Combined Cerebrospinal Fluid Neurofilament Light Chain Protein and Chitinase-3 Like-1 Levels in Defining Disease Course and Prognosis in Multiple Sclerosis.

Sara Gil-Perotin,Jose Andres Dominguez,David Hervas,Carmen Alcala,Josep Gomez-Mateu,Francisco Gascon,Laura Cubas-Nuñez,Jessica Castillo-Villalba,Francisco Perez-Miralles,Bonaventura Casanova,Raquel Gasque

doi:10.3389/fneur.2019.01008

Sara Gil-Perotin, Jose Andres Dominguez + Show 9 more

Open Access

https://doi.org/10.3389/fneur.2019.01008

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Abstract

Background: Neurofilament light chain protein (NFL) and chitinase3-like1 (CHI3L1) have gained importance recently as prognostic biomarkers in multiple sclerosis (MS).Objectives: We aimed to investigate NFL and CHI3L1 cerebrospinal fluid (CSF) profiles in multiple sclerosis and the informative and prognostic potential of the individual and combined measures.Methods: CSF NFL and CHI3L1 levels were measured in a cross-sectional cohort of 157 MS patients [99 relapsing-remitting (RRMS), 35 secondary progressive (SPMS), and 23 primary progressive (PPMS)]. Clinical relapse and/or gadolinium-enhanced lesions (GEL) in MRI within 90 days from CSF collection by lumbar puncture (LP) were registered and considered as indicators of disease activity. Longitudinal treatment and disability data were evaluated during medical visits with a median follow-up of 50 months.Results: CSF levels of NFL and CHI3L1 were higher in MS patients compared to non-MS controls. In RRMS and SPMS patients, increased NFL levels were associated with clinical relapse, and gadolinium-enhanced lesions in MRI (p < 0.001), while high CHI3L1 levels were characteristic of progressive disease (p = 0.01). In RRMS patients, CSF NFL, and CHI3L1 levels correlated with each other (r = 0.58), and with IgM-oligoclonal bands (p = 0.02 and p = 0.004, respectively). In addition, CSF CHI3L1 concentration was a predictor for 1-point EDSS worsening {HR = 2.99 [95% CI (1.27, 7.07)]} and progression during follow-up {HR = 18 [95% CI (2.31, 141.3)]}. The pattern of combined measure of biomarkers was useful to discriminate MS phenotypes and to anticipate clinical progression: RRMS more frequently presented high NFL combined with low CHI3L1 levels, compared to SPMS (HR 0.41 [0.18–0.82]), and PPMS (HR 0.46 [0.19–0.87]), while elevation of both biomarkers preceded diagnosis of clinical progression in RRMS patients (log rank = 0.02).Conclusions: Individual measures of CSF NFL and CHI3L1 are biomarkers of disease activity and progression, respectively. The pattern of combined measure discriminates MS phenotypes. It also predicts the subset of RRMS patients that will progress clinically allowing early intervention.

Highlights

Neurofilament light protein (NFL), a cytoskeletal polypeptide of the axon [1], and chitinase 3-like 1 (CHI3L1- known as YKL40 or gp39), a glycoprotein secreted by activated glia in the central nervous system (CNS) [2], have both shown to be biomarkers of axonal destruction, and inflammation in multiple sclerosis (MS), respectively.NFL is not a specific biomarker but a reflection of axonal destruction in several neurological diseases [3,4,5,6]
With a cohort of 157 patients including relapsing-remitting MS (RRMS) and progressive phenotypes (SPMS; primary progressive MS (PPMS)) and with prospectively collected disability data, we aimed to demonstrate that the combined measure of both biomarkers in the cerebrospinal fluid (CSF) might have value, in identifying distinct MS phenotypes and in predicting accrual of disability and further diagnosis of progressive disease in RRMS patients
We studied 157 MS patients, 99 RRMS (63%), and 58 progressive MS (37%), of which 35 were secondary progressive MS (SPMS) (22%), and 23 PPMS (15%) (Figure 1)

Summary

Introduction

Neurofilament light protein (NFL), a cytoskeletal polypeptide of the axon [1], and chitinase 3-like 1 (CHI3L1- known as YKL40 or gp39), a glycoprotein secreted by activated glia in the central nervous system (CNS) [2], have both shown to be biomarkers of axonal destruction, and inflammation in multiple sclerosis (MS), respectively.NFL is not a specific biomarker but a reflection of axonal destruction in several neurological diseases [3,4,5,6]. Neurofilament light protein (NFL), a cytoskeletal polypeptide of the axon [1], and chitinase 3-like 1 (CHI3L1- known as YKL40 or gp39), a glycoprotein secreted by activated glia in the central nervous system (CNS) [2], have both shown to be biomarkers of axonal destruction, and inflammation in multiple sclerosis (MS), respectively. In MS, cerebrospinal fluid (CSF), and serum levels of NFL have been suggested as markers for disease activity in MS [7] and predictors of clinically isolated syndrome (CIS) conversion to MS [8,9,10,11]. Neurofilament light chain protein (NFL) and chitinase3-like (CHI3L1) have gained importance recently as prognostic biomarkers in multiple sclerosis (MS)

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