Relapsing Multiple Sclerosis Exhibits Reduced Normal Appearing White Matter Glutamate Levels (P6.132)

OBJECTIVE: The objective of this study was to compare glutamate, and other brain metabolite, concentrations in patients with relapsing multiple sclerosis (RMS) and healthy controls using an advanced magnetic resonance spectroscopy (MRS) analysis technique. BACKGROUND: Glutamate is the major excitatory neurotransmitter in the brain and is also used for communication between axons and myelin. Reduced communication leads to diminished repair mechanisms, which may be related to neurodegeneration in MS. MRS provides an effective tool to non-invasively and quantitatively measure glutamate levels in the brain. DESIGN/METHODS: 26 RMS subjects participating in a Phase III clinical trial of ocrelizumab (OPERA) and 40 age and gender-matched healthy controls were scanned at baseline. A 6.5x4.5x1.8cm^3 white matter voxel was analyzed with MRS and the spectra were fit with LCModel version 6.3. Glutamate, N-acetyl-aspartate (primary role: neuronal integrity), creatine (energy storage), choline (membrane synthesis), and myo-Inositol (glial marker) concentrations were calculated relative to the water peak and corrected for voxel compartmentation and relaxation to obtain institutional mM values. RESULTS: Glutamate was significantly lower in RMS subjects compared to controls. The median glutamate concentration was 7.0 (6.7 - 7.5) mM in RMS and 7.5 (7.1 - 7.9) mM in healthy controls (p=0.009). There were no significant differences between RMS patients and controls for all other metabolites. CONCLUSIONS: Glutamate concentrations were lower in RMS subjects compared to healthy controls. This result could be indicative of reduced axo-myelinic communication in RMS. Our previous finding of declining glutamate and glutamine levels over 2 years in patients with secondary progressive MS is consistent with the results of the present study. Both of these studies suggest that abnormal glutamate homeostasis is a common feature of MS and could be a potential biomarker of neurodegeneration. These brain metabolites will be measured longitudinally in the OPERA Phase III RMS clinical trials. Disclosure: Dr. Schubert has nothing to disclose. Dr. MacMillan has received personal compensation for activities with Roche Diagnostics Corporation as a consultant. Dr. Tam has nothing to disclose. Dr. Leppert has received personal compensation for activities with Roche Diagnostics Corp. as an employee. Dr. Seneca has received personal compensation for activities with Roche Diagnostics Corporation as an employee. Dr. Morawski Vianna has received personal compensation for activities with Roche Diagnostics Corporation as an employee. Dr. Dzyakanchuk has nothing to disclose. Dr. Kolind has received personal compensation for activities with Roche Diagnostics Corp., Genzyme, and EMD Serono as a speaker and/or scientific advisory board member. Dr. Traboulsee has received personal compensation for activities with Roche Diagnostics Corporation, EMD Serono, Teva Neuroscience, and Biogen Idec, Novartis, and Genzyme Corporation.