Lesion accumulation is predictive of long-term cognitive decline in multiple sclerosis

Objective: To investigate the long-term progression of cognitive dysfunction and its neuroanatomical correlates and predictors in multiple sclerosis (MS). Methods: A cohort of 37 MS patients reflecting five decades of disease duration and all subtypes was followed over 17.5 years. Matched controls were recruited at the last follow-up. Global cognitive functioning was assessed using a principal component cognitive index based on comprehensive neuropsychological testing. During the last 8.5 years of the study, brain MRI was performed to analyze normalized volumetrics of three global tissue compartments (white and gray matter, lesions) and strategic regions (corpus callosum, thalamus, hippocampus). Results: Cognitive decline progressed continuously throughout the study paralleled by atrophy and lesion accumulation. The cognitive index partly correlated with Expanded Disability Status Scale (p = -0.47, p < 0.001) and was mainly associated with the lesion fraction (beta = -0.48, p < 0.001) and callosal fraction (beta = 0.39, p = 0.002) in multiple linear regression analysis. The lesion fraction was an independent predictor of the cognitive performance 8.5 years later (beta = -0.35, p = 0.008). Symbol Digit Modalities Test was most frequently abnormal (40%), while Rey-Osterrieth Complex Figure Test was more sensitive to detect cognitive decline. Conclusions: Cognitive impairment progresses continuously in MS, associated with atrophy and lesion accumulation, suggesting that interventions targeting these processes could be beneficial at all disease stages. Widespread cognitive functions are more profoundly affected, associated with lesions and corpus callosal atrophy, supporting the idea of an underlying disconnection mechanism for cognitive decline in MS.