Mapping Activated Microglia and Their Effect on Cognitive Deficits in Adults with Sickle Cell Disease

About This Grant

Project Summary Sickle cell disease (SCD) is associated with progressive cognitive deficits beginning in infancy and which cause significant impacts on academic achievement and later job attainment. Increasingly there is evidence from preclinical SCD mice and other human neurodegenerative disorders that neuroinflammation, and specifically activated microglia, independently contribute to these cognitive deficits. Recent advances in diffusion MRI (dMRI) have led to validated neuroimaging biomarkers of neuroinflammation. When microglia are activated, alterations in cell shape and density can be detected based on changes in water dispersion within and around microglia. We hypothesize that individuals with SCD have a significantly greater density and distribution of global and regional activated microglia, particularly in the hippocampus and frontal lobes compared to healthy controls and that the density of activated microglia is inversely correlated with executive functioning and attention abilities. In this proposal, we aim to: 1) measure the density and distribution of regional and whole brain activated microglia in 45 individuals with SCD compared to 15 healthy controls frequency matched for age, sex, and race using this novel dMRI sequence; and 2) determine the correlation between global and/or regional activated microglial density and the presence of cognitive deficits using the NIH Toolbox: Cognition Battery. Finally, in an exploratory aim, we will quantify systemic inflammatory and neurodegeneration markers and will assess for correlation with the density of activated microglia in all study subjects. In the long term, the knowledge gained from this study will have both clinical and investigational implications, to monitor for and follow the development of neuroinflammation in the brains of individuals with SCD and as a means for assessing response to interventions targeting neuroinflammation and cognitive deficits. Dr. Karkoska’s long-term goal is to become an independent investigator focused on understanding the pathophysiology of cognitive deficits in adults and children with SCD and identifying/implementing interventions to slow or even prevent SCD-related cognitive decline. She will pursue the following career development objectives during her K23 training through a combination of formal coursework, practical experiences with mentors/collaborators, and conference/seminar attendance: 1) focus on the design and implementation of translational and multisite research trials; 2) acquire skilled training and collaboration in advanced neuroimaging techniques, processing, and analysis as a foundation for future independent study design; and 3) obtain formal training in cognition and neuropsychological battery selection and interpretation. The completion of these objectives, along with the study aims will place Dr. Karkoska in the ideal position to apply for NIH R-level funding during this proposed funding mechanism.