In vivo cortical glutathione response to oral fumarate therapy in relapsing-remitting multiple sclerosis: A single-arm open-label phase IV trial using 7-Tesla (1)H MRS

BACKGROUND: This is an open-label, single-arm, single-center pilot study using 7-Tesla in vivo proton magnetic resonance spectroscopy ((1)H MRS) to measure brain cortical glutathione concentration at baseline before and during the use of oral fumarates as a disease-modifying therapy for multiple sclerosis. The primary endpoint of this research was the change in prefrontal cortex glutathione concentration relative to a therapy-naïve baseline after one year of oral fumarate therapy. METHODS: Brain glutathione concentrations were examined by (1)H MRS in single prefrontal and occipital cortex cubic voxels (2.5 × 2.5 × 2.5 cm(3)) before and during initiation of oral fumarate therapy (120 mg b.i.d. for 7 days and 240 mg b.i.d. thereafter). Additional measurements of related metabolites glutamate, glutamine, myoinositol, total N-acetyl aspartate, and total choline were also acquired in voxels centered on the same regions. Seven relapsing-remitting multiple sclerosis patients (4 f / 3 m, age range 28–50 years, mean age 40 years) naïve to fumarate therapy were scanned at pre-therapy baseline and after 1, 3, 6 and 12 months of therapy. A group of 8 healthy volunteers (4 f / 4 m, age range 33–48 years, mean age 41 years) was also scanned at baseline and Month 6 to characterize (1)H-MRS measurement reproducibility over a comparable time frame. RESULTS: In the multiple sclerosis cohort, general linear models demonstrated a significant positive linear relationship between prefrontal glutathione and time either linearly across all time points (+0.05 ± 0.02 mM/month, t(27) = 2.6, p = 0.02) or specifically for factor variable Month 12 (+0.6 ± 0.3 mM/12 months, t(24) = 2.2, p = 0.04) relative to baseline. No such effects of time on glutathione concentration were demonstrated in the occipital cortex or in the healthy volunteer group. Changes in occipital total choline were further observed in the multiple sclerosis cohort as well as prefrontal total choline and occipital glutamine and myoinositol in the control cohort throughout the study duration. CONCLUSIONS: While the open-label single-arm pilot study design and abbreviated control series cannot support firm conclusions about the influence of oral fumarate therapy independent of test–retest factors or normal biological variation in a state of either health or disease, these results do justify further investigation at a larger scale into the potential relationship between prefrontal cortex glutathione increases and oral fumarate therapy in relapsing-remitting multiple sclerosis.