Sid Gilman, MD, University of California Los Angeles 1957 - US grants

neural plasticity; nervous system regeneration; brain injury;

The overall goal of this program is to determine the basic mechanisms underlying the regulation of the physiology and pharmacology of basal ganglia amino acid and peptidergic pathways. Within this context, our interests proceed from the behavioral level to the synaptic and molecular level. We are interested in understanding the regulation of the physiological properties of the basal ganglia after selective lesions in relation to motor behavior, the neurotransmitters used in accomplishing this behavior, and the fundamental characteristics of the neurotransmitter receptors that are involved. Our specific goals are as follows: 1. Study the effects of excitotoxic lesions of GABAergic and glutamatergic connections of the basal ganglia on unit activity and motor performance in animals trained to carry out a motor task. 2. Test the hypothesis that the subthalamic nucleus is glutamatergic and is a convergence point for the regulation of striatal and pallidal output and determine whether cortical and thalamic striatal afferents differentially affect striatal neuron subpopulations. 3. Determine the kinetic properties of the GABAA, NMDA and quisqualate receptor channels and the mechanisms by which drugs and ions regulate these properties. 4. Investigate the mechanisms by which neuropeptide Y and somatostatin receptors are coupled to voltage dependent calcium channels.

[unreadable] DESCRIPTION (provided by applicant): Michigan Alzheimer's Disease Research Center (MADRC) [unreadable] In this competing continuation application, we propose to initiate three new scientific projects, continue an active pilot grants program, and support multiple scientific investigations of the dementias funded through additional NIH grants utilizing four cores, Administrative, Clinical, Data Management and Statistics and Neuropathology. All three new projects investigate Alzheimer's disease (AD), and two focus on the transition from normal aging to mild cognitive impairment (MCI) and subsequent dementia. Project 1 will examine the mechanism underlying the inhibitory effects of X11a upon cleavage of amyloid precursor protein utilizing transgenic and knockout mice and probe the genetic linkage of X11a to chromosome 9. Project 2 will determine whether positron emission tomography (PET) with [unreadable] fluorodeoxyglucose can predict the rate of progression of dementia in MCI and mild dementia. Project 3 will evaluate the risk factors, clinical characteristics and outcomes of cognitive impairment that does not meet criteria for dementia (CIND) and its subtypes. A minority satellite diagnostic and treatment center will continue to recruit underrepresented urban, predominantly African American, patients to research studies. The scientific approaches utilize major strengths in neurology, neuroscience and epidemiology at the University of Michigan, including the availability of large numbers of normal aged subjects, patients with MCI and with AD, longitudinal studies with autopsy verification, biostatistics, [unreadable] PET, molecular biology, molecular pharmacology, and survey research. The MADRC interacts with multiple components of the University to achieve its scientific and educational objectives, particularly the Schools of Medicine, Public Health, and Nursing; the Institute for Social Research; Claude Pepper Center, Nathan Shock Center, Institute of Gerontology, and Geriatric Research Education and Clinical Center at the Ann Arbor Veterans Affairs Medical Center, It collaborates with other ADCs on research projects and with the National Alzheimer's Coordinating Center in datasharing. It plays a leadership role in statewide dementia initiatives and works closely with national and local chapters of the Alzheimer Association. It provides a rich environment for attracting fellows, junior and senior scientists into cutting-edge basic and clinical research. [unreadable] [unreadable]

Optimal care for persons with Alzheimer's disease and related disorders (AD) requires the mobilization of a broad array of community health services and the collaboration of many health professionals and community leaders. The education of these groups is usually provided separately and in a context divorced from the collaborative process, but this method is insufficient to prepare communities to meet the needs of persons with AD and their caregivers. We propose to take a different approach, one that will include the development of cooperation within local communities as part of the educational process. We will take advantage of the ongoing Michigan Dementia Program (MDP) to develop educational programs for two rural and two urban communities in Michigan. These communities have been proposed as locations for demonstration regional diagnostic and assessment centers for the MDP. Underserved rural and minority populations and women are well represented in these communities, which have a variety of characteristics similar to those of the range of communities in Michigan. With the assistance of local participants in the MDP and local chapters of the Alzheimer Association, we will work closely within each community to identify community resources and needs, community leaders, and health professionals whose contributions will be needed to achieve significant improvements in the care of people with dementia. We will then design, develop, and implement specific educational interventions that present state-of-the-art information on the detection, diagnosis, assessment, treatment and management of AD within the local community's collaborative context. The results of these interventions will be assessed by comparing baseline measures with outcomes, assessing knowledge, attitudes, practice, behavior and levels of collaboration among the participants. By tailoring the educational interventions to the specific needs of each community, we will be best able to a) improve community responses for supportive assistance to persons with AD and their families and b) develop more rapid and effective referral to appropriately trained health care providers for diagnosis, assessment, treatment and management of AD. The experience gained through these interventions then can be used to provide more effective education to other communities in Michigan in the future.

This is a competing continuation application for the Michigan Alzheimer's Disease Research Center (MADRC). Since it was established in September of 1989, the MADRC has supported highly productive research projects in neurodegenerative diseases and integrated and coordinated research in Alzheimer's disease and related disorders at the University of Michigan and throughout the State of Michigan, fostering new research endeavors and attracting the interest and efforts of others in this field. The MADRC has come to play a central role in the expanding commitment of the University to issues of aging and dementia. Building upon the internationally recognized strengths of the University in the neurological, medical and social sciences, the MADRC has developed an environment that has enhanced the quality and productivity of research, generated interdisciplinary discussion and collaboration, and attracted others to join the efforts to combat neurodegenerative diseases. The MADRC has also become a regional, state and national resource for collaborative efforts to improve our understanding and treatment of Alzheimer's disease and related disorders. This application reflects the significant strides made by the MADRC. We propose to increase the number of research projects from three to six, incorporating several of the most promising projects from a much larger collection of investigations underway at the University of Michigan. These projects span the full range of inquiry needed to address neurodegenerative diseases, including clinical studies of affected persons (Projects 1 and 2), postmortem studies of neurodegenerative diseases associated with cognitive and movement disorders (Projects 2 and 4), animal models for study of pathophysiology and treatment (Project 5) and assessment of the public knowledge of and attitudes toward dementia and awareness and utilization of services for dementia in the state (Project 6). These and many other currently funded and developing projects will continue to utilize the resources provided by four established and two newly developed Cores of the MADRC. The Administrative Core integrates and coordinates the entire MADRC, critically reviews scientific projects, funds pilot projects, and manages resources; the Clinical Core identifies, characterizes and classifies patients with neurodegenerative diseases, gives clinical consultation for investigators and brings the resources of the MADRC to underserved persons in rural and urban sites; the Neuropathology Core provides postmortem diagnosis and tissue for research; the Education and Information Transfer Core generates innovative outreach and training efforts, drawing upon the Michigan Dementia Program; the Neuropsychology Core provides neuropsychological evaluation and consultation; and the Biostatistics Core supplies biostatistical consultation and central data management. Under vigorous new leadership, the MADRC plans to continue its productive and collaborative research and service activities.

This is a request for continuing support to study the density of gamma-aminobutyric acid (GABA)-A/benzodiazepine neurotransmitter receptors in the central nervous system in the neurodegenerative disease, progressive supranuclear palsy (PSP), and relate the findings to the cognitive and motor disturbances in this disease. Evidence suggests that changes in these receptors may be important in the pathophysiology of this disorder. In PSP the cognitive and movement disorders are thought to result from neuropathological changes in subcortical structures, but positron emission tomography (PET) studies with [18F]fluorodeoxyglucose (FDG) demonstrate widespread hypometabolism in the central nervous system (CNS), including the cerebral cortex. This raises the possibility that the cognitive disorders result from cerebral cortical and not subcortical pathology. The development of a ligand, [11C]flumazenil (FMZ), to study gamma-aminobutyric acid (GABA)-A/benzodiazepine (BDZ) neurotransmitter receptors with PET makes it possible to examine functional alterations localized to cortical and subcortical structures. In the studies proposed, PET scans with FMZ will be used to examine the density of BDZ neurotransmitter receptors in the cerebral cortex and subcortical structures in patients with PSP as compared with normal control subjects. The findings will be correlated with studies of local cerebral metabolic rates for glucose (LCMRG) measured with FDG and PET and with quantitative tests of cognitive, motor and speech function. Preliminary studies suggest that in PSP, FMZ binding will be decreased in the frontal regions of the cerebral cortex but normal in the parietal and occipital regions. These studies also suggest that the decrease in binding will correspond to performance on neuropsychological tasks mediated by this region of the brain.

Postmortem neuropathological studies indicate that excessive chronic intake of ethanol decreases the number of neurons in the superior frontal region of the cerebral cortex. Biochemical studies on postmortem tissue of chronically alcohol-dependent subjects suggest that GABA- A/benzodiazepine (BDZ) receptors may be decreased in the frontal cortex and hippocampus but not in other areas of the cerebral cortex. Utilizing positrons emission tomography (PET) with [11C]Flumazenil, we propose to determine whether the density of BDZ receptors is reduced within the frontal cortex in living chronically alcohol-dependent persons as compared with a group of normal control subjects with similar age and sex distributions. Using PET with [18F]fluorodeoxyglucose in the same subjects, we will examine the local cerebral metabolic rate for glucose (LCMRG) and compare the distribution of BDZ receptor binding with the pattern of LCMRG. We anticipate finding in chronically alcohol-dependent patients a decrease in the density of BDZ receptors and a decrease in LCMRG in the superior frontal region of the cerebral cortex. We will use neuropsychological tests t study frontal lobe function in the same patients, and anticipate finding that performance is diminished and correlated with the level of reduction of BDZ receptors and of LCMRG in the superior frontal cortex. Neuropathological studies also demonstrate that excessive chronic intake of ethanol decreases the number of neurons in the superior vermis of the cerebellum, even in patients who had no symptoms of cerebellar disorder in life. Biochemical studies on postmortem tissue of chronically alcohol-dependent subjects suggest that BDZ receptor binding may be decreased in the cerebellum. We propose to use [11C]flumazenil and [18F]fluorodeoxyglucose with PET to examine the density of BDZ receptors and the pattern of LCMRG in patients with clinically symptomatic alcoholic cerebellar degeneration (ACD), in chronically alcohol-dependent patients without evidence of cerebellar degeneration and in normal control subjects of similar age and sex distribution. In order to detect any biochemical changes resulting from the anatomical connections between the cerebral cortex and the cerebellum, we also propose to study patients with a chronic cerebellar degeneration (dominantly inherited olivopontocerebellar atrophy, OPCA) using the same PET probes to determine whether focal disturbances in BDZ binding and decrease LCMRG confined to the anterior superior cerebellum. We anticipate finding decreased BDZ binding and decreased LCMRG confined to and in alcohol- dependent patients without ACD, and reduced BDZ binding and decreased LCMRG widely i the cerebellum but not focally in the cerebral cortex in patients with OPCA.

This is an application for competing continuation of an ongoing project currently designed to test five hypotheses. (1) The densities of striatal of monoaminergic presynaptic terminals are markedly decreased in patients with clinically diagnosed dementia with Lewy bodies (DLB), and mildly reduced or unchanged in patients with clinically diagnosed Alzheimer's disease without extrapyramidal signals (Adw/oEPs). Positron emission tomography (PET) scanning with (+)[11C]dihydrotetrabenazine will be performed in patients meeting current clinical criteria for DLB and AD2/oEPs, and in elderly normal control subjects, with approximately the same level of dementia (clinical dementia rating scale 3 or 4) in the two patient groups. (2) In patients with clinical diagnosed DLB, the densities of striatal monoaminergic presynaptic terminals are negatively correlated with the intensity of the extrapyramidal features detected clinically. Correlations will be made between the densities of striatal monoaminergic presynaptic terminals and the intensity of the extrapyrimidal features as determined at the time of scanning with the Unified Parkinson's Disease Rating Scale by a clinician blinded to the results of the PET studies. (3) Local cerebral metabolic rates for glu8cose (lCMRglc) in the medial occipital lobes are markedly decreased in patients with clinically diagnosed DLB, and mildly reduced or unchanged in patients in patients with clinically diagnosed AD2/oEPs. PET with [18F]fluorodeoxyglucose will be performed in patients with DLB and AD2/oEPs and in the elderly normal control subjects identified in hypothesis 1, and medial occipital lCMRglc will be compared between groups. (4) In clinically diagnosed DLB, lCMRglc in the medial occipital lobes is positively correlated with the severity of visuospatial of visuoconstructive disorders. Correlations will be made between medial occipital lCMRglc and the results of neuropsychological tests of visual functioning in the DLB patients identified in hypothesis 1. (5) Measures of striatal monoaminergic presynaptic terminal density and of accuracy even further. Patients with DLB and AD2/oEPs studies in this project will be followed to postmortem examination for neuropathological diagnosis, and the accuracy of the clinical diagnostic criterial alone will be compared with the results of including measures of striatal monoaminergic presynaptic terminal density and of medial occipital lCMRglc.

genetics

[unreadable] DESCRIPTION (provided by applicant): Recent advances in structural and functional imaging and in neuropathology have revealed distinctive changes in multiple system atrophy (MSA), and now can be added to current diagnostic guidelines, which utilize clinical criteria alone. This is a proposal to plan, develop and convene a consensus conference on the diagnosis of MSA and create a new set of diagnostic criteria incorporating recent advances in imaging and neuropathology. A Steering Committee has selected the participants from a large group of internationally recognized experts in the specific manifestations of MSA. Participants were selected based upon their expertise in the diagnosis of MSA, and special efforts were made to include women and minorities. In advance of the conference, the Steering Committee will divide the participants into five groups based upon their specific expertise, appoint a chair for each group, and give each group the task of developing draft consensus guidelines from its unique perspective. The groups include neuropathology, imaging, and the parkinsonian, cerebellar and autonomic manifestations of MSA. Upon receipt of these draft guidelines, the Steering Committee will integrate them and develop a unified draft consensus document for consideration at the conference. The conference will be convened in Boston on April 26 and 27, 2007 in association with the annual meeting of the American Academy of Neurology. Utilizing consensus methodology, the participants will develop new guidelines for the clinical diagnosis of MSA based upon the draft from the Steering Committee. The results will be incorporated into abstracts for appropriate clinical meetings and a full manuscript will be developed for publication in a prominent neurological journal. MSA, Parkinson's disease and the ataxias are within the province of interest of NINDS, which funds a program project on MSA and numerous grants in the remaining areas. Three of the participants in the current proposal are investigators in the NINDS Program Project on MSA. Relevance to public health: MSA is a progressive neurodegenerative disorder that is often mistaken for Parkinson's disease. Accurate early diagnosis is important for medical therapy of many of the treatable features of MSA and for selecting subjects for clinical trials of new medications. This conference will assist with early diagnosis by developing new guidelines for diagnosis using newly available imaging and neuropathological criteria. [unreadable] [unreadable] [unreadable]

2-hydroxy-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11bH-benzo(a)quinolizine; 2-hydroxytetrabenazine; ANS Diseases; Adrenergic Agents; Adrenergic Drugs; Adrenergics; Affect; Age; Age of Onset; Anterior; Atrophic; Atrophy; Autonomic Diseases; Autonomic Nervous System Diseases; Autonomic nervous system; Autonomic nervous system disorders; Axon; Bladder Dysfunction; Blood Pressure, Low; Cardiac; Caudate Nucleus; Caudate nucleus structure; Clinical; Clinical Evaluation; Clinical Testing; Cognitive Discrimination; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive function abnormal; Color; Constipation; Contrast Sensitivity; Denervation; Deposit; Deposition; Discrimination; Discrimination (Psychology); Disease; Disease Progression; Disorder; Disturbance in cognition; Dysfunction; Elements; Evaluation; Functional disorder; Gait; Gamma Camera Imaging; Gender; Genetic; Grant; Heart; Heterogeneity; Hypokinesia; Hypotension; Hypotension, Orthostatic; Hypotension, Postural; Idiopathic Parkinson Disease; Impaired cognition; Impairment; Investigation; Investigators; Lewy Bodies; Lewy Body Parkinson Disease; Measures; Medical Imaging, Positron Emission Tomography; Medical Imaging, Single Photon Emission Computed Tomography; Michigan; Motor; Motor Manifestations; Muscle Rigidity; Muscle, Cardiac; Muscle, Heart; Myocardium; Nerve Cells; Nerve Degeneration; Nerve Transmitter Substances; Nerve Unit; Neural Cell; Neurocyte; Neuron Degeneration; Neurons; Neurotransmitters; Nucleus Caudatus; Olfaction; Olfactions; Orthostatic Hypotension; PET; PET Scan; PET imaging; PETSCAN; PETT; Paralysis Agitans; Parkinson; Parkinson Disease; Parkinson's; Parkinson's disease; Parkinsonian; Parkinsonian Condition; Parkinsonian Diseases; Parkinsonian Disorders; Parkinsonian Syndrome; Parkinsonism; Parkinsons disease; Patients; Performance; Physiopathology; Positron Emission Tomography Scan; Positron-Emission Tomography; Primary Parkinsonism; Principal Investigator; Programs (PT); Programs [Publication Type]; Progressive Supranuclear Ophthalmoplegia; Progressive Supranuclear Palsy; Prospective Studies; Proton Magnetic Resonance Spectroscopic Imaging; Putamen; REM Behavior Disorder; REM Sleep Behavior Disorder; Rad.-PET; Radionuclide Imaging; Radionuclide Tomography, Single-Photon Emission-Computed; Rapid Eye Movement Sleep Behavior Disorder; Rate; Reflex; Reflex action; Reporting; Research Personnel; Researchers; Rigidity; Rigidity, Muscular; SPECT; SPECT imaging; SUBGP; Salivation; Scanning; Scanning, Radioisotope; Scintigraphy; Score; Severities; Sight; Smell; Smell Perception; Staging; Steele-Richardson-Olszewski Disease; Steele-Richardson-Olszewski Syndrome; Structure of postganglionic sympathetic fiber; Structure of putamen; Subgroup; Supranuclear Palsy, Progressive; Survey Instrument; Surveys; Sweat; Sweating; Sympathectomy; Sympathetic Denervation; Sympathetic Fibers, Postganglionic; Symptoms; System; System, LOINC Axis 4; Testing; Tomography, Emission-Computed, Single-Photon; Tremor; Vascular Hypotensive Disorder; Vision; Visual; Visual Contrast Sensitivity; adrenergic; autonomic disorder; base; cardiac innervation; cardiac muscle; caudate nucleus; clinical test; cognitive dysfunction; cognitive loss; cognitively impaired; density; dihydrotetrabenazine; disease/disorder; heart innervation; heart muscle; innervation; loss of function; male; motor disease; motor disorder; nerve supply; neural degeneration; neurodegeneration; neuronal; neuronal degeneration; new approaches; novel; novel approaches; novel strategies; novel strategy; pathophysiology; perspiration; presynaptic; programs; putamen; radionuclide imaging/scanning; radionuclide scanning; research clinical testing; saliva secretion; salivary secretion; secretion of saliva; uptake; urinary; visual motor; visuomotor

This study of patients with multiple system atrophy (MSA) will test the following hypotheses: (1) prospective longitudinal investigation will demonstrate that the phenotypic class at onset predicts the course of the disease.;(2) postganglionic sympathetic cardiac denervation occurs with disease progression in a subgroup of patients who have rapidly progressive autonomic dysfunction irrespective of the rate of change in parkinsonian or cerebellar symptoms;and (3) owing to its ability to inhibit formation of a-synuclein fibrils and disaggregate fibrils already formed, Rifampicin will delay progression or reverse neurological and autonomic abnormalities in MSA. Prospective natural history studies of 175 patients with probable MSA in 12 different sites in the US initiated during the previous funding cycle will be continued and augmented by 100 subjects recruited at the earlier stage of possible MSA, and in equal numbers from the University of Michigan and the Mayo Medical Center sites. Regular, detailed clinical appraisals, including autonomic and neurologic function, will be augmented by postmortem examination of subjects to verify diagnosis. Post-ganglionic sympathetic cardiac innervation will be evaluated every 2 years in 20 newly recruited subjects with possible MSA and 20 normal control subjects with approximately equal distributions of age and gender. Studies will utilize clinical evaluation, [13NJNH3 and [11C]hydroxylephedrlne with positron emission tomography (PET) to evaluate cardiac perfusion and innervation. All subjects will be followed prospectively to postmortem. Projects 1 and 4 will undertake a double-blind placebo controlled clinical trial to determine whether Rifampicin will retard or reverse the progression of neurologic and autonomic disorders in MSA. Preliminary studies suggest that results will robust, as current data already indicate: (1) accurate diagnosis in 28 of 29 cases studied at autopsy;(2) clinical observations suggesting a strong association of phenotypic class with subsequent course;and (3) cardiac denervation In a substantial proportion of late-stage MSA subjects. These studies will generate novel information about the natural history of MSA and reveal methods of predicting differences in progression that need to be understood for case selection in future clinical trials.