A multicenter longitudinal study of cholinergic subgroups in Parkinson disease

Nicolaas I. Bohnen (), Stiven Roytman, Sygrid Zee, Giulia Carli, Fotini Michalakis, Austin Luker, Sofie Slingerland, Kirk A. Frey, Peter J. H. Scott, Robert A. Koeppe, Teus Laar, Roger L. Albin and Prabesh Kanel
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Nicolaas I. Bohnen: University of Michigan
Stiven Roytman: University of Michigan
Sygrid Zee: University of Groningen
Giulia Carli: University of Michigan
Fotini Michalakis: University of Michigan
Austin Luker: University of Michigan
Sofie Slingerland: University of Groningen
Kirk A. Frey: University of Michigan
Peter J. H. Scott: University of Michigan
Robert A. Koeppe: University of Michigan
Teus Laar: University of Groningen
Roger L. Albin: University of Michigan
Prabesh Kanel: University of Michigan

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Parkinson disease (PD) is a heterogeneous syndrome. There is a need for biology-driven subtyping to inform specific therapeutic strategies. In a two-center study with de novo and established PD cohorts, we use vesicular acetylcholine transporter ligand [18F]FEOBV brain PET to assess cholinergic systems changes in early to moderate PD. Principal component analysis (PCA) is applied to data from 245 PD subjects to define cholinergic subgroups at baseline. Three PD subgroups are identified: hypercholinergic (regional upregulation; 29%), mixed (regional upregulation and regional deficits; 40.8%) and hypocholinergic (regional deficits only; 30.2%). Evidence of upregulation is observed in the subcortical-anterior cortical regions, whereas cholinergic downregulation is found in posterior cortical regions. Cholinergic upregulation and downregulation exhibit distinct associations with clinical symptoms. Longitudinal analysis (2-3 year interval) in 128 PD subjects reveals differential progressions by subgroup. This subtyping approach expands understanding of cholinergic progression in PD and may inform identification of new therapeutic targets.

Date: 2025
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DOI: 10.1038/s41467-025-60815-0

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