A multicenter longitudinal study of cholinergic subgroups in Parkinson disease

• Published in: Nature communications Vol. 16; no. 1; pp. 5655 - 14
• Main Authors: Bohnen, Nicolaas I., Roytman, Stiven, van der Zee, Sygrid, Carli, Giulia, Michalakis, Fotini, Luker, Austin, Slingerland, Sofie, Frey, Kirk A., Scott, Peter J. H., Koeppe, Robert A., van Laar, Teus, Albin, Roger L., Kanel, Prabesh
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 59/57; 59/78; 631/378/2587; 692/699/375/1718; Acetylcholine - metabolism; Aged; Biology; Brain - diagnostic imaging; Brain - metabolism; Cholinergic transmission; Cholinergics; Cognition & reasoning; Denervation; Disease Progression; Down-regulation; Female; Gait; Humanities and Social Sciences; Humans; Longitudinal Studies; Male; Middle Aged; Movement disorders; multidisciplinary; Neurodegenerative diseases; Parkinson Disease - classification; Parkinson Disease - diagnostic imaging; Parkinson Disease - metabolism; Parkinson's disease; Positron-Emission Tomography; Principal Component Analysis; Principal components analysis; Regions; Science; Science (multidisciplinary); Subgroups; Therapeutic targets; Up-regulation; Variables; Vesicular Acetylcholine Transport Proteins - metabolism; Vesicular acetylcholine transporter; United States > US; Michigan
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-60815-0

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 [ 18 F]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. In a two-center longitudinal study, the authors present evidence in support of cholinergic system subgroups in Parkinson’s disease (PD), which exhibit both downregulation and upregulation of signaling. Subgroup-specific cholinergic changes associated with clinical PD features.