Gray-Matter Atrophy Progresses Swiftly In MS Patients

By Steve Cimino


Gray-matter atrophy was found in almost all the brain networks of patients with multiple sclerosis (MS), yet varies across phenotypes, a multicenter European study has confirmed, with atrophy in certain areas predicting disability and clinical worsening.

“Although MS is traditionally considered a white-matter disease, gray-matter involvement has been recognized as a crucial determinant of clinical manifestations and prognosis,” wrote Maria A. Rocca, MD, of the neuroimaging research unit at the IRCCS San Raffaele Scientific Institute in Milan. The study was published online Jan. 13, 2021, in Neurology.

To measure gray-matter atrophy and its impact on MS progression and disease activity, the researchers launched a study of 568 patients from eight centers across Europe. Approximately 60% were women, and the MS patients had a mean disease duration of just over 14 years. All participants – 398 patients with MS and 170 healthy controls – underwent MRI and clinical screening at baseline, including calculating their Expanded Disability Status Scale (EDSS) score; 144 and 57, respectively. The study participants were assessed again after 1 year.

Of the 398 MS patients, 226 had relapsing remitting MS, 95 had secondary progressive, 43 had primary progressive, and 34 had clinically isolated syndromes (CIS). Through source-based morphometry, which had never before been applied to MS patients on a large scale, 26 distinct gray-matter components were identified, including 4 cerebellar networks, 3 subcortical,
4 sensorimotor, 2 visual, and 2 auditory.

Compared with healthy controls at baseline, MS patients experienced significant gray-matter atrophy in nearly all components (P between 0.001 and 0.036) excepting one in the frontoparietal network and one in the default mode, confirming the “strong neurogenerative component in MS leading to irreversible tissue loss.” CIS patients displayed circumscribed atrophy in several cerebellar, subcortical, and auditory components, compared with controls
(P between .001 and .04), as did relapsing remitting MS patients with widespread atrophy in most components (P between .001 and .05) and primary progressive MS patients with pinpointed atrophy in the cerebellar, subcortical, sensorimotor, visual, auditory, frontoparietal, default mode, and salience components
(P between .001 and .02).

At 1-year follow-up, while gray-matter volume remained stable among the healthy controls, atrophy progressed noticeably in five components of the MS patients, including cerebellar, subcortical, sensorimotor, auditory, and frontoparietal networks (P between .001 and .04). This was largely because of the patients with progressive MS, who saw significant decreases in gray-matter volume in the cerebellar, sensorimotor, auditory, frontoparietal, and salience networks. CIS patients had significant atrophy in the cerebellar (P = .02) network, and both CIS (P between .02 and .04) and relapsing remitting MS (P = .03) patients saw notable atrophy in the sensorimotor network.

Top image credit: Jessica Wilson / Science Source
Image credit: Living Art Enterprises / Science Source


Both clinically worsened patients – as 21 participants in the MS group were classified because of an increased EDSS score – and stable patients showed surprisingly similar patterns of gray-matter atrophy at follow-up, including significant decreases in cerebellar, sensorimotor, and auditory networks. The researchers offered several potential explanations, most notably that a year may not be long enough to detect clinically relevant discrepancies.

“Further studies with longer follow-up are needed to better assess possible differences between these two groups,” they wrote.

After univariate analyses, a higher EDSS score at baseline was significantly associated with gray-matter atrophy in primarily the subcortical, sensorimotor, cerebellar, frontoparietal and salience networks (beta. –0.07/–0.17; P between .001 and .03). Multivariate analyses also associated a higher EDSS score with increased atrophy in the sensorimotor network
(beta, –0.12; P = .002) and longer disease duration (beta, 0.09; P = .04). After univariate logistic regression analysis, lower gray-matter volume in the cerebellar network was significantly associated with disability worsening (odds ratio, 0.47; 95% confidence interval, 0.24-0.99, P = .02).




credit: Simon Fraser/ SPL / Science Source


The authors acknowledged their study’s potential limitations, including the small number of primary progressive MS and CIS patients overall – likely because of their “smaller prevalence in the general MS population” – and the limited number of progressive MS patients who completed the 1-year follow-up. In addition, the MS patients were older than the controls – aged just under 47 years, compared with 40 years – which could have played a part in augmenting the differences in gray-matter volume between groups.

The study was supported by the German Federal Ministry of Education and Research and the German Competence Network Multiple Sclerosis. The authors reported numerous potential conflicts of interest, including receiving speaker honoraria, grants, research support, and personal fees from various organizations, pharmaceutical companies, and governmental bodies.