Evolution of Cortical Lesions and Function-Specific Cognitive Decline in People With Multiple Sclerosis

Background and Objectives Cortical lesions in multiple sclerosis (MS) severely affect cognition, but their longitudinal evolution and impact on specific cognitive functions remain understudied. This study investigates the evolution of function-specific cognitive functioning over 10 years in people with MS and assesses the influence of cortical lesion load and formation on these trajectories. Methods In this prospectively collected study, people with MS underwent 3T MRI (T1 and fluid-attenuated inversion recovery) at 3 study visits between 2008 and 2022. Cognitive functioning was evaluated based on neuropsychological assessment reflecting 7 cognitive functions: attention; executive functioning (EF); information processing speed (IPS); verbal fluency; and verbal, visuospatial, and working memory. Cortical lesions were manually identified on artificial intelligence–generated double-inversion recovery images. Linear mixed models were constructed to assess the temporal evolution between cortical lesion load and function-specific cognitive decline. In addition, analyses were stratified by MS disease stage: early and late relapsing-remitting MS (cutoff disease duration at 15 years) and progressive MS. Results The study included 223 people with MS (mean age, 47.8 ± 11.1 years; 153 women) and 62 healthy controls. All completed 5-year follow-up, and 37 healthy controls and 94 with MS completed 10-year follow-up. At baseline, people with MS exhibited worse functioning of IPS and working memory. Over 10 years, cognitive decline was most severe in attention, verbal memory, and EF. At baseline, people with MS had a median cortical lesion count of 7 (range 0–73), which was related to subsequent decline in attention (B[95% CI] = −0.22 [−0.40 to −0.03]) and verbal fluency (B[95% CI] = −0.23[−0.37 to −0.09]). Over time, cortical lesions increased by a median count of 4 (range −2 to 71), particularly in late and progressive disease, and was related to decline in verbal fluency (B [95% CI] = −0.33 [−0.51 to −0.15]). The associations between (change in) cortical lesion load and cognitive decline were not modified by MS disease stage. Discussion Cognition worsened over 10 years, particularly affecting attention, verbal memory, and EF, while preexisting impairments were worst in other functions such as IPS. Worse baseline cognitive functioning was related to baseline cortical lesions, whereas baseline cortical lesions and cortical lesion formation were related to cognitive decline in functions less affected at baseline. Accumulating cortical damage leads to spreading of cognitive impairments toward additional functions.