Acute Neurofilament Light Chain Plasma Levels Correlate With Stroke Severity and Clinical Outcome in Ischemic Stroke Patients

Abstract

Background: Ischemic stroke causes increased blood-brain barrier permeability and release of markers of axonal damage and inflammation. To investigate diagnostic and prognostic roles of neurofilament light chain (NF-L), we assessed levels of NF-L, S100B, interleukin-6 (IL-6), E-selectin, vascular endothelial growth factor-A (VEGF-A), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) in patients with acute ischemic stroke or transient ischemic attack (TIA) and healthy controls. Methods: We studied neurofilament (NF) expression in 2 cases of human postmortem ischemic stroke, representing infarcts aged 3- to >7-days. In a prospective study, we measured plasma NF-L and inflammatory markers <8 h of symptom onset and at 72 h in acute ischemic stroke (n = 31), TIA (n = 9), and healthy controls (n = 29). We assessed whether NF-L, S100B, and IL-6 were associated with clinical severity on admission (Scandinavian Stroke Scale, SSS), diagnosis of ischemic stroke vs. TIA, and functional outcome at 3 months (modified Rankin Scale, mRS). Results: NF expression increased in ischemic neurons and in the infarcted brain parenchyma after stroke. Plasma NF-L levels were higher in stroke patients than in TIA patients and healthy controls, but IL-6 levels were similar. Higher acute NF-L levels were associated with lower SSS scores at admission and higher mRS scores at 3 months. No correlation was observed between NF-L and S100B, NF-L and IL-6, nor between S100B or IL-6 and SSS or mRS. Compared to controls, stroke patients had significantly higher VEGF-A and VCAM-1 at <8 h that remained elevated at 72 h, with significantly higher VEGF-A at <8 h; ICAM-1 was significantly increased at <8 h, while S100B and E-selectin were unchanged. Conclusions: Plasma NF-L levels, but not IL-6 and S100B, were significant predictors of clinical severity on admission and functional outcome at 3 months. Plasma NF-L is a promising biomarker of functional outcome after ischemic stroke.

Keywords: Scandinavian Stroke Scale; biomarkers; functional outcome; modified rankin scale; transient ischemic attack.

Copyright © 2020 Nielsen, Soares, Høgedal, Madsen, Hansen, Christensen, Madsen, Clausen, Frich, Degn, Sibbersen and Lambertsen.

Figures

Figure 1

Immunohistochemical staining of neurofilament-positive neurons in postmortem human ischemic brain tissue. (A,B) Neurofilament immunofluorescent staining in a >7-day-old right parietal lobe infarct demonstrating increased NF staining in the infarct (A) compared to the peri-infarct (B). Scale bar: 100 μm. (C,D) High magnifications of neurofilament-positive neurons in paraffin sections from a 3–7-day-old left temporal lobe infarct. Scale bar: 40 μm.

Figure 2

Neurofilament-light chain changes in patients with ischemic stroke. (A) NF-L concentrations (pg/mL) increased significantly in the blood of ischemic stroke patients compared to controls (CV = 3.9%). Line: median. Box: interquartile range. Whiskers: 5th–95th percentiles. Kruskal–Wallis test with Dunn's post-hoc test. (B) NF-L levels in the blood of patients with ischemic stroke correlated negatively with Scandinavian Stroke Scale (SSS). (C) NF-L levels in the blood correlated positively with modified Rankin Scale (mRS) measured 3 months after the ischemic stroke. (D) S100B concentrations (pg/mL) increased significantly in the blood of TIA patients compared to controls (CV = 11.5%). Line: median. Box: interquartile range. Whiskers: 5th–95th percentiles. Kruskal–Wallis test with Dunn's post hoc test. *p < 0.05, **p < 0.01. R: Spearman's rho; TIA, transient ischemic attack.

Figure 3

Interleukin-6 levels in patients with ischemic stroke. Blood IL-6 concentrations (pg/mL) were similar in healthy controls and ischemic stroke patients (CV = 4.1%). Line: median. Box: interquartile range. Whiskers: 5th–95th percentiles.

Figure 4

Endothelial and vascular markers in ischemic stroke patients. (A) E-selectin concentrations (pg/mL) were similar in healthy controls and ischemic stroke patients (CV = 6.6%). (B) VEGF-A concentrations (pg/mL) increased significantly in the first 8 h in ischemic stroke patients compared to healthy controls and showed a further significant increase 72 h after symptom onset (CV = 8.8%). (C) VCAM-1 concentrations (pg/mL) were significantly increased both acutely (<8 h) and later (72 h) in ischemic stroke patients compared to healthy controls (CV = 3.6%). (D) ICAM-1 concentrations (pg/mL) increased significantly in the first 8 h in ischemic stroke patients compared to healthy controls (CV = 5.8%). Line: median. Box: interquartile range. Whiskers: 5th–95th percentiles. Kruskal–Wallis test with Dunn's post-hoc test. *p < 0.05, **p < 0.01, ***p < 0.001.