MR spectroscopic evidence for glial increase but not for neuro‐axonal damage in MS normal‐appearing white matter

Abstract

Quantitative single-voxel, short echo-time (TE) MR spectroscopy (MRS) was used to determine metabolite concentrations in the cerebral normal-appearing white matter (NAWM) of 76 patients with multiple sclerosis (MS), and the WM of 25 controls. In NAWM of all MS disease types (primary progressive, relapsing-remitting, and secondary progressive), the concentration ratio of total N-acetyl-aspartate (tNAA)/total creatine (tCr) was decreased compared to controls. Remarkably, this was entirely due to an increase of tCr in MS patients, whereas there was no difference in tNAA. Separate quantification of the two tNAA components yielded no significant difference in NAA (N-acetylaspartate), while the concentration of NAAG (N-acetyl-aspartylglutamate) was slightly-but significantly-elevated in MS patients. Myo-inositol (Ins) was strongly increased in MS patients, and choline-containing compounds (Cho) were mildly increased. There were no metabolite differences between disease types, and no correlations with disability scores. The results are supported by measures of spectral quality, which were identical for patients and controls. The cerebral normal-appearing white matter (NAWM) in multiple sclerosis (MS) patients has received much attention in MR research. Although large areas of WM appear normal on conventional T 1 -and T 2 -weighted MR images, several (semi-) quantitative techniques have shown differences with the normal WM of healthy controls. The reported abnormalities suggest the presence of either distinct lesions that are too small to be detected using common pixel sizes and magnetic field strengths, or diffuse disease processes that take place outside the focal lesions.The magnetization transfer ratio (MTR) has been found to be decreased in MS NAWM compared to control WM (e.g., Ref. 1), indicating damage to the macromolecular matrix. In addition, increases have been reported for T 1 and T 2 relaxation times (e.g., Ref.2). The apparent diffusion coefficient (ADC) of water is also increased, which along with observed reductions of the anisotropy as derived from the water diffusion tensor, is suggestive of loss of integrity of WM tracts (e.g., Ref.3).Investigations of MS NAWM using MR spectroscopy (MRS) have reported, among other findings, a decrease in the tNAA/tCr ratio (4,5) (where tNAA [abbreviated in some papers as NAA or NA] indicates total NAA, meaning the summed concentrations of N-acetyl-aspartate [NAA], and N-acetyl-aspartyl-glutamate [NAAG]; and tCr indicates the summed concentrations of creatine and phosphocreatine). Although a decrease of tNAA/tCr is thus a common finding in MS NAWM, there is still controversy about the underlying cause of this phenomenon. On the assumption that tCr is constant, it has been inferred from the decreased ratio that the concentration of tNAA is reduced in MS NAWM in comparison with control WM. Because tNAA is generally regarded as a marker of neuro-axonal viability, a decrease in the concentration of tNAA in MS NAWM could be interpreted as an indication of axonal damage. Some...

Inhibition of Glutamate Carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis

“…Neither brain NAAG levels in MS patients nor the relationship of brain NAAG levels to cognition are well defined. To our knowledge only one other MRS study has attempted to examine brain NAAG concentrations in MS patients (46). This study did not measure hippocampal NAAG levels or correlate cognitive function to NAAG levels, making a comparison between studies impossible.…”

Hippocampal N-Acetylaspartate Concentration and Response to Riluzole in Generalized Anxiety Disorder

“…Third, while the NAA resonance peak in MRSI consists predominantly of NAA (20), there are contributions of up to 25% from other N-acetyl compounds, including the dipeptide N-acetylaspartylglutamate (NAAG) (48). Thus, it is possible, although unlikely, that the increased hippocampal NAA in GAD responders with chronic riluzole administration may reflect increased NAAG with normal NAA, a pattern observed in normal-appearing white matter in multiple sclerosis (49). Finally, studies designed to measure the glutamate resonance (which includes glutamate and glutamine), using either high-field 1 H MRS or appropriate spectral editing techniques, could also advance our understanding of the effects of riluzole on this metabolic pathway.…”

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

“…This finding coincides with the results obtained from recent studies that investigated patients with RRMS and also patients with primary progressive MS, even in the early courses of the disease. [19][20][21]23,42 The reproducible assessment of mIns is getting increasingly important because it has been shown that NAWM mIns concentrations are linked to functional impairment on the Multiple Sclerosis Functional Composite Scale and to clinical disability on the EDSS. [19][20][21] Furthermore, mIns might be helpful to narrow the differential diagnosis of pathologic changes in white matter and to distinguish between inflammatory and age-related abnormalities.…”

“…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.…”