Unraveling the substrates of cognitive impairment in multiple sclerosis: A multiparametric structural and functional MRI study.

Background Cognitive impairment frequently affects multiple sclerosis (MS) patients. However, its neuroanatomical correlates still need to be fully explored. We investigated the contribution of structural and functional magnetic resonance imaging (MRI) abnormalities in explaining cognitive impairment in MS. Methods Brain dual-echo, diffusion tensor, 3D T1-weighted and resting-state (RS) MRI sequences were acquired from 276 MS patients and 102 healthy controls. Using random forest analysis, the contribution of regional white matter (WM) lesions, WM fractional anisotropy (FA) abnormalities, gray matter (GM) atrophy and RS functional connectivity (FC) alterations to cognitive impairment in MS patients was investigated. Results Eighty-four MS patients (30.4%) were cognitively impaired. The best MRI predictors of cognitive impairment (relative importance [%]) (out-of-bag area under the curve [AUC]=0.795) were (a) WM lesions in the right superior longitudinal fasciculus (100%), left anterior thalamic radiation (93.4%), left posterior corona radiata (78.5%), left medial lemniscus (74.2%), left inferior longitudinal fasciculus (70.4%), left optic radiation (68.7%), right middle cerebellar peduncle (60.6%) and right optic radiation (53.5%); (b) decreased FA in the splenium of the corpus callosum (64.3%), left optic radiation (61.0%), body of the corpus callosum (51.9%), and fornix (50.9%); (c) atrophy of the left precuneus (91.4%), right cerebellum crus I (84.4%), right caudate nucleus (78.6%), left thalamus (76.2%) and left supplementary motor area (59.8%). The relevance of these MRI measures in explaining cognitive impairment was confirmed in a cross-validation analysis (AUC=0.765). Conclusions Structural damage in strategic WM and GM regions more than RS FC abnormalities explains cognitive impairment in MS patients.