Thursday, 24 July 2014

What causes damage in MS

Azevedo CJ, Kornak J, Chu P, Sampat M, Okuda DT, Cree BA, Nelson SJ, Hauser SL, Pelletier D. In vivo evidence of glutamate toxicity in multiple sclerosis.Ann Neurol. 2014 Jul 9. doi: 10.1002/ana.24202. [Epub ahead of print]

OBJECTIVE: There is increasing evidence that altered glutamate (Glu) homeostasis is involved in the pathophysiology of multiple sclerosis (MS). The aim of this study was to evaluate the in vivo effects of excess brain Glu on neuroaxonal integrity measured by N-acetylaspartate (NAA), brain volume, and clinical outcomes in a large, prospectively followed cohort of MS subjects.
METHODS: We used multivoxel spectroscopy at 3T to longitudinally estimate Glu and NAA concentrations from large areas of normal-appearing white and gray matter (NAWM and GM) in MS patients (n = 343) with a mean follow-up time of 5 years. Using linear mixed-effects models, Glu was examined as a predictor of NAA decline, annualized percentage brain volume change, and evolution of clinical outcomes (Multiple SclerosisFunctional Composite [MSFC], Paced Auditory Serial Addition Test-3 [PASAT], and Expanded Disability Status Scale). Glu/NAA ratio was tested as a predictor of brain volume loss and clinical outcomes.
RESULTS: Baseline Glu[NAWM] was predictive of accelerated longitudinal decline in NAA[GM] (-0.06mM change in NAA[GM] /yr for each unit increase in Glu; p = 0.004). The sustained elevation of Glu[NAWM] was predictive of a loss of 0.28mM/yr in NAA[NAWM] (p < 0.001) and 0.15mM/yr in NAA[GM] (p = 0.056). Each 10% increase in Glu/NAA[NAWM] was associated with a loss of 0.33% brain volume/yr (p = 0.001), 0.009 standard deviations/yr in MSFC z-score (p < 0.001), and 0.17 points/yr on the PASAT (p < 0.001).
INTERPRETATION: These results indicate that higher Glu concentrations increase the rate of NAA decline, and higher Glu/NAA[NAWM] ratio increases the rate of decline of brain volume, MSFC, and PASAT. This provides evidence of a relationship between brain Glu and markers of disease progression in MS

Glutamate is the major excitatory neurotransmitter that control nerve function. However if too much is produced it can cause excitotoxicity. NAA is the second-most-concentrated molecule in the brain after the amino acid glutamate. It is detected in the adult brain in neurons, and is a marker of nerve content. The more glutamate that is present is associated with nerve loss and associates with brain shrinkage. This process occurs in stroke, but there are few good treatments for human stroke but loads of treatments for experimental stroke. In humans such treatments for stroe invariably fail because they are not given early enough after the stroke. In MS however you could give the stroke drug even before the excitotoxicity has occurred and so the chances of success are greater.

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