combine an accelerated search for causes, an assault on the effects of the disease, and vigorous efforts to prevent onset, will energize the fight against AD and bring us closer to the day when we will be able to prevent or even cure this terrible disease, which robs our older relatives and friends of their most precious faculty – their minds.

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APPENDIX I. NIA ALZHEIMER’S DISEASE CENTERS PROGRAM DIRECTORY Overview59 The National Institute on Aging currently funds 29 Alzheimer’s Disease Centers (ADC’s) at major medical institutions across the nation. In addition, there are three Affiliate Centers. Researchers at these centers are working to translate research advances into improved care and diagnosis for Alzheimer’s disease (AD) patients while, at the same time, focusing on the program’s long-term goal--finding a way to cure and possibly prevent AD. Areas of investigation range from the basic mechanisms of AD to managing the symptoms and helping families cope with the effects of the disease. Center staff conduct basic, clinical, and behavioral research, and train scientists and health care providers new to AD research. Although each center has its own unique area of emphasis, a common goal of the ADC’s is to enhance research on AD by providing a network for sharing new ideas as well as research results. Collaborative studies draw upon the expertise of scientists from many different disciplines. The National Alzheimer’s Coordinating Center (see listing under Washington State) coordinates data collection and fosters collaborative research among the ADC’s. Many ADC’s have satellite facilities, which offer diagnostic and treatment services and collect research data in underserved, rural, and minority communities. Adapted from the National Institute on Aging: http://www.alzheimers.org/pubs/adcdir.html.

59

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For patients and families affected by AD, many ADC’s offer: •

Diagnosis and medical management (costs may vary–centers may accept Medicare, Medicaid, and private insurance).

•

Information about the disease, services, and resources.

•

Opportunities for volunteers to participate in drug trials, support groups, clinical research projects, and other special programs for volunteers and their families.

For more information, you may contact any of the centers on the following list. While the name, address, and telephone number given are for the center director, you may ask for information about any of the activities described above and about offices and satellite clinics at other locations throughout the country. For e-mail addresses of the directors and URL’s of ADC’s with Web sites, see below.

Alabama University of Alabama at Birmingham Lindy E. Harrell, M.D., Ph.D. Director Alzheimer’s Disease Center University of Alabama at Birmingham 454 Sparks Center 1720 7th Avenue South Birmingham, AL 35294-0017 E-mail: [email protected] Web Site: http://main.uab.edu/show.asp?durki=11627 Director’s Tel: 205-934-3847 Director’s Fax: 205-975-7365 Information Line: 205-934-2178

Arizona Sun Health Research Institute/Arizona Consortium Eric Reiman, M.D. Director

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Arizona Alzheimer’s Disease Center 1111 East McDowell Road Phoenix, AZ 85006 E-Mail: [email protected] Web Site: under development Director’s Tel: 602-239-6999 Director’s Fax: 602-239-6988

Arkansas University of Arkansas for Medical Sciences Cornelia M. Beck, RN, Ph.D. Director Alzheimer’s Disease Center Donald W. Reynolds Department of Geriatrics University of Arkansas for Medical Sciences 4301 W. Markham, Slot 811 Little Rock, AR 72205-7199 Director’s E-Mail: [email protected] Web Site: http://alzheimer.uams.edu Director’s Tel: 501-526-5751 Director’s Fax: 501-526-5760 Information: 501-603-1294

California Stanford University Jerome A. Yesavage, M.D. Director Stanford/VA Alzheimer’s Disease Center Department of Psychiatry 3801 Miranda Avenue (151Y) Palo Alto, CA 94304 ADC’s E-Mail: [email protected] Director’s E-Mail: [email protected] Web Site: http://alzheimer.stanford.edu Director’s Tel: 650-852-3287 Director’s Fax: 650-852-3297 University of California, Davis William J. Jagust, M.D.

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Director Alzheimer’s Disease Center Department of Neurology University of California, Davis 4860 Y Street, Suite 3900 Sacramento, CA 95817 E-Mail: [email protected] Web Site: http://alzheimer.ucdavis.edu/adc/ Information Line: 916-734-5496 Fax: 916-456-9350 University of California, Irvine Carl W. Cotman, Ph.D. Director Alzheimer’s Disease Center Institute for Brain Aging and Dementia University of California, Irvine 1113 Gillespie Neuroscience Research Facility Irvine, CA 92697 E-Mail: [email protected] Web Site: http://www.alz.uci.edu/ Director’s Tel: 949-824-5847 Director’s Fax: 949-824-2071 University of California, Los Angeles Jeffrey L. Cummings, M.D. Director Alzheimer’s Disease Center Department of Neurology University of California, Los Angeles 710 Westwood Plaza Los Angeles, CA 90095-1769 E-mail: [email protected] Web Site: http://www.adc.ucla.edu Director’s Tel: 310-206-5238 Director’s Fax: 310-206-5287 University of California, San Diego Leon Thal, M.D. Director Alzheimer’s Disease Research Center Department of Neurosciences UCSD School of Medicine

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9500 Gilman Drive La Jolla, CA 92093-0624 ADC’s E-Mail: [email protected] Director’s E-Mail: [email protected] Web Site: http://adrc.ucsd.edu/ Director’s Tel: 858-534-4606 Director’s Fax: 858-534-2985 Information Line: 858-622-5800 University of Southern California Caleb E. Finch, Ph.D. Director University of Southern California Ethel Percy Andrus Gerontology Center 3715 McClintock Avenue Los Angeles, CA 90089-0191 ADC’s E-mail: [email protected] Director’s E-mail: [email protected] Web Site: http://www.usc.edu/dept/gero/ADRC/ Director’s Tel: 213-740-1756 Director’s Fax: 213-740-0853 Information Line: 213-740-7777 (for current studies and enrollment only)

Georgia Emory University* Allan I. Levey, M.D., Ph.D., Director Emory Alzheimer’s Disease Center 1841 Clifton Road, NE Atlanta, GA 30329 E-Mail: [email protected] Web Site: http://www.emory.edu/WHSC/MED/ADC Information Line: 404-728-6950 Fax: 404-728-6955 *Affiliate Center

Illinois Northwestern University Marsel Mesulam, M.D. Director

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Cognitive Neurology and Alzheimer’s Disease Center Northwestern University Medical School 320 East Superior Street Searle 11-453 Chicago, IL 60611 ADC’s E-Mail: [email protected] Director’s E-Mail: [email protected] Web Site: http://www.brain.nwu.edu Director’s Tel: 312-908-9339 Director’s Fax: 312-908-8789 Rush-Presbyterian-St. Lukes Medical Center Denis A. Evans, M.D. Director Alzheimer’s Disease Center Rush-Presbyterian-St. Luke’s Medical Center Rush Institute for Healthy Aging 1645 West Jackson Boulevard, Suite 675 Chicago, IL 60612 Web Site: http://www.rush.edu/patients/radc/ Director’s Tel: 312-942-4463 Director’s Fax: 312-942-2861 Information: 312-942-4463

Indiana Indiana University Bernardino Ghetti, M.D. Director Indiana Alzheimer’s Disease Center Indiana University School of Medicine 635 Barnhill Drive, MS-A142 Indianapolis, IN 46202-5120 ADC’s E-Mail: [email protected] Director’s E-Mail: [email protected] Web Site: http://iadc.iupui.edu Director’s Tel: 317-274-7818 Director’s Fax: 317-274-4882 Information Line: 317-278-2030

NIA Alzheimer’s Disease Centers Program Directory 569

Kentucky University of Kentucky William R. Markesbery, M.D. Director Sanders-Brown Research Center on Aging University of Kentucky 101 Sanders-Brown Building Lexington, KY 40536-0230 E-Mail: [email protected] Web Site: http://www.coa.uky.edu/ Information Line: 859-323-6040 Fax: 859-323-2866

Maryland The Johns Hopkins Medical Institutions Donald L. Price, M.D. Director Alzheimer’s Disease Research Center Division of Neuropathology The Johns Hopkins University School of Medicine 558 Ross Research Building 720 Rutland Avenue Baltimore, MD 21205-2196 E-Mail: [email protected] Web Site: http://www.alzresearch.org Director’s Tel: 410-955-5632 Director’s Fax: 410-955-9777

Massachusetts Boston University Neil William Kowall, M.D. Director Alzheimer’s Disease Center GRECC Program (182B) Bedford VAMC 200 Springs Road Bedford, MA 01730

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ADC’s E-Mail: [email protected] Director’s E-Mail: [email protected] Web Site: http://www.xfaux.com/Alzheimer/ Director’s Tel: 781-687-2632 Director’s Fax: 781-687-3515 Information Line: 781-687-2916 Harvard Medical School/Massachusetts General Hospital John H. Growdon, M.D. Director Massachusetts General Hospital Department of Neurology 15 Parkman Street Boston, MA 02114 E-Mail: [email protected] Web Site: http://neuro-oas.mgh.harvard.edu/alzheimers Director’s Tel: 617-726-1728 Director’s Fax: 617-726-4101

Michigan University of Michigan Sid Gilman, M.D. Director University of Michigan Alzheimer’s Disease Research Center Department of Neurology 1500 E. Medical Center Drive 1914 Taubman Street Ann Arbor, MI 48109-0316 E-Mail: [email protected] Web Site: http://www.med.umich.edu/madrc/ Director’s Tel: 734-936-9070 Director’s Fax: 734-763-5059 Information Line: 734-764-2190

Minnesota Mayo Clinic Ronald Petersen, M.D., Ph.D. Director

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Department of Neurology Mayo Clinic 200 First Street, SW Rochester, MN 55905 E-Mail: [email protected] Web Site: http://www.mayo.edu/research/alzheimers_center/ Director’s Tel: 507-538-0487 Director’s Fax: 507-284-4074 Information Line: 507-284-1324 Main Fax: 507-538-0878

Missouri Washington University Eugene M. Johnson, Jr., Ph.D. John C. Morris, M.D. Co-Directors Alzheimer’s Disease Research Center Washington University Medical Center 4488 Forest Park Avenue, Suite 130 St. Louis, MO 63108-2293 E-Mail: [email protected] Web Site: http://www.adrc.wustl.edu/adrc Director’s Tel: 314-286-2881 Director’s Fax: 314-286-2763

New York Columbia University Michael L. Shelanski, M.D., Ph.D. Director ADRC Co-Director Taub Institute Richard Mayeux, M.D., MSC Co-Director Taub Institute Taub Institute for Research on Alzheimer’s Disease and the Aging Brain 630 West 168th Street P&S Box 16 New York, NY 10032 E-Mail: [email protected] Web Site: http://www.alzheimercenter.org Director’s Tel: 212-305-3300

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Director’s Fax: 212-305-5498 Information Line: 212-305-1818 Mount Sinai School of Medicine/Bronx VA Medical Center Kenneth L. Davis, M.D. Director Alzheimer’s Disease Research Center Department of Psychiatry Box 1230 Mount Sinai School of Medicine One Gustave L. Levy Place New York, NY 10029-6574 E-Mail: [email protected] Web Site: http://www.mssm.edu/psychiatry/adrc.shtml Director’s Tel: 212-659-8760 Fax: 212-860-3945 Information Line: 212-241-8329 New York University Steven H. Ferris, Ph.D. Director Alzheimer’s Disease Center New York University School of Medicine Silberstein Aging and Dementia Research Center Alzheimer’s Disease Center 550 First Avenue Room THN 310 New York, NY 10016 E-mail: [email protected] Web Site: http://aging.med.nyu.edu/ Director’s Tel: 212-263-5703 Director’s Fax: 212-263-6991 Information Line: 212-263-5700 University of Rochester* Paul D. Coleman, Ph.D. Director Alzheimer’s Disease Center Center for Aging and Developmental Biology University of Rochester Medical Center 601 Elmwood Avenue, Box 645 Rochester, NY 14642 E-Mail: [email protected]

NIA Alzheimer’s Disease Centers Program Directory 573

Web Site: http://www.urmc.rochester.edu/adc/index.html Director’s Tel: 716-275-2581 Director’s Fax: 716-273-1132 *Affiliate Center

North Carolina Duke University Donald E. Schmechel, M.D. Director Joseph and Kathleen Bryan Alzheimer’s Disease Research Center 2200 West Main Street Suite A-230 Durham, NC 27705 E-Mail: [email protected] Web Site: http://adrc.mc.duke.edu/ Director’s Tel: 919-416-5380 Director’s Fax: 919-286-3406 ADRC: 866-444-2372

Ohio Case Western Reserve University Karl Herrup, Ph.D. Director University Memory and Aging Center University Hospitals of Cleveland Case Western Reserve University 12200 Fairhill Road Cleveland, OH 44120-1013 E-Mail: [email protected] Web Site: http://www.ohioalzcenter.org Main Tel: 800-252-5048 Director’s Tel: 216-844-6422 Director’s Fax: 216-844-6446

Oregon Oregon Health Sciences University Jeffrey Kaye, M.D.

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Director Aging and Alzheimer’s Disease Center Oregon Health Sciences University 3181 SW Sam Jackson Park Road Department of Neurology CR 131 Portland, OR 97201-3098 E-Mail: [email protected] Web Site: http://www.ohsu.edu/som-alzheimers/ Director’s Tel: 503-494-6976 Director’s Fax: 503-494-7499

Pennsylvania University of Pennsylvania John Q. Trojanowski, M.D., Ph.D. Director Alzheimer’s Disease Center Center for Neurodegenerative Disease Research University of Pennsylvania School of Medicine 3rd Floor Maloney Building 3600 Spruce Street Philadelphia, PA 19104-4283 E-Mail: [email protected] Web Site: http://www.med.upenn.edu/ADC Director’s Tel: 215-662-6399 Director’s Fax: 215-349-5909 Information Line: 215-662-4708 University of Pittsburgh Steven T. DeKosky, M.D. Director Alzheimer’s Disease Research Center University of Pittsburgh 4-West Montefiore University Hospital 200 Lothrop Street Pittsburgh, PA 15213-2582 E-Mail: [email protected] Web Site: http://www.adrc.pitt.edu/ Director’s Tel: 412-624-6889 Director’s Fax: 412-692-2710 Information Line: 412-692-2700

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Texas Baylor College of Medicine* Rachelle S. Doody, M.D., Ph.D. Director Alzheimer’s Disease Research Center Department of Neurology Baylor College of Medicine 6550 Fannin Street Smith Tower, Suite 1801 Houston, TX 77030 E-Mail: [email protected] Web Site: http://www.bcm.tmc.edu/neurol/struct/adrc/adrc1.html Director’s Tel: 713-798-7416 Director’s Fax: 713-798-5326 Information Line: 713-798-6660 *Affiliate Center University of Texas, Southwestern Medical Center Roger N. Rosenberg, M.D. Director Alzheimer’s Disease Research Center University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard Dallas, TX 75390-9070 Web Site: http://www2.swmed.edu/alzheimer/ Director’s Tel: 214-648-3239 Information Line : 214-648-7444 Fax: 214-648-7460

Washington University of Washington Murray Raskind, M.D. Director Alzheimer’s Disease Center Mental Health Service S116 1660 S. Columbian Way Seattle, WA 98108

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E-Mail: [email protected] Web Site: http://depts.washington.edu/adrcweb/ Information Line: 206-277-3491 Fax: 206-768-5456 Patient Recruitment: 800-317-5382

National Alzheimer’s Coordinating Center (NACC) National Alzheimer’s Coordinating Center Walter Kukull, Ph.D., Director 4225 NE Roosevelt Way Suite 301 Seattle, WA 98105 E-Mail: [email protected] Web Site: http://www.alz.washington.edu Phone (206)543-3121 Fax: (206)543-8791 The NACC coordinates data collection and fosters collaborative research among the ADC’s.

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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries and glossaries. 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

•

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

•

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

•

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

•

On-line Medical Dictionary (CancerWEB): http://www.graylab.ac.uk/omd/

•

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

•

Terms and Definitions (Office of Rare Diseases): http://rarediseases.info.nih.gov/ord/glossary_a-e.html

Beyond these, MEDLINEplus contains a very user-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed via the following Web site address: http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a) and drkoop.com (http://www.drkoop.com/). Topics of interest can be researched by using keywords before continuing elsewhere, as these basic definitions and concepts will be useful in more advanced areas of research. You may choose to print various pages specifically relating to Alzheimer’s disease and keep them on file. The NIH, in particular, suggests that patients with Alzheimer’s disease visit the following Web sites in the ADAM Medical Encyclopedia:

578 Alzheimer’s Disease

•

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

•

Signs & Symptoms for Alzheimer’s Disease Agitation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003212.htm Anxiety Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm Aphasia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003204.htm Apraxia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003203.htm Depression Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003213.htm Incontinence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003142.htm Insomnia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003210.htm Memory loss Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003257.htm Restlessness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003212.htm

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Seizures Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003200.htm •

Diagnostics and Tests for Alzheimer’s Disease BUN Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003474.htm CBC Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003642.htm Computed Tomography Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm CT 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 MRI Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003335.htm Sedimentation rate Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003638.htm Serology Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003511.htm Thyroid function tests Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003444.htm

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Urinalysis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003579.htm VDRL Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003515.htm •

Background Topics for Alzheimer’s Disease Autosomal dominant Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002049.htm Systemic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002294.htm

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

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

•

MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

•

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

•

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

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ALZHEIMER’S DISEASE GLOSSARY The following is a complete glossary of terms used in this sourcebook. The definitions are derived from official public sources including the National Institutes of Health [NIH] and the European Union [EU]. After this glossary, we list a number of additional hardbound and electronic glossaries and dictionaries that you may wish to consult. Ablation: The removal of an organ by surgery. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [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] 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] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH]

Analytes: A component of a test sample the presence of which has to be demonstrated. The term "analyte" includes where appropriate formed from the analyte during the analyses. [NIH] Anchorage: In dentistry, points of retention of fillings and artificial restorations and appliances. [NIH] Antibiotic: A substance usually produced by vegetal micro-organisms capable of inhibiting the growth of or killing bacteria. [NIH] Aphasia: An inability, caused by cerebral dysfunction, to communicate in reading, writing or speaking or to receive meaning from spoken or written words. [NIH] Apraxia: Loss of ability to perform purposeful movements, in the absence of paralysis or sensory disturbance, caused by lesions in the cortex. [NIH] Articulation: The relationship of two bodies by means of a moveable joint. [NIH]

Aspartate: A synthetic amino acid. [NIH] Aspartic: The naturally occurring substance is L-aspartic acid. One of the

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acidic-amino-acids is obtained by the hydrolysis of proteins. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Axonal: Condition associated with metabolic derangement of the entire neuron and is manifest by degeneration of the distal portion of the nerve fiber. [NIH] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Basalis: Chiasmatic cistern. [NIH] Bernstein: A sensitive means of determining whether acid reflux is the cause of pain, but may be falsely negative in the patient receiving treatment. [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] Bowen: Intraepithelial epithelioma affecting the skin and sometimes the mucous membranes. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH] Breakdown: A physical, metal, or nervous collapse. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Cataracts: In medicine, an opacity of the crystalline lens of the eye obstructing partially or totally its transmission of light. [NIH] CD8: A protein embedded in the cell surface of killer and suppresser Tlymphocytes. [NIH] CDC2: It is crucial for entry into mitosis of eukaryotic cells. [NIH] CDNA: Synthetic DNA reverse transcribed from a specific RNA through the action of the enzyme reverse transcriptase. DNA synthesized by reverse transcriptase using RNA as a template. [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] CMV: A virus that belongs to the herpes virus group. [NIH] Compacta: Part of substantia nigra. [NIH] Compassionate: A process for providing experimental drugs to very sick

Glossary 583

patients who have no treatment options. [NIH] Competency: The capacity of the bacterium to take up DNA from its surroundings. [NIH] Confounder: A factor of confusion which blurs a specific connection between a disease and a probable causal factor which is being studied. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Continuum: An area over which the vegetation or animal population is of constantly changing composition so that homogeneous, separate communities cannot be distinguished. [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] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Crawford: Variation of the luminosity of a light stimulus with position of entry of the light pencil through the pupil. [NIH] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Davidson: Light seen through the pupil when a light source is held in the mouth. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Delusion: A false belief, not susceptible to argument or reason, and determined, pathologically, by some form of mental disorder. [NIH] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Deoxyribonucleic: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Dissection: Cutting up of an organism for study. [NIH] Duke:

A lamp which produces ultraviolet radiations for certain

584 Alzheimer’s Disease

ophthalmologic therapy. [NIH] Dystrophic: Pertaining to toxic habitats low in nutrients. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] ELISA: A sensitive analytical technique in which an enzyme is complexed to an antigen or antibody. A substrate is then added which generates a color proportional to the amount of binding. This method can be adapted to a solid-phase technique. [NIH] Embryogenesis: The process of embryo or embryoid formation, whether by sexual (zygotic) or asexual means. In asexual embryogenesis embryoids arise directly from the explant or on intermediary callus tissue. In some cases they arise from individual cells (somatic cell embryoge). [NIH] EMG: Recording of electrical activity or currents in a muscle. [NIH] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Enanthate: An oily injectable contraceptive given every 8 weeks. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Epilepticus: Repeated and prolonged epileptic seizures without recovery of consciousness between attacks. [NIH] Epistasis: The degree of dominance exerted by one gene on the expression of a non-allelic gene. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH] Epstein: Failure of the upper eyelid to move downward on downward movement of the eye, occurring in premature and nervous infants. [NIH] Estrogen: One of the two female sex hormones. [NIH] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Excitotoxicity: Excessive exposure to glutamate or related compounds can kill brain neurons, presumably by overstimulating them. [NIH] Exhaustion: The feeling of weariness of mind and body. [NIH] 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]

Glossary 585

Fatigue: The feeling of weariness of mind and body. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Fornix: A bundle of nerves connected to the hippocampus. [NIH] Galanin: A neurotransmitter. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Gould: Turning of the head downward in walking to bring the image of the ground on the functioning position of the retina, in destructive disease of the peripheral retina. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Greig: A very rare inherited disorder characterized by physical abnormalities affecting the fingers and toes (digits) and the head and facial (craniofacial) area. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Haloperidol: Butyrophenone derivative. [NIH] Harmony: Attribute of a product which gives rise to an overall pleasant sensation. This sensation is produced by the perception of the product components as olfactory, gustatory, tactile and kinaesthetic stimuli because they are present in suitable concentration ratios. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [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] Heterozygotes: Having unlike alleles at one or more corresponding loci on homologous chromosomes. [NIH] Hospice: Institution dedicated to caring for the terminally ill. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infections: The illnesses caused by an organism that usually does not cause disease in a person with a normal immune system. [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell

586 Alzheimer’s Disease

changes; being a step in a carcinogenic process. [NIH] Initiator: A chemically reactive substance which may cause cell changes if ingested, inhaled or absorbed into the body; the substance may thus initiate a carcinogenic process. [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] Isoenzyme: Different forms of an enzyme, usually occurring in different tissues. The isoenzymes of a particular enzyme catalyze the same reaction but they differ in some of their properties. [NIH] Jefferson: A fracture produced by a compressive downward force that is transmitted evenly through occipital condyles to superior articular surfaces of the lateral masses of C1. [NIH] Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Ligands: A RNA simulation method developed by the MIT. [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] Lipitor: Cholesterol-lowering drug. [NIH] Lod: The lowest analyte content which, if actually present, will be detected with reasonable statistical certainty and can be identified according to the identification criteria of the method. If both accuracy and precision are constant over a concentration range. [NIH] Mange: Sarcoptic infestation of human skin, particularly a contagious skin disease caused by invasion of the epidermis with Sarcoptes scabiei. [NIH] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH]

Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Mononuclear: A cell with one nucleus. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH]

MRNA: The RNA molecule that conveys from the DNA the information that is to be translated into the structure of a particular polypeptide molecule. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH]

Glossary 587

Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neuritis: Inflammation of a nerve or nerves. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Olfaction: Function of the olfactory apparatus to perceive and discriminate between the molecules that reach it, in gas form from an external environment, directly or indirectly via the nose. [NIH] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH]

Palsy: Disease of the peripheral nervous system occurring usually after many years of increased lead absorption. [NIH] Paralysis: Loss or impairment of muscle function or sensation. [NIH] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pediatrics: The branch of medical science concerned with children and their diseases. [NIH] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Phenotypes: An organism as observed, i. e. as judged by its visually perceptible characters resulting from the interaction of its genotype with the environment. [NIH] Phosphorylates: Attached to a phosphate group. [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]

588 Alzheimer’s Disease

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] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Potassium: It is essential to the ability of muscle cells to contract. [NIH] Potentiate: 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] Pregnenolone: Steroid hormone. [NIH] Premarin: A hormone replacement therapy drug developed by AHP (USA). [NIH]

Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Protease: Any enzyme that catalyzes hydrolysis of a protein. [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] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Quinolinic: It is produced by immune cells and slowly infiltrates the brain tissues after an injury. [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]

Radiopharmaceutical: Any medicinal product which, when ready for use, contains one or more radionuclides (radioactive isotopes) included for a medicinal purpose. [NIH] 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] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH]

Glossary 589

Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Rett Syndrome: A neurological disorder seen almost exclusively in females, and found in a variety of racial and ethnic groups worldwide. [NIH] Salivary: The duct that convey saliva to the mouth. [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] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH]

Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Senescence: The bodily and mental state associated with advancing age. [NIH]

Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Shedding: Release of infectious particles (e. g., bacteria, viruses) into the environment, for example by sneezing, by fecal excretion, or from an open lesion. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] 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]

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] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [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]

590 Alzheimer’s Disease

Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [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] 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] 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] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [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] Wound: Any interruption, by violence or by surgery, in the continuity of the external surface of the body or of the surface of any internal organ. [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]

General Dictionaries and Glossaries While the above glossary is essentially complete, the dictionaries listed here cover virtually all aspects of medicine, from basic words and phrases to more

Glossary 591

advanced terms (sorted alphabetically by title; hyperlinks provide rankings, information and reviews at Amazon.com): •

Dictionary of Medical Acronymns & Abbreviations by Stanley Jablonski (Editor), Paperback, 4th edition (2001), Lippincott Williams & Wilkins Publishers, ISBN: 1560534605, http://www.amazon.com/exec/obidos/ASIN/1560534605/icongroupinter na

•

Dictionary of Medical Terms : For the Nonmedical Person (Dictionary of Medical Terms for the Nonmedical Person, Ed 4) by Mikel A. Rothenberg, M.D, et al, Paperback - 544 pages, 4th edition (2000), Barrons Educational Series, ISBN: 0764112015, http://www.amazon.com/exec/obidos/ASIN/0764112015/icongroupinter na

•

A Dictionary of the History of Medicine by A. Sebastian, CD-Rom edition (2001), CRC Press-Parthenon Publishers, ISBN: 185070368X, http://www.amazon.com/exec/obidos/ASIN/185070368X/icongroupinter na

•

Dorland’s Illustrated Medical Dictionary (Standard Version) by Dorland, et al, Hardcover - 2088 pages, 29th edition (2000), W B Saunders Co, ISBN: 0721662544, http://www.amazon.com/exec/obidos/ASIN/0721662544/icongroupinter na

•

Dorland’s Electronic Medical Dictionary by Dorland, et al, Software, 29th Book & CD-Rom edition (2000), Harcourt Health Sciences, ISBN: 0721694934, http://www.amazon.com/exec/obidos/ASIN/0721694934/icongroupinter na

•

Dorland’s Pocket Medical Dictionary (Dorland’s Pocket Medical Dictionary, 26th Ed) Hardcover - 912 pages, 26th edition (2001), W B Saunders Co, ISBN: 0721682812, http://www.amazon.com/exec/obidos/ASIN/0721682812/icongroupinter na/103-4193558-7304618

•

Melloni’s Illustrated Medical Dictionary (Melloni’s Illustrated Medical Dictionary, 4th Ed) by Melloni, Hardcover, 4th edition (2001), CRC PressParthenon Publishers, ISBN: 85070094X, http://www.amazon.com/exec/obidos/ASIN/85070094X/icongroupintern a

•

Stedman’s Electronic Medical Dictionary Version 5.0 (CD-ROM for Windows and Macintosh, Individual) by Stedmans, CD-ROM edition (2000), Lippincott Williams & Wilkins Publishers, ISBN: 0781726328,

592 Alzheimer’s Disease

http://www.amazon.com/exec/obidos/ASIN/0781726328/icongroupinter na •

Stedman’s Medical Dictionary by Thomas Lathrop Stedman, Hardcover - 2098 pages, 27th edition (2000), Lippincott, Williams & Wilkins, ISBN: 068340007X, http://www.amazon.com/exec/obidos/ASIN/068340007X/icongroupinter na

•

Tabers Cyclopedic Medical Dictionary (Thumb Index) by Donald Venes (Editor), et al, Hardcover - 2439 pages, 19th edition (2001), F A Davis Co, ISBN: 0803606540, http://www.amazon.com/exec/obidos/ASIN/0803606540/icongroupinter na

593

INDEX A Ablation ....................................................156 Adjustment.........................76, 148, 456, 465 Ageing.......................................................389 Ameliorated .............................................157 Ameliorating ..............................................90 Amplification ...........................................166 Analytes......................................................17 Aphasia.....................................................332 Apraxia .....................................................226 Articulation ..............................................461 Aspartate .................. 134, 154, 158, 240, 241 Aspartic.............................154, 233, 508, 581 Attenuated................................................367 Attenuation ..............................................125 Axonal.......................................................194 B Bacterium .................................233, 444, 583 Basalis ...............................................165, 199 Branch . 41, 237, 408, 419, 496, 587, 589, 590 Breakdown .......................250, 442, 489, 526 C Caspase ............... 87, 125, 149, 154, 511, 545 Cataracts ...........................................186, 518 CDC2.........................................................107 Cloning .......................................................98 Compacta..................................................115 Compassionate ........................................255 Competency ...............................................75 Consultation................... ii, iii, 3, 71, 88, 101 Consumption .....................................54, 386 Continuum . 78, 460, 463, 465, 467, 470, 478 Cortisol .............................191, 366, 377, 393 Cytokine .... 56, 113, 122, 123, 125, 151, 156, 208, 218 Cytotoxicity..............................100, 397, 398 D Deletion ......................................................95 Density......................................106, 224, 525 Deoxyribonucleic.............................482, 496 Discrimination .........................................484 Dissection .................................................158 Duke..........................................................573 Dystrophic..................................89, 113, 223 E Effector................................................99, 511 Embryogenesis.........................154, 234, 584 Empirical ..........................................274, 468

Enhancer .................................................. 247 Enzymatic .......................................... 97, 150 Epilepticus ............................................... 241 Epistasis ................................................... 148 Epitope ..................................................... 249 Estrogen .....14, 47, 52, 85, 87, 206, 367, 389, 443, 507, 527, 528, 532, 559 Excitatory ................................. 135, 241, 396 Excitotoxicity ................................... 134, 158 Exhaustion ............................................... 537 F Fold ............................. 83, 135, 148, 420, 519 Fornix ......................................................... 88 G Galanin ............................................. 103, 396 Glutamate ..56, 158, 221, 234, 241, 397, 444, 584 H Haloperidol.......................... 57, 74, 533, 549 Harmony.......................................... 355, 497 Hereditary................................................ 300 Heterogeneity..121, 130, 186, 204, 235, 273, 274, 520, 585 Heterozygotes ......................................... 167 Hospice............................................. 471, 476 I Infancy...................................................... 534 Infections.......................................... 429, 489 Initiation........................... 125, 148, 154, 499 Initiator..................................................... 154 Insight..........92, 107, 123, 139, 158, 163, 275 J Joint....................101, 140, 270, 271, 561, 581 L Ligands..................................... 111, 122, 157 Linkage.......98, 108, 118, 119, 121, 122, 163, 195, 242, 300 Lod ............................................................ 120 M Mange....................................................... 476 Medial....................................................... 136 Modification ............................ 143, 534, 537 Mononuclear ............................................. 89 Morphological .107, 112, 185, 232, 274, 275, 581 Myotonic .................................................. 313 N Networks.............. 3, 172, 227, 446, 461, 478

594 Alzheimer’s Disease

Neuritis .....................................................185 Nucleus.... 165, 166, 192, 199, 236, 249, 419, 432, 482, 496, 503, 586 O Olfaction ...................................................142 Outpatient ..................................................63 P Paralysis............................233, 246, 518, 581 Patch..........................................247, 251, 587 Pathologies .......................................109, 201 Peroxide............................................146, 196 Phenotypes...............................109, 128, 139 Phosphorylates ................................124, 245 Plasticity ............. 87, 117, 124, 236, 519, 588 Polymorphism .... 95, 98, 163, 175, 177, 182, 193, 208, 209, 215, 514, 547 Potassium .........................................243, 386 Potentiation ......................................106, 535 Probe .........................................................523 Promoter.....................................97, 113, 201 Prone .........................................................151 Protease..................... 129, 153, 162, 545, 546 Protocol....................... 44, 58, 64, 88, 96, 108 Psychoactive.............................................458 Q Quinolinic.................................................394 R Race .....................................45, 224, 458, 478 Recombination.................................242, 243 Reductase .................................................203 Reliability ...................................................78 Restoration .......................................355, 356

S Salivary..................................... 191, 366, 393 Satellite ............................. 132, 541, 563, 564 Schizophrenia.................................. 546, 549 Secretory .................................................. 249 Segregation .............................. 242, 251, 588 Shedding .................................................. 521 Specialist ................................ 35, 37, 40, 399 Specificity................................... 93, 152, 170 Spectroscopic........................................... 397 Stimulus ....110, 234, 237, 366, 373, 583, 590 Superoxide............................................... 150 Suppression ............................................. 376 T Temporal....82, 107, 112, 113, 123, 136, 223, 276, 365 Terminator ............................................... 511 Therapeutics ....122, 138, 145, 248, 348, 373, 375 Threshold ................................. 108, 237, 590 Transduction ................................... 123, 134 Translation......................................... 83, 145 Trauma ..............126, 135, 240, 241, 521, 553 U Ubiquitin .......................................... 170, 554 V Vitro....97, 106, 117, 121, 127, 136, 141, 150, 152, 162, 172, 205, 366, 369, 373, 394, 399 Vivo.......96, 99, 117, 122, 124, 127, 136, 145, 152, 158, 162, 169, 172, 221, 228, 295, 368 W Wound...............238, 251, 495, 530, 587, 590 Z Zymogen .................................. 163, 238, 590

Index 595

596 Alzheimer’s Disease

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