Fluid biomarkers for mild traumatic brain injury and related conditions

Abstract

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.

Effects of concussion on the blood–brain barrier in humans and rodents

“…Studies in humans are constrained by procedural and ethical issues, but researchers have investigated both leakage of known brain parenchymal molecules into the circulating blood and the leakage of red blood cells or serum proteins into brain parenchyma. 31 …”

The current state of biomarkers of mild traumatic brain injury

“…An increased CSF/serum albumin ratio has been reported in patients with severe TBI and indicates that albumin from the blood has passed into the CSF, indicative of BBB damage (25). While an elevated CSF/serum albumin ratio is commonly reported for severe TBI, such changes have not been seen in concussion/mTBI, suggesting that either the BBB remains largely intact or the damage is transient, such that the CSF/serum albumin ratio is not sensitive enough to detect mTBI-associated BBB damage (11). Results from Shahim et al support this notion, as in their small cohort study, the CSF/serum albumin ratio was unaltered in 28 professional athletes with postconcussive symptoms (26).…”

“…Given that student athletes are typically highly motivated to return to the field, it is reasonable to suspect that athletic activities are likely to be resumed more quickly than they should and that young athletes might even minimize symptom severity. Furthermore, an athlete may appear asymptomatic using standardized concussion interview instruments; however, the biological mechanisms that underlie complete recovery appear to lag behind (11).…”

Considerations for Experimental Animal Models of Concussion, Traumatic Brain Injury, and Chronic Traumatic Encephalopathy—These Matters Matter

“…Recent studies have shown that contact sport athletes with mild TBI demonstrate elevated blood levels of CNS-derived proteins, including S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), neurofilament light chain protein (NFL), and tau protein (including various phosphorylated tau proteoforms and cleavage products) (72–74). Investigators in Israel recently used dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to detect and map TBI-related cerebrovascular permeability defects in amateur American football players after a session of play (75).…”

“…Taken together, these findings indicate that even mild TBI may be associated not only with structural damage involving brain cells and their processes but also with microvascular injury and BBB breakdown that results in release of brain cell products into the peripheral circulation. Development of new ultrasensitive biomarker assays designed to detect elevated blood levels of brain proteins, lipids, and even subcellular products (e.g., exosomes) affords a promising strategy for TBI diagnosis, prognosis, and monitoring (74, 76–79). …”