NEUROBEHAVIOR NEUROCHEMISTRY AND NEUROPATHOLOGY OF OPCA

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The LONG-TERM GOAL of our proposal is to understand both the physiologic and etiological bases of the neurobehavioural changes of patients with dominantly-inherited olivopontocerebellar atrophy (OPCA), a cerebellar ataxia disorder. This will be accomplished through neurobehavioural and brain neurochemical and neuropathological examination of 30 patients from five U.S. OPCA families. The four specific aims of our interdisciplinary study are the following: 1) to understand in OPCA the role of the brain cholinergic system and the,cerebellum in the cognitive deficits typical of patients with frontal lobe damage; 2) to provide a biochemical explanation for the excitatory amino acid and phospholipid metabolite changes in OPCA brain; 3) to investigate the possibility of a "dying-back" phenomenon involving the OPCA nigrostriatal dopamine neurone; and 4) to improve the quality of life of our OPCA patients through dysphagia intervention. The SPECIAL FEATURES of our proposal include the unique ability of the applicants to follow prospectively and carefully patients from five U.S. OPCA families with annual neurobehavioural assessment until autopsy, and the demonstrated expertise of each of the applicants in the relevant neurobehavioural assessment, dysphagia intervention, and human brain neurochemical and neuropathological techniques. We suggest that the information to be obtained is important in its own right for characterizing aspects of a disorder which have been relatively neglected by the scientific community and, more generally, is likely to lead to new brain-behavioural correlations relevant to our understanding of both normal and abnormal brain functioning.