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

## TL;DR

People with Parkinson's disease who experience freezing of gait have reduced volume in a specific brain region, suggesting a link between this structural change and the symptom.

## Contribution

The study identifies a right-lateralized cholinergic basal forebrain atrophy specifically associated with freezing of gait in Parkinson's disease.

## Key findings

- FoG patients showed significantly reduced Ch4p volume in the right hemisphere compared to non-FoG groups.
- The association between Ch4p volume and FoG was not explained by global cognitive performance.
- Right Ch4p degeneration may indicate a structural vulnerability linked to gait and attentional functions.

## Abstract

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.

Participants with freezing of gait (FoG) showed selectively reduced cholinergic basal forebrain volume in the right Ch4p subregion, even after accounting for disease severity, sex, levodopa equivalent dose and most affected side. This association between Ch4p volume and FoG status was not mediated by global cognitive performance (MoCA score). These findings support a right‐hemisphere cholinergic vulnerability in FoG and suggest that longitudinal studies should assess Ch4p degeneration as an early prognostic marker of future FoG.