Over the past several years, the Principal Investigator and his colleagues have developed a non-human model primarily for studying cognitive deficits associated with Parkinson's disease, a common disease of aging. They found that chronic-low-dose (CLD) 1-methyl-4-phenyl-1,2,3,6-tetrahydropridine (MPTP) treatment to monkeys over many months produces a behavioral syndrome characterized primarily by fronto-striatal cognitive deficits and that continued MPTP exposure leads to Parkinson-like motor impairments. They established that the CLD MPTP monkey provides an excellent means for studying the characteristics of cognitive and motor decline associated with parkinsonism and allows the study of mechanistic issues not possible in human clinical studies. In this application, the Investigator proposes to track the progression of, and examine the relationship between, cognitive, and motor decline at different stages of the CLD MPTP syndrome and determine the relative responsiveness of cognitive and motor deficits to specific pharmacological manipulations during different clinical stages of parkinsonism. He hypothesizes that progression of cognitive and motor deficits will follow a relatively predictable pattern initially dominated by fronto-striatal cognitive impairments and later by a combination of these deficits plus motor impairments. He hypothesizes, further, that new cognitive domains may not be affected as motor disability progresses. In this research plan, the Investigator proposes a longitudinal study of performance on well-established tests of cognitive and motor function. He and his colleagues will characterize further the nature of the cognitive deficits in CLD MPTP-treated monkeys by examining the extent to which these deficits will be related to attentional impairments and increased distractability. If attentional deficits exist, the researchers will examine the extent to which they can be reversed pharmacologically. Last, the researchers will assess the neuroanatomical and neurochemical substrates of cognitive and motor deficits associated with different stages of parkinsonism. They will use immunohistochemical and in situ hybridization techniques, together with state-of-the-art image analysis methods, to examine the extent to which different functional degrees of dopamine denervation affect the prefrontal cortex and different functional striatal territories, and the extent to which striatal and downstream peptide levels and expression are influenced by these functionally different dopaminergic lesions.
