CoChat
Sign Up
Cited by 108Multiple Sclerosis Research StudiesPsoriasis: Treatment and PathogenesisInflammatory Bowel Disease

Dimethyl fumarate decreases neurofilament light chain in CSF and blood of treatment naïve relapsing MS patients

Open access
Sejbaek, Tobias, Nielsen, Helle Hvilsted, Penner, Natasha, Plavina, Tatiana, Mendoza, Jason P, Martin, Nellie Anne, Elkjaer, Maria Louise, Ravnborg, Mads Henrik +1 more·2019·Journal of Neurology, Neurosurgery & Psychiatry
DOI 10.1136/jnnp-2019-321321PMC PMC6902070
Open this paper in CoChat — free accountOpen PDF

Abstract

Objectives: In a prospective phase IV trial of the first-line oral treatment dimethyl fumarate (DMF), we examined dynamics of neurofilament light (NFL) chain in serum, plasma and cerebrospinal fluid (CSF) samples collected over 12 months from relapsing-remitting multiple sclerosis (RRMS) patients. NFL changes were related to disease activity. Methods: We examined NFL levels by single-molecule array in 88 CSF, 348 plasma and 131 sera from treatment-naïve RRMS patients (n=52), healthy controls (n=23) and a placebo group matched by age, sex and NFL (n=52). Plasma/sera were collected at baseline, and 1, 3, 6 and 12 months after DMF. CSF samples were collected at baseline and 12 months after DMF. Results: NFL concentration in CSF, plasma and serum correlated highly (p<0.0001 for all), but plasma levels were only 76.9% of paired serum concentration. After 12 months of DMF treatment, NFL concentration decreased by 73%, 69% and 55% in the CSF, serum and plasma (p<0.0001, respectively). Significant reduction in blood was observed after 6 and 12 months treatment compared with baseline (p<0.01 and p<0.0001, respectively) and to placebo (p<0.0001). Patients with NFL above the 807.5 pg/mL cut-off in CSF had 5.0-times relative risk of disease activity (p<0.001). Conclusions: This study provides Class II evidence that first-line DMF reduces NFL in both blood and CSF after 6 months and normalises CSF levels in 73% of patients. High NFL concentration in CSF after a year reflected disease activity. NFL levels were higher in serum than in plasma, which should be considered when NFL is used as a biomarker.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1136/jnnp-2019-321321

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Four studies consistently reported higher NfL levels in serum than in plasma.

    “They consistently reported higher NfL levels in serum than in plasma.”

    From A Method to Combine Neurofilament Light Measurements From Blood Serum and Plasma in Clinical and Population-Based Studies (2022) · cites this paper as [17]

    The Results section (‘NFL levels correlate in body fluids and are the lowest in plasma’) reports that plasma NfL averaged 76.9% of serum NfL in paired samples; the Discussion describes plasma values as 23% lower. This supports the serum-versus-plasma finding for this study, but this paper alone does not establish that four studies consistently reported it. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • We confirm the numerical differences between serum and EDTA-plasma NfL levels that have been found in other studies.

    “We confirm the numerical differences between serum and EDTA-plasma NfL levels that have been found in other studies (15–18).”

    From A Method to Combine Neurofilament Light Measurements From Blood Serum and Plasma in Clinical and Population-Based Studies (2022) · cites this paper as [17]

    The Results section reports that plasma NfL levels averaged 76.9% of paired serum levels, and the Discussion describes a significant difference. The Methods section does not identify the plasma as EDTA-plasma, so the source supports the numerical serum–plasma difference but not that specific sample type. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • In those four studies, strengths of correlation were tested via Spearman's correlation coefficient.

    “In all studies, however, strengths of correlation were tested via Spearman's correlation coefficient.”

    From A Method to Combine Neurofilament Light Measurements From Blood Serum and Plasma in Clinical and Population-Based Studies (2022) · cites this paper as [17]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 30

  1. [1]Norgren N, Rosengren L, Stigbrand T Elevated neurofilament levels in neurological diseases. Brain Res 2003; 987: 25– 31. 10.1016/S0006-8993(03)03219-0 14499942 · DOI
  2. [2]Deisenhammer F, Egg R, Giovannoni G, et al EFNS guidelines on disease-specific CSF investigations. Eur J Neurol 2009; 16: 760– 70. 10.1111/j.1468-1331.2009.02595.x 19475759 · DOI
  3. [3]Khalil M, Teunissen CE, Otto M, et al Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol 2018; 14: 577– 89. 10.1038/s41582-018-0058-z 30171200 · DOI · Paper page
  4. [4]Kuhle J, Barro C, Andreasson U, et al Comparison of three analytical platforms for quantification of the neurofilament light chain in blood samples: ELISA, electrochemiluminescence immunoassay and Simoa. Clin Chem Lab Med 2016; 54: 1655– 61. 10.1515/cclm-2015-1195 27071153 · DOI · Paper page
  5. [5]Lycke JN, Karlsson JE, Andersen O, et al Neurofilament protein in cerebrospinal fluid: a potential marker of activity in multiple sclerosis. J Neurol Neurosurg Psychiatry 1998; 64: 402– 4. 10.1136/jnnp.64.3.402 9527161 PMC2170011 · DOI
  6. [6]Barro C, Benkert P, Disanto G, et al Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. Brain 2018; 141: 2382– 91. 10.1093/brain/awy154 29860296 · DOI · Paper page
  7. [8]Axelsson M, Malmeström C, Gunnarsson M, et al Immunosuppressive therapy reduces axonal damage in progressive multiple sclerosis. Mult Scler 2014; 20: 43– 50. 10.1177/1352458513490544 23702432 · DOI
  8. [9]Gunnarsson M, Malmeström C, Axelsson M, et al Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab. Ann Neurol 2011; 69: 83– 9. 10.1002/ana.22247 21280078 · DOI
  9. [10]Kuhle J, Disanto G, Lorscheider J, et al Fingolimod and CSF neurofilament light chain levels in relapsing-remitting multiple sclerosis. Neurology 2015; 84: 1639– 43. 10.1212/WNL.0000000000001491 25809304 PMC4409586 · DOI
  10. [11]Novakova L, Axelsson M, Khademi M, et al Cerebrospinal fluid biomarkers of inflammation and degeneration as measures of fingolimod efficacy in multiple sclerosis. Mult Scler 2017; 23: 62– 71. 10.1177/1352458516639384 27003946 · DOI
  11. [12]Kuhle J, Kropshofer H, Haering DA, et al Blood neurofilament light chain as a biomarker of MS disease activity and treatment response. Neurology 2019; 92: e1007– 15. 10.1212/WNL.0000000000007032 30737333 PMC6442011 · DOI
  12. [13]Hyun JW, Kim Y, Kim G, et al Longitudinal analysis of serum neurofilament light chain: a potential therapeutic monitoring biomarker for multiple sclerosis. Mult Scler 2019; 1352458519840757. 30912689
  13. [14]de Flon P, Gunnarsson M, Laurell K, et al Reduced inflammation in relapsing-remitting multiple sclerosis after therapy switch to rituximab. Neurology 2016; 87: 141– 7. 10.1212/WNL.0000000000002832 27316241 · DOI
  14. [15]Piehl F, Kockum I, Khademi M, et al Plasma neurofilament light chain levels in patients with MS switching from injectable therapies to fingolimod. Mult Scler 2018; 24: 1046– 54. 10.1177/1352458517715132 28627962 · DOI
  15. [16]Mellergård J, Tisell A, Blystad I, et al Cerebrospinal fluid levels of neurofilament and tau correlate with brain atrophy in natalizumab-treated multiple sclerosis. Eur J Neurol 2017; 24: 112– 21. 10.1111/ene.13162 27699930 · DOI
  16. [17]Cai L, Huang J Neurofilament light chain as a biological marker for multiple sclerosis: a meta-analysis study. Neuropsychiatr Dis Treat 2018; 14: 2241– 54. 10.2147/NDT.S173280 30214214 PMC6126505 · DOI
  17. [18]Calabresi PA, Kieseier BC, Arnold DL, et al Pegylated interferon beta-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol 2014; 13: 657– 65. 10.1016/S1474-4422(14)70068-7 24794721 · DOI
  18. [20]Tintore M, Rovira Àlex, Río J, et al Defining high, medium and low impact prognostic factors for developing multiple sclerosis. Brain 2015; 138: 1863– 74. 10.1093/brain/awv105 25902415 · DOI · Paper page
  19. [21]Thompson AJ, Banwell BL, Barkhof F, et al Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 2018; 17: 162– 73. 10.1016/S1474-4422(17)30470-2 29275977 · DOI · Paper page
  20. [22]Kurtzke JF Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33: 1444– 52. 10.1212/WNL.33.11.1444 6685237 · DOI · Paper page
  21. [24]Teunissen CE, Petzold A, Bennett JL, et al A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking. Neurology 2009; 73: 1914– 22. 10.1212/WNL.0b013e3181c47cc2 19949037 PMC2839806 · DOI · Paper page
  22. [25]Disanto G, Adiutori R, Dobson R, et al Serum neurofilament light chain levels are increased in patients with a clinically isolated syndrome. J Neurol Neurosurg Psychiatry 2016; 87: 126– 9. 10.1136/jnnp-2014-309690 25716934 · DOI
  23. [27]Håkansson I, Tisell A, Cassel P, et al Neurofilament levels, disease activity and brain volume during follow-up in multiple sclerosis. J Neuroinflammation 2018; 15: 209 10.1186/s12974-018-1249-7 30021640 PMC6052680 · DOI
  24. [30]Novakova L, Axelsson M, Malmeström C, et al Reduced cerebrospinal fluid concentrations of oxysterols in response to natalizumab treatment of relapsing remitting multiple sclerosis. J Neurol Sci 2015; 358: 201– 6. 10.1016/j.jns.2015.08.1537 26342940 · DOI
  25. [31]Rosengren LE, Karlsson JE, Karlsson JO, et al Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF. J Neurochem 1996; 67: 2013– 8. 10.1046/j.1471-4159.1996.67052013.x 8863508 · DOI · Paper page
  26. [32]Fox RJ, Miller DH, Phillips JT, et al Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012; 367: 1087– 97. 10.1056/NEJMoa1206328 22992072 · DOI
  27. [33]Gold R, Kappos L, Arnold DL, et al Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012; 367: 1098– 107. 10.1056/NEJMoa1114287 22992073 · DOI
  28. [34]Amor S, van der Star BJ, Bosca I, et al Neurofilament light antibodies in serum reflect response to natalizumab treatment in multiple sclerosis. Mult Scler 2014; 20: 1355– 62. 10.1177/1352458514521887 24515731 · DOI
  29. [35]Yildiz O, Mao Z, Adams A, et al Disease activity in progressive multiple sclerosis can be effectively reduced by cladribine. Mult Scler Relat Disord 2018; 24: 20– 7. 10.1016/j.msard.2018.05.010 29860198 · DOI
  30. [36]Komori M, Kosa P, Stein J, et al Pharmacodynamic effects of daclizumab in the intrathecal compartment. Ann Clin Transl Neurol 2017; 4: 478– 90. 10.1002/acn3.427 28695148 PMC5497534 · DOI

Cited by

Sorted by citations

Authors
Sejbaek, T., Nielsen, H. H., Penner, N., Plavina, T., Mendoza, J. P., Martin, N. A., Elkjaer, M. L., Ravnborg, M. H., & Illes, Z.
Affiliations
  • University of Southern Denmark (DK)
  • Biogen (United States) (US)
  • Odense University Hospital (DK)
ORCID
Venue
Journal of Neurology, Neurosurgery & Psychiatry
Publisher
BMJ
Published
2019-10-13
Volume
90
Issue
12
Pages
jnnp-2019-321321
ISSN
  • 0022-3050 (ISSN-L)
  • 1468-330X
DOI
10.1136/jnnp-2019-321321
PMC
PMC6902070
OpenAlex
W2979502567
Cited by
108
References
5
Citations by year
2026: 3 · 2025: 10 · 2024: 14 · 2023: 18 · 2022: 15 · 2021: 27 · 2020: 19 · 2019: 2
FWCI
11.59
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Journal of Neurology Neurosurgery & Psychiatry (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, cc-by-nc)
Funders
  • The Danish Multiple Sclerosis Society. (R367-A25341)
  • Biogen
  • Odense University Hospital (5798002573633)
  • Syddansk Universitet (14/24200)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
Keywords
dimethyl fumarate, neurofilament light chain, relapsing-remitting multiple sclerosis, cerebrospinal fluid biomarkers, serum biomarkers, disease activity, treatment-naive patients, biomarker cut-off values
MeSH terms
Dimethyl Fumarate, Adult, Female, Humans, Intermediate Filaments, Male, Middle Aged, Prospective Studies, Biomarkers, Treatment Outcome, Neurofilament Proteins, Multiple Sclerosis, Relapsing-Remitting

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review