Structural MRI correlates of cognitive impairment in patients with multiple sclerosis

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.

Hippocampal and Deep Gray Matter Nuclei Atrophy Is Relevant for Explaining Cognitive Impairment in MS: A Multicenter Study

“…This finding confirms a previous voxelwise investigation of the same cohort, 16 which showed that hippocampal atrophy was among the best MR imaging variables discriminating patients with MS who were CI from those who were CP. The thalamus, hippocampus, and striatal structures represent convergence points across multiple cortical, limbic, brain stem, and cerebellar systems and have a key role for efficient information processing.…”

“…In line with previous studies, we found significantly reduced cortical, hippocampal, and deep GM volumes in patients with MS who were CI compared with CP. Reduced neocortical volume 2,3,7,9 and a widespread pattern of regional GM atrophy 15,16,29 have been frequently associated with cognitive impairment in MS, as also shown by a previous investigation of the same patient cohort. 16 GM pathology is known to be substantially present in MS from the earliest stages of the disease and is strongly associated with CI not only in cross-sectional but also in longitudinal studies.…”

“…Reduced neocortical volume 2,3,7,9 and a widespread pattern of regional GM atrophy 15,16,29 have been frequently associated with cognitive impairment in MS, as also shown by a previous investigation of the same patient cohort. 16 GM pathology is known to be substantially present in MS from the earliest stages of the disease and is strongly associated with CI not only in cross-sectional but also in longitudinal studies. 30 GM pathology has traditionally been thought to occur secondary to injury from focal WM lesions (so-called Wallerian degeneration), but recent studies have convincingly shown that cortical inflammatory pathology from subpial demyelination also plays a critical role.…”

“…This result is in line with several previous studies, 2,3,9 including a previous voxelwise investigation of the same cohort. 16 This similarity suggests that the findings hold across a wide spectrum of the MS population. Moreover, because normalized cortical GM volume and normalized volume of deep GM nuclei predict cognitive deterioration with time, 27,37 they might be used as reliable outcome measures in multicenter observational or treatment studies of cognitive impairment in MS. Our study has limitations.…”

Hippocampal neuroplasticity and inflammation: relevance for multiple sclerosis

“…This synaptic pauperization could contribute to cognitive dysfunction [16]. During last years, neuroimaging studies showed that hippocampal atrophy is associated with memory dysfunction and depression [18,29,89]. In particular, a recent multicentre study used several structural MRI modalities to assess how the involvement of different brain regions links to the specific cognitive deficit suffered by the patient [89].…”