Investigation of Cognitive Impairment in Parkinson Disease

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Parkinson Disease (PD) causes progressive motor and non-motor deficits with 75% of patients developing dementia after 10 years. A growing body of evidence suggests the involvement of amyloid beta (Aβ) in the cortical pathology of PD that has been linked to accumulation of α-synuclein and neurodegeneration. Yet, how regional Aβ accumulation relates to decline in specific cognitive domains and to deficits in regional neuromodulatory transmitter systems remains unknown. This study will test the hypotheses that 1) Aβ measurements made by Pittsburgh Compound B (PiB) correlate to postmortem proteinopathy. 2) deficits in selected cognitive domains (executive function, attention, visuospatial ability, and memory scores) will correlate regionally to PiB and postmortem measures of tau, Aβ, and α-syn proteinopathy; 2) PiB imaging and cognitive deficits will correspond to regional neurochemical changes in postmortem tissue; and 3) accumulated Aβ predicts deterioration in specific cognitive domains and the time to dementia. To test these questions, I will use a large, previously-recruited cohort of 287 participants with PD and controls that have undergone baseline PET imaging scans of PiB and ongoing longitudinal (baseline and 3-year follow-up) comprehensive cognitive testing. Cross-sectional analyses of PiB uptake and selected cognitive deficits will be assessed using appropriate statistical techniques with a data-drive, whole-brain, parameterized voxel-based approach to identify regions associated with PD-driven cognitive impairment. Neurochemical and pathophysiological analyses will be conducted on postmortem tissue from the 47 deceased participants with pathologically confirmed PD who had PET PiB scans in life to determine the relationship between PiB uptake and post- mortem deposition of Aβ and α-synuclein. Correlations between PiB uptake in life and changes in regional distribution of pathological protein aggregates and behaviorally-relevant neuromodulators (dopamine, serotonin, norepinephrine, and acetylcholine) will then be compared in regions associated with cognitive impairment. Whether PiB uptake can predict decline in specific cognitive domains or time to onset of dementia will be determined using baseline PiB imaging and longitudinal cognitive data. This study and my mentorship team will provide training relating to neuroimaging, neurochemistry, and behavioral manifestations of PD and analytical approaches to integrating questions of transmitter activity and cognitive output. This training will provide the basis for moving forward toward a career as an independent investigator through formal and informal professional development and laboratory management training. This study will help elucidate the relationship between cognitive dysfunction in PD and regional pathology, identifying new targets for treatment in PD. Findings from this study will inform the development of PET tracers and help identify deficits related to specific behavioral symptoms including depression, apathy, executive dysfunction, or visuospatial dysfunction.