Saturday, 4 May 2013

Research: Glutamate in Normal white matter

Tisell et al. Increased Concentrations of Glutamate and Glutamine in Normal-Appearing White Matter of Patients with Multiple Sclerosis and Normal MR Imaging Brain Scans. PLoS One. 2013 Apr 17;8(4):e61817. doi: 10.1371/journal.pone.0061817.

Background: 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.

Objective and methods: 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).

Results: 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. Furthermore, the MRIpos patients had lower N-acetylaspartate (thought to be a marker of nerve loss) and elevated mIns (thought to be a marker of gliosis) concentrations in NAWM compared to both controls (mIns p<0.001) and MRIneg (mIns: p = 0.002).

Conclusions: 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 were only observed in NAWM of typical CDMS patients with white matter lesions.

Glutamate is the major nerve transmitter molecule and GABA is the major inhibitory nerve transmitter molecule. The glutamate-glutamine cycle is a sequence of events by which an adequate supply of the neurotransmitter glutamate is maintained in the central nervous system. Neurons are not able to perform new synthesis of the neurotransmitter glutamate and γ-aminobutyric acid (GABA) from glucose. The glutamate/GABA-glutamine cycle is a metabolic pathway that describes the release of glutamate or GABA from neurons and then taken up into astrocytes (star shaped glial cells). In return, astrocytes release glutamine to be taken up into neurons for use as a precursor to the synthesis of glutamate or GABA.

In this study irrespective of whether there are MRI detectable MRI lesions there are changes in this cycle in MSers. The failure to detect lesions in the MRIneg group may be a problem of resolution but normal appearing white matter in MS has been often found to have stuff going on. Too much glutamate has been suggested to be potentially damaging to cells. In animals blocking glutamate activity can slow down nerve damage. One of the drugs in the MS-SMART trial will be a glutamate receptor blocker. Hope the study translates.

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