Cortical lesions at diagnosis predict long-term cognitive impairment in multiple sclerosis: A 20-year study

Background and purpose: Although cognitive impairment (CI) is frequent in multiple scle-rosis (MS) patients, few studies (and with conflicting results) have evaluated early predic-tors of CI in the long term. We aimed at determining associations between early clinical/ neuroradiological variables with reference to CI after 20 years of MS.Methods: We investigated in 170 MS patients the relationship between clinical/magnetic resonance imaging (MRI) data at diagnosis and cognitive status almost 20 years after MS onset. Among others, number and volume of both white matter lesions (WMLs) and corti-cal lesions (CLs) were evaluated at diagnosis and after 2 years. All MS patients were fol-lowed over time and underwent a comprehensive neuropsychological assessment at the end of study. Advanced statistical methods (unsupervised cluster analysis and random forest model) were conducted.Results: CI patients showed higher focal cortical pathology at diagnosis compared to cog-nitively normal subjects (p < 0.001). Volumes of both WMLs and CLs emerged as the MRI metrics most associated with long- term CI. Moreover, number of CLs (especially >= 3) was also strongly associated with long- term CI (>= 3 CLs: odds ratio [OR] = 3.7, 95% confidence interval = 1.8-7.5, p < 0.001), more than number of WMLs; the optimal cutoff of three CLs (area under the curve = 0.67, specificity = 75%, sensitivity = 55%) was estimated ac-cording to the risk of developing CI.Conclusions: These results highlight the impact of considering both white and gray mat -ter focal damage from early MS stages. Given the low predictive value of WML number and the poor clinical applicability of lesion volume estimation in the daily clinical context, the evaluation of number of CLs could represent a reliable prognostic marker of CI.