MONOAMINERGIC PATHWAYS IN NEURODEGENERATIVE DISEASES

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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.