Objective: Cognitive decline in Parkinson disease (PD) is a disabling and highly variable nonmotor feature. While cholinergic systems degeneration is linked to cognitive impairments in PD, most prior research reported cross-sectional associations. We aimed to fill this gap by investigating whether baseline regional cerebral vesicular acetylcholine transporter ligand [18F]- fluoroethoxybenzovesamicol ([18F]-FEOBV) binding predicts longitudinal cognitive changes in mild to moderate, non-demented PD subjects. Methods: Seventy-five non-demented, mild-moderate PD subjects received baseline standardized cognitive evaluations and [18F]-FEOBV PET imaging with repeat cognitive evaluations 2 years later. Participants were classified into four cognitive classes based on stability or change in cognition: Persistent normal (no MCI at baseline and follow-up), Persistent MCI, MCI conversion, and MCI reversion. Whole-brain voxel comparisons with normal controls, and voxel-based and cluster volume-of-interest correlation analyses with longitudinal cognitive changes were performed. Results: Whole-brain voxel comparisons of each class with a matched control group revealed unique bi-directional differences in baseline regional [18F]-FEOBV binding. Increased regional [18F]-FEOBV binding in predominantly anterior cortical and sub-cortical regions was found in the persistent normal and MCI reversion groups. Whole-brain voxel correlation analysis between baseline [18F]-FEOBV binding and two-year longitudinal percent changes in cognition identified a specific regional pattern of reduced posterior cortical, limbic and paralimbic [18F]-FEOBV binding predictive of global cognitive declines and across five cognitive domains at two-year follow-ups. Interpretation: Cholinergic system changes correlate with varying cognitive trajectories in mild-moderate PD. Upregulation of cholinergic neurotransmission may be an important compensatory process in mild-moderate PD.

Roger Albin serves on the Data Safety and Monitoring Boards for the CELIA, SIGNAL-AD, TOPAS-MSA, and Zilgenersen trials. The other authors report no competing interests.

This study was funded by the National Institutes of Health, the Department of Veterans Affairs, and the Parkinsons Foundation.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The IRBs of the University of Michigan and the VA Ann Arbor Health System gave ethical approvals for this work.

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All data produced in the present study are available upon reasonable request to the authors.