ABSTRACT & COMMENTARY

A Novel Magnetic Resonance Spectroscopy Marker for Multiple Sclerosis

By Susan Gauthier, DO, MPH

Assistant Professor of Neurology, Weill Cornell Medical College

Dr. Gauthier reports she receives research support from EMD Serono, Biogen Idec, and Novartis Pharmaceuticals, and is on the speakers bureau for Biogen Idec and Teva Neurosciences.

SYNOPSIS: The metabolite ratio of myo-inositol to N-acetylaspartate was utilized as a novel magnetic resonance spectroscopy marker to study the combined influence of gliosis and axonal loss on degeneration in multiple sclerosis (MS). This novel metabolite ratio within normal appearing white matter predicted annualized brain atrophy and clinical disease metrics in both preliminary and confirmatory cohorts of MS patients.

SOURCE: Llufriu S, et al. Magnetic resonance spectroscopy markers of disease progression in multiple sclerosis. JAMA Neurol 2014;71:840-847.

Multiple sclerosis (MS) is a complicated disease having both inflammatory (relapsing) and degenerative (progressive) stages. Most agree that the degenerative aspect of MS is multifactorial and relates to events occurring throughout the lifetime of a disease. Contributing factors leading to end-stage neuronal loss, as measured by brain atrophy and sustained clinical progression, are likely to encompass all facets of the disease such as myelin loss, axonal injury, and astrogliosis. Currently, we have a number of new imaging modalities to study each of these pathological processes in vivo and gain an improved understanding of the individual impact and interaction of these different pathological events on disease progression.

The current study utilizes both magnetic resonance spectroscopy (MRS) and myelin water fraction (MWF) imaging as non-conventional imaging parameters to predict annualized brain atrophy, annualized clinical progression (as measured by EDSS and MSFC), and sustained (12 months) disability progression (EDSS and MSFC) over a mean follow-up of 4 years. The MRS metabolites measured included both N-acetylaspartate (NAA) and myo-inositol (mI); the former is a marker of neuronal/axonal integrity and the latter originates from intracellular astrocyte stores and elevates with astroglial hypertrophy. Multi-component T2 relaxometry is an imaging modality that derives MWF; this fraction represents the water within the myelin bilayers over the total brain tissue water and thus is an indirect measure for myelin. In the preliminary cohort of patients, NAA and mI were measured in normal appearing white matter (NAWM) and gray matter (GM) from a region covering four slices above the corpus callosum, and median MWF was calculated within the NAWM. In the modeling steps of the analysis, the authors found a statistically significant interaction between NAA and mI measurements. Using these findings and the biological inference that increased gliosis is associated with reduced axonal integrity, the metabolite measurements were combined into a novel ratio of mI:NAA. In the preliminary cohort (59 patients), the ratio of mI:NAA in NAWM was predictive of annualized brain volume loss (P = 0.02), annualized decrease in MSFC z-scores (P < 0.001), and sustained decrease in MSFC (P = 0.01). Individual metabolite measurements within the NAWM and GM as well as GM mI:NAA and NAWM MWF were not significant predictors. No predictors had a statistically significant influence on EDSS progression. In the confirmatory cohort (220 patients), MRS metabolite measurements were derived from only a single 1.5 cm thick slice above the corpus callosum and MWF was not used. In this cohort, NAWM mI:NAA similarly predicted annualized brain volume loss (P = 0.02), EDSS, and MSFC worsening per year as well as sustained EDSS progression (not sustained MSFC progression).

COMMENTARY

These authors were the first to apply the novel MRS metabolite mI:NAA ratio to a well-designed study of MS. The combined mI:NAA ratio, as opposed to individual metabolites, demonstrated an impact of disease progression, which suggests that neuronal degeneration is partially dependent on an interactive relationship between white matter axonal loss and increased gliosis. Biologically, these results have plausibility and there was a similar result in the confirmatory cohort. NAWM and MWF were not predictive of disease progression and, consequently, the authors proposed that myelin loss has a minimal impact on degeneration. Pathological studies suggest that focal myelin loss at lesions contributes to chronic axonal loss; therefore, the contribution of myelin content on degeneration was potentially underestimated in this study. GM metabolite measurements were not predictive and were felt to be a limitation of the instrument; however, with continued MR advancements, we hope to gain a better understanding of GM pathology and its contribution. Finally, the results on clinical disability varied between cohorts and are less straightforward to interpret. However, differences in progression rates between the two groups may potentially explain this discrepancy. In conclusion, this study demonstrates the application of a novel MRS marker and has provided new insight into the pathological processes leading to degeneration in MS.