Brain Barrier and Glymphatic Clearance Disruptions as Biomarkers for Schizophrenia Spectrum Disorders

About This Grant

PROJECT SUMMARY Pathophysiological studies in first episode psychosis (FEP) have been inconsistent due to the heterogeneity in age of onset, clinical presentation, and neurobiology in schizophrenia spectrum disorders (SSD). Neuroimaging studies, postmortem investigations, and blood-based biomarker experiments provide intriguing insights into potential abnormalities related to the barriers of the brain of individuals with SSD, but only 1% of existing studies have focused on mid- to late-life FEP. Clinical and biomarker studies in SSD have repeatedly shown three phenomena: First, is blood brain barrier (BBB) dysfunction in neuroimaging, postmortem, blood- and CSF-based studies in individuals with SSD. Second, is the involvement of the blood cerebral spinal fluid barrier (BCSFB) as evidenced by enlargement of the choroid plexus (ChP) in SSD, FEP and in individuals at high risk for psychosis. Third, there is a nascent but growing research area related to the disruption of the glymphatic system (GS) in SSD. Moreover, there is a growing body of evidence in aging, sleep, and neurodegenerative studies suggesting a link between disruptions in the BBB, BCSFB, and GS to clinical outcomes. These barrier systems, regulate trafficking between the blood and the brain through physical, enzymatic, transport, and immunological processes, and they have tightly regulated interrelationships between them to ensure a healthy brain environment. However, despite the complementary roles between the BBB, BCSFB, and GS, the interaction between these systems in mid- to late-life FEP has not been explored. Advances in neuromaging and blood-based techniques have improved upon existing tools to assess BBB, BCSFB, and GS function and they include gadolinium-enhanced MRI methods like dynamic contrast enhanced-MRI (DCE-MRI) and the isolation of circulating brain microvascular endothelial cells (cBMECs) in the blood. Therefore, the critical need and overall objectives for this study are to unite neuroimaging, cBMEC, and clinical phenotypes in the same individuals to mechanistically link barrier disruptions to clinical outcomes in mid- to late-life FEP. Our central hypothesis is that biomarkers of BBB, BSCFB, and GS dysfunction are associated with poorer clinical outcomes in mid- to late-life FEP. Here, we aim to test the hypothesis that: 1) barrier/GS disruptions are associated with mid- to late-life FEP, 2) cBMECs are a proxy of BBB deficits in mid- to late-life FEP, and 3) barrier/GS deficits are associated with worse symptoms, cognition, and functioning in mid- to late-life FEP. Lastly, we will determine the interrelationship between barrier and GS deficits in mid- to late-life FEP. The proposed research is innovative in combining in vivo imaging of the BBB, BCSFB, and GS with clinical measures in the same individuals to better understand the barrier/GS deficits associated with clinical outcomes in mid- to late-life FEP. The proposed research is significant because it will lay the groundwork for a robust non-invasive platform to screen for cBMECs to pathophysiologically stratify patients, a first for SSD, that may lead to the prioritization of novel therapeutic approaches to regulate barrier dysfunction in SSD.