Sex-related differences in clinical and neuroimaging features have been described in MS. Advanced MRI techniques may better investigate possible sex-associated differences in structural damage extent and their relations with cognitive impairment.

Brain 3.0 T MRI scans were acquired from 287 PwMS (women=173) and 172 HC (women=92). PwMS underwent Rao’s battery. Voxel-wise analyses were used to investigate sex differences in regional GM volumes (p<0.001, uncorrected) and fractional anisotropy (FA) abnormalities (p<0.05, FWE) between PwMS and HC and their associations with cognitive performances.

In HC and PwMS, females vs males, showed a significant GM atrophy in several fronto-temporo-parietal regions, with larger effects of MS in males in the left cingulate cortex and right precuneus. The majority of WM tracts showed a significantly higher FA in female vs male HC and in male vs female PwMS with a larger effect of MS in females in most of the WM tracts. Verbal memory was significantly worse in male vs female PwMS (p=0.001), whereas verbal fluency was worse in female vs male PwMS (p=0.001). Cognitive performance was positively associated with GM volumes and FA in most of brain regions. Female vs male PwMS showed stronger associations between global cognitive performances and bilateral middle frontal gyrus and left calcarine cortex volumes and FA in several WM tracts. Male PwMS showed stronger associations between global cognitive performances and right temporal pole, lingual gyrus and parahippocampal gyrus volumes, and between verbal fluency and FA in several WM tracts.