A Longitudinal, Observational Study of the Effect of Dimethyl Fumarate on Hippocampal Metabolites in RRMS using 1H-MR Spectroscopy

Abstract

Background: Dimethyl fumarate (DMF), an oral diseasemodifying treatment for Multiple Sclerosis (MS), displays anti-oxidative properties, thought to be via modulation of glutathione (GSH). However, to date, the effect of DMF on the metabolic profile of MS brains has not been evaluated. The aim of this study was to measure cross-sectional changes in hippocampal neurometabolites in Relapsing-Remitting MS (RRMS) patients, compared to Healthy Controls (HCs) and then evaluate the metabolic impact of DMF treatment longitudinally over 24 months.Methods: 1 H-MRS was undertaken on 20 RRMS patients prior to and up to 24 months post-inception of DMF treatment and 20 age sex-matched HCs. Spectroscopic data was acquired from the hippocampus using single voxel spectroscopy (6.75 mL, PRESS, TE 30 ms) at 3T. Results:We identified a significant reduction in hippocampal N-acetylaspartate (NAA, -13%, p=0.0001) and increased myoinositol (mI, +9%, p=0.02) in RRMS patients, before starting DMF, compared to HCs. Following treatment onset, GSH levels differed significantly over 24 months in the RRMS group (F=3.5, p<0.05). There was a reduction in GSH from baseline to 1 month of treatment (p=0.014). This reduction remained statistically significant after 6 months of treatment (p=0.04), but slightly increased after 12 and 24 months of treatment (p=0.15 and 0.18, respectively), approaching levels seen in HCs. Conclusions:The trend for the rebound effect of GSH following 24 months of DMF treatment is suggestive of recovery from the inflammatory event and is the first demonstration of an anti-oxidative effect in the MS brain following DMF treatment.

Current Status of Oral Disease-Modifying Treatment Effects on Cognitive Outcomes in Multiple Sclerosis: A Scoping Review

“…Observation of the data shows that in four studies, patients presented a longitudinal improvement in cognitive performance over time [58,[60][61][62], while in two studies, cognitive assessment remained stable with no significant differences vs. FTY [57,59]. On the contrary, there was a significant worsening of PASAT in the study by Glasmacher et al, where DMF was analysed together with TFL as Category 3 vs. Category 1 (NTZ and ATZ) and Category 2 (FTY and CLAD) DMTs [56].…”

“…Following DMF clinical indication, all the included patients suffered from RRMS. PASAT was used as an assessment tool in most studies (n = 4) [56,58,60,62], and the SDMT, the Processing Speed Test (PST) and the Rao's Brief Repeatable Battery (BRB) with Stroop Test were also used in four studies [57,59,61,62], respectively.…”