The biomarker neurofilament light chain (NfL) is used for assessment of neuronal damage and is normally measured in cerebrospinal fluid (CSF) obtained through a lumbar puncture, a sometimes-harmful procedure for the patient. During recent years, novel methods have given the possibility to measure NfL in plasma instead, which could be a convenient tool to estimate severity of disease and prognosis in neurological disorders. The novel ultra-sensitive method, a digital enzyme-linked immunosorbent assay (ELISA), has been shown to be a both reliable and compelling alternative for analysis of plasma NfL in patients with central nervous system (CNS) disease, such as multiple sclerosis (MS).
Despite its proved efficacy for patients with highly active relapsing-remitting MS, the use of natalizumab (anti-¿4 integrin) is limited due to the increased risk of progressive multifocal leukoencephalopathy (PML) caused by the polyomavirus JC (JCV). In addition to existing PML risk stratification algorithms based on natalizumab treatment duration, previous immunosuppressive therapies, and JC virus index, other biomarkers may certainly contribute to estimate the risk of PML at an individual level. Yet, the usefulness of measuring plasma NfL levels in patients with PML is scarcely elucidated. Here, we propose to investigate the correlation of serum and CSF NFL in MS patients with PML treated with natalizumab, assessing the potential useful for serum NFL levels to predict the risk of PML and to discriminate PML from MS relapses.
In the management of neurological diseases, the identification and quantification of axonal damage could allow for the improvement of diagnostic accuracy and prognostic assessment. Neurofilament light chain (NfL) is a neuronal cytoplasmic protein highly expressed in large caliber myelinated axons (Gaetani et al. 2019). Its levels increase in cerebrospinal fluid (CSF) and blood proportionally to the degree of axonal damage in a variety of neurological disorders, including inflammatory, neurodegenerative, traumatic, and cerebrovascular diseases (Gaetani et al. 2019). New immunoassays able to detect biomarkers at ultralow levels have allowed for the measurement of NfL in blood, thus making it possible to measure NfL easily and repeatedly for monitoring diseases' courses. Evidence that both CSF and blood NfL may serve as diagnostic, prognostic and monitoring biomarkers in neurological diseases is progressively increasing, and NfL is one of the most promising biomarkers to be used in clinical and research setting in the next future (Gaetani et al. 2019).
Here, we propose to evaluate NfL blood levels in MS patients under natalizumab treatment to assess the prognostic value of blood NfL levels and to identify potential applications and future directions as a diagnostic, severity, and treatment-response biomarker.
Few molecular biomarker studies have aimed to identify patients with MS at increased risk for PML under natalizumab treatment (Schwab et al. 2013; Pignolet et al. 2016; Nicolas Fissolo et al. 2017; Iannetta et al. 2019). However, none of the proposed biomarkers are at present routinely measured in clinical practice to estimate PML risk in patients with MS receiving natalizumab.
In this scenario, we will search to understand whether CNS tissue damage biomarkers (plasma NfL, MMPs and TIMPs levels as well as MMP-9 plasma activities) are early predictors of PML onset.
In a recent study, plasma NfL levels measured with an electrochemiluminescence assay were found to be 10-fold higher at PML onset compared with the pre-PML condition (Dalla Costa et al. 2019). Furthermore, plasma NfL levels also demonstrated high performance to discriminate between patients with MS at PML onset and natalizumab-treated patients who did not develop PML and treated patients with clinical or neuroradiologic evidence of disease activity 4 weeks before sample collection (Dalla Costa et al. 2019).
In conclusion, this study could support the use of plasma NfL levels in clinical practice to identify patients with MS at higher risk for PML based on Nfl levels at 2 years of natalizumab treatment and to differentiate PML from clinical relapses in patients receiving natalizumab. The study is designed to assess the prognostic value of blood NfL levels. We believe that longitudinal plasma NfL evaluation could be a useful tool in patients receiving natalizumab treatment. Moreover, after 2 years of treatment MS patients should be monitored more closely for neurologic symptoms with additional NfL and MRI measures to rule out PML.