Electrical impedance myography (EIM), a non-invasive, electrophysiological technique, has preliminarily shown value as an ALS biomarker. Here we perform a multicenter study to further assess EIM’s potential for tracking ALS. ALS patients were enrolled across eight sites. Each subject underwent EIM, handheld dynamometry (HHD), and the ALS Functional Rating Scale-revised (ALSFRS-R) regularly. Techniques were compared by assessing the coefficient of variation (CoV) in the rate of decline and each technique’s correlation to survival. Results showed that in the 60 patients followed for one year, EIM phase measured from the most rapidly progressing muscle in each patient had a CoV in the rate of decline of 0.62, compared to HHD (0.82) and the ALSFRS-R (0.74). Restricting the measurements to the first six months gave a CoV of 0.55 for EIM, 0.93 for HHD, and 0.84 for ALSFRS-R. For both time-periods, all three measures correlated with survival. Based on these data, a six-month clinical trial designed to detect a 20% treatment effect with 80% power using EIM would require only 95 patients/arm compared to the ALSFRS-R, which would require 220 subjects/arm. In conclusion, EIM can serve as a useful ALS biomarker that offers the prospect of greatly accelerating phase 2 clinical trials.

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ContributorsGIW wrote and revised the manuscript in response to co-author comments. He finalized all the figures and tables, performed the literature search, and assisted with data interpretation. HJK critically reviewed the manuscript and made important suggestions to improve it. He assisted with data interpretation. IBA performed the data analysis, constructed the figures and tables, and made important suggestions to improve the manuscript. H-CK assisted with the data analysis and also reviewed the manuscript. GRC critically reviewed the manuscript and made important suggestions to improve it. He assisted with data interpretation. All other authors were given the opportunity to review the manuscript and make suggestions which GIW received, either revising the paper or providing explanations. All who are not deceased were involved with approval of the manuscript.

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The objective of this study was to use magnetic resonance spectroscopy (MRS) to compare metabolite ratios in the cervical spinal cord of ALS patients to healthy controls. Fourteen ALS patients and 16 controls were scanned using a 3T scanner. A rectangular voxel (8 × 5 × 35 mm) was placed along the main axis of the cord with the lower limit at the inferior aspect of the C2 vertebral body. MRS was performed with a point-resolved spectroscopy (PRESS) sequence. Water signals were suppressed using a three-pulse chemical shift selective (CHESS) saturation sequence. Relative concentrations of choline (Cho), creatine (Cr), myo-inositol (Myo), and NAA were computed from metabolite peaks. Differences in metabolite ratios between ALS patients and controls were assessed with a Wilcoxon rank-sum test. The relationship of metabolite ratios to clinical measures (ALSFRS-R and FVC) was determined by Pearson correlation. The NAA/Cr and NAA/Myo ratios were reduced by 40% and 38%, respectively, in ALS patients. The reduction in NAA/Myo and NAA/Cho correlated significantly with FVC, with correlation coefficients of 0.66 and 0.60, respectively. In conclusion, MR spectra can reliably be obtained from the cervical spinal cord in ALS. MRS of the cervical cord may be a useful biomarker of disease progression.