The Role of Blood-Brain Barrier Disruption on Ischemic Brain Injury and Cognitive Impairment in Sickle Cell Disease

PROJECT SUMMARY/ABSTRACT Despite advances in sickle cell disease (SCD) treatment, patients continue to experience stroke, endure lifelong cognitive disability, and have a reduced life expectancy of 43 years. While previous imaging studies have focused on anemia and hypoxia as risk factors for stroke, they have not adequately explored other potential disease mechanisms in SCD, such as systemic thromboinflammation and blood-brain barrier (BBB) disruption, which may contribute to increased stroke risk. Although thromboinflammation-targeted approaches have shown promise in mitigating BBB disruption and reducing brain injury in animal models of SCD, their effectiveness in humans remains unexplored. To bridge this gap, this K23 proposes a prospective cohort study to investigate the central hypothesis that BBB dysfunction, associated with specific thromboinflammatory pathways, predicts silent infarct progression and cognitive decline in patients with SCD. The study has three main aims. In Aim 1, using both a well-validated MR sequence and a novel MR sequence, it will assess BBB permeability in patients with SCD compared to healthy controls, stratified in relation to existing infarct burden. In Aim 2, the study will investigate specific thromboinflammatory pathways associated with BBB dysfunction by examining unique gene expressions associated with elevated BBB permeability. Finally, in Aim 3, during a 30-month follow-up period, the study will determine whether baseline BBB permeability can predict the progression of ischemic brain injury and cognitive decline (executive function). This K23 proposal will be implemented with the support of an interdisciplinary team comprising the PI, as well as, mentors and consultants who are experts in relevant fields including: SCD, cerebral small vessel disease, advanced MRI methods, platelets and thromboinflammatory disorders, cognitive function in SCD, and biostatistics. The candidate, an adult cerebrovascular neurologist, has a long term goal to become an independent physician-scientist and to integrate advanced neuroimaging with blood-based markers of thromboinflammation to best achieve a comprehensive understanding of cerebral microvasculopathy and its cognitive consequences. The career development plan outlines three key areas: (1) expertise in advanced neuroimaging acquisition, data processing, and application; (2) foundation in systemic thromboinflammation; and (3) foundation in cognitive testing to translate MRI findings into clinically relevant outcomes. Successful completion of the proposed research and career development activities will fill knowledge gaps for the developing PI and provide compelling evidence on the role of BBB integrity and thromboinflammation in ischemic injury and cognitive decline in SCD. Furthermore, it will guide the development of an independent R01 proposal aimed at investigating BBB integrity as a novel neuroprotective strategy for treatment of cerebral small vessel diseases.