Brain metabolite changes in cortical grey and normal-appearing white matter in clinically early relapsing–remitting multiple sclerosis
Chard DT, Griffin CM, McLean MA, Kapeller P, Kapoor R, Thompson AJ and Miller DH;
Commented by , 22 Nov 2002
Background
During the last decade a growing bulk of evidence has shown that multiple sclerosis (MS) pathology is not restricted to focal lesions but is spread about in the normal appearing white matter (NAWM) and in the grey matter as well.
Interest has focused on axonal degeneration in the early stages of the disease, recently described by Kuhlmann et al. (Brain 2002; 125; 2202-2212). In this context it is also interesting that tissue and axonal injury is found in patients with low MRI cerebral lesion load and no disability (De Stefano et al., Arch Neurol. 2002; 59; 1565-1571).
Aim
To investigate clinically early MS disease effects in both NAWM and cortical grey matter and asses this with relation to clinical impairment.
Methods
Proton magnetic resonance spectroscopic imaging (H-MRSI) was used to measure cerebral metabolites from 27 relapsing-remitting MS patients with early disease course as well as 29 normal controls. H-MRSI voxel (2,3 ml) contents were estimated using tissue and semi-automatic lesion segmentations of 3-D fast spoiled gradient recall scans.
The authors estimated concentrations of choline-containing compounds (Cho); creatinie and phosphocreatinine (Cr); myo-inositol (Ins); N-acetyl-aspartate plus N-acetyl-aspartyl-glutamate (tNAA); and glutamate plus glutamine (Glx).
A further description of the scanning protocols, equipment or software will not be given here.
The clinical assessment comprised EDSS score and MS functional composite (MSFC).
Results
Metabolite concentrations were compared between the two groups using multiple linear regression analysis. Reductions (p < 0,05) of cortical grey matter Cho, tNAA and Glx was found in MS patients. In NAWM tNAA was reduced whereas Ins was elevated.
Spearman correlations of MFSC with tissue metabolite concentrations were significant in cortical grey matter Cr (p = 0,009) and Glx (p = 0,003). In NAWM a significant negative correlation was found with Ins (p = 0,004).
Discussion
Marked reduction of Cho was found in cortical grey matter indicating reduced cellular density. The reduction in tNAA is suggested to relate to cell loss, and together with the reduction in Cho this also points towards metabolic dysfunction of the cortex.
In NAWM, Ins was elevated indicating glial proliferation and widespread inflammation. The reduction of tNAA in NAWM is compatible with axonal dysfunction or/and loss.
Clinical outcome correlated with cortical Cr and Glx, showing a relationship between neuronal metabolic dysfunction and impairment. In NAWM the clinical outcome was related to gliosis (Ins).
Surprisingly there was no correlation between tNAA and disability as shown in previous studies, were cohorts with longer disease duration were investigated. It should be noted that correlations were not corrected for multiple comparisons.
Important conclusions can be derived from the study. First of all it shows that there is a metabolic dysfunction of the cerebral cortex in the early stages of the disease which has not been described yet. This may indicate ongoing disease activity eventually leading to neuronal loss.
The study thus confirms the notion, that both normal appearing grey and white matter are involved in pathological processes in the primary course of the disease, and emphasizes the need for early therapeutic intervention in MS.