Unraveling neurotransmitter changes in de novo GBA-related and idiopathic Parkinson's disease.

Background: Presently, neurotransmitter deficits in GBA-related Parkinson's disease (GBA-PD) and relationships with cognitive impairment are poorly understood. A better understanding of neurotransmitter impairments in GBA-PD - particularly in the newly diagnosed drug-naïve phase - may support developing targeted intervention strategies. We aimed to investigate patterns of neurotransmitter deficits in GBA-PD and idiopathic PD (iPD) and cognitive performance correlations.

Methods: We recruited 189 newly diagnosed PD patients for GBA sequencing. Voxel-wise gray matter volume (GMV) was evaluated in a subgroup of 17 GBA-PD, 100 iPD, and 32 age- and sex-matched healthy controls (HCs). The JuSpace toolbox covering various neurotransmitter maps helped assess whether the spatial patterns of GMV alterations in GBA-PD or iPD patients (relative to HCs) were associated with specific neurotransmitter systems.

Results: GBA-PD patients indicated widespread GM atrophy in the fronto-temporal-occipital region compared with HCs. GMV atrophy was spatially correlated in GBA-PD and iPD with serotonergic, dopaminergic, and acetylcholinergic pathway distributions (p < 0.05, false discovery rate corrected). Executive function and language in cognitive domains were also associated with the strength of GMV colocalization of serotonergic, dopaminergic, and acetylcholinergic circuits.

Conclusions: Regional GM atrophy related to specific neurotransmitter deficits in de novo GBA-PD and iPD patients could provide new insights into pathophysiological processes, facilitating potential therapeutic targets to support PD management.