Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2022, 166(3):304-311 | DOI: 10.5507/bp.2021.034

Associations between neurofilament light chain levels, disease activity and brain atrophy in progressive multiple sclerosis

Jarmila Szilasiovaa, e, Pavol Mikulab, Jaroslav Rosenbergerc, d, Miriam Fedicovae, Peter Urbanf, Lydia Frigovag, Marianna Vitkovaa, e, Zuzana Gdovinovaa, e, Jozef Hanesh, i, Eva Stevensi
a Department of Neurology, Pavol Jozef Safarik University in Kosice, Slovak Republic
b Department of Social and Behavioral Medicine, Pavol Jozef Safarik University in Kosice, Slovak Republic
c Department of Health Psychology and Methodology of Research, II. Internal Clinic, Pavol Jozef Safarik University in Kosice, Slovak Republic
d Olomouc University Social Health Institute, Palacky University Olomouc, Czech Republic
e Department of Neurology, L. Pasteur University Hospital, Kosice, Slovak Republic
f Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Safarik University in Kosice, Slovak Republic
g Pro Magnet Kosice, Slovak Republic
h Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovak Republic
i AXON Neuroscience R&D Services SE, Bratislava, Slovak Republic

Background: Neurofilament light chain is a promising biomarker of disease activity and treatment response in relapsing-remitting multiple sclerosis (MS). Its role in progressive MS is less clear.

Aim: The aim of the study was to assess the relationship between plasma neurofilament light chain (pNfL) and disease activity as defined by the concept NEDA-3 (No Evident Disease Activity), and brain volumetry, in a cohort of patients with the progressive disease form (PMS).

Methods: Levels of pNfL (SIMOA technology) were examined in 52 PMS patients and analysed in relationship to NEDA-3 status and annual brain volume loss (BVL) during the last 12 months. The statistical model was developed using logistic regression analysis, including demographic, clinical and magnetic resonance imaging (MRI) data as independent variables. Dependent variables were NEDA-3 status and BVL.

Results: The mean age of the study participants (n=52, 50% females) was 45.85 (SD, 9.82) and the median disability score was 5.0 (IQR: 5.0-5.5). ROC analysis showed that pNfL predicts NEDA-3 (the sensitivity and specificity of the model were 77.8% and 87.6%, respectively, P<0.001) and abnormal BVL (the sensitivity and specificity were 96.6% and 68.2%, respectively, P<0.001).

Conclusions: The results show that pNfL levels are a useful biomarker of disease activity determined by NEDA-3 status, including brain MRI-volumetry, in patients with the progressive form of MS.

Keywords: multiple sclerosis, progressive MS, neurofilament light chain, no evident disease activity, brain volume loss

Received: January 25, 2021; Revised: April 13, 2021; Accepted: May 24, 2021; Prepublished online: June 1, 2021; Published: September 14, 2022  Show citation

ACS AIP APA ASA Harvard Chicago Chicago Notes IEEE ISO690 MLA NLM Turabian Vancouver
Szilasiova, J., Mikula, P., Rosenberger, J., Fedicova, M., Urban, P., Frigova, L., ... Stevens, E. (2022). Associations between neurofilament light chain levels, disease activity and brain atrophy in progressive multiple sclerosis. Biomedical papers166(3), 304-311. doi: 10.5507/bp.2021.034
Download citation

References

  1. Kuhle J, Barro C, Disanto G, Mathias A, Soneson Ch, Bonnier G, Yaldizi O, Regeniter A, Derfuss T, Canales M, Schluep M, Du Pasquier R, Krueger G, Granziera C. Serum neurofilament light chain in early relapsing remitting MS is increased and correlates with CSF levels and with MRI measures of disease severity. Mult Scler 2016;22(12):1550-59. doi: 10.1177/1352458515623365 Go to original source... Go to PubMed...
  2. Håkansson I, Tisell A, Cassel P, Blennow K, Zettenberg H, Lundberg P, Dahle C, Vrethem M, Ernerudh J. Neurofilament levels, disease activity and brain volume during follow-up in multiple sclerosis. J Neuroinflammation 2018;15:209. doi: 10.1186/s12974-018-1249-7 Go to original source... Go to PubMed...
  3. Kuhle J, Kropshofer H, Haering DA, Kundu U, Meinert R, Barro C, Dahlke F, Tomic D, Leppert D, Kappos L. Blood neurofilament light chain as a biomarker of MS disease activity and treatment response. Neurology 2019;92(10):e1007-e1015. doi: 10.1212/WNL.0000000000007032 Go to original source... Go to PubMed...
  4. Siller N, Kuhle J, Muthuraman M, Barro Ch, Uphaus T, Groppa S, Kappos L, Zipp F, Bittner S. Serum neurofilament light chain is a biomarker of acute and chronic neuronal damage in early multiple scleosis. Mult Scler 2019;25(5):678-86. doi: 10.1177/1352458518765666 Go to original source... Go to PubMed...
  5. Novakova L, Zetterberg H, Sundström P, Axelsson M, Khademi M, Gunnarson M, Malmestrom C, Svenningsson A, Olsson T, Piehl F, Blennow K, Lycke J. Monitoring disease activity in multiple sclerosis using serum neurofilament light protein. Neurology 2017;89(22):2230-37. doi: 10.1212/WNL.0000000000004683 Go to original source... Go to PubMed...
  6. Disanto G, Barro C, Benkert P, Naegelin Y, Schadelin S, Giardiello A, Zecca C, Blennow K, Zettenberg H, Leppert D, Kappos L, Gobbi C, Kuhle J, Swiss multiple sclerosis cohort study group. Serum neurofilament light chain: a biomarker of neuronal damage in multiple sclerosis. Ann Neurol 2017;81(6):857-70. doi: 10.1002/ana.24954 Go to original source... Go to PubMed...
  7. Gionvannoni G, Tomic D, Bright JR, Havrdova E. "No evident disease activity": The use of combined assessments in the management of patients with multiple sclerosis. Mult Scler 2017;23(9):1179-187. doi: 10.1177/1352458517703193 Go to original source... Go to PubMed...
  8. Lublin FD, Reingold SC, Cohen JA, Cutter GR, Soelberg Sørensen P, Thompson AJ, Wolinsky JS, Balcer LJ, Banwell B, Barkhof F, Bebo B, Calabresi PA, Clanet M, Comi, G, Fox RJ, Freedman MS, Goodman AD, Inglese M, Kappos L, Kieseier BC, Lincoln JA, Lubetzki C, Miller AE, Montalban X, O'Connor PW, Petkau J, Pozzilli C, Rudick RA, Sormani MP, Stüve O, Waubant E, Polman CH. Defining the clinical course of multiple sclerosis. Neurology 2014;83:278-86. doi: 10.1212/WNL.0000000000000560 Go to original source... Go to PubMed...
  9. Radue EW, Barkhof F, Kappos L, Sprenger T, Haring DA, de Vera A, von Rosentiel P, Bright JR, Francis G, Cohen JA. Correlation between brain volume loss and clinical and MRI outcomes in multiple sclerosis. Neurology 2015;84(8):784-93. doi: 10.1212/WNL.0000000000001281 Go to original source... Go to PubMed...
  10. Sormani MP, Arnold DL, De Stefano N. Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Ann Neurol 2014;75(1):43-49. doi: 10.1002/ana.24018 Go to original source... Go to PubMed...
  11. Sormani MP, Kappos L, Häring DA, Kropshofer H, Barro C, Leppert D, Tomic D, Kuhle J. Including blood neurofilament light chain in the NEDA concept in relapsing-remitting multiple sclerosis trials. Neurology (15 Supplement) S24.007 (2018) Corpus ID: 79895041 https://www.semanticscholar.org/paper Go to original source...
  12. Weinstock-Guttman B, Medin J, Khan N, Korn JR, Lathi E, Silversteen J, Calkwood J, Silva D, Zivadinov R. MS-MRIUS Study Group. Assessing 'No Evidence of Disease Activity' status in patients with relapsing-remitting multiple sclerosis receiving fingolimod in routine clinical practice: a retrospective analysis of the multiple sclerosis clinical and magnetic resonance imaging outcomes in the USA (MS-MRIUS) Study. CNS Drugs 2018;(329313):1-10. doi: 10.1007/s40263-017-0482-4 Go to original source... Go to PubMed...
  13. Khalil M, Teunissen CE, Otto M, Piehl F, Sormani MP, Gattringer T, Barro C, Kappos L, Comabella M, Fazekas F, Petzold A, Blennow K, Zetterberg H, Kuhle J. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol 2018;14(10):577-89. doi: 10.1038/s41582-018-0058-z Go to original source... Go to PubMed...
  14. De Stefano N, Stromillo ML, Giorgio A, Bartolozzi ML, Battaglini M, Baldini M, Portaccio E, Amato MP, Sormani MP. Establishing pathological cut-offs of brain atrophy rates in multiple sclerosis. J Neurol Neurosurg Psychiatry 2016;87(1):93-99. doi: 10.1136/jnnp-2014-309903 Go to original source... Go to PubMed...
  15. Uher T, Havrdova E, Sobisek L, Krasensky J, Vaneckova M, Seidl Z, Tyblova M, Ramasamy D, Zivadinov R, Horakova D. Is no evidence of disease activity an achieavable goal in MS patients on intramuscular interferon-beta-1a treatment over long-term follow-up? Mult Scler 2017;23(2):242-52. doi: 10.1177/1352458516650525 Go to original source... Go to PubMed...
  16. Kappos L, De Stefano N, Freedman MS, Cree BA, Radue EW, Sprenger T, Sormani MP, Smith T, Haring DA, Meier DP, Tomic D. Inclusion of brain volume loss in a revised measure of 'no evidence of disease activity' (NEDA-4) in relapsing-remitting multiple sclerosis. Mult Scler 2016;22(10):1297-305. doi: 10.1177/1352458515616701 Go to original source... Go to PubMed...
  17. Kurtzke RF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33(11):1444-452. doi: 10.1212/wnl.33.11.1444 Go to original source... Go to PubMed...
  18. Kuhle J, Barro C, Andreasson U, Derfuss T, Lindberg R, sandelius A, Liman V, Norgren N, Blennow K, Zettenberg H. Comparison of three annalytical platforms for quantification of of the neurofilament light chain in blood samples: ELISA, electrochemiluminiscence immunoassay and Simoa. Clin Chem Lab Med 2016;54(10):1655-661. doi: 10.1515/cclm-2015-1195 Go to original source... Go to PubMed...
  19. Steenwijk MD, Amiri H, Schoonheim MM, de Sitter A, Barkhof F, Pouwels PJW, Vrenken H. Agreement of MSmetrix with established methods for measuring cross-sectional and longitudinal brain atrophy. Neuroimage Clin 2017;5:843-53. doi: 10.1016/j.nicl.2017.06.034 Go to original source... Go to PubMed...
  20. Koch MW, Cutter GR, Giovannoni G, Uitdehaag BMJ, Wolinsky JS, Steinerman JR, Knappertz V. Comparative study of disability progression measures in PPMS. Analysis of the PROMiSe data set. Neuro Neuroimmuno Neuroinflamm 2017;4(4):e358. doi: 10.1212/NXI.0000000000000358 Go to original source... Go to PubMed...
  21. European Medicines Agency Committee for medicinal products for human use. Guideline on clinical investigation of medical products for the treatment of multiple sclerosis EMA/CHPM/771815/2011, Rev.2, https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-medicinal-products-treatment-multiple-sclerosis (accessed 26 March 2015)
  22. Kuhle J, Kropshofer H, Haring DA, Meinert R, Barro C, Dahlke F, Leppert D, Tomic D, Kappos L. Neurofilament light levels in the blood of patients with secondary progressive MS are higher than in primary progressive MS and may predict brain atrophy in both MS subtypes. Mult Scler J 2018;24:111.ECTRIMS Online Library.10/12/18; 232039; 286 https://onlinelibrary.ectrims-congress.eu/ectrims/2018/ectrims-2018/232039
  23. Sellebjerg F, Börnsen L, Ammitzbøll C, Nielsen JE, Vinther-Jensen T, Hjermind LE, von Essen M, Ratzer RL, Sorensen PS, Christensen JR. Defining active progressive multiple sclerosis. Mult Scler 2017;23(13):1727-35. doi: 10.1177/1352458517726592 Go to original source... Go to PubMed...
  24. Bar-Or A, Cross AH, Bennett JL, von Budingen HC, Carruthers R, Edwards K, Eggers E, Fallis R, Fiore D, Gelfand JM, Giacomini P, Greenberg B, Hafler DA, Longbrake EE, Assman B, Ionete C, Kaunzner U, Lock C, Ma X, Musch B, Piehl F, Weber MS, Ziemssen T, Herman AE, Harp CT. Pretreatment cerebrospinal fluid (CSF) and serum neurofilament light (NfL) levels in patients with PPMS in the OBOE study are correlated and are higher in patients with PPMS with T1 Gd+ brain lesions. Mult Scler J 2019;25:494-95. ECTRIMS Online Library.09/12/19; 279308; P948 . https://onlinelibrary.ectrims-congress.eu/ectrims/2019/stockholm/279308
  25. Kapoor R, Sellebjerg F, Hartung HP, Arnold DL, Freedman MS, Jeffery D, Miller A, Edwards KR, Singh CM, Chang I, Ren Z, Sangurdekar D, Zhu B, Sheikh S, Mehta D, Ho PR, Campbell N, Edwards M, Fisher E, Kieseier BC, Rudick RA, Plavina T. Natalizumab reduced serum levels of neurofilament light chain in secondary progressive multiple sclerosis patients from the phase 3 ASCEND study. Mult Scler J 24(2 Suppl):988. doi: 10.1177/1352458518799980 Go to original source...
  26. Ferraro D, Guicciardi C, De Biasi S, Pinti M, Bedin R, Camera V, Vitetta F, Nasi M, Meletti S, Sola P. Plasma neurofilaments correlate with disability in progressive multiple sclerosis patients. Acta Neurol Scand 2020;141(1):16-21. doi: 10.1111/ane.13152 Go to original source... Go to PubMed...
  27. Barro C, Benkert P, Disanto G, Tsagkas C, Amann M, Naegelin Y, Leppert D, Gobbi C, Granziera C, Yaldizli Ö, Michalak Z, Wuerfel J, Kappos L, Parmar K, Kuhle J. Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. Brain 2018;141:2382-91. doi: 10.1093/brain/awy154 Go to original source... Go to PubMed...

This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0), which permits use, distribution, and reproduction in any medium, provided the original publication is properly cited. No use, distribution or reproduction is permitted which does not comply with these terms.