New Study Clarifies Gray Matter Atrophy in MS Phenotypes

Maria A. Rocca, MD

Data from a recent study published in Neurology suggest that gray matter (GM) atrophy differs across multiple sclerosis (MS) phenotypes and progresses after 1 year.

GM atrophy was found in almost all of the 26 cerebellar, subcortical, sensory, motor, and cognitive independent components (IC) identified by source-based morphometry (SBM) in patients with MS compared to control (P range <.001–.04)). Patients with clinically isolated syndromes (CIS) showed circumscribed subcortical, cerebellar, temporal and salience GM atrophy (P range <.001–.04) while patients with relapsing-remitting MS (RRMS) showed more widespread GM atrophy compared to control (P range <.001–.05). Primary-progressive MS (PPMS) showed greater cerebellar, subcortical, sensorimotor, salience and fronto-parietal GM atrophy than controls and other phenotypes (P range <.001–.02).

First author Maria A. Rocca, MD, head, neuroimaging of CNS white matter unit, Institute of Experimental Neurology, IRCCS Ospedale San Raffaele, and colleagues wrote that “although MS is traditionally considered a white matter disease, GM involvement has been recognized as a crucial determinant of clinical manifestations and prognosis. Trajectories of GM atrophy development in MS are not completely understood, and a variable number of cortical and subcortical GM structures have been shown to be affected. Previous studies substantially agree in showing that GM atrophy is clinically relevant, being useful in characterizing the main disease clinical phenotypes, and being able to explain specific disease-related symptoms, disability progression and cognitive deficits.”

Rocca and colleagues analyzed data from 398 patients with MS from 8 European sites in the MAGNIMS consortium and 170 control participants. Of the patients with MS, 34 had CIS, 226 had RRMS, 95 had secondary progressive MS (SPMS) and 43 had PPMS. At 1 year, 144 patients with MS and 57 were available for follow-up.

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Patients with SPMS showed greater GM atrophy except for the cerebellar network in comparison to RRMS (P range <.001–.04) and more GM atrophy in subcortical IC in comparison to PPMS (P <.001–.01). Patients with PPMS showed more GM atrophy in 1 sensorimotor IC in comparison to SPMS (P <.001). Disease-modifying therapy influenced GM atrophy in 2 sensorimotor ICs, with untreated patients having larger GM volume loss in SMPS versus RRMS patients (P = .02 and .04) and no other comparisons.

Baseline greater disability was associated with baseline lower normalized brain volume (NBV; R2, 0.65; beta, –0.13; P = .001), greater sensorimotor GM atrophy (beta, –0.12; P = .002) and longer disease duration (beta, 0.09; P = .04). Baseline normalized GM volume (odds ratio [OR], 0.98; P = .008) and cerebellar GM atrophy (OR, 0.40; P = .01) independently predicted clinical worsening (area under the curve, 0.83). 

At 1-year follow-up, 21 (15%) of patients had clinically worsened. GM atrophy had progressed in subcortical, cerebellar, sensorimotor, and fronto-temporo-parietal components (P range <.001–.04). This GM volume change was mainly driven by progressive MS. CIS progressed to RRMS in 2 patients and RRMS to SPMS in 3. Expanded disability status scale (EDSS) score, T2 lesion volume (T2 LV), and T1 LV did not significantly change over time. Percentage brain volume change did not differ between patients with MS and controls. 

Between clinically stable and worsened patients with MS, a statistically significant difference was seen in sex (P = .01), baseline EDSS (P = .05), T2 LV (P = .04) and percentage brain volume change (P = .02), but they did not differ in terms of age, disease duration, or T1 LV. Univariate analysis found statistically significant associations with disease worsening were found with male sex (OR, 3.2; 95% CI, 1.2–11.7; P = .02), higher T2 LV (OR, 2.5; 95% CI, 1.1–6.3; P = .03), higher T1 LV (OR, 2.7; 95% CI, 1.0–5.4; P = .04) and lower NBV (OR, 0.99; 95% CI, 0.98–1.0; P = .04).

“Despite...encouraging results, SBM has never been applied to large cohorts of MS patients including all main clinical phenotypes and follow-up evaluations. We hypothesize that the use of this technique in such a population would be useful to characterize patterns of atrophy development in the main large-scale GM networks across different disease phenotypes and their relationship with clinical disability and deterioration,” Rocca and colleagues wrote in the paper’s conclusion.

REFERENCE

Rocca MA, Valsasina P, Meani A, et al. Association of gray matter atrophy patterns with clinical phenotype and progression in Multiple Sclerosis. Neurology. Published online January 13, 2021. doi: 10.1212/WNL.0000000000011494