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This study aimed to identify serum lipids that are reproducibly altered in relapsing\u2013remitting MS (RRMS) and correlated with indicators of disease severity. Lipids were quantified using liquid chromatography\u2013tandem mass spectrometry in a discovery cohort of 47 RRMS, 42 other neurological disorders, and 30 healthy control serum samples, and a validation cohort of 81 RRMS, 18 progressive MS and 33 control samples. Levels were compared between groups using ANOVA adjusted for age, sex, collection site, and treatment status. Correlations of lipids with age, sex, relapse status, and expanded disability severity scale (EDSS) and multiple sclerosis severity scale (MSSS) scores were determined. Eight lysophosphatidylcholines (LPC), five lysophosphatidylethanolamines (LPE), two acylcarnitines, five diacylglycerols, three sphingomyelins (SM), one ceramide, and one hexosylceramide were significantly higher in both RRMS cohorts compared to healthy controls. Random forest models including five lipids predicted RRMS with 83% sensitivity and 77% specificity (discovery), or 89% sensitivity and 61% specificity (validation cohort). Three acylcarnitines, one brain\u2010enriched ceramide (d18:1\/18:0), and two myelin\u2010enriched hexosylceramides were positively correlated with EDSS scores in the validation cohort, of which two were also correlated with MSSS scores. However, these associations were not observed in the discovery cohort. The neuron\u2010enriched lipid SM(d18:1\/18:0) was significantly higher during relapse in the validation and combined cohorts. In conclusion, this study identifies a set of 25 lipids that are reproducibly elevated in serum of people with RRMS. Higher serum LPCs, LPEs, diacylglycerols and acylcarnitines may reflect a peripheral lipolysis signature, while higher levels of neuron\u2010enriched sphingolipids could reflect neurodegeneration. Future studies should investigate if these serum lipids predict brain atrophy and disability progression.<\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70285-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70285","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T05:36:17Z","timestamp":1762407377000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Serum Lipid Profile of Relapsing Multiple Sclerosis Differs Reproducibly From Healthy 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