Dergai, Oleksandr, Koziczak-Holbro, Magdalena, Bidinosti, Michael, FLOTTE, Ludivine, Nash, Mark, Bruijn, Lucie, Jennings, Lori, Lemire, Sophie, Berry, James, Malaspina, Andrea, Wuu, Joanne, Benatar, Michael, Sachdev, Ruchika and Yu, Lili (2025) Skeletal Muscle Biomarkers of Amyotrophic Lateral Sclerosis: A Large-Scale, Multi-Cohort Proteomic Study. Annals Neurology.

Abstract

Importance. Biomarkers are increasingly recognized as essential tools to advance Amyotrophic Lateral Sclerosis (ALS) therapy development, but their utility is critically dependent on having well-defined contexts-of-use.

Objective. Proteomic-based discovery and replication of plasma and cerebrospinal fluid biomarkers.

Design. Clinical phenotypic data and biofluid samples, collected from patients with ALS and healthy controls through several longitudinal observational studies, were used for the discovery and replication of biomarkers identified using SomaScan Version 4.1

Setting. Academic medical centers.

Participants. The discovery cohort included 161 people with ALS and 165 healthy controls. Longitudinal biological samples (median 4) were available from 132 people with ALS and 108 controls. The replication cohort included 83 people with ALS and 28 healthy controls. Longitudinal biological samples (3 visits) were available from 40 people with ALS.

Exposures. Disease state (ALS vs. healthy control).

Main Outcome(s) and Measure(s). SOMAmer (Slow Off-rate Modified Aptamer)-based semiquantitative measurement of ~7,000 proteins in plasma and CSF. Immunoassay validation of TNNT2 (Troponin T2) as a candidate biomarker of disease progression.

Results. We identified 329 plasma markers significantly differentially regulated between ALS and healthy controls (adjusted p.value <0.05), with 25 of these >40% higher/lower relative abundance. PDLIM3, TNNT2, and MYL11 had the greatest log fold elevation. ANTXR2 and ART3 had the greatest log fold reduction. An overlapping set of plasma markers was found to increase (e.g. PDLIM3, TNNT2, and MYL11) or decrease (e.g. ANTXR2, ART3, and MSTN) with disease progression. CSF proteins with the greatest log fold elevation include NEFL, NEFH, CHIT1, CA3, MYL11 and GPNMB. Tissue specific signature enrichment based on GTEX and HPA suggest a significant contribution of muscle as a source of these biomarkers. Immunoassay validation of TNNT2, one of our lead biomarker candidates, shows strong correlation between SOMAmer intensity and TNNT2 concentration (R=0.81, p<2.2e-16), with TNNT2 increasing by 0.44ng/L per month.

Conclusions and Relevance. In addition to confirming previously reported biomarkers in plasma and CSF, we identified an array of biomarkers that not only differentiate ALS from controls but also change as the disease progresses. Several of these candidates are likely contributed by degenerating muscles. These candidate biomarkers have the potential to be implemented in the clinic to aid therapy development and to shed light on the underlying biology of the disease.

Item Type:	Article
Keywords:	biomarkers, Amyotrophic Lateral Sclerosis, proteomics
Date Deposited:	13 Dec 2025 00:45
Last Modified:	13 Dec 2025 00:45
URI:	https://oak.novartis.com/id/eprint/55906