The experiments proposed in this project will examine the neurochemistry of the extrapyramidal motor system in patients with idiopathic Parkinson's disease and with essential tremor, for comparison with age-similar normal subjects. We will determine the relationships between clinical measures of parkinsonian severity and the degree of presynaptic dopaminergic dysfunction in the striatum, as revealed by positron emission tomographic imaging of (11C]dihydrotetrabenazine binding to presynaptic monoaminergic vesicles. We hypothesize, on the basis of our recent studies in experimental animals, that the vesicular binding sites are less prone to disease-compensatory and drug-induced regulation than are alternative image-based measures of dopamine terminals. We will investigate dihydrotetrabenazine binding as a quantitative index of dopaminergic synaptic integrity. First, we will examine the relationship between striatal dopaminergic terminal density and the severity of parkinsonian symptoms in cross-sectional studies. We will also conduct longitudinal studies to characterize the progressive loss of dopamine terminals within individual patients. A second aspect of the project will examine benzodiazepine receptors in the cerebellar cortex as a potential substrate for the expression of essential tremor. Our recent findings document an age-associated increase in cerebellar benzodiazepine binding sites, and suggest further increase (adjusted for age effect) in essential tremor. We will characterize both striatal dopaminergic innervation as well as cerebellar benzodiazepine receptors in essential tremor and mild Parkinson's disease, providing neurochemical data for comparison with clinical features. Further, we will evaluate the possibility of intrinsic striatal neurochemical change (trans-synaptic reorganization) in the striatum of patients with advanced Parkinson's disease with the use of a positron- emitting ligand for the muscarinic cholinergic receptor. We will compare muscarinic receptor density in parkinsonian patients across a spectrum of severity, with particular emphasis on those patients with complex levodopa responses (prominent dyskinesias, """"""""on/off""""""""', or """"""""wearing-off"""""""" fluctuations), to determine whether these features are associated with progression of dopaminergic denervation alone, or whether secondary intrinsic striatal changes are present. In the latter instance, alternative symptomatic interventions, including possible cholinergic therapies, may be expected to benefit patients.
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