Cholinergic Degeneration and Cognitive Function in Early GBA1-Related Parkinson's Disease

Objective: The phenotype of patients with Parkinson's disease carrying GBA1 variants (GBA-PD) suggest similarities to symptomatology associated with early cholinergic system degeneration. Therefore, this study aims to investigate the clinical features and the cholinergic innervation pattern in patients with early GBA-PD versus those without the GBA1 mutation (non-GBA-PD). Methods: A total of 46 GBA-PD and 104 non-GBA-PD subjects were included. Clinical assessments included motor and non-motor evaluation, as well as a comprehensive neuropsychological examination. Cholinergic system integrity was assessed using 18F-Fluoroethoxybenzovesamicol (18F-FEOBV) positron emission tomography (PET) to investigate the differences between GBA-PD and non-GBA-PD. Given the higher prevalence of females in GBA-PD, analyses were repeated when stratified by sex. Additionally, we examined the association between cognitive domains and whole-brain cholinergic binding in both groups. Exploratory analyses examined clinical and 18F-FEOBV binding differences among GBA1 variants. Results: GBA-PD patients exhibited a higher burden of non-motor symptoms and lower cognitive performance on executive functions and attention. We observed a more pronounced cholinergic denervation in GBA-PD, compared to non-GBA-PD, primarily in the anterior, central, and limbic regions. However, the distribution of cholinergic loss and its association with attention and executive dysfunction was comparable between GBA-PD and non-GBA-PD. In addition, the clinical presentation and cholinergic binding differed significantly between sexes. Interpretation: These results suggest an important role of early cholinergic denervation in GBA-PD patients, which is related to more severe cognitive dysfunction. ANN NEUROL 2025;98:398–409.