Cerebellar Atrophy Modulates Freezing of Gait in Multiple System Atrophy Through Cognitive Dysfunction

Cerebellar atrophy is a prevalent condition in multiple system atrophy (MSA) associated with cognitive impairment; however, whether this cognitive dysfunction contributes to freezing of gait (FOG) in affected patients remains unclear.

To investigate whether cognitive deficits mediate the relationship between cerebellar atrophy and FOG in patients with MSA.

Cognitive function was assessed in 106 patients with MSA: 58 with FOG (MSA-FOG) and 48 without FOG (MSA-nFOG) using standardized neuropsychological tests. Structural T1-weighted MRI scans were processed using FreeSurfer and the Spatially Unbiased Infratentorial toolbox (SUIT) for cerebellar lobule segmentation. Multivariate linear regression and mediation analyses were conducted to examine associations among cerebellar lobular volumes, cognitive domains, and New Freezing of Gait Questionnaire (N-FOGQ) scores.

Patients with MSA-FOG exhibited deficits in executive function, visuospatial ability, attention, working memory, language, and delayed recall, alongside significant atrophy in global cerebellar gray matter and lobules I-X. Regression analyses revealed that Crus II atrophy independently predicted higher N-FOGQ scores, alongside deficits in executive function and attention, with impairments in these two cognitive domains mediating the association between Crus II volume reduction and FOG severity.

Reduced Crus II volume may be associated with severity of FOG through impaired executive function/attention; thus, cerebellar atrophy may serve as a potential biomarker for FOG in patients with MSA.