Metabolic dysregulation in amyotrophic lateral sclerosis: insights from 1H NMR-based metabolomics in a tertiary care center in India.

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron loss, leading to severe physical impairment and mortality. Despite available treatments like Riluzole and Edaravone, their limited efficacy highlights the need for improved understanding of ALS pathology. This study has explored metabolic alterations in North Indian ALS patients using ¹H Nuclear Magnetic Resonance (NMR)-based metabolomics. A case-control study, involving 45 ALS patients and 30 healthy controls (HCs) was performed. Serum samples were analyzed using 600-MHz NMR spectrometer, revealing significant metabolic differences between ALS and HC groups. Multivariate analyses identified nine dysregulated metabolites-pyruvate, glutamine, histidine, isoleucine, leucine, imidazole, arginine, creatinine, and choline-with ROC analysis showing isoleucine as a promising biomarker (AUC 83%). Pathway enrichment analysis highlighted disruptions in key metabolic pathways, including the Glucose-Alanine Cycle, Urea Cycle, Ammonia Recycling, and the Warburg Effect, suggesting potential links to neuroinflammatory and mitochondrial dysfunction in ALS pathogenesis. This pilot study provides insight into ALS-specific metabolic alterations in Indian cohort and demonstrates the potential of these metabolites as diagnostic biomarkers. Our findings identify potential biomarkers that require validation in larger, multi-centric cohorts to support diagnosis, prognosis, and improved management of ALS.