Huntington's Disease - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

HUNTINGTON’S DISEASE A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES ...

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HUNTINGTON’S DISEASE A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

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: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Huntington’s Disease: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-83933-6 1. Huntington’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. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

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

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

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the 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 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 FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON HUNTINGTON’S DISEASE.......................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Huntington’s Disease ................................................................... 5 E-Journals: PubMed Central ....................................................................................................... 60 The National Library of Medicine: PubMed ................................................................................ 62 CHAPTER 2. NUTRITION AND HUNTINGTON’S DISEASE .............................................................. 109 Overview.................................................................................................................................... 109 Finding Nutrition Studies on Huntington’s Disease ................................................................ 109 Federal Resources on Nutrition ................................................................................................. 117 Additional Web Resources ......................................................................................................... 118 CHAPTER 3. ALTERNATIVE MEDICINE AND HUNTINGTON’S DISEASE ....................................... 119 Overview.................................................................................................................................... 119 National Center for Complementary and Alternative Medicine................................................ 119 Additional Web Resources ......................................................................................................... 127 General References ..................................................................................................................... 127 CHAPTER 4. DISSERTATIONS ON HUNTINGTON’S DISEASE ......................................................... 129 Overview.................................................................................................................................... 129 Dissertations on Huntington’s Disease ..................................................................................... 129 Keeping Current ........................................................................................................................ 130 CHAPTER 5. CLINICAL TRIALS AND HUNTINGTON’S DISEASE .................................................... 131 Overview.................................................................................................................................... 131 Recent Trials on Huntington’s Disease ..................................................................................... 131 Keeping Current on Clinical Trials ........................................................................................... 133 CHAPTER 6. BOOKS ON HUNTINGTON’S DISEASE ........................................................................ 135 Overview.................................................................................................................................... 135 Book Summaries: Online Booksellers......................................................................................... 135 The National Library of Medicine Book Index ........................................................................... 136 Chapters on Huntington’s Disease ............................................................................................ 137 CHAPTER 7. MULTIMEDIA ON HUNTINGTON’S DISEASE ............................................................. 139 Overview.................................................................................................................................... 139 Bibliography: Multimedia on Huntington’s Disease................................................................. 139 CHAPTER 8. PERIODICALS AND NEWS ON HUNTINGTON’S DISEASE .......................................... 141 Overview.................................................................................................................................... 141 News Services and Press Releases.............................................................................................. 141 Academic Periodicals covering Huntington’s Disease............................................................... 145 CHAPTER 9. RESEARCHING MEDICATIONS .................................................................................. 147 Overview.................................................................................................................................... 147 U.S. Pharmacopeia..................................................................................................................... 147 Commercial Databases ............................................................................................................... 149 Researching Orphan Drugs ....................................................................................................... 149 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 153 Overview.................................................................................................................................... 153 NIH Guidelines.......................................................................................................................... 153 NIH Databases........................................................................................................................... 155 Other Commercial Databases..................................................................................................... 157 APPENDIX B. PATIENT RESOURCES ............................................................................................... 159 Overview.................................................................................................................................... 159 Patient Guideline Sources.......................................................................................................... 159 Associations and Huntington’s Disease .................................................................................... 163

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Finding Associations.................................................................................................................. 164 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 167 Overview.................................................................................................................................... 167 Preparation................................................................................................................................. 167 Finding a Local Medical Library................................................................................................ 167 Medical Libraries in the U.S. and Canada ................................................................................. 167 ONLINE GLOSSARIES................................................................................................................ 173 Online Dictionary Directories ................................................................................................... 175 HUNTINGTON’S DISEASE DICTIONARY ........................................................................... 177 INDEX .............................................................................................................................................. 233

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with Huntington’s disease is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about Huntington’s disease, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to Huntington’s disease, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on Huntington’s disease. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to Huntington’s disease, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on Huntington’s disease. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON HUNTINGTON’S DISEASE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on Huntington’s disease.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and Huntington’s disease, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “Huntington’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 what you can expect from this type of search: •

Dysphagia Caused by Neurologic Deficits Source: Otolaryngologic Clinics of North America. 31(3): 507-524. June 1998. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. Summary: Normal swallowing is a complex, dynamic neuromuscular activity that depends on a set of physiologic behaviors resulting in liquid and solid material moving efficiently and safely from the mouth to the stomach. Problems with swallowing in the oropharynx (oropharyngeal dysphagia) are often linked to neurologic or muscular diseases. This article reviews the neurologic lesions and conditions that account for the majority of oropharyngeal dysphagia cases. The authors first review the physiology and

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neurophysiology of both normal and abnormal swallowing, then outline the recommended patient physical examination and laboratory work up. Each neurological disease that may contribute to oropharyngeal dysphagia is then discussed: amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, multiple sclerosis, myasthenia gravis, stroke (cerebrovascular accident), and laryngeal nerve injury. Dysphagia secondary to acute neurologic deficits, along with other abnormalities, tends to improve with time. Dysphagia resulting from chronic neurologic conditions, however, often worsens as the disease process evolves. 4 tables. 62 references. •

Severity of Cognitive Impairment in Juvenile and Late-Onset Huntington Disease Source: Archives of Neurology. 55: 835-843. June 1998. Summary: This journal article describes a study of the severity of cognitive impairment and the influence of motor and cognitive deficits on functional disability across different ages of onset of Huntington's disease (HD). The participants were 71 patients seen at the HD program in the Departments of Neurology and Genetics at the Fundacion Jimenez Diaz in Madrid, Spain. The patients were divided into three groups based on onset of motor symptoms: juvenile onset (at age 25 years or younger, n=15), adult onset (at age 26 to 50 years, n=43), and late onset (at age 51 years or older, n=13). Healthy controls, matched on age and education to groups 1 and 3, also were studied. All patients were assessed with a battery of neuropsychological tests, measures of motor and functional abilities, and a genetic analysis to determine the number of CAG trinucleotide repeats. Patients with juvenile onset had the longest CAG repeat lengths and those with late onset had the shortest. Cognitive impairment was less severe in the juvenile-onset group than at other ages of onset. Visuospatial function was more impaired in patients with late onset, and prefrontal functions were more impaired in those with juvenile onset. Functional disability was associated with global cognitive status in patients with late onset, and with motor deficits and prefrontal dysfunction in those with early onset. 3 figures, 5 tables, 54 references.

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Electrophysiological Analysis of Altered Cognitive Functions in Huntington Disease Source: Archives of Neurology. 54: 1089-1098. September 1997. Summary: This journal article describes an electrophysiological analysis of altered cognitive functions in Huntington's disease (HD) in the domains of visual processing and memory. Nine patients with HD and 9 controls matched for age, sex, and education participated. Cognitive event-related potentials (ERPs) were measured, using an electroencephalogram, under three conditions: a parallel visual search task, a serial visual search task, and a word-recognition memory task. The components of averaged ERPs were quantified by latency and amplitude measures, and analyzed along with behavioral measures (search time, hit rate, and recognition accuracy). The results suggest that compared with controls, the patients with HD showed a significant delay in the early visual components and abnormalities in the ERP indexes of word recognition and target detection. These changes were accompanied by a marked delay in search times and a greatly reduced accuracy on the memory task. The ERPs on the memory task were different from those found in studies of patients with Alzheimer's disease, suggesting a different neural basis for the deficits in HD. 6 figures, 4 tables, 77 references.

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Inherited Neurodegenerative Diseases and Transgenic Models Source: Brain Pathology. 6(4): 467-480. 1996.

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Summary: This journal describes the clinical features, neuropathological changes, and genetics of several neurodegenerative diseases, outlines transgenic strategies for creating animal models, and reviews investigations in which these approaches have been used to model several genetic neurodegenerative diseases. The discussion focuses on the familial forms of Alzheimer's disease (FAD) and amyotrophic lateral sclerosis (FALS), and the spectrum of triplet-repeat disorders. Researchers have linked some cases of FAD to mutations in genes encoding the amyloid precursor protein or presenilin 1 or 2. Some cases of FALS have been linked to mutations in the superoxide dismutase 1 gene. Spinocerebellar ataxia and Huntington's disease are associated with trinucleotide repeat expansions in the genes encoding ataxin 1 and huntington, respectively. Recently, investigators have used transgenic mouse models of these disorders to examine the mechanisms by which the expression of mutant proteins causes autosomal dominant disease. Their collective experience suggests that the expression of high levels of mutant transgenes in nervous tissue can significantly increase the chance that the transgenic mice will develop phenotypes resembling those occurring in autosomal dominant human diseases. The emerging view is that each of these diseases results from the gain of a toxic property by the mutant protein. Future research will be aimed at understanding the biological basis of these toxic properties and, ultimately, to the development of new treatments for the neurodegenerative disorders. 220 references. •

Apolipoprotein E Alleles as Risk Factors in Alzheimer's Disease Source: Annual Review of Medicine. 47: 387-400. 1996. Summary: This review article discusses apolipoprotein E (apoE) alleles as risk factors in Alzheimer's disease (AD). Three early-onset forms of AD inherited as autosomal dominant traits account for less than 2 percent of prevalent AD. A major susceptibility locus, apoE, is associated with risk and age of onset distributions for the common familial and sporadic late-onset AD. The identification of additional genetic susceptibility genes in the etiology of AD and the metabolic mechanisms leading to differences in age of onset and disease pathogenesis are active areas of current research. The operational difference between using apoE genotyping in differential diagnosis from the application of autosomal dominant traits, such as the triplet repeat size of the Huntington gene in Huntington's disease, is that the absence of the disease-associated marker does not rule out the disease. 1 table, 2 figures, 66 references. (AA- M).

Federally Funded Research on Huntington’s Disease The U.S. Government supports a variety of research studies relating to Huntington’s disease. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 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.

2 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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Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to Huntington’s disease. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore Huntington’s disease. The following is typical of the type of information found when searching the CRISP database for Huntington’s disease: •

Project Title: 2001 CAG TRIPLET REPEAT DISORDERS Principal Investigator & Institution: Brundin, Patrick; Gordon Research Conferences Box 984, 512 Liberty Ln West Kingston, Ri 02892 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2002 Summary: This application is to request funding for the 2001 Gordon Research Conference on CAG triplet repeat disorders to be held in Mount Holyoke College, MA, USA, July 15-20, 2001. Two major groups of genetic neurological disorders were recently identified as unstable triplet repeat diseases. Their discovery represents the foundation of a new set of principles in genetics. One group of diseases includes fragile X, myotonic dystrophy and Friedreich's ataxia. Patients with these disorders all exhibit an expansion of triplet repeats in a non-coding sequence of the DNA genome. In the contrast, the other group of neurologic disorders exhibit expanded triplet repeats (coding for CAG bases) in the coding part of the genome, resulting in a polyglutamine tract. This latter group includes Huntington's disease, spino-cerebellar ataxia 1, 2, 3, 6 and 7, spinobulbar muscular atrophy and dentato-rubral pallido-luysian atrophy. These disorders results in a selective loss of neurons in the brain and spinal cord, with a different anatomical distribution in each disease. Although the genetic defects are established, it remains to be elucidated how the mutant gene in each case generates the specific pathogenetic process and how this leads to a characteristic anatomical pattern of changes. The identification of these mutant genes raises hopes for many affected by severe genetic disease. However, before development of novel therapies can be expected, it is necessary to better understand the disease processes. This requires a multi-disciplinary research effort with collaborative projects between scientists from diverse specialties ranging from fruit fly genetics to clinical neurology and neuropathology. This conference on CAG triplet repeat disorders will gather both young and senior, key scientists who will present provoking lectures on the cuttingedge of science. In keeping with the Gordon Research Conference format, there will be generous time allocated to both structured discussions led by peers and for informal discussions and social generous time allocated to both structured discussions led by peers and for informal discussions and social interaction. Strong emphasis is placed on training and mentoring of young scientists and time is also devoted to career issues. All participants (except speakers and discussants) will be encouraged to present posters. When participants are selected there will also be priority given to women, minorities, and persons with disabilities Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: A NEW METHOD OF DRUG DISCOVERY FOR CNS DISEASES Principal Investigator & Institution: Lowe, David; Envivo Pharmaceuticals, Inc. 3696 Haven Ave, Ste B Redwood City, Ca 94063 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-DEC-2003

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Summary: (provided by applicant): The discovery and development of small molecule therapeutics for disorders of the Central Nervous System (CNS), particularly for neurodegenerative diseases, is one of the major challenges of modern biomedical research. Although great advances have been made in understanding the biological basis of neurological disorders, this scientific progress has not yet been translated into effective new treatments for these devastating disorders. This application proposes to exploit recently developed disease models in the fruit fly Drosophila melanogaster to develop a new and innovative method of small molecule drug discovery that is articularly well suited for CNS diseases. We propose to use automated procedures to screen well-validated disease models of two trinucleotide repeat disorders, Huntington's disease and spinocerebellar ataxia type I, for compounds that improve motor function. In Phase I of this project, we will use an automated screening system to develop and validate disease-specific assays, and establish by proof-of-principle experiments that the system can provide high-throughput assays that are rapid, reproducible, and highly sensitive to improved motor function in the two disease models. In Phase II, we will use this system to carry out a moderately large-scale screen (12,000 compounds) against both disorders and will begin a characterization of the "hits" that we obtain in both Drosophila and mouse disease models. The proposed project has two important outcomes. The first is to validate a method of drug discovery by in vivo screening of disease models that can be used not only for further screening for these two diseases, but also as a more general method for neurological and behavioral disorders. The second is the discovery of new bioactive compounds that can ameliorate these diseases in Drosophila, and are thus suitable lead candidates for further preclinical and clinical development in mammals, and ultimately in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACTIVATION OF STRESS RESPONSE IN NEURODEGENERATION Principal Investigator & Institution: Sagara, Yutaka; Neurosciences; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 92093 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2004 Summary: (Applicant s abstract) The deleterious effects of age-related neurodegenerative diseases are not only felt at the personal level but also as an everincreasing financial burden on the national healthcare system. However, there is no cure or a preventive treatment currently available for neurodegenerative diseases such as Alzheimer's disease (AD). Elucidation of the mechanisms underlying selective neuronal death observed in AD may help conceptualize a new treatment or a therapeutic approach. Oxidative stress, though a culprit of neuronal death observed in AD and other neurodegenerative diseases, may also activate a survival response by regulating a subset of proteins and genes, resulting in selective protection of neurons. Characterization of such a survival response, therefore, is an important step toward prevention of neuronal death as well as promotion of neuronal survival. The central hypothesis of this proposal is that the activation of the signal transduction cascade involving phosphatidylinositol 3-OH kinases (PI3K) confers resistance to oxidative injury caused by amyloid beta (ABI-42), while the down regulation of this pathway by chronic exposure to AB results in neurodegeneration. In this context, the main objectives of this project is to define the role of PI3K cascade in neurodegeneration observed in AD by investigating the effects of AB on PI3K in a comprehensive multi-system which includes human brains with AD, APP transgenic mice, and neuronal cell cultures. During the course of the proposal, the applicant will receive additional training in clinical aspects of neuroscience such as neuropathology in the context of AD

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neurodegeneration. Also, with the aid of the sponsor and consultants, the applicant will obtain training in the transgenic mouse models, which can be used to test the above hypothesis as well as to develop therapies for treatment of age-related neurological disorders. Finally, the award will assist the applicant to become an independent faculty member actively involved in research in age-related neuro-degeneration as well as in teaching at a biomedical research institution such as UCSD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACTIVITY-DEPENDENT REGULATION OF SYNAPSES BY SHANK Principal Investigator & Institution: Hung, Albert Y.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): The goal of this project is to investigate the role of a newly discovered postsynaptic protein, Shank, in the regulation of dendritic spine morphology and cytoskeleton. Local electrical stimulation induces growth of dendritic spines, suggesting that synaptic activity directly modulates neuronal architecture and circuitry. The molecular basis for these activitydependent changes is not known, but probably involves postsynaptic proteins that interact with receptors and/or cytoskeletal elements. Shank acts as a putative scaffold for multiple glutamate receptor subtypes and also binds to the actinbinding protein cortactin, which has been implicated in dynamic cytoskeletal rearrangement and translocates to synapses in response to glutamate. This study examines the role of Shank in the regulation of dendritic spines and its in vivo function through three specific aims. First a combination of cell biological, biochemical, and dominant inhibitory approaches will be used to determine the mechanism for glutamateregulated cortactin translocation to synapses, and to identify if Shankcortactin interaction is required for this response. Second, how Shank induces spine growth will be studied by structurefunction analysis. Finally, a genetic approach, generation of a Shank1 "knockout" mouse, will be used to investigate the role of Shank proteins in brain development, in postsynaptic receptor organization, and in learning and memory. The longterm goal of the candidate is to understand how aberrant synaptic transmission contributes to neurologic disease. Synapses are the signal processing units of the brain, and overexcitation of synapses by glutamate is thought to play a role in both acute neuronal injury (such as stroke and seizure) and chronic neurodegenerative conditions (including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis). Understanding how postsynaptic proteins, such as Shank, regulate activitydependent synaptic plasticity may shed light on mechanisms of glutamate toxicity. The immediate goal is to obtain training in the most uptodate techniques in molecular genetics, protein biochemistry, and cellular neurobiology, sponsored by Dr. Morgan Sheng, which will enable him to become a productive, independent molecular neurologist. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANALYSIS OF TORSIN PROTEIN FUNCTION IN C. ELEGANS Principal Investigator & Institution: Caldwell, Guy A.; Biological Sciences; University of Alabama in Tuscaloosa Tuscaloosa, Al 35487 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2006 Summary: (provided by applicant): Dystonia is estimated to be six times more prevalent than Huntington's Disease, ALS, or Muscular Dystrophy. However, as few as 5% of the over 350,000 persons in North America estimated to be affected have been correctly

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diagnosed and are under treatment (NIH Budget Office). The most severe early-onset form of this disorder has been linked to a mutation in a human gene named TOR1A that encodes torsinA, a protein that is also localized to inclusions in the brains of Parkinson's patients termed Lewy bodies. While a causative genetic mutation has been identified, the cellular mechanisms of pathogenesis underlying dystonia remain unknown. We are applying the advantages of the model organism, Caenorhabditis elegans, towards a detailed analysis of two specific torsin-related gene products in this nematode. The chromosomal positioning of these genes suggests that they may represent a functionally co-expressed unit and preliminary studies from our laboratory indicate they act neuronally. Phylogenetic analysis of the torsin family indicates these proteins share distant sequence similarity with the functionally diverse AAA+ family of proteins. We have determined that ectopic overexpression of a C. elegans torsin homolog results in a reduction of polyglutamine repeat-induced protein aggregation in a manner similar to that previously reported for molecular chaperones. The suppressive effects of torsin overexpression quantitatively persisted as animals aged. Antibody staining of transgenic animals using antisera specific to TOR-2 indicated this protein was highly localized to sites of protein aggregation. We propose to extend these preliminary studies through a combination of reverse genetic approaches designed to investigate the cellular role of torsin proteins in the nematode. The specific aims of the proposed project include: 1) to determine what phenotypes are associated with C. elegans torsin homologues; 2) to define sites of C. elegans torsin protein function; and 3) to determine potential effectors of torsin activity. These studies will further our understanding of the molecular mechanisms responsible for early-onset torsion dystonia. Moreover, the aberrant protein deposition associated with diverse neurodegenerative disorders like Parkinson's Disease and those caused by polyglutamine expansion such as Huntington's Disease warrants further investigation of any putative neuroprotective effects of torsins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AUTOMATED BRAIN PARCELLATION AND MORPHOMETRY Principal Investigator & Institution: Halgren, Eric; President; Cortechs Labs, Inc. Charlestown, Ma 02129 Timing: Fiscal Year 2002; Project Start 15-JUN-2002; Project End 31-DEC-2002 Summary: Non-invasive visualization of the living human brain with MRI (magnetic resonance imaging) is an essential part of clinical neurology. Until now, evaluation of structural changes in diseases have mainly relied upon qualitative visual judgements, or tedious hand labeling. This project aims to develop MRI image processing software that will automatically segment the entire brain volume into its constituent tissues and structures. This segmentation allows quantification of tissue volumes and intrinsic parameters. The software will be interoperable with our suite of structural and functional MRI software tools, allowing, for example, subcortical regions of interest to be examined for functional activation. We propose to base the tissue segmentation of intrinsic properties of brain tissue, thus rendering it independent of pulse sequence or scanner manufacturer. This will greatly increase scan/rescan reliability which is crucial for multi-site clinical trials, or for within-subject repeated measures (e.g., comparing tumors or multiple sclerosis plaques over time). The proposed software will allow MRI data to be used to detect neuropsychiatric disease monitor the course of such diseases, and evaluate the effectiveness of treatments. Research and clinical applications can be expected in several neurodegenerative and psychiatric diseases such as schizophrenia, Alzheimer's and Huntington's disease. PROPOSED COMMERCIAL APPLICATIONS:

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Huntington’s Disease

The proposed product would be of interest to researchers and clinicians using MRI, i.e., >10000 scanners worldwide. The proposed software could become a standard part of many brain MRI scans, in order to detect and quantify pathology, and thus could potentially be used in a substantial proportion of the millions of brain scans performed every year. Initially, the software would be used to perform surrogate markers of CNS effectiveness in drug evaluation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BEHAVIORAL ASSESSMENT OF HUNTINGTON'S DISEASE Principal Investigator & Institution: Bazzett, Terence J.; Psychology; College at Geneseo 1 College Cir Geneseo, Ny 14454 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2005 Summary: (provided by applicant): Huntington's disease (HD) is a devastating neurodegenerative disease that manifests initially as motor and cognitive dysfunction followed by a relentlessly chronic progression of symptoms culminating in death. The cause of HD is a genetic aberration on the short arm of the 4th chromosome identified as an expansion of a CAG trinucleotide repeat. Molecular biologists have very recently begun developing genetically altered mice, designed to mimic the expanded CAG repeat in HD. Technology advances have created a unique situation whereby development of new lines of mice has outpaced careful behavioral analysis of phenotypes. As a result, numerous models have been created without a clear understanding of how genetic differences affect phenotype differences. Perhaps more importantly, there is currently no consensus on what features of these models best mimic features of the disease they represent. Lacking a clear understanding of behavioral deficits vastly reduces the usefulness of any genetic model designed to mimic a disease that manifests with profound behavioral symptoms. The current proposal is a series of experiments designed to undertake detailed assessment of motor abnormalities and some cognitive dysfunction in mouse models of HD. In particular abnormalities in coordinated limb movements will be assessed beginning at a relatively early age. The first aim is to conduct experiments in a model currently known to express other gross behavioral abnormalities later in development. Once methods for assessing early subtle motor/cognitive deficits are established, the second aim is to assess genetically more appropriate models that reportedly express few gross behavioral abnormalities. The long-term objective will be initiated in the third aim where potentially therapeutic drugs will be assessed. Drug therapies that attenuate early/subtle deficits in mice may be useful in treating HD. Such therapeutic potential may not be recognized using current methods that assess only major dysfunction expressed late in development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BEOWULF LINUX CLUSTER COMPUTER Principal Investigator & Institution: Destefano, Anita L.; Neurology; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2004 Summary: (provided by applicant): A major goal of the human genome initiative is to access genetic information to understand and to prevent and/or treat human disease. The recently completed "draft" sequencing of the human genome and the recent advances in biotechnology that allow rapid throughput of samples for genotyping have created a vast resource of information. However, the challenge to dissect the genetic and

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environmental factors influencing susceptibility for common diseases remains statistically complex and computationally intensive. The genetic epidemiologists and statistical geneticists at the Boston University Medical Campus have a long history of success in identifying genes associated with risk for both simple Mendelian diseases as well as complex traits. In order to continue this success and to implement the most recent advances in statistical genetics, we are requesting, a Beowulf class LINUX cluster of 192 Intel processors. This computing system will be dedicated to genetic analysis including linkage analyses and association testing. The system will support the research of 14 NIH funded projects. Although the phenotypes and study populations differ widely among the funded projects of the major users, there is substantial overlap in the computationally intensive genetic analysis techniques that will be performed on this system. This cluster will enable computation of identity by decent relationships in extended pedigrees, computation of empirical p-values via simulation, and application of complex gene by gene and gene by environment interaction models. There is strong institutional support for this system evidenced by the administration's commitment to funding a full time systems administrator and long term support of upgrades and maintenance The placement of this computing resource among the investigators of this proposal will have a broad impact in the field of genetics and further our understanding of the genetics of Huntington's Disease, Alzheimer's Disease, Obesity, Stroke and Hemostatic Factors, Cognitive Decline, Hypertension, Cardiovascular traits, and Cocaine and Opioid Dependency among others. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOENERGETICS IN ANIMAL MODELS OF HUNTINGTON'S DISEASE Principal Investigator & Institution: Beal, M Flint.; Professor; Neurology and Neuroscience; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2003; Project Start 15-APR-1999; Project End 31-MAR-2008 Summary: (provided by applicant): The pathogenesis of Huntington's Disease (HD) is as yet unknown but there is substantial evidence that both altered gene transcription as well as mitochondrial dysfunction play an important role. There is evidence that huntingtin binds to transcription factors which results in decreased expression of genes which may play a critical role in neuronal survival. A secondary consequence of this appears to be impaired oxidative phosphorylation and increased generation of reactive oxygen species. In our prior grant, we showed that there was impaired oxidative phosphorylation in transgenic mouse models of Huntington's disease, and that this was associated with increased oxidative damage. We also showed that agents such as creatine and coenzyme Q, which improve cellular bioenergetics, exert neuroprotective effects in transgenic mouse models of Huntington's disease. In the present proposal, we intend to extend these studies to two further unique transgenic mouse models of Huntington's disease. We will determine whether there is mitochondrial dysfunction and oxidative damage in a knock-in mouse model developed by MacDonald and colleagues. These mice are a very accurate genetic model of Huntington's disease. We will also examine the tetracycline-off model developed by Yamamoto and colleagues to determine whether there is mitochondrial dysfunction and oxidative damage with the gene turned on, which then resolves once the gone is turned off. We will carry out similar studies with an inducible cell culture model. We will investigate whether histone deacetylase (HDAC) inhibitors exert neuroprotective effects by altering gene transcription in transgenic mouse models of Huntington's disease. We will examine whether a phosphodiesterase IV inhibitor can exert neuroprotective effects in transgenic

12

Huntington’s Disease

mouse models of HD by increasing cyclic AMP levels, leading to increased CREB transcriptional activity, and whether this improves mitochondrial function. Our prior studies showed that combinations of agents, which target different disease mechanisms in Huntington's disease, may exert additive neuroprotective effects. We will, therefore, examine whether a combination of creatine or coenzyme Q with either a HDAC inhibitor or a phosphodiesterase IV inhibitor can exert additive neuroprotective effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CELL GROWTH AND DIFFERENTIATION IN THE VERTEBRATE EMBRYO Principal Investigator & Institution: Lacy, Elizabeth H.; Professor; Sloan-Kettering Institute for Cancer Res New York, Ny 10021 Timing: Fiscal Year 2001; Project Start 01-JAN-1999; Project End 31-DEC-2001 Summary: (Adapted from the Investigator's Abstract): Gastrulation is a fundamental developmental process, and in the mouse it coordinates complex cell and tissue movements with cell growth and proliferation to reorganize and differentiate the embryonic ectoderm into the definitive ectoderm, mesoderm, and endoderm germ layers of the fetus. The genetic pathways directing gastrulation are only beginning to be unraveled by both targeted and random mutagenesis in the mouse and fish. Intriguingly, a number of gastrulation stage mouse mutants have been discovered through the targeted disruption of genes that are known, through their involvement with human disease, to participate in the basic cellular processes of proliferation, differentiation, and signal transduction. Recent examples include the fibroblast growth factor receptor (Fgfr-1), Brca1, Brca2, Huntington's disease homologue (Hdh), and the tumor suppressor Smad4/Dpc4. Thus the study of novel gastrulation stage mouse mutants is likely to lead to the identification of genes that serve pivotal functions in the coordination of cell growth, proliferation, and differentiation. The subject of this proposal is amnionless (amn), a recessive transgene insertional mutation that disrupts the assembly of the middle streak, this portion of the primitive streak that gives rise to non-axial embryonic mesoderm, such as somitic mesoderm. This novel phenotype reveals that the formation of the middle streak is mediated by a previously unknown pathway, one that is genetically separable from those directing the formation and specification of the proximal and distal streak regions. Therefore, a disrupted gene at the amn locus must play a key role in this pathway. Chimera analyses have shown that this gene, the amn gene, functions in the visceral endoderm to direct the formation of the middle streak and thus, that amn defines a new role for the visceral endoderm during gastrulation. The primary objective of this proposal is to positionally clone the amn gene. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CELLULAR PATHOGENIC MECHANISMS IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Tobin, Allan J.; Professor and Director; Brain Research Institute; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 25-JAN-2001; Project End 31-DEC-2004 Summary: Huntington's disease is a devastating neurodegenerative disease that is inherited as an autosomal dominant. Disease-causing alleles encode expanded polyglutamine tracts in the aminoterminal region of huntingtin (htt), a large protein

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whose normal function is unknown. The unifying hypothesis in this proposal is that htt containing an expanded polyglutamine tract (htt-ex) causes proteasome poisoning by irreversibly blocking proteasomes. We argue that poisoned proteasomes in postmitotic neurons results in a failure of normal protein turnover and in cell dysfunction and death. Wild-type htt (htt-wt should not produce such effect. The proposed studies will consider not only the poisoned- proteasome hypothesis but also alternative hypotheses, in which the pathogenic action of htt-ex does not depend on proteasomes. We have organized these studies around three Specific Aims: 1. To determine whether the intracellular distribution and the pathogenic effects of htt-ex expression vary with cell type and proliferative state. 2. To examine the effect of htt-ex expression on proteasome function and on the turnover of specific proteins, including htt itself. 3. To examine the effects of htt-ex expression on neuronal function and to determine whether known proteasome inhibitors can mimic these effects. At the conclusion of these three sets of proposed experiments we will know 1) whether proteasome location and function change in response to cell cycle and htt expression; (2) whether htt affects proteasome function and protein turnover either directly or indirectly; (3) whether htt-ex alters cellular function in dividing and stationary, differentiated cells; and (4) whether proteasome inhibitors mimic htt-ex-induced changes in neuronal function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CENTER FOR GENE-ENVIRONMENT STUDIES IN PARKINSON DISEASE Principal Investigator & Institution: Chesselet, Marie-Francoise S.; Charles H. Markham Professor of Neurolog; Brain Research Institute; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 26-AUG-2002; Project End 31-JUL-2007 Summary: The Center for Gene-Environment studies in Parkinson disease at UCLA (UCLA-CGEP) will bridge three major NIH and VA-supported awards in Parkinson's disease (PD) and one NIH-sponsored study of Huntington's disease. The central hypothesis of the proposed UCLA-CGEP is that gene and environmental toxins combine to increase the risk for PD in susceptible individuals through an interplay between pesticides and mechanisms regulating dopamine homeostasis. We postulate that critical factors in this interaction are oxidative stress and resulting alterations in proteasomal function. Project I "Environmental toxins and genes that influence dopamine in Drosophila and humans" will examine interindividual variability of dopamine vesicular transporter (VMAT) expression due to promoter variants in two human populations in parallel with a reporter gene assay. These populations will be genotyped for functional VMAT2 variants and association analyses of gene-environment interactions and pesticide exposures collected in the parent grant will be conducted. In addition, Drosophila genetics will be used to determine how the expression of VMAT affects dopamine-mediated toxicity and identify genes that modulate VMAT function, which will then be examined in the human population for their relevance to increased risk of PD. Project II "Interaction between pesticides and genetic alterations in dopamine homeostasis in mice" will test the hypothesis that pesticides and genetic variations in combination increase the vulnerability of dopaminergic neurons, and that one of the mechanisms involved is oxidative stress. Genetically engineered mice with a reduction in expression of VMAT or the cytoplasmic dopamine transporters, and mice with altered expression of alpha-synuclein and parkin, two proteins known to cause familial PD, will be examined. Behavior and quantitative anatomy will be used to assess the effect of pesticides on dopaminergic neurons in these genetically altered mice.

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Huntington’s Disease

Histology, gene expression profiling, in vivo neurochemistry and slice electrophysiology will be used to examine the role of oxidative stress in this interaction. Project III, "Pesticides and Proteasomal Dysfunction: genetic susceptibility in cellular models" will test the hypothesis that proteasomal dysfunction is central to the deleterious effects of the combined environmental and genetic insults. Cell lines, primary neuronal cultures from genetically altered mice, and human lymphoblasts will be examined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CEREBRAL NEURODEGENERATION

MITOCHONDRIAL

METABOLISM

IN

Principal Investigator & Institution: Powers, William J.; Associate Professor; Neurology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 15-JUN-2001; Project End 31-MAY-2005 Summary: (Adapted from the abstract provided by the applicant): Several lines of evidence suggest that Huntington's disease (HD) and Parkinson's disease (PD) have defects in mitochondrial function that impair oxidative phosphorylation and play a key role in the mechanism of neuronal death. To date, however, there have been no direct measurements of cerebral oxygen to glucose metabolic ratios to demonstrate an in vivo defect in cerebral mitochondrial metabolism in these diseases. We will use positron emission tomography (PET) to measure in vivo regional cerebral oxygen metabolism (CMR02) and cerebral glucose metabolism (CMRglc) to test two primary hypotheses: 1) Patients with HD have a generalized defect in cerebral mitochondrial metabolism. To test this hypothesis, we will measure whole brain CMR02/CMRgIc in 15 gene-positive pre-symptomatic patients with HD, 15 gene-positive patients with HD and definite motor signs and 30 age/gender-matched normal controls. 2) Patients with PD have a generalized defect in cerebral mitochondrial metabolism. To test this hypothesis, we will measure whole brain CMR02/CMRgIc in 15 never-medicated, early PD patients and 15 age/gender-matched normal controls. In the same subjects, we also will test two secondary hypotheses: 3) Regions vulnerable to pathologic insult have larger magnitude or selective defects in cerebral mitochodrial metabolism - caudate and putamen in HD and substantia nigra and putamen in PD. 4) In PD and HD, the degree of dysfunction in platelet electron transport complex function measured in vitro correlates with the degree of abnormal cerebral mitochondrial metabolism measured in vivo. At this time it is not clear how the abnormalities in electron transport chain activity measured in vitro in these two diseases correspond to cerebral mitochondrial metabolism in vivo. Direct in vivo regional PET measurements of CMR02 and CMRglc will allow us to demonstrate the extent and magnitude of mitochondrial dysfunction in vivo. Establishing the existence of cerebral mitochondrial dysfunction early in the course of these diseases will not only provide insights into the pathogenesis, but it will provide a measurable biological abnormality that can be monitored to determine the effect of treatments aimed at slowing or halting the progression of neuronal loss. The opportunity to determine the relation between platelet mitochondrial function and cerebral mitochondrial metabolism in patients with PD and HD is uniquely important. If such a relationship can be established in untreated patients in this study, then we would pursue further studies to determine the effects on cerebral mitochondrial metabolism of agents that alter platelet mitochondrial function. If such studies yield consistent results, they will establish the basis for the utilization of platelet rnitochondrial function assays to monitor cerebral mitochondrial metabolism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHEMICAL MODELS OF PROTEIN BETA SHEET INTERACTIONS Principal Investigator & Institution: Nowick, James S.; Professor; Chemistry; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2001; Project Start 01-APR-1994; Project End 31-MAR-2003 Summary: beta-Sheet interactions between proteins play a critical role in many biological processes associated with diseases and with normal function. Examples including the binding of Ras and Rap by the serine/threonine kinase Raf in cell signaling and oncogene expression, the dimerization of HIV protease, and the interaction between the CD4 receptor and the HIV viral protein gp120. beta-Sheet formation is also involved in the aggregation of peptides and proteins to form insoluble beta-sheet structures that are associated with a variety of devastating neurological disorders, including Alzheimer's disease, Creutzfeld-Jacob disease and other prion diseases, and Huntington's disease. This proposal seeks to mimic and to disrupt betasheet interactions by using chemical model systems called "artificial beta-sheets." The broad, long-term objectives of this research encompass both the development of drugs for diseases involving beta-sheet formation between proteins (e.g., cancer, Huntington's disease, and Alzheimer's disease) and the development for general strategies for creating compounds that disrupt beta-sheet interactions. The specific aims are as follows: (1) Artificial beta-sheet structures based upon the beta-sheet at the interface of the two halves of the met repressor dimer will be synthesized dimer will be synthesized, and their structures will be studied by NMR and CD spectroscopy. (2) An artificial betasheet designed to mimic the protein G binding region of the Fab portion of the immunoglobulin G will be synthesized, and its interaction with domain III of protein G will be studied by NMR spectroscopy. (3) An artificial beta sheet designed to mimic the beta-sheet interface between Ras proteins and the c-Rafl kinase (Raf) and artificial betasheets that mimic the binding regions of Ras and Raf will be synthesized. Their structures and interactions will be studied by CD and NMR spectroscopy, and the latter two compounds will be evaluated for anti-cancer activity by the NCI using an in vitro 60 human tumor cell line screen. (4) Artificial beta-sheets designed to mimic polyglutamine beta-sheet aggregates, which are involved in Huntington's disease and other genetic neurodegenerative diseases will be synthesized. Their structures will be studied by CD and NMR spectroscopy, and their ability to block polyglutamine beta-sheet aggregation will be determined using an in vitro assay. (5) Artificial beta-sheets designed to block beta-amyloid aggregation will be synthesized, and their abilities to block its aggregation and deposition will be studied using in vitro assays. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHROMATIN REMODELING IN TRANSGENIC MOUSE MODELS OF HD Principal Investigator & Institution: Cha, Jang-Ho J.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2008 Summary: Huntington's disease is an autosomal dominant neurodegenerative disease for which there is currently no effective treatment. Although a number of pathogenic mechanisms have been proposed, transcriptional dysregulation has emerged as a potential critical aspect. In transgenic mouse models of HD, numerous alterations in the steady state levels of mRNA have been described. However, the mechanisms underlying mRNA perturbation are undefined. Elucidation of such mechanisms will have significant relevance to the understanding and development of future treatment of

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HD. In eukaryotes, gene expression is regulated through modification of chromatin and association with specific transcription factors. While alteration of steady state mRNA levels in transgenic HD mouse (R6/2) brain is de facto evidence of transcriptional dysregulation, it is yet unknown whether there are specific alterations in chromatin structure. In this project, we will explore chromatin remodeling in a transgenic HD mouse model. First, we will determine if mithramycin--an aureolic antibiotic that binds to GC-rich regions of DNA and which has been shown to extend lifespan in R6/2 mice-corrects mRNA expression abnormalities that we have previously described in these mice. We will use receptor binding autoradiography and in situ hybridization to perform these analyses. Next, we will seek to determine the role of a fatnily of transcription factors, the Sp family, with a set of genes whose expression is known to be altered in R6/2 mice. We will explore the interactions of Sp and related zinc finger transcription factors by using Chromatin ImmunoPrecipitation (CHIP) assays with realtime PCR detection. Finally, we will explore the ability of mithramycin to reverse chromatin abnormalities in the R6/2 mice. Taken together, these experiments will elucidate the molecular mechanisms underlying transcriptional dysregulation in a model of Huntington's disease. Such elucidation of a central pathogenic mechanism will open the way towards rational, mechanism-targeted therapy for this devastating disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISEASES

COMPARATIVE

MODELING

OF

NEURODEGENERATIVE

Principal Investigator & Institution: Link, Christopher D.; Inst of Behavioral Genetics; University of Colorado at Boulder Boulder, Co 80309 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Numerous age-associated neurodegenerative diseases [e.g., Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), etc.] are associated with aggregation of disease-specific proteins. The finding that the genes encoding these proteins are mutated in some familial forms of these diseases strongly argues that these aggregating proteins cause these diseases. However, for all these diseases the relationship between protein aggregation and cellular pathology has not been clearly established. It is also unknown if the common association of protein aggregation with these diseases reflects a common underlying toxic mechanism, or, alternatively, a common downstream result of cell pathology. We will seek to identify the molecular consequences resulting from the aggregation of three different disease-associated proteins by individually expressing these proteins in a transgenic Caenorhabditis elegans model system. These molecular consequences will be determined by DNA microarray-based gene expression studies and co-immunoprecipitation analyses. Comparison of the molecular responses to expression of different disease-associated proteins will allow identification of common and disease-specific responses. We will then use the molecular genetic tools available in C. elegans to manipulate these molecular responses to determine their role in disease protein toxicity. These studies will directly test whether there is a common underlying toxic mechanism for these neurodegenerative diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COMPUTATIONAL ANALYSIS OF HUMAN 'AT-RISK' DNA MOTIFS Principal Investigator & Institution: Stenger, Judith E.; Assistant Professor; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: (Taken from the Candidate's Abstract) At-Risk DNA Motifs (ARMS), which include repetitive elements such as Alu sequences, homonucleotide runs and triplet repeats, are potentially unstable segments of the human genome. ARMS are a factor in genetic susceptibility to disease, requiring particular combinations of genetic backgrounds and environmental triggers to express a disease phenotype. While some of the mechanisms are understood, it is not clear under what circumstances repetitive DNA elements mediate pathological mutagenesis. Although a high burden of these sequences is generally tolerated in humans, they can have an enormous impact on health by contributing to diseases that have devastating effects on afflicted individuals. For example, Alus have been linked to numerous diseases including Fanconi anemia, alphazerothalassemia, leukemia, hypertension, neurofibromatosis, breast, and colon cancers. Trinucleotide repeat expansions have been linked with Kennedy's Disease, Huntington's Disease, myotonic muscular dystrophy, and Friedreich ataxia. The long term objective of this proposal is to gain insight into the genetic factors that mitigate gene rearrangement in hopes of predicting when the presence of a repetitive element truly constitutes a threat to the health of an individual. The hypothesis is that the characterization of ARMS according to all possible attributes (i.e. size of repeats, separation distances between repeats, orientation, sequence similarity between repeats, nucleotide base constitution and proximity and/or containment of mutagenic and/or toxicological agent targets, DNA processive or other enzymatic target sites) can reveal largely excluded situations that can be viewed as unstable. It is also postulated that a multidimensional database of repetitive sequences characterized according to the aforementioned attributes can be used to predict repetitive elements that are most prone to mutation, ARMS, while increasing our understanding of the interactions between these genetic elements and their environment. The approach is to use a combination of computational biology and molecular genomic analysis to locate and analyze ARMS. The specific aims of this proposal are to: 1) characterize available data according to the conceivable relevant attributes of size, distance, orientation, degree of homology, base constitution and containment of known target sequences. 2) To test the hypothesis by computationally identifying loci that have already known to contain ARMS linked to a mutation resulting in disease, and then to identify specific genes that may be at-risk for mutation and experimentally testing them using molecular biological approaches. 3) To set up an interactive on-line database and program server so that the scientific community can use the information and apply it to drive experimental research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--GENE EXPRESSION PROFILING Principal Investigator & Institution: Luthi-Carter, Ruth; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2008 Summary: Extensive genome sequencing efforts and advances in microarray technology have converged to create revolutionary new opportunities for high-throughput analyses of gene expression. Within the context of the Program, gene expression analyses will provide information critical to elucidating the mechanisms by which huntingtin and

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Huntington’s Disease

DNA-binding therapeutic agents alter gene expression. The Gene Expression Profiling Core will support the Program's individual Projects by tracking the expression of thousands of mRNAs simultaneously in the respective experimental systems, thereby identifying the specific gene targets of a given pathological or pharmacologic manipulation. Identifying the gene promoters subject to a particular effect will allow the promoter elements and transcription factor(s) responsible for the change to be elucidated. The Gene Expression Core will provide expertise in the design, execution and analysis of microarray profiling studies and will carry out confirmatory analyses using independent methodologies, such as northern blotting. The Principal Investigator of the Core has extensive experience in microarray based expression analyses, including several previous studies of mouse models of polyglutamine disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEPRESSION IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Nehl, Carissa R.; Psychiatry; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 06-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): The proposed study will examine depression in presymptomatic Huntington's disease (HD). Presymptomatic individuals will be recruited through the NIH-funded PREDICT-HD study. This training proposal consists of two distinct stages. During the first stage, data collected during the PREDICT-HD study will be analyzed. The relationship between reported depression symptom severity, approximate nearness to disease onset, verbal memory, working memory, and visuospatial ability will be assessed. Additional information will be collected during the second stage of this proposal: a subgroup of individuals participating in PREDICT-HD will be assessed for mood disorders using the SCID and will complete a measure of relationship distress. This study will assess the relationship between mood disorders, nearness to disease onset, relationship distress, working, memory, and visuospatial ability. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DOES CORTEX KILL STRIATUM IN HD? Principal Investigator & Institution: Meade, Christopher A.; Anatomy and Neurobiology; University of Tennessee Health Sci Ctr Health Science Center Memphis, Tn 38163 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2005 Summary: (provided by applicant): An important question in Huntington's disease (HD) pathogenesis is whether mutant huntingtin (Ht) effects striatal cell death directly by perturbing striatal cell fL motion or whether it alters areas outside the striatum (notably cortex) that influence the striatum, leading indirectly to striatal cell death. This could be studied by examining the effect of a 100% mutant cortex on a 100% wild-type (VVT) striatum, and vice versa. We propose to develop a novel model system, creating in oculo co-transplants of mixed genotypic pairings, using embryonic HD mutant mouse and WT tissue, of cortex and striatum. Our studies will develop the in oculo method to test the competing hypotheses: 1) that a cortical action of mutant Ht drives striatal injury, even in the absence of the HD mutation in striatum, 2) that striatal injury can occur in a mutant striatum, even in the presence of an input from a WT cortex or in the absence of any cortical input or 3) that striatal injury is driven by a combination of a cortical and striatal action of mutant Ht. In Aim 1 we will create in oculo co-transplants

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using embryonic HD mutant cortical tissue and embryonic WT striatal tissue and look for signs of striatal cell injury as compared to co-transplants of WT cortex and WT striatum. If the hypothesis is correct, WT striatum wilt show increased signs of injury when co-transplanted with a HD mutant cortex. In Aim 2 we will create in oculo co transplants using embryonic WT cortical tissue and embryonic HD mutant striatal tissue and look for signs of striatal injury as compared to WT controls. If striatal injury depends on cortical input, but not mutant input per se, a HD mutant striatum will show signs of injury when co-transplanted with a WT cortex. Additionally, we will create single transplants of embryonic mutant striatum and look for signs of striatal injury. If striatal cell death is entirely cell autonomous, even in the absence of cortical input, striatal injury will occur in a HD mutant striatum, in Aim 3 we will create co-transplants using embryonic HD mutant cortex and embryonic HD mutant striatum and look for signs of striatal injury as compared to controls. This hypothesis predicts that striatal injury will only occur when an HD mutant cortex is co-transplanted with an HD mutant striatum or that it will be more severe than if only cortex or striatum is mutant. These studies will validate the in oculo technique as an effective HD model system, which might be useful in further testing hypotheses of mutant Ht mechanism of action and in testing possible drug therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DOPAMINERGIC MODULATION OF WORKING MEMORY IN PD Principal Investigator & Institution: Hershey, Tamara G.; Psychiatry; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 15-JUL-2001; Project End 31-MAY-2006 Summary: (provided by applicant): The applicant is a clinical neuropsychologist with graduate training in neuropsychology and postdoctoral training in neuropharmacology and positron emission tomography (PET). The goal of this career development award is to integrate and advance these two areas of interest to answer questions about the neuropharmacological and neurophysiological basis of cognitive dysfunction in movement disorders such as Parkinson's disease (PD). This award will provide the applicant with training in the technical and theoretical issues related to using cognitive and pharmacological activation techniques in functional magnetic resonance imaging (fMRI). Long-term objectives are to address questions about the neural basis of cognitive dysfunction in movement disorders related to dopaminergic and/or basal ganglia dysfunction, such as PD, Tourette's syndrome and Huntington's disease. In addition, questions about the effects of dopaminergic treatments for these and other disorders (e.g. dystonia) on cognitive and neurophysiological functioning are also of interest. Cognitive dysfunction in these diseases, either due to the disease process itself or its treatments, can be limiting and disabling. Understanding the neurophysiologic basis for these symptoms may aid in assessing the effectiveness of current treatments or in developing better treatments. During the award period, the applicant will develop expertise in the use of fMRI, cognitive and neuropharmacological techniques to study these disorders, and will continue to hone her clinical skills in the neuropsychological assessment of movement disorders. The applicant will apply these new techniques to investigate the role of dopamine in working memory. The specific aims of the proposed studies are to test the hypothesis that 1) PD affects prefrontal cortex involvement in working memory and 2) dopaminergic modulation of working memory primarily occurs due to changes in lateral prefrontal cortical activity. To test these hypotheses, the applicant will first perform a behavioral study examining the effects of a steady-state infusion of levodopa, a dopamine precursor, on verbal and spatial working memory in

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PD patients and controls. The results of this study will then guide the choices of working memory tasks for an fMRl study. Subjects will be asked to perform working memory tasks before and during a steady-state infusion of levodopa. Modulation of the lateral prefrontal cortex is predicted during levodopa infusion. The degree of modulation is predicted to depend on baseline dopaminergic status (PD vs control) and the degree of memory load (low vs high). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EDUCATING PHYSICIANS ABOUT GENETICS AND BRAIN DISORDERS Principal Investigator & Institution: Tanner, T Bradley.; President; Clinical Tools, Inc. 431 W Franklin St, #30 Chapel Hill, Nc 27516 Timing: Fiscal Year 2001; Project Start 20-SEP-2001; Project End 31-MAR-2002 Summary: The expanding field of molecular genetics has quickly outpaced the knowledge of medical providers, due in part to the Human Genome Project. The genetics of brain illnesses are only beginning to be understood, nevertheless, providers treating patients with mental health, substance abuse and neurological disorders need to understand clearly what is and is not known about genetics and brain illnesses. It is likely that genetic aspects of schizophrenia, autism, mental retardation, bipolar disorder, among others, will be further identified in the near future, creating confusion and difficult choices for patients and families. Current and future providers must be prepared to explain and understand genetic susceptibility as it applies to a full range of illnesses. In Phase I, we will develop and evaluate an Internet-based CE program focusing on genetic issues related to alcoholism. We will also use the course the discuss upcoming technologies as well as issues related to discussing genetic risk with a patient. Phase II will produce 7 additional course on a variety of topic related to illnesses of the brain including Mixed Substance Abuse, Alzheimer's Disease, Schizophrenia, Affective Disorders, Attention Deficit, Huntington's Disease, and Mental Retardation. For each course we will highlight: 1) how genetic knowledge may affect patients and be used in clinical practice; 2) communication of genetic knowledge with patients and families: preparing for patients' questions; 3) where relevant, ethical, legal and psychosocial issues related to genetic testing, and 4) understanding emerging technologies and findings in genetics. A multidisciplinary team including representatives from psychiatry, genetics, genetic counseling, and primary care will create the content. We will evaluate the courses' effect on knowledge, clinical skills and self-efficacy using simple randomized studies comparing subjects using the genetics course to subjects using an online CE course on another topic. If successful, the training will expand the capabilities of the existing pool of providers and improve the training of future providers regarding the role of genetics in illnesses of the brain. PROPOSED COMMERCIAL APPLICATIONS: Physicians are required to obtain CME credit to maintain licensure and privileges. Managed care organizations (MCOs), such as large HMOs, may be interested in purchasing access to CE that can be offered to participant professionals. Pharmaceutical companies may also want to support development of courses based on the model described in this application. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EMBRYONIC STEM CELL MODEL OF POLYGLUTAMINE DISEASE Principal Investigator & Institution: Lorincz, Matthew T.; Neurology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274

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Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Huntington's disease (HD) is one of nine fatal neurodegenerative disorders without effective treatment or cure, caused by an expanded CAG/polyglutamine repeat. The roles of the normal and mutant HD gene product, huntingtin remain uncertain. The objective of the proposed Mentored Clinical Scientist Development Award is to explore huntingtin mediated neurodegeneration. We propose to evaluate the roles of transcriptional dysregulation and protein processing in HD by pursuing the following Specific Aims: Specific Aim 1: Define the role of the NMDA receptor subunit NR2B, CBP, histone acetylation, and BDNF in aberrant neurite outgrowth and decreased survival of embryonic stem (ES) cells with expanded CAG repeats. Specific Aim 2: Identify transcripts involved in expanded polyglutaminemediated transcriptional dysregulation. Specific Aim 3: Characterize the processing of polyglutamine containing proteins in undifferentiated and neuronally differentiated ES cells. We will pursue these Specific Aims utilizing an accurate, easily accessible, murine ES cell model. We find that neuronally differentiated ES cells with expanded CAG repeat domains develop features consistent with polyglutamine-mediated toxicity. Proposed experiments are expected to characterize full-length huntingtin protein processing and identify if the NMDA receptor subunit NR2B, CBP, histone acetylation, or BDNF are mediating neuronal dysfunction that precedes neurodegeneration in HD. Comparison of transcriptional profiles from neuronally differentiated ES cells with and without CAG repeats will be utilized to identify novel factors involved in HD pathogenesis. Once the pathologic mechanisms of mutant huntingtin are understood it will become possible to design rational therapeutics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXPRESSION PROFILING FROM MICRODISSECTED SAMPLES Principal Investigator & Institution: Goldrick, Marianna M.; Senior Scientist; Ambion, Inc. 2130 Woodward St, #200 Austin, Tx 78746 Timing: Fiscal Year 2003; Project Start 01-FEB-2001; Project End 31-MAR-2005 Summary: (provided by applicant): One objective of the proposal is to develop a product line that will consist of amplified RNA (aRNA) derived from pure populations of cells from various regions of mouse brain. The target cells will be selected by Laser Capture Micro-dissection (LCM). The product line will include aRNA derived from normal mice and from mutant mice that serve as models of human neurodegenative disorders, including Alzheimer's disease, Huntington's disease, and ataxia telangiectasia. The product will be targeted to researchers carrying out expression profiling studies that aim to understand the molecular basis of normal neurological function and the molecular pathology of neurological disease. During the first year, efforts will be focused on scaling up procedures for sample processing, micro-dissection, and RNA isolation and amplification from normal mice. During the second year the procedures will be applied to the mutant strains. The aRNA will be produced using T7mediated in vitro transcription. In order to help meet the anticipated Production-scale goals, efforts will be directed to adapting the procedures, especially RNA amplification, to a robotic platform. In order to assess the RNA from micro-dissected samples for quality assurance purposes, molecular markers will be identified to use for verifying that the RNA is derived from the intended cell population. Efforts will also be directed to improving methods for identifying target cells for micro-dissection in samples such as tumors, where target cells (e.g. malignant cells) cannot always be distinguished by histological staining. The methods will be compatible with isolation of intact RNA from the selected cells, so that it can be amplified for use in microarray expression profiling

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assays. To meet this goal we will develop rapid fluorescent detection methods using primary fluorescent antibodies directed to tumor antigens, and we will also adapt detection of target cells in transgenic animals expressing Green Fluorescent Protein for use with LCM. Achieving these goals will provide aRNA from distinct cellular subtypes to neuroscience researchers who do not currently have access to this resource. Use of aRNA from defined cell subtypes, as opposed to bulk tissue, will improve the ability to make biologically meaningful conclusions from expression profiling experiments carried out on highly heterogeneous tissues such as brain. Another goal of the project is to release a kit for recovery of high-quality total RNA from microdissected samples, especially those obtained by LCM. The kit will be of general use to life science researchers working with micro-scale samples. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXTRAPYRAMIDAL SYSTEMS Principal Investigator & Institution: Graybiel, Ann M.; Professor; Brain and Cognitive Sciences; Massachusetts Institute of Technology Cambridge, Ma 02139 Timing: Fiscal Year 2001; Project Start 01-JUL-1988; Project End 31-MAY-2002 Summary: (Investigator's Abstract): Dysfunctions of the basal ganglia have been implicated in extrapyramidal movement disorders such as Parkinson's disease and Huntington's disease, and the basal ganglia are abnormal in some neuropsyctuatric disorders as well. No clear idea has yet emerged, however, about what neural operations are performed in the basal ganglia. Strong evidence suggests that the functions of the basal ganglia must depend heavily on their cortical inputs, because the neocortex provides most of the inputs that the basal ganglia receive. These inputs enter mainly by way of corticostriatal projections to the striatum, and indirectly via the thalamus. The largest outputs of the basal ganglia in turn link these nuclei, through series of synaptic steps, to the motor, promotor and prefrontal cortex. The basal ganglia thus appear. to receive cortical input, process it under the influence of modulatory inputs (for example dopaminergic) and return it to the frontal lobes (and to some brainstem sites). We propose a coordinated series of experiments in monkeys and rats to study cortical-based ganglia linkages. Specifically, we propose to analyze in detail the sensorimotor cortical projections to the striatum. This sensorimotor system has significant advantages for study: the inputs are strong, they can be identified electrophysiologically by recording and microstimulation in the cortex, they can be mapped rigorously with sensitive tracer methods, and they thus can be analyzed in depth to permit stud of the map-transformations that occur between cortex and striatum. Much of the proposed work on this system (AIMS 1,2 and 4) is to be in squirrel monkey, in which we and others have found a distributed, catchy organization of inputs from primary somatosensory and motor cortex to the putamen. We will attempt to determine the rules of organization of these distributed and modular sensorimotor inputs. A series of studies is also proposed in the rat to attempt delineation of striatal cells activated by the sensorimotor cortex. In these experiments we propose (in AIM 3, with follow-up in the squirrel monkey in AIM 4) to use electrical and chemical stimulation of sensorimotor cortex to activate immediatearly genes in striatal neurons. The gene expression will be used as a cellular-level readout of neural ensembles activated by cortical input in the striatum and its output targets, and the pathways necessary for this activation will be determined. With these two complimentary techniques, our goal is to delineate the organization of corticostriatal sensorimotor maps in sufficient detail to gain insight into the functions of the striatum. The significance of this work is twofold. First, it may help uncover the neural substrates of focal and

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somatotypically distributed banal ganglia movement disorders. Second, it should help identifying what transformations occur in cortical-basal ganglia loops. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTIONAL NEUROANATOMY OF MOVEMENT DISORDERS Principal Investigator & Institution: Brown, Lucy L.; Associate Professor; Neurology; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAY-2007 Summary: (provided by applicant): Although the gene for Huntington's disease (HD) has been identified, the processes that lead to cell pathology and degeneration are still unclear. The proposed studies examine early pathology and pathophysiology in two transgenic mouse models of Huntington's disease. Our preliminary data in one mutant model, the reversible HD94 model, suggest that the chemoarchitecture of the striatum is altered in early symptomatic stages of the disease: there are more mu opioid receptorrich striosomes in mutants than in controls, which may lead to an imbalance of activity between the striosome and matrix compartments and produce the symptoms of chorea and involuntary activity. The studies will determine whether there are more striosomes in mutants by using immunocytochemical methods to identify striosomes. The working hypothesis states that the early stages of the disease are associated with abnormal developmental processes. The specific hypothesis is that a critical part of the pathology underlying the symptoms and final degenerative process of Huntington's disease is abnormal neurogenesis prenatally and postnatally, and that the number of striosomes in mutants reflects neurogenesis abnormalities. In addition, our model of the behavioral functions of striosomes predicts that mutants will be more sensitive to dopamine agonists. Finally, the studies will investigate prenatal and adult cell proliferation and neurogenesis in mutants and their controls by using a thymidine analogue, bromodeoxyuridine (BrdU). The studies may provide clues to the function of the gene huntingtin, and define a target for therapeutic strategies. In addition, these studies address the plastic and proliferative capacity of the adult brain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE-ENVIROMENT INTERACTION IN COGNITION Principal Investigator & Institution: Gilliam, T Conrad.; Borne Professor of Genetics and Developm; Genome Center; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2005 Summary: (provided by applicant): We propose a collaborative effort between Columbia University (CU) and University of Zulia (LUZ), Maracaibo-Venezuela, to investigate the effects of life conditions and environmental exposures together with genetic factors upon the expression of specific cognitive abilities. We aim to strengthen the capacity of Venezuelan scientists to design and execute research centered on cognitive impairment from birth to advanced age, with emphasis in disorders common in the State of Zulia; including Alzheimer's disease, Huntington's disease and Vascular Dementia. We propose the following specific aims for this exploratory project: 1. To assess the social impact of dementias in the State of Zulia. We will conduct a qualitative ethnographic study among family and caregivers of demented patients, as well as among primary care health professionals, identifying beliefs about cognitive impairment, dementia, knowledge, impact of disease on family life, self esteem, family identity, social reactions, access to health care and quality of care by professionals. 2. To assess current resources and needs and develop and initiate a plan to address these needs to promote the

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successful conduct of the proposed research and capacity building. 3. To show feasibility and generate preliminary data to justify submission of collaborative research via an R01 grant mechanism and to identify specific research questions that show the greatest promise for advancement. We will test whether a catecoI-O-methyltransferase (COMT) gene variant affects working memory and executive function in Venezuelan families segregating subcortical white matter hyperintensities. Variance accounted for by the gene variant and life conditions and environmental exposures will be examined. 4. To identify training and other capacity-building opportunities in the context of brain health promotion throughout life. At the end of the planning period, we hope to have initiated preliminary studies and to have organized, planned, prepared and assembled an application for a more comprehensive R01 grant involving collaboration between CU and LUZ investigators incorporating both research and capacity building. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC MODEL OF NEURODEGENERATION Principal Investigator & Institution: Feany, Mel B.; Assistant Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 31-AUG-2004 Summary: (Adapted from the application): Neurodegenerative diseases exact a massive toll on human and health care resources. They also pose the fundamental question of the mechanisms underlying selective degeneration of particular neuronal populations. Recent identification of the genes involved in several major neurodegenerative disorders, including Huntington's disease and Alzheimer's disease, represent major advances, but have not yet revealed how the encoded proteins produce cell death. Additional components of the neurodegenerative pathway must be identified. The applicants propose to use Drosophila as a model system to identify proteins required for neuronal degeneration. Both Huntington's disease and Alzheimer s disease are dominantly inherited neurodegenerative disorders most likely produced by toxic actions of the encoded gene products. Appropriate forms of both proteins will be expressed in Drosophila using the GAL4 system that facilitates transgene expression in a variety of defined tissue-specific and temporal patterns. The anatomic and behavioral abnormalities resulting from expression of the human transgenes will be characterized, and a phenotype suitable for generating second site suppressors and enhancers will be defined. Flies will then be mutagenized and genetic modifiers isolated. Mammalian homologues of these Drosophila modifiers will be human disease gene candidates and likely components of mammalian neurodegenerative pathways. The ability of many Drosophila proteins, including several discussed in the current application, to substitute functionally for their mammalian counterparts, suggests close analogies between the two systems. Even seemingly highly unique processes such as hindbrain compartmentalization and learning and memory show remarkable similarities. The basic cell biology of neurodegeneration should prove no exception. The applicant is an M.D./Ph.D. who will have completed a residency in anatomic pathology and subspecialty training in neuropathology prior to the proposed start date. She also holds a doctoral degree in neurobiology. The research will be carried out in a Drosophila laboratory group within the Harvard Medical School. A co-sponsor expert in human molecular genetics and neurodegenerative diseases has been selected to complement the primary laboratory's expertise in Drosophila molecular genetics and development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GLUTAMATE TRANSPORTER REGULATION IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Widnell, Katherine L.; Neurology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 15-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): Glutamate transport is essential for the synaptic inactivation of the neurotransmitter glutamate. A family of glutamate transporters has been identified in both astroglia and neurons. These transporters play important roles in the pathophysiology of neurologic disorders, notably amyotrophic lateral sclerosis and stroke. GLT1 is a glutamate transporter localized on astrocytes. We have determined that in a murine transgenic model of Huntington's Disease (HD) expressing Nterminally truncated huntingtin (N I 7182Q), there are decreased levels of GLT1, but not other glutamate transporter subtypes, in the striatum. In this proposal, experiments are presented to study the possible role of GLT1 and other molecular transporter subtypes in the development of striatal cell pathology seen in HD. First, a technique for the establishment of organotypic striatal cultures will be developed. These cultures will provide the ability to manipulate conditions, assess factors that affect GLT1 expression, and monitor for excitotoxic changes. Second, in order to further assess the role of GLT1 downregulation, behavior and striatal histology will be examined after GLT1 anti-sense infusion into rat striatum. Third, the regulation of glutamate transporters in N17182Q transgenic mice will be further evaluated in various brain regions and at various time points related to behavioral and histologic abnormalities. Human tissue from HD postmortem brains will also be evaluated. The effect of upregulation of the GLT1 transporter subtype by the neurotrophin glialcell linederived neurotrophin (GDNF), and by the neuroinimunophilin GPI1046, will be evaluated in organotypic striatal cultures, and in vivo in transgenic HD mice. Finally, an EAAT2 (GLT1) overexpressing mouse will be crossed with transgenic mouse models of HD to determine if GLT1 over-expression can reverse some of the observed behavioral or pathologic phenotypes of HD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HUNTINGTON AND VESICLE TRANSPORT Principal Investigator & Institution: Difiglia, Marian; Associate Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 15-AUG-1998; Project End 31-JUL-2002 Summary: Huntington's disease causes motor and cognitive dysfunctions, the degeneration of striatal and cortical neurons in the brain, and death of its victim within 15-20 years. The genetic mutation is an expanded region of polyglutamines at the Nterminus of huntingtin. The function of wild-type huntingtin and the mechanism of HD pathogenesis caused by mutant huntingtin are unknown. We have observed an abnormal accumulation and transport of huntintin in affected neurons of the HD brain. Similar patterns of mutant huntintin accumulation appear in clonal striatal cells transfected with cDNAs encoding huntingtin with an expanded polyglutamine region. Published studies and our preliminary observations suggest that wild-type huntingtin may function in receptor- mediated endocytosis. Mutant huntintin, like wild-type huntingtin, associates with clathrin-enriched membranes. Our overall hypothesis is that mutant huntintin causes neuronal dysfunction through its direct effects on receptormediated endocytosis and by its abnormal accumulation and transport. We propose a series of studies in clonal striatal cells to explore wild-type huntingtin's association with endosomes (Aimsl), to analyze the consequences of polyglutamine expansion in

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huntintin on endocytic function (Aim 2), and to evaluate the subcellular compartments that accumulate mutant huntingtin and contribute to cell death (Aim 3). Our studies will include techniques in confocal immunofluorescence microscopy, immunogold/electron microscopy, subcellular membrane fractionation, immunoisolation and Western blot. The results will identify the subcellular processes involved in HD pathogenesis and will lead to a rational strategy for treatment of this devastating disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HUNTINGTON DISEASE IN VENEZUELA AND OTHER STUDIES Principal Investigator & Institution: Wexler, Nancy S.; Higgins Professor of Neuropsychology; Hereditary Disease Foundation 1427 7Th St, Ste 2 Santa Monica, Ca 90401 Timing: Fiscal Year 2001; Project Start 01-APR-1985; Project End 31-JUL-2002 Summary: (Investigator's Abstract): Through the study of a unique Venezuelan Huntington's disease kindred the gene for HD was localized to chromosome 4p using new molecular genetic techniques; homozygotes for the disease were identified "and the phenomenon of complete dominance" genetically documented for the first time in human medical genetics; key genetic recombinants were found, permitting more precise chromosomal localization of the HD gene and high resolution geneiic and physical mapping of the candidate region; and the HD gene itself was discovered to be an unstable trinucleotide CAG repeat in a novel protein called "huntington." The Venezuelan kindred now has an unparalleled role to play in this next phase of understanding the disorder, from the molecular behavior of the repeat to its clinical manifestations. It is the only existing kindred in which the HD allele has been inherited from a progenitor and passed through ten generations and hundreds of meioses, eliminating allelic heterogeneity and ensuring that all those in the kindred who have inherited the HD gene have the identical allele and terrain surrounding it. The enormity of the kindred, over 14,000 people, the huge sibship size, the shared background genes and environment, and the cooperativity of family members provide an unmatched research resource. The aims of the project are: 1 ) To understand the relationship between genotype and phenotype in their natural habitat, unbiased by ascertainment. To study the behavior of the CAG repeat segregating on a single haplotype as it has already afflicted over 400 people and as it now threatens 4,697 at risk children, 1,653 of whom will die of the disease in the ensuing years. To learn how genetic characteristics contribute to clinical consequences and seek to explain why people with the same number repeat units have widely varying clinical manifestations. 2) To discover modifiers, either genetic or environmental, that may regulate the frequency or magnitude of CAG expansion or influence phenotypic expression. 3) To analyze juvenile cases in more detail and the fathers who produce them; to understand what governs the plasticity of the repeat and why huge expansion produce juvenile onset. 4) To characterize genetically and phenotypically the growing population of homozygotes and learn how they cope with two doses of expanded alleles. The Venezuelan HD kindred is the largest single source of these rare homozygous individuals in the world; 8 have been identified already and 28 should be in the kindred. 5) To collect tissue samples that can provide insight on the expansion process, including lymphoblast lines and sperm samples. As a prospective, longitudinal study, to examine the effect of age, disease duration, birth order or environmental factors on sperm, in which mosaicism has been identified. 6) To collect brain and other post-mortem tissues from genetically and clinically well characterized members of the kindred to understand how the huntington protein specifically devastates striatal neurons. These tissues will enable us

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to tie together the behavior of the gene, its target in the brain and the clinical repercussions these two produce. 7) To develop a molecular cognitive neuroscience approach to understanding how the expansion produces profound cognitive and behavioral disturbances. To develop a more precise neuropsychological battery to ascertain capacities and limitations that are germane to the underlying neuropathology. 8) To explore how psychiatric and cognitive symptomatology can also be regulated by the expanded repeat or some other genetic modifiers. 9) To characterize the kind-red for common disorders and genetic traits or markers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IN VIVO EFFECTS OF A LONG REPEAT IN THE HD GENE Principal Investigator & Institution: Detloff, Peter J.; Assistant Professor; Biochem & Molecular Genetics; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 31-JUL-2002 Summary: The long term goal for this work is to determine the molecular basis of Huntington's disease (HD). The basis for this progressive neurological disorder is an expanded CAG repeat in the Huntington gene that codes for a long polyglutamine repeat (11, 28, 51, 63, 69). The work proposed in this competitive renewal extends work completed during the first 2 years of funding during which the PI made a mouse with a 90 unit CAG repeat in the murine HD homolog (Hdh (CAG) 90). Recent work has shown the presence of Neuronal intranuclear inclusions (NIIs). The PI will also make mice with modifications of Hdh (CAG) 90 designed to enhance access of the polyglutamine-containing portion of the mutant protein to the nucleus. The PI will assess the role these modifications play in the formation of NIIs and the possible role NIIs play in causing abnormalities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INHIBITION OF FIBRILLOGENESIS WITH B-STRAND MIMICS Principal Investigator & Institution: Hammer, Robert P.; Associate Professor; Chemistry; Louisiana State Univ A&M Col Baton Rouge Office of Sponsored Programs Baton Rouge, La 70803 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: (Adapted from the Application). Several age-associated degenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease are characterized by the formation of fibrillar structures called amyloid plaques. The long-range goal of this work is to develop inhibitors of amyloidogenesis and to test whether or not such "blocker" molecules can be effective suppressors of toxicity and ultimately therapeutic agents for amyloid associated diseases. The specific aims and the hypotheses to be tested are: (1) Design and synthesis of new B-strand mimics that block the fibril and protofibril formation of the Alzheimer-associated B-amyloid peptide (All). Oligomerization of B-sheet structures, like those in A-Beta fibrils, can be inhibited or reversed by extended peptide structures that have only one edge available for hydrogen bonding. (2) Determination of the inhibition mechanism of protofibrillogenesis with Bstrand mimics. Potentially neurotoxic protofibril formation can also be inhibited by "blocker" molecules, the formation and dissolution of A-Beta protofibrils in the presence and absence of molecules known to inhibit fibril formation will be studied using scanning force microscopy (SFM), static light scattering (SLS), dynamic light scattering (DLS), analytical ultracentrifugation (AU) and fluorescence photobleaching recovery

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(FPR). (3) Detection of early intermediates in protofibril assembly by fluorescence photobleaching recovery (FPR) and AU and determination of molecularity of these early intermediates. Early aggregates can be dissociated in the presence of p-strand mimics. (4) Initiation of fibrillogenesis on hydrophobic and hydrophilic surfaces. Formation of protofibrils and fibrils of A-Beta in vivo is the result of interactions between soluble ABeta and various moieties on the surface of neuronal cells and "surface-induced" or nucleated A-Beta polymerization can be stopped or reversed by the presence of B-strand mimics. The potential impact of this work is gaining a better understanding of the etiology of AD and development of pharmaceutical agents for treating AD and other amyloid diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTRABODY THERAPY OF PARKINSON'S DISEASE Principal Investigator & Institution: Messer, Anne; Director/Research Scientist; Wadsworth Center Empire State Plaza Albany, Ny 12237 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2004 Summary: (provided by applicant) This proposal seeks to develop engineered intracellular antibodies (intrabodies) as novel potential clinical reagents and drug discovery tools for the treatment of Parkinson's disease (PD). Intrabodies make use of the specificity of antibodies to form complexes with intracellular proteins, and are already in clinical trials for treatment of cancers and AIDS. Recently, we published the first application of this powerful technology to a neurodegenerative disease, showing that human single-chain Fv intrabodies, selected from a phage display library, can counteract in situ Huntington aggregation in cellular models of Huntington's Disease (HD). By choosing an epitope adjacent to the abnormally folding expanded polyglutamine of the HD protein, we can alter the abnormal protein-protein interactions that characterize the mutant protein. Parkinson's Disease brains show formation of filamentous intracellular inclusions (Lewy bodies) as their most striking pathology. These appear to be composed of abnormally aggregated alpha-synuclein in both sporadic and hereditary forms of the disease. The alpha-synuclein protein data to date suggest several candidate target sequences that might prevent misfolding of synuclein, or be used to clear abnormal material in Parkinson's cells. We propose to select antisynuclein single-chain Fv intrabodies against unique, defined domains and forms of asyn, using human phage display libraries. These will then be tested for their capacity to reverse reported physiological defects in model systems. Models will include several that over-express wild-type alpha-synuclein to mimic sporadic P.D: transient transfections in cell lines and brain slice cultures, moving on to transgenic Drosophila and eventually transgenic mice. All of these studies will take advantage of the technologies and expertise coming out of the HD studies, which are actively and successfully ongoing in the lab. Long-term goals include administering these antibody reagents via gene therapy vectors, or as stable, multi-functional proteins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ION CHANNEL DYSFUNCTION IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Cantrell, Angela R.; Assistant Professor; Anatomy and Neurobiology; University of Tennessee Health Sci Ctr Health Science Center Memphis, Tn 38163 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008

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Summary: (provided by applicant): It has recently been suggested that neuronal degeneration may occur as a secondary phenomenon in response to neuronal dysfunction in HD. In support of this idea, recent reports have indicated that electrophysiological abnormalities occur in the brains of HD transgenic animals. These abnormalities include altered somatic discharge, broadening of the excitatory postsynaptic potential and failure to induce long term potentiation following high frequency stimulation. These abnormalities precede neurobehavioral and neuropathological alterations suggesting to some researchers that cytoplasmic functions including neurotransmitter regulation of ion channels and regulation of intracellular Ca2+ may play a role in this disease. If this is in fact the case, then understanding neuronal dysfunction in HD may be critical to the development of rational treatment strategies and early intervention programs. An extrinisic mechanism such as glutamate excitotoxicity has been proposed to account for the ultimate degeneration of medium spiny neostriatal neurons, therefore, we hypothesized that changes in the membrane properties of the cortical projection neurons which provide input to the medium spiny neostriatal neurons might be important in HD. This idea, while intriguing, has not been fully investigated using the newly available animal models of HD. We present preliminary data to support this idea and demonstrate that electrophysiological abnormalities occur in the presynaptic corticostriatal projection neurons in HD transgenic mice. Since the electrical activity of a neuron is regulated by its own intrinsic cytoplasmic properties as well as its synaptic inputs, it will be important to conduct a thorough study of these alterations in the electrophysiological properties of the presynaptic cortical projection neurons in HD. These electrophysiological abnormalities in corticostriatal projection neurons may contribute to neuronal dysfunction and the subsequent neuropathology observed in HD. This hypothesis will be tested in acutely isolated, identified cortical projection neurons obtained from HD mouse models in which expression of mutant huntingtin has been induced. Techniques employed include patch-clamp recording methods, single-cell RT-PCR and immunohistochemistry. This proposal has 3 Specific Aims: 1) To define the physiological properties of pharmacologically isolated HVA Ca2+ channels, voltage-gated Na+ channels and voltage-gated K+ channels in acutely isolated corticostriatal projection neurons from HD transgenic mouse models. 2) To determine the molecular mechanisms underlying the observed increase in HVA Ca2+ channel activity in corticostriatal neurons from R6/2 transgenic mice. 3) To expand our studies to include other classes of cortical projection neurons. These studies will provide valuable information for the elucidation and treatment of a variety of motor deficits and neurodegeneration observed in HD and a host of other neurological disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LONGITUDINAL STUDIES AMONG AT-RISK HD GENE CARRIERS Principal Investigator & Institution: Foroud, Tatiana M.; Associate Professor; Molecular and Medical Genetics; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant) To identify and quantify changes among presymptomatic Huntington disease gene carriers who had not yet developed definite chorea, we performed the largest, study of individuals at-risk for HD (n=657) Subtle abnormalities in oculomotor, extrapyramidal and pyramidal motor, and cognitive measures were identified. We propose to reexamine this unique sample of at-risk individuals using an expanded test battery that includes more sensitive and specific

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quantitative measures for each subset of variables for which significant differences between presymptomatic gene carriers and nongene carriers were initially observed. These new measures increase the power of our proposed longitudinal studies of the rate of change among presymptomatic gene carriers as they approach the manifestation of clinically diagnosable HD. These novel studies are designed to: 1) Further delineate the deficits observed in the subclinical and early symptomatic phase of disease; 2) measure the rate of increasing abnormality among presymptomatic gene carriers; 3) investigate the interrelationships among the variables so as to identify measures with similar rates of deterioration, which might suggest common pathways affected early in the disease process; 4) quantify the relationship of CAG repeat number with disease onset and progression. The results of these studies will improve the understanding of the presymptomatic and early symptomatic phase of HD allowing for earlier diagnosis and identify subclinical biomarkers that can be utilized in clinical trials to evaluate therapeutic agents designed to slow progression and delay the onset of clinical HD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF ATAXIN-1 MEDIATED PURKINJE CELL DEATH Principal Investigator & Institution: Vig, Parminder J.; Neurology; University of Mississippi Medical Center 2500 N State St Jackson, Ms 39216 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2007 Summary: (provided by applicant): Spinocerebellar ataxia-1 (SCA-1) belongs to a group of dominantly inherited neurodegenerative diseases caused by a mutant expansion of a polyglutamine-repeated sequence within the affected gene product ataxin-1. One of the major cell types affected by ataxin-1 is the cerebellar Purkinje cell. The mechanism by which ataxin-1 causes Purkinje cell degeneration in SCA-1 is not known, however, ataxin-1 down regulates Purkinje cell specific proteins involved in calcium homeostasis and signaling in patients with SCA-1, and in presymptomatic SCA-1 transgenic mice. Therefore, the present proposal is designed to determine if targeted deprivation of one of the specific proteins involved in calcium homeostasis will further enhance ataxin-1 toxicity and if trophic upregulation of this protein will rescue SCA-1 Purkinje cells from degeneration. The long-term goal of this project is to understand the role of calcium signaling pathways in neuronal degeneration in order to design therapeutic approaches in clinical management of SCA-1 and other dominantly inherited cerebellar ataxias. To determine if decreased expression of calcium binding protein calbindin-D 28k (CAB) will increase the toxic effects of ataxin-1 on Purkinje cells, double mutant mice will be generated by mating CaB null mice with SCA-1 transgenic mice. To determine if overexpression of insulin-like growth factor - I (IGF-I) will rescue SCA-1 Purkinje cells from degeneration, double mutant mice will be generated by mating mice overexpressing IGF-I with SCA-1 transgenic mice. The changes in Purkinje cells will be assessed by behavioral, biochemical, immunochemical and immunohistochemical methods, focusing on the alterations in the expression of Purkinje cell markers, calcium binding proteins, and proteins involved in calcium signaling. Purkinje cells cultured from 0-1 day old SCA-1 transgenic mice will be used to determine if cultured Purkinje cells expressing mutant ataxin-1 show (i) altered expression of calcium binding proteins and proteins involved in calcium signaling (ii) sensitivity to increased Ca 2+-influx (iii) altered response to the inhibitors of calcium-dependent proteases and (iv) if treatment with IGF-I can reverse ataxin-1 mediated pathological changes. Purkinje cell cultures from non-transgenic mice will be used as controls. Complementary analysis to compare changes in cultured Purkinje cells with those cultured from CaB null and transgenics with Huntington's disease will also be performed. Further, changes observed in SCA-1

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patients and in transgenic mice will be compared with that in Machado-Joseph disease/SCA-3, other cerebellar ataxias and normal controls. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF GENE DYSREGULATION IN HD Principal Investigator & Institution: Olson, James M.; Assistant Professor; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2001; Project Start 15-AUG-2001; Project End 31-JUL-2005 Summary: (Adapted from applicant's abstract): Several lines of evidence suggest that mutant huntingtin affects gene transcription by sequestering transcription activating and repressing proteins. This does not explain the gene expression changes that occur before mutant huntingtin is detectable in the nucleus, nor does it account for transcription changes caused by abnormal signaling from damaged afferent neurons. The overall aim of this application is to test the hypothesis that the earliest gene expression changes in Huntington's disease (HD) reflect a response of the neuron to misfolded huntingtin protein and to abnormal signaling between afferent and target neurons. To accomplish this the investigator proposes two Specific Aims 1) use mice and cell culture models that express mutant huntingtin protein in eitherthe nucleus orthe cytoplasm to determine how cells transcriptionally respond to each and 2) use mice that express mutant huntingtin protein in eitherafferent neurons ortarget neurons to determine transcriptional responses in neurons. The transcriptional responses will be correlated with pathogenic changes that occur in response to the transgenes. This will generate information and tools needed to further model and test early processes in Huntington's disease. Our long-term goal is to identify early pathogenic events in Huntington's disease in order to provide rational targets for the development of prophylactic drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF LONG-TERM DEPRESSION IN THE STRIATUM Principal Investigator & Institution: Kreitzer, Anatol C.; Psychiatry and Behavioral Sci; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2006 Summary: (provided by applicant): Long-term changes in synaptic strength are thought to represent a cellular correlate of learning and memory. In the hippocampus, long-term potentiation (LTP) and long-term depression (LTD) have been studied extensively, and a number of different mechanisms have been elucidated, some of which coexist at the same synapses. In the striatum, changes in synaptic function are thought to correlate with behaviors such as habit formation, as well as with pathologies such as Parkinson's and Huntington's disease and drug addiction. However, the mechanisms, or even the types of plasticities present at these synapses, have not been fully described. The goal of this research proposal is to examine LTD in both the dorsal striatum and its ventral extension, the nucleus accumbens. A number of studies have found various and conflicting results regarding LTD in these areas. To examine the types of LTD present at synapses in both dorsal striatum and nucleus accumbens, various induction protocols and experimental paradigms will be tested. Specific mechanisms of LTD induction and expression will then be studied using electrophysioiogical recordings combined with molecular techniques such as viral-mediated gene transfer. These studies will provide a framework for understanding how long-term changes in synaptic strength in the striatum are related to such health issues as addiction and neurodegenerative disease.

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

Project Title: MECHANISMS OF MOTOR LEARNING IN NEUROLOGICAL DISEASE Principal Investigator & Institution: Krakauer, John W.; Assistant Professor; Neurology; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: The proposed award is designed to develop the candidate's clinical research skills to prepare him for a career as an independent investigator in the application of motor psychophysics and functional brain imaging to the study of neurological disease. Research Plan: Stroke, Huntington's disease (HD), and Idiopathic Torsion Dystonia (ITD) are diseases that rob people of motor function in the prime of life. Many of the measures of motor performance and functional status commonly used in clinical trials and rehabilitation suffer from subjectivity and lack of scientific validation. The first goal of the proposed study is to characterize and quantify the motor deficit in these diseases using methods previously developed in the study of arm movements in normal subjects. In particular, we will emphasize the importance of examining motor learning abnormalities because we hypothesize that these will give a direct measure of a patient's capacity to compensate or recover from neurological disease. The second goal is to correlate psychophysical parameters of motor performance and motor learning to the degree of expression of brain networks as revealed by functional imaging. This will provide considerable insight into the brain mechanisms underlying abnormalities in motor control. HD and ITD each have an established genetic basis allowing asymptomatic carriers to be identified. Our preliminary studies indicate that these subjects have psychophysical and network abnormalities even though more conventional assessments fail to find any evidence of neurological disturbance. If we confirm and extend these observations, then we will have the tools to follow therapeutic intervention at the earliest stages of disease. In the long term, we hope that our work will lead to the development of a battery of motor tasks that, in conjunction with functional imaging, will be applicable to any neurological disease. This battery will quantify motor deficits; allow monitoring of therapy; provide insight into brain mechanisms: and may serve a rehabilitative function. Educational Plan: By completing this project, I will accomplish six main educational objectives: (1) The design and application of motor psychophysics to neurological disease; (2) Learning PET imaging techniques; (3) The development of skills in brain network analysis and modeling; (4) Learning advanced statistical methods; (5) Learning the principles of functional magnetic resonance imaging; (5) Learning to conduct ethical scientific research, collaborate with colleagues, and produce high quality presentations and publications; and (6) Learning to place experimental findings within their clinical context, and relate them to clinical assessments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: METABOTROPIC NEURODEGENERATION

GLUTAMATE

RECEPTORS

IN

Principal Investigator & Institution: Young, Anne B.; Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 15-AUG-1995; Project End 31-JUL-2005 Summary: Description (From the applicant's abstract): Human neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's

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disease (HD) and amyotrophic lateral sclerosis (ALS) are characterized by adult onset, progressive neurologic dysfunction, and a paucity of effective therapies. These common disorders produce substantial disability, and their importance to public health is expected to increase as the population ages. One or more causative genes have now been isolated for familial forms of each of these four devastating neurologic illnesses, making possible the development of transgenic mouse models. Although such animals now exist, the exact mechanisms by which mutant genes cause neurologic disease remains unclear. Unless the etiologic mechanisms underlying the neurodegenerative diseases are clearly identified, rational therapeutic interventions will be impossible. The neurotransmitter glutamate has been implicated as a causative factor in the etiology of neurodegenerative disorders. Specifically, one class of glutamate receptors, the metabotropic glutamate receptors (mGluRs), may be specifically abnormal in many of the neurodegenerative disorders. This project will examine metabotropic glutamate receptors in transgenic mouse models of AD, PD, HD, and ALS using ligand binding, in situ hybridization, immunohistochemistry, and Western blotting. Alteration of mGluR expression level is also predicted to have direct implications for the abnormal synaptic functioning which is characteristic of neurodegenerative diseases. Thus, we will also explore glutamate-related intracellular signaling pathways in the brains of transgenic mice. Finally, if mGluR dysfunction is an important part of disease etiology, drugs targeting mGluRs may ameliorate symptoms in certain of these models. We will test if administration of mGluR-active medications improves clinical outcome in mouse models of these diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MODULATION OF CASPASE PATHWAYS IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Friedlander, Robert M.; Associate Director; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-JAN-2000; Project End 31-DEC-2004 Summary: The interleukin-1beta converting enzyme (caspase-1 or caspase-1) cell death gene family, also known as the caspase family, plays an important role in apoptosis. Evidence indicates that caspase- 1 is involved in mediating brain damange in ischemia, trauma, and in amyotrophic lateral sclerosis. We have evidence implicating caspase-1 as an important mediator of cell dysfunction and disease progression in Huntington s disease (HD). The broad objective of this project is to evaluate the mechanisms of caspase-1-mediates disease progression in HD. Preliminary results indicate that caspase1 is activated in human and mouse HD brain specimens. In addition, inhibiting caspase function slows the progression and delays the mortality in a mouse model of HD. The specific aims are: 1) evaluate the expression and activation status of different members of the caspase family in human and mouse HD brain specimens, 2) evaluate the role of mature IL-1beta, a product of caspase-1 activation, in the pathogenesis of HD, 3) determine whether bc1-2 might be a neuroprotector in HD, and whether its effects might be synergistic with caspase-1 inhibition, 4) evaluate pharmacological approaches to slow the progression of HD, and 5) evaluate the mechanism of inhibition of weight loss in HD mice by caspase-1 inhibition, 6) evaluate the impact of HD on neural stem cell proliferation and differentiation. Significance: To elucidate the mechanistic pathways by which caspase-1 mediates disease progression and death in HD. Since caspase-1-mediated cell death is a common pathway shared by a variety of neurological disorders, understanding the mechanistic pathways mediating neurodegeneration in

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HD should provide important information for the development of treatments for diseases sharing this cell death pathway. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR GENETIC APPROACHES TO LEARNING AND MEMORY Principal Investigator & Institution: Tonegawa, Susumu; None; Massachusetts Institute of Technology Cambridge, Ma 02139 Timing: Fiscal Year 2001; Project Start 06-SEP-1994; Project End 31-MAR-2006 Summary: (provided by applicant): The long-term objectives of this competing renewal are to apply conditional gene manipulation techniques developed for mice to the analyses of molecular, cellular, and neuronal ensemble mechanisms underlying hippocampus-dependent learning and memory. Using the molecular genetic methods developed in this laboratory, mouse strains will be generated in which the gene encoding the a isoform of Ca2+/calmodulin-dependent protein kinase-II (CaMKII), or the g or B isoform of protein kinase C (PKC) is deleted (knocked out) specifically and separately in CAl or CA3 pyramidal cells of the hippocampus. Several transgenic mice will be generated in which the CaMKII inhibitor protein (CaMKII-IN) is overexpressed specifically in CAl or CA3 pyramidal cells, or a dominant negative form of Ca2+/calmodulin-dependent protein kinase-IV (dnCaMKIV) is overexpressed in the forebrain. The issue of whether expression of long term potentiation (LTP) at Schaffer collateral CAl synapses is based on a pre- or postsynaptic mechanism will be examined by subjecting the CAl- or CA3- specific CaMKII knockout, PKC knockout and CaMKIIIN transgenic mice to electrophysiological analysis of brain slices. This study will also examine whether LTP underlies learning and memory by analyzing the CAl-specific alphaCaMKII knockout, CAl-specific CaMKII-IN transgenic, and the forebrain-specific CaMKIV transgenic mice with electrophysiological and behavioral methods. Furthermore, the role of CaMKIV in different phases of the mnemonic process, namely acquisition, consolidation, and retrieval of memory, will be assessed by analyzing dnCaMKIV transgenic mice in which the level of expression of dnCaMKIV can be reversibly controlled. It is proposed to identify and characterize genes that are activated in the CAl region upon the formation of a long term memory by combining mouse genetics technology developed in this laboratory with DNA chip and DNA microarray technologies. Finally, it is proposed to study roles of CA3 NMDA receptors and the CA3 recurrent network in learning and memory, and in the formation of memory representation in the hippocampus by creating CA3-specific NMDA receptor knockout mice and subjecting them to a variety of memory tasks and to in vivo multielectrode recordings, respectively. The knowledge gained from these studies will constitute the basis for developing diagnostic and therapeutic methods for neurodegenerative diseases such as Alzheimer's disease and Huntington's disease as well as for the development of learning enhancement methods. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR MECHANISMS OF AXONAL TRANSPORT Principal Investigator & Institution: Brady, Scott T.; Professor and Head; Cell Biology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2001; Project Start 01-JUL-1986; Project End 31-AUG-2005 Summary: (From the Applicant's Abstract): Understanding axonal transport processes is a key to understanding the dynamics of the nervous system, because they underlie

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neuronal growth, maintenance and regeneration. As a result, elucidation of molecular mechanisms for fast axonal transport can provide essential insights into the function and pathology of the nervous system. Functions as diverse as conduction of the action potential, release of neurotransmitter, creating and sustaining the presynaptic terminal, neuronal development and regeneration, and maintenance of neuronal architecture depend critically on fast axonal transport of membrane bounded organelles (MBOs) along microtubules. Similarly, disruption of fast axonal transport has been implicated in pathogenesis for a wide range of neuropathological conditions, including diabetic and toxic neuropathies, motor neuron disease (ALS and others) and degenerative diseases of the nervous system (Huntington's disease and others). Our original studies of fast axonal transport in isolated axoplasm from the squid giant axon led to discovery of a new family of mechanochemical ATPases: the kinesins. Kinesins are motors for movement of membrane bounded organelles in the anterograde direction of fast axonal transport. Previous work supported by this application answered many questions about the biochemistry and molecular biology, cell biology, and neurobiology of kinesin. Future experiments will extend our current studies on molecular mechanisms of fast axonal transport in three areas. First, we propose that physiological properties of different kinesins are determined by variation within specific functional domains among kinesin isoforms of the neuron. Studies proposed in this application combine methods from biophysics, cell biology, and molecular biology to delineate the functional architecture of neuronal kinesins and determine physiological functions for each domain. Second, specificity of kinesin interactions with different organelles suggest that kinesin isoforms are uniquely targeted to specific classes of MBOs through a combination of specific membrane receptors and general kinesin interacting proteins. Proposed experiments will identify kinesin receptors and interacting proteins in nervous tissues. Finally, kinesins are subject to posttranslational modifications in neurons that vary among the different isoforms. We propose that posttranslational modifications of kinesin serve to regulate kinesin function in neurons. Pathways associated with these modifications may control kinesin interactions with specific classes of MBOs as well as kinesin-mediated motility and ATPase activity. Planned experiments will determine the functional significance of posttranslational modifications on kinesin heavy and light chains, as well as defining relevant regulatory pathways. The proposed studies will help us understand the role of the kinesins in both normal neuronal function and neuropathology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOTOR LEARNING AND MEMORY IN HEALTH AND DISEASE Principal Investigator & Institution: Shadmehr, Reza; Biomedical Engineering; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-APR-1999; Project End 31-MAR-2007 Summary: (provided by applicant): When one moves their hand from one point to another, the brain guides the arm by relying on neural structures that estimate physical dynamics of the task and transform the desired motion into motor commands. If our hand is holding an object, the subtle changes in the dynamics of the arm are taken into account by these neural structures and this is reflected in the altered motor commands. These observations have suggested that in generating motor commands, the brain strongly relies on internal models that predict physical dynamics of the external world. The internal models are learned with practice, and appear to be a fundamental part of voluntary motor control. However, we know very little about which neural structures in the brain are involved in formation of internal models for motor control and how they

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learn to represent these models. Our aim here is to combine behavioral and mathematical tools to infer how humans learn internal models, and how the process is affected when there is damage to specific motor structures in the brain. We approach the problem by considering a task where physical dynamics of reaching movements are altered. As people practice the task, we ask how did an error that was experienced in a given movement affect subsequent movements? We arrive at a generalization function that mathematically describes how the brain changes the internal model in response to an error. The shape of the generalization function predicts the receptive field of the elements that took part in representing the internal model with respect to movement kinematics. We study these generalization functions in position, velocity, and acceleration space of the arm. Preliminary results demonstrate a remarkable similarity between these behaviorally inferred bases and typical tuning properties of cells in the primary motor cortex. This suggests that tuning properties of these cells might be reflected in human behavior in the way that we learn and generalize patterns of force. We extend the studies to include generalization from one arm to the other. We further extend the studies to movements where dynamics are not dependent only on arm kinematics, but also on other cues: external cues where dynamics are linked to an arbitrary spatial or color cue, internal cues where dynamics depends on position of a movement with in a sequence. We compare how damage to the brain in Huntington's disease vs. cerebellar disease affects this learning. However, motor memories are not static. Their functional properties change within hours after a task is learned. We ask how this change affects the generalization function. Is the brain different in the way it responds to an error after a memory has consolidated vs. early in the learning phase? Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MTDNA DAMAGE AND APOPTOSIS IN NEURODEGENERATION Principal Investigator & Institution: Ayala-Torres, Sylvette; Universidad Central Del Caribe Bayamon, Pr 009606032 Timing: Fiscal Year 2002; Project Start 01-AUG-1994; Project End 31-DEC-2005 Summary: Many forms of neurodegeneration are associated with oxidative stress. Although the molecular mechanisms of neurodegeneration remain unknown, it has been proposed that the symptoms associated with several late-onset neurodegenerative diseases are the result of mitochondrial dysfunction and increased production of mitochondrial- generated reactive oxygen species (ROS). Preliminary studies using quantitative polymerase chain reaction show an age-associated increase in basal levels of mouse brain mitochondrial DNA (mrDNA) damage. We hypothesize that oxidative damage to mtDNA leads to a decline in mitochondrial function with concomitant increase in mitochondrial- generated ROS. The hypothesis predicts that impairment of mitochondrial function due to oxidative mtDNA damage can lead to neuronal apoptosis. Increasing evidence implicates apoptosis as a major mechanism of cell death in neurodegeneration is yet not known. This project will explore the molecular mechanisms of neuronal cell death by using the 3-nitropropionic acid (3-NPA) animal model of Huntington's disease. Recent evidence has suggested that 3-NPA, a mitochondrial neurotoxin, can lead to striatal apoptosis and neurodegeneration. is caused by an accumulation of mtDNA damage induced by oxidative stress. To test this hypothesis this application proposes: 1) to examine the association between mtDNA damage and apoptosis in mouse brain exposed to 3-NPA; 3) to examine the association between mitochondrial dysfunction and oxidative stress exposed to 3-NPA; 3) to determine the association between mtDNA damage, ROS production, and apoptosis in mouse striatum exposed to 3-NPA; and 4) to analyze the effect of inhibitors of caspases

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in mouse striatum on mtDNA damage, generation of mitochondrial ROS, and apoptosis after treatment with 3-NPA. This study will lead to a better understanding of the role of oxidative stress and mitochondria in apoptosis associated with neurodegeneration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MTOR ACTIVATION AND FUNCTION DURING CNTF SIGNALING Principal Investigator & Institution: Reeves, Steven A.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114

Assistant

Professor;

Timing: Fiscal Year 2003; Project Start 24-JUL-1998; Project End 31-JAN-2008 Summary: (provided by applicant): Signal transduction initiated by the neuroregulatory cytokine ciliary neurotrophic factor (CNTF) has been shown to promote neuronal survival in the injured or diseased nervous system. These findings have provided a basis for using CNTF as a therapeutic agent aimed at the treatment or prevention of a variety of neuropathological diseases, including amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, stroke, and several forms of cerebellar ataxias. The precise manner in which CNTF activates and coordinately regulates the signaling cascades it employs for its neuroprotective effects remains largely undefined. One important component in this cascade that we have recently identified is the mammalian target of rapamycin (mTOR). The TOR proteins have been shown to be key regulators of a diverse set of cell processes, and recent reports have indicated that mTOR may play a critical role in synaptic plasticity and memory. We hypothesize that mTOR is a critical link in one or more of the CNTF signal transduction pathways. Thus the research we are proposing in this application aims to determine the mechanism by which CNTF activates mTOR and to identify the role(s) that mTOR plays in CNTF-stimulated sympathetic neurons. This work could identify novel targets for therapies aimed at the treatment or prevention of a variety of central nervous system disorders as well as provide a sound scientific foundation for the clinical use of CNTF and CNTF analogues now being tested in clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NANOSCALE IRON PHASES IN NEURODEGENERATIVE DISEASES Principal Investigator & Institution: Dobson, Jon P.; Keele University Keele St5 5Bg, England Keele, Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2006 Summary: (provided by applicant): AIMS:. To develop multi-modal imaging methods for high-resolution mapping of iron in neurodegenerative brain tissue. To examine the magnetic properties of neurodegenerative tissue for the possible presence of anomalous magnetic iron oxides. To examine the effects of biogenic, magnetic iron biominerals (primarily magnetite) on amyloid-beta aggregation in vitro. Research Design & Methods: The primary method for mapping iron distribution in tissue sections is via synchrotron x-ray scanning which will be conducted at Argonne National Laboratory. This technique will be used to identify iron anomalies eventually on a cellular level. And to compose composit images using a variety of imaing techniques. This work will enable correlation of iron anomalies and structural form to specific cellular and tissue structures for the first time. Examination of the magnetic properties of neurodegenerative tissue will be carried out pdmarily using Superconducting Quantum Interference Device (SQUID) magnetometry and Magnetic Force Microscopy (MFM). Using these methods the magnetic iron biominerals in the tissue will be characterized and compared to published data on non-pathologic and epileptic tissue samples. This

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will provide information on the relative abundance and type of magnetic iron biomineral present in the tissue and will help to either confirm or refute preliminary studies of nanoscale magnetic iron biominerals in Alzheimer's disease (AD) tissue. The effects of strong, local magnetic fields generated by nanoscale magnetic iron biominerals on amyloid-beta peptide aggregation rates will be examined using thioflavin-T assay and TEM imaging of peptide aggregates. Aggregation rates will be assessed in control solutions, solutions of peptide with coated magnetic nanoparticles and sham solutions containing the same concentrations of non-magnetic nanoparticles with the same size distribution and surface chemistry. Gla: FOREIGN GRANT: As the PI is a US citizen based at Keele University in the United Kingdom, the project will be administered through a foreign institution - Keele. The PI has considerable and unique experience in the analysis of magnetic iron biominerals in the brain (he has led all of the previous work described in this proposal) and is one of the few people in the wodd working in this field. The proposed project is highly interdisciplinary, incorporating aspects of biophysics, chemistry, neurobiology and biomedical engineering. The PI has a uniquely diverse background related to the proposed research, having worked in physics, chemistry and biomedical engineering departments and the UF Brain Institute since obtaining his PhD in 1991. He has published extensively in nanoscale magnetic iron biomineralization in the brain and his work has been featured by the media in such journals as Science,The Economist, Fact/Switzerland, The Los Angeles Times/Washington Post wire service as well as newspaper, radio and television coverage in six countries. The Pl's combination of skills and experience related to the research proposed here is unique and unavailable in the US. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEURAL BASIS OF INSTRUMENTAL ACTION Principal Investigator & Institution: Balleine, Bernard W.; Assistant Professor; Psychology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 15-JAN-1997; Project End 31-DEC-2002 Summary: (Adapted from applicant's abstract): The organization of goal-directed action is influenced significantly by the agent's ability to inhibit or gate responses to sensory, motor and cognitive information. Deficits in these central inhibitory mechanisms are manifest in a number of neuropsychiatric syndromes characterized by disorders of 'voluntary' movement, e.g., Parkinson's disease, and intrusive involuntary movement, e.g., Tourette's syndrome and Huntington's disease. These cases make it clear that the capacity for goal-directed action is highly adaptive, indeed it is this capacity that allows us and other animals to control the environment in the service of our needs and desires. Nevertheless, although research into the physiological systems that subserve learning processes in humans and other animals has been of ongoing concern to the neuroscience research community, the neural basis of instrumental action is very poorly understood. The broad, long term objective of the current project is, therefore, to understand the neural mechanisms that control the learning and performance of goal directed or instrumental actions. Over the last decade striking advances have been achieved in the PI's understanding of the behavioral determinants of instrumental conditioning in animals. Specifically, instrumental performance has been found to reflect the integration of (I) representations of the relations between an action and its consequences; with (ii) representations of the incentive value of those consequences. Elegant but powerful behavioral procedures will be used to focus on the role of cortico-striatal interactions and feedback to cortex via pallidal and limbic structures on processes involved in the

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representation of the relation between an action and its consequences. In other experiments, the role of parallel interactions between insular cortex and basal forebrain structures in the representation of the incentive or 'goal' value of the instrumental outcome will be assessed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROBIOLOGICAL PREDICTORS OF HUNTINGTON'S DISEASE Principal Investigator & Institution: Paulsen, Jane S.; Professor; Psychiatry; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2004 Summary: The proposal is a longitudinal study of potential neurobiological and neurobehavioral markers of disease onset and progression in pre-symptomatic individuals who have the CAG expansion in the HD gene. A total of 500 subjects will be enrolled. Study subjects will be 30 to 55 years old and have a parental history of Huntington's disease. The study will enroll 425 cases with >39 CAG repeats (affected), and 75 controls with <30 CAG repeats (wildtype). The patients will be recruited from 20 research sites in the United States and Canada. Subjects will be evaluated every 12 months for up to 5 years. At baseline, blood will be drawn for centralized confirmatory gene testing. At every visit, subjects will undergo standardized assessments of motor, cognitive, functional, and psychiatric signs of HD using the Unified Huntington's Disease Rating Scale (UHDRS). More comprehensive evaluations will be done at baseline, and 24 and 48 months of follow-up. These more comprehensive evaluations will include a videotaped examination, volumetric magnetic resonance imaging, detailed neuropsychometric testing and behavioral ratings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEURODEGENERATION AND POLYGLUTAMINE TOXICITY DRPLA Principal Investigator & Institution: Ross, Christopher A.; Professor; Psychiatry and Behavioral Scis; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-MAY-1995; Project End 31-MAY-2008 Summary: (provided by applicant): DentatoRubral and PallidoLuysian Atrophy (DRPLA) is a progressive neurodegenerative disease caused by a polyglutamine expansion in atrophin-1. The clinical features and areas of the brain affected resemble the more common Huntington's disease (HD), and we study the two diseases in parallel, since changes observed in both may represent common pathogenic features for all of the polyglutamine neurodegenerative diseases. In the previous grant period we generated a transgenic mouse model of DRPLA, and gathered some preliminary evidence suggesting the hypotheses that atrophin-1 undergoes proteolytic cleavage and nuclear translocation, resulting in gene transcription changes, as part of the pathogenesis of DRPLA. We gathered cell culture data to suggest that atrophin-1 has nuclear localization and export signals and that these are involved in toxicity. We now propose to conduct mechanistic in vivo experiments to test these ideas. In Specific Aim 1, we will generate transgenic mice expressing mutant full-length atrophin-1 with the putative nuclear localization signal altered, in order to determine whether nuclear localization contributes to pathogenesis in vivo. In Specific Aim 2, we will generate transgenic mice expressing mutant full-length atrophin-1 with the putative nuclear export signal altered, in order to determine whether nuclear localization contributes to pathogenesis in vivo. In Specific Aim 3, we will establish the site of cleavage of atrophin-

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1 with our collaborators at the Buck Institute, and generate mice transgenic for a construct expressing full-length atrophin-1 with this site altered. We will cross our atrophin-1 transgenic mice with mice hemizygous for a targeted deletion in the CBP gene in order to test the hypothesis that transcriptional misregulation contributes to pathogenesis in vivo. We predict that these experiments taken together will confirm roles in vivo for proteolytic cleavage, and nuclear localization, and support a role for alterations in gene transcription as critical for pathogenesis in DRPLA, and supporting the idea that these are general features of polyglutamine pathogenesis. Proteolytic cleavage would be an especially good target for therapeutic interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROIMAGING OF HYPERKINETIC MOVEMENT DISORDERS Principal Investigator & Institution: Hutchinson, Michael; Neurology; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2001; Project Start 13-AUG-1997; Project End 31-JUL-2003 Summary: Despite recent progress, there is still uncertainty about the pathophysiology of movement disorders in man. However there is an awareness that neurologic disease affects motor and cognitive processes by altering neural networks in functionally specific ways. Recently, covariance analysis has been applied to the analysis of Positron Emission Tomography (PET) images of brain glucose metabolism, and has identified some of the underlying abnormal circuitry in idiopathic torsion dystonia and Parkinson's disease. Yet there studies require fairly large numbers of patients and normal controls. Furthermore they do not definitively identify the primary locus of metabolic abnormality, since the abnormal profiles may be an epiphenomenon reflecting maintenance of the dystonic posture. A way of increasing sensitivity is to use the fact that in most movement disorders the abnormal movements disappear in sleep. Sleep is therefore a useful internal reference state uncontaminated by movement. Brain regions showing focal differences between wake and sleep are therefore associated with the anatomic substrate of the disorder. This approach has been validated in a study of craniocervical dystonia (Meige syndrome). Yet is does not reveal the functional interactions of these brain regions. It is therefore proposed to combine the two approaches, in order to obtain a sensitive measure of the underlying neural circuitry. Four hyperkinetic disorders will be studied using regional measures of cerebral glucose metabolism and blood flow: blepharospasm, idiopathic torsion dystonia, Huntington's chorea and levodopa-induced dyskinesia. In addition, covariance analysis of sleeping patients and sleeping normals is expected, finally, to reveal the primary metabolic substrate. Validation of this approach will mediate between existing theories of corticalsubcortical interactions, and may suggest possible surgical or pharmacological intervention in these disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEUROPATHOLOGY AND PATHOGENESIS OF HUNTINGTON' DISEASE Principal Investigator & Institution: Reiner, Anton J.; Professor; Anatomy and Neurobiology; University of Tennessee Health Sci Ctr Health Science Center Memphis, Tn 38163 Timing: Fiscal Year 2001; Project Start 15-JUL-1990; Project End 31-MAR-2005 Summary: (Verbatim from the Applicant's Abstract) This is a competing continuation of NS 28721. In this upcoming 5-year project, the applicant will examine the hypothesis

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that Huntington's disease (HD) is caused by AMPA receptor (AMPAR)-mediated excitotoxicity. He proposes that the HD gene defect leads to selective striatal neuronal death by 1) enrichment in AMPARs and cortical inputs in striatal projection neurons and parvalbuminergic interneurons in HD. 2) A preponderance of GluR2 containing AMPARs in striatal neurons projecting to the internal pallidal segment accounts for their lesser vulnerability in HD and 3) The HD mutation decreases the numbers of group II mGluRs on corticostriatal terminals, thereby increasing cortical activation and excitotoxicity of striatal neurons. The main hypotheses are based on the following observations: a. The HD gene product is widely expressed in the brain, whereas the neurons killed in HD are localized to the striatum b. No cell-type specific proteins that interact with HD proteins are specific to vulnerable striatal neurons. c. The level of huntingtin in a given type of striatal neuron does not seem to correlate with vulnerability. d. There is suggestion that in HD transgenic mice (Bates R6/2), group II mGluRs are downregulated and that sEPSP frequency is increased. e. HD pathology can be reproduced by 3-NP and by quinolinic acid administration f. Neurons that die are rich in cortical input. g. Neurons that die are rich in AMPARs, some of which appear to be more deficient in GluR2 (the GluR2 hypothesis). From these observations, the applicant concludes "the HD mutation may render corticostriatal neurons destructive rather than render striatal neurons vulnerable." These hypotheses will be tested in 5 Specific Aims: Aim 1: Use single cell RT-PCR, immunoprecipitation and LM and EM immunolabeling to characterize the abundance and subunit composition of AMPA receptors present on HD-vulnerable and HD-resistant striatal interneuron and projection neuron types in rats. Aim 2: Characterize differences between striatal interneurons and projection neurons in AMPAR mediated synaptic responses to cortical input and in subunit dependent AMPA physiology (Ca permeability, rectification and desensitization) in rats Aim 3: Pharmacologically characterize the role of AMPARs and mGluR2/3-regulatable corticostriatal glutamate release in the selective death of striatal neurons in rats chronically administered 3NP, a model of HD. Aim 4: Use in-situ hybridization histochemistry, LM and EM immuno to determine in striatal neurons in monkey and in HD striatum whether the distribution of AMPAR subunits in HD vulnerable and HD resistant striatal neurons is consistent with their hypothesized role in selective neurodegeneration. Aim 5: Use in-situ hybridization histochemistry, LM and EM immuno to determine in a transgenic rat model of HD and in human HD specimens whether or not the HD mutation decreases mGluR2/3 in corticostriatal neurons and their intrastriatal terminals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROSCIENCE EDUCATION--TEACHING BRAIN ATLAS Principal Investigator & Institution: Anderson, William J.; Professor; Arizona Institute for Bio-Medical Res Bio-Medical Research Scottsdale, Az 85260 Timing: Fiscal Year 2001; Project Start 01-JUN-1999; Project End 31-JAN-2003 Summary: (Verbatim from the Applicant's Abstract) Neuroscience is a compelling area of science that not only touches upon a diverse array of disciplines, but also provides insights to the essence of what it is to be human. We propose to develop and create a multimedia CD-ROM aimed at teaching neuroscience (particularly Neuroanatomy) to college level students. This CD-ROM would be useful in disseminating this information and insights to this audience in a manner that is both engaging and educational. We will deliver this information in a computer-based, multimedia format series of electronic lessons that will be mastered onto a user-friendly CD-ROM, and delivered on both major personal computer platforms used in colleges and schools in the United States

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Huntington’s Disease

today: Macintosh and PC. The neuroscience information will be in the form of a selflearning program, such that students will be able to learn at any place and any time. The neuroscience information will reflect on brain disorders and neuropathological correlations of disease. For example, such a CD-ROM will enable the study of neuron perturbations in aging, synaptic degeneration in Huntington's Disease, Parkinson's, schizophrenia and cortical atrophy in AIDS-associated dementia. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEURTURIN DELIVERY FOR HUNTINGTON'S DISEASE Principal Investigator & Institution: Brandon, Eugene P.; Ceregene, Inc. 9381 Judicial Dr, Ste 130 San Diego, Ca 92121 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2004 Summary: (provided by applicant): Huntington's disease (HD) is a severely debilitating heritable neurodegenerative condition for which there currently is no treatment. Because there is a genetic test available for HD, intervention prior to disease onset would be possible if an effective treatment were available. The growth factor neurturin (NTN) has been shown to effectively ameliorate neural degeneration in rodent models of HD when delivered to the brain. However, as a protein growth factor, NTN will not readily access brain targets following systemic administration. Gene transfer using a viral vector is a promising method for delivering growth factors to specific regions of the brain, and the adeno-associated virus (AAV) based vector is in many ways the bestsuited vector for this application. As a first step towards developing AAV-delivered NTN (AAV-NTN) for the treatment of HD, we will test the efficacy of AAV-NTN in two distinct rodent models of HD: the 3-nitroproprionic acid (3NP) lesion in Lewis rats, and N171-82Q transgenic mice. The ability of AAV-NTN to prevent neurodegeneration and motor deficits in 3NP lesioned rats, and reduce accumulation of neuronal intranuclear inclusions, and motor and cognitive deficits in N171-82Q transgenic mice will be assessed. Successful results from these studies will lead to safety studies in rats, safety and efficacy studies in non-human primates, and if indicated, the filing of an IND and clinical trials in HD patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: N-METHYL FIBRILLOGENESIS

AND

OTHER

PEPTIDE

INHIBITORS

OF

Principal Investigator & Institution: Meredith, Stephen C.; Associate Professor; Pathology; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2003; Project Start 15-JAN-2003; Project End 31-DEC-2007 Summary: (provided by applicant): We have synthesized several potent inhibitors of beta-amyloid and other peptide fibrillogenesis containing N-methyl amino acids in alternate positions of sequences homologous to putative aggregation sites. Thus far, we have made inhibitors of beta-amyloid and prion peptide, and have recently synthesized a peptide designed to inhibit aggregation of huntingtin. The overall goal of this research is to understand the forces that promote the binding of these inhibitors to Alzheimer's beta-amyloid and related fibrils, in particular, the relative importance of hydrogen bonds involving the peptide backbone, and side chain interactions, including hydrophobic interactions and hydrogen bonds. Specific aim 1 is to determine the modes of interaction between Abeta(1-40) and inhibitors of Abeta fibrillogenesis. We will determine the site of binding and orientation (parallel or antiparallel) between

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fibrillogenesis inhibitor peptides and Abeta(1-40) using solid state NMR spectroscopy, in particular, heteronuclear 15N-13C-REDOR pulse sequence NMR, with Dr. Robert Tycko of N.I.H. We will also study these peptide interactions and determine the structure of complexes between a fibrillogenesis inhibitor, Abeta(16-20)m and Abeta(140), using solution state NMR and other biophysical approaches. Specific aim 2 is to understand the modes of association of inhibitor peptides with Abeta, and to understand the roles of hydrogen bonds, the hydrophobic effect, and conformational rigidity in these interactions. Specific Aim 3 is to examine the role of amphiphilicity in determining the orientation, parallel or antiparallel of beta-sheet fibrils. We hope, with these to resolve a controversy in the Abeta literature. We hypothesize that whereas nonamphiphilic peptides tend to form fibrils with antiparallel beta-sheets, amphiphilic peptides such as Abeta(1-40) are driven towards forming fibrils with parallel betasheets. This hypothesis will be tested using REDOR and other biophysical techniques on short Abeta peptides known to form antiparallel beta-sheet fibrils. We will test the hypothesis that the addition of fatty acids to render these peptides amphiphilic will reverse their orientation to parallel beta-sheets. Specific aim 4 is to examine the ability of a peptide backbone and side chain methylated polyglutaminyl peptide to inhibit aggregation and disaggregate fibrils of huntingtin, and to examine their mode of interaction with huntingtin peptides in vitro and in vivo. These inhibitor designs may be useful for understanding the forces that promote fibrillogenesis in neuro-degenerative diseases, and in designing novel diagnostic or therapeutic agents for these diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOPHYSIOLOGY OF CHOREA Principal Investigator & Institution: Mink, Jonathan W.; Associate Professor, Chief Child Neurolo; Neurology; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2001; Project Start 19-JUN-2000; Project End 31-MAY-2003 Summary: Chorea is a movement disorder that results from basal ganglia injury due to a variety of causes in children. Chorea is characterized by sudden, brief, involuntary muscle contractions causing movements that appear to flow from body part to body part in an unpredictable manner. Disorders associated with chorea include CNS infections, post-infectious and other autoimmune diseases, ischemia during cardiopulmonary bypass, 'extrapyramidal' cerebral palsy, a variety of toxic and acute metabolic processes, degenerative conditions, and inborn errors of metabolism. In many cases the cause is unknown. In diseases with well defined neuropathology, chorea has been associated with abnormalities in the striatum (caudate and putamen) and the subthalamic nucleus (STN). However, the fundamental pathophysiology of chorea is not known. This is due in part to the lack of non-primate models and in part to the difficulty of measuring involuntary movements in the primate models that do exist. Current medical treatment options for chorea are few, may have significant side effects, and are often ineffective. The proposed experiments will develop quantitative 3-dimensional kinematic measures of chorea and use them measure spatial and temporal properties of chorea in adults and children with different disorders. Focal pharmacologic manipulation of basal ganglia nuclei will be used in monkeys to produce chorea. The resulting chorea will be measured in the monkeys and compared to human chorea in order to validate the monkey models, especially with respect to childhood chorea. The monkey models will then be used to investigate the fundamental pathophysiology of chorea by recording the activity of individual globus pallidus internal segment neurons before and during chorea. Through a combination of neurophysiologic and kinematic techniques to study experimentally produced chorea, the prevailing hypotheses of

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Huntington’s Disease

chorea pathophysiology can be tested rigorously. There is strong potential to identify the fundamental mechanisms of chorea. Development of a non-invasive method to quantify chorea in children and in monkeys will be an important advance toward better characterization of the pathophysiology of involuntary movements and development of more effective medical therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: POLYCYSTIN-1 INTERACTION WITH TSC-2 IN POLYCYSTIC KIDNEY DISEASE Principal Investigator & Institution: Guan, Kun-Liang; Associate Professor; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic disorders in humans. In the United States, ADPKD is more common than cystic fibrosis, Huntington's disease, and muscular dystrophy. ADPKD is characterized by the formation of cysts in kidney and caused by mutation in either PKD1 (85%) or PKD2 (15%) gene. Tuberous sclerosis (TSC) is an autosomal dominant inheritable genetic disorder due to mutation in either TSC1 or TSC2 gene. TSC is characterized by formation of hamartomas in various tissues. Cyst formation in kidney is also observed in TSC. The PKD1 and TSC2 genes are located adjacent to each other on human chromosome 16p and deletion of both genes results in a contiguous gene syndrome responsible for the severe infantile polycystic kidney disease. TSC2 has been implicated to play a role in the proper functions of polycystin-1, the product of PKD1 gene. The long-term goals of this project are to understand the functional relationship between TSC2 and PKD1 and to elucidate the molecular mechanism of TSC2 in regulation of PKD1 function and ADPKD. The specific aims of this proposal are to elucidate the mechanism of TSC2 regulation by osmotic stress and to investigate the function of TSC2 in regulation of the plasma membrane localization of polycystin-1. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: POLYGLUTAMINE AGGREGATES Principal Investigator & Institution: Wetzel, Ronald B.; Professor; Medicine; University of Tennessee Knoxville Knoxville, Tn 37996 Timing: Fiscal Year 2001; Project Start 15-JUN-2001; Project End 31-MAY-2005 Summary: (Adapted from applicant's abstract): In the expanded CAG repeat diseases, such as Huntington's Disease, abnormally long polyglutamine sequences have been implicated as the principle causative factor of the disease. The mechanism by which these molecules promote neurodegeneration is not clear, but a large body of evidence suggests that the mechanism has something to do with the enhanced ability of lengthened polyglutamine sequences to self-associate into oligomers or aggregates. While there is an imperfect correlation of disease physiology with the appearance of large aggregates in cellular nuclei, there is also a lot of indirect evidence, such as the widely reported involvement of cellular chaperones, that a misfolding / aggregation process is involved in these diseases. One limitation in our ability to progress more deeply into the disease mechanism is our ignorance of the details of the process and products of polyglutamine aggregation. For example, improved correlation of disease development with polyglutamine aggregation might be obtained if it were possible to distinguish different sizes and types of aggregates. There is significant information on the behavior of polyglutamine sequences from cellular expression experiments, but,

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owing to the very poor solubility properties of these molecules, there is much less mechanistic and structural information on defined polyglutamine sequences at the in vitro chemical level. This application is based on recent advances in this laboratory in the ability to solubilize these molecules and control their aggregation in vitro. A series of chemically synthesized polyglutamine sequences of different lengths will be developed and used to pursue the following aims. The length dependence of the kinetics and thermodynamics of the aggregation process will be characterized. The length dependence of aggregate structure will also be characterized. Mutational analysis o f the polyglutamine sequence will be conducted in order to better define the unique role of glutamine in aggregation and to better understand aggregate structure at the atomic level. Finally, the abilities of a series of molecular chaperones to retard and reverse the aggregation process will be characterized in vitro. The work should lead to a better understanding of the role of polyglutamine self-association in the disease mechanism and the nature of the toxic entity in turn; this should stimulate new work on the therapeutic intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: POLYGLUTAMINE NEURODEGENERATION

CONFORMATION

AND

Principal Investigator & Institution: Finkbeiner, Steven M.; Assistant Professor; J. David Gladstone Institutes 365 Vermont St San Francisco, Ca 94103 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: Huntington's disease belongs to a family of eight inherited, untreatable neurodegenerative diseases. Each is caused by an abnormal polyglutamine expansion in a different protein, In all eight, disease occurs when the polyglutamine stretch exceeds a certain length and symptom onset is inversely related to its length. Abnormal deposits of protein called inclusion bodies characterize many of these diseases. Whether Inclusion bodies are pathogenic, an epiphenomenon, or a beneficial defense response is controversial. Abnormal polyglutamine expansions probably cause degeneration by conferring a toxic gain of function to proteins. Polyglutamine expansions may adopt a conformation that is different depending on whether huntingtin is in Inclusion bodies or not. We hypothesize that abnormal polyglutamine expansion alters the conformation of soluble mutant huntingtin, enabling it to interact with cellular targets and produce neurodegeneration, independent of inclusion body formation. Certain heat shock proteins can protect cells against polyglutamine and regulate inclusion body formation. It is unknown whether they act mainly on inclusion bodies, oligomers, or malfolded monomers. It is unknown whether huntingtin needs to oligornerize to adopt a toxic conformation and whether the length or the composition of the polyglutamine stretch is critical to conformation or aggregation. We have used primary neurons to develop a model of Huntington's disease that recapitulates polyglutamine-dependent and neuron-specific death and inclusion body formation. We have also developed monoclonal antibodies that bind a conformation of huntingtin that correlates closely with Huntington's disease symptoms and which distinguishes huntingtin in inclusion bodies from more soluble forms. Finally, we have built a robotic microscope so we can simultaneously measure inclusion body formation within living neurons and then track their individual fates. We propose to use these tools to accomplish the following specific aims: Aim 1. To determine whether the availability of a disease-associated conformation is a better predictor of neurodegeneration than inclusion body formation. Aim 2. To determine whether heat shock proteins regulate huntingtin conformation and to relate the effects of heat shock proteins on neuronal survival to conformation and to inclusion

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body formation. Aim 3. To examine how the oligomeric state of mutant huntingtin and the length and composition of the polyglutamine stretch determine its ability to form a disease-associated conformation and to aggregate. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROTEIN AGGREGATION AND INCLUSION BODY FORMATION Principal Investigator & Institution: Kopito, Ron R.; Professor; Biological Sciences; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: (provided by applicant): Deposition of aggregates of misfolded protein into intracellular inclusion bodies is a prominent cytopathological feature of nearly every known neurodegenerative disease. Despite mounting genetic and biochemical evidence linking protein aggregation to pathogenesis in these and other diseases, it is unclear bow -or indeed whether- protein aggregation and inclusion body formation are primary toxic events or cytoprotective responses. My lab has recently described a general pathway by which aggregated proteins in mammalian cells are collected into specialized inclusion bodies called aggresomes (AG). The studies described in this proposal are intended to test the hypothesis that delivery of protein aggregates to AG is a specific, microtubuledependent transport process which facilitates the neutralization and elimination of potentially toxic gene products. Towards this end, three specific aims are proposed. The first aim will use biochemical and biophysical techniques to study the cellular mechanism of AG formation to identify transport intermediates in AG formation. These intermediates will be subject to extensive biochemical, biophysical and structural characterization. The second aim of the proposed research will be to reconstitute AG formation in a cell-free system in order to identify the cytoplasmic components required for retrograde transport of protein aggregates on microtubule tracks. Finally, the last aim will investigate the role of retrograde transport in the neutralization and elimination of protein aggregates. These last studies will specifically test the hypothesis that retrograde transport of aggregated protein is linked to the lysosomal/autophagic pathway of protein degradation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PROTEIN PALMITOYLATION IN YEAST Principal Investigator & Institution: Davis, Nicholas G.; Surgery; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2006 Summary: (provided by applicant): Palmitoylation is one of several different lipid modifications that serve to target and anchor proteins to membranes in eukaryotic cells. Palmitoylation has been long-recognized for its role in directing the localization of a variety of signaling proteins, including key players in cancer like H- and K-Ras, Src, Lck, and Rho, to plasma membrane sites of action. Despite the long history, little has been learned regarding the enzymology of this modification - the responsible enzymatic activities have not been identified. Our recent work in the yeast Saccharornyces cerevisiae, indicates that the ankyrin-repeat protein Akr1p is required for palmitoylation and consequent membrane localization of the type I casein kinase, Yck2p; in akr1delta cells, Yck2p is not palmitoylated and as a consequence is mislocalized diffusely throughout the cytoplasm, rather than to the plasma membrane. The major goal of this proposal is to characterize the role of Akr1p in the palmitoylation process. Preliminary work indicates that Akr1p is a strong candidate to be an enzymatic component of the

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palmitoyl transferase. This will be tested. In addition, Akr1p-containing complexes will be purified from yeast to identify the proteins that collaborate with Akr1p for palmitoylation. Another significant fact regarding Akr1p is that is its closest human homolog is a protein identified for its possible role in Huntington's disease. Thus, these fundamental studies on the function of Akr1p in yeast may well impact our understanding of the disease processes in both cancer and in Huntington's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROTEOPATHIES OF THE AGING CENTRAL NERVOUS SYSTEM Principal Investigator & Institution: Mucke, Lennart; Associate Professor; J. David Gladstone Institutes 365 Vermont St San Francisco, Ca 94103 Timing: Fiscal Year 2003; Project Start 15-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): We will address the hypothesis that different neurodegenerative diseases are caused by the accumulation of distinct proteins with pathogenic conformations (proteopathies). These disorders are a complex biomedical, behavioral, and social problem as they are increasing in frequency, cause major disability, and remain largely untreatable. If the ways in which different proteins damage nerve cells overlap, treatments may be developed to prevent and reverse more than one of these conditions. We have assembled five interactive projects and four essential cores to study the mechanisms by which proteins associated with Alzheimer's, Parkinson's, or Huntington's disease impair neuronal function and survival. The program is multidisciplinary and relies on state-of the-art technology, including X-ray crystallography, robotic microscopy, transgenic and gene-targeted mouse models, cellular biology, neuropathology, and behavioral neuroscience. Project 1, "Polyglutamine Conformation and Neurodegeneration," aims to differentiate whether visible aggregates or other conformational states of mutant huntingtin are responsible for Huntington's disease-related neurodegeneration. Project 2, "Protein Structure in Apolipoprotein E4-associated Neurodegeneration," will test whether the Alzheimer's disease-promoting effect of apolipoprotein E4 depends on the conformation and stability of this molecule. Project 3, "Apolipoprotein E in Neurobiology: Cellular Mechanisms," will examine whether apolipoprotein E4 promotes Alzheimer's diseaselike pathology through amyloid beta peptide (Abeta)-dependent pathways or via independent mechanisms. Project 4, "Causes and Consequences of alpha-Synuclein Aggregation," will assess whether pathogenic interactions between Abeta and alphasynuclein could contribute to the development of Parkinson's disease and other Lewy body diseases. Project 5, "Mechanisms of AbetaD-induced Neuronal Deficits," will analyze the molecular cascades that link the formation of neurotoxic Abeta assemblies to Alzheimer's disease-related cognitive decline and test whether these cascades can be modulated by apolipoprotein E isoforms and alpha-synuclein. The Cores (A: Administrative; B: Tissue Culture; C: Animal; D: Neuropathology/Imaging) will provide the common services necessary to accomplish the goals of the program project. Our studies will shed light on diverse neurodegenerative diseases and could provide the knowledge needed to better treat and prevent them. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULATION AND FUNCTION OF ERK5 IN CNS NEURONS Principal Investigator & Institution: Xia, Zhengui; Associate Professor; Environmental Health; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 01-MAY-2001; Project End 31-MAR-2005

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Huntington’s Disease

Summary: (provided by applicant): Apoptosis is a form of programmed cell death and is evolutionarily conserved. Apoptosis plays an important role in the nervous system both during development and in homeostasis of adults. Inappropriate apoptosis may contribute to various neurodegenerative conditions including stroke, epilepsy, Down's syndrome, Parkinson's disease, Huntington's disease, ALS, and Alzheimer's disease. Hence, elucidation of mechanisms that regulate neuronal apoptosis is of fundamental importance for neurobiology and may ultimately contribute to the development of pharmacological interventions and clinical strategies for treatment of various neurodegenerative disorders. Neuronal activity and neurotrophins are critical for the differentiation, survival, and adaptive responses of neurons both during development and in the adult brain. Activation of the extracellular signal regulated kinases (ERK) 1 and 2 by neurotrophins, Ca2+ and cAMP have been strongly implicated in these processes. Recently, a new member of the mitogen-activated protein (MAP) kinase family, ERK5, was discovered. Like ERK1 and ERK2, EGF stimulation of ERK5 is blocked by the MEK inhibitors, PD98059 and U0126. This suggests the interesting possibility that some of the functions attributed to ERK1/2 may be mediated by ERK5. However, the regulatory properties of ERK5 in neurons have not been reported. Our preliminary data suggest that neurotrophins including BDNF activated ERK5 in primary cultured cortical neurons. We hypothesize that mechanisms for regulation of ERK5 and downstream transcriptional pathways regulated by ERK5 are distinct from ERK1/2 in neurons. We also hypothesize that ERK5 has unique physiological functions in the central nervous system (CNS). The overall objective of this proposal is to define the signal transduction pathway for ERK5 activation in primary cultured neurons, and the role for the ERK5 pathway in promoting neuronal survival. Cortical neurons were chosen because cerebral cortex is important for higher order learning and memory, and neurons in the cortex are frequently damaged in neurodegenerative diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RETROGRADE SIGNALING BY ENDOGENOUS CANNABINOIDS Principal Investigator & Institution: Regehr, Wade G.; Professor; Neurobiology; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-MAY-2007 Summary: (provided by applicant): Cannabinoids, such as d9-THC, affect the brain by activating G-protein coupled CB1 receptors that can inhibit adenylate cyclase, modulate a variety of ion channels, and inhibit synaptic transmission. These receptors are expressed widely throughout the brain, with particularly high levels of expression found in the cerebellum, the cortex, the hippocampus and the striatum. Recent studies provide new insight into the physiological role of the cannabinoid system and suggest that cannabinoids can act as retrograde messengers. Elevations of calcium in the dendrites of some types of neurons result in the cleavage of phospholipids leading to the formation and liberation of endogenous cannabinoids, which bind to presynaptic CB1 receptors to inhibit synaptic transmission. This retrograde inhibition lasts for tens of seconds. Our primary goal is to clarify the properties and mechanisms of this retrograde inhibition and to determine its physiological role. Studies will be performed in rodent cerebellar brain slice on excitatory and inhibitory synapses that are known to be retrogradely inhibited by cannabinoids released from Purkinje cell dendrites. These synapses are well suited to these studies because cells are readily identified, whole cell voltage clamp is straight forward, and both presynaptic and postsynaptic calcium levels can be monitored optically. Mechanistic studies will concentrate on the calcium dependence of cannabinoid release, identification of the presynaptic targets of that

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modulation, and determination of the factors governing its time course. Factors governing the spread of retrograde inhibition to synapses onto neighboring cells and its spatial extent will also be determined. In addition, we will determine the physiological role of retrograde inhibition in controlling synaptic strength and determine if it is a mechanism that can provide synapse-specific regulation or if it provides a homeostatic mechanism for a cell to regulate all of the synaptic inputs it receives. These basic mechanistic studies promise to help cannabinoids realize their great therapeuptic potential as an appetite stimulant, as an anticonvulsant, and in the treatment of Huntington's disease and Parkinson's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE NEURODEGENERATION

OF

SOMATIC

MTDNA

MUTATIONS

IN

Principal Investigator & Institution: Khrapko, Konstantin; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 31-MAY-2006 Summary: (Adapted from the abstract provided by the applicant): The long-term goal of the proposed research is to study the mechanisms responsible for the slow progression of late-onset neurodegenerative diseases. The understanding of these mechanisms may help to find ways to make these processes even slower, thus moving the onset of these debilitating diseases outside the normal human lifespan. Specifically, we propose to test the hypothesis that accumulation of somatic mutations in mtDNA of critical cell types in the brain is one of the conditions necessary for the progression of at least some neurodegenerative processes. One of the possibilities is that once the fraction of mutated mtDNA in specific cells exceeds a certain threshold, these cells become sensitive to biochemical insults associated with some diseases. This hypothesis has arisen from the preliminary finding that individual pigmented neurons in substantia nigra accumulate very high levels of mtDNA deletions, which are highly likely to compromise cell's resistance to various stresses. Moreover, there are indications that cells with a heavy mutational load are the first to die in Parkinson's brain. It is also possible that progression of the disease accelerates accumulation of mutations thus creating a positive feedback. The efforts will be focused first on Parkinson's Disease (PD) patients and pigmented neurons of substantia nigra. Then research will be extended to Alzheimer's Disease (AD), Huntington's Disease (HD) and the various corresponding brain areas and critical cell types. The Specific Aims of the proposal are: 1) To develop and optimize the arsenal of methods necessary for the precise quantification and characterization of mtDNA mutations in single cells of the brain. These methods will include laser capture micro-dissection for single cell isolation, amplification of full-length mitochondrial genomes from single cells, single cell competitive PCR, and single cell limiting dilution PCR. 2) To identify brain areas and cell types in which mtDNA mutations are most likely to contribute to neurodegeneration. This will be done by measuring mutation load in individual cells of substantia nigra, cortex and putamen that are known to be rich in mtDNA deletions and are critical for PD, AD, and HD, respectively. 3) To test the hypothesis that clonal expansions of mtDNA mutations in individual cells contribute to mitochondrial defects and to neurodegeneration and death of neurons. This will be done by comparing the mutational load of cells that stained positive for various markers of mitochondrial dysfunction, cell degeneration and death to non-staining control cells. We will also study the distribution the mutations as a function of age and the presence and severity of the disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Huntington’s Disease

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Project Title: STRIATAL CONTRIBUTIONS TO CATEGORY LEARNING Principal Investigator & Institution: Filoteo, J V.; Veterans Medical Research Fdn/San Diego Foundation of San Diego San Diego, Ca 92161 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-JAN-2006 Summary: (provided by applicant): Previous studies indicate that patients with damage to the striatum, such as patients with Parkinson's disease (PD) or Huntington's disease (HD), are impaired in certain categorization tasks, but show no impairment in other categorization tasks. These studies suggest that the striatum may be involved in category learning under some circumstances but not others. One possible role of the striatum in category learning is that these structures are involved in learning nonverbal rules, but only when learning is based on corrective feedback under supervised learning conditions. Such a hypothesis is consistent with current models of striatal functioning. However, it is difficult to draw strong conclusions regarding the proposed role of the striatum based on past work because most of these studies used very different categorization tasks that vary along a number of important dimensions. The proposed research remedies these problems by conducting highly systematic studies of category learning in patients with PD. Factors known to impact the verbalizability of categorization rules will be explored, including (1) whether the rule is linear or nonlinear, (2) whether the rule requires information integration across dimensions or selective attention, and (3) whether the stimulus dimensions are separable or integral. In addition, the nature of training (corrective feedback or observation) will also be examined. These factors likely determine the extent to which the striatum is involved in category learning. Each of these factors will be explored within the framework of a highly successful categorization paradigm that has been used extensively in studies of normal cognition, and recently has been extended to some patient populations and normal aging. The paradigm, called the perceptual categorization task, is rigid enough that strong controls can be placed on factors that vary widely across other tasks, but is flexible enough that each of the factors outlined above can be studied in isolation. Further, quantitative models will be applied to the data of PD patients and controls in order to determine more precisely the nature of any observed category learning deficits in the PD patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STRIATAL ENERGETICS AND HUNTINGTON'S DISEASE Principal Investigator & Institution: Dubinsky, Janet M.; Associate Professor; Neuroscience; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2004 Summary: (Adapted from the Aplicant's Abstract) Metabolic impairment is a physiological characteristic in the selective neurodegeneration associated with Huntington's disease and transgenic and knock-in mouse models of Huntington's disease. Most importantly, it is not known how the unique striatal ener aboutv deficit activated or aggravated by ubiquitous, mutant huntington expression leads to selective striatal cell death. The objective of the current proposal is to investigate the relationship between the expression of expanded CGA repeats and the bioenergetic defects associated with Huntington's disease and activation of the mitochondrial permeability transition. Our working hypothesis postulates that the metabolic impairment results in a restricted substrate supply to neuronal mitochondria. Application of exogenous metabolic inhibitors used to model Huntington's disease, e.g. 3-nitropropionic acid

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(3NP), would mimic this genetic defect. Under these conditions, elevations in cytosolic Ca2+, perhaps accompanying normal postsynaptic glutamate receptor activation, would cause activation of the mitochondrial permeability transition (mPT) in its low conductance state. Sustained opening of this proton permeable pathway would depolarize mitochondria, inhibit energy-dependent transhydrogenases, lowering antioxidant defenses and increasing the probability of high conductance mPT activation. Striatal neurons may be metabolically more susceptible to this sequence of events than neurons from other brain regions. Experiments are proposed to investigate key elements in this hypothesis: 1) the substrate dependence of induction of the low conductance mPT and the increased vulnerability to reactive oxygen species production, 2) antagonist sensitivity of the permeability transition in brain, 3) the ability of expanded CGA repeats and 4) 3NP to shift mitochondrial responses to Ca2+ towards low conductance mPT induction, and 5) the selective susceptibility of striatal mitochondria to this type of injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE INFLUENCE OF NICOTINE ON FRACTIONATED REACTION TIMEN Principal Investigator & Institution: Marzilli, Thomas S.; Health/Leisure & Exercise Sci; University of West Florida 11000 University Pky Pensacola, Fl 32514 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): This R03 grant, in response to NIDA's PAR-00-059 "Small Grant Program," will importantly support the implementation of exploratory research that incorporates a novel and extremely fine-grained approach to the study of nicotine and human performance. This innovative methodology uses electromyography to dissociate the central (cognitive) and peripheral (neuromuscular) processing related to the successful completion of a variety of reaction time tasks. To further discriminate at what level of the central processing stream nicotine is most likely to have an effect, a basic chronometric approach to studying information processing will be incorporated. This chronometric approach will allow for the independent examination of each of the three theoretically nonoverlapping information processing stages which include stimulus identification, response selection and response programming. This methodology provides the opportunity to investigate nicotine's effects on the time between the initiation of the stimulus and the initiation of the motor response (central processing) as well as the time delay between the initiation of the motor response and the actual movement or button release (neuromuscular processing) during a variety of reaction time tasks. This paradigm has been shown to be sensitive to a number of variables such as: intensity of stimulus, number of response alternatives, complexity of movement, age, physical activity and pathologies, but has yet to be used to investigate the affects of nicotine on movement preparation, initiation and execution. These methodologies are well grounded in the field of Motor Learning and Cognitive Psychology, and will be a definite addition to the literature in regards to nicotine effects on human performance. Moreover, the methodologies offered herein could have clinical payoffs in populations, such as Parkinson's disease, Huntington's disease and other pathologies where the planning of movement is thought to be intact, but the initiation of movement may be compromised. This laboratory-based project uses cigarette smokers to better understand how nicotine affects the individual components (pre-motor and motor time) of a variety of reaction time tasks. This disassociation of central and neuromuscular components within a reaction time paradigm offers a substantial positive deviation from previous research utilizing only simple or choice reaction time

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Huntington’s Disease

methodologies because it may be that individual task components are influenced differentially by nicotine, which would not be evident if only a single, summary measure of reaction time was used. This study will be accomplished by systematically varying experimenter supplied nicotinised and denicotinised cigarettes while administering a variety of subjective, physiological and performance measures under double blind, placebo controlled conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE RGS-9 MOUSE: INDUCIBLE EXPRESSION IN THE STRIATUM Principal Investigator & Institution: Lai, Cary H.; Assistant Professor; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): Our ability to develop useful treatments for neurodegenerative diseases such as Parkinson's and Huntington's disease is hampered by our lack of understanding of the etiology of these disorders. One way of addressing the problem is to develop animal models of the disease and to use these to test hypotheses concerning the origin and progression of the neural degeneration. The ability to test these hypotheses and to create new models for these disorders would be greatly facilitated by the ability to generate mice that express a selected gene exclusively in the striatum. Here we propose to produce transgenic mice permitting the regulated expression of genes in a subset of striatal neurons. We propose to construct a transgenic mouse line ("the RGS-9 mouse") using the promoter and other regulatory elements for the gene encoding the regulator of G-protein signaling-9 (RGS-9) to drive the expression of the tetracycline transactivator. When mated to a distinct transgenic line containing a candidate gene whose transcription is regulated by the tetracycline operator, the resulting offspring should express the candidate gene in striatal neurons in the presence of the inducer, tetracycline. The availability of mice that inducibly express genes in striatal neurons should help neuroscientists tackle Parkinson's and Huntington's disease by facilitating the production of new models for these diseases. As additional genetic loci related to the etiology or progression of these diseases emerge from our improved understanding of the human genome, these genes or altered versions of these genes can be specifically re-inserted into striatal neurons to assess their effects. Use of the RGS-9 mouse would be superior to currently available systems, which express genes in larger collections of cells. Through these efforts, we hope to create a genetic tool that will accelerate the development of therapeutics for the patient with Parkinson's and Huntington's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE ROLE OF NFKB IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Patterson, Paul H.; None; California Institute of Technology Mail Code 201-15 Pasadena, Ca 91125 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2006 Summary: (provided by applicant): Huntington's disease (HD) is a fatal neurodegenerative disorder caused by the expansion of CAG repeats in the huntingtin (Htt) gene. Mutant Htt forms intracellular aggregates and is cytotoxic to specific neurons in the striatum and cortex. Causes of cell death in HD include the activation of cell death genes and/or alteration of normal transcription. The objective of this proposal is to investigate how mutant Htt interacts with NF-kappaB signaling pathway. This pathway regulates expression of pro-survival genes, is central to the function of neurotrophic

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factors and cytokines, and is activated during excitotoxic cell death mediated by NMDA receptors. We are investigating the interaction of mutant Htt with the IkappaB kinase (IKK) complex that regulates NF-kappaB, and how this affects neuronal responses to extracellular signals. We will focus on the mechanism of how the direct interaction between mutant Htt and IKKgamma, a regulatory component of IKK, influences neurodegeneration in HD. Molecular, cell culture, brain slice and animal model approaches will help to explore the nature and consequence of this interaction. We have preliminary evidence that IKKgamma influences NF- kappaB-regulated neuronal gene expression, as well as mutant Htt-induced cell death and aggregation. (i) Using in vitro and cellular assays, we are mapping the domains in mutant Htt and IKKgamma that mediate their binding. (ii) The functional consequences of Htt-IKKgamma interaction are assessed by isolating IKK complex from mutant and normal Htt-expressing cultured cells and HD transgenic mouse brain. Its kinase activity and ability to regulated NFkappaB mediated gene expression is then tested using in vitro kinase and gene reporter assays. (iii) Downstream genes influenced by the Htt-IKKgamma interaction will be identified by cDNA mini-arrays. mRNA will be isolated from several brain regions from HD and normal mice. (iv) The influence of IKKgamma on mutant Htt-induced cell death and aggregation is being examined in HD transgenic mice and in PC12 cells that inducibly express Htt and/or IKKgamma. We have constructed lentiviral vectors expressing a dominant negative form of IKKgamma as well as cell permeable peptides that block IKKgamma activity in cells. These reagents will be injected into the brains of HD mice in tests of their efficacy in inhibiting mutant Htt toxicity and aggregation. They will also be tested on brain slices from HD mice, in the presence and absence of NMDA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TISSUE TRANSGLUTAMINASE: A ROLE IN HUNTINGTON'S DISEASE Principal Investigator & Institution: Lesort, Mathieu J.; Assistant Professor; Psychiatry & Behav Neurobiol; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: (Provided by applicant): Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a pathological expansion of a polyglutamine domain within the protein huntingtin. The precise mechanisms involved in the etiology are still unknown, however there is evidence that impaired mitochondrial function is likely an important factor in HD. A possible clue to the pathogenesis of HD came with the discovery of neuronal intranuclear and cytoplasmic inclusions composed of mutant huntingtin. It has been suggested that Tissue Transglutaminase (tTG) may be a contributing factor to the formation of these aggregates. Tissue TG is a calcium-dependent transamidating enzyme that catalyzed the formation of isopeptide bonds between specific proteins to produce insoluble polymeric structures. Recently we have demonstrated that TG activity and tTG levels are significantly increased in specific brain regions affected by the disease as compared to control cases. Further, studies from the laboratory demonstrated that tTG associates with a truncated huntingtin protein and activation of tTG resulted in the modification of specific proteins associated only with the mutant truncated huntingtin protein. These results suggest that tTG may have a role in the etiology of HD. Our working hypothesis is that impaired mitochondrial function results in an increase in tTG activity and this subsequently results in an increased association of tTG with truncated huntingtin and modification of specific mutant huntingtin associated protein. In this proposal the

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Huntington’s Disease

majority of the experiments will be carried out in human neuroblastoma cells that express in a stable or inducible manner, physiological or pathological huntingtin protein constructs. In this proposal we will: (1) test the hypothesis that mitochondria impairment results in an increase in TG activity, and that the presence of mutant huntingtin potentiates this response, (2) test the hypothesis that tTG interacts selectively with the N-terminal truncated huntingtin protein, and that mitochondria impairment results in an increase in this interaction, (3) test the hypothesis that tTG contributes to the formation and/or stabilization of the aggregates, and that mitochondrial impairment may potentiate this effect, and (4) identify the mutant huntingtin-associated proteins that are tTG substrates and test the hypothesis that modification of these proteins may contribute to the selective neuronal death in HD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TOWARDS MECHANISTIC EXPLANATIONS OF STRIATAL DISORDERS Principal Investigator & Institution: Thomas, Elizabeth A.; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: (provided by applicant): The broad goals of this application are to identify mechanisms associated with the functions of the striatum under normal and pathological conditions. The striatum is the primary region of dysfunction in several neurodegenerative disorders, such as Huntington's and Parkinson's diseases, and is also associated with movement disorders and psychiatric disturbances. Presently, treatment strategies for these disorders are not curative, but rather are aimed at reducing symptoms. Hence, a better understanding of the mechanisms and pathways that contribute to striatal function is essential. The logic that has motivated our studies is that mRNA molecules with restricted expression in the striatum are likely to encode proteins that are preferentially associated with particular physiological processes of this region. In Specific Aim 1, we will identify and isolate all known genes with specific or enriched expression in the striatum using the systematic, automated mRNA display technology TOGA (Total Gene expression Analysis). We will then create a cDNA microarray chip containing all known and newly discovered striatal-enriched species ( 100). This will provide us with a DNA tool for analyzing the expression status of all striatal-evident genes under various pathological conditions. In this application, we will focus on the pathology of Huntington's disease (HD), (although additional/future studies will investigate other striatum disorders). HD is an inherited, neurodegenerative disorder characterized by progressive motor, psychiatric, and cognitive disturbances. In Specific Aim 2, we will identify genes associated with HD by screening the striatal-enriched DNA chip with RNA from the brains of transgenic HD mice. These mice express exon 1 of the human HD gene carrying an extremely expanded CAG repeat. Finally, we will test the hypothesis that the HD gene product, huntingtin, interacts with proteins that are enriched in the striatum, hence, giving rise to the tissue-specific degenerative patterns observed in this disease. We will screen all striatum-enriched proteins simultaneously for specific interactions with both normal and mutated forms of the huntingtin. This will be achieved by creating a protein microarray chip containing GST-fusion proteins of each striatal-enriched gene and then probing with biotinylated-labeled huntingtin. The molecules identified in these studies could targets for novel therapies that would prevent or slow the onset of symptoms as well as the progression of Huntington's disease, and very well may lead to cures for this and other devastating

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neurodegenerative disorders. An important advantage of these potential pharmaceutical targets is that they would act only at the restricted site of expression, the striatum. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRAFFICKING DEFECTS IN HUNTINGTONS DISEASE Principal Investigator & Institution: Mcmurray, Cynthia T.; Professor; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: (from applicant's abstract) It is the aim of this grant to understand defects in vesicular trafficking and cytoskeleton that may underlie Huntington's disease. Expansion of a trinucleotide repeat CAG, encoding glutamine, results in at least eight progressive neurodegenerative disorders, including Huntington's disease (HD). The mechanism by which polyglutamine expansion selectively kills neurons is largely unknown. Aggregation is generally accepted as part of pathogenesis, but it is not known whether toxicity initiates in the nucleus or the cytoplasm. Using time lapse imaging, we have tracked the localization of huntingtin in individual neurons from expression of the mutant protein to cell death. Toxicity initiates in the cytoplasm of primary neurons. Further, we have identified targets of huntingtin-mediated aggregation directly from aggregates in human brain. We show that the expanded Huntington's protein sequesters tubulin and vesicular trafficking motors into insoluble complexes. Direct video imaging of vesicles indicates that the mutant protein indeed inhibits vesicular transport particularly in the anterograde direction. The motor that is most affected appears to be kinesin and the cargo that appears most affected is mitochondria. Our data support a model for HD pathogenesis in which aggregation inhibits proteolysis of the HD protein, disrupts cytoskeletal architecture and impairs motors required for vesicular/organelle trafficking. In this proposal, we aim to test the hypothesis that sequestration of tubulindependent motors underlies HD regional pathology. Using gel filtration, immunoblotting and immunoprecipitation reactions, we will evaluate whether sequestration of tubulin-dependent complexes underlies HD regional pathology in human brain. By establishing primary cultures of affected and resistant neurons, we will directly test whether vesicular trafficking is altered in the presence of normal and expanded HD protein. Since mitochondria are reduced in number in the presence of the mutant huntingtin, we will monitor the fate and subcellular localization of mitochondria by confocal imaging. Alteration in transport will be correlated with the subcellular localization of the HD protein and trafficking motors using fluorescence-labeled proteins and confocal microscopy. Finally, we will refine our understanding of pathogenesis by identifying other proteins present in aggregates by mass spectrometry. The recent observations that tubulin-dependent complexes and vesicular transport may play a role in pathogenesis of ALS and Alzheimer's disease suggest that there may be common aspects to these neurological diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: APPROACH

TRANSCRIPTIONAL

DYSREGULATION

IN

HD:

THERAPY

Principal Investigator & Institution: Ferrante, Robert J.; Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2008 Summary: Huntington's disease (HD) is a progressive and fatal neurological disorder caused by an expanded CAG repeat in the gene coding for a protein of unknown

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function, huntingtin (HD). There is no known treatment for HD. Although the exact cause of neuronal death in HD remains unknown, there is substantial evidence linking oxidative stress, apoptosis, mitochonddal and energy metabolism dysfunction, and excitotoxicity. These events may be secondary to transcriptional dysregulation caused by direct binding of the mutant HD protein or cleaved products to DNA. Altered protein-protein interactions associated with mutant htt are a consistent finding in HD. Mutant htt recruits other proteins into insoluble aggregates. Mutant HD-induced transcriptional dysregulation may occur early on in the disease process, altering gene expression in those pathogenic mechanisms proposed in HD and causing subsequent neuronal death. We hypothesize that compounds that inhibit or modify transcription factors and also prevent their sequestration may provide novel therapeutic interventions in HD. This hypothesis is based on our novel preliminary data that mithramycin A, an aureolic acid antibiotic that inhibits transcriptional initiation; sodium butyrate, a histone deacetylase inhibitor that modifies transcription by reducing levels of acetylated histones; and cystamine, which blocks huntingtin aggregation, are all effective in significantly extending survival and delaying the neuropathological phenotype in transgeniC HD mice. We will examine the therapeutic effects of mithramycin A and its analogs in HD mouse models, determine optimal intraperitoneal dosing, and complete cross-longitudinal studies on behavioral and neuropathological outcome measures, as pre-clinical trials for human studies. We will compare treatment started both before and after clinical symptoms appear. Secondly, we will characterize the efficacy of histone deacetylase inhibitors and determine whether their administration will improve the clinical and neuropathological phenotype found in transgenic HD mice. Lastly, we propose to identify any cumulative synergies using mithramycin and HDAC inhibitors, while using these compounds in combination with cystamine in targeting eady molecular events in the pathogenesis of HD. Cystamine significantly reduces huntingtin aggregates in HD mice and early treatment may reduce transcription factor sequestration, preventing relocalization of transcription factors, co-activators, and repressor proteins over the temporal sequence of disease in HD mice. This combined multi-pharmaceutical treatment may have a significant neuroprotective effect in HD mice and provide preclinical data for prospective clinical drug-trials in HD patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSCRIPTIONAL REGULATION OF OXIDATIVE DEATH Principal Investigator & Institution: Ratan, Rajiv R.; Director; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2008 Summary: Huntington's Disease (HD) is an autosomal dominant disorder resulting from selective loss of neurons in the striatum and cerebral cortex. Loss of neurons in HD results from pathological expansion of CAG repeats encoding glutamine. Though the precise mechanisms by which glutamine repeats lead to neuronal loss in HD are unclear, oxidative stress, apoptosis, and transcriptional dysregulation have all been implicated in disease pathogenesis. To understand better oxidative and transcriptional mechanisms that may lead to neuronal loss in HD, we have utilized an in vitro model of oxidative stress in primary cortical neurons. In preliminary studies we have shown that oxidative cell death can be fully abrogated by sequence-selective DNA binding drugs, including mithramycin A (MMA) and chromomcyin A3. These agents are members of the aureolic acid antitumor antibiotics that share a common chromophore, aglycon ring, but differ in the nature of the sugar moieties connected to either side of the aglycone ring. Both antibiotics inhibit transcription during macromoleclar biosynthesis by

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binding to the "GC" rich transcriptional response elements. To test whether aureolic antibiotics can protect neurons in an in vivo model ofneurodegeneration that may inolve oxidative stress, we examined the effect of MMA in the R6/2 transgenic model of HD. We found that MMA prolongs survival in these mice by nearly 30%, a magnitude superior to any other single neuroprotective agent. These preliminary data are consistent with the overall hypothesis to be tested in this proposal: MMA inhibits neuronal death due to oxidative stress and/or mutant Huntington protein in vitro and in vivo by inhibiting the binding of pro-apoptotic zinc finger transcription factors such as TIEG, and enhancing the DNA binding of pro-survival transcription factors such as CREB. We will examine this hypothesis by determining whether protective concentrations of MMA inhibit TIEG binding to its GC rich DNA binding sites and whether TIEG is critical for oxidative death in cortical neurons. In the second aim, we will determine how MMA affects CREB DNA binding and whether increases in CREB DNA binding contribute to MMA's salutary effects. In the last specific aim, we will compare the mechanism of neuroprotection of MMA to those ofhistone deacetylase inhibitors, another class of transcriptional regulators. These studies will provide critical, mechanistic data on neuroprotective modulators of transcription. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSGENIC MOUSE MODELS OF HUNTINGTON'S DISEASE Principal Investigator & Institution: Levine, Michael S.; Professor; Mental Retardation Res Center; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: (provided by applicant): This proposal will examine cellular mechanisms underlying the dysfunctions detected in Huntington's disease (HD) using four different murine models. The lethal mutation in HD produces an expanded trinucleotide (GAG) repeat within the protein huntingtin. It causes selective neurodegeneration especially in the striatum and cortex, by an unidentified mechanism. Each of the HD models we will examine exhibits a different phenotype produced by unique transgene constructs or 'knocked-in" GAG repeat lengths. By evaluating multiple models we will be able to examine the dysfunctions in more detail and understand the specificity and sequence of physiological changes common to HD and the models. Based on our preliminary studies, we have uncovered several common cellular deficits in two models. These are enhanced responsiveness of N-methyl-D-aspartate (NMDA) receptors in the striatum associated with increased Ca2+ flux, a marked decrease in K+ conductances and a change in the corticostriatal synaptic response. A third model also displays the enhanced response to NMDA. Some of these changes potentially predispose striatal medium-sized spiny neurons to excitotoxic damage. Using a physiological approach, we will examine four hypotheses concerning the cellular mechanisms of dysfunction in HD: 1) alterations in ionotropic glutamate receptor function and changes in evoked and spontaneous excitatory synaptic inputs to striatal neurons 2) alterations in metabotropic glutamate and dopaminergic receptor modulation of ionotropic glutamate receptor function, 3) alterations in K+ conductances and 4) alterations in Ca2+ conductances. The precise onset of changes will be investigated in relationship to the expression of behavioral deficits by using animals that are presymptomatic or after development of overt motor signs. We will examine striatal and corticostriatal neurons, visualized in the slice preparation or acutely dissociated cells, to characterize basic functions by currentand voltage-clamp analyses. Because HD destroys so many different capabilities intellectual, physical and emotional - the insights gained from this research elucidating

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the cellular malfunctions in HD are relevant to understanding other GAG repeat disorders and neurological diseases associated with protein aggregate pathologies like Alzheimer's and Parkinson's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISEASE

TRANSGENIC

XENOTRANSPLANTS

FOR

HUNTINGTON'S

Principal Investigator & Institution: Isacson, Ole; Professor; Mc Lean Hospital (Belmont, Ma) Belmont, Ma 02478 Timing: Fiscal Year 2001; Project Start 01-JAN-1992; Project End 31-MAR-2003 Summary: (Verbatim from the Applicant's Abstract) Brain cell transplantation research has shown that structural and functional repair of the adult brain is possible. We are testing the functional hypothesis that embryonic striatal neurons can replace neurons lost in adult primate striatum and improve signs of Huntinton's disease (HD). The lack of an optimal human donor cell source in a clinical scenario has led us to utilize zenogeneic (here transgenic pig) embryonic donor cells. Our preliminary in vivo data show that successful xenografts survival in the primate brain requires immunosuppression by cyclosporine, azathiopirne, methylprednisolone and complement inhibition (CD59 transgenic donor tissue and monoclonal antibodies against complement C5). To test the functional hypothesis, we proposed the following experiments: We will transplant CD59 complement aggregation inhibitor expressing transgenic porcine fetal striatal (E35 LGE) cells to the caudate-putamen of non-human primate (Macaca mulatta) with neuronal loss similar to that seen in HD. To determine how functional recovery depends on survival and growth of porcine striatal transplants, we will collect physiological in vivo data by PET/MRI/MRS and behavioral data by examining motor and cognitive function. The physiological analysis of LBE graft function by in vivo imaging and behavioral assays is followed by detailed morphological studies. Combine, these studies will provide essential data on the relationship between structural and functional integration of embryonic neuronal xenografts in a HD primate model. These experiments will improve our knowledge of basal ganglia function and plasticity, as well as determine parameters for optimal cell transplantation in patients with neurological disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSGLUTAMINASE IN NEURODEGENERATIVE DISEASES Principal Investigator & Institution: Johnson, Gail V W.; Professor; Psychiatry; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2004 Summary: (provided by applicant): Transglutaminases (TGs) are highly regulated, calcium-dependent enzymes that likely play key roles in several critical processes in the nervous system. TGs catalyze a transamidating reaction that results in the incorporation of polyamines into specific glutatmine residues within proteins, or if a protein-bound lysine is the amine donor, the tTG-catalyzed reaction results in the formation of a crosslink between the glutamine and lysine residues in proteins. This is highly specific reaction and only a limited number of proteins have been identified as in situ substrates of TG. Tissue TG (tTG), a member of this family, is the most abundant TG in the human brain and is found within neurons. The levels of tTG and TG activity are increased in neurodegenerative conditions such as Alzheimer's disease and Huntington's disease, and increases in tTG can facilitate neuronal cell death in response to specific stressors.

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Further, in a recent study it was found that treatment with cystamine, a drug that inhibits transglutaminase in vitro, prolonged surviv approximately 8-10% in a mouse model of Huntington's disease. These and other results suggest that transglutaminase inhibitors may be beneficial in studying the pathological mechanisms and in the treatment of neurodegenerative diseases such as Huntington's Disease and Alzheimer's Disease. However, there are numerous problems with using cystamine as a drug to treat human neurodegenerative diseases, including the fact that it is a non-specific drug with a very steep toxicity curve. Further, it is a charged molecule that likely does not efficiently cross the blood brain barrier. Therefore it is clear that more selective and efficacious TG inhibitors need to be developed for the study and treatment of neurodegenerative disorders. This laboratory has a longstanding interest in the regulation and function of TGs, and therefore is optimally suited to develop TG assays, both in vitro and in situ, that can be used in high throughput drug screening to identify and develop TG inhibitors that are neuroprotective. The aims of this proposal are to: 1. To develop an assay to measure TG activity for a 96 well format that is robust, reproducible and has a simple readout. 2. To develop an assay to measure TG activity in a cellular model using a 96 well format that is reproducible and easily measured. 3. To validate the assays using pharmacological standards, and then use these assays in an initial screen of a small but diverse collection of FDA approved drugs to demonstrate feasibility. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VIEWS OF PRIVACY OF GENETIC INFORMATION Principal Investigator & Institution: Klitzman, Robert; New York State Psychiatric Institute 1051 Riverside Dr New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 08-FEB-2002; Project End 31-JAN-2006 Summary: The increasing availability of genetic information on individuals raises a series of critical questions concerning privacy and confidentiality that have not been fully explored. The rise of computers, the Internet, and managed care all threaten the privacy of individuals' health information; and the sequencing of the human genome makes these issues particularly acute. Sharing genetic information may lead to stigma, discrimination, and threats to jobs and life and health insurance. Former President Clinton released privacy regulations, and some states have genetic privacy laws, yet numerous questions and controversies remain. The implementation of such safeguards remains unclear, and patient advocates feel further policies are needed. It is also unclear how privacy concerns and such regulations may affect behavior (e.g., participation in genetic testing) and to what degree new safeguards will allay patient concerns. It is critical to understand patients' underlying conceptions, views and approaches to privacy, and to policy and threats to privacy, and factors involved in these views. Yet no published research has investigated in-depth the perspectives and experiences of individuals confronting genetic diseases, concerning these issues. The aims of this study are thus 1) to explore views of privacy issues among individuals who are at risk of or have genetic disorders concerning privacy of genetic and other health information, threats to privacy, possible policies, and tradeoffs between privacy and benefits that might accrue from sharing genetic information (e.g., for research); 2) to explore the experiences of these individuals concerning privacy and disclosure - to whom they have disclosed that they confront a genetic disease (e.g., to health care professionals, family members, co-workers, employers, and insurance companies); when, why and what they disclosed; what reactions (e.g., stigma and discrimination) they have encountered; and how they view and make these privacy and disclosure decisions; 3) to explore the

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relationship of these views of privacy to health behaviors (e.g., delaying or avoiding diagnostic tests or treatment); and 4) to assess how type of genetic or other illness, or other factors may affect these views and experiences. We will conduct in-depth semistructured interviews with 160 individuals -40 each who confront Huntington's Disease, genetically-linked breast cancer, alpha 1 antitrypsin deficiency, and, as a comparison group, coronary artery disease. We have chosen the first 3 of these disorders because our pilot work suggests that critical privacy concerns arise with all 3 of these genetic diseases, but are related to different aspects of these conditions. The findings of this study can enhance further policy, professional and public education, and future research in this area. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

E-Journals: PubMed Central3 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).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “Huntington’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 Huntington’s disease in the PubMed Central database: •

Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington's disease. by Carmichael J, Chatellier J, Woolfson A, Milstein C, Fersht AR, Rubinsztein DC.; 2000 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16928

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Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis. by Kim YJ, Yi Y, Sapp E, Wang Y, Cuiffo B, Kegel KB, Qin ZH, Aronin N, DiFiglia M.; 2001 Oct 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=60131

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Cdc42-interacting protein 4 binds to huntingtin: Neuropathologic and biological evidence for a role in Huntington's disease. by Holbert S, Dedeoglu A, Humbert S, Saudou F, Ferrante RJ, Neri C.; 2003 Mar 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151406

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Counting CAG repeats in the Huntington's disease gene by restriction endonuclease EcoP15I cleavage. by Moncke-Buchner E, Reich S, Mucke M, Reuter M, Messer W, Wanker EE, Kruger DH.; 2002 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=134256

3 4

Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.

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. 5 The value of PubMed Central, in addition to its role as an archive, lies in 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.

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Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease. by Wyttenbach A, Carmichael J, Swartz J, Furlong RA, Narain Y, Rankin J, Rubinsztein DC.; 2000 Mar 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16027

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Human single-chain Fv intrabodies counteract in situ huntingtin aggregation in cellular models of Huntington's disease. by Lecerf JM, Shirley TL, Zhu Q, Kazantsev A, Amersdorfer P, Housman DE, Messer A, Huston JS.; 2001 Apr 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=31908

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Huntington's disease age-of-onset linked to polyglutamine aggregation nucleation. by Chen S, Ferrone FA, Wetzel R.; 2002 Sep 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=129363

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Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay. by Heiser V, Engemann S, Brocker W, Dunkel I, Boeddrich A, Waelter S, Nordhoff E, Lurz R, Schugardt N, Rautenberg S, Herhaus C, Barnickel G, Bottcher H, Lehrach H, Wanker EE.; 2002 Dec 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139900

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Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: Implications for Huntington's disease therapy. by Heiser V, Scherzinger E, Boeddrich A, Nordhoff E, Lurz R, Schugardt N, Lehrach H, Wanker EE.; 2000 Jun 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18723

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Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington's disease. by Turmaine M, Raza A, Mahal A, Mangiarini L, Bates GP, Davies SW.; 2000 Jul 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16675

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Novel therapies in the search for a cure for Huntington's disease. by Beal MF, Hantraye P.; 2001 Jan 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33346

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Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: Implications for Huntington's disease pathology. by Scherzinger E, Sittler A, Schweiger K, Heiser V, Lurz R, Hasenbank R, Bates GP, Lehrach H, Wanker EE.; 1999 Apr 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16379

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Severe deficiencies in dopamine signaling in presymptomatic Huntington's disease mice. by Bibb JA, Yan Z, Svenningsson P, Snyder GL, Pieribone VA, Horiuchi A, Nairn AC, Messer A, Greengard P.; 2000 Jun 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18747

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Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. by Hockly E, Richon VM, Woodman B, Smith DL, Zhou X, Rosa E, Sathasivam K, Ghazi-Noori S, Mahal A, Lowden PA, Steffan JS, Marsh JL, Thompson LM, Lewis CM, Marks PA, Bates GP.; 2003 Feb 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149955

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Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease. by Keene CD, Rodrigues CM, Eich T, Chhabra MS, Steer CJ, Low WC.; 2002 Aug 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125009

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The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: Neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis. by Holbert S, Denghien I, Kiechle T, Rosenblatt A, Wellington C, Hayden MR, Margolis RL, Ross CA, Dausset J, Ferrante RJ, Neri C.; 2001 Feb 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=29339

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The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. by Steffan JS, Kazantsev A, Spasic-Boskovic O, Greenwald M, Zhu YZ, Gohler H, Wanker EE, Bates GP, Housman DE, Thompson LM.; 2000 Jun 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18731

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Transgenic mice expressing a Huntington's disease mutation are resistant to quinolinic acid-induced striatal excitotoxicity. by Hansson O, Petersen A, Leist M, Nicotera P, Castilho RF, Brundin P.; 1999 Jul 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17584

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Transglutaminase aggregates huntingtin into nonamyloidogenic polymers, and its enzymatic activity increases in Huntington's disease brain nuclei. by Karpuj MV, Garren H, Slunt H, Price DL, Gusella J, Becher MW, Steinman L.; 1999 Jun 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22095

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Transplanted fetal striatum in Huntington's disease: Phenotypic development and lack of pathology. by Freeman TB, Cicchetti F, Hauser RA, Deacon TW, Li XJ, Hersch SM, Nauert GM, Sanberg PR, Kordower JH, Saporta S, Isacson O.; 2000 Dec 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17669

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.6 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 use. 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 Huntington’s disease, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “Huntington’s disease” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for Huntington’s disease (hyperlinks lead to article summaries):

6 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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A case of unilateral neglect in Huntington's disease. Author(s): Ho AK, Manly T, Nestor PJ, Sahakian BJ, Bak TH, Robbins TW, Rosser AE, Barker RA. Source: Neurocase : Case Studies in Neuropsychology, Neuropsychiatry, and Behavioural Neurology. 2003 June; 9(3): 261-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12925932&dopt=Abstract

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A clinical study of patients with genetically confirmed Huntington's disease from India. Author(s): Murgod UA, Saleem Q, Anand A, Brahmachari SK, Jain S, Muthane UB. Source: Journal of the Neurological Sciences. 2001 September 15; 190(1-2): 73-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11574110&dopt=Abstract

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A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion. Author(s): Margolis RL, O'Hearn E, Rosenblatt A, Willour V, Holmes SE, Franz ML, Callahan C, Hwang HS, Troncoso JC, Ross CA. Source: Annals of Neurology. 2001 December; 50(6): 373-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11761463&dopt=Abstract

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A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion. Author(s): Margolis RL, O'Hearn E, Rosenblatt A, Willour V, Holmes SE, Franz ML, Callahan C, Hwang HS, Troncoso JC, Ross CA. Source: Annals of Neurology. 2001 September; 50(3): 373-80. Corrected and Republished In: http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11558794&dopt=Abstract

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A randomised, placebo-controlled, double blind study of treatment of Huntington's disease with unsaturated fatty acids. Author(s): Vaddadi KS, Soosai E, Chiu E, Dingjan P. Source: Neuroreport. 2002 January 21; 13(1): 29-33. Erratum In: Neuroreport 2002 February; 13(2): Inside Back Cover. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11924889&dopt=Abstract

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A regression-based method to identify differentially expressed genes in microarray time course studies and its application in an inducible Huntington's disease transgenic model. Author(s): Xu XL, Olson JM, Zhao LP. Source: Human Molecular Genetics. 2002 August 15; 11(17): 1977-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12165559&dopt=Abstract

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A study of arm movements in Huntington's disease under visually controlled and blindfolded conditions. Author(s): Carella F, Bressanelli M, Piacentini S, Soliveri P, Geminiani G, Monza D, Albanese A, Girotti F. Source: Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2003 February; 23(6): 287-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12624715&dopt=Abstract

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Abnormalities in the synaptic vesicle fusion machinery in Huntington's disease. Author(s): Morton AJ, Faull RL, Edwardson JM. Source: Brain Research Bulletin. 2001 September 15; 56(2): 111-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11704347&dopt=Abstract

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Advances in Huntington's disease: implications for experimental therapeutics. Author(s): Feigin A. Source: Current Opinion in Neurology. 1998 August; 11(4): 357-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9725082&dopt=Abstract

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Alteration of nuclear glyceraldehyde-3-phosphate dehydrogenase structure in Huntington's disease fibroblasts. Author(s): Mazzola JL, Sirover MA. Source: Brain Research. Molecular Brain Research. 2002 April 30; 100(1-2): 95-101. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12008025&dopt=Abstract

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Alterations in the mouse and human proteome caused by Huntington's disease. Author(s): Zabel C, Chamrad DC, Priller J, Woodman B, Meyer HE, Bates GP, Klose J. Source: Molecular & Cellular Proteomics : Mcp. 2002 May; 1(5): 366-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12118078&dopt=Abstract

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Altered functional MRI responses in Huntington's disease. Author(s): Clark VP, Lai S, Deckel AW. Source: Neuroreport. 2002 April 16; 13(5): 703-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11973474&dopt=Abstract

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Amantadine in Huntington's disease: open-label video-blinded study. Author(s): Lucetti C, Gambaccini G, Bernardini S, Dell'Agnello G, Petrozzi L, Rossi G, Bonuccelli U. Source: Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2002 September; 23 Suppl 2: S83-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12548355&dopt=Abstract

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An overview of psychiatric symptoms in Huntington's disease. Author(s): Anderson KE, Marder KS. Source: Current Psychiatry Reports. 2001 October; 3(5): 379-88. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11559474&dopt=Abstract

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Anonymous predictive testing for Huntington's disease in the United States. Author(s): Visintainer CL, Matthias-Hagen V, Nance MA; U.S. Huntington Disease Genetic Testing Group. Source: Genetic Testing. 2001 Fall; 5(3): 213-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11788086&dopt=Abstract

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Apolipoprotein E polymorphism in Pick's disease and in Huntington's disease. Author(s): Kalman J, Juhasz A, Majtenyi K, Rimanoczy A, Jakab K, Gardian G, Rasko I, Janka Z. Source: Neurobiology of Aging. 2000 July-August; 21(4): 555-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10924769&dopt=Abstract

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Apoptosis in Huntington's disease. Author(s): Hickey MA, Chesselet MF. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2003 April; 27(2): 255-65. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12657365&dopt=Abstract

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Apraxia of eyelid closure in Huntington's disease. Author(s): Bonelli RM, Niederwieser G. Source: Journal of Neural Transmission (Vienna, Austria : 1996). 2002 February; 109(2): 197-201. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12075860&dopt=Abstract

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Atrophy of caudate nucleus in Huntington's disease measured by computed tomography. Author(s): Roth J, Havrdova E, Ruzicka E. Source: Journal of Neurology. 2000 November; 247(11): 880-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11151423&dopt=Abstract

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Autonomic nervous system function in Huntington's disease. Author(s): Andrich J, Schmitz T, Saft C, Postert T, Kraus P, Epplen JT, Przuntek H, Agelink MW. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2002 June; 72(6): 726-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12023413&dopt=Abstract

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Basal ganglia alterations and brain atrophy in Huntington's disease depicted by transcranial real time sonography. Author(s): Postert T, Lack B, Kuhn W, Jergas M, Andrich J, Braun B, Przuntek H, Sprengelmeyer R, Agelink M, Buttner T. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 1999 October; 67(4): 45762. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10486391&dopt=Abstract

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Behavior in Huntington's disease: dissociating cognition-based and mood-based changes. Author(s): Thompson JC, Snowden JS, Craufurd D, Neary D. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 2002 Winter; 14(1): 37-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11884653&dopt=Abstract

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Behavioral and morphological comparison of two nonhuman primate models of Huntington's disease. Author(s): Rafael H. Source: Neurosurgery. 2002 September; 51(3): 852-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12229869&dopt=Abstract

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Behavioral and morphological comparison of two nonhuman primate models of Huntington's disease. Author(s): Roitberg BZ, Emborg ME, Sramek JG, Palfi S, Kordower JH. Source: Neurosurgery. 2002 January; 50(1): 137-45; Discussion 145-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11844244&dopt=Abstract

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Behavioural complaints in participants who underwent predictive testing for Huntington's disease. Author(s): Witjes-Ane MN, Zwinderman AH, Tibben A, van Ommen GJ, Roos RA. Source: Journal of Medical Genetics. 2002 November; 39(11): 857-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12414829&dopt=Abstract

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Bilateral fetal striatal grafts in the 3-nitropropionic acid-induced hypoactive model of Huntington's disease. Author(s): Borlongan CV, Koutouzis TK, Poulos SG, Saporta S, Sanberg PR. Source: Cell Transplantation. 1998 March-April; 7(2): 131-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9588595&dopt=Abstract

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Bilateral human fetal striatal transplantation in Huntington's disease. Author(s): Hauser RA, Sandberg PR, Freeman TB, Stoessl AJ. Source: Neurology. 2002 June 11; 58(11): 1704; Author Reply 1704. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12058114&dopt=Abstract

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Bilateral human fetal striatal transplantation in Huntington's disease. Author(s): Hauser RA, Furtado S, Cimino CR, Delgado H, Eichler S, Schwartz S, Scott D, Nauert GM, Soety E, Sossi V, Holt DA, Sanberg PR, Stoessl AJ, Freeman TB. Source: Neurology. 2002 March 12; 58(5): 687-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11889229&dopt=Abstract

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Bimanual co-ordination in Huntington's disease. Author(s): Johnson KA, Bennett JE, Georgiou N, Bradshaw JL, Chiu E, Cunnington R, Iansek R. Source: Experimental Brain Research. Experimentelle Hirnforschung. Experimentation Cerebrale. 2000 October; 134(4): 483-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11081830&dopt=Abstract

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Biochemical abnormalities and excitotoxicity in Huntington's disease brain. Author(s): Tabrizi SJ, Cleeter MW, Xuereb J, Taanman JW, Cooper JM, Schapira AH. Source: Annals of Neurology. 1999 January; 45(1): 25-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9894873&dopt=Abstract

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Bioenergetics in Huntington's disease. Author(s): Grunewald T, Beal MF. Source: Annals of the New York Academy of Sciences. 1999; 893: 203-13. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10672239&dopt=Abstract

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Borderline repeat expansion in Huntington's disease. Author(s): de Rooij KE, de Koning Gans PA, Losekoot M, Bakker E, den Dunnen JT, Vegter-van der Vlis M, Roos RA, van Ommen GJ. Source: Lancet. 1993 December 11; 342(8885): 1491-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7902514&dopt=Abstract

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Bradykinesia and movement precision in Huntington's disease. Author(s): Phillips JG, Bradshaw JL, Chiu E, Teasdale N, Iansek R, Bradshaw JA. Source: Neuropsychologia. 1996 December; 34(12): 1241-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8951836&dopt=Abstract

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Bradykinesia in early Huntington's disease. Author(s): Sanchez-Pernaute R, Kunig G, del Barrio Alba A, de Yebenes JG, Vontobel P, Leenders KL. Source: Neurology. 2000 January 11; 54(1): 119-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10636136&dopt=Abstract

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Bradykinesia in Huntington's disease. Author(s): Garcia Ruiz PJ, Gomez Tortosa E, Sanchez Bernados V, Rojo A, Fontan A, Garcia de Yebenes J. Source: Clinical Neuropharmacology. 2000 January-February; 23(1): 50-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10682231&dopt=Abstract

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Bradykinesia in Huntington's disease. A prospective, follow-up study. Author(s): Garcia Ruiz PJ, Hernandez J, Cantarero S, Bartolome M, Sanchez Bernardos V, Garcia de Yebenez J. Source: Journal of Neurology. 2002 April; 249(4): 437-40. Erratum In: J Neurol 2002 June; 249(6): 790. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11967649&dopt=Abstract

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Brain SPECT imaging in Huntington's disease before and after therapy with olanzapine. Case report. Author(s): Etchebehere EC, Lima MC, Passos W, Maciel Junior JA, Santos AO, Ramos CD, Camargo EE. Source: Arquivos De Neuro-Psiquiatria. 1999 September; 57(3B): 863-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10751925&dopt=Abstract

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Bruxism in Huntington's disease. Author(s): Tan EK, Jankovic J, Ondo W. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 2000 January; 15(1): 171-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10634263&dopt=Abstract

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Bruxism in Huntington's disease. Author(s): Louis ED, Tampone E. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 2001 July; 16(4): 785-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11481718&dopt=Abstract

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Buspirone in the management of disruptive behaviors due to Huntington's disease and other neurological disorders. Author(s): Bhandary AN, Masand PS. Source: Psychosomatics. 1997 July-August; 38(4): 389-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9217410&dopt=Abstract

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CAG mutation effect on rate of progression in Huntington's disease. Author(s): Squitieri F, Cannella M, Simonelli M. Source: Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2002 September; 23 Suppl 2: S107-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12548366&dopt=Abstract

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CAG/CTG repeat expansions at the Huntington's disease-like 2 locus are rare in Huntington's disease patients. Author(s): Stevanin G, Camuzat A, Holmes SE, Julien C, Sahloul R, Dode C, HahnBarma V, Ross CA, Margolis RL, Durr A, Brice A. Source: Neurology. 2002 March 26; 58(6): 965-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11914418&dopt=Abstract

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Calpain activation in Huntington's disease. Author(s): Gafni J, Ellerby LM. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2002 June 15; 22(12): 4842-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12077181&dopt=Abstract

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Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis. Author(s): Kim YJ, Yi Y, Sapp E, Wang Y, Cuiffo B, Kegel KB, Qin ZH, Aronin N, DiFiglia M. Source: Proceedings of the National Academy of Sciences of the United States of America. 2001 October 23; 98(22): 12784-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11675509&dopt=Abstract

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Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease. Author(s): Wellington CL, Ellerby LM, Gutekunst CA, Rogers D, Warby S, Graham RK, Loubser O, van Raamsdonk J, Singaraja R, Yang YZ, Gafni J, Bredesen D, Hersch SM, Leavitt BR, Roy S, Nicholson DW, Hayden MR. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2002 September 15; 22(18): 7862-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12223539&dopt=Abstract

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Caspases in Huntington's disease. Author(s): Sanchez Mejia RO, Friedlander RM. Source: The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry. 2001 December; 7(6): 480-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11765125&dopt=Abstract

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Cdc42-interacting protein 4 binds to huntingtin: neuropathologic and biological evidence for a role in Huntington's disease. Author(s): Holbert S, Dedeoglu A, Humbert S, Saudou F, Ferrante RJ, Neri C. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 March 4; 100(5): 2712-7. Epub 2003 February 25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12604778&dopt=Abstract

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Cell therapy for Huntington's disease, the next step forward. Author(s): Peschanski M, Dunnett SB. Source: Lancet. Neurology. 2002 June; 1(2): 81. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12849508&dopt=Abstract

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Centrosome disorganization in fibroblast cultures derived from R6/2 Huntington's disease (HD) transgenic mice and HD patients. Author(s): Sathasivam K, Woodman B, Mahal A, Bertaux F, Wanker EE, Shima DT, Bates GP. Source: Human Molecular Genetics. 2001 October 1; 10(21): 2425-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11689489&dopt=Abstract

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Clinical and counselling implications of preimplantation genetic diagnosis for Huntington's disease in the UK. Author(s): Lashwood A, Flinter F. Source: Hum Fertil (Camb). 2001; 4(4): 235-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11719718&dopt=Abstract

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Clinical and research advances in Huntington's disease. Author(s): SuttonBrown M, Suchowersky O. Source: The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques. 2003 March; 30 Suppl 1: S45-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12691476&dopt=Abstract

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Clinical relevance of electrophysiological tests in the assessment of patients with Huntington's disease. Author(s): Lefaucheur JP, Bachoud-Levi AC, Bourdet C, Grandmougin T, Hantraye P, Cesaro P, Degos JD, Peschanski M, Lisovoski F. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 2002 November; 17(6): 1294-301. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12465071&dopt=Abstract

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Cognitive and motor functioning in gene carriers for Huntington's disease: a baseline study. Author(s): Witjes-Ane MN, Vegter-van der Vlis M, van Vugt JP, Lanser JB, Hermans J, Zwinderman AH, van Ommen GJ, Roos RA. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 2003 Winter; 15(1): 7-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12556566&dopt=Abstract

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Cognitive and psychiatric characterization of patients with Huntington's disease and their at-risk relatives. Author(s): Soliveri P, Monza D, Piacentini S, Paridi D, Nespolo C, Gellera C, Mariotti C, Albanese A, Girotti F. Source: Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2002 September; 23 Suppl 2: S105-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12548365&dopt=Abstract

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Complex language functions and subcortical mechanisms: evidence from Huntington's disease and patients with non-thalamic subcortical lesions. Author(s): Chenery HJ, Copland DA, Murdoch BE. Source: International Journal of Language & Communication Disorders / Royal College of Speech & Language Therapists. 2002 October-December; 37(4): 459-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12396844&dopt=Abstract

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Control of manipulative forces during unimanual and bimanual tasks in patients with Huntington's disease. Author(s): Serrien DJ, Burgunder JM, Wiesendanger M. Source: Experimental Brain Research. Experimentelle Hirnforschung. Experimentation Cerebrale. 2002 April; 143(3): 328-34. Epub 2002 January 30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11889510&dopt=Abstract

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Counting CAG repeats in the Huntington's disease gene by restriction endonuclease EcoP15I cleavage. Author(s): Moncke-Buchner E, Reich S, Mucke M, Reuter M, Messer W, Wanker EE, Kruger DH. Source: Nucleic Acids Research. 2002 August 15; 30(16): E83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12177311&dopt=Abstract

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Crime in Huntington's disease. Author(s): Ring HA. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 1998 October; 65(4): 435. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9771762&dopt=Abstract

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Crime in Huntington's disease: a study of registered offences among patients, relatives, and controls. Author(s): Jensen P, Fenger K, Bolwig TG, Sorensen SA. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 1998 October; 65(4): 46771. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9771767&dopt=Abstract

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Cytochrome C and caspase-9 expression in Huntington's disease. Author(s): Kiechle T, Dedeoglu A, Kubilus J, Kowall NW, Beal MF, Friedlander RM, Hersch SM, Ferrante RJ. Source: Neuromolecular Medicine. 2002; 1(3): 183-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12095160&dopt=Abstract

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De novo expansion of a CAG repeat in a Japanese patient with sporadic Huntington's disease. Author(s): Watanabe M, Satoh A, Kanemoto M, Ohkoshi N, Shoji S. Source: Journal of the Neurological Sciences. 2000 September 15; 178(2): 159-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11018708&dopt=Abstract

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Decreased expression of striatal signaling genes in a mouse model of Huntington's disease. Author(s): Luthi-Carter R, Strand A, Peters NL, Solano SM, Hollingsworth ZR, Menon AS, Frey AS, Spektor BS, Penney EB, Schilling G, Ross CA, Borchelt DR, Tapscott SJ, Young AB, Cha JH, Olson JM. Source: Human Molecular Genetics. 2000 May 22; 9(9): 1259-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10814708&dopt=Abstract

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Decreased plasma alanine and isoleucine in Huntington's disease. Author(s): Reilmann R, Rolf LH, Lange HW. Source: Acta Neurologica Scandinavica. 1995 March; 91(3): 222-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7793240&dopt=Abstract

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Deep brain stimulation in Huntington's disease. Author(s): Bonelli RM, Gruber A. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 2002 March; 17(2): 429-30; Author Reply 431-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11921144&dopt=Abstract

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Deficits in sensorimotor control during precise hand movements in Huntington's disease. Author(s): Schwarz M, Fellows SJ, Schaffrath C, Noth J. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2001 January; 112(1): 95-106. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11137666&dopt=Abstract

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Detection of subclinical brain electrical activity changes in Huntington's disease using artificial neural networks. Author(s): de Tommaso M, De Carlo F, Difruscolo O, Massafra R, Sciruicchio V, Bellotti R. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2003 July; 114(7): 1237-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12842720&dopt=Abstract

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Diagnostic re-evaluation of a case of 'cerebellar atrophy with Huntington's disease'. Author(s): White SM, Gubbay SS, Norbury CG, Rosser EM, Huson SM. Source: Journal of the Neurological Sciences. 2000 March 1; 174(1): 47-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10798915&dopt=Abstract

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Differential deficits in expression recognition in gene-carriers and patients with Huntington's disease. Author(s): Milders M, Crawford JR, Lamb A, Simpson SA. Source: Neuropsychologia. 2003; 41(11): 1484-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12849766&dopt=Abstract

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Disclosure of Huntington's disease to family members: the dilemma of known but unknowing parties. Author(s): Hakimian R. Source: Genetic Testing. 2000; 4(4): 359-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11216659&dopt=Abstract

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Dissociation between intentional and incidental sequence learning in Huntington's disease. Author(s): Brown RG, Redondo-Verge L, Chacon JR, Lucas ML, Channon S. Source: Brain; a Journal of Neurology. 2001 November; 124(Pt 11): 2188-202. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11673321&dopt=Abstract

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Distractibility during selection-for-action: differential deficits in Huntington's disease and following frontal lobe damage. Author(s): Aron AR, Sahakian BJ, Robbins TW. Source: Neuropsychologia. 2003; 41(9): 1137-47. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12753954&dopt=Abstract

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Distribution of CAG repeats in normal and Huntington's disease patients in Israel. Author(s): Gazit E, Lubomirov L, Munakov O, Topper A, Frydman M, Fried K, Borochovitz Z, Dangoor N, Bogolubov A, Carp HJ. Source: Clinical Genetics. 1998 September; 54(3): 250-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9788733&dopt=Abstract

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Disturbance of “extrinsic alertness” in Huntington's disease. Author(s): Muller SV, Jung A, Preinfalk J, Kolbe H, Ridao-Alonso M, Dengler R, Munte TF. Source: J Clin Exp Neuropsychol. 2002 June; 24(4): 517-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12187464&dopt=Abstract

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Does CAG repeat number predict the rate of pathological changes in Huntington's disease? Author(s): Rosenblatt A, Margolis RL, Becher MW, Aylward E, Franz ML, Sherr M, Abbott MH, Lian KY, Ross CA. Source: Annals of Neurology. 1998 October; 44(4): 708-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9778276&dopt=Abstract

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Does mRNA translation starting from an alternative initiation site contribute to the pathology of Huntington's disease? Author(s): Santos AD, Padlan EA. Source: Medical Hypotheses. 2000 May; 54(5): 689-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10859666&dopt=Abstract

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Does tissue transglutaminase play a role in Huntington's disease? Author(s): Lesort M, Chun W, Tucholski J, Johnson GV. Source: Neurochemistry International. 2002 January; 40(1): 37-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11738471&dopt=Abstract

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Donepezil for Huntington's disease. Author(s): Fernandez HH, Friedman JH, Grace J, Beason-Hazen S. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 2000 January; 15(1): 173-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10634264&dopt=Abstract

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Dopamine and cognitive functioning: brain imaging findings in Huntington's disease and normal aging. Author(s): Backman L, Farde L. Source: Scandinavian Journal of Psychology. 2001 July; 42(3): 287-96. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11501742&dopt=Abstract

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Dose-dependent neuroprotective effect of ciliary neurotrophic factor delivered via tetracycline-regulated lentiviral vectors in the quinolinic acid rat model of Huntington's disease. Author(s): Regulier E, Pereira de Almeida L, Sommer B, Aebischer P, Deglon N. Source: Human Gene Therapy. 2002 November 1; 13(16): 1981-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12427308&dopt=Abstract

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Double-stranded RNA-dependent protein kinase, PKR, binds preferentially to Huntington's disease (HD) transcripts and is activated in HD tissue. Author(s): Peel AL, Rao RV, Cottrell BA, Hayden MR, Ellerby LM, Bredesen DE. Source: Human Molecular Genetics. 2001 July 15; 10(15): 1531-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11468270&dopt=Abstract

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Early alterations in gene expression and cell morphology in a mouse model of Huntington's disease. Author(s): Iannicola C, Moreno S, Oliverio S, Nardacci R, Ciofi-Luzzatto A, Piacentini M. Source: Journal of Neurochemistry. 2000 August; 75(2): 830-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10899961&dopt=Abstract

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Early kynurenergic impairment in Huntington's disease and in a transgenic animal model. Author(s): Guidetti P, Reddy PH, Tagle DA, Schwarcz R. Source: Neuroscience Letters. 2000 April 14; 283(3): 233-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10754231&dopt=Abstract

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Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines. Author(s): Panov AV, Gutekunst CA, Leavitt BR, Hayden MR, Burke JR, Strittmatter WJ, Greenamyre JT. Source: Nature Neuroscience. 2002 August; 5(8): 731-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12089530&dopt=Abstract

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Effect of an attentional strategy on movement-related potentials recorded from subjects with Huntington's disease. Author(s): Johnson KA, Cunnington R, Bradshaw JL, Chiu E, Iansek R. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 2002 September; 17(5): 998-1003. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12360549&dopt=Abstract

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Effectiveness of physiotherapy, occupational therapy, and speech pathology for people with Huntington's disease: a systematic review. Author(s): Bilney B, Morris ME, Perry A. Source: Neurorehabilitation and Neural Repair. 2003 March; 17(1): 12-24. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12645441&dopt=Abstract

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Effects of depression on working memory in presymptomatic Huntington's disease. Author(s): Nehl C, Ready RE, Hamilton J, Paulsen JS. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 2001 Summer; 13(3): 342-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11514640&dopt=Abstract

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Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease. Author(s): Wyttenbach A, Carmichael J, Swartz J, Furlong RA, Narain Y, Rankin J, Rubinsztein DC. Source: Proceedings of the National Academy of Sciences of the United States of America. 2000 March 14; 97(6): 2898-903. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10717003&dopt=Abstract

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Effects of multisensory stimulation in people with Huntington's disease: a randomized controlled pilot study. Author(s): Leng TR, Woodward MJ, Stokes MJ, Swan AV, Wareing LA, Baker R. Source: Clinical Rehabilitation. 2003 February; 17(1): 30-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617377&dopt=Abstract

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Electrophysiological and morphological changes in striatal spiny neurons in R6/2 Huntington's disease transgenic mice. Author(s): Klapstein GJ, Fisher RS, Zanjani H, Cepeda C, Jokel ES, Chesselet MF, Levine MS. Source: Journal of Neurophysiology. 2001 December; 86(6): 2667-77. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11731527&dopt=Abstract

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Encapsulated CNTF-producing cells for Huntington's disease. Author(s): Emerich DF. Source: Cell Transplantation. 1999 November-December; 8(6): 581-2. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10701486&dopt=Abstract

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Endogenous sodium-potassium ATPase inhibition related biochemical cascade in trisomy 21 and Huntington's disease: neural regulation of genomic function. Author(s): Kumar AR, Kurup PA. Source: Neurology India. 2002 June; 50(2): 174-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12134182&dopt=Abstract

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Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and knockin mouse models of Huntington's disease. Author(s): Levine MS, Klapstein GJ, Koppel A, Gruen E, Cepeda C, Vargas ME, Jokel ES, Carpenter EM, Zanjani H, Hurst RS, Efstratiadis A, Zeitlin S, Chesselet MF. Source: Journal of Neuroscience Research. 1999 November 15; 58(4): 515-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10533044&dopt=Abstract

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Environmental stimulation increases survival in mice transgenic for exon 1 of the Huntington's disease gene. Author(s): Carter RJ, Hunt MJ, Morton AJ. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 2000 September; 15(5): 925-37. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11009201&dopt=Abstract

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Evidence for a recruitment and sequestration mechanism in Huntington's disease. Author(s): Preisinger E, Jordan BM, Kazantsev A, Housman D. Source: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 1999 June 29; 354(1386): 1029-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10434302&dopt=Abstract

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Evidence for a role for transglutaminase in Huntington's disease and the potential therapeutic implications. Author(s): Karpuj MV, Becher MW, Steinman L. Source: Neurochemistry International. 2002 January; 40(1): 31-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11738470&dopt=Abstract

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Evidence for both the nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington's disease in cell culture and in transgenic mice expressing mutant huntingtin. Author(s): Hackam AS, Hodgson JG, Singaraja R, Zhang T, Gan L, Gutekunst CA, Hersch SM, Hayden MR. Source: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 1999 June 29; 354(1386): 1047-55. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10434304&dopt=Abstract

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Evidence for the GluR6 gene associated with younger onset age of Huntington's disease. Author(s): MacDonald ME, Vonsattel JP, Shrinidhi J, Couropmitree NN, Cupples LA, Bird ED, Gusella JF, Myers RH. Source: Neurology. 1999 October 12; 53(6): 1330-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10522893&dopt=Abstract

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Exclusion mapping of the benign hereditary chorea gene from the Huntington's disease locus: report of a family. Author(s): Yapijakis C, Kapaki E, Zournas C, Rentzos M, Loukopoulos D, Papageorgiou C. Source: Clinical Genetics. 1995 March; 47(3): 133-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7634535&dopt=Abstract

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Expanded CAG repeats in exon 1 of the Huntington's disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration. Author(s): Petersen A, Larsen KE, Behr GG, Romero N, Przedborski S, Brundin P, Sulzer D. Source: Human Molecular Genetics. 2001 June 1; 10(12): 1243-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11406606&dopt=Abstract

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Experience in prenatal testing for Huntington's disease in The Netherlands: procedures, results and guidelines (1987-1997). Author(s): Maat-Kievit A, Vegter-van der Vlis M, Zoeteweij M, Losekoot M, van Haeringen A, Kanhai H, Roos R. Source: Prenatal Diagnosis. 1999 May; 19(5): 450-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10360514&dopt=Abstract

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Familial aggregation of psychotic symptoms in Huntington's disease. Author(s): Tsuang D, Almqvist EW, Lipe H, Strgar F, DiGiacomo L, Hoff D, Eugenio C, Hayden MR, Bird TD. Source: The American Journal of Psychiatry. 2000 December; 157(12): 1955-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11097960&dopt=Abstract

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Familial aggregation of schizophrenia-like symptoms in Huntington's disease. Author(s): Tsuang D, DiGiacomo L, Lipe H, Bird TD. Source: American Journal of Medical Genetics. 1998 July 10; 81(4): 323-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9674979&dopt=Abstract

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Family history and DNA analysis in patients with suspected Huntington's disease. Author(s): Siesling S, Vegter-van de Vlis M, Losekoot M, Belfroid RD, Maat-Kievit JA, Kremer HP, Roos RA. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2000 July; 69(1): 54-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10864604&dopt=Abstract

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Fas and Fas-L expression in Huntington's disease and Parkinson's disease. Author(s): Ferrer I, Blanco R, Cutillas B, Ambrosio S. Source: Neuropathology and Applied Neurobiology. 2000 October; 26(5): 424-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11054182&dopt=Abstract

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Features of the blink reflex in individuals at risk for Huntington's disease. Author(s): de Tommaso M, Sciruicchio V, Spinelli A, Specchio N, Difruscolo O, Puca F, Specchio LM. Source: Muscle & Nerve. 2001 November; 24(11): 1520-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11745955&dopt=Abstract

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Fetal neural grafts for Huntington's disease: a prospective view. Author(s): Bachoud-Levi AC, Hantraye P, Peschanski M. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 2002 May; 17(3): 439-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12112189&dopt=Abstract

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Fetal striatal transplantation in Huntington's disease: time for a pause. Author(s): Albin RL. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2002 December; 73(6): 612. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12438457&dopt=Abstract

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Fetal striatal transplants restore electrophysiological sensitivity to dopamine in the lesioned striatum of rats with experimental Huntington's disease. Author(s): Chen GJ, Jeng CH, Lin SZ, Tsai SH, Wang Y, Chiang YH. Source: Journal of Biomedical Science. 2002 July-August; 9(4): 303-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12145527&dopt=Abstract

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Fetal tissue transplants in animal models of Huntington's disease: the effects on damaged neuronal circuitry and behavioral deficits. Author(s): Nakao N, Itakura T. Source: Progress in Neurobiology. 2000 June; 61(3): 313-38. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10727778&dopt=Abstract

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First diagnostic applications of transcallosal inhibition in diseases affecting callosal neurones (multiple sclerosis, hydrocephalus, Huntington's disease). Author(s): Meyer BU, Roricht S, Schmierer K, Irlbacher K, Meierkord H, Niehaus L, Grosse P. Source: Electroencephalogr Clin Neurophysiol Suppl. 1999; 51: 233-42. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10590955&dopt=Abstract

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First step towards cell therapy for Huntington's disease. Author(s): Lindvall O, Bjorklund A. Source: Lancet. 2000 December 9; 356(9246): 1945-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11130518&dopt=Abstract

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Fluorescence PCR and GeneScan analysis for the detection of CAG repeat expansions associated with Huntington's disease. Author(s): Vnencak-Jones CL. Source: Methods in Molecular Biology (Clifton, N.J.). 2003; 217: 101-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12491925&dopt=Abstract

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Fluoxetine in the treatment of Huntington's disease. Author(s): De Marchi N, Daniele F, Ragone MA. Source: Psychopharmacology. 2001 January 1; 153(2): 264-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11205429&dopt=Abstract

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Fluoxetine-induced exacerbation of chorea in Huntington's disease? A case report. Author(s): Chari S, Quraishi SH, Jainer AK. Source: Pharmacopsychiatry. 2003 January; 36(1): 41-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12649776&dopt=Abstract

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From neuronal inclusions to neurodegeneration: neuropathological investigation of a transgenic mouse model of Huntington's disease. Author(s): Davies SW, Turmaine M, Cozens BA, Raza AS, Mahal A, Mangiarini L, Bates GP. Source: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 1999 June 29; 354(1386): 981-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10434295&dopt=Abstract

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Full length huntingtin is not detected in intranuclear inclusions in Huntington's disease brain. Author(s): Thomas P, Wilkinson F, Nguyen TM, Harper PS, Neal JW, Morris GE, Jones AL. Source: Biochemical Society Transactions. 1998 August; 26(3): S243. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9765962&dopt=Abstract

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Functional analysis of the Huntington's disease (HD) gene promoter. Author(s): Coles R, Caswell R, Rubinsztein DC. Source: Human Molecular Genetics. 1998 May; 7(5): 791-800. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9536082&dopt=Abstract

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Functional characterization of the human Huntington's disease gene promoter. Author(s): Holzmann C, Schmidt T, Thiel G, Epplen JT, Riess O. Source: Brain Research. Molecular Brain Research. 2001 August 15; 92(1-2): 85-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11483245&dopt=Abstract

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Functional decline in Huntington's disease. Author(s): Feigin A, Kieburtz K, Bordwell K, Como P, Steinberg K, Sotack J, Zimmerman C, Hickey C, Orme C, Shoulson I. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 1995 March; 10(2): 211-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7753064&dopt=Abstract

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Future directions in research with presymptomatic individuals carrying the gene for Huntington's disease. Author(s): Georgiou-Karistianis N, Smith E, Bradshaw JL, Chua P, Lloyd J, Churchyard A, Chiu E. Source: Brain Research Bulletin. 2003 January 30; 59(5): 331-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12507683&dopt=Abstract

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Gait dysfunction in Huntington's disease: parkinsonism and a disorder of timing. Implications for movement rehabilitation. Author(s): Churchyard AJ, Morris ME, Georgiou N, Chiu E, Cooper R, Iansek R. Source: Adv Neurol. 2001; 87: 375-85. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11347241&dopt=Abstract

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Gait variability and basal ganglia disorders: stride-to-stride variations of gait cycle timing in Parkinson's disease and Huntington's disease. Author(s): Hausdorff JM, Cudkowicz ME, Firtion R, Wei JY, Goldberger AL. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 1998 May; 13(3): 428-37. Erratum In: Mov Disord 1998 July; 13(4): 757. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9613733&dopt=Abstract

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Gametic but not somatic instability of CAG repeat length in Huntington's disease. Author(s): MacDonald ME, Barnes G, Srinidhi J, Duyao MP, Ambrose CM, Myers RH, Gray J, Conneally PM, Young A, Penney J, et al. Source: Journal of Medical Genetics. 1993 December; 30(12): 982-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8133508&dopt=Abstract

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Gender of the embryo contributes to CAG instability in transgenic mice containing a Huntington's disease gene. Author(s): Kovtun IV, Therneau TM, McMurray CT. Source: Human Molecular Genetics. 2000 November 1; 9(18): 2767-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11063736&dopt=Abstract

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Genetic association of Huntington's disease and restless legs syndrome? A family report. Author(s): Evers S, Stogbauer F. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 2003 February; 18(2): 225-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12539222&dopt=Abstract

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Genetic discrimination: Huntington's disease and the Americans with Disabilities Act. Author(s): Gin BR. Source: Columbia Law Rev. 1997 June; 97(5): 1406-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10175166&dopt=Abstract

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Genetic fitness in Huntington's Disease and Spinocerebellar Ataxia 1: a population genetics model for CAG repeat expansions. Author(s): Frontali M, Sabbadini G, Novelletto A, Jodice C, Naso F, Spadaro M, Giunti P, Jacopini AG, Veneziano L, Mantuano E, Malaspina P, Ulizzi L, Brice A, Durr A, Terrenato L. Source: Annals of Human Genetics. 1996 September; 60 ( Pt 5): 423-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8912795&dopt=Abstract

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Genetic polymorphisms adjacent to the CAG repeat influence clinical features at onset in Huntington's disease. Author(s): Vuillaume I, Vermersch P, Destee A, Petit H, Sablonniere B. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 1998 June; 64(6): 758-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9647305&dopt=Abstract

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Genetic screening for Huntington's disease in Chinese patients with involuntary movements. Author(s): Shan DE, Soong BW, Yeh SI, Cheng CH, Wu ZA. Source: Clinical Neurology and Neurosurgery. 1997 December; 99(4): 244-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9491297&dopt=Abstract

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Genetic testing for Huntington's disease--a family issue. Author(s): Hayes CV. Source: The New England Journal of Medicine. 1992 November 12; 327(20): 1449-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1406861&dopt=Abstract

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Genetic testing of children at risk for Huntington's disease. US Huntington Disease Genetic Testing Group. Author(s): Nance MA. Source: Neurology. 1997 October; 49(4): 1048-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9339688&dopt=Abstract

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Genetically confirmed clinical Huntington's disease with no observable cell loss. Author(s): Caramins M, Halliday G, McCusker E, Trent RJ. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 July; 74(7): 968-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12810795&dopt=Abstract

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Genetics and molecular biology of Huntington's disease. Author(s): Albin RL, Tagle DA. Source: Trends in Neurosciences. 1995 January; 18(1): 11-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7535483&dopt=Abstract

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Genomic organization and expression analysis of mouse kynurenine aminotransferase II, a possible factor in the pathophysiology of Huntington's disease. Author(s): Yu P, Mosbrook DM, Tagle DA. Source: Mammalian Genome : Official Journal of the International Mammalian Genome Society. 1999 September; 10(9): 845-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10441733&dopt=Abstract

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Geographical distribution of haplotypes in Swedish families with Huntington's disease. Author(s): Almqvist E, Andrew S, Theilmann J, Goldberg P, Zeisler J, Drugge U, Grandell U, Tapper-Persson M, Winblad B, Hayden M, et al. Source: Human Genetics. 1994 August; 94(2): 124-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8045558&dopt=Abstract

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Glucose transporter isoform expression in Huntington's disease brain. Author(s): Gamberino WC, Brennan WA Jr. Source: Journal of Neurochemistry. 1994 October; 63(4): 1392-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7931291&dopt=Abstract

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Glutamate in Huntington's disease. Author(s): Reynolds GP, Pearson SJ. Source: Lancet. 1994 July 16; 344(8916): 189-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7912778&dopt=Abstract

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Glycogen synthase kinase-3beta inhibitors prevent cellular polyglutamine toxicity caused by the Huntington's disease mutation. Author(s): Carmichael J, Sugars KL, Bao YP, Rubinsztein DC. Source: The Journal of Biological Chemistry. 2002 September 13; 277(37): 33791-8. Epub 2002 July 03. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12097329&dopt=Abstract

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Grafts of EGF-responsive neural stem cells derived from GFAP-hNGF transgenic mice: trophic and tropic effects in a rodent model of Huntington's disease. Author(s): Kordower JH, Chen EY, Winkler C, Fricker R, Charles V, Messing A, Mufson EJ, Wong SC, Rosenstein JM, Bjorklund A, Emerich DF, Hammang J, Carpenter MK. Source: The Journal of Comparative Neurology. 1997 October 13; 387(1): 96-113. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9331174&dopt=Abstract

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Grip force scaling and sequencing of events during a manipulative task in Huntington's disease. Author(s): Serrien DJ, Burgunder JM, Wiesendanger M. Source: Neuropsychologia. 2001; 39(7): 734-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11311303&dopt=Abstract

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High-dose olanzapine in Huntington's disease. Author(s): Bonelli RM, Niederwieser G, Tribl GG, Koltringer P. Source: International Clinical Psychopharmacology. 2002 March; 17(2): 91-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11890191&dopt=Abstract

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Homozygosity in Huntington's disease: new ethical dilemma caused by molecular diagnosis. Author(s): Alonso ME, Yescas P, Rasmussen A, Ochoa A, Macias R, Ruiz I, Suastegui R. Source: Clinical Genetics. 2002 June; 61(6): 437-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12121351&dopt=Abstract

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How does the Huntington's disease mutation damage cells? Author(s): Rubinsztein DC. Source: Science of Aging Knowledge Environment [electronic Resource] : Sage Ke. 2003 September 17; 2003(37): Pe26. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13679594&dopt=Abstract

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Hunting for excitement: NMDA receptors in Huntington's disease. Author(s): Ellerby LM. Source: Neuron. 2002 March 14; 33(6): 841-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11906690&dopt=Abstract

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Huntingtin aggregation and toxicity in Huntington's disease. Author(s): Bates G. Source: Lancet. 2003 May 10; 361(9369): 1642-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12747895&dopt=Abstract

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Huntington's disease age-of-onset linked to polyglutamine aggregation nucleation. Author(s): Chen S, Ferrone FA, Wetzel R. Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 September 3; 99(18): 11884-9. Epub 2002 August 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12186976&dopt=Abstract

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Huntington's disease provides cancer clues. Author(s): Kerr C. Source: The Lancet Oncology. 2002 September; 3(9): 518. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12217772&dopt=Abstract

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Huntington's disease transgenic mice are resistant to global cerebral ischemia. Author(s): Schiefer J, Alberty A, Dose T, Oliva S, Noth J, Kosinski CM. Source: Neuroscience Letters. 2002 December 13; 334(2): 99-102. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12435481&dopt=Abstract

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Huntington's disease. Author(s): Davies S, Ramsden DB. Source: Molecular Pathology : Mp. 2001 December; 54(6): 409-13. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11724916&dopt=Abstract

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Huntington's disease. A sports star and a cook. Author(s): McMurray SE, McMurray CT. Source: Lancet. 2001 December; 358 Suppl: S38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11784587&dopt=Abstract

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Huntington's disease. Expanding horizons for treatment. Author(s): McMurray CT. Source: Lancet. 2001 December; 358 Suppl: S37. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11784586&dopt=Abstract

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Huntington's disease: a decade beyond gene discovery. Author(s): Hogarth P. Source: Curr Neurol Neurosci Rep. 2003 July; 3(4): 279-84. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12930696&dopt=Abstract

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Huntington's disease: a randomized, controlled trial using the NMDA-antagonist amantadine. Author(s): Verhagen Metman L, Morris MJ, Farmer C, Gillespie M, Mosby K, Wuu J, Chase TN. Source: Neurology. 2002 September 10; 59(5): 694-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12221159&dopt=Abstract

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Huntington's disease: a review of the literature on prevalence and treatment of neuropsychiatric phenomena. Author(s): Naarding P, Kremer HP, Zitman FG. Source: European Psychiatry : the Journal of the Association of European Psychiatrists. 2001 December; 16(8): 439-45. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11777733&dopt=Abstract

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Huntington's disease: new hope for therapeutics. Author(s): McMurray CT. Source: Trends in Neurosciences. 2001 November; 24(11 Suppl): S32-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11881743&dopt=Abstract

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Huntington's disease: seldom seen--seldom heard? Author(s): McGarva K. Source: Health Bull (Edinb). 2001 September; 59(5): 306-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12664744&dopt=Abstract

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Huntington's disease: the mystery unfolds? Author(s): Petersen A, Brundin P. Source: Int Rev Neurobiol. 2002; 53: 315-39. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12512345&dopt=Abstract

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Huntington's disease: what we learned from the original essay. Author(s): Okun MS. Source: The Neurologist. 2003 July; 9(4): 175-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12864927&dopt=Abstract

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Huntington's disease-like phenotype due to trinucleotide repeat expansions in the TBP and JPH3 genes. Author(s): Stevanin G, Fujigasaki H, Lebre AS, Camuzat A, Jeannequin C, Dode C, Takahashi J, San C, Bellance R, Brice A, Durr A. Source: Brain; a Journal of Neurology. 2003 July; 126(Pt 7): 1599-603. Epub 2003 May 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12805114&dopt=Abstract

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Hypometric primary saccades and increased variability in visually-guided saccades in Huntington's disease. Author(s): Winograd-Gurvich CT, Georgiou-Karistianis N, Evans A, Millist L, Bradshaw JL, Churchyard A, Chiu E, White OB. Source: Neuropsychologia. 2003; 41(12): 1683-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12887992&dopt=Abstract

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Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay. Author(s): Heiser V, Engemann S, Brocker W, Dunkel I, Boeddrich A, Waelter S, Nordhoff E, Lurz R, Schugardt N, Rautenberg S, Herhaus C, Barnickel G, Bottcher H, Lehrach H, Wanker EE. Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 December 10; 99 Suppl 4: 16400-6. Epub 2002 August 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12200548&dopt=Abstract

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Ideomotor limb apraxia in Huntington's disease: implications for corticostriate involvement. Author(s): Hamilton JM, Haaland KY, Adair JC, Brandt J. Source: Neuropsychologia. 2003; 41(5): 614-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12559154&dopt=Abstract

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Impaired antagonist inhibition may contribute to akinesia and bradykinesia in Huntington's disease. Author(s): van Vugt JP, Stijl M, Roos RA, van Dijk JG. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2003 February; 114(2): 295-305. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12559237&dopt=Abstract

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In vitro effects of polyglutamine tracts on Ca2+-dependent depolarization of rat and human mitochondria: relevance to Huntington's disease. Author(s): Panov AV, Burke JR, Strittmatter WJ, Greenamyre JT. Source: Archives of Biochemistry and Biophysics. 2003 February 1; 410(1): 1-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12559971&dopt=Abstract

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Increased cell proliferation and neurogenesis in the adult human Huntington's disease brain. Author(s): Curtis MA, Penney EB, Pearson AG, van Roon-Mom WM, Butterworth NJ, Dragunow M, Connor B, Faull RL. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 July 22; 100(15): 9023-7. Epub 2003 Jul 09. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12853570&dopt=Abstract

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Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington's disease. Author(s): Chan EY, Luthi-Carter R, Strand A, Solano SM, Hanson SA, DeJohn MM, Kooperberg C, Chase KO, DiFiglia M, Young AB, Leavitt BR, Cha JH, Aronin N, Hayden MR, Olson JM. Source: Human Molecular Genetics. 2002 August 15; 11(17): 1939-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12165556&dopt=Abstract

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Inducible PC12 cell model of Huntington's disease shows toxicity and decreased histone acetylation. Author(s): Igarashi S, Morita H, Bennett KM, Tanaka Y, Engelender S, Peters MF, Cooper JK, Wood JD, Sawa A, Ross CA. Source: Neuroreport. 2003 March 24; 14(4): 565-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12657886&dopt=Abstract

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Inhibition of subliminally primed responses is mediated by the caudate and thalamus: evidence from functional MRI and Huntington's disease. Author(s): Aron AR, Schlaghecken F, Fletcher PC, Bullmore ET, Eimer M, Barker R, Sahakian BJ, Robbins TW. Source: Brain; a Journal of Neurology. 2003 March; 126(Pt 3): 713-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12566291&dopt=Abstract

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Inhibition of tryptophan hydroxylase activity and decreased 5-HT1A receptor binding in a mouse model of Huntington's disease. Author(s): Yohrling IV GJ, Jiang GC, DeJohn MM, Robertson DJ, Vrana KE, Cha JH. Source: Journal of Neurochemistry. 2002 September; 82(6): 1416-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12354289&dopt=Abstract

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Insight into the psychosocial aspects of Huntington's disease in Chinese society. Author(s): Leung TY, Leung CM. Source: International Journal of Psychiatry in Medicine. 2002; 32(3): 305-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12489705&dopt=Abstract

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Insoluble TATA-binding protein accumulation in Huntington's disease cortex. Author(s): van Roon-Mom WM, Reid SJ, Jones AL, MacDonald ME, Faull RL, Snell RG. Source: Brain Research. Molecular Brain Research. 2002 December 30; 109(1-2): 1-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12531510&dopt=Abstract

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Juvenile form of Huntington's disease: MR imaging appearance. Author(s): Comunale JP Jr, Heier LA, Chutorian AM. Source: Ajr. American Journal of Roentgenology. 1995 August; 165(2): 414-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7618569&dopt=Abstract

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Juvenile Huntington's disease confirmed by genetic examination in twins. Author(s): Levy G, Nobre ME, Cimini VT, Raskin S, Engelhardt E. Source: Arquivos De Neuro-Psiquiatria. 1999 September; 57(3B): 867-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10751926&dopt=Abstract

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Juvenile Huntington's disease presenting as progressive myoclonic epilepsy. Author(s): Gambardella A, Muglia M, Labate A, Magariello A, Gabriele AL, Mazzei R, Pirritano D, Conforti FL, Patitucci A, Valentino P, Zappia M, Quattrone A. Source: Neurology. 2001 August 28; 57(4): 708-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11524486&dopt=Abstract

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Juvenile Huntington's disease. Author(s): Srivastava T, Lal V, Prabhakar S. Source: Neurology India. 1999 December; 47(4): 340-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10625918&dopt=Abstract

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Juvenile Huntington's disease: report of one case. Author(s): Sue WC, Hwu WL, Chen CY. Source: Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1998 September-October; 39(5): 342-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9823684&dopt=Abstract

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Juvenile onset Huntington's disease in an Omani child with asymptomatic, at risk parents. Author(s): Scrimgeour EM, Koul RL, Chand PR, Tharakan JK, Frew CA. Source: Journal of Medical Genetics. 1997 August; 34(8): 701. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9279769&dopt=Abstract

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Juvenile onset Huntington's disease--clinical and research perspectives. Author(s): Ann Neurol. 2001 Dec;50(6):373-80 Source: Mental Retardation and Developmental Disabilities Research Reviews. 2001; 7(3): 153-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11761463

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Kinematic analysis of the reach to grasp movement in Parkinson's and Huntington's disease subjects. Author(s): Bonfiglioli C, De Berti G, Nichelli P, Nicoletti R, Castiello U. Source: Neuropsychologia. 1998 November; 36(11): 1203-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9842765&dopt=Abstract

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Knowledge, attitude, and the decision to be tested for Huntington's disease. Author(s): Quaid KA, Brandt J, Faden RR, Folstein SE. Source: Clinical Genetics. 1989 December; 36(6): 431-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2531636&dopt=Abstract

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Kynurenic acid concentrations are reduced in Huntington's disease cerebral cortex. Author(s): Beal MF, Matson WR, Storey E, Milbury P, Ryan EA, Ogawa T, Bird ED. Source: Journal of the Neurological Sciences. 1992 March; 108(1): 80-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1385624&dopt=Abstract

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Kynurenine pathway measurements in Huntington's disease striatum: evidence for reduced formation of kynurenic acid. Author(s): Beal MF, Matson WR, Swartz KJ, Gamache PH, Bird ED. Source: Journal of Neurochemistry. 1990 October; 55(4): 1327-39. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2144582&dopt=Abstract

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Late onset levodopa responsive Huntington's disease with minimal chorea masquerading as Parkinson plus syndrome. Author(s): Reuter I, Hu MT, Andrews TC, Brooks DJ, Clough C, Chaudhuri KR. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2000 February; 68(2): 23841. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10644798&dopt=Abstract

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Late-life obsessive-compulsive disorder and Huntington's disease. Author(s): Scicutella A. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 2000 Spring; 12(2): 288-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11001616&dopt=Abstract

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Lessons from animal models of Huntington's disease. Author(s): Rubinsztein DC. Source: Trends in Genetics : Tig. 2002 April; 18(4): 202-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11932021&dopt=Abstract

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Levodopa responsive parkinsonism in an adult with Huntington's disease. Author(s): Racette BA, Perlmutter JS. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 1998 October; 65(4): 577-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9771791&dopt=Abstract

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Living with Huntington's disease: illness perceptions, coping mechanisms, and spouses' quality of life. Author(s): Helder DI, Kaptein AA, Van Kempen GM, Weinman J, Van Houwelingen JC, Roos RA. Source: International Journal of Behavioral Medicine. 2002; 9(1): 37-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12112995&dopt=Abstract

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Longitudinal evaluation of cognitive disorder in Huntington's disease. Author(s): Snowden J, Craufurd D, Griffiths H, Thompson J, Neary D. Source: Journal of the International Neuropsychological Society : Jins. 2001 January; 7(1): 33-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11253840&dopt=Abstract

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Longitudinal study evaluating neuropsychological changes in so-called asymptomatic carriers of the Huntington's disease mutation after 1 year. Author(s): Lemiere J, Decruyenaere M, Evers-Kiebooms G, Vandenbussche E, Dom R. Source: Acta Neurologica Scandinavica. 2002 September; 106(3): 131-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12174172&dopt=Abstract

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Long-lasting improvement following (-)-OSU6162 in a patient with Huntington's disease. Author(s): Tedroff J, Ekesbo A, Sonesson C, Waters N, Carlsson A. Source: Neurology. 1999 October 22; 53(7): 1605-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10534281&dopt=Abstract

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Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Author(s): Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S, Cattaneo E. Source: Science. 2001 July 20; 293(5529): 493-8. Epub 2001 June 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11408619&dopt=Abstract

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Loss of normal huntingtin function: new developments in Huntington's disease research. Author(s): Cattaneo E, Rigamonti D, Goffredo D, Zuccato C, Squitieri F, Sipione S. Source: Trends in Neurosciences. 2001 March; 24(3): 182-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11182459&dopt=Abstract

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Maintained improvement with minocycline of a patient with advanced Huntington's disease. Author(s): Denovan-Wright EM, Devarajan S, Dursun SM, Robertson HA. Source: Journal of Psychopharmacology (Oxford, England). 2002 December; 16(4): 393-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12503842&dopt=Abstract

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Maintenance of susceptibility to neurodegeneration following intrastriatal injections of quinolinic acid in a new transgenic mouse model of Huntington's disease. Author(s): Petersen A, Chase K, Puschban Z, DiFiglia M, Brundin P, Aronin N. Source: Experimental Neurology. 2002 May; 175(1): 297-300. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12009780&dopt=Abstract

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Metabolic changes in the basal ganglia of patients with Huntington's disease: an in situ hybridization study of cytochrome oxidase subunit I mRNA. Author(s): Gourfinkel-An I, Vila M, Faucheux B, Duyckaerts C, Viallet F, Hauw JJ, Brice A, Agid Y, Hirsch EC. Source: Journal of Neurochemistry. 2002 February; 80(3): 466-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11905993&dopt=Abstract

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Mice transgenic for exon 1 of Huntington's disease: properties of cholinergic and dopaminergic pre-synaptic function in the striatum. Author(s): Vetter JM, Jehle T, Heinemeyer J, Franz P, Behrens PF, Jackisch R, Landwehrmeyer GB, Feuerstein TJ. Source: Journal of Neurochemistry. 2003 May; 85(4): 1054-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12716437&dopt=Abstract

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Minocycline and other tetracycline derivatives: a neuroprotective strategy in Parkinson's disease and Huntington's disease. Author(s): Thomas M, Le WD, Jankovic J. Source: Clinical Neuropharmacology. 2003 January-February; 26(1): 18-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12567160&dopt=Abstract

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Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington's disease. Author(s): Wang X, Zhu S, Drozda M, Zhang W, Stavrovskaya IG, Cattaneo E, Ferrante RJ, Kristal BS, Friedlander RM. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 September 2; 100(18): 10483-7. Epub 2003 August 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12930891&dopt=Abstract

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Mirtazapine in suicidal Huntington's disease. Author(s): Bonelli RM. Source: The Annals of Pharmacotherapy. 2003 March; 37(3): 452. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12639181&dopt=Abstract

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Modeling protein homopolymeric repeats: possible polyglutamine structural motifs for Huntington's disease. Author(s): Lathrop RH, Casale M, Tobias DJ, Marsh JL, Thompson LM. Source: Proc Int Conf Intell Syst Mol Biol. 1998; 6: 105-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9783215&dopt=Abstract

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Modulation of age at onset in Huntington's disease and spinocerebellar ataxia type 2 patients originated from eastern India. Author(s): Chattopadhyay B, Ghosh S, Gangopadhyay PK, Das SK, Roy T, Sinha KK, Jha DK, Mukherjee SC, Chakraborty A, Singhal BS, Bhattacharya AK, Bhattacharyya NP. Source: Neuroscience Letters. 2003 July 17; 345(2): 93-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12821179&dopt=Abstract

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Mutation analysis and association studies of the ubiquitin carboxy-terminal hydrolase L1 gene in Huntington's disease. Author(s): Naze P, Vuillaume I, Destee A, Pasquier F, Sablonniere B. Source: Neuroscience Letters. 2002 August 2; 328(1): 1-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12123845&dopt=Abstract

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N(epsilon)-(gamma-L-glutamyl)-L-lysine (GGEL) is increased in cerebrospinal fluid of patients with Huntington's disease. Author(s): Jeitner TM, Bogdanov MB, Matson WR, Daikhin Y, Yudkoff M, Folk JE, Steinman L, Browne SE, Beal MF, Blass JP, Cooper AJ. Source: Journal of Neurochemistry. 2001 December; 79(5): 1109-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11739625&dopt=Abstract

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Neural transplantation for the treatment of Huntington's disease. Author(s): Freeman TB, Hauser RA, Sanberg PR, Saporta S. Source: Prog Brain Res. 2000; 127: 405-11. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11142038&dopt=Abstract

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Neural transplantation in patients with Huntington's disease. Author(s): Rosser AE, Dunnett SB. Source: Cns Drugs. 2003; 17(12): 853-67. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12962526&dopt=Abstract

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Neurophysiological study of facial chorea in patients with Huntington's disease. Author(s): Munoz E, Cervera A, Valls-Sole J. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2003 July; 114(7): 1246-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12842721&dopt=Abstract

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Neuroprotection by neurotrophins and GDNF family members in the excitotoxic model of Huntington's disease. Author(s): Alberch J, Perez-Navarro E, Canals JM. Source: Brain Research Bulletin. 2002 April; 57(6): 817-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12031278&dopt=Abstract

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Neuroprotective possibilities for Huntington's disease. Author(s): Emerich DF. Source: Expert Opinion on Biological Therapy. 2001 May; 1(3): 467-79. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11727519&dopt=Abstract

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Neuropsychological manifestations of the genetic mutation for Huntington's disease in presymptomatic individuals. Author(s): Brandt J, Shpritz B, Codori AM, Margolis R, Rosenblatt A. Source: Journal of the International Neuropsychological Society : Jins. 2002 November; 8(7): 918-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12405543&dopt=Abstract

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New therapeutic approaches for the treatment of Huntington's disease. Author(s): Mazurova Y. Source: Acta Medica (Hradec Kralove). 2001; 44(4): 119-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11836846&dopt=Abstract

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No difference in plasma or urinary F2-isoprostanes among patients with Huntington's disease or Alzheimer's disease and controls. Author(s): Montine TJ, Shinobu L, Montine KS, Roberts LJ 2nd, Kowall NW, Beal MF, Morrow JD. Source: Annals of Neurology. 2000 December; 48(6): 950. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11117557&dopt=Abstract

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Novel therapies in the search for a cure for Huntington's disease. Author(s): Beal MF, Hantraye P. Source: Proceedings of the National Academy of Sciences of the United States of America. 2001 January 2; 98(1): 3-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11136240&dopt=Abstract

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Objective assessment of progression in Huntington's disease: a 3-year follow-up study. Author(s): Reilmann R, Kirsten F, Quinn L, Henningsen H, Marder K, Gordon AM. Source: Neurology. 2001 September 11; 57(5): 920-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11552034&dopt=Abstract

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Odor detection, learning, and memory in Huntington's disease. Author(s): Hamilton JM, Murphy C, Paulsen JS. Source: Journal of the International Neuropsychological Society : Jins. 1999 November; 5(7): 609-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10645703&dopt=Abstract

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Of mice and men: solving the molecular mysteries of Huntington's disease. Author(s): Shelbourne PF. Source: Journal of Anatomy. 2000 May; 196 ( Pt 4): 617-28. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10923992&dopt=Abstract

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Olanzapine and Huntington's disease. Author(s): Bogelman G, Hirschmann S, Modai I. Source: Journal of Clinical Psychopharmacology. 2001 April; 21(2): 245-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11270928&dopt=Abstract

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Olanzapine for Huntington's disease: an open label study. Author(s): Bonelli RM, Mahnert FA, Niederwieser G. Source: Clinical Neuropharmacology. 2002 September-October; 25(5): 263-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12410058&dopt=Abstract

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Olanzapine in Huntington's disease. Author(s): Paleacu D, Anca M, Giladi N. Source: Acta Neurologica Scandinavica. 2002 June; 105(6): 441-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12027832&dopt=Abstract

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On the pathological progression of Huntington's disease. Author(s): Sieradzan KA, Mann DM. Source: Annals of Neurology. 1998 July; 44(1): 148-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9667607&dopt=Abstract

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Onset and pre-onset studies to define the Huntington's disease natural history. Author(s): Squitieri F, Cannella M, Giallonardo P, Maglione V, Mariotti C, Hayden MR. Source: Brain Research Bulletin. 2001 October-November 1; 56(3-4): 233-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11719256&dopt=Abstract

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Open interconnected model of basal ganglia-thalamocortical circuitry and its relevance to the clinical syndrome of Huntington's disease. Author(s): Joel D. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 2001 May; 16(3): 407-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11391734&dopt=Abstract

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Overexpression of heat shock protein 70 in R6/2 Huntington's disease mice has only modest effects on disease progression. Author(s): Hansson O, Nylandsted J, Castilho RF, Leist M, Jaattela M, Brundin P. Source: Brain Research. 2003 April 25; 970(1-2): 47-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12706247&dopt=Abstract

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Perceptual categorization is impaired in Huntington's disease: an electrophysiological study. Author(s): Antal A, Beniczky S, Kincses TZ, Jakab K, Benedek G, Vecsei L. Source: Dementia and Geriatric Cognitive Disorders. 2003; 16(4): 187-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14512712&dopt=Abstract

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Polyglutamine expansion and Huntington's disease. Author(s): Bates GP, Mangiarini L, Wanker EE, Davies SW. Source: Biochemical Society Transactions. 1998 August; 26(3): 471-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9765898&dopt=Abstract

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Predictive testing for Huntington's disease: a universal model? Author(s): Hayden MR. Source: Lancet. Neurology. 2003 March; 2(3): 141-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12849232&dopt=Abstract

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Predictors of neuropathological severity in 100 patients with Huntington's disease. Author(s): Rosenblatt A, Abbott MH, Gourley LM, Troncoso JC, Margolis RL, Brandt J, Ross CA. Source: Annals of Neurology. 2003 October; 54(4): 488-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14520661&dopt=Abstract

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Prenatal diagnosis requests for Huntington's disease when the father is at risk and does not want to know his genetic status: clinical, legal, and ethical viewpoints. Author(s): Tassicker R, Savulescu J, Skene L, Marshall P, Fitzgerald L, Delatycki MB. Source: Bmj (Clinical Research Ed.). 2003 February 8; 326(7384): 331-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12574051&dopt=Abstract

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Progressive striatal and cortical dopamine receptor dysfunction in Huntington's disease: a PET study. Author(s): Pavese N, Andrews TC, Brooks DJ, Ho AK, Rosser AE, Barker RA, Robbins TW, Sahakian BJ, Dunnett SB, Piccini P. Source: Brain; a Journal of Neurology. 2003 May; 126(Pt 5): 1127-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12690052&dopt=Abstract

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Proprioceptive sensory function in Parkinson's disease and Huntington's disease: evidence from proprioception-related EEG potentials. Author(s): Seiss E, Praamstra P, Hesse CW, Rickards H. Source: Experimental Brain Research. Experimentelle Hirnforschung. Experimentation Cerebrale. 2003 February; 148(3): 308-19. Epub 2002 November 30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12541142&dopt=Abstract

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Psychiatric and neuropsychological abnormalities in Huntington's disease: a case study. Author(s): Madhusoodanan S, Brenner R, Moise D, Sindagi J, Brafman I. Source: Annals of Clinical Psychiatry : Official Journal of the American Academy of Clinical Psychiatrists. 1998 September; 10(3): 117-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9781475&dopt=Abstract

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Psychological distress in the 5-year period after predictive testing for Huntington's disease. Author(s): Decruyenaere M, Evers-Kiebooms G, Cloostermans T, Boogaerts A, Demyttenaere K, Dom R, Fryns JP. Source: European Journal of Human Genetics : Ejhg. 2003 January; 11(1): 30-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12529703&dopt=Abstract

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Psychopathological changes preceding motor symptoms in Huntington's disease: a report on four cases. Author(s): Amann B, Sterr A, Thoma H, Messer T, Kapfhammer HP, Grunze H. Source: World J Biol Psychiatry. 2000 January; 1(1): 55-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12607233&dopt=Abstract

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Quantitative analysis of morphological features in Huntington's disease. Author(s): Roos RA, Bots GT, Hermans J. Source: Acta Neurologica Scandinavica. 1986 February; 73(2): 131-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2939683&dopt=Abstract

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Quantitative and qualitative analyses of clock drawings in Alzheimer's and Huntington's disease. Author(s): Rouleau I, Salmon DP, Butters N, Kennedy C, McGuire K. Source: Brain and Cognition. 1992 January; 18(1): 70-87. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1543577&dopt=Abstract

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Quantitative assessment of daytime motor activity provides a responsive measure of functional decline in patients with Huntington's disease. Author(s): van Vugt JP, Siesling S, Piet KK, Zwinderman AH, Middelkoop HA, van Hilten JJ, Roos RA. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 2001 May; 16(3): 481-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11391742&dopt=Abstract

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Quantitative longitudinal assessment of saccades in Huntington's disease. Author(s): Rubin AJ, King WM, Reinbold KA, Shoulson I. Source: J Clin Neuroophthalmol. 1993 March; 13(1): 59-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8501265&dopt=Abstract

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Quantitative neuropathological changes in presymptomatic Huntington's disease. Author(s): Gomez-Tortosa E, MacDonald ME, Friend JC, Taylor SA, Weiler LJ, Cupples LA, Srinidhi J, Gusella JF, Bird ED, Vonsattel JP, Myers RH. Source: Annals of Neurology. 2001 January; 49(1): 29-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11198293&dopt=Abstract

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Questions and problems in direct predictive testing for Huntington's disease. Author(s): Toth T, Papp C, Nemeti M, Papp Z. Source: American Journal of Medical Genetics. 1997 August 8; 71(2): 238-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9217232&dopt=Abstract

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Quetiapine in Huntington's disease: a first case report. Author(s): Bonelli RM, Niederwieser G. Source: Journal of Neurology. 2002 August; 249(8): 1114-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12420714&dopt=Abstract

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Quinolinic acid phosphoribosyltransferase in human and rat brain: activity in Huntington's disease and in quinolinate-lesioned rat striatum. Author(s): Foster AC, Whetsell WO Jr, Bird ED, Schwarcz R. Source: Brain Research. 1985 June 17; 336(2): 207-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3159462&dopt=Abstract

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Quinolinic acid-induced increases in calbindin D28k immunoreactivity in rat striatal neurons in vivo and in vitro mimic the pattern seen in Huntington's disease. Author(s): Huang Q, Zhou D, Sapp E, Aizawa H, Ge P, Bird ED, Vonsattel JP, DiFiglia M. Source: Neuroscience. 1995 March; 65(2): 397-407. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7777157&dopt=Abstract

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Recent advances in Huntington's disease: implications for experimental therapeutics. Author(s): Feigin A, Zgaljardic D. Source: Current Opinion in Neurology. 2002 August; 15(4): 483-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12151847&dopt=Abstract

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Recognition memory for hand positions and spatial locations in patients with Huntington's disease: differential visuospatial memory impairment? Author(s): Davis JD, Filoteo JV, Kesner RP, Roberts JW. Source: Cortex. 2003 April; 39(2): 239-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12784887&dopt=Abstract

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Regional and progressive thinning of the cortical ribbon in Huntington's disease. Author(s): Rosas HD, Liu AK, Hersch S, Glessner M, Ferrante RJ, Salat DH, van der Kouwe A, Jenkins BG, Dale AM, Fischl B. Source: Neurology. 2002 March 12; 58(5): 695-701. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11889230&dopt=Abstract

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Relationship between CAG repeat length and late-stage outcomes in Huntington's disease. Author(s): Marder K, Sandler S, Lechich A, Klager J, Albert SM. Source: Neurology. 2002 November 26; 59(10): 1622-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12451208&dopt=Abstract

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Riluzole and olanzapine in Huntington's disease. Author(s): Bonelli RM, Niederwieser G, Diez J, Koltringer P. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2002 March; 9(2): 183-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11882065&dopt=Abstract

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Riluzole in Huntington's disease (HD): an open label study with one year follow up. Author(s): Seppi K, Mueller J, Bodner T, Brandauer E, Benke T, Weirich-Schwaiger H, Poewe W, Wenning GK. Source: Journal of Neurology. 2001 October; 248(10): 866-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11697523&dopt=Abstract

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Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse model of Huntington's disease. Author(s): Schiefer J, Landwehrmeyer GB, Luesse HG, Sprunken A, Puls C, Milkereit A, Milkereit E, Kosinski CM. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 2002 July; 17(4): 748-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12210870&dopt=Abstract

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Risky decision making in Huntington's disease. Author(s): Stout JC, Rodawalt WC, Siemers ER. Source: Journal of the International Neuropsychological Society : Jins. 2001 January; 7(1): 92-101. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11253845&dopt=Abstract

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Risperidone in chorea and psychosis of Huntington's disease. Author(s): Erdemoglu AK, Boratav C. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2002 March; 9(2): 182-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11882064&dopt=Abstract

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Rivastigmine in the treatment of Huntington's disease. Author(s): Rot U, Kobal J, Sever A, Pirtosek Z, Mesec A. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2002 November; 9(6): 689-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12453090&dopt=Abstract

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Selective loss of striatal preprotachykinin neurons in a phenocopy of Huntington's disease. Author(s): Richfield EK, Vonsattel JP, MacDonald ME, Sun Z, Deng YP, Reiner A. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 2002 March; 17(2): 327-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11921119&dopt=Abstract

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Sensation of effort is altered in Huntington's disease. Author(s): Lafargue G, Sirigu A. Source: Neuropsychologia. 2002; 40(10): 1654-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11992653&dopt=Abstract

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Severe deficiencies in dopamine signaling in presymptomatic Huntington's disease mice. Author(s): Bibb JA, Yan Z, Svenningsson P, Snyder GL, Pieribone VA, Horiuchi A, Nairn AC, Messer A, Greengard P. Source: Proceedings of the National Academy of Sciences of the United States of America. 2000 June 6; 97(12): 6809-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10829080&dopt=Abstract

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Single photon emission computerized tomography (SPECT) in detecting neurodegeneration in Huntington's disease. Author(s): Reynolds NC Jr, Hellman RS, Tikofsky RS, Prost RW, Mark LP, Elejalde BR, Lebel R, Hamsher KS, Swanson S, Benezra EE. Source: Nuclear Medicine Communications. 2002 January; 23(1): 13-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11748433&dopt=Abstract

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Social cognition in frontotemporal dementia and Huntington's disease. Author(s): Snowden JS, Gibbons ZC, Blackshaw A, Doubleday E, Thompson J, Craufurd D, Foster J, Happe F, Neary D. Source: Neuropsychologia. 2003; 41(6): 688-701. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12591026&dopt=Abstract

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Somatosensory evoked potentials correlate with genetics in Huntington's disease. Author(s): Beniczky S, Keri S, Antal A, Jakab K, Nagy H, Benedek G, Janka Z, Vecsei L. Source: Neuroreport. 2002 December 3; 13(17): 2295-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12488814&dopt=Abstract

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Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease. Author(s): Dunah AW, Jeong H, Griffin A, Kim YM, Standaert DG, Hersch SM, Mouradian MM, Young AB, Tanese N, Krainc D. Source: Science. 2002 June 21; 296(5576): 2238-43. Epub 2002 May 02. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11988536&dopt=Abstract

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Sub-movement cueing and motor sequence execution in patients with Huntington's disease. Author(s): Curra A, Agostino R, Galizia P, Fittipaldi F, Manfredi M, Berardelli A. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2000 July; 111(7): 1184-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10880791&dopt=Abstract

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Subtle changes among presymptomatic carriers of the Huntington's disease gene. Author(s): Kirkwood SC, Siemers E, Hodes ME, Conneally PM, Christian JC, Foroud T. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2000 December; 69(6): 7739. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11080230&dopt=Abstract

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Successful multimodality treatment of severe behavioral disturbance in a patient with advanced Huntington's disease. Author(s): Blass DM, Steinberg M, Leroi I, Lyketsos CG. Source: The American Journal of Psychiatry. 2001 December; 158(12): 1966-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11729010&dopt=Abstract

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Task-set switching deficits in early-stage Huntington's disease: implications for basal ganglia function. Author(s): Aron AR, Watkins L, Sahakian BJ, Monsell S, Barker RA, Robbins TW. Source: Journal of Cognitive Neuroscience. 2003 July 1; 15(5): 629-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12965037&dopt=Abstract

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Teacher was refused job because relatives have Huntington's disease. Author(s): Burgermeister J. Source: Bmj (Clinical Research Ed.). 2003 October 11; 327(7419): 827. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14551070&dopt=Abstract

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The distribution of structural neuropathology in pre-clinical Huntington's disease. Author(s): Thieben MJ, Duggins AJ, Good CD, Gomes L, Mahant N, Richards F, McCusker E, Frackowiak RS. Source: Brain; a Journal of Neurology. 2002 August; 125(Pt 8): 1815-28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12135972&dopt=Abstract

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The enigma of Huntington's disease. Author(s): Cattaneo E, Rigamonti D, Zuccato C. Source: Scientific American. 2002 December; 287(6): 92-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12469651&dopt=Abstract

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The hung-up knee jerk in Huntington's Disease. Author(s): Brannan T. Source: Parkinsonism & Related Disorders. 2003 June; 9(5): 257-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12781590&dopt=Abstract

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The midlatency auditory evoked potential P50 is abnormal in Huntington's disease. Author(s): Uc EY, Skinner RD, Rodnitzky RL, Garcia-Rill E. Source: Journal of the Neurological Sciences. 2003 August 15; 212(1-2): 1-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12809992&dopt=Abstract

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The primary structure and genomic organization of five novel transcripts located close to the Huntington's disease gene on human chromosome 4p16.3. Author(s): Hadano S, Ishida Y, Ikeda JE. Source: Dna Res. 1998 June 30; 5(3): 177-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9734812&dopt=Abstract

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Therapeutic effects of cystamine in a murine model of Huntington's disease. Author(s): Dedeoglu A, Kubilus JK, Jeitner TM, Matson SA, Bogdanov M, Kowall NW, Matson WR, Cooper AJ, Ratan RR, Beal MF, Hersch SM, Ferrante RJ. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2002 October 15; 22(20): 8942-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12388601&dopt=Abstract

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Therapeutic options for Huntington's disease. Author(s): Grimbergen YA, Roos RA. Source: Curr Opin Investig Drugs. 2003 January; 4(1): 51-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12625029&dopt=Abstract

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Trinucleotide (CAG) repeat length is positively correlated with the degree of DNA fragmentation in Huntington's disease striatum. Author(s): Butterworth NJ, Williams L, Bullock JY, Love DR, Faull RL, Dragunow M. Source: Neuroscience. 1998 November; 87(1): 49-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9722140&dopt=Abstract

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UK allows insurers to use gene test for Huntington's disease. Author(s): Mayor S. Source: Bmj (Clinical Research Ed.). 2000 October 21; 321(7267): 977. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11039944&dopt=Abstract

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Ultrastructural localization and progressive formation of neuropil aggregates in Huntington's disease transgenic mice. Author(s): Li H, Li SH, Cheng AL, Mangiarini L, Bates GP, Li XJ. Source: Human Molecular Genetics. 1999 July; 8(7): 1227-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10369868&dopt=Abstract

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Understanding the neuropsychiatric symptoms of Huntington's disease. Author(s): Hofmann N. Source: The Journal of Neuroscience Nursing : Journal of the American Association of Neuroscience Nurses. 1999 October; 31(5): 309-13. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10633308&dopt=Abstract

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Unilateral transplantation of human primary fetal tissue in four patients with Huntington's disease: NEST-UK safety report ISRCTN no 36485475. Author(s): Rosser AE, Barker RA, Harrower T, Watts C, Farrington M, Ho AK, Burnstein RM, Menon DK, Gillard JH, Pickard J, Dunnett SB; NEST-UK. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2002 December; 73(6): 67885. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12438470&dopt=Abstract

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Unimanual and bimanual voluntary movement in Huntington's disease. Author(s): Verbessem P, Op't Eijnde B, Swinnen SP, Vangheluwe S, Hespel P, Dom R. Source: Experimental Brain Research. Experimentelle Hirnforschung. Experimentation Cerebrale. 2002 December; 147(4): 529-37. Epub 2002 October 15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12444485&dopt=Abstract

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United Kingdom experience with presymptomatic testing of individuals at 25% risk for Huntington's disease. Author(s): Benjamin CM, Lashwood A. Source: Clinical Genetics. 2000 July; 58(1): 41-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10945660&dopt=Abstract

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Use of risperidone in psychosis associated with Huntington's disease. Author(s): Madhusoodanan S, Brenner R. Source: The American Journal of Geriatric Psychiatry : Official Journal of the American Association for Geriatric Psychiatry. 1998 Fall; 6(4): 347-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9793585&dopt=Abstract

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Usefulness of molecular testing in Huntington's disease. Author(s): Wang V, Yeh TP, Chen CM, Yan SH, Soong BW. Source: Zhonghua Yi Xue Za Zhi (Taipei). 1999 September; 62(9): 586-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10502848&dopt=Abstract

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Utilisation of predictive, prenatal and diagnostic testing for Huntington's disease in Johannesburg. Author(s): Kromberg JG, Krause A, Spurdle AB, Temlett JA, Lucas M, Rodseth D, Stevens G, Jenkins T. Source: South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. 1999 July; 89(7): 774-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10470316&dopt=Abstract

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UVB irradiation-induced apoptosis increased in lymphocytes of Huntington's disease patients. Author(s): Jakab K, Novak Z, Engelhardt JI, Kemeny L, Kalman J, Vecsei L, Rasko I. Source: Neuroreport. 2001 June 13; 12(8): 1653-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11409734&dopt=Abstract

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Variability in cognitive function among persons at high genetic risk of Huntington's disease. Author(s): Lundervold AJ, Reinvang I. Source: Acta Neurologica Scandinavica. 1995 June; 91(6): 462-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7572041&dopt=Abstract

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Vasomotor hyporeactivity in the anterior cerebral artery during motor activation in Huntington's disease patients. Author(s): Deckel AW, Duffy JD. Source: Brain Research. 2000 July 28; 872(1-2): 258-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10924705&dopt=Abstract

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Velocity modulation and rhythmic synchronization of gait in Huntington's disease. Author(s): Thaut MH, Miltner R, Lange HW, Hurt CP, Hoemberg V. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 1999 September; 14(5): 808-19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10495043&dopt=Abstract

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Verbal fluency in Huntington's disease: a longitudinal analysis of phonemic and semantic clustering and switching. Author(s): Ho AK, Sahakian BJ, Robbins TW, Barker RA, Rosser AE, Hodges JR. Source: Neuropsychologia. 2002; 40(8): 1277-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11931930&dopt=Abstract

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Vesicular neurotransmitter transporters in Huntington's disease: initial observations and comparison with traditional synaptic markers. Author(s): Suzuki M, Desmond TJ, Albin RL, Frey KA. Source: Synapse (New York, N.Y.). 2001 September 15; 41(4): 329-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11494403&dopt=Abstract

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Visual attention and perception in patients with Huntington's disease: comparisons with other subcortical and cortical dementias. Author(s): Filoteo JV, Delis DC, Roman MJ, Demadura T, Ford E, Butters N, Salmon DP, Paulsen J, Shults CW, Swenson M, et al. Source: J Clin Exp Neuropsychol. 1995 October; 17(5): 654-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8557807&dopt=Abstract

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Visual attention in Huntington's disease: the effect of cueing on saccade latencies and manual reaction times. Author(s): Tsai TT, Lasker A, Zee DS. Source: Neuropsychologia. 1995 December; 33(12): 1617-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8745119&dopt=Abstract

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Visual object and visuospatial cognition in Huntington's disease: implications for information processing in corticostriatal circuits. Author(s): Lawrence AD, Watkins LH, Sahakian BJ, Hodges JR, Robbins TW. Source: Brain; a Journal of Neurology. 2000 July; 123 ( Pt 7): 1349-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10869048&dopt=Abstract

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Visual processing disorders in patients with Huntington's disease and asymptomatic carriers. Author(s): Gomez-Tortosa E, del Barrio A, Barroso T, Garcia Ruiz PJ. Source: Journal of Neurology. 1996 March; 243(3): 286-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8936361&dopt=Abstract

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Visuospatial cognition in Huntington's disease. Author(s): Mohr E, Brouwers P, Claus JJ, Mann UM, Fedio P, Chase TN. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 1991; 6(2): 127-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1829137&dopt=Abstract

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We need something better, and we need it now: fetal striatal transplantation in Huntington's disease? Author(s): Greenamyre JT, Shoulson I. Source: Neurology. 2002 March 12; 58(5): 675-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11889226&dopt=Abstract

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Weight loss in early stage of Huntington's disease. Author(s): Djousse L, Knowlton B, Cupples LA, Marder K, Shoulson I, Myers RH. Source: Neurology. 2002 November 12; 59(9): 1325-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12427878&dopt=Abstract

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Weight loss in Huntington's disease. Author(s): Stoy N, McKay E. Source: Annals of Neurology. 2000 July; 48(1): 130-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10894233&dopt=Abstract

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What is needed versus what would be interesting to know before undertaking neural transplantation in patients with Huntington's disease. Author(s): Peschanski M, Cesaro P, Hantraye P. Source: Neuroscience. 1996 April; 71(3): 899-900. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8867058&dopt=Abstract

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When does Huntington's disease begin? Author(s): Campodonico JR, Aylward E, Codori AM, Young C, Krafft L, Magdalinski M, Ranen N, Slavney PR, Brandt J. Source: Journal of the International Neuropsychological Society : Jins. 1998 September; 4(5): 467-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9745236&dopt=Abstract

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When is it not Huntington's disease? Author(s): Heckmann JM, Bryer A, Greenberg LJ. Source: South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. 2001 February; 91(2): 132-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11288392&dopt=Abstract

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Which diagnostic procedures in the elderly? The case of late-onset Huntington's disease. Author(s): Appollonio I, Frisoni GB, Curto N, Trabucchi M, Frattola L. Source: Journal of Geriatric Psychiatry and Neurology. 1997 January; 10(1): 39-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9100158&dopt=Abstract

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Wild type Huntingtin reduces the cellular toxicity of mutant Huntingtin in mammalian cell models of Huntington's disease. Author(s): Ho LW, Brown R, Maxwell M, Wyttenbach A, Rubinsztein DC. Source: Journal of Medical Genetics. 2001 July; 38(7): 450-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11432963&dopt=Abstract

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Wild-type huntingtin up-regulates BDNF transcription in Huntington's disease. Author(s): Reilly CE. Source: Journal of Neurology. 2001 October; 248(10): 920-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11697536&dopt=Abstract

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CHAPTER 2. NUTRITION AND HUNTINGTON’S DISEASE Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and Huntington’s disease.

Finding Nutrition Studies on Huntington’s Disease 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; 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]). 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.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: 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. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “Huntington’s disease” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

7 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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The following information is typical of that found when using the “Full IBIDS Database” to search for “Huntington’s disease” (or a synonym): •

3-Nitropropionic acid induces a spectrum of Huntington's disease-like neuropathology in rat striatum. Author(s): Department of Neurology; Department of Pathology, University Hospital Nijmegen, The Netherlands. [email protected] Source: Vis, J C Verbeek, M M De Waal, R M Ten Donkelaar, H J Kremer, H P Neuropathol-Appl-Neurobiol. 1999 December; 25(6): 513-21 0305-1846

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A controlled trial of idebenone in Huntington's disease. Author(s): Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Source: Ranen, N G Peyser, C E Coyle, J T Bylsma, F W Sherr, M Day, L Folstein, M F Brandt, J Ross, C A Folstein, S E Mov-Disord. 1996 September; 11(5): 549-54 0885-3185

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A randomised, placebo-controlled, double blind study of treatment of Huntington's disease with unsaturated fatty acids. Author(s): Department of Psychological Medicine, Monash University, Maroondah Hospital, Victoria, Australia. Source: Vaddadi, K S Soosai, E Chiu, E DingJanuary, P Neuroreport. 2002 Jan 21; 13(1): 29-33 0959-4965

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A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease. Source: Neurology. 2001 August 14; 57(3): 397-404 0028-3878

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Abnormalities in the functioning of adipocytes from R6/2 mice that are transgenic for the Huntington's disease mutation. Author(s): Departments of Molecular Sciences and Anatomy and Neurobiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA. [email protected] Source: Fain, J N Del March , N A Meade, C A Reiner, A Goldowitz, D Hum-Mol-Genet. 2001 January 15; 10(2): 145-52 0964-6906

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Administration of recombinant human Activin-A has powerful neurotrophic effects on select striatal phenotypes in the quinolinic acid lesion model of Huntington's disease. Author(s): Research Centre for Developmental Medicine and Biology, School of Medicine, University of Auckland, New Zealand. Source: Hughes, P E Alexi, T Williams, C E Clark, R G Gluckman, P D Neuroscience. 1999; 92(1): 197-209 0306-4522

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Age-dependent changes in nitric oxide synthase activity and protein expression in striata of mice transgenic for the Huntington's disease mutation. Author(s): Departamento de Fisiologi;a, Biofi;sica y Neurociencias, Centro de Investigacion y de Estudios Avanzados del IPN, Avenida Instituto Politecnico Nacional # 2508, 07300, DF, Mexico, Mexico. Source: Perez Severiano, F Escalante, B Vergara, P Rios, C Segovia, J Brain-Res. 2002 September 27; 951(1): 36-42 0006-8993

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Alleviation of motor hyperactivity and neurochemical deficits by endocannabinoid uptake inhibition in a rat model of Huntington's disease. Author(s): Departamento de Bioquimica y Biologia Molecular, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain.

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Source: Lastres Becker, Isabel Hansen, Henrik H Berrendero, Fernando De Miguel, Rosario Perez Rosado, Alberto Manzanares, Jorge Ramos, Jose A Fernandez Ruiz, Javier Synapse. 2002 April; 44(1): 23-35 0887-4476 •

Amantadine in Huntington's disease: open-label video-blinded study. Author(s): Department of Neuroscience, University of Pisa, Pisa, Italy. Source: Lucetti, C Gambaccini, G Bernardini, S Dell'Agnello, G Petrozzi, L Rossi, G Bonuccelli, U Neurol-Sci. 2002 September; 23 Suppl 2: S83-4 1590-1874

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An abnormal striatal synaptic plasticity may account for the selective neuronal vulnerability in Huntington's disease. Author(s): Neurosciences Department, University of Rome Tor Vergata, Rome, Italy. Source: Centonze, D Gubellini, P Picconi, B Saulle, E Tolu, M Bonsi, P Giacomini, P Calabresi, P Neurol-Sci. 2001 February; 22(1): 61-2 1590-1874

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Assessment of coenzyme Q10 tolerability in Huntington's disease. Author(s): Department of Neurology, University of Rochester School of Medicine and Dentistry, New York, USA. Source: Feigin, A Kieburtz, K Como, P Hickey, C Claude, K Abwender, D Zimmerman, C Steinberg, K Shoulson, I Mov-Disord. 1996 May; 11(3): 321-3 0885-3185

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Behavioral and morphological comparison of two nonhuman primate models of Huntington's disease. Author(s): Department of Neurosurgery, University of Illinois, 912 S. Wood Street, M/C 799, Chicago, IL 60612, USA. [email protected] Source: Roitberg, Ben Zion Emborg, Marina E Sramek, Joseph G Palfi, Stephane Kordower, Jeffrey H Neurosurgery. 2002 January; 50(1): 137-45; discussion 145-6 0148396X

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Calpain activation in Huntington's disease. Author(s): Buck Institute for Age Research, Novato, California 94945, USA. Source: Gafni, Juliette Ellerby, Lisa M J-Neurosci. 2002 June 15; 22(12): 4842-9 1529-2401

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Cerebrospinal fluid acetylcholinesterase and choline measurements in Huntington's disease. Author(s): Department of Medicine, Southern Illinois University School of Medicine, Springfield 62794-9230. Source: Manyam, B V Giacobini, E Colliver, J A J-Neurol. 1990 August; 237(5): 281-4 0340-5354

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Changes in endocannabinoid transmission in the basal ganglia in a rat model of Huntington's disease. Author(s): Departamento de Bioquimica y Biologia Molecular, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain. Source: Lastres Becker, I Fezza, F Cebeira, M Bisogno, T Ramos, J A Milone, A Fernandez Ruiz, J Marzo, V D Neuroreport. 2001 July 20; 12(10): 2125-9 0959-4965

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Characterization of a yeast artificial chromosome contig spanning the Huntington's disease gene candidate region. Source: Bates, G.P. Valdes, J. Hummerich, H. Baxendale, S. Le Paslier, D.L. Monaco, A.P. Tagle, D. MacDonald, M.E. Altherr, M. Ross, M. Nat-Gen. New York, NY : Nature Publishing Co. June 1992. volume 1 (3) page 180-187. 1061-4036

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Coenzyme Q10 and remacemide hydrochloride ameliorate motor deficits in a Huntington's disease transgenic mouse model. Author(s): Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. [email protected]

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Source: Schilling, G Coonfield, M L Ross, C A Borchelt, D R Neurosci-Lett. 2001 November 27; 315(3): 149-53 0304-3940 •

Cognitive deficits in Huntington's disease are predicted by dopaminergic PET markers and brain volumes. Author(s): Department of Psychology, Goteborg University, Sweden. Source: Backman, L Robins Wahlin, T B Lundin, A Ginovart, N Farde, L Brain. 1997 December; 120 ( Pt 12)2207-17 0006-8950

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Compounds acting at the endocannabinoid and/or endovanilloid systems reduce hyperkinesia in a rat model of Huntington's disease. Author(s): Departamento de Bioquimica y Biologia Molecular, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain. Source: Lastres Becker, I de Miguel, R De Petrocellis, L Makriyannis, A Di Marzo, V Fernandez Ruiz, J J-Neurochem. 2003 Mar; 84(5): 1097-109 0022-3042

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Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington's disease. Author(s): Neurochemistry Laboratory, Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusets, USA. Source: Andreassen, O A Dedeoglu, A Ferrante, R J Jenkins, B G Ferrante, K L Thomas, M Friedlich, A Browne, S E Schilling, G Borchelt, D R Hersch, S M Ross, C A Beal, M F Neurobiol-Dis. 2001 June; 8(3): 479-91 0969-9961

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Dietary arginine alters time of symptom onset in Huntington's disease transgenic mice. Author(s): Department of Psychiatry, MC 2103, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-2103, USA. [email protected] Source: Deckel, A W Volmer, P Weiner, R Gary, K A Covault, J Sasso, D Schmerler, N Watts, D Yan, Z Abeles, I Brain-Res. 2000 September 1; 875(1-2): 187-95 0006-8993

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Differential regulation of the expression of nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 after excitotoxicity in a rat model of Huntington's disease. Author(s): Departament de Biologia Cellular i Anatomia Patologica, Facultat de Medicina, Universitat de Barcelona, IDIBAPS, Spain. Source: Canals, J M Marco, S Checa, N Michels, A Perez Navarro, E Arenas, E Alberch, J Neurobiol-Dis. 1998 November; 5(5): 357-64 0969-9961

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Dysregulation of ascorbate release in the striatum of behaving mice expressing the Huntington's disease gene. Author(s): Program in Neural Science, Department of Psychology, Indiana University, Bloomington, Indiana 47405-7007, USA. [email protected] Source: Rebec, George V Barton, Scott J Ennis, Michelle D J-Neurosci. 2002 January 15; 22(2): RC202 1529-2401

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Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines. Author(s): Department of Neurology, Emory University School of Medicine, Whitehead Biomedical Research Building, 615 Michael Street, Atlanta, Georgia 30322, USA. Source: PaNovember, Alexander V Gutekunst, Claire Anne Leavitt, Blair R Hayden, Michael R Burke, James R Strittmatter, Warren J Greenamyre, J Timothy Nat-Neurosci. 2002 August; 5(8): 731-6 1097-6256

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Effects of nerve and fibroblast growth factors on the production of nitric oxide in experimental model of Huntington's disease. Author(s): Military Medical Academy, Institute for Medical Research, Belgrade. Source: Maksimovic, Ivana D Jovanovic, Marina D Malicevic, Zivorad Colic, Miodrag Ninkovic, Milica Vojnosanit-Pregl. 2002 Mar-April; 59(2): 119-23 0042-8450

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Embryonic striatal grafts restore neuronal activity of the globus pallidus in a rodent model of Huntington's disease. Author(s): Department of Neurological Surgery, Wakayama Medical College, Japan. Source: Nakao, N Ogura, M Nakai, K Itakura, T Neuroscience. 1999 January; 88(2): 46977 0306-4522

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Environmental stimulation increases survival in mice transgenic for exon 1 of the Huntington's disease gene. Author(s): Department of Pharmacology, University of Cambridge, UK. Source: Carter, R J Hunt, M J Morton, A J Mov-Disord. 2000 September; 15(5): 925-37 0885-3185

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Essential fatty acids given from conception prevent topographies of motor deficit in a transgenic model of Huntington's disease. Author(s): Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland. [email protected] Source: Clifford, J J Drago, J Natoli, A L Wong, J Y F Kinsella, A Waddington, J L Vaddadi, K S Neuroscience. 2002; 109(1): 81-8 0306-4522

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Evaluation of R6/2 HD transgenic mice for therapeutic studies in Huntington's disease: behavioral testing and impact of diabetes mellitus. Author(s): Department of Neurology, University Hospital RWTH Aachen, Pauwelsstrasse 30, D-52074, Aachen, Germany Source: Luesse, H G Schiefer, J Spruenken, A Puls, C Block, F Kosinski, C M BehavBrain-Res. 2001 November 29; 126(1-2): 185-95 0166-4328

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Evidence for dysfunction of the nigrostriatal pathway in the R6/1 line of transgenic Huntington's disease mice. Author(s): Section for Neuronal Survival, Wallenberg Neuroscience Center, Lund University, Sweden. Source: Petersen, A Puschban, Z Lotharius, J NicNiocaill, B Wiekop, P O'Connor, W T Brundin, P Neurobiol-Dis. 2002 October; 11(1): 134-46 0969-9961

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Fetal striatal transplants restore electrophysiological sensitivity to dopamine in the lesioned striatum of rats with experimental Huntington's disease. Author(s): Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC. Source: Chen, G J Jeng, C H Lin, S Z Tsai, S H Wang, Y Chiang, Y H J-Biomed-Sci. 2002 Jul-August; 9(4): 303-10 1021-7770

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Huntington's disease and low tryptophan diet. Author(s): Royal Children's Hospital, Melbourne, Australia. Source: Pascoe, M Med-Hypotheses. 1993 October; 41(4): 325-6 0306-9877

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Hyperactivity and hypoactivity in a rat model of Huntington's disease: the systemic 3nitropropionic acid model. Author(s): Department of Surgery, University of South Florida College of Medicine, Tampa 33612, USA. [email protected] Source: Borlongan, C V Koutouzis, T K Freeman, T B Hauser, R A Cahill, D W Sanberg, P R Brain-Res-Brain-Res-Protoc. 1997 August; 1(3): 253-7 1385-299X

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Impaired glutamate uptake in the R6 Huntington's disease transgenic mice. Author(s): Medical and Molecular Genetics, GKT School of Medicine, London, UK. Source: Lievens, J C Woodman, B Mahal, A Spasic Boscovic, O Samuel, D Kerkerian Le Goff, L Bates, G P Neurobiol-Dis. 2001 October; 8(5): 807-21 0969-9961

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Impaired phospholipid-related signal transduction in advanced Huntington's disease. Author(s): MRI Unit, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London W12 0HS, UK. [email protected] Source: Puri, B K Exp-Physiol. 2001 September; 86(5): 683-5 0958-0670

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In vitro effects of polyglutamine tracts on Ca2+-dependent depolarization of rat and human mitochondria: relevance to Huntington's disease. Author(s): Emory Center for Neurodegenerative Diseases, Emory University School of Medicine, Whitehead Biomedical Research Building, 615 Michael Street, Room 575, Atlanta, GA 30322, USA. [email protected] Source: PaNovember, A V Burke, J R Strittmatter, W J Greenamyre, J T Arch-BiochemBiophys. 2003 February 1; 410(1): 1-6 0003-9861

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Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease. Author(s): Kinsmen Laboratory of Neurological Research, Department of Psychiatry, 221 84, Lund, Sweden. Source: Zeron, M M Hansson, O Chen, N Wellington, C L Leavitt, B R Brundin, P Hayden, M R Raymond, L A Neuron. 2002 March 14; 33(6): 849-60 0896-6273

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Intranuclear inclusions in subtypes of striatal neurons in Huntington's disease transgenic mice. Author(s): Department of Neurology, University Hospital RWTH Aachen, Germany. Source: Kosinski, C M Cha, J H Young, A B Mangiarini, L Bates, G Schiefer, J Schwarz, M Neuroreport. 1999 December 16; 10(18): 3891-6 0959-4965

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Leuprolide acetate for exhibitionism in Huntington's disease. Author(s): Department of Psychiatry, University of Chicago, Illinois. Source: Rich, S S Ovsiew, F Mov-Disord. 1994 May; 9(3): 353-7 0885-3185

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Lipoic acid improves survival in transgenic mouse models of Huntington's disease. Author(s): Neurochemistry Laboratory, Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Source: Andreassen, O A Ferrante, R J Dedeoglu, A Beal, M F Neuroreport. 2001 October 29; 12(15): 3371-3 0959-4965

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Lithium suppresses excitotoxicity-induced striatal lesions in a rat model of Huntington's disease. Author(s): Section on Molecular Neurobiology, Biological Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1363, USA. Source: Wei, H Qin, Z H Senatorov, V V Wei, W Wang, Y Qian, Y Chuang, D M Neuroscience. 2001; 106(3): 603-12 0306-4522

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Mice transgenic for exon 1 of the Huntington's disease gene display reduced striatal sensitivity to neurotoxicity induced by dopamine and 6-hydroxydopamine. Author(s): Section for Neuronal Survival, Wallenberg Neuroscience Center, Lund University, Sweden. [email protected] Source: Petersen, A Hansson, O Puschban, Z Sapp, E Romero, N Castilho, R F Sulzer, D Rice, M DiFiglia, M Przedborski, S Brundin, P Eur-J-Neurosci. 2001 November; 14(9): 1425-35 0953-816X

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Modeling Huntington's disease in cells, flies, and mice. Author(s): Department of Pharmacological Sciences, University of Milano, Center of Excellence on Neurodegenerative Diseases, Italy. Source: Sipione, S Cattaneo, E Mol-Neurobiol. 2001 February; 23(1): 21-51 0893-7648

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Mouse models of Huntington's disease. Author(s): Dept of Neurology, Reed Neurological Research Center, UCLA School of Medicine, 710 Westwood Plaza, Los Angeles, CA 90095, USA. [email protected] Source: Menalled, Liliana B Chesselet, Marie Francoise Trends-Pharmacol-Sci. 2002 January; 23(1): 32-9 0165-6147

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Nabilone increases choreatic movements in Huntington's disease. Author(s): Department of Clinical Psychiatry and Psychotherapy Medical School, Hannover, Germany. Source: Muller Vahl, K R Schneider, U Emrich, H M Mov-Disord. 1999 November; 14(6): 1038-40 0885-3185

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N-Acetylaspartate and DARPP-32 levels decrease in the corpus striatum of Huntington's disease mice. Author(s): University Laboratory of Physiology, University of Oxford. Source: van Dellen, A Welch, J Dixon, R M Cordery, P York, D Styles, P Blakemore, C Hannan, A J Neuroreport. 2000 November 27; 11(17): 3751-7 0959-4965

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Neurochemistry and toxin models in Huntington's disease. Author(s): Massachusetts General Hospital, Boston 02114. Source: Beal, M F Curr-Opin-Neurol. 1994 December; 7(6): 542-7 1350-7540

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Neuroprotective role for the p50 subunit of NF-kappaB in an experimental model of Huntington's disease. Author(s): Sanders-Brown Research Center on Aging, National Institute on Aging Gerontology Research Center, Baltimore, MD 21224, USA. Source: Yu, Z Zhou, D Cheng, G Mattson, M P J-Mol-Neurosci. 2000 August; 15(1): 31-44 0895-8696

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Neurturin protects striatal projection neurons but not interneurons in a rat model of Huntington's disease. Author(s): Departament de Biologia Cellular i Anatomia Patologica, Facultat de Medicina, IDIBAPS, Universitat de Barcelona, Casanova 143, E-08036, Barcelona, Spain. Source: Perez Navarro, E Akerud, P Marco, S Canals, J M Tolosa, E Arenas, E Alberch, J Neuroscience. 2000; 98(1): 89-96 0306-4522

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NGF attenuates 3-nitrotyrosine formation in a 3-NP model of Huntington's disease. Author(s): Neuroregeneration Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA 02178, USA. Source: Galpern, W R Matthews, R T Beal, M F Isacson, O Neuroreport. 1996 November 4; 7(15-17): 2639-42 0959-4965

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PET study of the pre- and post-synaptic dopaminergic markers for the neurodegenerative process in Huntington's disease. Author(s): Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Source: Ginovart, N Lundin, A Farde, L Halldin, C Backman, L Swahn, C G Pauli, S Sedvall, G Brain. 1997 March; 120 ( Pt 3)503-14 0006-8950

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Possible cellular mechanism accounting for the cell type-specific vulnerability in Huntington's disease. Author(s): Neurological Clinic, Department of Neurosciences, University Tor Vergata and IRCCS S. Lucia Hospital, Rome, Italy. Source: Centonze, D Giacomini, P Tolu, M Bernardi, G Calabresi, P Funct-Neurol. 2000 Oct-December; 15(4): 253-8 0393-5264

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Progressive formation of inclusions in the striatum and hippocampus of mice transgenic for the human Huntington's disease mutation. Author(s): Departments of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QJ, UK. Source: Morton, A J Lagan, M A Skepper, J N Dunnett, S B J-Neurocytol. 2000 September; 29(9): 679-702 0300-4864

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Proteasomal-dependent aggregate reversal and absence of cell death in a conditional mouse model of Huntington's disease. Author(s): Centro de Biologia Molecular “Severo Ochoa,” Consejo Superior de Investigaciones Cientificas-Universidad Autonoma de Madrid, 28049 Madrid, Spain. Source: Martin Aparicio, E Yamamoto, A Hernandez, F Hen, R Avila, J Lucas, J J JNeurosci. 2001 November 15; 21(22): 8772-81 1529-2401

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Quantifiable bradykinesia, gait abnormalities and Huntington's disease-like striatal lesions in rats chronically treated with 3-nitropropionic acid. Author(s): Service Hospitalier Frederic Joliot, Unite de Recherche Associee 2210,Commissariat a l'Energie Atomique-Centre National de Recherche Scientifique, Departement de Recherche Medicale, Orsay, France. Source: Guyot, M C Hantraye, P Dolan, R Palfi, S Maziere, M Brouillet, E Neuroscience. 1997 July; 79(1): 45-56 0306-4522

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Quinolinic acid-induced increases in calbindin D28k immunoreactivity in rat striatal neurons in vivo and in vitro mimic the pattern seen in Huntington's disease. Author(s): Laboratory of Cellular Neurobiology, Massachusetts General Hospital, Boston 02114, USA. Source: Huang, Q Zhou, D Sapp, E Aizawa, H Ge, P Bird, E D Vonsattel, J P DiFiglia, M Neuroscience. 1995 March; 65(2): 397-407 0306-4522

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Restoration of cognitive and motor functions by ciliary neurotrophic factor in a primate model of Huntington's disease. Author(s): URA CEA CNRS 2210, SHFJ, DRM, DSV, CEA, Orsay, France. Source: Mittoux, V Joseph, J M Conde, F Palfi, S Dautry, C Poyot, T Bloch, J Deglon, N Ouary, S Nimchinsky, E A Brouillet, E Hof, P R Peschanski, M Aebischer, P Hantraye, P Hum-Gene-Ther. 2000 May 20; 11(8): 1177-87 1043-0342

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Steroid therapy in Huntington's disease. Author(s): Institute of Clinical Neurology, University of Pisa, Italy. Source: Bonuccelli, U Nuti, A Maremmani, C Ceravolo, R Muratorio, A Adv-BiochemPsychopharmacol. 1992; 47149-54 0065-2229

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Striatal and cortical neurochemical changes induced by chronic metabolic compromise in the 3-nitropropionic model of Huntington's disease. Author(s): Laboratoire de Neurophysiologie, ULB-Erasme, CP601, 808 Route de Lennik, 1070 Brussels, Belgium. [email protected] Source: Blum, D Galas, M C Gall, D Cuvelier, L Schiffmann, S N Neurobiol-Dis. 2002 August; 10(3): 410-26 0969-9961

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Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease. Author(s): Graduate Program in Neuroscience and Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA. Source: Keene, C D Rodrigues, C M Eich, T Chhabra, M S Steer, C J Low, W C Proc-NatlAcad-Sci-U-S-A. 2002 August 6; 99(16): 10671-6 0027-8424

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The differential vulnerability of striatal projection neurons in 3-nitropropionic acidtreated rats does not match that typical of adult-onset Huntington's disease. Author(s): Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. Source: Sun, Z Xie, J Reiner, A Exp-Neurol. 2002 July; 176(1): 55-65 0014-4886

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The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis. Author(s): Laboratory of Genomic Biology, Fondation Jean Dausset, Centre d'Etude du Polymorphisme Humain, 75010 Paris, France. Source: Holbert, S Denghien, I Kiechle, T Rosenblatt, A Wellington, C Hayden, M R Margolis, R L Ross, C A Dausset, J Ferrante, R J Neri, C Proc-Natl-Acad-Sci-U-S-A. 2001 February 13; 98(4): 1811-6 0027-8424

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The role of dopamine in motor symptoms in the R6/2 transgenic mouse model of Huntington's disease. Author(s): Department of Pharmacology, University of Cambridge, UK. Source: Hickey, Miriam A Reynolds, Gavin P Morton, A Jennifer J-Neurochem. 2002 April; 81(1): 46-59 0022-3042

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Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease. Author(s): Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, Massachusetts 01730, USA. [email protected] Source: Ferrante, Robert J Andreassen, Ole A Dedeoglu, Alpaslan Ferrante, Kimberly L Jenkins, Bruce G Hersch, Steven M Beal, M Flint J-Neurosci. 2002 March 1; 22(5): 1592-9 1529-2401

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&page=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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Healthnotes: http://www.healthnotes.com/

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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

The following is a specific Web list relating to Huntington’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: •

Minerals Creatine Source: Prima Communications, Inc.www.personalhealthzone.com Iron Source: Healthnotes, Inc.; www.healthnotes.com

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CHAPTER 3. ALTERNATIVE HUNTINGTON’S DISEASE

MEDICINE

AND

Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to Huntington’s disease. At the conclusion of this chapter, we will provide additional sources.

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 facilitate research for articles that specifically relate to Huntington’s disease and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “Huntington’s disease” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to Huntington’s disease: •

A primate model of Huntington's disease: functional neural transplantation and CTguided stereotactic procedures. Author(s): Schumacher JM, Hantraye P, Brownell AL, Riche D, Madras BK, Davenport PD, Maziere M, Elmaleh DR, Brownell GL, Isacson O. Source: Cell Transplantation. 1992; 1(4): 313-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1344304&dopt=Abstract

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Aspects of PET imaging relevant to the assessment of striatal transplantation in Huntington's disease. Author(s): Besret L, Kendall AL, Dunnett SB. Source: Journal of Anatomy. 2000 May; 196 ( Pt 4): 597-607. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10923990&dopt=Abstract

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Assessing Huntington's disease. Author(s): Fillingham K. Source: Community Nurse. 1998 October; 4(9): 51. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10326374&dopt=Abstract

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Behavioural relaxation training with Huntington's disease patients: a pilot study. Author(s): Fecteau GW, Boyne J. Source: Psychological Reports. 1987 August; 61(1): 151-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2959978&dopt=Abstract

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Bilateral human fetal striatal transplantation in Huntington's disease. Author(s): Hauser RA, Furtado S, Cimino CR, Delgado H, Eichler S, Schwartz S, Scott D, Nauert GM, Soety E, Sossi V, Holt DA, Sanberg PR, Stoessl AJ, Freeman TB. Source: Neurology. 2002 March 12; 58(5): 687-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11889229&dopt=Abstract

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Brain SPECT imaging in Huntington's disease before and after therapy with olanzapine. Case report. Author(s): Etchebehere EC, Lima MC, Passos W, Maciel Junior JA, Santos AO, Ramos CD, Camargo EE. Source: Arquivos De Neuro-Psiquiatria. 1999 September; 57(3B): 863-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10751925&dopt=Abstract

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Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease. Author(s): Wellington CL, Ellerby LM, Gutekunst CA, Rogers D, Warby S, Graham RK, Loubser O, van Raamsdonk J, Singaraja R, Yang YZ, Gafni J, Bredesen D, Hersch SM, Leavitt BR, Roy S, Nicholson DW, Hayden MR. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2002 September 15; 22(18): 7862-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12223539&dopt=Abstract

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Cdc42-interacting protein 4 binds to huntingtin: neuropathologic and biological evidence for a role in Huntington's disease. Author(s): Holbert S, Dedeoglu A, Humbert S, Saudou F, Ferrante RJ, Neri C. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 March 4; 100(5): 2712-7. Epub 2003 February 25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12604778&dopt=Abstract

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Cell therapy for Huntington's disease, the next step forward. Author(s): Peschanski M, Dunnett SB.

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Source: Lancet. Neurology. 2002 June; 1(2): 81. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12849508&dopt=Abstract •

Cellular delivery of trophic factors for the treatment of Huntington's disease: is neuroprotection possible? Author(s): Kordower JH, Isacson O, Leventhal L, Emerich DF. Source: Prog Brain Res. 2000; 127: 414-30. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11142039&dopt=Abstract

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Characterization of progressive motor deficits in mice transgenic for the human Huntington's disease mutation. Author(s): Carter RJ, Lione LA, Humby T, Mangiarini L, Mahal A, Bates GP, Dunnett SB, Morton AJ. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 1999 April 15; 19(8): 3248-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10191337&dopt=Abstract

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Comparison of ribosomal subunit proteins from normal human and Huntington's disease skin fibroblasts. Author(s): Prashad N, Rosenberg RN. Source: Annals of Neurology. 1977 May; 1(5): 475-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=152599&dopt=Abstract

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Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington's disease. Author(s): Andreassen OA, Dedeoglu A, Ferrante RJ, Jenkins BG, Ferrante KL, Thomas M, Friedlich A, Browne SE, Schilling G, Borchelt DR, Hersch SM, Ross CA, Beal MF. Source: Neurobiology of Disease. 2001 June; 8(3): 479-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11447996&dopt=Abstract

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Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington's disease transgenic mice. Author(s): Dedeoglu A, Kubilus JK, Yang L, Ferrante KL, Hersch SM, Beal MF, Ferrante RJ. Source: Journal of Neurochemistry. 2003 June; 85(6): 1359-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12787055&dopt=Abstract

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Cytochrome C and caspase-9 expression in Huntington's disease. Author(s): Kiechle T, Dedeoglu A, Kubilus J, Kowall NW, Beal MF, Friedlander RM, Hersch SM, Ferrante RJ. Source: Neuromolecular Medicine. 2002; 1(3): 183-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12095160&dopt=Abstract

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Effects of multisensory stimulation in people with Huntington's disease: a randomized controlled pilot study. Author(s): Leng TR, Woodward MJ, Stokes MJ, Swan AV, Wareing LA, Baker R. Source: Clinical Rehabilitation. 2003 February; 17(1): 30-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12617377&dopt=Abstract

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Electrodermal activity in patients with Huntington's disease and their progeny. Author(s): Iacono WG, Roshi D, Lacoste D. Source: Psychophysiology. 1987 September; 24(5): 522-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2960997&dopt=Abstract

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First step towards cell therapy for Huntington's disease. Author(s): Lindvall O, Bjorklund A. Source: Lancet. 2000 December 9; 356(9246): 1945-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11130518&dopt=Abstract

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Functional caudate imaging in symptomatic Huntington's disease: positron emission tomography versus single-photon emission computed tomography. Author(s): Martin WR, Hoskinson M, Kremer B, Maguire C, McEwan A. Source: Journal of Neuroimaging : Official Journal of the American Society of Neuroimaging. 1995 October; 5(4): 227-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7579751&dopt=Abstract

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Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice. Author(s): Ferrante RJ, Kubilus JK, Lee J, Ryu H, Beesen A, Zucker B, Smith K, Kowall NW, Ratan RR, Luthi-Carter R, Hersch SM. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2003 October 15; 23(28): 9418-27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14561870&dopt=Abstract

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Huntington's chorea: striking the right chord. Author(s): Hoskyns S. Source: Nurs Mirror. 1982 June 2; 154(22): 14-7. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6211657&dopt=Abstract

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Huntington's disease: prospects for neuroprotective therapy 10 years after the discovery of the causative genetic mutation. Author(s): Hersch SM. Source: Current Opinion in Neurology. 2003 August; 16(4): 501-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12869810&dopt=Abstract

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Hydrotherapy in Huntington's disease. Author(s): Sheaff F. Source: Nurs Times. 1990 January 24-30; 86(4): 46-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2137214&dopt=Abstract

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Hypnosis and the treatment of Huntington's disease. Author(s): Witz M, Kahn S. Source: Am J Clin Hypn. 1991 October; 34(2): 79-90. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1835562&dopt=Abstract

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Hypnosis as an adjunctive treatment in Huntington's disease. Author(s): Moldawsky RJ. Source: Am J Clin Hypn. 1984 April; 26(4): 229-31. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6237574&dopt=Abstract

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Imagery, encoding, and retrieval of information from memory: some specific encoding--retrieval changes in Huntington's disease. Author(s): Weingartner H, Caine ED, Ebert MH. Source: Journal of Abnormal Psychology. 1979 February; 88(1): 52-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=154532&dopt=Abstract

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Impaired prepulse inhibition of acoustic and tactile startle response in patients with Huntington's disease. Author(s): Swerdlow NR, Paulsen J, Braff DL, Butters N, Geyer MA, Swenson MR. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 1995 February; 58(2): 192200. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7876851&dopt=Abstract

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Late onset levodopa responsive Huntington's disease with minimal chorea masquerading as Parkinson plus syndrome. Author(s): Reuter I, Hu MT, Andrews TC, Brooks DJ, Clough C, Chaudhuri KR. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2000 February; 68(2): 23841. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10644798&dopt=Abstract

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Learning to live at risk for Huntington's disease. Author(s): Hunt V, Walker FO. Source: The Journal of Neuroscience Nursing : Journal of the American Association of Neuroscience Nurses. 1991 June; 23(3): 179-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1831483&dopt=Abstract

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Motor and cognitive improvements in patients with Huntington's disease after neural transplantation.

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Author(s): Bachoud-Levi AC, Remy P, Nguyen JP, Brugieres P, Lefaucheur JP, Bourdet C, Baudic S, Gaura V, Maison P, Haddad B, Boisse MF, Grandmougin T, Jeny R, Bartolomeo P, Dalla Barba G, Degos JD, Lisovoski F, Ergis AM, Pailhous E, Cesaro P, Hantraye P, Peschanski M. Source: Lancet. 2000 December 9; 356(9246): 1975-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11130527&dopt=Abstract •

Motor imagery in Huntington's disease. Author(s): McLennan NL, Georgiou NL, Mattingley JL, Bradshaw JL, Chiu E. Source: J Clin Exp Neuropsychol. 2000 June; 22(3): 379-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10855045&dopt=Abstract

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Motor learning by imagery is differentially affected in Parkinson's and Huntington's diseases. Author(s): Yaguez L, Canavan AG, Lange HW, Homberg V. Source: Behavioural Brain Research. 1999 July; 102(1-2): 115-27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10403020&dopt=Abstract

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Neurophysiological study of facial chorea in patients with Huntington's disease. Author(s): Munoz E, Cervera A, Valls-Sole J. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2003 July; 114(7): 1246-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12842721&dopt=Abstract

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Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease. Author(s): Ferrante RJ, Andreassen OA, Jenkins BG, Dedeoglu A, Kuemmerle S, Kubilus JK, Kaddurah-Daouk R, Hersch SM, Beal MF. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2000 June 15; 20(12): 4389-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10844007&dopt=Abstract

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Neuroprotective gene therapy for Huntington's disease using a polymer encapsulated BHK cell line engineered to secrete human CNTF. Author(s): Bachoud-Levi AC, Deglon N, Nguyen JP, Bloch J, Bourdet C, Winkel L, Remy P, Goddard M, Lefaucheur JP, Brugieres P, Baudic S, Cesaro P, Peschanski M, Aebischer P. Source: Human Gene Therapy. 2000 August 10; 11(12): 1723-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10954906&dopt=Abstract

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PET scan investigations of Huntington's disease: cerebral metabolic correlates of neurological features and functional decline. Author(s): Young AB, Penney JB, Starosta-Rubinstein S, Markel DS, Berent S, Giordani B, Ehrenkaufer R, Jewett D, Hichwa R.

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Source: Annals of Neurology. 1986 September; 20(3): 296-303. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2945510&dopt=Abstract •

Predictive genetic test decisions for Huntington's disease: context, appraisal and new moral imperatives. Author(s): Taylor SD. Source: Social Science & Medicine (1982). 2004 January; 58(1): 137-49. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14572927&dopt=Abstract

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Regional and progressive thinning of the cortical ribbon in Huntington's disease. Author(s): Rosas HD, Liu AK, Hersch S, Glessner M, Ferrante RJ, Salat DH, van der Kouwe A, Jenkins BG, Dale AM, Fischl B. Source: Neurology. 2002 March 12; 58(5): 695-701. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11889230&dopt=Abstract

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Relationship between evoked potential and neuropsychological findings in persons “at risk” for Huntington's disease. Author(s): Josiassen RC, Curry LM, Mancall EL, Shagass C, Roemer RA. Source: J Clin Exp Neuropsychol. 1986 January; 8(1): 21-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2935556&dopt=Abstract

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Replicating Huntington's disease phenotype in experimental animals. Author(s): Brouillet E, Conde F, Beal MF, Hantraye P. Source: Progress in Neurobiology. 1999 December; 59(5): 427-68. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10515664&dopt=Abstract

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Self-help groups: association to combat Huntington's chorea. Author(s): Jones IH. Source: Nurs Times. 1979 November 8; 75(45): 1949. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=160034&dopt=Abstract

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Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease. Author(s): Dunah AW, Jeong H, Griffin A, Kim YM, Standaert DG, Hersch SM, Mouradian MM, Young AB, Tanese N, Krainc D. Source: Science. 2002 June 21; 296(5576): 2238-43. Epub 2002 May 02. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11988536&dopt=Abstract

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Striatal grafts in a rat model of Huntington's disease: time course comparison of MRI and histology. Author(s): Guzman R, Meyer M, Lovblad KO, Ozdoba C, Schroth G, Seiler RW, Widmer HR.

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Source: Experimental Neurology. 1999 March; 156(1): 180-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10192789&dopt=Abstract •

The midlatency auditory evoked potential P50 is abnormal in Huntington's disease. Author(s): Uc EY, Skinner RD, Rodnitzky RL, Garcia-Rill E. Source: Journal of the Neurological Sciences. 2003 August 15; 212(1-2): 1-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12809992&dopt=Abstract

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The problem of antipsychotic treatment for functional imaging in Huntington's disease: receptor binding, gene expression and locomotor activity after sub-chronic administration and wash-out of haloperidol in the rat. Author(s): Besret L, Page KJ, Dunnett SB. Source: Brain Research. 2000 January 17; 853(1): 125-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10627316&dopt=Abstract

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The scintigraphic evaluation of Huntington's disease and other movement disorders using single photon emission computed tomography perfusion brain scans. Author(s): Nagel JS, Ichise M, Holman BL. Source: Semin Nucl Med. 1991 January; 21(1): 11-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1825359&dopt=Abstract

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Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease. Author(s): Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, Jenkins BG, Hersch SM, Beal MF. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2002 March 1; 22(5): 1592-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11880489&dopt=Abstract

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Therapeutic effects of cystamine in a murine model of Huntington's disease. Author(s): Dedeoglu A, Kubilus JK, Jeitner TM, Matson SA, Bogdanov M, Kowall NW, Matson WR, Cooper AJ, Ratan RR, Beal MF, Hersch SM, Ferrante RJ. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2002 October 15; 22(20): 8942-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12388601&dopt=Abstract

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Tracing Woody Guthrie and Huntington's disease. Author(s): Arevalo J, Wojcieszek J, Conneally PM. Source: Seminars in Neurology. 2001 June; 21(2): 209-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11442329&dopt=Abstract

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Velocity modulation and rhythmic synchronization of gait in Huntington's disease. Author(s): Thaut MH, Miltner R, Lange HW, Hurt CP, Hoemberg V.

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Source: Movement Disorders : Official Journal of the Movement Disorder Society. 1999 September; 14(5): 808-19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10495043&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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drkoop.com®: http://www.drkoop.com/InteractiveMedicine/IndexC.html

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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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Healthnotes: http://www.healthnotes.com/

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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine

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

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HealthGate: http://www.tnp.com/

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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

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

The following is a specific Web list relating to Huntington’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 Parkinson's Disease Source: Integrative Medicine Communications; www.drkoop.com Tardive Dyskinesia Source: Healthnotes, Inc.; www.healthnotes.com

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

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MEDLINEplus site at http://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.

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CHAPTER 4. DISSERTATIONS ON HUNTINGTON’S DISEASE Overview In this chapter, we will give you a bibliography on recent dissertations relating to Huntington’s disease. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “Huntington’s disease” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on Huntington’s disease, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Huntington’s Disease ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to Huntington’s disease. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •

3-nitropropionic Acid: a Mode for Huntington's Disease by Nasr, Payman; PhD from University of Kentucky, 2003, 225 pages http://wwwlib.umi.com/dissertations/fullcit/3082702

•

A Genealogy of Genealogical Practices: the Development and Use of Medical Pedigrees in the Case of Huntington's Disease by Nukaga, Yoshio; PhD from McGill University (Canada), 2001, 392 pages http://wwwlib.umi.com/dissertations/fullcit/NQ70116

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A Model for the Early Identification of Individuals with Juvenile Onset Huntington's Disease (huntington Disease) by Artigliere-cavalier, Julia Marie, PhD from University of Colorado at Boulder, 1989, 155 pages http://wwwlib.umi.com/dissertations/fullcit/8923478

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Coping with the Risk of Huntington's Disease by Dorn, Margaret Beatty, PhD from University of Denver, 1990, 282 pages http://wwwlib.umi.com/dissertations/fullcit/9102132

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Energy Needs in People with Huntington's Disease by Gaba, Ann; EDD from Columbia University Teachers College, 2002, 157 pages http://wwwlib.umi.com/dissertations/fullcit/3052880

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Olfactory Psychophysics and Electrophysiology in Huntington's Disease by Wetter, Spencer Ryan; PhD from University of California, San Diego and San Diego State University, 2003, 140 pages http://wwwlib.umi.com/dissertations/fullcit/3083456

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Performance on the Repeated Patterns Test by Individuals with Brain Injury, Huntington's Disease, and Stroke by Nijhawan, Sunita R.; PsyD from Argosy University/twin Cities, 2002, 88 pages http://wwwlib.umi.com/dissertations/fullcit/3041665

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Testing an Action Selection Model of Basal Ganglia Function in Parkinson's Disease and Huntington's Disease by Wylie, Scott Alan; PhD from Indiana University, 2002, 156 pages http://wwwlib.umi.com/dissertations/fullcit/3076073

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Transplantation of Sertoli Cells into a 3-nitropropionic Acid Rat Model of Huntington's Disease by Rodriguez, Alba I.; PhD from University of South Florida, 2002, 137 pages http://wwwlib.umi.com/dissertations/fullcit/3052667

Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.

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CHAPTER 5. CLINICAL TRIALS AND HUNTINGTON’S DISEASE Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning Huntington’s disease.

Recent Trials on Huntington’s Disease The following is a list of recent trials dedicated to Huntington’s disease.8 Further information on a trial is available at the Web site indicated. •

Minocycline in Patients with Huntington's Disease Condition(s): Huntington's Disease Study Status: This study is currently recruiting patients. Sponsor(s): FDA Office of Orphan Products Development Purpose - Excerpt: This is a study to determine whether treatment with minocycline is safe and tolerable in patients with Huntington's disease (HD) and whether minocycline reduces symptoms of HD in these patients. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00029874

•

Neurobiological Predictors of Huntington's Disease (PREDICT-HD) Condition(s): Huntington Disease Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS)

8

These are listed at www.ClinicalTrials.gov.

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Purpose - Excerpt: The purpose of this trial is to study early brain and behavioral changes in people who have the gene expansion for Huntington's disease, but are currently healthy and have no symptoms. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00051324 •

Creatine Therapy for Huntington's Disease Condition(s): Huntington's Disease Study Status: This study is no longer recruiting patients. Sponsor(s): National Center for Complementary and Alternative Medicine (NCCAM) Purpose - Excerpt: This study, CREST-HD, will examine the safety and tolerability of 8 grams of creatine in subjects affected by Huntington's disease (HD). Biochemistry and neuroimaging will be used to examine the potential effects of creatine on HD. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00026988

•

Long-Term Study of Cerebral Glucose Metabolism in Huntington's Disease Condition(s): Huntington's Disease Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); National Institute of Neurological Disorders and Stroke (NINDS); University of California, Los Angeles Purpose - Excerpt: Objectives: I. Correlate clinical outcome with cerebral glucose metabolism in patients with Huntington's disease (HD) and their at-risk relatives. II. Evaluate the efficacy of cerebral glucose metabolism in observing the pathophysiologic development of HD, monitoring responses to experimental therapy, and predicting HD genotype. III. Identify, define, and describe the natural history of pathophysiologic lesions in HD. IV. Characterize the genotypic and phenotypic expression of the HD gene. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004753

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Treatment of Huntington's Chorea with Amantadine Condition(s): Chorea; Huntington's Disease Study Status: This study is completed. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS) Purpose - Excerpt: Huntington's disease is a chronic disorder passed on through genetic autosomal dominant inheritance. The condition usually begins between the ages of 30 and 50 years and it is characterized by involuntary movements in the face and extremities, (chorea), accompanied by changes in behavior and gradual loss of the

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mental function. The disease typically ends in a state of disorientation, impaired memory, judgement, and intellect (dementia). The objective of this study is to test the effectiveness of the drug amantadine for the treatment of chorea associated with Huntington's disease. Amantadine is an antiviral drug that has been used to treat a variety of illnesses including Parkinson's disease. Amantadine works by attaching to special sites called NMDA (N-methyl-D-aspartate) receptors and blocking the normal activity of glutamate there. Glutamate is an amino acid released by brain cells and has been associated with the symptoms of Parkinson's disease. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001930

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. 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 the Web site at http://www.clinicaltrials.gov/ and search by “Huntington’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

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For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/

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For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm

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For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm

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

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For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp

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For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm

134 Huntington’s Disease

•

For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/

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For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm

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For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm

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For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm

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For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm

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For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm

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For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials

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CHAPTER 6. BOOKS ON HUNTINGTON’S DISEASE Overview This chapter provides bibliographic book references relating to Huntington’s disease. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on Huntington’s disease include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

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®). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “Huntington’s disease” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “Huntington’s disease” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “Huntington’s disease” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

A physician's guide to the management of Huntington's disease; ISBN: 096377302X; http://www.amazon.com/exec/obidos/ASIN/096377302X/icongroupinterna

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Cell Transplantation for Huntington's Disease (Medical Intelligence Unit) by Paul R. Sanberg (Editor), et al; ISBN: 1570590796; http://www.amazon.com/exec/obidos/ASIN/1570590796/icongroupinterna

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Genetic Disorders Sourcebook: Basic Consumer Health Information About Hereditary Diseases and Disorders, Including Cystic Fibrosis, Down Syndrome, Hemophilia, Huntington's Disease by Kathy Massimini (Editor) (2000); ISBN: 0780802411; http://www.amazon.com/exec/obidos/ASIN/0780802411/icongroupinterna

•

Heading for Better Care: Commissioning and Providing Mental Health Services for People with Huntington's Disease, Acquired Brain Injury and Early Onset Dementia

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(An NHS Health Advisory Service Thematic Review) by Richard Williams, et al (1997); ISBN: 0113219377; http://www.amazon.com/exec/obidos/ASIN/0113219377/icongroupinterna •

Huntington's Chorea by Michael R. Hayden; ISBN: 0387105883; http://www.amazon.com/exec/obidos/ASIN/0387105883/icongroupinterna

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Huntington's chorea : a booklet for the families and friends of patients with the disease by David Lawrence Stevens; ISBN: 0950536407; http://www.amazon.com/exec/obidos/ASIN/0950536407/icongroupinterna

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Huntington's disease; ISBN: 0890043744; http://www.amazon.com/exec/obidos/ASIN/0890043744/icongroupinterna

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Huntington's Disease (Oxford Monographs on Medical Genetics, 45) by Gillian Bates (Editor), et al (2002); ISBN: 0198510608; http://www.amazon.com/exec/obidos/ASIN/0198510608/icongroupinterna

•

Huntington's disease : hope through research (SuDoc HE 20.3502:H 92/998) by Stephanie E. Clipper; ISBN: B00010WRK0; http://www.amazon.com/exec/obidos/ASIN/B00010WRK0/icongroupinterna

•

Huntington's Disease: A Disorder of Families (Johns Hopkins Series in Contemporary Medicine and Public Health) by Susan E. Folstein; ISBN: 0801838606; http://www.amazon.com/exec/obidos/ASIN/0801838606/icongroupinterna

•

Huntington's Disease: The Facts by Oliver Quarrell; ISBN: 0192629301; http://www.amazon.com/exec/obidos/ASIN/0192629301/icongroupinterna

•

Living With Huntington's Disease: A Book for Patients and Families by Dennis Phillips; ISBN: 0299086704; http://www.amazon.com/exec/obidos/ASIN/0299086704/icongroupinterna

•

The Official Patient's Sourcebook on Huntington's Disease: A Revised and Updated Directory for the Internet Age by Icon Health Publications (2002); ISBN: 0597830487; http://www.amazon.com/exec/obidos/ASIN/0597830487/icongroupinterna

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 “Huntington’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:9

9

In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently 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.

Books

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•

A centennial bibliography of Huntington's chorea, 1872-1972 by G. W. Bruyn, F. Baro, and N. C. Myrianthopoulos. Author: Bruyn, G. W.; Year: 1982; Louvain, Leuven Univ. Press, 1974; ISBN: 9061860113 http://www.amazon.com/exec/obidos/ASIN/9061860113/icongroupinterna

•

A physician's guide to the management of Huntington's disease: pharmacologic and non-pharmacologic interventions Author: Ranen, Neal G.; Year: 1999; New York:; ISBN: 0963773003

•

Cell transplantation for Huntington's disease Author: Sanberg, Paul R.; Year: 1994; Austin: R.G. Landes; Boca Raton, FL: CRC Press [distributor], 1994; ISBN: 1570590790

•

Huntington's chorea Author: Hayden, Michael R.; Year: 1983; Berlin; New York: Springer-Verlag, 1981; ISBN: 3540105883

•

Huntington's chorea: a booklet for family doctors and other professionals. Author: Association to Combat Huntington's Chorea (Great Britain); Year: 1998; Hinckley, Leicestershire: Association to Combat Hungtington's Chorea, 1983

•

Huntington's chorea, 1872-1972. Editors: André Barbeau, Thomas N. Chase [and] George W. Paulson. Author: Barbeau, André.; Year: 1981; New York, Raven Press [c1973]; ISBN: 091216405

•

Huntington's disease Author: Harper, Peter S.; Year: 2002; London; Philadelphia: W.B. Saunders, c1996; ISBN: 0702021539 http://www.amazon.com/exec/obidos/ASIN/0702021539/icongroupinterna

•

Huntington's disease (Huntington's chorea). Author: National Institute of Neurological Diseases and Stroke.; Year: 1971; [Bethesda, Md., For sale by the Supt. of Docs., U. S. Govt. Print. Off., Washington, 1971]

•

Huntington's disease: hearing before a subcommittee of the Committee on Appropriations, United States Senate, Ninety-fifth Congress, first session. Author: United States. Congress. Senate. Committee on Appropriations. Subcommittee on Departments of Labor, and Health, Education, and Welfare, and Related Agencies.; Year: 1977; Washington: U. S. Govt. Print. Off., 1977

•

Huntington's disease: research highlights, 1992 Author: National Institute of Neurological Disorders and Stroke (U.S.); Year: 1992; [Bethesda, Md.?: The Institute, 1992?]

•

Neostriatal and thalamic interneurons: their role in the pathophysiology of Huntington's chorea, Parkinson's disease, and catatonic schizophrenia Author: Dom, René.; Year: 1976; Leuven: ACCO, 1976

•

On nursing Huntington's chorea Author: Gardham, Frank.; Year: 1992; Hinckley, Leicestershire: Association to Combat

Chapters on Huntington’s Disease In order to find chapters that specifically relate to Huntington’s disease, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and Huntington’s disease using the “Detailed Search” option. Go 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.” Type “Huntington’s disease” (or synonyms) into the “For these words:” box.

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CHAPTER 7. MULTIMEDIA ON HUNTINGTON’S DISEASE Overview In this chapter, we show you how to keep current on multimedia sources of information on Huntington’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.

Bibliography: Multimedia on Huntington’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 Huntington’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 Huntington’s disease: •

[Huntington's chorea] [motion picture] Source: [production company unknown]; produced by Max Rossman; Year: 1939; Format: Huntington's chorea; United States: [s.n.], 1939

•

Clinical features of myotonic dystrophy and Huntington's disease [videorecording] Source: a presentation of Films for the Humanities & Sciences; produced for the Centre for Human Genetics by Sheffield University Television; Year: 1998; Format: Videorecording; Princeton, N.J.: Films for the Humanities & Sciences, c1998

•

Huntington's chorea [slide] Source: K.W.G. Heathfield; Year: 1981; Format: Slide; Chelmsford, Essex, UK: Graves Medical Audiovisual Library, [1981]

•

Huntington's chorea [videorecording] Source: W. O. McCormick; Year: 1976; Format: Videorecording; Toronto: IMS, Faculty of Medicine, University of Toronto, c1976

•

Huntington's disease [videorecording]: the Woody Guthrie story Source: as told by Marjorie Guthrie; Year: 1983; Format: Videorecording; Washington, DC: National Audiovisual Center, [1983]

•

The Pharmacology and biochemical pathology of choreatic disorders [sound recording]; Biochemical pathology of Huntington's chorea Source: Dept. of Neurology,

140 Huntington’s Disease

University of Miami, School of Medicine; Year: 1977; Format: Sound recording; Dallas: Medisette, 1977

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CHAPTER 8. PERIODICALS AND NEWS ON HUNTINGTON’S DISEASE Overview In this chapter, we suggest a number of news sources and present various periodicals that cover Huntington’s disease.

News Services and Press Releases One of the simplest ways of tracking press releases on Huntington’s disease is to search the news wires. 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. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “Huntington’s disease” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to Huntington’s disease. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “Huntington’s disease” (or synonyms). The following was recently listed in this archive for Huntington’s disease: •

NaPro shares jump on Huntington's disease news Source: Reuters Industry Breifing Date: June 09, 2003

142 Huntington’s Disease

•

Amarin to conduct another phase III trial of Huntington's disease treatment Source: Reuters Industry Breifing Date: February 03, 2003

•

Findings support protein aggregation as key factor in Huntington's disease Source: Reuters Medical News Date: January 22, 2003

•

Study zeroes in on causes of Huntington's disease Source: Reuters Health eLine Date: August 01, 2002

•

Mitochondrial calcium defect seen early in Huntington's disease Source: Reuters Medical News Date: July 16, 2002

•

DNA transcription reduced before symptom onset in Huntington's disease Source: Reuters Industry Breifing Date: May 03, 2002

•

Fetal striatal cell transplant feasible for Huntington's disease, but benefit unclear Source: Reuters Medical News Date: March 22, 2002

•

Environmental stimulation slows course of experimental Huntington's disease Source: Reuters Medical News Date: March 08, 2002

•

Amarin reports clinical advance with Huntington's disease drug Source: Reuters Industry Breifing Date: January 23, 2002

•

Cognitive testing detects early Huntington's disease Source: Reuters Medical News Date: September 05, 2001

•

Tetrabenazine can be helpful in chorea associated with Huntington's disease Source: Reuters Industry Breifing Date: May 08, 2001

•

Research offers new hope for Huntington's disease Source: Reuters Health eLine Date: March 22, 2001

•

Mechanism of Huntington's disease cellular toxicity revealed Source: Reuters Industry Breifing Date: March 22, 2001

•

Carbamazepine may prevent precipitate micturition in Huntington's disease Source: Reuters Medical News Date: January 12, 2001

•

Fetal cells 'take' in Huntington's disease patient Source: Reuters Health eLine Date: January 02, 2001

•

Neurologic deficits precede clinical diagnosis of Huntington's disease Source: Reuters Medical News Date: December 21, 2000

Periodicals and News

•

Amarin to launch study of first Huntington's disease therapy Source: Reuters Industry Breifing Date: December 11, 2000

•

Fetal nerve cell grafts may improve outcome in Huntington's disease Source: Reuters Medical News Date: November 29, 2000

•

Fetal cell therapy promising for Huntington's disease Source: Reuters Health eLine Date: November 29, 2000

•

Better test for Huntington's disease raises questions and concerns Source: Reuters Medical News Date: October 27, 2000

•

Aurora in Huntington's disease research pact Source: Reuters Industry Breifing Date: September 13, 2000

•

Jellyfish chemical may help Huntington's disease research Source: Reuters Health eLine Date: September 12, 2000

•

Minocycline slows Huntington's disease in mice Source: Reuters Industry Breifing Date: June 28, 2000

•

Antibiotic may treat Huntington's disease Source: Reuters Health eLine Date: June 27, 2000

•

Early reduction in striatal signaling seen in model of Huntington's disease Source: Reuters Industry Breifing Date: June 12, 2000

•

Heat shock protein reverses Huntington's disease-like pathology in C. elegans Source: Reuters Medical News Date: May 30, 2000

•

Mouse model suggests Huntington's disease may be reversible Source: Reuters Medical News Date: April 19, 2000

•

Growth factor delivery beneficial in monkey model of Huntington's disease Source: Reuters Medical News Date: April 18, 2000

•

Enriched environment may delay Huntington's disease Source: Reuters Health eLine Date: April 12, 2000

•

Symptoms of Huntington's disease present up to 7 years before onset in mutation carriers Source: Reuters Medical News Date: February 03, 2000

•

New clues identified in Huntington's disease Source: Reuters Health eLine Date: February 03, 2000

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144 Huntington’s Disease

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Huntington's disease testing should be a family affair Source: Reuters Medical News Date: January 03, 2000

•

Caspase-1 inhibition slows Huntington's disease in mice Source: Reuters Medical News Date: May 20, 1999

•

Blocking enzyme may help Huntington's disease Source: Reuters Health eLine Date: May 19, 1999

•

Striatal allografts successful in primate model of Huntington's disease Source: Reuters Medical News Date: June 02, 1998

•

Transplants help Huntington's disease Source: Reuters Health eLine Date: June 01, 1998

•

Two Orphan Drugs May Help Advanced Parkinson's, Huntington's Disease Source: Reuters Medical News Date: January 13, 1997

•

Regeneron And Medtronic To Collaborate On Huntington's Disease Therapies Source: Reuters Medical News Date: July 01, 1996 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 the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its 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, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “Huntington’s disease” (or synonyms) into the search box, and click on “Search News.” As this service is

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technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “Huntington’s disease” (or synonyms). If you know the name of a company that is relevant to Huntington’s disease, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. 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 “Huntington’s disease” (or synonyms).

Academic Periodicals covering Huntington’s Disease Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to Huntington’s disease. In addition to these sources, you can search for articles covering Huntington’s disease that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: 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.”

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CHAPTER 9. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.

U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for Huntington’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 http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting 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, located at http://www.fda.gov/cder/da/da.htm. 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 Pharmacopeia (USP). Below, we have compiled a list of medications associated with Huntington’s disease. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.).

148 Huntington’s Disease

The following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to Huntington’s disease: Anticholinergics/Antispasmodics •

Systemic - U.S. Brands: Anaspaz; A-Spas S/L; Banthine; Bentyl; Cantil; Cystospaz; Cystospaz-M; Donnamar; ED-SPAZ; Gastrosed; Homapin; Levbid; Levsin; Levsin/SL; Levsinex Timecaps; Pro-Banthine; Quarzan; Robinul; Robinul Forte; Symax SL; Transderm-Scop http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202049.html

Anticonvulsants, Dione •

Systemic - U.S. Brands: http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202049.html

Anticonvulsants, Hydantoin •

Systemic - U.S. Brands: Cerebyx; Dilantin; Dilantin Infatabs; Dilantin Kapseals; Dilantin-125; Mesantoin; Peganone; Phenytex http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202052.html

Anticonvulsants, Succinimide •

Systemic - U.S. Brands: Celontin; Zarontin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202053.html

Baclofen •

Systemic - U.S. Brands: http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202053.html

•

Systemic - U.S. Brands: Lioresal http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202080.html

Fluoxetine •

Systemic - U.S. Brands: Prozac; Sarafem http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202247.html

Haloperidol •

Systemic - U.S. Brands: Haldol http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202278.html

Isoniazid •

Systemic - U.S. Brands: Laniazid; Nydrazid http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202307.html

Isoniazid and Thiacetazone •

Systemic - U.S. Brands: http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202307.html

Levodopa •

Systemic - U.S. Brands: Atamet; Larodopa; Sinemet; Sinemet CR http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202326.html

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Levodopa and Benserazide •

Systemic - U.S. Brands: http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202326.html

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.html

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. Or, you may be able to access these sources from your local medical library.

Mosby’s Drug Consult™ Mosby’s Drug Consult™ 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. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. 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 Drugs.com (www.drugs.com) 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. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee.

Researching Orphan Drugs Although the list of orphan drugs is revised on a daily basis, you can quickly research orphan drugs that might be applicable to Huntington’s disease by using the database managed by the National Organization for Rare Disorders, Inc. (NORD), at http://www.rarediseases.org/. Scroll down the page, and on the left toolbar, click on

150 Huntington’s Disease

“Orphan Drug Designation Database.” On this page (http://www.rarediseases.org/search/noddsearch.html), type “Huntington’s disease” (or synonyms) into the search box, and click “Submit Query.” When you receive your results, note that not all of the drugs may be relevant, as some may have been withdrawn from orphan status. Write down or print out the name of each drug and the relevant contact information. From there, visit the Pharmacopeia Web site and type the name of each orphan drug into the search box at http://www.nlm.nih.gov/medlineplus/druginformation.html. You may need to contact the sponsor or NORD for further information. NORD conducts “early access programs for investigational new drugs (IND) under the Food and Drug Administration’s (FDA’s) approval ‘Treatment INDs’ programs which allow for a limited number of individuals to receive investigational drugs before FDA marketing approval.” If the orphan product about which you are seeking information is approved for marketing, information on side effects can be found on the product’s label. If the product is not approved, you may need to contact the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for Huntington’s disease: •

Remacemide (trade name: Ecovia) http://www.rarediseases.org/nord/search/nodd_full?code=1029

•

Ethyl eicosapentaenoate (trade name: Venticute) http://www.rarediseases.org/nord/search/nodd_full?code=1037

•

Coenzyme Q10 http://www.rarediseases.org/nord/search/nodd_full?code=1097

•

Coenzyme Q10 http://www.rarediseases.org/nord/search/nodd_full?code=1102

•

Coenzyme Q10 (trade name: NONE Assigned) http://www.rarediseases.org/nord/search/nodd_full?code=1155

•

Porcine fetal neural gabaergic cells and/or precur (trade name: anti-MHC-1 Ab for intracerebral implantation. TN=) http://www.rarediseases.org/nord/search/nodd_full?code=827

•

Porcine fetal neural gabaergic cells and/or precur (trade name: implantation for Huntington's disease. TN=Ne) http://www.rarediseases.org/nord/search/nodd_full?code=828

•

Riluzole (trade name: Rilutek) http://www.rarediseases.org/nord/search/nodd_full?code=799

•

Tetrabenzine http://www.rarediseases.org/nord/search/nodd_full?code=866

If you have any questions about a 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, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.

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APPENDICES

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APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute10: •

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

•

National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/

•

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

•

National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25

•

National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm

•

National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm

•

National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375

•

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

10

These publications are typically written by one or more of the various NIH Institutes.

154 Huntington’s Disease

•

National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm

•

National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/

•

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm

•

National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm

•

National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/

•

National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/

•

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm

•

National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html

•

National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm

•

National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm

•

National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm

•

National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html

•

National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm

•

Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp

•

National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/

•

National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp

•

Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html

•

Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm

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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.11 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:12 •

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

•

HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

•

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

•

Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

•

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/

•

Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

•

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

•

Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

•

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

11

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). 12 See http://www.nlm.nih.gov/databases/databases.html.

156 Huntington’s Disease

•

Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

•

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

The NLM Gateway13 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.14 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “Huntington’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 Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total

Items Found 6111 164 1038 5 0 7318

HSTAT15 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.16 These documents include clinical practice guidelines, quickreference 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.17 Simply search by “Huntington’s disease” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

13

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

14

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). 15 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 16 17

The HSTAT URL is http://hstat.nlm.nih.gov/.

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.

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Coffee Break: Tutorials for Biologists18 Coffee Break is 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. Here you will find 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.19 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.20 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

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/.

18 Adapted 19

from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

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. 20 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.

159

APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. 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. Since new guidelines on Huntington’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.

Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to Huntington’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. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to Huntington’s disease. 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 when searched for “Huntington’s disease”:

160 Huntington’s Disease

•

Other guides AIDS http://www.nlm.nih.gov/medlineplus/aids.html Alcohol Consumption http://www.nlm.nih.gov/medlineplus/alcoholconsumption.html Alcoholism http://www.nlm.nih.gov/medlineplus/alcoholism.html Alzheimer's Disease http://www.nlm.nih.gov/medlineplus/alzheimersdisease.html Brain Diseases http://www.nlm.nih.gov/medlineplus/braindiseases.html Cancer Alternative Therapy http://www.nlm.nih.gov/medlineplus/canceralternativetherapy.html Degenerative Nerve Diseases http://www.nlm.nih.gov/medlineplus/degenerativenervediseases.html Dementia http://www.nlm.nih.gov/medlineplus/dementia.html Gaucher's Disease http://www.nlm.nih.gov/medlineplus/gauchersdisease.html Hearing Disorders & Deafness http://www.nlm.nih.gov/medlineplus/hearingdisordersdeafness.html Huntington's Disease http://www.nlm.nih.gov/medlineplus/huntingtonsdisease.html Movement Disorders http://www.nlm.nih.gov/medlineplus/movementdisorders.html Neuromuscular Disorders http://www.nlm.nih.gov/medlineplus/neuromusculardisorders.html Parkinson's Disease http://www.nlm.nih.gov/medlineplus/parkinsonsdisease.html Peripheral Nerve Disorders http://www.nlm.nih.gov/medlineplus/peripheralnervedisorders.html

Within the health topic page dedicated to Huntington’s disease, the following was listed: •

General/Overviews Huntington's Disease Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DS00401

•

Diagnosis/Symptoms How Is Huntington Disease Diagnosed? Source: Dolan DNA Learning Center http://www.yourgenesyourhealth.org/hd/diagnosis.htm

Patient Resources

•

161

Treatment Scientists Identify Potential New Treatment for Huntington's Disease Source: National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/news_and_events/news_article_huntington_cystamine .htm

•

Specific Conditions/Aspects Huntington's Disease: Why Communication and Swallowing Symptoms Arise Source: American Speech-Language-Hearing Association http://www.asha.org/public/speech/disorders/Huntington-Disease.htm Symptoms, Findings, and Clinical Course of Huntington's Disease Source: We Move http://www.wemove.org/hd_sym.html

•

Children What Is the Best Way to Discuss Huntington's Disease with Young Children if a Parent Has HD or Is at Risk? Source: Huntington's Disease Society of America http://www.hdsa.org/edu/AskADoctor.pl?show=9

•

From the National Institutes of Health Huntington's Disease Source: National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/health_and_medical/disorders/huntington.htm Huntington's Disease: Hope through Research Source: National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/health_and_medical/pubs/huntington_diseasehtr.htm

•

Latest News 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_silencing.htm

•

Organizations Huntington's Disease Society of America http://www.hdsa.org/ National Center for Biotechnology Information http://www.ncbi.nlm.nih.gov/ National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/ We Move http://www.wemove.org/

162 Huntington’s Disease

Your Genes, Your Health Source: Dolan DNA Learning Center http://www.yourgenesyourhealth.org/ •

Research Fasting Forestalls Huntington's Disease in Mice Source: National Institute on Aging http://www.nia.nih.gov/news/pr/2003/0210.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_silencing.htm Trial Drugs for Huntington's Disease Inconclusive in Slowing Disease Source: National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov/news_and_events/pressrelease_huntingtons_drugs_08 1301.htm

•

Teenagers How Can an HDSA Social Worker Help My Family Deal with Juvenile Huntington's Disease (HD)? Source: Huntington's Disease Society of America http://www.hdsa.org/edu/AskADoctor.pl?show=1 Juvenile HD Source: We Move http://www.wemove.org/hd_sym_jhd.html

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. Healthfinder™ Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and 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: •

Huntington's Disease Information Summary: A general overview of Huntington's disease that includes a description of the disorder, and treatment, prognosis and research information. Source: National Institute of Neurological Disorders and Stroke, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=781

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The NIH Search Utility The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to Huntington’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 are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

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

•

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

•

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

•

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

•

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

•

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

•

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

Associations and Huntington’s Disease The following is a list of associations that provide information on and resources relating to Huntington’s disease: •

Huntington's Disease Society of America Telephone: (212) 242-1968 Toll-free: (800) 345-4372 Fax: (212) 239-3430 Email: [email protected] Web Site: http://www.hdsa.org Background: The Huntington's Disease Society of America (HDSA) is a national voluntary health organization dedicated to improving the lives of people with Huntington's disease and to finding a cure for this disease. Huntington's disease is an inherited degenerative brain disorder characterized by irregular, involuntary movements; abnormal gait; slurred speech; and progressive disorientation and loss of intellectual function (dementia). Currently consisting of 40,000 members and 32 chapters across the United States, the society supports medical research into the causes and treatment of Huntington's disease, maintains a national network of services and referrals to assist affected individuals and families and offers a variety of materials through its brochures, newsletters, reports, audiovisual aids, and directory.

164 Huntington’s Disease

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

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The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “Huntington’s disease” (or a synonym) into the search box, and click “Submit Query.”

167

APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.

Preparation 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. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.21

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

21

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

168 Huntington’s Disease

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)22: •

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://wwwmed.stanford.edu/healthlibrary/

•

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/

22

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

Finding Medical Libraries

169

•

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

•

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 LibraryShreveport, 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/

170 Huntington’s Disease

•

Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

•

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://med-libwww.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

•

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/

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•

Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark 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

•

Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.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/

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•

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

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

•

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://cancerweb.ncl.ac.uk/omd/

•

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

•

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

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

Basic Guidelines for Huntington’s Disease Huntington's disease Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000770.htm

•

Signs & Symptoms for Huntington’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 Anxiety, stress, and tension Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm Behavior changes Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003255.htm

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Bowel incontinence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003135.htm Change in mental status Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003205.htm Chorea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003196.htm Confusion Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003205.htm Depression Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003213.htm Difficulty swallowing Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003115.htm Dysarthria Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003204.htm Dysphagia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003115.htm Hallucinations Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003258.htm Hypotonia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003298.htm Incontinence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003142.htm Loss of memory Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003257.htm Movement, uncontrolled - slow Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003197.htm Movement, unpredictable - jerky Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003196.htm Primitive reflexes Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003292.htm Restless Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003212.htm Speech impairment Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003204.htm

Online Glossaries 175

Unsteady gait Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003199.htm Wasting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003188.htm •

Diagnostics and Tests for Huntington’s Disease ANA Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003535.htm CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm Dopamine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003561.htm Head CT scan Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003786.htm Head MRI scan Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003791.htm MRI Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003335.htm PET (isotope) scan of the brain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003827.htm

•

Background Topics for Huntington’s Disease Genetics Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002048.htm Symptomatic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002293.htm

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

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

•

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/

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•

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

177

HUNTINGTON’S DISEASE DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 3-dimensional: 3-D. A graphic display of depth, width, and height. Three-dimensional radiation therapy uses computers to create a 3-dimensional picture of the tumor. This allows doctors to give the highest possible dose of radiation to the tumor, while sparing the normal tissue as much as possible. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetylcholinesterase: An enzyme that catalyzes the hydrolysis of acetylcholine to choline and acetate. In the CNS, this enzyme plays a role in the function of peripheral neuromuscular junctions. EC 3.1.1.7. [NIH] Acoustic: Having to do with sound or hearing. [NIH] Actin: Essential component of the cell skeleton. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenylate Cyclase: An enzyme of the lyase class that catalyzes the formation of cyclic AMP and pyrophosphate from ATP. EC 4.6.1.1. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is

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present. [NIH] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Akathisia: 1. A condition of motor restlessness in which there is a feeling of muscular quivering, an urge to move about constantly, and an inability to sit still, a common extrapyramidal side effect of neuroleptic drugs. 2. An inability to sit down because of intense anxiety at the thought of doing so. [EU] Akinesia: 1. Absence or poverty of movements. 2. The temporary paralysis of a muscle by the injection of procaine. [EU] Alanine: A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system. [NIH] Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allografts: A graft of tissue obtained from the body of another animal of the same species but with genotype differing from that of the recipient; tissue graft from a donor of one genotype to a host of another genotype with host and donor being members of the same species. [NIH] Allylamine: Possesses an unusual and selective cytotoxicity for vascular smooth muscle cells in dogs and rats. Useful for experiments dealing with arterial injury, myocardial

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fibrosis or cardiac decompensation. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Amantadine: An antiviral that is used in the prophylactic or symptomatic treatment of Influenza A. It is also used as an antiparkinsonian agent, to treat extrapyramidal reactions, and for postherpetic neuralgia. The mechanisms of its effects in movement disorders are not well understood but probably reflect an increase in synthesis and release of dopamine, with perhaps some inhibition of dopamine uptake. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Amygdala: Almond-shaped group of basal nuclei anterior to the inferior horn of the lateral ventricle of the brain, within the temporal lobe. The amygdala is part of the limbic system. [NIH]

Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH]

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Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]

Anomalies: Birth defects; abnormalities. [NIH] Anterior Cerebral Artery: Artery formed by the bifurcation of the internal carotid artery. Branches of the anterior cerebral artery supply the caudate nucleus, internal capsule, putamen, septal nuclei, gyrus cinguli, and surfaces of the frontal lobe and parietal lobe. [NIH] Anterograde: Moving or extending forward; called also antegrade. [EU] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] Antiemetic: An agent that prevents or alleviates nausea and vomiting. Also antinauseant. [EU]

Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the

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maturation and proliferation of malignant cells. [EU] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antipsychotic: Effective in the treatment of psychosis. Antipsychotic drugs (called also neuroleptic drugs and major tranquilizers) are a chemically diverse (including phenothiazines, thioxanthenes, butyrophenones, dibenzoxazepines, dibenzodiazepines, and diphenylbutylpiperidines) but pharmacologically similar class of drugs used to treat schizophrenic, paranoid, schizoaffective, and other psychotic disorders; acute delirium and dementia, and manic episodes (during induction of lithium therapy); to control the movement disorders associated with Huntington's chorea, Gilles de la Tourette's syndrome, and ballismus; and to treat intractable hiccups and severe nausea and vomiting. Antipsychotic agents bind to dopamine, histamine, muscarinic cholinergic, a-adrenergic, and serotonin receptors. Blockade of dopaminergic transmission in various areas is thought to be responsible for their major effects : antipsychotic action by blockade in the mesolimbic and mesocortical areas; extrapyramidal side effects (dystonia, akathisia, parkinsonism, and tardive dyskinesia) by blockade in the basal ganglia; and antiemetic effects by blockade in the chemoreceptor trigger zone of the medulla. Sedation and autonomic side effects (orthostatic hypotension, blurred vision, dry mouth, nasal congestion and constipation) are caused by blockade of histamine, cholinergic, and adrenergic receptors. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Aorta: The main trunk of the systemic arteries. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Approximate: Approximal [EU] Apraxia: Loss of ability to perform purposeful movements, in the absence of paralysis or sensory disturbance, caused by lesions in the cortex. [NIH] Aqueous: Having to do with water. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Aspartate: A synthetic amino acid. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions)

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is not well understood. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Audiovisual Aids: Auditory and visual instructional materials. [NIH] Auditory: Pertaining to the sense of hearing. [EU] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autoradiography: A process in which radioactive material within an object produces an image when it is in close proximity to a radiation sensitive emulsion. [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] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU]

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Behavioral Symptoms: Observable manifestions of impaired psychological functioning. [NIH]

Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Beta-pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Beta-sheet: Two or more parallel or anti-parallel strands are arranged in rows. [NIH] Bewilderment: Impairment or loss of will power. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biomedical Engineering: Application of principles and practices of engineering science to biomedical research and health care. [NIH] Biophysics: The science of physical phenomena and processes in living organisms. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Bipolar Disorder: A major affective disorder marked by severe mood swings (manic or major depressive episodes) and a tendency to remission and recurrence. [NIH] Birth Order: The sequence in which children are born into the family. [NIH] Bladder: The organ that stores urine. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH]

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Blepharospasm: Excessive winking; tonic or clonic spasm of the orbicularis oculi muscle. [NIH]

Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood-Brain Barrier: Specialized non-fenestrated tightly-joined endothelial cells (tight junctions) that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blotting and transferred to strips of nitrocellulose paper. The blots are then detected by radiolabeled antibody probes. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] Bradykinesia: Abnormal slowness of movement; sluggishness of physical and mental responses. [EU] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Neoplasms: Neoplasms of the intracranial components of the central nervous system, including the cerebral hemispheres, basal ganglia, hypothalamus, thalamus, brain stem, and cerebellum. Brain neoplasms are subdivided into primary (originating from brain tissue) and secondary (i.e., metastatic) forms. Primary neoplasms are subdivided into benign and malignant forms. In general, brain tumors may also be classified by age of onset, histologic type, or presenting location in the brain. [NIH]

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Brain Stem: The part of the brain that connects the cerebral hemispheres with the spinal cord. It consists of the mesencephalon, pons, and medulla oblongata. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU] Bromodeoxyuridine: A nucleoside that substitutes for thymidine in DNA and thus acts as an antimetabolite. It causes breaks in chromosomes and has been proposed as an antiviral and antineoplastic agent. It has been given orphan drug status for use in the treatment of primary brain tumors. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium Signaling: Signal transduction mechanisms whereby calcium mobilization (from outside the cell or from intracellular storage pools) to the cytoplasm is triggered by external stimuli. Calcium signals are often seen to propagate as waves, oscillations, spikes or puffs. The calcium acts as an intracellular messenger by activating calcium-responsive proteins. [NIH]

Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. [NIH] Calpain: Cysteine proteinase found in many tissues. Hydrolyzes a variety of endogenous proteins including neuropeptides, cytoskeletal proteins, proteins from smooth muscle, cardiac muscle, liver, platelets and erythrocytes. Two subclasses having high and low calcium sensitivity are known. Removes Z-discs and M-lines from myofibrils. Activates phosphorylase kinase and cyclic nucleotide-independent protein kinase. [NIH] Cannabidiol: Compound isolated from Cannabis sativa extract. [NIH] Cannabinoids: Compounds extracted from Cannabis sativa L. and metabolites having the cannabinoid structure. The most active constituents are tetrahydrocannabinol, cannabinol, and cannabidiol. [NIH] Cannabinol: A physiologically inactive constituent of Cannabis sativa L. [NIH] Carboxy: Cannabinoid. [NIH] Carboxy-terminal: The end of any polypeptide or protein that bears a free carboxyl group. [NIH]

Carcinogenic: Producing carcinoma. [EU] Carcinogens: Substances that increase the risk of neoplasms in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. [NIH] Cardiac: Having to do with the heart. [NIH] Cardiopulmonary: Having to do with the heart and lungs. [NIH] Cardiopulmonary Bypass: Diversion of the flow of blood from the entrance of the right atrium directly to the aorta (or femoral artery) via an oxygenator thus bypassing both the heart and lungs. [NIH]

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Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Caudate Nucleus: Elongated gray mass of the neostriatum located adjacent to the lateral ventricle of the brain. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis; and prion diseases may involve the central nervous system as a primary or secondary

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process. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Infarction: The formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction). [NIH]

Cerebral Palsy: Refers to a motor disability caused by a brain dysfunction. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Chaperonins: A class of sequence-related molecular chaperones found in bacteria, mitochondria, and plastids. Chaperonins are abundant constitutive proteins that increase in amount after stresses such as heat shock, bacterial infection of macrophages, and an increase in the cellular content of unfolded proteins. Bacterial chaperonins are major immunogens in human bacterial infections because of their accumulation during the stress of infection. Two members of this class of chaperones are chaperonin 10 and chaperonin 60. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemoreceptor: A receptor adapted for excitation by chemical substances, e.g., olfactory and gustatory receptors, or a sense organ, as the carotid body or the aortic (supracardial) bodies, which is sensitive to chemical changes in the blood stream, especially reduced oxygen content, and reflexly increases both respiration and blood pressure. [EU] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chorea: Involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. Hypotonia and pendular reflexes are often associated. Conditions which feature recurrent or persistent episodes of chorea as a primary manifestation of disease are referred to as choreatic disorders. Chorea is

188 Huntington’s Disease

also a frequent manifestation of basal ganglia diseases. [NIH] Choreatic Disorders: Acquired and hereditary conditions which feature chorea as a primary manifestation of the disease process. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chromosome Fragility: Susceptibility of chromosomes to breakage and translocation or other aberrations. Chromosome fragile sites are regions that show up in karyotypes as a gap (uncondensed stretch) on the chromatid arm. They are associated with chromosome break sites and other aberrations. A fragile site on the X chromosome is associated with fragile X syndrome. Fragile sites are designated by the letters "FRA" followed by the designation for the specific chromosome and a letter which refers to the different fragile sites on a chromosome (e.g. FRAXA). [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Ciliary: Inflammation or infection of the glands of the margins of the eyelids. [NIH] Ciliary Neurotrophic Factor: A neurotrophic factor that promotes the survival of various neuronal cell types and may play an important role in the injury response in the nervous system. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clathrin: The main structural coat protein of coated vesicles which play a key role in the intracellular transport between membranous organelles. Clathrin also interacts with cytoskeletal proteins. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]

Clonic: Pertaining to or of the nature of clonus. [EU] Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coated Vesicles: Vesicles formed when cell-membrane coated pits invaginate and pinch off. The outer surface of these vesicles are covered with a lattice-like network of coat proteins,

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such as clathrin, coat protein complex proteins, or caveolins. [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [NIH] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease). [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such

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as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Conjugated: Acting or operating as if joined; simultaneous. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Consolidation: The healing process of a bone fracture. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Constriction: The act of constricting. [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] Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a

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pathologic involvement of them. [EU] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Corpus: The body of the uterus. [NIH] Corpus Striatum: Striped gray and white matter consisting of the neostriatum and paleostriatum (globus pallidus). It is located in front of and lateral to the thalamus in each cerebral hemisphere. The gray substance is made up of the caudate nucleus and the lentiform nucleus (the latter consisting of the globus pallidus and putamen). The white matter is the internal capsule. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] Creatine: An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. [NIH]

Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Cues: Signals for an action; that specific portion of a perceptual field or pattern of stimuli to which a subject has learned to respond. [NIH] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cystamine: A radiation-protective agent that interferes with sulfhydryl enzymes. It may also protect against carbon tetrachloride liver damage. [NIH] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types,

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including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytoskeletal Proteins: Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible. [NIH]

Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [NIH] Decision Making: The process of making a selective intellectual judgment when presented with several complex alternatives consisting of several variables, and usually defining a course of action or an idea. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Delirium: (DSM III-R) an acute, reversible organic mental disorder characterized by reduced ability to maintain attention to external stimuli and disorganized thinking as manifested by rambling, irrelevant, or incoherent speech; there are also a reduced level of consciousness, sensory misperceptions, disturbance of the sleep-wakefulness cycle and level of psychomotor activity, disorientation to time, place, or person, and memory impairment. Delirium may be caused by a large number of conditions resulting in derangement of cerebral metabolism, including systemic infection, poisoning, drug intoxication or withdrawal, seizures or head trauma, and metabolic disturbances such as hypoxia, hypoglycaemia, fluid, electrolyte, or acid-base imbalances, or hepatic or renal failure. Called also acute confusional state and acute brain syndrome. [EU] Delusions: A false belief regarding the self or persons or objects outside the self that persists despite the facts, and is not considered tenable by one's associates. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dentate Gyrus: Gray matter situated above the gyrus hippocampi. It is composed of three layers. The molecular layer is continuous with the hippocampus in the hippocampal fissure.

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The granular layer consists of closely arranged spherical or oval neurons, called granule cells, whose axons pass through the polymorphic layer ending on the dendrites of pyramidal cells in the hippocampus. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [NIH] Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] Dissection: Cutting up of an organism for study. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU]

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Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] Dopa: The racemic or DL form of DOPA, an amino acid found in various legumes. The dextro form has little physiologic activity but the levo form (levodopa) is a very important physiologic mediator and precursor and pharmacological agent. [NIH] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dopamine Agonists: Drugs that bind to and activate dopamine receptors. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Evaluation: Any process by which toxicity, metabolism, absorption, elimination, preferred route of administration, safe dosage range, etc., for a drug or group of drugs is determined through clinical assessment in humans or veterinary animals. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Duodenum: The first part of the small intestine. [NIH] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dyskinesia: Impairment of the power of voluntary movement, resulting in fragmentary or incomplete movements. [EU] Dysphagia: Difficulty in swallowing. [EU] Dystonia: Disordered tonicity of muscle. [EU] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Ectoderm: The outer of the three germ layers of the embryo. [NIH] Ectopic: Pertaining to or characterized by ectopia. [EU] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus

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becomes capable of conducting electricity; an ionic solute. [EU] Electromyography: Recording of the changes in electric potential of muscle by means of surface or needle electrodes. [NIH] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]

Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endoderm: The inner of the three germ layers of the embryo. [NIH] Endosomes: Cytoplasmic vesicles formed when coated vesicles shed their clathrin coat. Endosomes internalize macromolecules bound by receptors on the cell surface. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Entorhinal Cortex: Cortex where the signals are combined with those from other sensory

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systems. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Induction: An increase in the rate of synthesis of an enzyme due to the presence of an inducer which acts to derepress the gene responsible for enzyme synthesis. [NIH] Enzyme Repression: The interference in synthesis of an enzyme due to the elevated level of an effector substance, usually a metabolite, whose presence would cause depression of the gene responsible for enzyme synthesis. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] 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]

Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Evoked Potentials: The electric response evoked in the central nervous system by stimulation of sensory receptors or some point on the sensory pathway leading from the receptor to the cortex. The evoked stimulus can be auditory, somatosensory, or visual, although other modalities have been reported. Event-related potentials is sometimes used synonymously with evoked potentials but is often associated with the execution of a motor, cognitive, or psychophysiological task, as well as with the response to a stimulus. [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] Exhibitionism: A disorder in which fantasies about or the act of exposing the genitals to an unsuspecting stranger produces sexual excitement with no attempt at further sexual activity with the stranger. [NIH]

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Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extrapyramidal: Outside of the pyramidal tracts. [EU] Facial: Of or pertaining to the face. [EU] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fathers: Male parents, human or animal. [NIH] Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Femoral: Pertaining to the femur, or to the thigh. [EU] Femoral Artery: The main artery of the thigh, a continuation of the external iliac artery. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibril: Most bacterial viruses have a hollow tail with specialized fibrils at its tip. The tail fibers attach to the cell wall of the host. [NIH] Fibroblast Growth Factor: Peptide isolated from the pituitary gland and from the brain. It is a potent mitogen which stimulates growth of a variety of mesodermal cells including chondrocytes, granulosa, and endothelial cells. The peptide may be active in wound healing and animal limb regeneration. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] Fissure: Any cleft or groove, normal or otherwise; especially a deep fold in the cerebral cortex which involves the entire thickness of the brain wall. [EU] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a

198 Huntington’s Disease

fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fossa: A cavity, depression, or pit. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Frontal Lobe: The anterior part of the cerebral hemisphere. [NIH] Functional magnetic resonance imaging: A noninvasive tool used to observe functioning in the brain or other organs by detecting changes in chemical composition, blood flow, or both. [NIH]

Gait: Manner or style of walking. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gap Junctions: Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Rearrangement: The ordered rearrangement of gene regions by DNA recombination such as that which occurs normally during development. [NIH] Generator: Any system incorporating a fixed parent radionuclide from which is produced a daughter radionuclide which is to be removed by elution or by any other method and used in a radiopharmaceutical. [NIH] Genetic Counseling: Advising families of the risks involved pertaining to birth defects, in order that they may make an informed decision on current or future pregnancies. [NIH] Genetic Techniques: Chromosomal, biochemical, intracellular, and other methods used in the study of genetics. [NIH]

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Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetic transcription: The process by which the genetic information encoded in the gene, represented as a linear sequence of deoxyribonucleotides, is copied into an exactly complementary sequence of ribonucleotides known as messenger RNA. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Layers: The three layers of cells comprising the early embryo. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Globus Pallidus: The representation of the phylogenetically oldest part of the corpus striatum called the paleostriatum. It forms the smaller, more medial part of the lentiform nucleus. [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]

Glycerophospholipids: Derivatives of phosphatidic acid in which the hydrophobic regions are composed of two fatty acids and a polar alcohol is joined to the C-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]

Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to

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replace diseased or injured tissue removed from another part of the body. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Gravis: Eruption of watery blisters on the skin among those handling animals and animal products. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Gyrus Cinguli: One of the convolutions on the medial surface of the cerebral hemisphere. It surrounds the rostral part of the brain and interhemispheric commissure and forms part of the limbic system. [NIH] Habitat: An area considered in terms of its environment, particularly as this determines the type and quality of the vegetation the area can carry. [NIH] Haloperidol: Butyrophenone derivative. [NIH] Haplotypes: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the major histocompatibility complex. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Health Behavior: Behaviors expressed by individuals to protect, maintain or promote their health status. For example, proper diet, and appropriate exercise are activities perceived to influence health status. Life style is closely associated with health behavior and factors influencing life style are socioeconomic, educational, and cultural. [NIH] Health Promotion: Encouraging consumer behaviors most likely to optimize health potentials (physical and psychosocial) through health information, preventive programs, and access to medical care. [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Heat-Shock Proteins: Proteins which are synthesized in eukaryotic organisms and bacteria in response to hyperthermia and other environmental stresses. They increase thermal tolerance and perform functions essential to cell survival under these conditions. [NIH] Heat-Shock Proteins 90: A class of molecular chaperones whose members act in the mechanism of signal transduction by steroid receptors. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to

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hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] 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] Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum, and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Histone Deacetylase: Hydrolyzes N-acetyl groups on histones. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homozygotes: An individual having a homozygous gene pair. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hydrocephalus: Excessive accumulation of cerebrospinal fluid within the cranium which may be associated with dilation of cerebral ventricles, intracranial hypertension; headache; lethargy; urinary incontinence; and ataxia (and in infants macrocephaly). This condition may be caused by obstruction of cerebrospinal fluid pathways due to neurologic abnormalities, intracranial hemorrhages; central nervous system infections; brain

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neoplasms; craniocerebral trauma; and other conditions. Impaired resorption of cerebrospinal fluid from the arachnoid villi results in a communicating form of hydrocephalus. Hydrocephalus ex-vacuo refers to ventricular dilation that occurs as a result of brain substance loss from cerebral infarction and other conditions. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Bonding: A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. [NIH]

Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophilic: Readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water. [EU] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxylation: Hydroxylate, to introduce hydroxyl into (a compound or radical) usually by replacement of hydrogen. [EU] Hyperkinesia: Abnormally increased motor function or activity; hyperactivity. [EU] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypokinesia: Slow or diminished movement of body musculature. It may be associated with basal ganglia diseases; mental disorders; prolonged inactivity due to illness; experimental protocols used to evaluate the physiologic effects of immobility; and other conditions. [NIH] Hypotension: Abnormally low blood pressure. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Imaging procedures: Methods of producing pictures of areas inside the body. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunoblotting: Immunologic methods for isolating and quantitatively measuring immunoreactive substances. When used with immune reagents such as monoclonal antibodies, the process is known generically as western blot analysis (blotting, western).

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[NIH]

Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infantile: Pertaining to an infant or to infancy. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical

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signs of pain, heat, redness, swelling, and loss of function. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insecticides: Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. [NIH] Insertional: A technique in which foreign DNA is cloned into a restriction site which occupies a position within the coding sequence of a gene in the cloning vector molecule. Insertion interrupts the gene's sequence such that its original function is no longer expressed. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Interindividual: Occurring between two or more individuals. [EU] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Internal Capsule: White matter pathway, flanked by nuclear masses, consisting of both afferent and efferent fibers projecting between the cerebral cortex and the brainstem. It consists of three distinct parts: an anterior limb, posterior limb, and genu. [NIH] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH]

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Interneurons: Most generally any neurons which are not motor or sensory. Interneurons may also refer to neurons whose axons remain within a particular brain region as contrasted with projection neurons which have axons projecting to other brain regions. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestines: The section of the alimentary canal from the stomach to the anus. It includes the large intestine and small intestine. [NIH] Intracellular: Inside a cell. [NIH] Intracranial Hemorrhages: Bleeding within the intracranial cavity, including hemorrhages in the brain and within the cranial epidural, subdural, and subarachnoid spaces. [NIH] Intracranial Hypertension: Increased pressure within the cranial vault. This may result from several conditions, including hydrocephalus; brain edema; intracranial masses; severe systemic hypertension; pseudotumor cerebri; and other disorders. [NIH] Intraperitoneal: IP. Within the peritoneal cavity (the area that contains the abdominal organs). [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Involuntary: Reaction occurring without intention or volition. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isoleucine: An essential branched-chain amino acid found in many proteins. It is an isomer of LEUCINE. It is important in hemoglobin synthesis and regulation of blood sugar and energy levels. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage.

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Also called nephropathy. [NIH] Kinesin: A microtubule-associated mechanical adenosine triphosphatase, that uses the energy of ATP hydrolysis to move organelles along microtubules toward the plus end of the microtubule. The protein is found in squid axoplasm, optic lobes, and in bovine brain. Bovine kinesin is a heterotetramer composed of two heavy (120 kDa) and two light (62 kDa) chains. EC 3.6.1.-. [NIH] Kinetics: The study of rate dynamics in chemical or physical systems. [NIH] Kynurenic Acid: A broad-spectrum excitatory amino acid antagonist used as a research tool. [NIH]

Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Labyrinth: The internal ear; the essential part of the organ of hearing. It consists of an osseous and a membranous portion. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Laryngeal: Having to do with the larynx. [NIH] Larynx: An irregularly shaped, musculocartilaginous tubular structure, lined with mucous membrane, located at the top of the trachea and below the root of the tongue and the hyoid bone. It is the essential sphincter guarding the entrance into the trachea and functioning secondarily as the organ of voice. [NIH] Latency: The period of apparent inactivity between the time when a stimulus is presented and the moment a response occurs. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Lethargy: Abnormal drowsiness or stupor; a condition of indifference. [EU] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]

Leukemia: Cancer of blood-forming tissue. [NIH] Levodopa: The naturally occurring form of dopa and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonism and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Ligaments: Shiny, flexible bands of fibrous tissue connecting together articular extremities of bones. They are pliant, tough, and inextensile. [NIH] Limbic: Pertaining to a limbus, or margin; forming a border around. [EU] Limbic System: A set of forebrain structures common to all mammals that is defined functionally and anatomically. It is implicated in the higher integration of visceral, olfactory, and somatic information as well as homeostatic responses including fundamental survival behaviors (feeding, mating, emotion). For most authors, it includes the amygdala, epithalamus, gyrus cinguli, hippocampal formation (see hippocampus), hypothalamus,

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parahippocampal gyrus, septal nuclei, anterior nuclear group of thalamus, and portions of the basal ganglia. (Parent, Carpenter's Human Neuroanatomy, 9th ed, p744; NeuroNames, http://rprcsgi.rprc.washington.edu/neuronames/index.html (September 2, 1998)). [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lithium: An element in the alkali metals family. It has the atomic symbol Li, atomic number 3, and atomic weight 6.94. Salts of lithium are used in treating manic-depressive disorders. [NIH]

Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Locomotor: Of or pertaining to locomotion; pertaining to or affecting the locomotive apparatus of the body. [EU] Longitudinal Studies: Studies in which variables relating to an individual or group of individuals are assessed over a period of time. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Long-Term Potentiation: A persistent increase in synaptic efficacy, usually induced by appropriate activation of the same synapses. The phenomenological properties of long-term potentiation suggest that it may be a cellular mechanism of learning and memory. [NIH] Lymphoblasts: Interferon produced predominantly by leucocyte cells. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH]

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Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Manic: Affected with mania. [EU] Manic-depressive psychosis: One of a group of psychotic reactions, fundamentally marked by severe mood swings and a tendency to remission and recurrence. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [EU] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]

Mesoderm: The middle germ layer of the embryo. [NIH] Mesolimbic: Inner brain region governing emotion and drives. [NIH]

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Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metabotropic: A glutamate receptor which triggers an increase in production of 2 intracellular messengers: diacylglycerol and inositol 1, 4, 5-triphosphate. [NIH] Methyltransferase: A drug-metabolizing enzyme. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Micturition: The passage of urine; urination. [EU] Minocycline: A semisynthetic staphylococcus infections. [NIH]

antibiotic

effective

against

tetracycline-resistant

Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Chaperones: A family of cellular proteins that mediate the correct assembly or disassembly of other polypeptides, and in some cases their assembly into oligomeric structures, but which are not components of those final structures. It is believed that chaperone proteins assist polypeptides to self-assemble by inhibiting alternative assembly pathways that produce nonfunctional structures. Some classes of molecular chaperones are the nucleoplasmins, the chaperonins, the heat-shock proteins 70, and the heat-shock proteins 90. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other

210 Huntington’s Disease

procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH] Mood Disorders: Those disorders that have a disturbance in mood as their predominant feature. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Mosaicism: The occurrence in an individual of two or more cell populations of different chromosomal constitutions, derived from a single zygote, as opposed to chimerism in which the different cell populations are derived from more than one zygote. [NIH] Motility: The ability to move spontaneously. [EU] Motor Activity: The physical activity of an organism as a behavioral phenomenon. [NIH] Motor Cortex: Area of the frontal lobe concerned with primary motor control. It lies anterior to the central sulcus. [NIH] Motor nerve: An efferent nerve conveying an impulse that excites muscular contraction. [NIH]

Movement Disorders: Syndromes which feature dyskinesias as a cardinal manifestation of the disease process. Included in this category are degenerative, hereditary, post-infectious, medication-induced, post-inflammatory, and post-traumatic conditions. [NIH] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Multimodality treatment: Therapy that combines more than one method of treatment. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Muscle Contraction: A process leading to shortening and/or development of tension in muscle tissue. Muscle contraction occurs by a sliding filament mechanism whereby actin filaments slide inward among the myosin filaments. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Diseases: Acquired, familial, and congenital disorders of skeletal muscle and

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smooth muscle. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagenic: Inducing genetic mutation. [EU] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Myasthenia: Muscular debility; any constitutional anomaly of muscle. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myofibrils: Highly organized bundles of actin, myosin, and other proteins in the cytoplasm of skeletal and cardiac muscle cells that contract by a sliding filament mechanism. [NIH] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] 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] Neocortex: The largest portion of the cerebral cortex. It is composed of neurons arranged in six layers. [NIH] Neostriatum: The phylogenetically newer part of the corpus striatum consisting of the caudate nucleus and putamen. It is often called simply the striatum. [NIH] Nephropathy: Disease of the kidneys. [EU] 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] Nerve Growth Factor: Nerve growth factor is the first of a series of neurotrophic factors that were found to influence the growth and differentiation of sympathetic and sensory neurons. It is comprised of alpha, beta, and gamma subunits. The beta subunit is responsible for its growth stimulating activity. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and

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ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [NIH] Neuroleptic: A term coined to refer to the effects on cognition and behaviour of antipsychotic drugs, which produce a state of apathy, lack of initiative, and limited range of emotion and in psychotic patients cause a reduction in confusion and agitation and normalization of psychomotor activity. [EU] Neurologic: Having to do with nerves or the nervous system. [NIH] Neurologist: A doctor who specializes in the diagnosis and treatment of disorders of the nervous system. [NIH] Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropeptides: Peptides released by neurons as intercellular messengers. Many neuropeptides are also hormones released by non-neuronal cells. [NIH] Neuropharmacology: The branch of pharmacology dealing especially with the action of drugs upon various parts of the nervous system. [NIH] Neurophysiology: The scientific discipline concerned with the physiology of the nervous system. [NIH] Neuropil: A dense intricate feltwork of interwoven fine glial processes, fibrils, synaptic terminals, axons, and dendrites interspersed among the nerve cells in the gray matter of the central nervous system. [NIH] Neuropsychological Tests: Tests designed to assess neurological function associated with certain behaviors. They are used in diagnosing brain dysfunction or damage and central nervous system disorders or injury. [NIH] Neuropsychology: A branch of psychology which investigates the correlation between experience or behavior and the basic neurophysiological processes. The term neuropsychology stresses the dominant role of the nervous system. It is a more narrowly defined field than physiological psychology or psychophysiology. [NIH] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]

Neurotoxin: A substance that is poisonous to nerve tissue. [NIH]

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Neurotrophins: A nerve growth factor. [NIH] Neutralization: An act or process of neutralizing. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear Localization Signal: Short, predominantly basic amino acid sequences identified as nuclear import signals for some proteins. These sequences are believed to interact with specific receptors at nuclear pores. [NIH] Nuclear Pore: An opening through the nuclear envelope formed by the nuclear pore complex which transports nuclear proteins or RNA into or out of the cell nucleus and which, under some conditions, acts as an ion channel. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH]

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Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleus Accumbens: Collection of pleomorphic cells in the caudal part of the anterior horn of the lateral ventricle, in the region of the olfactory tubercle, lying between the head of the caudate nucleus and the anterior perforated substance. It is part of the so-called ventral striatum, a composite structure considered part of the basal ganglia. [NIH] Occupational Therapy: The field concerned with utilizing craft or work activities in the rehabilitation of patients. Occupational therapy can also refer to the activities themselves. [NIH]

Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Oculi: Globe or ball of the eye. [NIH] Oculomotor: Cranial nerve III. It originate from the lower ventral surface of the midbrain and is classified as a motor nerve. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] On-line: A sexually-reproducing population derived from a common parentage. [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Orbicularis: A thin layer of fibers that originates at the posterior lacrimal crest and passes outward and forward, dividing into two slips which surround the canaliculi. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Oropharynx: Oral part of the pharynx. [NIH] Orthostatic: Pertaining to or caused by standing erect. [EU] Osmosis: Tendency of fluids (e.g., water) to move from the less concentrated to the more concentrated side of a semipermeable membrane. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidative Phosphorylation: Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds. [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH]

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Oxides: Binary compounds of oxygen containing the anion O(2-). The anion combines with metals to form alkaline oxides and non-metals to form acidic oxides. [NIH] Oxygenator: An apparatus by which oxygen is introduced into the blood during circulation outside the body, as during open heart surgery. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Paralysis: Loss of ability to move all or part of the body. [NIH] Parietal: 1. Of or pertaining to the walls of a cavity. 2. Pertaining to or located near the parietal bone, as the parietal lobe. [EU] Parietal Lobe: Upper central part of the cerebral hemisphere. [NIH] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] Particle: A tiny mass of material. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH]

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Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Pesticides: Chemicals used to destroy pests of any sort. The concept includes fungicides (industrial fungicides), insecticides, rodenticides, etc. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phosphodiesterase: Effector enzyme that regulates the levels of a second messenger, the cyclic GMP. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylase: An enzyme of the transferase class that catalyzes the phosphorylysis of a terminal alpha-1,4-glycosidic bond at the non-reducing end of a glycogen molecule, releasing a glucose 1-phosphate residue. Phosphorylase should be qualified by the natural substance acted upon. EC 2.4.1.1. [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH]

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Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Pleomorphic: Occurring in various distinct forms. In terms of cells, having variation in the size and shape of cells or their nuclei. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called

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tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postherpetic Neuralgia: Variety of neuralgia associated with migraine in which pain is felt in or behind the eye. [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-synaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-traumatic: Occurring as a result of or after injury. [EU] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [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] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Prefrontal Cortex: The rostral part of the frontal lobe, bounded by the inferior precentral fissure in humans, which receives projection fibers from the mediodorsal nucleus of the thalamus. The prefrontal cortex receives afferent fibers from numerous structures of the diencephalon, mesencephalon, and limbic system as well as cortical afferents of visual, auditory, and somatic origin. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Prion: Small proteinaceous infectious particles that resist inactivation by procedures modifying nucleic acids and contain an abnormal isoform of a cellular protein which is a major and necessary component. [NIH] Procaine: A local anesthetic of the ester type that has a slow onset and a short duration of action. It is mainly used for infiltration anesthesia, peripheral nerve block, and spinal block. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1016). [NIH] Progeny: The offspring produced in any generation. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH]

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Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Promotor: In an operon, a nucleotide sequence located at the operator end which contains all the signals for the correct initiation of genetic transcription by the RNA polymerase holoenzyme and determines the maximal rate of RNA synthesis. [NIH] Prone: Having the front portion of the body downwards. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Proprioception: The mechanism involved in the self-regulation of posture and movement through stimuli originating in the receptors imbedded in the joints, tendons, muscles, and labyrinth. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Psychophysics: The science dealing with the correlation of the physical characteristics of a

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stimulus, e.g., frequency or intensity, with the response to the stimulus, in order to assess the psychologic factors involved in the relationship. [NIH] Psychophysiology: The study of the physiological basis of human and animal behavior. [NIH]

Psychosis: A mental disorder characterized by gross impairment in reality testing as evidenced by delusions, hallucinations, markedly incoherent speech, or disorganized and agitated behaviour without apparent awareness on the part of the patient of the incomprehensibility of his behaviour; the term is also used in a more general sense to refer to mental disorders in which mental functioning is sufficiently impaired as to interfere grossly with the patient's capacity to meet the ordinary demands of life. Historically, the term has been applied to many conditions, e.g. manic-depressive psychosis, that were first described in psychotic patients, although many patients with the disorder are not judged psychotic. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]

Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Putamen: The largest and most lateral of the basal ganglia lying between the lateral medullary lamina of the globus pallidus and the external capsule. It is part of the neostriatum and forms part of the lentiform nucleus along with the globus pallidus. [NIH] P-value: A statistics term. A measure of probability that a difference between groups during an experiment happened by chance. For example, a p-value of .01 (p = .01) means there is a 1 in 100 chance the result occurred by chance. The lower the p-value, the more likely it is that the difference between groups was caused by treatment. [NIH] Pyramidal Cells: Projection neurons in the cerebral cortex and the hippocampus. Pyramidal cells have a pyramid-shaped soma with the apex and an apical dendrite pointed toward the pial surface and other dendrites and an axon emerging from the base. The axons may have local collaterals but also project outside their cortical region. [NIH] Pyramidal Tracts: Fibers that arise from cells within the cerebral cortex, pass through the medullary pyramid, and descend in the spinal cord. Many authorities say the pyramidal tracts include both the corticospinal and corticobulbar tracts. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quinolinic: It is produced by immune cells and slowly infiltrates the brain tissues after an injury. [NIH] Quinolinic Acid: 2,3-Pyridinedicarboxylic acid. A metabolite of tryptophan with a possible

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role in neurodegenerative disorders. Elevated CSF levels of quinolinic acid are significantly correlated with the severity of neuropsychological deficits in patients who have AIDS. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Reaction Time: The time from the onset of a stimulus until the organism responds. [NIH] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reality Testing: The individual's objective evaluation of the external world and the ability to differentiate adequately between it and the internal world; considered to be a primary ego function. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH]

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Reflex: An involuntary movement or exercise of function in a part, excited in response to a stimulus applied to the periphery and transmitted to the brain or spinal cord. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Rehabilitative: Instruction of incapacitated individuals or of those affected with some mental disorder, so that some or all of their lost ability may be regained. [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]

Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH] Repressor Proteins: Proteins which are normally bound to the operator locus of an operon, thereby preventing transcription of the structural genes. In enzyme induction, the substrate of the inducible enzyme binds to the repressor protein, causing its release from the operator and freeing the structural genes for transcription. In enzyme repression, the end product of the enzyme sequence binds to the free repressor protein, the resulting complex then binds to the operator and prevents transcription of the structural genes. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Response Elements: Nucleotide sequences, usually upstream, which are recognized by specific regulatory transcription factors, thereby causing gene response to various regulatory agents. These elements may be found in both promotor and enhancer regions. [NIH]

Restless legs: Legs characterized by or showing inability to remain at rest. [EU] Retrograde: 1. Moving backward or against the usual direction of flow. 2. Degenerating, deteriorating, or catabolic. [EU] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Risperidone: A selective blocker of dopamine D2 and serotonin-5-HT-2 receptors that acts as an atypical antipsychotic agent. It has been shown to improve both positive and negative

Dictionary 223

symptoms in the treatment of schizophrenia. [NIH] Rod: A reception for vision, located in the retina. [NIH] Rodenticides: Substances used to destroy or inhibit the action of rats, mice, or other rodents. [NIH]

Saccades: An abrupt voluntary shift in ocular fixation from one point to another, as occurs in reading. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Segmentation: The process by which muscles in the intestines move food and wastes through the body. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Septal: An abscess occurring at the root of the tooth on the proximal surface. [NIH] Septal Nuclei: Neural nuclei situated in the septal region. They have afferent and cholinergic efferent connections with a variety of forebrain and brainstem areas including the hippocampus, the lateral hypothalamus, the tegmentum, and the amygdala. Included are the dorsal, lateral, medial, and triangular septal nuclei, septofimbrial nucleus, nucleus of diagonal band, nucleus of anterior commissure, and the nucleus of stria terminalis. [NIH] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH]

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Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic mutations: Alterations in DNA that occur after conception. Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children. These alterations can (but do not always) cause cancer or other diseases. [NIH] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Spasm: An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. [NIH]

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Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Stabilization: The creation of a stable state. [EU] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Staphylococcus: A genus of gram-positive, facultatively anaerobic, coccoid bacteria. Its organisms occur singly, in pairs, and in tetrads and characteristically divide in more than one plane to form irregular clusters. Natural populations of Staphylococcus are membranes of warm-blooded animals. Some species are opportunistic pathogens of humans and animals. [NIH] Steady state: Dynamic equilibrium. [EU] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stereotactic: Radiotherapy that treats brain tumors by using a special frame affixed directly to the patient's cranium. By aiming the X-ray source with respect to the rigid frame, technicians can position the beam extremely precisely during each treatment. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are

226 Huntington’s Disease

coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stria: 1. A streak, or line. 2. A narrow bandlike structure; a general term for such longitudinal collections of nerve fibres in the brain. [EU] Striatum: A higher brain's domain thus called because of its stripes. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subiculum: A region of the hippocampus that projects to other areas of the brain. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substrate: A substance upon which an enzyme acts. [EU] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Symptomatic treatment: Therapy that eases symptoms without addressing the cause of disease. [NIH] Symptomatology: 1. That branch of medicine with treats of symptoms; the systematic discussion of symptoms. 2. The combined symptoms of a disease. [EU] Synapses: Specialized junctions at which a neuron communicates with a target cell. At classical synapses, a neuron's presynaptic terminal releases a chemical transmitter stored in synaptic vesicles which diffuses across a narrow synaptic cleft and activates receptors on the postsynaptic membrane of the target cell. The target may be a dendrite, cell body, or axon of another neuron, or a specialized region of a muscle or secretory cell. Neurons may also communicate through direct electrical connections which are sometimes called electrical synapses; these are not included here but rather in gap junctions. [NIH] Synapsis: The pairing between homologous chromosomes of maternal and paternal origin

Dictionary 227

during the prophase of meiosis, leading to the formation of gametes. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synaptic Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] Synaptic Vesicles: Membrane-bound compartments which contain transmitter molecules. Synaptic vesicles are concentrated at presynaptic terminals. They actively sequester transmitter molecules from the cytoplasm. In at least some synapses, transmitter release occurs by fusion of these vesicles with the presynaptic membrane, followed by exocytosis of their contents. [NIH] Synchrotron: An accelerator in which the particles are guided by an increasing magnetic field while they are accelerated several times in an approximately circular path by electric fields produced by a high-frequency generator. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tardive: Marked by lateness, late; said of a disease in which the characteristic lesion is late in appearing. [EU] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Telencephalon: Paired anteriolateral evaginations of the prosencephalon plus the lamina terminalis. The cerebral hemispheres are derived from it. Many authors consider cerebrum a synonymous term to telencephalon, though a minority include diencephalon as part of the cerebrum (Anthoney, 1994). [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] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Tetrahydrocannabinol: A psychoactive compound extracted from the resin of Cannabis sativa (marihuana, hashish). The isomer delta-9-tetrahydrocannabinol (THC) is considered the most active form, producing characteristic mood and perceptual changes associated with this compound. Dronabinol is a synthetic form of delta-9-THC. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia;

228 Huntington’s Disease

intracranial hemorrhages; and infectious processes. [NIH] Thalamus: Paired bodies containing mostly gray substance and forming part of the lateral wall of the third ventricle of the brain. The thalamus represents the major portion of the diencephalon and is commonly divided into cellular aggregates known as nuclear groups. [NIH]

Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Third Ventricle: A narrow cleft inferior to the corpus callosum, within the diencephalon, between the paired thalami. Its floor is formed by the hypothalamus, its anterior wall by the lamina terminalis, and its roof by ependyma. It communicates with the fourth ventricle by the cerebral aqueduct, and with the lateral ventricles by the interventricular foramina. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]

Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tonic: 1. Producing and restoring the normal tone. 2. Characterized by continuous tension. 3. A term formerly used for a class of medicinal preparations believed to have the power of restoring normal tone to tissue. [EU] Tonicity: The normal state of muscular tension. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Tracer: A substance (such as a radioisotope) used in imaging procedures. [NIH]

Dictionary 229

Traction: The act of pulling. [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transgenes: Genes that are introduced into an organism using gene transfer techniques. [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] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Tremor: Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of Parkinson disease. [NIH] Trigger zone: Dolorogenic zone (= producing or causing pain). [EU] Trinucleotide Repeat Expansion: DNA region comprised of a variable number of repetitive, contiguous trinucleotide sequences. The presence of these regions is associated with diseases such as Fragile X Syndrome and myotonic dystrophy. Many chromosome fragile sites (chromosome fragility) contain expanded trinucleotide repeats. [NIH] Trinucleotide Repeats: Microsatellite repeats consisting of three nucleotides dispersed in the euchromatic arms of chromosomes. [NIH] Trisomy: The possession of a third chromosome of any one type in an otherwise diploid cell. [NIH]

Trophic: Of or pertaining to nutrition. [EU] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tryptophan Hydroxylase: An enzyme that catalyzes the hydroxylation of tryptophan to 5hydroxytryptophan in the presence of NADPH and molecular oxygen. It is important in the biosynthesis of serotonin. EC 1.14.16.4 [NIH] Tubercle: A rounded elevation on a bone or other structure. [NIH] Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other

230 Huntington’s Disease

body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccines: Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa, or rickettsiae), antigenic proteins derived from them, or synthetic constructs, administered for the prevention, amelioration, or treatment of infectious and other diseases. [NIH]

Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasodilator: An agent that widens blood vessels. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Villi: The tiny, fingerlike projections on the surface of the small intestine. Villi help absorb nutrients. [NIH] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH]

Dictionary 231

Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] 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] Volition: Voluntary activity without external compulsion. [NIH] Voltage-gated: It is opened by the altered charge distribution across the cell membrane. [NIH]

White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

233

INDEX 3 3-dimensional, 43, 177 A Abdomen, 177, 184, 207, 216, 225, 231 Abdominal, 177, 205, 215, 216 Aberrant, 8, 9, 21, 177 Acetylcholine, 177, 187, 213 Acetylcholinesterase, 111, 177 Acoustic, 123, 177 Actin, 177, 210, 211 Adaptability, 177, 186 Adaptation, 177, 217 Adenosine, 177, 206, 216 Adenylate Cyclase, 48, 177 Adipocytes, 110, 177 Adrenergic, 177, 181, 194, 196, 226 Adverse Effect, 177, 224 Aerobic, 177, 209 Afferent, 31, 178, 204, 218, 223 Affinity, 178, 181, 224 Age of Onset, 5, 178, 184 Agonist, 178, 194, 213 Akathisia, 178, 181 Akinesia, 87, 178 Alanine, 72, 178 Alertness, 74, 178 Algorithms, 178, 183 Alkaline, 178, 179, 185, 215 Alkaloid, 178, 189, 213 Alleles, 5, 12, 26, 178, 201 Allergen, 178, 193 Allografts, 144, 178 Allylamine, 178, 179 Alternative medicine, 144, 179 Amantadine, 64, 85, 111, 132, 133, 179 Amine, 58, 179, 201 Amino Acid Sequence, 179, 180, 197, 213 Amino Acids, 42, 179, 215, 217, 219, 222, 223, 229 Ammonia, 179, 199 Amplification, 21, 49, 179 Amygdala, 179, 182, 206, 223, 227 Amyloid, 5, 7, 15, 27, 37, 42, 47, 61, 179 Anaesthesia, 179, 203 Anal, 179, 197, 207 Anaphylatoxins, 179, 189 Anatomical, 6, 180, 182, 203, 223 Anemia, 17, 180

Animal model, 5, 29, 36, 52, 53, 61, 75, 79, 90, 112, 117, 121, 180 Anions, 180, 205, 226 Annealing, 180, 217 Anomalies, 37, 180 Anterior Cerebral Artery, 104, 180, 187 Anterograde, 35, 55, 180 Antibacterial, 180, 225 Antibiotic, 16, 56, 143, 180, 185, 209, 225, 227 Antibodies, 22, 28, 61, 180, 203, 207, 210, 217 Antibody, 9, 28, 178, 180, 184, 189, 196, 201, 203, 205, 208, 210, 221, 225, 231 Anticoagulant, 180, 219 Anticonvulsant, 49, 180 Antiemetic, 180, 181 Antigen, 178, 180, 189, 201, 202, 203, 208 Antigen-Antibody Complex, 180, 189 Antimetabolite, 180, 185 Antineoplastic, 180, 185 Antioxidant, 51, 181, 214 Antipsychotic, 126, 181, 212, 222 Antiviral, 133, 179, 181, 185, 215 Aorta, 181, 185, 230 Apoptosis, 33, 36, 48, 56, 65, 104, 181, 186 Approximate, 18, 181 Apraxia, 65, 87, 181 Aqueous, 181, 182, 192, 195, 202 Arginine, 112, 179, 181, 213 Arterial, 178, 181, 187, 202, 219, 227 Arteries, 181, 184, 190, 209 Aspartate, 57, 77, 114, 133, 181 Assay, 13, 15, 38, 59, 61, 87, 181 Astrocytes, 25, 181 Asymptomatic, 32, 89, 91, 105, 182 Ataxia, 5, 6, 7, 17, 21, 30, 82, 93, 182, 201, 227 Atrium, 182, 185, 230 Atrophy, 6, 39, 42, 65, 66, 73, 182, 212 Attenuated, 182, 193, 230 Atypical, 182, 222 Audiovisual Aids, 163, 182 Auditory, 102, 126, 182, 196, 218 Autoimmune disease, 43, 182, 210 Autonomic, 65, 177, 181, 182, 213, 215 Autoradiography, 16, 182 Axonal, 34, 182

234 Huntington’s Disease

Axons, 182, 193, 205, 212, 220 B Bacteria, 180, 182, 183, 187, 200, 209, 221, 225, 229, 230 Bacteriophage, 182, 229 Basal Ganglia, 19, 22, 43, 58, 81, 92, 95, 101, 111, 130, 181, 182, 184, 188, 202, 207, 214, 220 Basal Ganglia Diseases, 182, 188, 202 Base, 9, 17, 182, 192, 205, 220, 227 Behavioral Symptoms, 10, 183 Benign, 78, 183, 184, 200, 221 Beta-pleated, 179, 183 Beta-sheet, 15, 43, 183 Bewilderment, 183, 190 Bile, 61, 117, 183, 198, 207 Bile Acids, 183 Bile Acids and Salts, 183 Binding Sites, 57, 183 Biochemical, 8, 30, 46, 49, 67, 76, 80, 96, 139, 178, 180, 183, 198, 223 Biological therapy, 183, 200 Biomarkers, 30, 183 Biomedical Engineering, 35, 38, 183 Biophysics, 35, 38, 87, 183 Biosynthesis, 56, 183, 223, 229 Biotechnology, 10, 60, 62, 136, 144, 155, 161, 183 Bipolar Disorder, 20, 183 Birth Order, 26, 183 Bladder, 183, 203, 210, 219, 230 Blastocyst, 183, 190 Blepharospasm, 40, 184 Blood Coagulation, 184, 185, 228 Blood pressure, 184, 187, 202, 209, 224 Blood vessel, 184, 187, 195, 205, 207, 215, 224, 226, 227, 228, 230 Blood-Brain Barrier, 184, 206 Blot, 26, 184, 202 Blotting, Western, 184, 202 Body Fluids, 183, 184, 224, 230 Bone Marrow, 184, 191, 210 Bone scan, 184, 223 Bowel, 174, 179, 184, 193, 225 Bowel Movement, 184, 193, 225 Brachytherapy, 184, 204, 205, 221, 231 Bradykinesia, 67, 68, 87, 116, 184 Bradykinin, 184, 213 Brain Neoplasms, 184, 202, 227 Brain Stem, 184, 185, 187 Branch, 114, 171, 185, 195, 212, 215, 220, 225, 226, 228

Broad-spectrum, 185, 206 Bromodeoxyuridine, 23, 185 C Calcium, 30, 48, 53, 58, 75, 112, 142, 185, 189, 224 Calcium Signaling, 30, 185 Calmodulin, 34, 185 Calpain, 60, 69, 111, 185 Cannabidiol, 185 Cannabinoids, 48, 185 Cannabinol, 185 Carboxy, 93, 185 Carboxy-terminal, 93, 185 Carcinogenic, 185, 204, 219 Carcinogens, 185, 214 Cardiac, 179, 185, 196, 211 Cardiopulmonary, 43, 185 Cardiopulmonary Bypass, 43, 185 Case report, 68, 80, 98, 120, 186, 188 Case series, 186, 188 Caspase, 33, 60, 69, 72, 92, 120, 121, 144, 186 Catecholamine, 186, 194 Caudal, 186, 193, 214, 218 Caudate Nucleus, 65, 180, 182, 186, 191, 211, 214 Cell Cycle, 13, 186 Cell Death, 18, 24, 26, 33, 36, 48, 50, 52, 55, 56, 58, 60, 92, 116, 181, 186, 211 Cell Differentiation, 186, 224 Cell Division, 182, 186, 200, 208, 209, 217, 219 Cell membrane, 186, 193, 198, 216, 231 Cell proliferation, 23, 33, 87, 186, 224 Cell Respiration, 186, 209, 222 Cell Survival, 186, 200 Cell Transplantation, 58, 66, 76, 119, 135, 186 Central Nervous System Infections, 186, 200, 201 Cerebellar, 6, 30, 36, 37, 48, 73, 182, 187, 221, 229 Cerebellum, 48, 184, 187, 221 Cerebral Infarction, 187, 202 Cerebral Palsy, 43, 187 Cerebrospinal, 93, 111, 187, 201 Cerebrospinal fluid, 93, 111, 187, 201 Cerebrovascular, 4, 182, 187, 227 Cerebrum, 187, 227 Chaperonins, 187, 209 Character, 187, 192 Chemoreceptor, 181, 187

Index 235

Chemotactic Factors, 187, 189 Chemotherapy, 122, 187 Cholesterol, 183, 187 Choline, 111, 177, 187 Cholinergic, 92, 181, 187, 213, 223 Choreatic Disorders, 139, 187, 188 Chromatin, 16, 181, 188 Chromosomal, 9, 26, 179, 188, 198, 210 Chromosome, 10, 26, 44, 102, 111, 188, 207, 229 Chromosome Fragility, 188, 229 Chronic, 4, 7, 8, 10, 116, 126, 132, 188, 193, 195, 203, 205, 217 Chronic renal, 188, 217 Ciliary, 37, 74, 116, 188 Ciliary Neurotrophic Factor, 37, 74, 116, 188 Clamp, 29, 48, 57, 188 Clathrin, 25, 188, 189, 195 Clinical Medicine, 188, 218 Clinical study, 63, 188 Clinical trial, 6, 9, 28, 30, 32, 37, 42, 56, 131, 133, 155, 188, 191, 221 Clone, 12, 188 Clonic, 184, 188 Cloning, 183, 188, 204 Coated Vesicles, 188, 195 Coenzyme, 11, 110, 111, 117, 126, 150, 189 Cofactor, 189, 219, 228 Cognition, 50, 66, 97, 100, 105, 189, 212 Colchicine, 189, 229 Collagen, 189, 197, 198, 217 Complement, 24, 58, 179, 189, 208 Complementary and alternative medicine, 119, 127, 189 Complementary medicine, 119, 189 Computational Biology, 17, 155, 190 Computed tomography, 65, 122, 126, 190, 223 Computerized axial tomography, 190, 223 Computerized tomography, 100, 190 Conception, 113, 190, 197, 224 Concomitant, 36, 190 Conduction, 35, 190 Confusion, 20, 174, 190, 193, 212 Congestion, 181, 190 Conjugated, 183, 190, 191 Connective Tissue, 184, 189, 190, 197, 198 Consciousness, 190, 192 Consolidation, 34, 190 Constipation, 181, 190 Constitutional, 190, 211

Constriction, 190, 205 Contraindications, ii, 190 Convulsions, 180, 190 Coordination, 12, 187, 190, 210 Coronary, 60, 190, 191, 209 Coronary Thrombosis, 191, 209 Corpus, 115, 191, 199, 211, 228 Corpus Striatum, 115, 191, 199, 211 Cortex, 18, 20, 22, 38, 48, 49, 52, 56, 57, 88, 90, 98, 181, 182, 191, 195, 196, 197, 204, 211, 218, 220 Cortical, 18, 19, 22, 25, 29, 40, 41, 42, 48, 56, 96, 99, 105, 116, 125, 191, 196, 218, 220, 227 Cranial, 187, 191, 200, 205, 214, 215 Craniocerebral Trauma, 182, 191, 200, 202, 227 Creatine, 11, 112, 118, 121, 124, 132, 191 Creatinine, 191 Cues, 36, 191 Cultured cells, 53, 191 Curative, 54, 191, 213, 228 Cyclic, 12, 177, 185, 191, 200, 213, 216 Cyclosporine, 58, 191 Cystamine, 56, 59, 102, 126, 161, 191 Cytochrome, 72, 92, 121, 191, 214 Cytokine, 37, 191 Cytoplasm, 31, 46, 55, 77, 181, 185, 186, 192, 195, 200, 210, 211, 222, 227 Cytoskeletal Proteins, 185, 188, 192 Cytoskeleton, 8, 55, 192, 209 Cytotoxic, 52, 192, 221, 224 D Databases, Bibliographic, 155, 192 Decision Making, 99, 192 Degenerative, 23, 27, 35, 43, 54, 160, 163, 192, 210 Deletion, 40, 44, 181, 192 Delirium, 181, 192 Delusions, 192, 220 Dementia, 23, 42, 96, 100, 133, 135, 160, 163, 181, 192 Denaturation, 192, 217 Dendrites, 48, 192, 193, 212, 220 Dendritic, 8, 192 Dentate Gyrus, 192, 201 Depolarization, 87, 114, 193, 224 Deprivation, 30, 193 Desensitization, 41, 193 Deuterium, 193, 202 Diabetes Mellitus, 113, 193, 199, 201 Diagnostic procedure, 106, 145, 193

236 Huntington’s Disease

Diastolic, 193, 202 Diencephalon, 193, 218, 227, 228 Diffusion, 193 Digestion, 183, 184, 193, 207, 225, 230 Digestive system, 134, 193, 210 Dilation, 184, 193, 201 Dilution, 49, 193 Dimerization, 15, 193 Diploid, 193, 217, 229 Direct, iii, 12, 14, 25, 32, 33, 53, 55, 56, 75, 98, 112, 147, 188, 193, 194, 221, 226 Discrimination, 59, 82, 193 Disease Progression, 33, 95, 193 Disorientation, 133, 163, 190, 192, 193 Dissection, 21, 49, 193 Distal, 12, 182, 193, 219 Dominance, 26, 194 Dopa, 194, 206 Dopamine, 13, 19, 23, 61, 74, 78, 79, 96, 100, 113, 114, 117, 175, 179, 181, 194, 206, 222 Dopamine Agonists, 23, 194 Dorsal, 31, 194, 218, 223 Dorsum, 194 Drive, ii, vi, 3, 17, 29, 52, 109, 194 Drug Evaluation, 10, 194 Drug Interactions, 149, 194 Duodenum, 183, 194, 225 Dyes, 179, 194 Dyskinesia, 40, 127, 181, 194 Dysphagia, 3, 174, 194 Dystonia, 8, 19, 32, 40, 181, 194 Dystrophy, 8, 17, 44, 194 E Ectoderm, 12, 194 Ectopic, 9, 194 Effector, 177, 189, 194, 196, 216 Efficacy, 20, 42, 53, 56, 132, 194, 207 Elective, 100, 194 Electrolyte, 192, 194, 218, 224 Electromyography, 51, 195 Electrons, 181, 182, 195, 205, 214, 221 Electrophysiological, 4, 29, 34, 70, 76, 79, 96, 113, 195 Embryo, 81, 183, 186, 194, 195, 199, 203, 208 Empirical, 11, 195 Emulsion, 182, 195, 198 Encapsulated, 76, 124, 195 Endemic, 195, 225 Endocytosis, 25, 195 Endoderm, 12, 195

Endosomes, 25, 195 Endothelial cell, 184, 195, 197, 228 Endothelium, 195, 213 Endothelium-derived, 195, 213 Endotoxins, 189, 195 End-stage renal, 188, 195, 217 Enhancer, 195, 222 Entorhinal Cortex, 195, 201 Environmental Exposure, 23, 196, 214 Environmental Health, 47, 154, 156, 196 Enzymatic, 17, 46, 62, 185, 189, 196, 201, 217 Enzyme Induction, 196, 222 Enzyme Repression, 196, 222 Epidemic, 196, 225 Epinephrine, 177, 194, 196, 213, 230 Epitope, 28, 196 Erythrocytes, 180, 184, 185, 196 Esophagus, 193, 196, 216, 225 Eukaryotic Cells, 46, 192, 196, 203, 214, 230 Evoke, 196, 225 Evoked Potentials, 100, 196 Excitatory, 29, 48, 57, 196, 199, 206 Excitotoxicity, 29, 41, 56, 62, 67, 112, 114, 196 Exhibitionism, 114, 196 Exogenous, 50, 197 Exon, 54, 77, 78, 92, 113, 114, 197 External-beam radiation, 197, 205, 221, 231 Extracellular, 48, 53, 179, 181, 190, 195, 197, 224 Extracellular Matrix, 190, 197 Extrapyramidal, 22, 29, 43, 178, 179, 181, 194, 197 F Facial, 93, 124, 197 Family Planning, 155, 197 Fat, 177, 183, 184, 197, 207, 210 Fathers, 26, 197 Fatty acids, 43, 63, 110, 113, 197, 199 Femoral, 185, 197 Femoral Artery, 185, 197 Fetus, 12, 197, 218, 230 Fibril, 27, 197 Fibroblast Growth Factor, 12, 113, 197 Fibroblasts, 64, 121, 197 Fibrosis, 44, 135, 179, 197, 223 Filtration, 55, 197 Fissure, 192, 197, 218 Fixation, 197, 223

Index 237

Fluorescence, 27, 55, 80, 198 Fossa, 187, 198 Fractionation, 26, 198 Frontal Lobe, 22, 73, 180, 187, 198, 210, 218 Functional magnetic resonance imaging, 19, 32, 198 G Gait, 81, 104, 116, 126, 163, 175, 198 Gallbladder, 177, 193, 198 Ganglia, 22, 43, 66, 177, 182, 198, 212, 215 Gap Junctions, 198, 226, 227 Gas, 179, 193, 198, 202, 213, 226 Gelatin, 198, 199, 228 Gene Expression, 14, 16, 17, 22, 31, 53, 56, 75, 87, 126, 198 Gene Rearrangement, 17, 198 Generator, 198, 227 Genetic Counseling, 20, 198 Genetic Techniques, 26, 198 Genetic testing, 20, 59, 82, 199, 217 Genetic transcription, 199, 219, 229 Genotype, 26, 132, 178, 199, 216 Germ Layers, 12, 194, 195, 199 Gland, 199, 215, 216, 219, 225 Globus Pallidus, 43, 113, 182, 191, 199, 220 Glucose, 14, 40, 83, 132, 193, 199, 200, 204, 216 Glucose Intolerance, 193, 199 Glutamate, 8, 25, 29, 33, 41, 51, 57, 83, 114, 133, 196, 199, 209 Glutamic Acid, 199 Glutamine, 45, 55, 56, 58, 199 Glycerol, 199, 216 Glycerophospholipids, 199, 216 Glycine, 183, 199, 223 Glycoprotein, 199, 228 Governing Board, 199, 218 Gp120, 15, 199, 215 Graft, 58, 178, 199, 201, 203 Grafting, 200, 203 Granulocytes, 200, 206, 224, 231 Gravis, 4, 200 Growth, 8, 12, 30, 35, 42, 58, 143, 180, 181, 186, 197, 200, 204, 208, 211, 214, 217, 229 Growth factors, 42, 200 Guanylate Cyclase, 200, 213 Gyrus Cinguli, 180, 200, 206 H Habitat, 26, 200 Haloperidol, 126, 148, 200 Haplotypes, 83, 200 Headache, 200, 201

Health Behavior, 60, 200 Health Promotion, 24, 200 Health Status, 200 Heat-Shock Proteins, 200, 209 Heat-Shock Proteins 90, 200, 209 Heme, 191, 200 Hemoglobin, 180, 196, 200, 205 Hemorrhage, 191, 200, 201, 226 Hereditary, 26, 28, 78, 135, 188, 201, 210, 212 Heredity, 198, 199, 201 Heterogeneity, 26, 178, 201 Heterozygotes, 194, 201 Hippocampus, 31, 34, 48, 116, 192, 201, 206, 220, 223, 226 Histamine, 179, 181, 201 Histology, 14, 25, 125, 201 Histone Deacetylase, 11, 56, 61, 201 Homeostasis, 13, 30, 48, 201 Homologous, 42, 178, 201, 226, 227 Homozygotes, 26, 194, 201 Hormonal, 182, 201 Hormone, 196, 201, 204, 224 Host, 29, 178, 182, 197, 201, 203, 231 Hybrid, 188, 201 Hybridization, 41, 201 Hydrocephalus, 79, 201, 205 Hydrogen, 27, 42, 179, 182, 192, 193, 202, 207, 209, 213, 214, 216, 219, 226 Hydrogen Bonding, 27, 202, 213 Hydrogen Peroxide, 202, 207, 226 Hydrolysis, 177, 202, 206, 216, 217, 219 Hydrophilic, 28, 202 Hydrophobic, 28, 42, 199, 202 Hydroxylation, 202, 229 Hyperkinesia, 112, 202 Hypersensitivity, 178, 193, 202 Hypertension, 11, 17, 202, 205 Hypokinesia, 202, 215 Hypotension, 181, 190, 202 I Id, 118, 127, 160, 163, 170, 172, 202 Idiopathic, 32, 40, 202 Imaging procedures, 202, 228 Immune response, 180, 182, 202, 208, 231 Immune system, 183, 202, 203, 207, 210, 231 Immunity, 178, 202 Immunoblotting, 55, 202 Immunofluorescence, 26, 203 Immunoglobulin, 15, 180, 203, 210 Immunohistochemistry, 29, 33, 203

238 Huntington’s Disease

Immunotherapy, 183, 193, 203 Impairment, 4, 23, 36, 50, 54, 75, 98, 174, 182, 183, 192, 194, 203, 208, 220 Implant radiation, 203, 204, 205, 221, 231 Implantation, 150, 190, 203 In situ, 16, 28, 33, 58, 61, 92, 203 In Situ Hybridization, 16, 33, 92, 203 In vitro, 14, 15, 21, 37, 43, 45, 53, 56, 59, 87, 98, 114, 116, 203, 217 In vivo, 7, 8, 14, 25, 28, 34, 39, 43, 57, 58, 98, 116, 203 Incision, 203, 205 Incontinence, 174, 201, 203 Indicative, 135, 203, 215, 230 Induction, 31, 51, 181, 203 Infancy, 203 Infantile, 44, 203 Infarction, 187, 191, 203, 209 Infection, 183, 187, 188, 192, 203, 207, 226, 231 Inflammation, 188, 197, 203 Infusion, 19, 25, 204 Ingestion, 204, 217 Inhalation, 204, 217 Initiation, 28, 51, 56, 74, 204, 219, 229 Inositol, 204, 209 Inotropic, 194, 204 Insecticides, 204, 216 Insertional, 12, 204 Insight, 17, 22, 26, 32, 48, 88, 204 Insulator, 204, 210 Insulin, 30, 204 Insulin-dependent diabetes mellitus, 204 Insulin-like, 30, 204 Interindividual, 13, 204 Interleukin-1, 33, 204 Interleukin-2, 204 Internal Capsule, 180, 191, 204 Internal radiation, 204, 205, 221, 231 Interneurons, 41, 115, 137, 205 Interstitial, 184, 204, 205, 231 Intestines, 177, 205, 223 Intracellular, 13, 28, 29, 33, 46, 52, 185, 188, 198, 203, 205, 209, 213, 218, 224 Intracranial Hemorrhages, 201, 205, 228 Intracranial Hypertension, 200, 201, 205 Intraperitoneal, 56, 205 Intravenous, 204, 205 Intrinsic, 9, 29, 178, 205 Invasive, 9, 44, 202, 205, 208 Involuntary, 23, 38, 43, 82, 132, 163, 182, 187, 205, 211, 222, 224

Ion Channels, 29, 48, 181, 205, 227 Ionizing, 196, 205, 221 Ions, 182, 185, 194, 202, 205 Irradiation, 104, 205, 231 Ischemia, 33, 43, 85, 182, 205 Isoleucine, 72, 205 K Kb, 154, 205 Kidney Disease, 44, 134, 154, 205 Kinesin, 35, 55, 206 Kinetics, 45, 206 Kynurenic Acid, 90, 206 L Labile, 189, 206 Labyrinth, 206, 219 Large Intestine, 193, 205, 206, 221 Laryngeal, 4, 206 Larynx, 206 Latency, 4, 206 Lesion, 42, 110, 206, 207, 227 Lethal, 57, 206 Lethargy, 201, 206 Leucocyte, 206, 207 Leukemia, 17, 206 Levodopa, 19, 40, 90, 123, 148, 149, 194, 206 Library Services, 170, 206 Ligaments, 190, 206 Limbic, 38, 179, 200, 206, 218 Limbic System, 179, 200, 206, 218 Linkage, 11, 207 Lipid, 46, 187, 199, 204, 207, 210, 214 Lipid Peroxidation, 207, 214 Lithium, 114, 181, 207 Liver, 177, 183, 185, 191, 193, 195, 198, 207, 223 Liver scan, 207, 223 Localization, 26, 39, 44, 46, 55, 103, 203, 207 Localized, 9, 25, 26, 41, 195, 198, 203, 207, 217 Locomotion, 207, 217 Locomotor, 126, 207 Longitudinal Studies, 30, 56, 207 Longitudinal study, 26, 39, 91, 207 Long-Term Potentiation, 31, 207 Lymphoblasts, 14, 207 Lymphocyte, 180, 207, 208 Lymphoid, 180, 206, 207 Lysine, 58, 93, 207 M Macrophage, 204, 207

Index 239

Magnetic Resonance Imaging, 9, 39, 208, 223 Major Histocompatibility Complex, 200, 208 Malignant, 21, 181, 184, 208, 221 Malnutrition, 182, 208, 210 Manic, 181, 183, 207, 208, 220 Manic-depressive psychosis, 208, 220 Manifest, 38, 182, 208 Medial, 199, 200, 208, 223 Mediate, 17, 40, 53, 194, 208, 209 Mediator, 33, 194, 204, 208, 223 MEDLINE, 155, 208 Medullary, 208, 220 Meiosis, 208, 227 Memory, 4, 8, 18, 19, 24, 31, 34, 36, 37, 48, 76, 94, 98, 123, 133, 174, 192, 207, 208 Meninges, 186, 191, 208 Mental Disorders, 134, 202, 208, 219, 220 Mental Health, iv, 5, 20, 114, 134, 135, 154, 156, 208, 220 Mental Retardation, 20, 57, 89, 208 Mesoderm, 12, 208 Mesolimbic, 181, 208 Metabolite, 196, 209, 220 Metabotropic, 33, 57, 209 Methyltransferase, 24, 209 MI, 175, 209 Microbe, 209, 228 Microorganism, 189, 209, 231 Microscopy, 26, 27, 37, 47, 55, 209 Microtubules, 35, 206, 209 Micturition, 142, 209 Minocycline, 91, 92, 131, 143, 209 Mitochondria, 37, 50, 54, 55, 87, 114, 187, 209, 214 Mitosis, 181, 209 Mobilization, 185, 209 Modeling, 32, 92, 115, 209 Modification, 16, 46, 53, 209, 220 Molecular Chaperones, 9, 45, 187, 200, 209 Molecule, 7, 47, 59, 180, 182, 183, 189, 194, 195, 196, 199, 202, 204, 209, 213, 214, 216, 221, 224, 230 Monitor, 9, 14, 25, 55, 191, 209, 213 Monoclonal, 45, 58, 202, 205, 210, 221, 231 Monoclonal antibodies, 45, 58, 202, 210 Monocytes, 204, 210 Mood Disorders, 18, 210 Morphological, 58, 66, 76, 97, 111, 195, 210 Morphology, 8, 75, 210 Mosaicism, 26, 210

Motility, 35, 210, 223 Motor Activity, 97, 190, 210 Motor Cortex, 22, 36, 210, 221 Motor nerve, 210, 214 Mucositis, 210, 228 Multimodality treatment, 101, 210 Multiple sclerosis, 4, 9, 79, 210 Muscle Contraction, 43, 210 Muscle Fibers, 210, 211 Muscular Atrophy, 6, 210 Muscular Diseases, 3, 210 Muscular Dystrophies, 194, 211 Mutagenesis, 12, 17, 211 Mutagenic, 17, 211 Mutagens, 211 Myasthenia, 4, 211 Myelin, 210, 211 Myocardium, 209, 211 Myofibrils, 185, 211 Myosin, 210, 211 Myotonic Dystrophy, 6, 139, 211, 229 N Nausea, 180, 181, 211 NCI, 1, 15, 133, 153, 211 Necrosis, 181, 187, 203, 209, 211 Need, 3, 20, 59, 105, 137, 150, 164, 177, 188, 211 Neocortex, 22, 211 Neostriatum, 186, 191, 211, 220 Nephropathy, 206, 211 Nerve Growth Factor, 112, 211, 213 Nervous System, 7, 34, 37, 48, 58, 65, 177, 178, 184, 186, 188, 196, 198, 199, 206, 208, 210, 211, 212, 215, 223, 226, 227 Networks, 32, 40, 73, 212 Neuroblastoma, 54, 212 Neuroleptic, 178, 181, 212 Neurologic, 3, 6, 8, 25, 33, 40, 142, 201, 212 Neurologist, 8, 86, 212 Neuromuscular, 3, 51, 160, 177, 212 Neuromuscular Junction, 177, 212 Neuropeptides, 185, 212 Neuropharmacology, 19, 68, 92, 95, 212 Neurophysiology, 4, 64, 68, 71, 72, 73, 76, 87, 93, 101, 124, 193, 212 Neuropil, 103, 212 Neuropsychological Tests, 4, 212 Neuropsychology, 19, 26, 63, 212 Neurotoxic, 27, 47, 212 Neurotoxicity, 114, 212 Neurotoxin, 36, 212 Neurotrophins, 48, 93, 213

240 Huntington’s Disease

Neutralization, 46, 213 Neutrons, 205, 213, 221 Niacin, 213, 229 Nicotine, 51, 213 Nitric Oxide, 110, 113, 213 Nitrogen, 178, 179, 198, 199, 213, 229 Norepinephrine, 177, 194, 213 Nuclear, 39, 64, 99, 100, 182, 195, 196, 204, 207, 211, 213, 228 Nuclear Localization Signal, 39, 213 Nuclear Pore, 213 Nuclei, 22, 43, 44, 62, 179, 195, 208, 209, 213, 217, 219, 223 Nucleic acid, 201, 203, 211, 213, 218, 220 Nucleic Acid Hybridization, 201, 213 Nucleus Accumbens, 31, 214 O Occupational Therapy, 75, 214 Ocular, 214, 223 Oculi, 184, 214 Oculomotor, 29, 214 Oncogene, 15, 214 On-line, 17, 173, 214 Operon, 214, 219, 222 Orbicularis, 184, 214 Organelles, 35, 188, 192, 206, 210, 214, 217 Oropharynx, 3, 214 Orthostatic, 181, 214 Osmosis, 214 Osmotic, 44, 214 Oxidation, 181, 191, 207, 214 Oxidative Phosphorylation, 11, 14, 214 Oxidative Stress, 13, 36, 56, 214 Oxides, 37, 215 Oxygenator, 185, 215 P Palliative, 215, 228 Pancreas, 177, 183, 193, 204, 215, 230 Paralysis, 178, 181, 215 Parietal, 180, 215 Parietal Lobe, 180, 215 Parkinsonism, 81, 90, 102, 181, 206, 215 Particle, 215, 224, 229 Patch, 29, 215 Pathogenesis, 5, 9, 11, 14, 18, 21, 25, 33, 35, 39, 46, 53, 55, 56, 62, 77, 117, 215 Pathologic, 14, 21, 25, 37, 181, 191, 202, 215, 222 Pathologic Processes, 181, 215 Pathologies, 31, 51, 58, 215 Pathophysiology, 23, 25, 40, 43, 83, 137, 215

Peptide, 27, 38, 42, 47, 197, 215, 217, 219 Peptide T, 43, 215 Perception, 105, 215 Perfusion, 126, 215 Peripheral Nervous System, 212, 215 Peritoneal, 205, 216 Peritoneal Cavity, 205, 216 Pesticides, 13, 204, 216 PH, 75, 90, 100, 122, 126, 216 Pharmacologic, 18, 43, 137, 216, 228 Pharynx, 214, 216 Phenotype, 10, 12, 17, 24, 26, 56, 57, 86, 122, 125, 216 Phosphodiesterase, 11, 216 Phospholipases, 216, 224 Phospholipids, 48, 197, 204, 216 Phosphorus, 185, 216 Phosphorylase, 185, 216 Phosphorylated, 189, 216 Phosphorylation, 11, 216 Physical Examination, 4, 216 Physiologic, 3, 178, 183, 194, 202, 216, 221, 222, 229 Physiology, 3, 41, 44, 115, 177, 195, 212, 216 Pilot study, 76, 120, 122, 216 Pituitary Gland, 197, 216 Plants, 178, 187, 199, 210, 213, 217, 228 Plasma, 44, 46, 72, 94, 178, 180, 186, 198, 199, 201, 217 Plasma cells, 180, 217 Plasticity, 8, 26, 37, 58, 111, 217 Plastids, 187, 214, 217 Platelet Activation, 217, 224 Platelet Aggregation, 179, 213, 217 Platelets, 185, 213, 217, 223 Pleomorphic, 214, 217 Poisoning, 13, 192, 211, 217 Polycystic, 44, 217 Polymerase, 36, 217, 219, 222 Polymerase Chain Reaction, 36, 217 Polymers, 62, 217, 219 Polymorphism, 65, 217 Polypeptide, 179, 185, 189, 201, 217, 231 Posterior, 179, 182, 187, 194, 204, 214, 215, 218 Postherpetic Neuralgia, 179, 218 Postnatal, 218, 225 Postsynaptic, 8, 29, 34, 48, 51, 218, 224, 226, 227 Post-synaptic, 115, 218 Post-traumatic, 210, 218

Index 241

Potassium, 76, 218 Potentiate, 54, 218 Potentiation, 29, 34, 207, 218, 224 Practice Guidelines, 156, 218 Preclinical, 7, 56, 218 Precursor, 5, 19, 187, 194, 196, 206, 213, 218, 229, 230 Prefrontal Cortex, 19, 22, 218 Prenatal, 23, 78, 96, 104, 195, 218 Presynaptic, 29, 35, 48, 218, 226, 227 Prevalence, 86, 218 Prion, 15, 42, 186, 218 Procaine, 178, 218 Progeny, 122, 218 Progression, 10, 14, 30, 33, 39, 49, 52, 54, 68, 94, 95, 180, 218 Projection, 29, 41, 115, 117, 205, 213, 218, 219, 220, 221 Promoter, 13, 18, 52, 80, 219 Promotor, 22, 219, 222 Prone, 17, 219 Prophase, 219, 227 Proprioception, 96, 219 Prospective study, 207, 219 Prostate, 183, 219, 230 Protease, 15, 219 Protein C, 8, 26, 30, 45, 48, 54, 179, 182, 189, 219 Protein S, 26, 47, 52, 55, 136, 183, 219, 222, 227 Proteolytic, 39, 189, 219 Protons, 202, 205, 219, 221 Proximal, 12, 193, 218, 219, 223 Psychiatric, 9, 27, 39, 54, 59, 65, 71, 97, 208, 219 Psychology, 10, 38, 51, 74, 112, 123, 212, 219 Psychophysics, 32, 130, 219 Psychophysiology, 122, 212, 220 Psychosis, 99, 103, 181, 220 Public Health, 33, 136, 156, 220 Public Policy, 155, 220 Publishing, 60, 111, 220 Pulse, 9, 43, 209, 220 Purines, 220, 223 Putamen, 14, 22, 43, 49, 58, 180, 182, 191, 211, 220 P-value, 11, 220 Pyramidal Cells, 34, 193, 220 Pyramidal Tracts, 197, 220 Q Quality of Life, 90, 220

Quinolinic, 41, 62, 74, 91, 98, 110, 116, 220 Quinolinic Acid, 41, 62, 74, 91, 110, 220 R Radiation, 177, 182, 191, 196, 197, 198, 204, 205, 221, 223, 231 Radiation therapy, 177, 197, 198, 204, 205, 221, 231 Radioactive, 182, 184, 202, 203, 204, 205, 207, 210, 213, 221, 223, 231 Radioisotope, 221, 228 Radiolabeled, 184, 205, 221, 231 Radiotherapy, 184, 205, 221, 225, 231 Randomized, 20, 76, 85, 110, 122, 194, 221 Reaction Time, 51, 105, 221 Reactive Oxygen Species, 11, 36, 51, 221 Reality Testing, 220, 221 Recombinant, 110, 221, 230 Recombination, 198, 221 Rectum, 184, 193, 198, 203, 206, 219, 221 Recurrence, 183, 208, 221 Red Nucleus, 182, 221 Refer, 1, 189, 197, 205, 207, 212, 213, 214, 220, 221 Reflex, 79, 222 Refraction, 222, 225 Regeneration, 35, 197, 222 Regimen, 194, 222 Rehabilitative, 32, 222 Reliability, 9, 222 Remission, 183, 208, 221, 222 Repressor, 15, 56, 214, 222 Repressor Proteins, 56, 222 Resorption, 202, 222 Respiration, 187, 209, 222 Response Elements, 57, 222 Restless legs, 82, 222 Retrograde, 46, 48, 222 Ribosome, 222, 229 Rigidity, 43, 215, 217, 222 Risk factor, 5, 219, 222 Risperidone, 99, 103, 222 Rod, 188, 223 Rodenticides, 216, 223 S Saccades, 86, 97, 223 Salivary, 193, 223 Salivary glands, 193, 223 Scans, 10, 126, 223 Schizophrenia, 9, 20, 42, 78, 137, 223 Sclerosis, 4, 5, 8, 16, 25, 33, 37, 44, 210, 223 Screening, 7, 54, 59, 82, 188, 223 Secretory, 223, 226, 227

242 Huntington’s Disease

Segmentation, 9, 223 Semisynthetic, 209, 223 Septal, 180, 207, 223 Septal Nuclei, 180, 207, 223 Sequence Homology, 215, 223 Sequencing, 10, 17, 59, 84, 217, 223 Serine, 15, 223 Serotonin, 181, 222, 223, 229 Serum, 179, 189, 223 Shock, 45, 61, 76, 95, 143, 187, 224, 229 Side effect, 43, 147, 150, 177, 178, 181, 183, 224, 228 Signal Transduction, 7, 12, 37, 48, 114, 200, 204, 224 Skeletal, 188, 210, 211, 224 Skull, 191, 224, 227 Smooth muscle, 178, 179, 185, 201, 211, 224 Social Environment, 220, 224 Sodium, 56, 76, 122, 224 Solvent, 199, 214, 224 Soma, 220, 224 Somatic, 29, 49, 81, 206, 208, 209, 215, 218, 224 Somatic mutations, 49, 224 Sound wave, 190, 224 Spasm, 184, 224 Specialist, 164, 193, 225 Species, 54, 178, 186, 189, 196, 201, 208, 209, 210, 221, 223, 225, 226, 229, 231 Specificity, 28, 35, 57, 178, 225 Spectrum, 5, 110, 225 Sperm, 26, 188, 224, 225, 229 Spinal cord, 6, 181, 185, 186, 187, 208, 211, 215, 220, 222, 225 Sporadic, 5, 28, 72, 212, 225 Stabilization, 54, 225 Staging, 223, 225 Staphylococcus, 209, 225 Steady state, 15, 225 Steel, 188, 225 Stem Cells, 84, 225 Stereotactic, 119, 225 Stimulant, 49, 201, 225 Stimulus, 50, 51, 194, 196, 205, 206, 220, 221, 222, 225, 228 Stomach, 3, 177, 193, 196, 201, 205, 211, 216, 225 Stool, 203, 206, 225 Strand, 27, 72, 87, 217, 225 Stress, 7, 13, 36, 44, 56, 173, 186, 187, 211, 214, 226

Stria, 110, 223, 226 Stroke, 4, 8, 11, 25, 32, 37, 48, 130, 131, 132, 134, 137, 154, 161, 162, 226 Subclinical, 30, 73, 203, 226 Subcutaneous, 177, 226 Subiculum, 201, 226 Subspecies, 225, 226 Substrate, 40, 50, 222, 226 Suction, 197, 226 Superoxide, 5, 226 Superoxide Dismutase, 5, 226 Suppression, 226 Suppressive, 9, 226 Sympathomimetic, 194, 196, 213, 226 Symptomatic, 14, 23, 30, 39, 122, 175, 179, 226 Symptomatic treatment, 179, 226 Symptomatology, 27, 226 Synapses, 8, 31, 34, 48, 207, 226, 227 Synapsis, 226, 227 Synaptic Transmission, 8, 48, 213, 227 Synaptic Vesicles, 226, 227 Synchrotron, 37, 227 Synergistic, 33, 227 Systemic, 42, 113, 148, 149, 181, 184, 192, 196, 203, 205, 221, 227, 231 Systolic, 202, 227 T Tardive, 127, 181, 227 Telangiectasia, 21, 227 Telencephalon, 182, 227 Temporal, 24, 43, 56, 179, 201, 227 Tetracycline, 11, 52, 74, 92, 209, 227 Tetrahydrocannabinol, 185, 227 Thalamic, 71, 137, 182, 227 Thalamic Diseases, 182, 227 Thalamus, 22, 88, 184, 191, 193, 207, 218, 227, 228 Therapeutics, 7, 21, 52, 64, 86, 98, 149, 228 Thermal, 200, 213, 217, 228 Third Ventricle, 228 Threonine, 15, 215, 223, 228 Threshold, 49, 202, 228 Thrombin, 217, 219, 228 Thrombomodulin, 219, 228 Thrombosis, 219, 226, 228 Thymidine, 23, 185, 228 Tomography, 14, 19, 40, 122, 228 Tonic, 184, 228 Tonicity, 194, 228 Torsion, 9, 32, 40, 203, 228

Index 243

Toxic, iv, 5, 16, 24, 30, 35, 43, 45, 46, 196, 202, 213, 228 Toxicity, 8, 13, 16, 21, 27, 30, 39, 53, 55, 59, 83, 84, 88, 106, 142, 194, 228 Toxicology, 156, 228 Toxins, 13, 180, 195, 203, 210, 228 Tracer, 22, 228 Traction, 188, 229 Transcription Factors, 11, 16, 56, 57, 222, 229 Transduction, 37, 185, 224, 229 Transfection, 183, 229 Transgenes, 5, 24, 31, 229 Translation, 74, 229 Translocation, 8, 39, 188, 229 Transmitter, 177, 181, 194, 205, 208, 213, 226, 227, 229 Transplantation, 58, 66, 67, 79, 93, 103, 105, 106, 119, 120, 123, 130, 137, 188, 208, 229 Trauma, 33, 192, 211, 229 Tremor, 215, 229 Trigger zone, 181, 229 Trinucleotide Repeat Expansion, 5, 86, 229 Trinucleotide Repeats, 4, 229 Trisomy, 76, 229 Trophic, 30, 84, 121, 229 Tryptophan, 88, 113, 189, 220, 223, 229 Tryptophan Hydroxylase, 88, 229 Tubercle, 214, 229 Tubulin, 55, 209, 229 Tumor marker, 183, 229 Tyrosine, 194, 230 U Ubiquitin, 93, 230 Unconscious, 202, 230 Urinary, 94, 201, 203, 230 Urine, 183, 191, 203, 209, 230 Uterus, 191, 230

V Vaccines, 230, 231 Vacuoles, 195, 214, 230 Vascular, 23, 178, 195, 203, 213, 230 Vasodilator, 184, 194, 201, 230 Vector, 42, 204, 229, 230 Vein, 205, 213, 230 Venous, 187, 219, 230 Ventral, 31, 214, 230 Ventricle, 179, 186, 201, 214, 220, 227, 228, 230 Ventricular, 202, 230 Vertebrae, 225, 230 Vesicular, 13, 55, 105, 230 Veterinary Medicine, 155, 230 Villi, 202, 230 Vinblastine, 229, 230 Vincristine, 229, 230 Viral, 15, 31, 42, 229, 231 Viral vector, 42, 231 Virulence, 182, 228, 231 Virus, 42, 182, 186, 195, 199, 229, 231 Viscera, 224, 231 Visceral, 12, 206, 231 Vitro, 14, 15, 45, 53, 57, 59, 231 Vivo, 14, 39, 57, 58, 231 Volition, 205, 231 Voltage-gated, 29, 231 W White blood cell, 180, 207, 217, 231 Wound Healing, 197, 231 X Xenograft, 180, 231 X-ray, 37, 47, 190, 198, 205, 213, 221, 223, 225, 231 X-ray therapy, 205, 231 Y Yeasts, 216, 231 Z Zygote, 190, 210, 231 Zymogen, 219, 231

244 Huntington’s Disease

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