title: In vivo evidence of glutamate toxicity in multiple sclerosis.
abstract: 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 Sclerosis Functional 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Yale University, New Haven, CT.
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Azevedo
authors.forename: John
authors.initials: J
authors.lastname: Kornak
authors.forename: Philip
authors.initials: P
authors.lastname: Chu
authors.forename: Mehul
authors.initials: M
authors.lastname: Sampat
authors.forename: Darin T
authors.initials: DT
authors.lastname: Okuda
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Cree
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Nelson
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.forename: Daniel
authors.initials: D
authors.lastname: Pelletier
mesh_terms: D000328:Adult; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005500:Follow-Up Studies; D018698:Glutamic Acid / Q000378:metabolism*; D049690:History, Ancient; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism*
chemical_list: D001224:Aspartic Acid; D018698:Glutamic Acid; C000179:N-acetylaspartate