[show abstract][hide abstract] ABSTRACT: Glatiramer acetate (GA) is a disease-modifying therapy for relapsing-remitting multiple sclerosis (RRMS) with several putative mechanisms of action. Currently, there is paucity of in vivo human data linking the well-established peripheral immunologic effects of therapy with GA to its potential effects inside the central nervous system (CNS). Brain proton magnetic resonance spectroscopy (MRS) allows in vivo examination of axonal integrity by quantifying the resonance intensity of the neuronal marker N-acetylaspartate (NAA). In a pilot study to investigate the effect of GA on axonal injury, we performed combined brain magnetic resonance imaging (MRI) and MRS studies in 18 treatment naïve RRMS patients initiating therapy with GA at baseline and annually for two years on therapy. A small group of four treatment naïve RRMS patients, electing to remain untreated, served as controls. NAA/Cr was measured in a large central brain volume of interest (VOI) as well as the normal appearing white matter (NAWM) within the VOI. After two years, NAA/Cr in the GA-treated group increased significantly by 10.7% in the VOI (2.17 +/- 0.26 versus 1.96 +/- 0.24, P = 0.03) and by 71% in the NAWM (2.23 +/- 0.26 versus 2.08 +/- 0.31, P = 0.04). In the untreated group, NAA/Cr decreased by 8.9% at two years in the VOI (2.01 +/- 0.16 versus 1.83 +/- 0.21, P = 0.03) and 8.2% in the NAWM (2.07 +/- 0.24 versus 1.90 +/- 0.29, P = 0.03). Our data shows that treatment with GA leads to axonal metabolic recovery and protection from sub-lethal axonal injury. These results support an in situ effect of GA therapy inside the CNS and suggest potential neuroprotective effects of GA.