Structural MRI correlates of cognitive impairment in patients with multiple sclerosis: A Multicenter Study

Abstract

In a multicenter setting, we applied voxel-based methods to different structural MR imaging modalities to define the relative contributions of focal lesions, normal-appearing white matter (NAWM), and gray matter (GM) damage and their regional distribution to cognitive deficits as well as impairment of specific cognitive domains in multiple sclerosis (MS) patients. Approval of the institutional review boards was obtained, together with written informed consent from all participants. Standardized neuropsychological assessment and conventional, diffusion tensor and volumetric brain MRI sequences were collected from 61 relapsing-remitting MS patients and 61 healthy controls (HC) from seven centers. Patients with ≥2 abnormal tests were considered cognitively impaired (CI). The distribution of focal lesions, GM and WM atrophy, and microstructural WM damage were assessed using voxel-wise approaches. A random forest analysis identified the best imaging predictors of global cognitive impairment and deficits of specific cognitive domains. Twenty-three (38%) MS patients were CI. Compared with cognitively preserved (CP), CI MS patients had GM atrophy of the left thalamus, right hippocampus and parietal regions. They also showed atrophy of several WM tracts, mainly located in posterior brain regions and widespread WM diffusivity abnormalities. WM diffusivity abnormalities in cognitive-relevant WM tracts followed by atrophy of cognitive-relevant GM regions explained global cognitive impairment. Variable patterns of NAWM and GM damage were associated with deficits in selected cognitive domains. Structural, multiparametric, voxel-wise MRI approaches are feasible in a multicenter setting. The combination of different imaging modalities is needed to assess and monitor cognitive impairment in MS.

Keywords: atrophy; cognitive impairment; diffusion tensor MRI; multicenter; multiple sclerosis; voxel-wise analysis.

Figure 1

Statistical parametric mapping (SPM) analysis showing regions of gray matter (GM) (yellow coded) and white matter (WM) (blue coded) volume loss and T2 lesion probability maps (LPMs) differences (red‐coded) superimposed on the customized GM template (P < 0.001 uncorrected; cluster extent = 5 voxels): a) GM and WM atrophy in cognitively preserved (CP) MS patients vs. healthy controls (HC); b) GM and WM atrophy in cognitively impaired (CI) MS patients vs. HC; c) GM and WM atrophy and regions with higher T2 occurrence in CI vs. CP MS patients; d) GM and WM atrophy in CI MS patients vs. both HC and CP MS patients. See text for further details. Images are in neurological convention (right side of the images is right side of the brain).

Figure 2

Statistical parametric mapping (SPM) analysis showing regions with increased mean diffusivity (MD) (blue‐coded), reduced fractional anisotropy (FA) (green‐coded) and T2 lesion probability maps (LPMs) differences (red‐coded) superimposed on the customized FA template (P < 0.05 family‐wise error corrected for multiple comparisons; cluster extent = 5 voxels): a) significantly increased MD and decreased FA in cognitively preserved (CP) MS patients versus healthy controls (HC); b) significantly increased MD and decreased FA in cognitively impaired (CI) MS patients versus HC; c) significantly increased MD and decreased FA and regions with higher T2 lesion occurrence in CI versus CP MS patients (the overlaps between diffusivity differences and T2 LPMs differences are yellow‐coded); d) significantly increased MD and decreased FA in CI MS patients versus both HC and CP MS patients. See text for further details. Images are in neurological convention (right side of the images is right side of the brain).

Figure 3

Statistical parametric mapping (SPM) analysis showing regions with gray matter (GM) (yellow coded) and white matter (WM) (blue coded) atrophy in multiple sclerosis patients significantly correlated to performance at different cognitive domains (P < 0.001 uncorrected; cluster extent = 5 voxels). Results are superimposed on the customized GM template. See text for further details. Images are in neurological convention (right side of the images is right side of the brain). WCST = Wisconsin Card Sorting Test.

Figure 4

Statistical parametric mapping (SPM) analysis showing regions with mean diffusivity (MD) (blue‐coded) and fractional anisotropy (FA) (green‐coded) being correlated to the performance at the different cognitive domains superimposed on the customized FA template in multiple sclerosis (MS) patients (P < 0.001 uncorrected; cluster extent = 5).

Figure 5

Results of the random forest analysis. Normalized variable importance, ranging from 0 (the less important) to 100 (the most important), of the five most important MRI variables in predicting global and specific cognitive scores. CI = cognitively impaired; CP = cognitively preserved; MS = multiple sclerosis; L = left; R = right; SLF = superior longitudinal fasciculus; FA = fractional anisotropy; MD = mean diffusivity; ILF = inferior longitudinal fasciculus; IFG = inferior frontal gyrus; CC = corpus callosum; MTG = middle temporal gyrus; IFOF = inferior fronto‐occipital fasciculus.