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      Temporal profile of serum neurofilament light in multiple sclerosis: Implications for patient monitoring

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          Abstract

          Objective:

          To understand how longitudinal serum neurofilament light chain (sNfL) patterns can inform its use as a prognostic biomarker in multiple sclerosis (MS) and evaluate whether sNfL reflects MS disease activity and disease-modifying therapy usage.

          Methods:

          This was a post hoc analysis of longitudinal data and samples from the ADVANCE trial (NCT00906399) of patients with relapsing–remitting MS (RRMS). sNfL was measured every 3 months for 2 years, then every 6 months for 4 years. Regression models explored how sNfL data predicted 4-year values of brain volume, expanded disability status scale score, and T2 lesions. sNfL levels were assessed in those receiving placebo, peginterferon beta-1a, and those with disease activity.

          Results:

          Baseline sNfL was a predictor of 4-year brain atrophy and development of new T2 lesions. Clinical ( p = 0.02) and magnetic resonance imaging (MRI) ( p < 0.01) outcomes improved in those receiving peginterferon beta-1a whose sNfL decreased to <16 pg/mL after 12 months versus those whose sNfL remained ⩾16 pg/mL. Mean sNfL levels decreased in peginterferon beta-1a-treated patients and increased in placebo-treated patients (–9.5% vs. 6.8%; p < 0.01). sNfL was higher and more variable in patients with evidence of active MS.

          Conclusion:

          These data support sNfL as a prognostic and disease-monitoring biomarker for RRMS.

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          Most cited references34

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          Neurofilaments as biomarkers in neurological disorders

          Neuroaxonal damage is the pathological substrate of permanent disability in various neurological disorders. Reliable quantification and longitudinal follow-up of such damage are important for assessing disease activity, monitoring treatment responses, facilitating treatment development and determining prognosis. The neurofilament proteins have promise in this context because their levels rise upon neuroaxonal damage not only in the cerebrospinal fluid (CSF) but also in blood, and they indicate neuroaxonal injury independent of causal pathways. First-generation (immunoblot) and second-generation (enzyme-linked immunosorbent assay) neurofilament assays had limited sensitivity. Third-generation (electrochemiluminescence) and particularly fourth-generation (single-molecule array) assays enable the reliable measurement of neurofilaments throughout the range of concentrations found in blood samples. This technological advancement has paved the way to investigate neurofilaments in a range of neurological disorders. Here, we review what is known about the structure and function of neurofilaments, discuss analytical aspects and knowledge of age-dependent normal ranges of neurofilaments and provide a comprehensive overview of studies on neurofilament light chain as a marker of axonal injury in different neurological disorders, including multiple sclerosis, neurodegenerative dementia, stroke, traumatic brain injury, amyotrophic lateral sclerosis and Parkinson disease. We also consider work needed to explore the value of this axonal damage marker in managing neurological diseases in daily practice.
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            Multiple Sclerosis

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              • Article: found

              Defining the clinical course of multiple sclerosis

              Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.
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                Author and article information

                Contributors
                Journal
                Mult Scler
                Mult Scler
                MSJ
                spmsj
                Multiple Sclerosis (Houndmills, Basingstoke, England)
                SAGE Publications (Sage UK: London, England )
                1352-4585
                1477-0970
                14 December 2020
                September 2021
                : 27
                : 10
                : 1497-1505
                Affiliations
                [1-1352458520972573]Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
                [2-1352458520972573]Montreal Neurological Institute, McGill University, Montreal, QC, Canada/NeuroRx, Montreal, QC, Canada
                [3-1352458520972573]Biogen, Cambridge, MA, USA
                [4-1352458520972573]Biogen, Cambridge, MA, USA
                [5-1352458520972573]Biogen, Cambridge, MA, USA
                [6-1352458520972573]Biogen, Cambridge, MA, USA
                [7-1352458520972573]Biogen, Cambridge, MA, USA
                [8-1352458520972573]Biogen, Cambridge, MA, USA
                [9-1352458520972573]Biogen, Cambridge, MA, USA
                [10-1352458520972573]Biogen, Cambridge, MA, USA
                [11-1352458520972573]Department of Neurology, Medical Faculty, Heinrich Heine University, Dusseldorf, Germany/Biogen, Cambridge, MA, USA
                [12-1352458520972573]Biogen, Cambridge, MA, USA
                [13-1352458520972573]Biogen, Cambridge, MA, USA
                Author notes
                [*]RA Rudick Biogen, 225 Binney Street, Cambridge, MA 02142, USA. rick.rudick@ 123456gmail.com
                [*]

                At the time of the analyses.

                Article
                10.1177_1352458520972573
                10.1177/1352458520972573
                8414824
                33307998
                a9b68e3e-22cc-4fba-9f10-9c742406d249
                © The Author(s), 2020

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 31 July 2020
                : 9 October 2020
                : 20 October 2020
                Funding
                Funded by: Biogen, FundRef https://doi.org/10.13039/100005614;
                Categories
                Original Research Papers
                Custom metadata
                ts1

                Immunology
                biomarker,serum neurofilament light chain,magnetic resonance imaging,prognosis,brain atrophy,multiple sclerosis

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