Neurofilament light chain predicts disease activity in relapsing-remitting MS

Kristin N Varhaug, Christian Barro, Kjetil Bjørnevik, Kjell-Morten Myhr, Øivind Torkildsen, Stig Wergeland, Laurence A Bindoff, Jens Kuhle, Christian Vedeler, Kristin N Varhaug, Christian Barro, Kjetil Bjørnevik, Kjell-Morten Myhr, Øivind Torkildsen, Stig Wergeland, Laurence A Bindoff, Jens Kuhle, Christian Vedeler

Abstract

Objective: To investigate whether serum neurofilament light chain (NF-L) and chitinase 3-like 1 (CHI3L1) predict disease activity in relapsing-remitting MS (RRMS).

Methods: A cohort of 85 patients with RRMS were followed for 2 years (6 months without disease-modifying treatment and 18 months with interferon-beta 1a [IFNB-1a]). Expanded Disability Status Scale was scored at baseline and every 6 months thereafter. MRI was performed at baseline and monthly for 9 months and then at months 12 and 24. Serum samples were collected at baseline and months 3, 6, 12, and 24. We analyzed the serum levels of NF-L using a single-molecule array assay and CHI3L1 by ELISA and estimated the association with clinical and MRI disease activity using mixed-effects models.

Results: NF-L levels were significantly higher in patients with new T1 gadolinium-enhancing lesions (37.3 pg/mL, interquartile range [IQR] 25.9-52.4) and new T2 lesions (37.3 pg/mL, IQR 25.1-48.5) compared with those without (28.0 pg/mL, IQR 21.9-36.4, β = 1.258, p < 0.001 and 27.7 pg/mL, IQR 21.8-35.1, β = 1.251, p < 0.001, respectively). NF-L levels were associated with the presence of T1 gadolinium-enhanced lesions up to 2 months before (p < 0.001) and 1 month after (p = 0.009) the time of biomarker measurement. NF-L levels fell after initiation of IFNB-1a treatment (p < 0.001). Changes in CHI3L1 were not associated with clinical or MRI disease activity or interferon-beta 1a treatment.

Conclusion: Serum NF-L could be a promising biomarker for subclinical MRI activity and treatment response in RRMS. In clinically stable patients, serum NF-L may offer an alternative to MRI monitoring for subclinical disease activity.

Clinicaltrialsgov identifier: NCT00360906.

Figures

Figure 1. Levels of neurofilament light chain…
Figure 1. Levels of neurofilament light chain (NF-L) associated with follow-up time (A) and MRI (B–D)
*p < 0.05.
Figure 2. Levels of chitinase 3-like 1…
Figure 2. Levels of chitinase 3-like 1 (CHI3L1) associated with follow-up time (A) and MRI (B–D)
Figure 3. Relationship between new T1 gadolinium-enhanced…
Figure 3. Relationship between new T1 gadolinium-enhanced lesions and time of biomarker measurement
*p < 0.05; **p < 0.005.

References

    1. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338:278–285.
    1. Lycke JN, Karlsson JE, Andersen O, Rosengren LE. Neurofilament protein in cerebrospinal fluid: a potential marker of activity in multiple sclerosis. J Neurol Neurosurg Psychiatry 1998;64:402–404.
    1. Bacioglu M, Maia LF, Preische O, et al. . Neurofilament light chain in blood and CSF as marker of disease progression in mouse models and in neurodegenerative diseases. Neuron 2016;91:56–66.
    1. Meeter LH, Dopper EG, Jiskoot LC, et al. . Neurofilament light chain: a biomarker for genetic frontotemporal dementia. Ann Clin Transl Neurol 2016;3:623–636.
    1. Steinacker P, Feneberg E, Weishaupt J, et al. . Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients. J Neurol Neurosurg Psychiatry 2016;87:12–20.
    1. Weydt P, Oeckl P, Huss A, et al. . Neurofilament levels as biomarkers in asymptomatic and symptomatic familial amyotrophic lateral sclerosis. Ann Neurol 2016;79:152–158.
    1. Soelberg Sorensen P, Sellebjerg F. Neurofilament in CSF-A biomarker of disease activity and long-term prognosis in multiple sclerosis. Mult Scler 2016;22:1112–1113.
    1. Modvig S, Degn M, Roed H, et al. . Cerebrospinal fluid levels of chitinase 3-like 1 and neurofilament light chain predict multiple sclerosis development and disability after optic neuritis. Mult Scler 2015;21:1761–1770.
    1. Kuhle J, Disanto G, Lorscheider J, et al. . Fingolimod and CSF neurofilament light chain levels in relapsing-remitting multiple sclerosis. Neurology 2015;84:1639–1643.
    1. 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.
    1. Gunnarsson M, Malmestrom C, Axelsson M, et al. . Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab. Ann Neurol 2011;69:83–89.
    1. Kuhle J, Barro C, Disanto G, et al. . 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;22:1550–1559.
    1. 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;87:126–129.
    1. Canto E, Tintore M, Villar LM, et al. . Chitinase 3-like 1: prognostic biomarker in clinically isolated syndromes. Brain 2015;138:918–931.
    1. Hinsinger G, Galeotti N, Nabholz N, et al. . Chitinase 3-like proteins as diagnostic and prognostic biomarkers of multiple sclerosis. Mult Scler 2015;21:1251–1261.
    1. Opsahl JA, Vaudel M, Guldbrandsen A, et al. . Label-free analysis of human cerebrospinal fluid addressing various normalization strategies and revealing protein groups affected by multiple sclerosis. Proteomics 2016;16:1154–1165.
    1. Comabella M, Fernandez M, Martin R, et al. . Cerebrospinal fluid chitinase 3-like 1 levels are associated with conversion to multiple sclerosis. Brain 2010;133:1082–1093.
    1. Torkildsen O, Wergeland S, Bakke S, et al. . ω-3 fatty acid treatment in multiple sclerosis (OFAMS Study): a randomized, double-blind, placebo-controlled trial. Arch Neurol 2012;69:1044–1051.
    1. Norgren N, Karlsson JE, Rosengren L, Stigbrand T. Monoclonal antibodies selective for low molecular weight neurofilaments. Hybrid Hybridomics 2002;21:53–59.
    1. Disanto G, Barro C, Benkert P, et al. . Serum Neurofilament light: a biomarker of neuronal damage in multiple sclerosis. Ann Neurol 2017;81:857–870.
    1. Axelsson M, Malmestrom C, Gunnarsson M, et al. . Immunosuppressive therapy reduces axonal damage in progressive multiple sclerosis. Mult Scler 2014;20:43–50.
    1. Novakova L, Axelsson M, Khademi M, et al. . Cerebrospinal fluid biomarkers as a measure of disease activity and treatment efficacy in relapsing-remitting multiple sclerosis. J Neurochem 2017;141:296–304.
    1. Matute-Blanch C, Rio J, Villar LM, et al. . Chitinase 3-like 1 is associated with the response to interferon-beta treatment in multiple sclerosis. J Neuroimmunol 2017;303:62–65.
    1. Canto E, Reverter F, Morcillo-Suarez C, et al. . Chitinase 3-like 1 plasma levels are increased in patients with progressive forms of multiple sclerosis. Mult Scler 2012;18:983–990.
    1. 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 Epub 2017 Jun 1.

Source: PubMed

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