Asymmetric Cholinergic Basal Forebrain Atrophy Marks Freezing of Gait in Parkinson's Disease

Freezing of gait (FoG) and falls are among the most disabling symptoms in late-stage Parkinson's disease (PD). While right-lateralised thalamic cholinergic denervation has been linked to FoG and gait impairment, it is unclear whether similar asymmetry exists within the cortically-projecting cholinergic basal forebrain (cBF), particularly the nucleus basalis of Meynert (Ch4). In this cross-sectional study, we assessed structural MRI in 136 nondemented people with PD, stratified into three groups: FoG (n = 18), fallers without FoG (n = 31) and nonfallers without FoG (n = 87). Subregional cBF volumes were quantified using volumetry, normalised by total intracranial volume and compared across groups. Mixed ANOVAs revealed significantly reduced Ch4 and Ch4p volumes in the FoG group compared to both other groups, with right-lateralised Ch4p atrophy observed specifically in FoG. After adjusting for disease severity, sex, levodopa equivalent dose (LEDD), and most affected side, the FoG group continued to show significantly reduced volumes in only the right Ch4p. A mediation model indicated that global cognitive performance (MoCA) did not significantly mediate the association between Ch4p volume and FoG status, suggesting that Ch4p degeneration may contribute to FoG through mechanisms not captured by global cognition alone. Overall, the findings support a right-hemisphere cholinergic vulnerability in FoG, implicating Ch4p degeneration in networks relevant to both gait regulation and attentional-visuospatial function. Future longitudinal studies are needed to determine whether this lateralised structural vulnerability predicts progression to FoG or cognitive decline in PD.