Biomarkers of Disruption of Blood-Brain Barrier

Blood-brain barrier (BBB) is a dynamic conduit for transport between blood and brain of those nutrients, peptides, proteins, or immune cells that have access to certain transport systems localized within the BBB membranes. Recent advances in cell and molecular biology have provided new insights into the function of the BBB. Several disorders of the central nervous system (CNS) are associated with increased permeability of the BBB. Two main approaches are used for studying the integrity of human BBB in vivo: (1) structural imaging employs contrast agents that only penetrate the BBB at sites of damage, and (2) functional imaging is used to study the transport of substances across the BBB - both intact and damaged. Structural imaging employs contrast agents with CT scanning and is relatively insensitive. MRI with the contrast agent gadolinium is more sensitive. Functional imaging is done with PET and can quantify cerebral uptake of therapeutic agents, such as cytotoxic agents and monoclonal antibodies. SPECT is less versatile than PET, but can provide semiquantitative measurement of BBB leakage of albumin or red blood cells. There is a need for biomarkers to detect early changes in BBB.

Loss of integrity of the BBB resulting from ischemia/reperfusion is believed to be a precursor to hemorrhagic transformation (HT) and poor outcome in acute stroke patients. An MRI biomarker has been used to characterize early BBB disruption in human focal brain ischemia and its association with reperfusion, HT, and poor outcome. Reperfusion was found to be the most powerful independent predictor of early BBB disruption and thus of HT and is important for the decision for acute thrombolytic therapy. Early BBB disruption as defined by this imaging biomarker is a promising target for adjunctive therapy to reduce the complications associated with thrombolytic therapy, broaden the therapeutic window, and improve clinical outcome in acute stroke.

The astrocytic protein S100B is a potentially useful peripheral biomarker of BBB permeability. Other biomarkers of BBB have been discovered by pro- teomic approaches. These proteins are virtually absent in normal blood, appear in serum from patients with cerebral lesions, and can be easily detected by commercially available ELISA tests. S100B levels in peripheral blood are raised in soldiers under stress leading to an increase BBB permeability secondary to immune activation, which is associated with stress-related depression and anxiety (Li et al. 2014a).

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