The Effect of Dimethyl Fumarate on Cerebral Gray Matter Atrophy in Multiple Sclerosis

Abstract

Introduction: The objective of this pilot study was to compare cerebral gray matter (GM) atrophy over 1 year in patients starting dimethyl fumarate (DMF) for multiple sclerosis (MS) to that of patients on no disease-modifying treatment (noDMT). DMF is an established therapy for relapsing-remitting (RR) MS.

Methods: We retrospectively analyzed 20 patients with RRMS at the start of DMF [age (mean ± SD) 46.1 ± 10.2 years, Expanded Disability Status Scale (EDSS) score 1.1 ± 1.2, timed 25-foot walk (T25FW) 4.6 ± 0.8 s] and eight patients on noDMT (age 42.5 ± 6.6 years, EDSS 1.7 ± 1.1, T25FW 4.4 ± 0.6 s). Baseline and 1-year 3D T1-weighted 3T MRI was processed with automated pipelines (SIENA, FSL-FIRST) to assess percentage whole brain volume change (PBVC) and deep GM (DGM) atrophy. Group differences were assessed by analysis of covariance, with time between MRI scans as a covariate.

Results: Over 1 year, the DMF group showed a lower rate of whole brain atrophy than the noDMT group (PBVC: -0.37 ± 0.49% vs. -1.04 ± 0.67%, p = 0.005). The DMF group also had less change in putamen volume (-0.06 ± 0.22 vs. -0.32 ± 0.28 ml, p = 0.02). There were no significant on-study differences between groups in caudate, globus pallidus, thalamus, total DGM volume, T2 lesion volume, EDSS, or T25FW (all p > 0.20).

Conclusions: These results suggest a treatment effect of DMF on GM atrophy appearing at 1 year after starting therapy. However, due to the retrospective study design and sample size, these findings should be considered preliminary, and require confirmation in future investigations.

Funding: Biogen.

Keywords: Cerebral gray matter atrophy; Dimethyl fumarate; Multiple sclerosis.

Fig. 1

Brain volume measurement techniques: regional and global metrics. A raw 3D T1-weighted magnetization-prepared rapid acquisition gradient echo (MPRAGE) image that has been re-sampled to axial (a) and an example of an FSL/FIRST [FMRIB (Oxford Centre for Functional MRI of the Brain) Software Library Integrated Registration and Segmentation Tool] deep gray matter segmentation (b) of the same MRI slice. In the present study, we utilized the FSL/FIRST outputs to assess the volume of the thalamus, caudate, putamen, and globus pallidus (and their sum = total deep gray matter). In addition, we employed SIENA (Structural Image Evaluation using Normalization of Atrophy) to create a difference map in each subject to assess the within-subject change in whole brain volume from baseline to 1-year follow-up. One anatomic slice from the SIENA output is shown (c) for a subject. The colors on the image indicate the brain parenchymal change between baseline and follow-up, based on shifts of the brain boundary. Lighter blue colors indicate brain tissue volume loss over time (atrophy), whereas yellow colors indicate tissue volume increase. In this case, the patient experienced whole brain atrophy-percentage whole brain volume change of −1.69%. The images are from a 31-year-old woman with multiple sclerosis from the no disease-modifying therapy group, disease duration 2.4 years, baseline Expanded Disability Status Scale score 2, and baseline timed 25-foot walk 5.2 s

Fig. 2

Brain volume change on-study: whole brain atrophy. Percentage whole brain volume changes (PBVC) from baseline to follow-up were assessed in patients with multiple sclerosis on dimethyl fumarate (DMF) therapy vs. patients on no disease-modifying therapy (noDMT). Means and standard deviation bars are shown. On average, the DMT group had a 64.4% lower rate of whole brain atrophy than the noDMT group (p = 0.02; p = 0.005, adjusted for MRI interval). *p < 0.05

Fig. 3

Brain volume change on-study: regional (deep gray matter) atrophy. Changes in cerebral deep gray matter (DGM) volume over 1 year in a group of multiple sclerosis (MS) patients on dimethyl fumarate (DMF) therapy (blue) in comparison to patients on no disease-modifying therapy (noDMT) (red). Means and standard deviations are shown. Total DGM = thalamus + caudate + putamen + globus pallidus. Exact Wilcoxon tests indicated that the putamen volume change differed significantly between the two groups, showing a lower rate of atrophy in the DMF group (p = 0.02); p values were calculated with time between scans as a covariate; *p < 0.05