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Original research
Plasma neurofilament light chain levels suggest neuroaxonal stability following therapeutic remyelination in people with multiple sclerosis
  1. Ahmed Abdelhak1,
  2. Christian Cordano1,
  3. W John Boscardin2,
  4. Eduardo Caverzasi1,
  5. Jens Kuhle3,4,
  6. Brandon Chan1,
  7. Jeffrey M Gelfand1,
  8. Hao H Yiu5,
  9. Frederike C Oertel1,
  10. Alexandra Beaudry-Richard1,
  11. Shivany Condor Montes1,
  12. Jorge R Oksenberg1,
  13. Argentina Lario Lago1,
  14. Adam Boxer1,
  15. Julio C Rojas-Martinez1,
  16. Fanny M Elahi1,
  17. Jonah R Chan1,
  18. Ari J Green1
  1. 1Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco (UCSF), San Francisco, California, USA
  2. 2Departments of Medicine and Epidemiology & Biostatistics, University of California at San Francisco, San Francisco, California, USA
  3. 3Multiple Sclerosis Centre, Neurology, Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland
  4. 4Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), University Hospital and University of Basel, Basel, Switzerland
  5. 5Department of Biology, University of Maryland, College Park, Maryland, USA
  1. Correspondence to Dr Ari J Green, Department of Neurology, University of California San Francisco, San Francisco, CA 94117, USA; agreen{at}ucsf.edu

Abstract

Background Chronic demyelination is a major contributor to axonal vulnerability in multiple sclerosis (MS). Therefore, remyelination could provide a potent neuroprotective strategy. The ReBUILD trial was the first study showing evidence for successful remyelination following treatment with clemastine in people with MS (pwMS) with no evidence of disease activity or progression (NEDAP). Whether remyelination was associated with neuroprotection remains unexplored.

Methods Plasma neurofilament light chain (NfL) levels were measured from ReBUILD trial’s participants. Mixed linear effect models were fit for individual patients, epoch and longitudinal measurements to compare NfL concentrations between samples collected during the active and placebo treatment period.

Results NfL concentrations were 9.6% lower in samples collected during the active treatment with clemastine (n=53, geometric mean=6.33 pg/mL) compared to samples collected during treatment with placebo (n=73, 7.00 pg/mL) (B=−0.035 [−0.068 to −0.001], p=0.041). Applying age- and body mass index-standardised NfL Z-scores and percentiles revealed similar results (0.04 vs 0.35, and 27.5 vs 33.3, p=0.023 and 0.042, respectively). Higher NfL concentrations were associated with more delayed P100 latencies (B=1.33 [0.26 to 2.41], p=0.015). In addition, improvement of P100 latencies between visits was associated with a trend for lower NfL values (B=0.003 [−0.0004 to 0.007], p=0.081). Based on a Cohen’s d of 0.248, a future 1:1 parallel-arm placebo-controlled study using a remyelinating agent with comparable effect as clemastine would need 202 subjects per group to achieve 80% power.

Conclusions In pwMS, treatment with the remyelinating agent clemastine was associated with a reduction of blood NfL, suggesting that neuroprotection is achievable and measurable with therapeutic remyelination.

Trial registration number NCT02040298.

  • MULTIPLE SCLEROSIS
  • NEUROBIOLOGY

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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Footnotes

  • Twitter @Ahmed_Abdelhak_

  • Contributors Conceptualisation: AA, AJG. Clinical trial conduction: AJG, JRC, JMG. Data collection, analysis, interpretation, and verification: AA, AL-L, AB, WJB, CC, JK, FCO, AB-R, SCM, EC, HHY, JRC and AJG. Biomarker collection and measurement: AA, BC, AL-L, AB-R, FME, JCR-R and JO. Supervision: AJG. Drafting, writing, and revising the manuscript: all authors. Guarantors: AG, AA

  • Funding Biomarker assessment was supported by the National Institute of Health (grant no. K23AG059888). The UCSF Biorepository is supported by the National Multiple Sclerosis Society (grant no. SI-2001–3571).

  • Competing interests None declared.

  • 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.

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