COPENHAGEN—Levels of glutamate may decline almost 10 times faster over time in patients with secondary progressive multiple sclerosis (MS) than in healthy controls, according to a study presented at the 29th Congress of the European Committee for Treatment and Research in MS (ECTRIMS). Levels of glutamine and the combination of glutamate and glutamine also may decrease faster in patients with secondary progressive MS than in healthy controls.
“The combined decline of glutamate and glutamine suggests a loss of synapse function or a loss of synapses over time,” said Erin MacMillan, PhD, postdoctoral research fellow at the University of British Columbia in Vancouver. The two metabolites may offer new biomarkers of progression and feasible outcome measures for multicenter clinical trials in secondary progressive MS.
“Few longitudinal proton magnetic resonance spectroscopy (1H-MRS) studies have been performed in a cohort of progressive MS patients, and, to our knowledge, this is the first with sufficient spectral quality and data analysis methods to reliably detect both glutamate and glutamine,” she added.
Monitoring Metabolite Concentrations in Patients With MS
Dr. MacMillan and colleagues analyzed data for patients with secondary progressive MS who were enrolled in a clinical trial at the University of British Columbia. The investigators focused on 47 subjects who completed MRS scans for at least two time points, including baseline, year one, and year two. Participants (median age, 51.7; median Expanded Disability Status Scale score, 6.0) were not on other disease-modifying therapies within three months before the start of the trial.
The researchers used 1H-MRS to examine concentrations of glutamate, glutamine, the combination of glutamate and glutamine, myo-inositol, choline-containing compounds, and other metabolites in a primarily white-matter region inside the brain. Concentration differences from year one and year two to baseline were tested with the two-sided Wilcoxon signed rank test. Concentrations at all three time points for each metabolite were fit with a linear random effects model to allow for individual offsets but the same slope across subjects.
Concentrations of Most Metabolites Changed Little
Participants’ level of N-acetyl-aspartate + N-acetyl-aspartylglutamate (tNAA) had no significant relationship with time. In contrast, glutamate concentration decreased from approximately 6.5 mM at baseline to approximately 6 mM at year two. Its rate of decrease was 4.9% per year. Glutamine concentration declined from approximately 2.5 mM at baseline to approximately 2 mM at year two. Its rate of decrease was 13.1% per year.
The lack of change in tNAA, creatine and phosphocreatine, and choline-containing compounds over two years is consistent with a previous study of participants with primary progressive MS over three years, said Dr. MacMillan.
“Glutamate and glutamine, as measured by 1H-MRS, are promising new biomarkers of MS disease progression that may be more sensitive than current state-of-the-art techniques, such as brain atrophy,” Dr. MacMillan told Neurology Reviews. “These new biomarkers may prove to be better prognostic measures and determinants of treatment efficacy.
“We hope to repeat this study with two regions of interest—one clearly within the cortical gray matter, and one clearly within the white matter—to distinguish whether the changes we have seen with disease progression are taking place in the gray matter or the white matter,” she concluded.
—Erik Greb