Longitudinal Metabolomics in Amyotrophic Lateral Sclerosis Implicates Impaired Lipid Metabolism

Area of Science:

• Neuroscience
• Metabolomics
• Biochemistry

Background:

• Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with known metabolic alterations and prognostic indicators like hypermetabolism.
• Previous studies characterized the cross-sectional metabolome in ALS, but lacked longitudinal data correlating metabolic changes with functional decline.

Purpose of the Study:

• To longitudinally evaluate the plasma and tissue metabolome in amyotrophic lateral sclerosis (ALS).
• To identify specific metabolites and metabolic pathways associated with disease progression and functional decline in ALS patients.

Main Methods:

• Longitudinal evaluation of plasma metabolomes and postmortem spinal cord and brain tissue from ALS patients.
• Development of three plasma models (linear mixed effects, interaction, progression) to correlate metabolite levels with functional scores and predict decline.
• Analysis of differential metabolites in spinal cord segments as a surrogate for disease progression and Mendelian randomization to assess causality.

Main Results:

• Plasma metabolomic models predominantly identified lipid metabolites (fatty acids, sphingomyelins, plasmalogens, phosphatidylcholines, lysophospholipids) and amino acids.
• Postmortem spinal cord tissue showed increased sphingomyelin and fatty acids, and decreased phosphatidylcholines and phosphatidylethanolamines in the onset segment.
• Mendelian randomization suggested potential genetic links between impaired carnitine metabolism, antioxidant derivatives, and ALS.

Conclusions:

• Metabolomic alterations, particularly in lipid classes and carnitine metabolism, are associated with ALS severity and progression.
• These findings provide insights into the metabolic underpinnings of ALS and potential therapeutic targets.