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Multiple sclerosis
Original research
Distinct plasma lipids predict axonal injury and multiple sclerosis activity
  1. Vinicius A Schoeps1,
  2. Pavan Bhargava2,
  3. Akash Virupakshaiah1,
  4. Dimitrios Christos Ladakis2,
  5. Carson Moseley1,
  6. Janet Chong1,
  7. Gregory Aaen3,
  8. Jennifer S Graves4,
  9. Leslie Benson5,
  10. Mark P Gorman5,
  11. Mary Rensel6,
  12. Aaron Abrams6,
  13. Soe Mar7,
  14. Timothy E Lotze8,
  15. Tanuja Chitnis9,
  16. Amy Waldman10,
  17. Lauren Krupp11,
  18. Moses Rodriguez12,
  19. Jan-Mendelt Tillema12,
  20. John Rose13,
  21. Teri Schreiner14,
  22. Ferhan Qureshi15,
  23. Skyler Peterson13,
  24. Lisa F Barcellos16,
  25. T Charles Casper13,
  26. John Newman17,18,19,
  27. Kamil Borkowski17,
  28. Emmanuelle Waubant1
  29. On behalf of the US Network of Pediatric MS Centers
  1. 1Department of Neurology, University of California San Francisco, San Francisco, California, USA
  2. 2Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
  3. 3Loma Linda University, Loma Linda, California, USA
  4. 4Department of Neurosciences, University of California San Diego, La Jolla, California, USA
  5. 5Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA
  6. 6Cleveland Clinic, Cleveland, Ohio, USA
  7. 7Washington University in St Louis, St Louis, Missouri, USA
  8. 8Baylor College of Medicine, Houston, Texas, USA
  9. 9Massachusetts General Hospital, Boston, Massachusetts, USA
  10. 10The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  11. 11Department of Neurology, NYU Langone Health, New York, New York, USA
  12. 12Mayo Clinic Rochester, Rochester, Minnesota, USA
  13. 13University of Utah Health, Salt Lake City, Utah, USA
  14. 14University of Colorado, Denver, Colorado, USA
  15. 15Octave Bioscience, Menlo Park, California, USA
  16. 16University of California, Berkeley, California, USA
  17. 17University of California Davis West Coast Metabolomics Center, Davis, California, USA
  18. 18Department of Agriculture, USDA-ARS Western Human Nutrition Research Center, Davis, California, USA
  19. 19Department of Nutrition, University of California Davis, Davis, CA, USA
  1. Correspondence to Dr Vinicius A Schoeps; vschoeps{at}fas.harvard.edu

Abstract

Background Lipids are of particular interest for the study of neuroinjury and neuroinflammation as structural lipids are major components of myelin, and a variety of lipid species modulate inflammation. In this study, we performed an in-depth lipidomics analysis to identify lipids associated with injury and disease activity.

Methods Plasma samples were collected from paediatric-onset multiple sclerosis (MS) cases within 4 years of disease onset from 17 sites. The lipidome was measured using untargeted and targeted mass spectrometry. For cross-sectional analyses, the agreement between multiple machine learning models was used to predict neurofilament light chain (NfL) levels. In longitudinal analyses, the association between clinical (relapse count) and imaging (MRI count with ≥1 enhancing or new T2 lesion) outcomes with each metabolite was estimated using adjusted negative binomial regression.

Results At sample collection, 68% of the 435 included individuals were treatment-naive, with a median disease duration of 0.8 years (IQR 0.3–1.7). For longitudinal analyses, 381 and 335 subjects had at least 1 year of clinical and imaging follow-up, respectively. In cross-sectional analyses, NfL chain levels identified structural lipids (phosphatidylcholines and phosphatidylethanolamines) as the highest-performing predictors, including external validation. In contrast, longitudinal analyses found polyunsaturated fatty acids (PUFAs) and their derivatives to be protective from subsequent disease activity (q<0.001, multiple outcomes).

Conclusion There are two categories of lipids associated with MS processes. First, structural lipids strongly associated with NfL levels may result from cell lysis secondary to acute inflammation. In contrast, PUFAs, especially ω−3, had a protective effect on subsequent disease activity.

  • MULTIPLE SCLEROSIS
  • PAEDIATRIC
  • NEUROIMMUNOLOGY

Data availability statement

Data are available on reasonable request. The data supporting this study’s findings are available from the study team on request to the corresponding author.

https://doi.org/10.1136/jnnp-2024-333652

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    Data availability statement

    Data are available on reasonable request. The data supporting this study’s findings are available from the study team on request to the corresponding author.

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    Footnotes

    • KB and EW are joint senior authors.

    • X @tweetsatakash

    • KB and EW contributed equally.

    • Contributors EW conceived the study design, obtained funding, accepted full responsibility for the conduct of the study, had access to the data, and controlled the decision to publish. VAS drafted the first version of the manuscript, contributed to the study design and conducted the data analysis. KB and JN supervised the lipidomics profiling and preprocessing of the data. JC supervised the data acquisition process. All authors contributed to the data interpretation and manuscript editing and approved the final version of the manuscript.

    • Funding This study was supported by the National Institute of Neurologic Disorders and Stroke (R01NS117541, PI: EW) and the National Multiple Sclerosis Society (SI-2110-38420, PI: TCC; RG4861A3/1, PI: EW).

    • Disclaimer The funding sources were not involved in the study design, the collection, analysis, and interpretation of the data, or in the decision to submit this article for publication.

    • Competing interests VAS, KB, JC, DCL, GA, AA, SM, LFB, MRodriguez, TEL, J-MT, SP and JN have no conflicts of interest to report. PB has received honoraria from Genentech and EMD-Serono, grants from Genentech, EMD-Serono, GSK and Amylyx Pharmaceuticals. AV has received a Fellowship Grant from Biogen, Novartis and EMD Serono. CM is supported by a Clinician Scientist Development Award, Grant # FAN-2107-38301 from the National Multiple Sclerosis Society. JSG has received research support from NMSS, Octave, Biogen, EMD Serono, Novartis, ATARA Biotherapeutics and ABM. She has served on advisory boards for TG therapeutics and a Horizon and a paediatric clinical trial steering committee for Novartis. She has consulted for Google. LB has participated in multicentre clinical trials funded by Roche, Alexion and Biogen. She has current support from ROHHAD Fight, NIH and Rosamund Stone Zander Translational Neuroscience Center. She has received speakers honorarium from Novartis. MPG has received research funding paid to his institution from Biogen, Genentech Roche and Pfizer and personal compensation from Arialys for medical advisory board work. MRensel has received grant funding from the National MS Society (NMSS) and Genzyme. She has served as a consultant and or speaker for; EMD Serono, Horizon, Genzyme, Sanofi and Genentech. She serves on a data safety monitoring board for Biogen. She serves on the Ohio Board of NMSS. JR has received research funding from NMSS, NIH, Biogen and VATS has received speakers fees from Cycle Pharmaceutics and Hoffman La Roche. She participates in research funded by Roche and the National MS Society. TC has consulted for Genentech-Roche and Novartis. She has received research support from Bristol Myers Squibb, Genentech-Roche, Novartis, Octave Biosciences, Sanofi and Tiziana Life Sciences. AW has received research funding from the National Multiple Sclerosis Society, Genentech and Novartis. LK has received research or programmatic funding or has received compensation for consulting, speaking, travel and meal allowances or serving on DSMB committees from Eisai, Peer View, Gerson Lehrman, WebMD, CME Outfitters, General Dynamics Information, At the Limits, Novartis, Biogen, F. Hoffman/LaRoche. She also receives royalties for use of the Fatigue Severity Scale by various biopharmaceutical entities. FQ is an employee of Octave Bioscience. TCC has received funding for research unrelated to this work from Hoffmann La Roche and Biogen. EW has participated in multicentre clinical trials funded by Genentech, Alexion and Biogen. She has current support from the NIH, NMSS, DoD, PCORI, CMSC and Race to Erase MS. She has received honorarium for talks from Advanced Curriculum, Yoga Moves MS and NeurologyLive.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.