Increased Concentrations of Glutamate and Glutamine in Normal-Appearing White Matter of Patients with Multiple Sclerosis and Normal MR Imaging Brain Scans

In Multiple Sclerosis (MS) the relationship between disease process in normal-appearing white matter (NAWM) and the development of white matter lesions is not well understood. In this study we used single voxel proton ‘Quantitative Magnetic Resonance Spectroscopy’ (qMRS) to characterize the NAWM and thalamus both in atypical ‘Clinically Definite MS’ (CDMS) patients, MRI neg (N = 15) with very few lesions (two or fewer lesions), and in typical CDMS patients, MRI pos (N = 20) with lesions, in comparison with healthy control subjects (N = 20). In addition, the metabolite concentrations were also correlated with extent of brain atrophy measured using Brain Parenchymal Fraction (BPF) and severity of the disease measured using ‘Multiple Sclerosis Severity Score’ (MSSS). Elevated concentrations of glutamate and glutamine (Glx) were observed in both MS groups (MRI neg 8.12 mM, p <0.001 and MRI pos 7.96 mM p <0.001) compared to controls, 6.76 mM. Linear regressions of Glx and total creatine (tCr) with MSSS were 0.16±0.06 mM/MSSS ( p =  0.02) for Glx and 0.06±0.03 mM/MSSS ( p =  0.04) for tCr, respectively. Moreover, linear regressions of tCr and myo -Inositol ( m Ins) with BPF were −6.22±1.63 mM/BPF ( p <0.001) for tCr and −7.71±2.43 mM/BPF (p = 0.003) for m Ins. Furthermore, the MRI pos patients had lower N-acetylaspartate and N-acetylaspartate-glutamate (tNA) and elevated m Ins concentrations in NAWM compared to both controls (tNA: p =  0.04 m Ins p <0.001) and MRI neg (tNA: p =  0.03 , m Ins: p =  0.002). The results suggest that Glx may be an important marker for pathology in non-lesional white matter in MS. Moreover, Glx is related to the severity of MS independent of number of lesions in the patient. In contrast, increased glial density indicated by increased m Ins and decreased neuronal density indicated by the decreased tNA, were only observed in NAWM of typical CDMS patients with white matter lesions.