In vivo evidence of differential frontal cortex metabolic abnormalities in progressive and relapsing‐remitting multiple sclerosis

Abstract

The pathophysiology of progressive multiple sclerosis remains elusive, significantly limiting available disease-modifying therapies. Proton MRS ( 1 H-MRS) enables in vivo measurement of small molecules implicated in multiple sclerosis, but its application to key metabolites glutamate, γ-aminobutyric acid (GABA), and glutathione has been sparse. We employed, at 7 T, a previously validated 1 H-MRS protocol to measure glutamate, GABA, and glutathione, as well as glutamine, N-acetyl aspartate, choline, and myoinositol, in the frontal cortex of individuals with relapsing-remitting (N = 26) or progressive (N = 21) multiple sclerosis or healthy control adults (N = 25) in a cross-sectional analysis. Only individuals with progressive multiple sclerosis demonstrated reduced glutamate (F 2,65 = 3.424, p = 0.04; 12.40 ± 0.62 mM versus control 13.17 ± 0.95 mM, p = 0.03) but not glutamine (F 2,65 = 0.352, p = 0.7; 4.71 ± 0.35 mM versus control 4.84 ± 0.42 mM), reduced GABA (F 2,65 = 3.89, p = 0.03; 1.29 ± 0.23 mM versus control 1.47 ± 0.25 mM, p = 0.05), and possibly reduced glutathione (F 2,65 = 0.352, p = 0.056; 2.23 ± 0.46 mM versus control 2.51 ± 0.48 mM, p < 0.1). As a group, multiple sclerosis patients demonstrated significant negative correlations between disease duration and glutamate or GABA (ρ = À0.4, p = 0.02) but not glutamine or glutathione. Alone, only relapsing-remitting multiple sclerosis patients exhibited a significant negative correlation between disease duration and GABA (ρ = À0.5, p = 0.03). Taken together, these results indicate that frontal cortex metabolism is differentially disturbed in progressive and relapsingremitting multiple sclerosis.

Multiple sclerosis diagnosis and phenotype identification by multivariate classification of in vivo frontal cortex metabolite profiles

“…Proton magnetic resonance spectroscopy is an experimental technique of low sensitivity that has historically led to findings of metabolic abnormality in multiple sclerosis that are subtle and inconsistent at best 8 . Notably, application of data derived from this method alone led to satisfactory differentiation between progressive multiple sclerosis and control, and between progressive and relapsing–remitting multiple sclerosis, in a cohort that exhibited unequivocally significant univariate differences between the former two groups for only two metabolites (GABA and glutamate), and between the latter for only one (GABA) 58 . Our classification pipelines distinguished patients from control with a clarity exceeding the subtle pattern of results yielded by univariate statistical techniques, demonstrating the additional information offered by multivariate approaches to multiple-sclerosis-related abnormalities in small molecule concentrations measurable by proton magnetic resonance spectroscopy.…”

“…Metabolite spectra were obtained as previously reported 58 from a single 27-cm 3 cubic voxel in the prefrontal cortex using a 7 T head-only scanner (Varian Medical Systems, Inc., Palo Alto, CA, USA) at the Yale University Magnetic Resonance Research Center (MRRC) with actively shielded gradients and zero- through third-order shims. Spin handling and signal reception were achieved via a custom-built eight-channel transceiving radiofrequency head coil as previously described in detail for a similar protocol 57 .…”

“…STEAM and at least one J -difference acquisition were completed for 68 of 72 original study participants 58 , leaving groups for progressive multiple sclerosis (N = 19; 6 primary, 13 secondary; 11 women, 8 men; 55 ± S.D. 8.3 years old; time since first MS diagnosis 20 ± 13 years), relapsing–remitting multiple sclerosis (N = 25; 17 women, 8 men; 45 ± 13 years old; time since first MS diagnosis 9 ± 7 years) and healthy controls with no multiple sclerosis (N = 24; 15 women, 9 men; 43 ± 15 years old).…”

“…Spectral processing was performed in 1 H MRS analysis freeware INSPECTOR 77 , 78 as described in detail previously 58 , 79 . Briefly, signals from individual receive channels were corrected for eddy currents using water-unsuppressed references 80 , phase- and frequency-aligned, and averaged with weighting by receive channel sensitivities 81 .…”

“…With a nested optimization pipeline designed with care to the considerations inherent in potentially overfitting flexible classifiers to the small data sets typical of 1 H MRS studies, here we apply a number of supervised classification algorithms to explore the feasibility of diagnosing multiple sclerosis from proton magnetic resonance spectroscopy measurements of prefrontal cortex metabolite concentrations alone (Fig. 1 ); details regarding the methodological validation of data collection procedures 57 ; the acquisition, processing, and univariate analysis 58 ; and proof-of-concept classification analysis 59 of this data set have been reported previously. Due to the low degrees of freedom offered by a small number of cases, we split our diagnostic pipeline into two independent problems: First, deciding whether an individual has multiple sclerosis; second, deciding whether individuals with multiple sclerosis exhibit a relapsing–remitting or progressive phenotype.…”