To characterize the cognitive profile of MSA and to investigate its cerebral and cerebellar structural correlates on MRI.

This prospective, cross-sectional cohort study enrolled 102 patients with MSA and 30 healthy controls (HCs). Participants underwent brain 3D T1-weighted imaging and a neuropsychological assessment comprising the MMSE, MoCA, and a modified version of the MACFIMS battery, covering five cognitive domains: verbal memory, visual memory, executive function, visuospatial perception, and information processing speed. Voxel-based morphometry (VBM) and region-of-interest (ROI) analyses were performed on the 3D T1-weighted images. Patients were subdivided into cognitively impaired (CI) and cognitively preserved (CP) groups, and clinical and MRI parameters were compared. Multivariate regression models were fitted to examine associations between cerebellar microstructural alterations and domain-specific cognitive deficits.

The neuropsychological battery demonstrated good reliability (Cronbach's α = 0.861) and validity (Kaiser–Meyer–Olkin = 0.826; Bartlett's test, P < 0.001). Compared with HCs, MSA patients scored significantly lower on the MMSE, MoCA, and all domain-specific tests (all P < 0.001). Information processing speed was the most frequently impaired domain (65.6%), followed by verbal memory (55.6%), visual memory (47.3%), executive function (22.7%), and visuospatial perception (14.1%). Overall, 66.7% (68/102) of MSA patients were classified as CI. The CI subgroup had significantly fewer years of education than the CP subgroup (8.0 ± 2.5 vs. 11.9 ± 3.1 years, *P* < 0.001), whereas age and disease duration were comparable between the two groups. After correcting for total intracranial volume, all ROIs showed significant volume atrophy in MSA patients (all P < 0.001), with the largest effect sizes observed in the bilateral cerebellar lobule VI (left: partial η² = 0.554; right: partial η² = 0.540) and right Crus I (partial η² = 0.504), followed by the left superior parietal lobule, right lobule IV–V, right middle frontal gyrus, and left caudate nucleus.

Our findings indicate that cognitive impairment in multiple system atrophy involves multiple domains and is associated with structural alterations in the posterior cerebellar lobules and subcortical–cerebral regions. These results support the conceptualization of MSA as a disorder affecting cerebello–cerebral network circuits and highlight the potential of volumetric MRI metrics as biomarkers for monitoring cognitive decline in MSA.