Biofluid Biomarkers by Charles Watson
Posted on December 3, 2022
Biomarkers within the blood, cerebrospinal fluid (CSF), and saliva show promise in detecting underlying pathologies of TBI and the risk for incomplete recovery.
A number of biomarkers are involved in recovery of tissue injury related to a TBI. Specifically, biomarkers include markers of inflammation and blood–brain barrier (BBB) integrity, as well axonal, neuronal, astroglial, and vascular injury. Initially, there is increased flow of immune cells into injured tissue, initiating a debriding process that is essential for tissue recovery. Yet, if this process is too extreme or prolonged, tissue injury can be substantial and can result in more injuries, termed the secondary injury process.
Other TBI biomarkers indicate specific brain cell types, including astrocytes and microglia, showing that there is a cascade of biomarker activity that facilitates recovery. When these activities are insufficiently regulated, long-term risks to neurons can result, placing the individual at greater risk for compromise in function and increasing the risk for symptoms and chronic deficits.
Research has shown high sensitivity and negative predictive value of the brain trauma indicator (BTI) test for predicting traumatic intracranial injuries on head CT scan acutely after TBI, and distinguishing CT-positive, more severely injured from CT-negative, mild TBI patients. In more mild cohorts, including sports concussions, elevated levels have been observed days following a concussion, indicating that these biomarkers are accurate predictors in even the mildest of brain injuries.
S100B, a marker of both astrocyte and oligodendrocyte activity, also shows promise as a biomarker of TBI, with higher levels being associated with greater TBI severity and poorer outcome. Other proteins may be of value for diagnosis and prediction following a TBI. Specifically, NFL is an intermediate filament that provides cytoskeleton support within neurons. Tau is an axonal protein that is associated with axonal damage, and has been implicated in both short- and long-term outcomes related to TBI. Serum levels of NFL correlate with CSF levels, indicating that NFL has a brain-specific activity that can be detected within samples of blood.
Recently, it has been shown to be elevated in mild to severe injuries and to be elevated years following a TBI, with the highest levels in individuals with more severe chronic symptoms. Recent studies of plasma tau in acute sports concussion collected within the first 6–24 hours after injury suggest that higher levels of tau may be prognostic biomarkers of prolonged recovery. Lastly, concentrations of total tau in the blood have been linked to chronic symptoms suggestive of CTE in athletes with high numbers of concussions over their careers.
Researchers are also studying exosomes, which are present in blood and carry biomarkers that may be useful in tracking TBI. Exosomes are lipid-membrane-bound extracellular vesicles whose cargo is rich in microRNA (miRNA) and protein, sequestered from the cytoplasm of the cell of origin. Exosomes are secreted by all cells and are known to have a range of biological functions, including cell-to-cell communication and signaling.
Exosomes easily cross the BBB and are abundant in peripheral circulation, and their cell of origin can be identified by the proteins they carry on their membrane. Studies of exosomes show that they coordinate response from TBIs. Exosomal activity has been shown to remain dysregulated years following the injury and to relate to chronic symptoms. Preclinical studies show that exosomal content can promote improved recovery. Therefore, additional studies are needed to better understand the role of exosomes in recovery from TBI and their role in acute and chronic symptoms.