Ultra-High Field Proton MR Spectroscopy in Early-Stage Amyotrophic Lateral Sclerosis

Abstract

A major hurdle in the development of effective treatments for amyotrophic lateral sclerosis (ALS) has been the lack of robust biomarkers for use as clinical trial endpoints. Neurochemical profiles obtained in vivo by high field proton magnetic resonance spectroscopy (1H-MRS) can potentially provide biomarkers of cerebral pathology in ALS. However, previous 1H-MRS studies in ALS have produced conflicting findings regarding alterations in the levels of neurochemical markers such as glutamate (Glu) and myo-inositol (mIns). Furthermore, very few studies have investigated the neurochemical abnormalities associated with ALS early in its course. In this study, we measured neurochemical profiles using single-voxel 1H-MRS at 7 tesla (T) and glutathione (GSH) levels using edited MRS at 3 T in 19 subjects with ALS who had relatively high functional status (ALS Functional Rating Scale-Revised mean ± SD = 39.8 ± 5.6) and 17 healthy controls. We observed significantly lower total N-acetylaspartate over mIns (tNAA/mIns) ratio in the motor cortex and pons of subjects with ALS versus healthy controls. No group differences were detected in GSH at 3 and 7 T. In subjects with ALS, the levels of tNAA, mIns, and Glu in the motor cortex were dependent on the extent of disease represented by El Escorial diagnostic subcategories. Specifically, combined probable/definite ALS had lower tNAA than possible ALS and controls (both p = 0.03), higher mIns than controls (p < 0.01), and lower Glu than possible ALS (p < 0.01). The effect of disease stage on MRS-measured metabolite levels may account for dissimilar findings among previous 1H-MRS studies in ALS.

Tract-specific analysis improves sensitivity of spinal cord diffusion MRI to cross-sectional and longitudinal changes in amyotrophic lateral sclerosis

“…All participants underwent imaging at time of enrollment, in compliance with all the ethical regulations, and were asked to return for follow-up visits at 6 and 12 months after enrollment. We recently reported magnetic resonance spectroscopy brain findings in this cohort 23,24 .…”

“…Scores on the total ECAS and its ALS-specific component were recorded. A UMN burden score was derived based on the neuromuscular examination as previously described 23 and ranged from 0 to 6, with a higher score indicating greater UMN burden. Current riluzole use was also documented.…”

Biomarkers in Motor Neuron Disease: A State of the Art Review

“…Total creatine (Cr and PCr) appears unchanged (248, 259, 282), but studies measuring Glu, mI, Cho, GABA, and GSH have produced conflicting results and, at present, it is unclear whether the concentration of these molecules is altered in ALS (255, 258, 259, 263, 264, 282).…”

Neurochemical correlates of functional decline in amyotrophic lateral sclerosis

“…Proton magnetic resonance spectroscopy ( 1 H-MRS) detects abnormal brain neurochemistry in ALS[2–6]. Reproducible findings include altered levels of motor cortex N -acetylaspartate (NAA; neuronal marker)[2, 4] and myo -inositol (mIns; putative glial marker)[4, 5] — in particular, a lower total NAA to mIns ratio (tNAA/mIns) in patients than in controls[3, 5] — as well as elevated levels of brainstem Glx (glutamate+glutamine)[4, 7].…”