Evaluation of neurofilament light chain in the cerebrospinal fluid and blood as a biomarker for neuronal damage in experimental pneumococcal meningitis

Ngoc Dung Le,Denis Grandgirard,Stephen L Leib,David Leppert,Jens Kuhle,Lukas Muri

doi:10.1186/s12974-020-01966-3

Ngoc Dung Le, Denis Grandgirard + Show 4 more

Open Access

https://doi.org/10.1186/s12974-020-01966-3

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Abstract

BackgroundPneumococcal meningitis (PM) remains a global public health concern and affects all age groups. If acquired during infancy or childhood, permanent neurofunctional deficits including cognitive impairment, cerebral palsy, and secondary epilepsy are typical sequelae of neuronal injury. Determination of patients at risk for the development of brain injury and subsequent neurofunctional sequelae could help to identify patients for focused management. Neurofilament light chain (NfL) is an axonal cytoskeletal protein released upon neuronal injury into the cerebrospinal fluid (CSF) and blood. As little is known about the course of neurofilament release in the course of PM, we measured CSF and serum NfL levels longitudinally in experimental PM (ePM).MethodsEleven-day-old infant Wistar rats were infected intracisternally with Streptococcus pneumoniae and treated with ceftriaxone. At 18 and 42 h post-infection (hpi), the blood and CSF were sampled for NfL measurements by a single molecule array technology. Inflammatory cytokines and MMP-9 in CSF were quantified by magnetic bead multiplex assay (Luminex®) and by gel zymography, respectively.ResultsIn ePM, CSF and serum NfL levels started to increase at 18 hpi and were 26- and 3.5-fold increased, respectively, compared to mock-infected animals at 42 hpi (p < 0.0001). CSF and serum NfL correlated at 18 hpi (p < 0.05, r = 0.4716) and 42 hpi (p < 0.0001, r = 0.8179). Both CSF and serum NfL at 42 hpi strongly correlated with CSF levels of IL-1β, TNF-α, and IL-6 and of MMP-9 depending on their individual kinetics.ConclusionCurrent results demonstrate that during the peak inflammatory phase of ePM, NfL levels in CSF and serum are the highest among CNS disease models studied so far. Given the strong correlation of CSF versus serum NfL, and its CNS-specific signal character, longitudinal measurements to monitor the course of PM could be performed based on blood sample tests, i.e., without the need of repetitive spinal taps. We conclude that NfL in the serum should be evaluated as a biomarker in PM.

Highlights

Pneumococcal meningitis (PM) remains a global public health concern and affects all age groups
Intracisternal puncture causes a minor increase in cerebrospinal fluid (CSF) Neurofilament light chain (NfL) levels In the present experimental PM (ePM) model, intracisternal punctures are performed to inoculate S. pneumoniae or saline in a first step and to collect CSF samples later
To determine whether this mechanical trauma leads to an artifactual neuronal damage, we measured serum NfL levels of animals before any intervention and compared them with animals at 18 hpi which have been inoculated with saline at baseline

Summary

Introduction

Pneumococcal meningitis (PM) remains a global public health concern and affects all age groups. Along with inflammatory signaling molecules like IL-1β, TNF-α, and IL-6, effector molecules such as matrix metalloproteinases (MMPs) are released in high amounts into the cerebrospinal fluid (CSF) [11], promoting blood-brain barrier (BBB) opening and neutrophil recruitment [12, 13] and may exert as well direct toxicity on neurons [14, 15] While their levels are linked to the likelihood for long-term sequelae [11, 14], their relevance as biomarkers in clinical practice is limited, as they reflect disease activity only in CSF, but not in the serum. They relate to neuronal damage only indirectly and no biofluid marker has been established in BM that measures neuronal damage itself

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