Biomarkers of ischemic risk in adults with sickle cell disease

About This Grant

PROJECT SUMMARY The goal of this work is to use non-invasive quantitative neuroimaging methods to test hypotheses regarding cerebral oxygen utilization in patients with sickle cell disease (SCD) undergoing current standard treatments as well as emerging curative and disease-modifying treatments. Completion will improve our understanding of neurological injury in anemia, which is critical for development of biomarkers that can be used to triage patients for therapies based on personalized risk profiles as well as evaluate the impact of these therapies on established indicators of brain health. More specifically, while cerebral oxygen delivery depends on the cerebral blood flow (CBF; ml blood/100g tissue/minute) and blood oxygen content, it is becoming increasingly recognized that blood capillary transit time itself can also influence tissue oxygen extraction. In individuals with anemia where accelerated capillary flow velocities may be present as a result of hyperemia and cerebral autoregulation, reduced arterial-to-venous transit time (AVTT) can lead to reduced times for tissue oxygen offloading. Compelling evidence has been provided for such heterogeneous capillary flow underlying abnormal oxygen delivery in multiple conditions including expansion of infarcts in acute ischemic stroke, traumatic brain injury, and Alzheimer's disease1. Despite evidence of increased risk for cerebral vasculopathies and stroke, the mechanisms by which these occur is not fully understood. In SCD, we have observed that rapid arterial-to- venous transit, visible on arterial spin labeling (ASL) CBF-weighted MRI, is present in more than 50% of adults and children2, 3. Importantly, we have observed that rapid arterial-to-venous transit is associated with reduced oxygen metabolism 2, suggesting that these transit times may provide a biomarker of cerebral ischemia in individuals with SCA who have greater than a 50% risk of cerebral infarcts by age 30 years4, though less than 16% show conventional stroke risk factors. In SCD, decreased AVTT can play a role in the breakdown of the blood-brain barrier (BBB) through increased shearing forces along the vascular endothelium, and further potentiate vaso-occulsive crises. Here, we propose to utilize noninvasive neuroimaging methods to assess hemodynamic changes such as AVTT in SCD across a variety of hemoglobin-altering therapies to provide quantifiable metrics of expected improvement to triage patients for new or more aggressive therapies. Furthermore, this project aims to evaluate how rapid arterial-to-venous transit times are related to BBB permeability, and overall brain health. In Aim (1), we hypothesize that in adults with SCD, there is a linear reduction in cerebral blood flow and arterial-to-venous flow velocity for treatment-induced increases in Hb. In Aim (2) of this study, we hypothesize that there is an inverse relationship between cerebral arterio-venous transit times and circulating markers of BBB impairment.