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

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.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.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.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.