Project Summary Silent cerebral infarction is a serious consequence of sickle cell disease (SCD), affecting ~40% of patients by age 15. Although these injuries accumulate occultly, they are linked with cognitive deficits, diminished school performance, and increased risk of overt stroke. Our long-term goal is to develop a low-cost brain monitoring tool that can screen for silent infarct risk in pediatric SCD to facilitate timely therapeutic intervention and that can optimize these interventions to mitigate adverse events. Silent infarcts in SCD are thought to arise from anemia- induced microvascular perfusion abnormalities and subsequent reduced cerebrovascular reserve that is insufficient to meet tissue metabolic demands. Thus, quantification of abnormalities in microvascular cerebral blood flow, vascular reactivity, and/or oxygen extraction may be useful in identifying infarct risk. Indeed, recent MRI studies have shown that SCD children with silent infarcts have globally elevated oxygen extraction in both white and grey matter compared to those without infarct. However, current modalities that quantify microvascular hemodynamic parameters (e.g., PET, MRI) are prohibitively expensive, have limited availability, and require anesthesia in children <6y, making them inappropriate as routine screening tools. Transcranial Doppler ultrasound measures of macrovascular blood flow velocity have had great success in reducing the risk of overt strokes of the macrovasculature by <80%; however, ultrasound is not sensitive to silent microvascular infarcts. Thus, there is an unmet clinical need for a low-cost, non-invasive tool sensitive to microvascular, tissue-level cerebral hemodynamic abnormalities in pediatric SCD to detect children at risk for silent infarcts. Diffuse optical spectroscopies (namely frequency domain near-infrared spectroscopy combined with diffuse correlation spectroscopy, FDNIRS/DCS) may provide a user-friendly, cost-effective alternative to current technologies. These non-invasive techniques use near-infrared light to relate measured changes in light intensity detected at the tissue surface to hemodynamic properties of the underlying tissue. Combined, FDNIRS/DCS enable assessment of oxygen extraction, an index of cerebral blood flow, and an index of cerebral oxygen metabolism. Further, using a simple breath hold challenge, FDNIRS/DCS can assess cerebrovascular reactivity, the vasculature’s ability to dilate in response to carbon dioxide. Our preliminary results show that FDNIRS/DCS can detect expected trends in brain oxygen extraction and blood flow in SCD patients (i.e., elevated compared to controls, inverse correlation with hemoglobin). Moreover, we have developed new analytical strategies that improve the accuracy of the DCS-measured blood flow index by accounting for the influence of hematocrit. Building on this preliminary data, the overall objective of this proposal is to validate our DCS hematocrit- correction against “gold-sta...