Why Molecular Biomarkers of Traumatic Brain Injury May Never Work:Effects of Glymphatic Pathway Dysfunction

Abstract

Traumatic brain injury (TBI) is the leading cause of death and disability in children and young adults around the world because it has been the most misunderstood and misdiagnosed problem among the central nervous system (CNS) disorders. Around 90% of TBIs are classified as mild (mTBI). The current detection of mTBI relies heavily on an assessment of behavioral symptoms, often with delay and subject to motivation. Despite notable advances in diagnostic magnetic resonance imaging (MRI), it remains a challenging issue to precisely make early evaluation of the severity of TBI and to predict the long-term outcomes. Currently there are no molecular biomarker-based blood tests that can accurately determine the presence and the severity of TBI because at present no clinical tools are available for measuring glymphatic-derived convective bulk flow in humans. There is an urgent need to call for a concerted effort to search for sensitive and reliable biomarkers of TBI, especially mTBI. There is a growing consensus that TBI, no matter what the cause, leads to dysfunction of the blood-brain barrier (BBB), which is mainly constituted by brain microvascular endothelial cells (BMEC). Our recent preclinical studies have shown that circulating BMEC in the peripheral blood, which are independent of the glymphatic system, could be used as cellbased biomarkers for quantitative assessment of BBB injury caused by various pathogenic insults, including trauma. The vimentin-α7 nAChR pathway significantly contributes to cBMEC shedding during the pathogenesis of BBB/CNS disorders. The cell-based biomarkers cBMEC along with the single cell technology will overcome the limitations of molecular biomarkers mentioned above and make the early diagnosis of TBI.