Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
Axonal injury is a key determinant of long-term outcomes after traumatic brain injury (TBI) but has been difficult to measure clinically. Fluid biomarker assays can now sensitively quantify neuronal proteins in blood. Axonal components such as neurofilament light (NfL) potentially provide a diagnostic measure of injury. In the multicenter BIO-AX-TBI study of moderate-severe TBI, we investigated relationships between fluid biomarkers, advanced neuroimaging, and clinical outcomes. Cerebral microdialysis was used to assess biomarker concentrations in brain extracellular fluid aligned with plasma measurement. An experimental injury model was used to validate biomarkers against histopathology. Plasma NfL increased after TBI, peaking at 10 days to 6 weeks but remaining abnormal at 1 year. Concentrations were around 10 times higher early after TBI than in controls (patients with extracranial injuries). NfL concentrations correlated with diffusion MRI measures of axonal injury and predicted white matter neurodegeneration. Plasma TAU predicted early gray matter atrophy. NfL was the strongest predictor of functional outcomes at 1 year. Cerebral microdialysis showed that NfL concentrations in plasma and brain extracellular fluid were highly correlated. An experimental injury model confirmed a dose-response relationship of histopathologically defined axonal injury to plasma NfL. In conclusion, plasma NfL provides a sensitive and clinically meaningful measure of axonal injury produced by TBI. This reflects the extent of underlying damage, validated using advanced MRI, cerebral microdialysis, and an experimental model. The results support the incorporation of NfL sampling subacutely after injury into clinical practice to assist with the diagnosis of axonal injury and to improve prognostication.
Date Issued
2021-09-29
Date Acceptance
2021-09-01
Citation
Science Translational Medicine, 2021, 13 (613), pp.1-15
ISSN
1946-6234
Publisher
American Association for the Advancement of Science
Start Page
1
End Page
15
Journal / Book Title
Science Translational Medicine
Volume
13
Issue
613
Copyright Statement
© 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Sponsor
Commission of the European Communities
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
National Institute for Health Research
UK DRI Ltd
Ministry Of Defence
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/34586833
Grant Number
MR/R004528/1
RDC04 79560
RDA03_79560
RDC04
NIHR-RP-011-048
'CR & T IMP'
BIOSAP
Subjects
06 Biological Sciences
11 Medical and Health Sciences
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2021-09-29