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

Abstract

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, MRIneg (N = 15) with very few lesions (two or fewer lesions), and in typical CDMS patients, MRIpos (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 (MRIneg 8.12 mM, p<0.001 and MRIpos 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 (mIns) 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 mIns. Furthermore, the MRIpos patients had lower N-acetylaspartate and N-acetylaspartate-glutamate (tNA) and elevated mIns concentrations in NAWM compared to both controls (tNA: p = 0.04 mIns p<0.001) and MRIneg (tNA: p = 0.03 , mIns: 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 mIns and decreased neuronal density indicated by the decreased tNA, were only observed in NAWM of typical CDMS patients with white matter lesions.

Quantitative Magnetic Resonance Imaging of the Brain : Applications for Tissue Segmentation and Multiple Sclerosis

“…Correlations were also calculated between qMRI measurements and NAWM metabolite concentrations in the same subjects, previously reported in (162). In these subjects a second qMRI measurement was also performed inside the MRS VOIs, and correlations between the qMRI measurements and WM metabolite concentrations were also calculated in the same VOIs.…”

“…Technological developments have therefore been suggested to characterise and quantify DAWM, as well as to detect changes in NAWM. These techniques include diffusion tensor imaging (DTI) (157,158,160), quantitative magnetisation transfer imaging (qMTI) (84,155,158), quantitative MR spectroscopy (qMRS) (161,162), and qMRI (84, 157, 158).…”

“…These patients constitute a subgroup of MS (162)(163)(164) that is of interest for investigating changes in NAWM and DAWM without WM lesions, and with probably less Wallerian degeneration. In this group of MS patients the clinical investigation must be extraordinarily thorough before the diagnose of MS can be established, especially concerning the radiological investigation (163).…”

“…In addition, the qMRI acquisition was part of a more extensive investigation including clinical imaging sequences, as well as measurements of WM metabolite concentrations assessed using quantitative MR spectroscopy (qMRS) (161,162). The qMRS acquisition was performed using the point-resolved spectroscopy sequence (PRESS) (205), with T R = 3000 ms, T E = 30 ms and 128 transients were averaged.…”

“…Furthermore, correlation analyses were performed between qMRI measurements and a battery of clinical parameters, and metabolite concentrations in NAWM. The latter were measured using quantitative magnetic resonance spectroscopy (qMRS), reported previously in (162). Finally, regression analyses were performed to determine the associations between qMRI measurements and BPF, MSSS and EDSS.…”