Cognitive impairment in early MS: contribution of white matter lesions, deep grey matter atrophy, and cortical atrophy

Abstract

Background Cognitive impairment (CI) is a frequent and debilitating symptom in MS. To better understand the neural bases of CI in MS, this magnetic resonance imaging (MRI) study aimed to identify and quantify related structural brain changes and to investigate their relation to each other. Methods We studied 51 patients with CI and 391 patients with cognitive preservation (CP). We analyzed three-dimensional T1-weighted and FLAIR scans at 3 Tesla. We determined mean cortical thickness as well as volumes of cortical grey matter (GM), deep GM including thalamus, cerebellar cortex, white matter, corpus callosum, and white matter lesions (WML). We also analyzed GM across the whole brain by voxel-wise and surface-based techniques. Results Mean disease duration was 5 years. Comparing MS patients with CI and CP, we found higher volumes of WML, lower volumes of deep and cortical GM structures, and lower volumes of the corpus callosum (all corrected p values < 0.05). Effect sizes were largest for WML and thalamic volume (standardized ß values 0.25 and − 0.25). By logistic regression analysis including both WML and thalamic volume, we found a significant effect only for WML volume. Inclusion of the interaction term of WML and thalamic volume increased the model fit and revealed a highly significant interaction of WML and thalamic volume. Moreover, voxel-wise and surface-based comparisons of MS patients with CI and CP showed regional atrophy of both deep and cortical GM independent of WML volume and overall disability, but effect sizes were lower. Conclusion Although several mechanisms contribute to CI already in the early stage of MS, WML seem to be the main driver with thalamic atrophy primarily intensifying this effect.

Iron Rims in Patients With Multiple Sclerosis as Neurodegenerative Marker? A 7-Tesla Magnetic Resonance Study

“…Brain atrophy results from years of chronic inflammation and axonal degeneration on top of physiological brain volume loss with age. However, it is also already found early in MS ( 74 – 77 ) but is most pronounced with disease duration ( 78 , 79 ). It is reported to correlate more closely with the clinical impairment than the T1 or T2 lesion load in the white matter and identifies patients at risk for progression ( 80 ), making it an important MRI biomarker ( 81 , 82 ).…”

Neuroimaging Correlates of Cognitive Dysfunction in Adults with Multiple Sclerosis

“…The role of white matter (WM) focal lesions as correlates of global cognitive impairment or deficit in specific cognitive functions has been widely explored in MS. Initial findings from cross-sectional studies [ 15 , 16 ] have been confirmed by longitudinal reports highlighting the role of short-term lesion load changes in predicting cognitive performance at follow-up [ 17 , 18 , 19 ], but evidence remains contradictory [ 16 ]. Although it is not possible to directly compare studies conducted with different designs in different populations, the overall emerging message is that demyelinating lesions play a minor role in comparison with atrophy and normal appearing tissue damage [ 20 , 21 ].…”

“…In particular, thalamus and other deep GM structural changes play an important role in the development of the full spectrum of cognitive impairment in MS [ 3 , 31 , 80 , 81 , 82 ], including attention-processing speed, executive function, fluency, visuo-spatial working memory and verbal memory [ 80 , 83 ]. Thalamic atrophy, induced by the interplay of local and remote pathologic processes [ 84 , 85 ], has been associated with cognitive impairment from the early stages of MS and could further enhance cognitive changes in patients with more pronounced WM lesion load [ 15 ]. During the course of the disease, the progression of cognitive changes mirrors deep GM volume changes, suggesting a direct association [ 77 ].…”

Smouldering multiple sclerosis: the ‘real MS’

“…The evolution of cognitive deterioration, which can occur from a very early stage of the disease, 130 is weakly associated with the inflammatory disease activity as measured by the accrual of new/enlarging T2w lesions. 131 , 132 By using functional MRI or DTI, it has been demonstrated that cognitive impairment is better accounted for by the subtle worsening of grey matter pathology, and by network disruption and axonal degeneration, irrespective of inflammatory changes. 133 …”