Fluid biomarkers for mild traumatic brain injury and related conditions

Key Points

  • Traumatic brain injury (TBI) is caused by an external mechanical force that injures the brain parenchyma; however, most patients with mild TBI show no signs of injury on a CT scan

  • Given that mild TBI cannot usually be diagnosed objectively, accurate fluid biomarkers would be a welcome addition to the diagnostic toolbox

  • Repetitive mild TBI can cause progressive neurodegeneration, known as chronic traumatic encephalopathy (CTE); however, estimating the risk of CTE is difficult, and the condition cannot be diagnosed in living patients

  • In future, biomarkers for mild TBI, postconcussive syndrome and CTE might help us predict the risk of long-term sequelae and improve our understanding of the underlying pathophysiology

  • Brain specificity or brain-enhanced expression is an important characteristic of blood-based biomarkers for mild TBI and related conditions, as extracerebral sources for biomarker molecules can compromise the interpretability of the test results

  • In mild TBI, fluid biomarkers for axonal injury and astroglial activation show the greatest promise at the moment, and several other promising biomarker candidates exist


Diagnostic and prognostic biomarkers for mild traumatic brain injury (TBI), also known as concussion, remain a major unmet clinical need. Moderate to severe TBI can be diagnosed definitively by clinical assessment and standard neuroimaging techniques that detect the gross damage to the brain parenchyma. Diagnostic tools for mild TBI are lacking and, currently, the diagnosis has to be made on clinical grounds alone, because most patients show no gross pathological changes on CT. Most patients with mild TBI recover quickly, but about 15% develop an ill-defined condition called postconcussive syndrome (PCS). Repeated concussions have been associated with a chronic neurodegenerative disorder called chronic traumatic encephalopathy (CTE), which can only currently be diagnosed post mortem. Fluid biomarkers are needed to better define and detect mild TBI and related conditions. Here, we review the literature on fluid biomarkers for neuronal, axonal, oligodendrocytic, astroglial and blood–brain barrier injury, as well as markers for neuroinflammation and metabolic dysregulation, in the context of mild TBI, PCS and CTE. We also discuss technical and standardization issues and potential pathways to advance the most promising biomarker candidates into clinical laboratory practice.

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Figure 1: Candidate fluid biomarkers for pathophysiological processes related to traumatic brain injury.
Figure 2: Hypothetical model of temporal brain changes in traumatic brain injury not complicated by secondary insults.


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Work in the authors' laboratories is supported by the European Research Council, the Swedish Research Council, Swedish State Support for Clinical Research, the Torsten Söderberg Foundation, the Knut and Alice Wallenberg Foundation, VINNOVA and the Wolfson Foundation.

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Both authors contributed to researching literature for the article, and provided substantial contributions to discussion of the content, and to writing, reviewing and editing of the manuscript.

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Correspondence to Henrik Zetterberg or Kaj Blennow.

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Competing interests

H.Z. and K.B. are listed as co-inventors on a US patent application for plasma tau as a brain injury marker, and are co-founders of Brain Biomarker Solutions in Gothenburg AB, a GU Venture-based platform company at the University of Gothenburg. K.B. has served on advisory boards for Eli Lilly, Kyowa Kirin Pharma, Pfizer and Roche.

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Glymphatic system

A recently discovered 'waste clearance' pathway from the vertebrate CNS into the bloodstream. Clearance of compounds that accumulate after mild traumatic brain injury through this pathway could influence blood biomarker concentrations.

Wallerian degeneration

When a nerve fibre is injured, the part of the axon separated from the neuron's cell body degenerates distal to the injury — this phenomenon is termed Wallerian degeneration.

CSF:serum albumin ratio

Albumin is produced by the liver, so it has to cross the blood–brain barrier to reach the cerebrospinal fluid (CSF). In healthy humans, the ratio of albumin in CSF versus blood is very small, but if the blood–brain barrier is compromised, the CSF:serum albumin ratio increases.

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Zetterberg, H., Blennow, K. Fluid biomarkers for mild traumatic brain injury and related conditions. Nat Rev Neurol 12, 563–574 (2016). https://doi.org/10.1038/nrneurol.2016.127

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