Abstract 51: Aging and Metabolic Stress Are Associated With Disrupted White Matter Integrity in Children and Young Adults With Sickle Cell Disease

Abstract

Introduction: Silent cerebral infarcts (SCIs) in sickle cell disease (SCD) begin in early childhood and increase with age, affecting 50% by age 30. SCIs often occur in the watershed area, where cerebral blood flow (CBF) is low, and oxygen extraction fraction (OEF) is high. Diffusion tensor imaging (DTI) measures white matter integrity; lower fractional anisotropy (FA) and higher mean diffusivity (MD) may precede the appearance of SCIs. We hypothesized that age and oxygen metabolic stress, defined by elevated watershed OEF, are associated with disruption of white matter integrity as measured by FA and MD. Methods: Children and young adults with and without SCD were recruited for brain MRI (T1, FLAIR, pseudocontinuous arterial spin label (CBF), asymmetric spin echo (OEF) and DTI). We averaged CBF maps of non-SCD participants and created a watershed region of interest (ROI), defined as CBF <30% of mean gray matter CBF, which was applied to individual maps. All SCIs were outlined and excluded. We evaluated age and SCD as predictors of FA and MD. Within the watershed ROI, we evaluated OEF and age as predictors of FA and MD. Results: Fifty SCD and 53 control participants, age 6-39 years, underwent MRI. Within all normal appearing white matter, FA decreased (p<0.001) and MD increased (p<0.001) with advancing age. MD, but not FA, changed at a faster rate with advancing age in SCD compared to controls (p=0.02). Within the watershed region, OEF significantly predicted FA (p=0.002) and MD (p <0.001), after adjusting for age. Conclusion: Disruption of white matter integrity worsens with early life aging, particularly in SCD. Oxygen metabolic stress within the watershed region, a region at high risk for SCIs, is associated with lower FA and higher MD, suggesting OEF may provide an early tissue marker of ischemic vulnerability in SCD, prior to developing SCIs.