The central hypothesis of this work is that radiolabeled enzyme markers of presynaptic dopaminergic function used with positron emission tomography (PET) are not linear indicators of nigrostriatal cell losses. It is expected that axonal sprouting with synapses would respond quickly to early signs of nigrostriatal dopaminergic degeneration as part of the compensatory mechanisms at play to maintain functional activity. If so, substantial changes in aromatic amino acid decarboxylase (AAAD) activities and dopamine reuptake sites are not expected to occur during this adjustment period and, therefore, the AAAD-dependent kinetics and dopamine reuptake ligand binding will not be sensitive to these initial changes. To test this hypothesis, we will use the MPTP-monkey-model of Parkinson's disease (both symptomatic and asymptomatic) to correlate in a controlled environment the graded effects of nigrostriatal cell loss on presynaptic function with the biochemistry and central kinetics of the radiolabeled probes. We will focus our in on the initial stages of cell degeneration, with the aim of providing probes that will detect vestigation neurochemical deficiencies preceding clinical symptoms. We will combine the unique expertise and resources of two leading centers in the world, namely the Parkinson's Institute (Dr. W. Langston, ector) in I methyl-4- phenyl- I ,2,3,6 tetrahydropyridine (MPTP)-exposure to non-humans primates and humans, and UCLA, in functional imaging with positron emission tomography. With a """"""""gold standard"""""""" provide-by concomitant cytological and neurochemical information, in-vivo PET data will be correlated with the functional integrity of the dopaminergic system. If this work is successful, we will have developed new in-vivo approaches to: 1) unveil otherwise undetected, early signs of nigrostriatal cell degeneration; 2) trace striatal AAAD activity allowing for evaluation of specific pharmacological interactions (e.g., methamphetamine) and the effects of cell degeneration. The combination of dopamine enzyme probes and, net dopamine re-uptake ligands (""""""""cocaine receptor"""""""" ligands), will provide the necessary tools and contribute to the logic necessary for the non-invasive evaluation of the functional activity of central dopaminergic mechanisms in health disease states.
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