{"doi":"10.1093/brain/awac025","title":"Metabolomics identifies shared lipid pathways in independent amyotrophic lateral sclerosis cohorts","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.","journal":"Brain","year":2022,"id":239191,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":50,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9409,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":282916,"name":"Kai Guo","orcid":"0000-0002-4651-781X","position":1,"is_corresponding":false},{"id":263298,"name":"Masha G. Savelieff","orcid":"0000-0001-5575-2494","position":2,"is_corresponding":false},{"id":763012,"name":"Adam Patterson","orcid":"0000-0003-3893-8670","position":3,"is_corresponding":false},{"id":483169,"name":"Stacey A. Sakowski","orcid":"0000-0002-5064-9022","position":4,"is_corresponding":false},{"id":675129,"name":"Hani Habra","orcid":"0000-0003-4838-0105","position":5,"is_corresponding":false},{"id":340030,"name":"Alla Karnovsky","orcid":"0000-0001-7388-8520","position":6,"is_corresponding":false},{"id":350442,"name":"Junguk Hur","orcid":"0000-0002-0736-2149","position":7,"is_corresponding":false},{"id":255269,"name":"Eva L. Feldman","orcid":"0000-0002-9162-2694","position":8,"is_corresponding":false},{"id":226511,"name":"Stephen A. Goutman","orcid":"0000-0001-8780-6637","position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":null,"created_at":"2026-07-19T00:22:36.865157Z","pmid":"35088843","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}