Sex-related differences in striatal functional connectivity in early Parkinson’s disease

Abstract

Abstract A sex-specific pattern within the dopaminergic pathways may underlie the clinical divergences between male and female patients with Parkinson’s disease (PD) over the disease course. One hundred forty-seven drug-naive PD patients and 38 controls were enrolled. Anatomical and rs-fMRI images were acquired at baseline. Clinical assessments were performed at baseline and (yearly) at follow-ups for 4 years. Using connectivity-based parcellation, we obtained three ROIs for the sensorimotor, limbic, and cognitive striatal functional subregions, which were used as seeds for functional connectivity (FC) analyses. Baseline and longitudinal clinical data at 4 years were correlated with baseline imaging findings. Female PD showed reduced sensorimotor FC with the superior frontal gyrus compared with male PD patients, while no significant sex-related effects emerged for limbic or cognitive striatal seeds. Compared with controls, PD males and females showed both increased and decreased FC involving the three striatal subregions and frontal, insula, hippocampus, and cingulate areas, while voxel-based morphometry revealed no significant sex-related structural differences. Baseline FC changes in limbic and cognitive striatal circuits were associated with slower motor and cognitive progression over 4 years. Although not supported by formal interaction effects, this pattern may underlie sex-specific vulnerability, possibly reflecting different plasticity responses shaped by biological sex.