NEUROCHEMICAL /SLEEP DISORDERS /MULTIPLE SYSTEM ATROPHY

$0P01FY2002NSNIH

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

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Abstract

This project will explore the neurochemical basis of rapid eye movement sleep (REM) behavior disorder (RBD) in multiple atrophy (MSA), including cases with predominantly cerebellar (MSA-C) and with predominantly parkinsonian features (MSA-P), The unifying concept is that RBD results from the direct results of decreased pedunculopontine (PPN) and a laterodorsal tegmental (LTD) cholinergic innervation of the brainstem reticular formation and thalamus and, to a lesser extent, from the indirect effects of decreased nigrostriatal monoaminergic innervation. Three specific hypotheses will be tested: (1) PPN/LTD cholinergic innervation is decreased in MSA-P and MSA-C patients as compared with normal control subjects. The decreased monoaminergic innervation is greater in MSA-P than in MSA-C patients (2) MSA-C and MSA-P patients with RBD have greater deficits of PPN/LTD cholinergic innervation than MSA-C and MSA-P patients, respectively, without RBD. MSA-C and MSA-P patients with RBD have no difference in nigrostriatal monoaminergic innervation as compared to MSA-C and MSA-P patients, respectively, without RBD. (3) In MSA-P and MSA-C patients who have RBD, the intensity of REM sleep abnormalities is negatively correlated with the degree of PPN/LTD cholinergic, and non correlated with the degree of nigrostriatal monoaminergic innervation. To test these hypotheses, nocturnal, laboratory-based polysomnography will be performed in normal controls and in patients who meet current diagnostic criteria for MSA-C and MSA-P, with similar ages and genders between groups. RBD will be quantified with measurements of the percentage of REM sleep that shows phasic EMG bursts. Positron emission tomography with (+)-[11C]dihydrotetrabenazine will be used to measure the density of striatal monoaminergic terminals and single photon emission computed tomography with (-)-5- [123i]iodobenzovesamicol will be used to measure the density of striatal monoaminergic terminals and single photon emission computer tomography with (-)-5-[123I)iodobenzovesamicol will be used to measure the density of thalamic cholinergic terminals. The data analysis will include comparisons of ligand binding across patient groups and normal controls, comparisons of RBD across subject groups, and correlations of ligand binding with RBD.

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