The Blood-Brain Barrier in Bipolar Disorders: A Systematic Review

Abstract

AbstractBackgroundBipolar disorders (BD) are chronic, debilitating disorders. Our understanding of the pathogenesis and functional biomarkers in BD remains limited. The blood-brain barrier (BBB), a highly selective, protective physical barrier which separates the central nervous system from the peripheral circulation, has been increasingly investigated in the BD. This systematic review aimed to assess the relationship between BD and markers of BBB dysfunction.MethodsStudies were identified in PubMed and Medline databases in January 2021. Articles were limited to full-length peer-reviewed journal publications with no date restrictions. Included studies compared blood, CSF, post-mortem, genetic and imaging measures of BBB function in people with BD compared to healthy controls.Results49 studies were identified, 34 of which found an association between BD and markers of BBB dysfunction. Blood QAlb, S100B and MMP levels were found to be increased in BD participants compared to controls in 57% of the studies. In post-mortem BD studies, ICAM, neurexin, claudin-5, and chondroitin sulphate proteoglycans were increased in the anterior cingulate cortex (ACC), prefrontal grey matter, occipital cortex and cerebellum, and lateral nucleus of the entorhinal cortex respectively compared to controls. Additionally, a study of BBB leakage measured by MRI found that nearly 30% of BD participants had extensive BBB leakage compared to controls. The mood state of BD participants was also associated with markers of BBB dysfunction, with participants experiencing mania generally having increased BBB marker levels compared to participants who were depressed or in remission.ConclusionsThis review suggests an association between BD and markers of BBB dysfunction. Further research is needed to control for a number of confounding factors, and to clarify whether this association provides a pathogenic mechanism, or is an epiphenomenon of BD.