Brain metabolite changes in cortical grey and normal-appearing white matter in clinically early relapsing-remitting multiple sclerosis

Abstract

While much work has concentrated on focal white matter (WM) lesions in multiple sclerosis, there is growing evidence to suggest that normal-appearing WM (NAWM) and grey matter (GM) are also involved in the disease process. This study investigated multiple sclerosis disease effects on NAWM and cortical GM (CGM) metabolite concentrations, and the relationships between these metabolite concentrations and clinical impairment. Proton magnetic resonance spectroscopic imaging ((1)H-MRSI) data acquired using point resolved spectroscopic (PRESS) localization (echo time 30 ms, repetition time 3000 ms, nominal voxel volume 2.3 ml) from 27 relapsing-remitting multiple sclerosis and 29 normal control (NC) subjects were processed using LCModel to estimate metabolite concentrations in millimoles per litre. (1)H-MRSI voxel tissue contents were estimated using SPM99 tissue and semi-automatic lesion segmentations of three-dimensional fast spoiled gradient recall scans acquired during the same scanning session. NAWM and CGM metabolite concentrations estimated were: choline-containing compounds (Cho); creatine and phosphocreatine (Cr); myo-inositol (Ins); N-acetyl-aspartate plus N-acetyl-aspartyl-glutamate (tNAA); and glutamate plus glutamine (Glx). CGM data came from 24 of the multiple sclerosis (mean age 35.2 years, mean disease duration 1.7 years) and 25 of the NC (mean age 34.9 years) subjects. NAWM data came from 25 of the multiple sclerosis (mean age 35.0 years, mean disease duration 1.7 years) and 28 of the NC (mean age 36.7 years) subjects. Metabolite concentrations were compared between multiple sclerosis and NC subjects using multiple (linear) regression models allowing for age, gender, (1)H-MRSI voxel tissue and CSF contents, and brain parenchymal volume. At a significance level of P < 0.05, CGM Cho, CGM and NAWM tNAA, and CGM Glx were all significantly reduced, and NAWM Ins was significantly elevated. Spearman correlations of multiple sclerosis functional composite scores with tissue metabolite concentrations were significant for the following: CGM Cr (r(s) = 0.524, P = 0.009), CGM Glx (r(s) = 0.580, P = 0.003) and NAWM Ins (r(s) = -0.559, P = 0.004). These results indicate that metabolite changes in NAWM and CGM can be detected early in the clinical course of multiple sclerosis, and that some of these changes relate to clinical status. The correlation of clinical impairment with CGM Cr and Glx but not tNAA suggests that it is more closely associated with neuronal metabolic dysfunction rather than loss in clinically early relapsing-remitting multiple sclerosis. The correlation of clinical impairment with a raised NAWM Ins may indicate that glial proliferation also relates to function at this stage of the disease.

Biomarkers and surrogate outcomes in neurodegenerative disease: Lessons from multiple sclerosis

“…Decreased NAA has also been observed in cortical gray matter in early relapsing remitting MS, suggesting that early neuronal cell body damage is occurring. 38 It is reduced by ϳ20% in thalamic gray matter in secondary progressive MS and in a postmortem study the decrease in NAA (accompanied by atrophy) was associated with decreased numbers of neurones. 7 In primary progressive MS, reduction of NAA and atrophy appear to be relatively independent of T2 lesion load.…”

“…37 It is also observed in NAWM, in which the elevation has been correlated with disability in MS patients with both short and long disease durations. 38,39 Ins is produced by glial cells and is a potential marker of astrocytosis, gliosis, or possibly microglial activation. Although Ins is difficult to quantify because of having a short T2 relaxation time (thus requiring MR spectroscopy with a short echo time), these interesting observations-suggesting it may detect a diffuse glial/inflammatory process associated with disease progression-should encourage further investigation of Ins in therapeutic trials.…”

Quantitative Cervical Spinal Cord 3T Proton MR Spectroscopy in Multiple Sclerosis

“…These abnormal conditions have been demonstrated both in lesions and in normal-appearing white matter (NAWM) and normal-appearing gray matter (NAGM). [1][2][3][4][5][6][7][8][9][10] T1-and T2-weighted MR imaging is currently the diagnostic reference to define and monitor MS, but it has poor specificity and sensitivity in detecting pathophysiologic MS changes correlated with clinical disability. 6,[11][12][13][14][15] For some years, brain proton MR spectroscopy ( 1 H-MR spectroscopy) has been used to study MS by offering a unique opportunity to evaluate biochemical changes that could shed light on the complex pathophysiology of the disease and potentially define new markers correlated with the clinical evolution of MS. 1,16 Many cerebral quantitative MR spectroscopy studies in patients with MS have evaluated the correlation of the specific single metabolites with specific physiologic events during the MS disease course.…”

Axonal Damage But No Increased Glial Cell Activity in the Normal-Appearing White Matter of Patients with Clinically Isolated Syndromes Suggestive of Multiple Sclerosis Using High-Field Magnetic Resonance Spectroscopy

“…11,[15][16][17][18][19][20] Besides the axonal damage within the NAWM, the glial cell activity is increasingly becoming an area of interest in patients with chronic inflammatory diseases of the central nervous system (CNS). Several studies have already demonstrated a significant increase of mIns in the NAWM of patients with definite MS. [20][21][22][23] Metabolic alterations in the NAWM of patients with CIS are also of particular interest because these changes might have prognostic relevance for the clinical outcome and might be helpful to exclude other differential diagnoses. The results of recently performed 1 H-MR spectroscopy studies focusing on this topic are inconclusive so far.…”