In vivo evidence of differential frontal cortex metabolic abnormalities in progressive and relapsing‐remitting multiple sclerosis

The pathophysiology of progressive multiple sclerosis remains elusive, significantly limiting available disease‐modifying therapies. Proton MRS ( 1 H‐MRS) enables in vivo measurement of small molecules implicated in multiple sclerosis, but its application to key metabolites glutamate, γ‐aminobutyric acid (GABA), and glutathione has been sparse. We employed, at 7 T, a previously validated 1 H‐MRS protocol to measure glutamate, GABA, and glutathione, as well as glutamine, N ‐acetyl aspartate, choline, and myoinositol, in the frontal cortex of individuals with relapsing‐remitting ( N = 26) or progressive ( N = 21) multiple sclerosis or healthy control adults ( N = 25) in a cross‐sectional analysis. Only individuals with progressive multiple sclerosis demonstrated reduced glutamate ( F 2,65 = 3.424, p = 0.04; 12.40 ± 0.62 mM versus control 13.17 ± 0.95 mM, p = 0.03) but not glutamine ( F 2,65 = 0.352, p = 0.7; 4.71 ± 0.35 mM versus control 4.84 ± 0.42 mM), reduced GABA ( F 2,65 = 3.89, p = 0.03; 1.29 ± 0.23 mM versus control 1.47 ± 0.25 mM, p = 0.05), and possibly reduced glutathione ( F 2,65 = 0.352, p = 0.056; 2.23 ± 0.46 mM versus control 2.51 ± 0.48 mM, p < 0.1). As a group, multiple sclerosis patients demonstrated significant negative correlations between disease duration and glutamate or GABA ( ρ = − 0.4, p = 0.02) but not glutamine or glutathione. Alone, only relapsing‐remitting multiple sclerosis patients exhibited a significant negative correlation between disease duration and GABA ( ρ = −0.5, p = 0.03). Taken together, these results indicate that frontal cortex metabolism is differentially disturbed in progressive and relapsing‐remitting multiple sclerosis.