Current progress in searching for clinically useful biomarkers of blood-brain barrier damage following cerebral ischemia

Ischemic stroke is a leading cause of death and disability. Fear of intracranial hemorrhage (ICH) has been the primary reason for withholding tissue plasminogen activator (tPA) and thrombectomy, the only two widely accepted treatments for ischemic stroke. Thrombolysis treatment is only allowed in a very narrow time window (within 4.5-6 h). However, so far, other than the time window guideline, there is no reliable indicator available in the clinic to predict ICH before thrombolysis treatment. Recently, extensive research efforts have been devoted to the development of reliable indicators to predict ICH and safely guide the thrombolysis treatment. Accumulating evidence suggests that ischemic brain regions with a compromised blood-brain barrier (BBB) before tPA treatment develop ICH at the later time during thrombolytic reperfusion. Assessing BBB damage before thrombolysis could potentially help predict the risk of ICH after thrombolysis. This article reviews the literature reports on BBB damage biomarkers that have been developed in recent years, including biochemical markers such as BBB structural proteins, circulating brain microvascular endothelial cells, plasma albumin, and brain parenchyma proteins, as well as image markers such as magnetic resonance imaging assessment for BBB damage.