NEUROPSYCHIATRIC CORRELATES OF BLOOD-BRAIN BARRIER LEAKAGE
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The research presented in this thesis studied the role of the blood-brain barrier in the development and progression of neuropathology. The blood-brain barrier is the specialized lining of the brain’s capillaries. The high selectivity of this lining is thought to have evolved to protect the brain by: a) barring the influx of neurotoxic molecules from the bloodstream to the brain; b) maintaining the precise ionic balance necessary for proper neuronal function; c) regulating the efflux of waste-products/pathogens from the brain; and d) allowing selective influx of nutrients/hormones/immune-factors into the brain. The barrier is formed by six primary elements, collectively referred to as the ‘neurovascular unit’: 1) specialized and highly selective endothelial cells, interconnected by dense/complex tight junctions; 2) a basement membrane enwrapping the endothelial layer; 3) pericytes, anchored in the basement membrane; 4) a layer of astrocytic end-feet; 5) neighboring microglial cells; and 6) neurons. These elements are key to proper development and maintenance of the specialized phenotype of cerebral capillaries, and can affect the selectivity of the endothelium by altering the expression/function of endothelial influx/efflux transporters, enzymes and/or tight-junctions. Altered blood-brain barrier (BBB) selectivity has been linked to numerous brain disorders, including brain insults (e.g., ischemic/hemorrhagic stroke, traumatic brain injury and seizures) and neuro-inflammatory diseases (e.g., multiple sclerosis, dementia, amyotrophic lateral sclerosis, and Parkinson’s disease). A consensus in the field of BBB research states that BBB dysfunction triggers neuro-inflammatory signaling (TGFβ, IL6, TNFα, IL1β) that can lead to reorganization/dysfunction of neuronal networks and mediate the development of neurological symptoms. However, many gaps remain in the current understanding of mechanisms that cause altered BBB selectivity, and the contribution of these selectivity changes to the development/progression of specific disorders. This thesis studied one facet of altered BBB selectivity – increased blood-to-brain influx, termed BBB leakage for simplicity. The first part of this thesis consists of a study in experimental animals, in which we explored mechanisms resulting in BBB leakage and the pathogenic processes that mediate subsequent brain tissue damage. The second part of this thesis consists of two clinical studies, examining the relevance of BBB leakage to neuropsychiatric symptoms in patients with bipolar disorder and patients with lupus. Our animal study demonstrated that pericytes are likely mediators of BBB leakage and loss of vascular responsiveness to neuronal energy demands (impaired neurovascular coupling). Our clinical studies revealed neuroimaging evidence of extensive BBB leakage in ~25% of patients in each cohort, and a link between extensive leakage and severity of neuropsychiatric symptoms. Moreover, our analysis suggests that the slow/subtle nature of the observed leakage represents an increase in trans-endothelial rather para-endothelial influx. We propose that the chronic systemic inflammation associated with both disorders is a likely cause of altered trans-endothelial leakage that may, in-turn, underlie neuro-functional changes that impact neuropsychiatric outcomes. These insights lay the foundation for the development of novel biomarkers and therapeutics that target mechanisms of BBB pathology. Moreover, the diagnostic software I developed for MRI-based quantification of BBB leakage has high translatability potential, and may enable routine assessment of BBB leakage in clinical settings. The ability to reliably identify patients with BBB leakage may serve as a stepping-stone towards diagnosis-coupled treatment strategies.