Abstract

Objective: To monitor metabolic changes within the cortex (Cx), thalamus (Th) and basal ganglia (BG) in Theiler’s murine encephalomyelitis virus (TMEV) animal model of multiple sclerosis (MS) over 9 months. To this end, we used proton magnetic resonance spectroscopy ( 1 H-MRS) to track metabolic consumption (glucose, lactate, alanine), cellular integrity (GPC, NAA), and neurotransmission (GABA, glutamate) during disease progression. Background: Under-characterized metabolic mechanisms active in MS pathology are crucial for determining therapeutic strategies. TMEV model of demyelination closely resembles biphasic MS pathology. Furthermore, 1 H-MRS allows for non-invasive quantification of metabolites and helps characterize pathological implications of TMEV. Design/Methods: 48 Swiss Jim Lambert (SJL) mice received an intracerebral inoculation of either TMEV (24) or saline (24). Mice were 1 H-MRS scanned at pre-induction, 2, 6 and 9 months post injection (mPI) and clinically monitored every 4 weeks. Glucose, lactate, alanine, NAA, GABA, GPC and glutamate were quantified within voxels of interest (VOI). VOIs were registered in the Cx and Th for all mice and in BG for TMEV-mice only. Results: TMEV cohort presented clinical symptoms starting 2 mPI. In the Cx and Th of TMEV mice, a shift in metabolic function was apparent as evidenced by a decline in glucose with a rise in lactate, compared to saline controls, by 9mPI. Similar metabolic trend was observed in the BG in TMEV infected mice. NAA declined within the Cx and Th at 6 and 9mPI of TMEV mice, indicating potential loss of neural integrity. Further, loss of synaptic function occurred in TMEV-mice, as evidenced by glutamate and GABA decline in all structures. Conclusions: TMEV is characterized by metabolic stress, as indicated by the shift in metabolic consumption from glucose to lactate, loss of synaptic functionality implied by the reduction in glutamate and GABA, and loss in cellular integrity within the Cx, Th and BG. Study Supported by: N/A Disclosure: Dr. Sudyn has nothing to disclose. Dr. Schweser has received research support from SynchroPET. Dr. Modica has nothing to disclose. Dr. Pol has nothing to disclose. Dr. Dwyer has received personal compensation for activities with Claret Medical and EMD Serono. Dr. Dwyer has received research support from Novartis. Dr. Siebert has nothing to disclose. Dr. Hagemeier has nothing to disclose. Dr. Preda has nothing to disclose. Dr. Bertolino has nothing to disclose. Dr. Zivadinov has received personal compensation for activities with EMD Serono, Genzyme, Novartis, for speaking and consultant fees. Dr. Zivadinov has received personal compensation in an editorial capacity for BioMed Research International, BMC Medicine, BMC Neurology, Clinical CNS Drugs, Conf Pap Neurosci, Journal of Alzheimer9s Disease, Vein and Lymphatics, and Word J Surg Proc. Dr. Zivadinov has received research support from Biogen Idec, Claret Medical, Genzyme, Intekrin-Coherus, Novartis, and Teva Pharmaceuticals.