Myelin Damage in Relapsing Multiple Sclerosis Is Associated with Decreased N-Acetylaspartate and Creatine Concentrations (P4.181)

Objective: To determine whether the levels of N-acetylaspartate (NAA) and total creatine (tCr; creatine and phosphocreatine) in normal-appearing white matter are correlated with myelin water fraction (MWF) in patients with relapsing multiple sclerosis (RMS) and healthy controls (HC). Background: Brain MRI offers a non-invasive measure of myelin content through the MWF. Magnetic resonance spectroscopy (MRS) measures tCr, which is involved in energy storage, and NAA, which supports myelin lipid synthesis. Given the roles of tCr and NAA in mitochondrial function and myelin production, we hypothesized that tCr and/or NAA would correlate with myelin content in the brain. Methods: A total of 25 patients recruited for an MRI substudy of a Phase III, randomized clinical trial of ocrelizumab versus interferon β-1a (OPERA II; NCT01412333) and 44 age- and gender-matched HC were scanned at 3T. MRS was measured from a 6.5x4.5x1.8cm³ white matter voxel and fit with LCModel v6.3. NAA, N-acetyl-aspartylglutamate, tCr, choline, myo-inositol and glutamate concentrations were calculated relative to the water peak and corrected for voxel compartmentation and relaxation. MWF was measured using a 32 echo gradient and spin echo imaging sequence to sample the water T2 decay curve, which was modelled with multiple exponential components. MRS voxels were mapped to MWF maps to extract the mean MWF in the voxel. Results: tCr (r²=0.24; p=0.01) and NAA (r²=0.16; p=0.05) both positively correlated with the mean voxel MWF in the RMS group. There were no correlations between MWF and any metabolite in the HC group or when both RMS and HC groups were included. Conclusions: The presence of positive, though weak, relationships between tCr and NAA with myelin content in the RMS cohort suggests that decreased mitochondrial function, as evidenced by reduced tCr and NAA, may be linked to loss of myelin in patients with RMS. Supported by F. Hoffmann-La Roche Disclosure: Dr. Schubert has received research support from F. Hoffmann-La Roche Ltd. Dr. MacMillan has received personal compensation for activities with Roche as a consultant. Dr. Vavasour has received research support from F. Hoffmann-La Roche, Genzyme Corporation, and the Multiple Sclerosis Society of Canada. Dr. Morawski Vianna has received personal compensation for activities with Roche Diagnostics Corporation as an employee. Dr. Dzyakanchuk has received personal compensation for activities with F. Hoffmann-La Roche as an employee. Dr. Yoo has nothing to disclose. Dr. Tam has received personal compensation for activities with Novartis. Dr. Tam has received research from Roche. Dr. Kolind has received personal compensation for activities Genzyme and Vertex Pharmaceuticals as a speaker and/or consultant. Dr. Traboulsee has received personal compensation for activities with Genzyme and Roche. Dr. Traboulsee has received research support from Genzyme, Roche, Chugai.