Modelling cholinergic and dopaminergic function over time in Parkinson’s disease with and without GBA1 variants

Abstract

Parkinson’s Disease (PD) patients carrying GBA1-variants (GBA-PD) often show a faster cognitive decline, suggesting accelerated cholinergic degeneration. This study investigated changes over time in whole-brain cholinergic innervation within the context of dopaminergic changes and clinical outcomes in GBA-PD versus non-GBA-PD. 171 PD participants (44 GBA-PD, 127 non-GBA-PD) underwent clinical and neuropsychological assessments, brain MRI, 18F-fluoroethoxy-benzovesamicol (18F-FEOBV) PET (cholinergic) and 3,4-dihydroxy-6-18F-fluoro-I-phenylalanine (18F-FDOPA) PET (dopaminergic) imaging. GBA-PD participants showed worse executive functioning than non-GBA-PD. Voxel-wise linear mixed-effects models showed that GBA-PD exhibited lower 18F-FEOBV binding in the right precentral and middle frontal gyrus, independent of age and sex, despite similar cholinergic decline over time. No GBA1-related differences were found in dopaminergic signal or its progression. Age and time since diagnosis were associated with progressive cholinergic and dopaminergic denervation in all patients. This first dual-tracer longitudinal PET study highlights early cholinergic involvement in GBA-PD and supports further evaluation of 18F-FEOBV PET as biomarker.