Background and Objectives:Cognitive impairment in multiple sclerosis (MS) is associated with functional connectivity abnormalities. While there have been calls to use functional connectivity measures as biomarkers there remains to be a full understanding of why they are affected in MS. In this cross-sectional study we tested the hypothesis that functional network regions may be susceptible to disease-related ‘wear-and-tear’ and that this can be observable on co-occuring abnormalities on other MR metrics. We tested whether functional connectivity abnormalities in cognitively impaired MS patients co-occur with either 1) overlapping, 2) local, or 3) distal changes in anatomical connectivity and cerebral blood flow abnormalities.Methods:Multimodal 3T MRI and assessment with the Brief Repeatable Battery of Neuropsychological tests was performed in 102 relapsing-remitting MS patients and 27 healthy controls. MS patients were classified as cognitively impaired if they scored ≥1.5 standard deviations below the control mean on ≥2 tests (n=55), or else cognitively preserved (n=47). Functional connectivity was assessed with Independent Component Analysis and dual regression of resting-state fMRI images. Cerebral blood flow maps were estimated and anatomical connectivity was assessed with anatomical connectivity mapping and fractional anisotropy of diffusion-weighted MRI. Changes in cerebral blood flow and anatomical connectivity were assessed within resting state networks that showed functional connectivity abnormalities in cognitively impaired MS patients.Results:Functional connectivity was significantly decreased in the anterior and posterior default mode networks and significantly increased in the right and left frontoparietal networks in cognitively impaired relative to cognitively preserved MS patients (TFCE-corrected at p≤0.05, two-sided). Networks showing functional abnormalities showed altered cerebral blood flow and anatomical connectivity locally and distally but not in overlapping locations.Discussion:We provide the first evidence that FC abnormalities are accompanied with local cerebral blood flow and structural connectivity abnormalities but also demonstrate that these effects do not occur in exactly the same location. Our findings suggest a possibly shared pathological mechanism for altered functional connectivity in brain networks in MS.