Fluid biomarkers for mild traumatic brain injury and related conditions

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.