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.
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