Cognitive impairment is a common and disabling feature of MS, but a precise characterization of cognitive phenotypes in MS patients is still lacking.

We sought to define homogeneous cognitive phenotypes in a large cohort of multiple sclerosis (MS) patients by using a data-driven approach, and to assess their distinctive clinical and MRI features. Our aim was to go beyond traditional preserved/impaired classification dichotomy, setting the stage for future research and tailored management approaches.

Five cognitive phenotypes were identified: “preserved-cognition” (19%), “mild verbal memory/semantic fluency” (30%), “mild-multi-domain” (19%), “severe-attention/executive” (14%), and “severe-multi-domain” (18%) involvement. “Preserved cognition” and “mild-verbal memory/semantic fluency” patients were younger and had shorter disease duration compared to the other phenotypes. Physical disability was lowest in “preserved cognition” and highest in “severe-multi-domain” patients. Severe cognitive phenotypes prevailed in progressive patients. At MRI evaluation, compared to “preserved-cognition”, “mild verbal memory/semantic fluency” patients exhibited reduced hippocampal volume, “mild-multi-domain” reduced cortical gray matter volume, “severe-attention/executive” higher T2-hyperintense lesion volume and “severe-multi-domain” extensive brain damage.

By defining homogenous and clinically-meaningful phenotypes, this study can pave the way to future research on neuroanatomical substrates of MS-related cognitive impairment and help define tailored management strategies.