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Metabolomics identifies shared lipid pathways in independent amyotrophic lateral sclerosis cohorts.
- Source :
-
Brain: A Journal of Neurology . Dec2022, Vol. 145 Issue 12, p4425-4439. 15p. - Publication Year :
- 2022
-
Abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease lacking effective treatments. This is due, in part, to a complex and incompletely understood pathophysiology. To shed light, we conducted untargeted metabolomics on plasma from two independent cross-sectional ALS cohorts versus control participants to identify recurrent dysregulated metabolic pathways. Untargeted metabolomics was performed on plasma from two ALS cohorts (cohort 1, n = 125; cohort 2, n = 225) and healthy controls (cohort 1, n = 71; cohort 2, n = 104). Individual differential metabolites in ALS cases versus controls were assessed by Wilcoxon, adjusted logistic regression and partial least squares-discriminant analysis, while group lasso explored sub-pathway level differences. Adjustment parameters included age, sex and body mass index. Metabolomics pathway enrichment analysis was performed on metabolites selected using the above methods. Additionally, we conducted a sex sensitivity analysis due to sex imbalance in the cohort 2 control arm. Finally, a data-driven approach, differential network enrichment analysis (DNEA), was performed on a combined dataset to further identify important ALS metabolic pathways. Cohort 2 ALS participants were slightly older than the controls (64.0 versus 62.0 years, P = 0.009). Cohort 2 controls were over-represented in females (68%, P < 0.001). The most concordant cohort 1 and 2 pathways centred heavily on lipid sub-pathways, including complex and signalling lipid species and metabolic intermediates. There were differences in sub-pathways that were enriched in ALS females versus males, including in lipid sub-pathways. Finally, DNEA of the merged metabolite dataset of both ALS and control cohorts identified nine significant subnetworks; three centred on lipids and two encompassed a range of sub-pathways. In our analysis, we saw consistent and important shared metabolic sub-pathways in both ALS cohorts, particularly in lipids, further supporting their importance as ALS pathomechanisms and therapeutics targets. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00068950
- Volume :
- 145
- Issue :
- 12
- Database :
- Academic Search Index
- Journal :
- Brain: A Journal of Neurology
- Publication Type :
- Academic Journal
- Accession number :
- 161225146
- Full Text :
- https://doi.org/10.1093/brain/awac025