PET Study of Biochemistry and Metabolism of the CNS

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This Program Project focuses on in vivo neurochemistry of human neurological disorders, emphasizing subcortical structures and their interactions in neurodegenerative and idiopathic functional disorders of movement. Studies in the proposal combine neurochemical phenotypes with functional measures, the latter including motor performance, blood flow activation, neurotransmitter release, ans aspects of sleep physiology. The Program consists of 4 Scientific Projects and 3 Cores. Project by Kilbourn, "New Radiotracers for Neurological PET", will introduce a novel functional approach to assessment of GABAA receptors through allosteric ligands of the chloride ionophore. GABAergic projects are critical components of striatal output and other extrapyrimidal sites. Assessment of GABAA function will complement glucose metabolism studies that may preferentially reflect excitatory glutamatergic pathways. Project by Frey, "Striatal Dopamine and Motor Performance in Aging and Parkinson's Disease" will determine functional motor correlates of nigrostriatal dopaminergic losses in aging and Parkinson's disease and will assess their reversal by acute dopaminergic challenge. Project by Gilman, "Neurochemical and Sleep Disorders in Multiple System Atrophy", will assess the relationships between disrupted sleep in extrapyrimidal neurodegeneration and brain stem cholinergic projections. Project by Albin, "Dopamine Synaptic Mechanisms in Tourette Syndrome", will assess striatal dopaminergic projects and their function from a multi-faceted approach, including measures of their density, their capacity for dopamine re-uptake, their capacity for dopamine release, and an assessment of ambient synaptic dopamine occupancy of D2-type dopamine receptors. Cyclotron/Radiochemistry, Tomography and Data Analysis, and Administrative Core functions support each Project. Overall , the disorders under study in this Program are of unknown pathogenesis and have only symptomatic therapies. The proposed studies will lead to enhanced insight into extrapyrimidal neurochemistry and will address important aspects of dysfunction and disability in these disorders. Novel and improved therapies and new pathophysiological mechanisms and insight may ultimately result.