John Herbert Growdon, MD - US grants

The overall goal of this project is to determine whether proton nuclear magnetic resonance (NMR) brain imaging can detect pathological changes in the brains of patients with Alzheimer's disease and patients with multi-infarct dementia, and whether NMR measures can distinguish these groups from each other and from age-matched control subjects. A related goal is to discover whether different regional abnormalities detected by NMR imaging correspond to specific positive findings in the neurological and neuropsychological examinations, CT scan, and ultimately neuropathological study. In order to accomplish these goals, 30 patients with Alzheimer's disease, 30 patients with multi-infarct dementia, and 30 nondemented control subjects will be examined during the next 3 years. The first 10 subjects in each group will be examined in all 3 years in order to plot NMR measures over time. The expectation is that patients with Alzheimer's disease will show changes in years 2 and 3, whereas patients with multi-infarct dementia and nondemented subjects will not. Three-demensional proton NMR studies with a variety of pulse sequences will provide images of cortical and subcortical structures, and will make it possible to quantify brain and cerebrospinal fluid volumes in relation to intracranial capacity. Quantitative determination of three NMR parameters, proton spin density (p), T1 relaxation time, and T2 relaxation time, will be performed in 14 homologous brain regions in the two cerebral hemispheres. Clinical data for comparison with NMR data will consist of results from comprehensive neurological examinations and neuropsychological tests of memory, attention, language, praxis, and visual perception. The contribution of this work could be to establish NMR imaging as a method of noninvasive brain biopsy, having extensive clinical and research application.

The overall goal is to determine the chromosomal localization of the gene causing familial Alzheimer's disease (FAD) using genetic linkage to DNA markers. We shall obtain family histories from all patients attending the Memory Disorders Unit at the Massachusetts General Hospital. From these histories, we shall complete comprehensive pedigrees on families of patients with AD who have multiple demented ancestors and siblings. The diagnosis of AD in the index cases will be established by contemporary research criteria. We shall obtain blood samples from all living individuals in FAD families for preparation of genomic DNA and establishment of permanent lymphoblastoid cell lines. The banked cells will serve as a permanent source of DNA for subsequent molecular analysis. We shall analyze subjects' DNA for segregation of DNA markers; initial emphasis will be placed upon markers derived from chromosome 21 and later, involve other regions of the genome if necessary. We shall use standard linkage techniques in order to link DNA markers to the FAD locus. Characterization of the FAD gene sequence and product would lead to an understanding of the basis for familial AD, afford insights into sporadic AD, and might allow the development of effective therapies for AD. Related benefits to society would include clinical information on such issues as the proportion of AD cases with and without a family history of dementia (any first degree relative demented), and whether patterns of inheritance of AD are related to familial age at onset, whether the sex of an affected parent influences risk of inheritance, and whether other illnesses are commonly associated with AD.

The overall goal of this project is to characterize the nature and extent of abnormalities in phospholipid (PL) metabolism that are associated with neuronal dysfunction and degeneration in Alzheimer's disease (AD). A related goal of the research is to determine whether PL abnormalities occurring in brain tissue can be detected in the cerebrospinal fluid (CSF) during life, and whether they are part of a systemic lesion and can be detected in peripheral blood (red cells and lymphocytes). There are two major hypotheses: 1. Abnormalities in the metabolism of phosphatidylcholine (PC) and possibly other PLs are associated with neuronal dysfunction and degeneration in AD and are distinct from findings in other neurodegenerative diseases or that may occur during normal aging. 2. Accuracy in the antemortem diagnosis of AD may be enhanced by detecting in body fluids the abnormalities of PL metabolism that occur in brain. In order to accomplish these goals, we will measure levels of water-soluble precursors and metabolites of PC and other PLs catalytic enzyme activities, in brain tissue obtained at autopsy from patients with AD, and Huntington's disease (HD), and from two groups of control subjects: one with ages between 20 and 40, and the second with ages between 60 and 80. Brain samples will be from frontal, parietal, temporal, and occipital cortex; dentate nucleus of cerebellum; and subcortical nuclei caudate, midline thalamus, ventral forebrain Ch 1-4 group, hippocampus, and amygdala. In clinical studies, CSF and blood samples will be obtained from patients with sporadic and familial forms of AD and from control subjects in ten 20 to 40 age range and in the 60 to 80 age range. The same water-soluble PL precursors and metabolites measured in brain will be measured in CSF and blood cells, and, in addition, PL catalytic enzyme activities will be measured in blood cells. This project is multidisciplinary and involves investigators from the fields of neurology,k neuropathology, biochemistry and statistics. The proposed research takes advantage of resources in the Massachusetts Alzheimer's Disease Research Center and also benefits from research at MGH on the genetics of AD. Identification of characteristic abnormalities in PL metabolism in brains of patients with AD may provide new explanations for neuronal dysfunction and death; detection of these abnormalities in blood or CSF samples would be a welcomed aid to the accurate antemortem diagnosis of AD.

A multi-institutional Clinical Core Unit (CCU) was established during the first five years of the Massachusetts ADRC and will continue during years 06 to 10. The three Units are at BAH, MGH, and UMMC. The overall goals of the CCU are to examine, diagnose, and enroll into the ADRC Patient Registry men and women with AD and related dementias , and health control subjects. An associated goal is to characterize the neurological, psychiatric, and neuropsychological features of AD across all stages of illness. The clinical experience at each Unit stimulates and supports new research initiatives, and enhances research productivity. In order to accomplish these goals, subjects are examined at one of the three clinical units; demographic and diagnostic information on all subjects are entered into the joint ADRC central Patient Registry. Standardized data are collected in each Unit on aspects of the clinical history of dementia, features of the neurological examination, results of cognitive tests, and laboratory diagnostic tests. These data are collected in a uniform manner at each of the three Units and maintained in separate but compatible databases. In order to track the course of illness, neurological and psychiatric examinations are repeated every six months; cognitive tests are performed every twelve months. Patients with AD are referred to specific research projects depending upon informed consent and the inclusion and exclusion criteria of each project. Patients with AD and control subjects are encouraged to sign a brain donation form indicating intent for postmortem examination.

The aim of the study is to gather safety information from the three year, long-term use of entacapone and to give the patients an opportunity to use entacapone after paticipating in the controlled, double-blind, study 2939044. In 1997, the study was extended until 12/31/99 or until entacapone is commercially available.

human therapy evaluation; female; postmenopause; estrogens; hysterectomy; hormone therapy; brain disorder chemotherapy; Alzheimer's disease; drug screening /evaluation; clinical trial phase I; psychomotor function; memory; cognition; language; human middle age (35-64); human old age (65+); drug administration rate /duration; attention; love /affection; performance; quality of life; functional ability; clinical research; human subject;

The Massachusetts Alzheimer's Disease Research Center (ADRC) is a multi- institutional consortium composed of Harvard-affiliated facilities including the Massachusetts General Hospital, Beth Israel Hospital, McLean Hospital, Brigham & Women's Hospital, and the Harvard Division on Aging; the Massachusetts Inst of Technology; Southwestern Vermont Medical Center; and the University of Massachusetts Medical Center. Each Institution supports research in AD and has a proven track record of excellence. We have joined together in order to amplify existing research and to accelerate the pace of understanding and treating AD. The ADRC consortium provides a framework for pooling technological resources and gaining sufficient aollaborative manpower, patient enrollment, and autopsy material to conduct and wide range of studies proposed. The overall broad goals of the Massachusetts ADRC are identical to those first proposed ten years ago: To enhance currently funded research, to propose new experiments in fields of neuroscience related to dementia, and to catalyze education, training and information transfer related to AD. In order to accomplish these goals, we will retain four Core facilities that were established during the initial grant cycle. The Administrative Core is responsible for organizing and maintaining the Center. The Clinical Core examines and diagnoses patients with AD and related dementias; enrolls them into the ADRC; and refers them for participation in specific research projects. The Neuropathology Core establishes diagnoses on all brains submitted to the Tissue Resource Center; stores tissue for molecular, neurochemical, and immunocytochemical studies; and distributes brain tissue to qualified investigators. The Education and Information Transfer Core has developed programs to train the future leaders in the academic fields relevant to aging and dementia; to promote exchange of information among ADRC professionals and with the lay community; and to enroll elderly non- demented control subjects into ADRC research. The overriding mission of the ADRC is to stimulate and support research of the highest quality. This application contains five full research projects plus eight pilot projects whose broad themes center on molecular genetics, amyloid metabolism, behavioral neuroscience, and neuropathology of AD. The Core facilities provide resources for the research projects and are in turn sustained by them. Overall, the framework of the ADRC increases the involvement of Massachusetts researchers in AD and amplifies their productivity.

human therapy evaluation; amyloid proteins; neuropharmacology; brain disorder chemotherapy; anticholinergic agent; Alzheimer's disease; pathologic process; molecular pathology; clinical research; human subject;

This grant application requests funds to support the ninth meeting of the International Study Group on the Pharmacology of Memory Disorders Associated with Aging (ISG). The ISG was founded in the belief that the development of effective treatments for Alzheimer's disease (AD) and other dementias would be accelerated by periodic meetings of scientists and physicians from around the world who are actively working on topics related to dementia. There have been eight ISG meetings: the first was held in Tucson, Az in 1979, and the rest (1981, 1984, 1987, 1989, 1991, 1993, and 1995) have been held in Zurich, Switzerland. The overall goals of the ISG remain the same as in 1979: to highlight discoveries that shed light on the potential causes and pathogenesis of Alzheimer's disease and other neurodegenerative dementias, and to identify the disturbed biological processes which, if corrected, might underlie their cures. Since its inception, the ISG has been a forum for interaction among academic scientists, scientists in industry, clinical investigators, and administrators in public and private agencies concerned with aging and dementia research. The sources of funds to support the Zurich meetings reflect this diverse constituency, and include donations from governmental agencies, private foundations, and industry. This broad base of support is crucial to the ISG's mission of stimulating research interest in dementia and speeding transfer of information from the basic sciences to clinical investigators and physicians caring for persons with dementia. Funds requested in this grant application will provide round trip economy airfare and three nights hotel accommodation in Zurich for invited academic scientists from the United States. The funds will also cover the cost of renting the hotel convention center, and help defray the cost of publishing manuscripts submitted by the participants.

levodopa; Parkinson's disease; drug administration rate /duration; brain disorder chemotherapy; clinical trial phase I; pathologic process; antiparkinson drugs; clinical research; human subject;

This protocol is supported by the Alzheimer's Disease Cooperative Study (ADCS) at the University of California-San Diego. The NIH grant number is 5U01 AG19483. The mild cognitive impairment protocol is entirely an investigator-sponsored protocol developed under the auspices of the Alzheimer's Disease Cooperation Study (ADCS, a consortium of investigators funded by the National Institutes of Aging. Pfizer/Eisai is contributing partial funding to this investigator-initiated study. The ADCS has unrestricted rights to the data and will publish the analyses from this trial as the investigators have done in all previous ADCS trials. Primary Objective: To evaluate the efficacy and safety of 1,000 IU of vitamin E bid or 10 mg of donepezil, administered daily, to delay the clinical diagnosis of Alzheimer's Disease when administerd orally, to 720 individuals with mild cognitive impairment for thirty six months. Efficacy will be determined by compairing the rate of conversion to AD for vitamin E or donepezil to that observed with placebo. Secondary Objective: To evaluate the efficacy of vitamin E and donepezil on cognition in MCI subjects. The cognitive measures will be the components of the Neuropsychological Battery (Digits Backward, Symbol Digit, a Maze, a Letter Cancellation Test, World List Recall, Immediate and Delayed Paragraph Recall a variation of the Boston Naming Test, Cagetory Fluency, and Clock Drawing) the ADAS-COG and the MMSE. The investigators will also measure global clinical and functional change utilizing the Clinical Dementia Rating Scale (CDR), a Clinical Global Impression of Change Scale designed for MCI subjects (MCI-CGIC), the ADAS- Activities of Daily Living Scale (ADCS-ADL), and the Global Deterioration Scale (GDS). A Pharmacoeconomic instrument under development by the ADAS and a Quality of Life assessment (Logsdon, 1997) will be obtained as additionaloutcome measures.

chemoprevention; tocopherols; cognition disorders; cholinesterase inhibitors; Alzheimer's disease; human therapy evaluation; piperidine; learning stimulant; brain disorder chemotherapy; clinical trials; vitamin therapy; patient oriented research; nutrition related tag; human subject; clinical research;

DESCRIPTION (provided by applicant): The Massachusetts Alzheimer's Disease Research Center (ADRC) is a multi-institutional consortium composed of Harvard-affiliated facilities including the Massachusetts General Hospital, the Brigham and Women's Hospital, the Harvard Division on Aging and the Hebrew Rehabilitation Center for the Aged. The broad goals of the Massachusetts ADRC have evolved from those first proposed in 1984 but remain constant in the mission to prevent, cure or at least treat effectively AD and related dementing diseases. The specific goals are: To propose and support new research in neuroscience directed toward uncovering the etiology and pathogenetic mechanisms of AD and related dementias; to enhance collaborative dementia research funded outside of the ADRC; and to catalyze education, training and information transfer related to AD and related dementias. To accomplish these goals, we will retain the four Core facilities that were established 20 years ago. Investigators in the Clinical Core examine and diagnose patients with AD and related disorders, and refer them for participation in specific research Projects. The purpose of the Neuropathology Core is to establish diagnoses on all brains submitted to the Tissue Resource Center, store fixed and frozen brain tissue and distribute brain tissue to qualified investigators. The Education and Information Transfer Core has developed programs to train future leaders in academic fields related to aging and dementia, to educate caregivers, and to enroll elderly, non-demented control subjects into ADRC research. To these four Cores, we have added a fifth: The Data Management and Statistics Core that will carry on and expand activities that had previously been housed in the Administrative Core. The overriding mission of the ADRC is to stimulate and support research of the highest quality. This application contains three R01-type Projects that are closely inter-related and also tightly linked to the Clinical, Neuropathological and Data Management and Statistics Cores.

The Clinical Core of the Massachusetts ADRC is housed in the Memory Disorders Unit at the Massachusetts General Hospital. The goal of the Clinical Core is to examine, diagnosis and enroll into the ADRC Patient registry men and women from all racial and ethnic backgrounds with AD and related dementias, including frontotemporal dementia, dementia with Lewy bodies, and other parkinsonian syndromes including progressive supranuclear palsy and cortical basoganglionic degeneration, along with individuals with mild cognitive impairment who are at heightened risk to develop AD. Associated goals of the Center are to characterize the neurological, psychiatric and neuropsychological features of dementia in these patient groups and to refer these carefully evaluated patients to specific research projects funded within the ADRC, as well as to national and local research projects. To this historical mission, we have added two new components for genetics and neuroimaging. The Genetic subcore will consolidate separate elements of existing ADRC genetic programs, including the systematic collection of family history on all patients who attend the Clinical Core, genetic counseling, ascertainment of subjects for local and national genetic research projects and DNA banking and genetic analyses. The Neuroimaging subcore will standardize the collection of MR, SPECT and PET images from individuals who attend the Core, refine and apply to these images automated quantitative analytic programs developed at MGH, and facilitate collaboration with MGH investigators and other local and national ADC projects. The Clinical Core supports a wide range of research funded outside of the Clinical Core, including research projects linked to the ADRC (i.e., Project 3) as well as local and national collaborative research.

This Core of the MGH/MIT Morris Udall Center of Excellence in PD Research wilt continue to serve the needs of the specific investigators of the research projects as well as other members of the PD investigative community. The Core has three components (Clinical, Training, Neuropathology), and each of these activities consists of multiple aspects. Specific Aim #1: Clinical activities: examine, diagnose and characterize the neurological, functional, and neuropsychologicat features of men and women with PD and related parkinsonian movement disorders; maintain a clinical and research database as well as add data to the developing national Udall Center data repository; and refer these carefully examined PD patients (and control subjects as required) to research projects within the Center and to funded projects outside of it. Specific Aim #2: Training activities: support PhD and/or MD post-doctoral fellows to learn and master scientific techniques applicable to the study of PD. Specific Aim #3: Neuropathology activities: development of DNA bank from clinically studied subjects (in coordination with the NINDS Human Genetics Resource Center); brain banking for accurate neuropathological diagnoses, clinicopathologic correlations and provision of brain tissue to investigators within the Center and to qualified investigators outside of the Center. The staff of the Clinical and Training Core has already established the infrastructure needed to continue and expand activity in all these specific aims. tn addition to supporting local training and research, we envision that the Core will become a national resource. We will export our expertise in patient diagnosis and information as well as brain tissue to investigators in other Udall Centers and to qualified investigators throughout the world.

[unreadable] DESCRIPTION (provided by applicant): Parkinson disease (PD) is one of the most common neurodegenerative diseases. The histopathological hallmark of PD is neuronal degeneration in the substantia nigra, with Lewy body inclusions in many of the remaining neurons. Idiopathic PD is traditionally considered a disease of the extrapyramidal motor system, but there is growing realization that cognitive impairments are common in PD and often culminate in dementia, one of its most feared consequences: estimates of the cumulative incidence of dementia range from 38% to 65%, and prevalence as high as 78%. There are two main clinical diagnoses of dementia in PD: PD-dementia (PDD) and dementia with Lewy bodies (DLB). In PDD, motor signs and symptoms are the dominant features and dementia develops only after many years. In DLB, dementia occurs early, within one year of motor signs, and is often the initial and dominant feature. Although these clinical phenotypes are markedly different, the neuropathological findings in PDD and DLB are usually identical. By examining PDD and DLB patients early in their course of dementia, research proposed in this biomarker grant application will address this central question: Are these two forms of dementia variants of the same disease, or do they have different underlying processes? To resolve this question, we will examine three groups of patients - PD, PDD & DLB - with comprehensive neurological and neuropsychological assessments, and will perform innovative PET imaging using the dopamine transporter (DAT) ligand Altropane and the amyloid ligand PiB. The central hypothesis is that the extent and regional pattern of amyloid burden and mesolimbic dopamine impairment will distinguish DLB from PDD, and both from PD. This project draws upon the patient populations and rich research environment of the MGH/MIT Udall PD Center and the MGH Alzheimer's Disease Research Center. Successful completion of the project will establish DAT and PiB PET scans as potential biomarkers for dementia in the spectrum of Lewy body diseases. These advances will be important steps in devising improved treatments for dementia in Lewy body diseases. . Impaired thinking and dementia are disabling features of Parkinson disease that eventually affect 80% of patients. Successful completion of the proposed research will 1) define brain mechanisms that cause dementia, and 2) establish brain imaging methods to aid in the diagnosis of dementia in parkinsonian diseases. These advances will be important steps in devising improved treatments for mental impairments and dementia in Parkinson disease. [unreadable] [unreadable] [unreadable]