To investigate the interaction between cognitive reserve (CR), atrophy of frontal gray matter (GM) areas and microstructural abnormalities of frontal white matter (WM) tracts and their associations with executive functioning (EF) in multiple sclerosis (MS) patients.

Ninety-three MS patients and 27 matched healthy controls (HC) underwent brain 3.0 T MRI scans. Frontal gyri GM volumes, lesional volume, fractional anisotropy (FA), mean diffusivity, intracellular volume fraction and orientation dispersion index (ODI) of frontal WM tracts were estimated. Cognitive reserve index (CRI), Wisconsin Card Sorting Test (WCST) and Word List Generation (WLG) of the Rao’s battery were assessed. Structural MRI measures and CRI interaction on cognitive performance were explored with linear models.

Compared to HC, MS patients showed significant GM atrophy and microstructural abnormalities in the majority of regions investigated (p≤0.046) and significant worse performances in categories and total errors of WCST and WLG (p≤0.034). In MS, higher CRI was correlated with better WLG performance, WCST-categories, frontal gyri volumes and diffusivity measures of frontal WM tracts (r from -0.212 to 0.455; p from 0.001 to 0.046). The combination of demographic, clinical, and measures of frontal lobe structural damage significantly explained EF (WLG: R²=0.44; p=0.022; WCST categories: R²=0.33; p=0.010). Higher CRI explained a further portion of variance in WLG (WLG: R²=0.50; p=0.002; ?R²=0.07; p=0.003).

In MS, CRI is associated with higher GM volumes of frontal gyri and higher microstructural integrity of frontal WM tracts. CRI may have a protective role in preserving semantic verbal fluency and cognitive flexibility, possibly moderating the impact of structural damage of the frontal lobe on cognitive performance.