Abstract
Objective: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by altered metabolome and energy homeostasis, manifesting with body mass index changes and hypermetabolism—both prognostic of disease progression and survival. The cross-sectional ALS metabolome has been characterized, but longitudinal correlations to functional decline are lacking. Methods: We longitudinally evaluated metabolomes from ALS plasma and terminal postmortem spinal cord and brain motor cortex tissue. We constructed 3 plasma models. A linear mixed effects model correlated all metabolite levels across all timepoints to their corresponding functional scores. An interaction model predicted a longitudinal change in function from baseline metabolites, whereas a progression model identified metabolites linked to a 20% or 50% drop in function. In postmortem samples, differential metabolites in onset versus second spinal cord segments served as a surrogate of disease progression. Mendelian randomization assessed potential causality from metabolites. Results: In plasma, all models primarily selected lipid metabolites and sub-pathways, in addition to amino acids, xenobiotics, and various less frequently selected pathways. Among lipids, fatty acids and sphingomyelins were predominant, along with plasmalogens, phosphatidylcholines, and lysophospholipids. Sex interaction findings were nominal. In the spinal cord, sphingomyelin and long-chain saturated and monounsaturated fatty acids were more abundant in the onset segment tissue, whereas phosphatidylcholines and phosphatidylethanolamines were less abundant. Mendelian randomization suggested that impaired carnitine and short chain acylcarnitine metabolism may be genetically determined in ALS, along with various antioxidant derivatives. Interpretation: Our findings suggest metabolomic changes primarily involving different lipid classes and carnitine metabolism may underscore ALS severity and progression. ANN NEUROL 2025.
| Original language | English (US) |
|---|---|
| Journal | Annals of neurology |
| DOIs | |
| State | Accepted/In press - 2025 |
Funding
The authors are grateful to the study participants and their families. We also thank Jayna Duell, RN, Caroline Piecuch, Amanda Williams, Hasan Farid, Blake Swihart, Daniel Burger, Crystal Pacut, Ian Webber\u2010Davis, and Matt Perkins at Michigan Medicine for facilitating participant consent and sample collection. This work was supported by the Michigan Institute for Clinical and Health Research (MICHR, UL1TR000433), the National Center for Advancing Translational Sciences at the National Institutes of Health (UL1TR002240), NINDS R01NS127188, NIEHS R01ES030049, and NIEHS K23ES027221, the Centers for Disease Control and Prevention (R01TS000289), the Coleman Therapeutic Discovery Fund, the Peter R. Clark Fund for ALS Research, the Sinai Medical Staff Foundation, the Robert A. Epstein and Joan M. Chernoff\u2010Epstein Emerging Scholar Fund, the Dr. Randall Whitcomb Fund for ALS Genetics, the Scott L. Pranger ALS Clinic Fund, the A. Alfred Taubman Medical Research Institute, and the NeuroNetwork for Emerging Therapies, University of Michigan.
ASJC Scopus subject areas
- Neurology
- Clinical Neurology