Introduction: One of the most severe complications of sickle cell disease (SCD) is ischemic brain injury, caused by a combination of decreased oxygen transport delivery related to intravascular vaso-occlusion of sickle erythrocytes and/or cerebral vasculopathy. While newborn screening programs diagnose SCD shortly after birth, routine risk assessment for stroke typically starts with transcranial ultrasound doppler (TCD) at two years of age or later. Yet, little is known about how SCD affects cerebral hemodynamics during infancy, a crucial period for brain development. To address this gap, we used advanced quantitative near-infrared spectroscopy (qNIRS) to non-invasively monitor cerebral tissue hemoglobin concentration (HbT), oxygenation (SO 2), oxygen extraction fraction (cFTOE), blood flow (CBF), and oxygen metabolism (CMRO 2) in infants with SCD. Abnormal CBF and cFTOE indicate hemodynamic stress that may increase stroke risk. Our study aims to investigate the effects of SCD on cerebral oxygen transport in infancy and its associations with age and blood hemoglobin concentration (HgB). Methods: This is a subgroup analysis of a prospective, observational neuroimaging study of SCD at Boston Children's Hospital (NCT 04166526). Inclusion criteria of this subgroup are SCD patients age less than 24 months old at the time of enrollment who are not receiving chronic transfusions. Families read and signed informed consent before participating in research activities. Measurements were conducted with the patients' normally scheduled hematology appointments at Boston Children's Hospital. During each measurement session, bilateral frontal regions of the head were measured up to six times for 30 seconds each. qNIRS variables were compared with literature values obtained with the same optical technologies from a cohort of typically developed infants around 1 year old, equivalent to the median age in this study 1. Correlation analysis was used to analyze qNIRS variables with age and HgB from clinical lab tests. Results: To date, 8 (F/M: 4/4; HbSS/HbS/B +-thalassemia/HbSC: 6/1/1) patients were enrolled with a total of 16 measurements. The meanSD age at measurement was 11.5 5.23 months and the median (IQR) HgB was 9.4 (8.9-10) g/dL. Seven (44%) measurements were performed while patients were receiving treatment with hydroxyurea. There was no difference in HgB in the groups with and without hydroxyurea, though the treatment group was older (mean age: 15.4 vs 8.4 months, P=0.002). Group averages of qNIRS variables are summarized Table 1. Average cFTOE was 0.53 ± 0.07, significantly higher than the reference value of 0.32 (mean difference: 0.21, P<0.001), while the cohort's mean SO 2 of 45.78 ± 7.13% was significantly lower than the reference value of 68% (mean difference: -22.2, P<0.001). Furthermore, cFTOE inversely correlated with HgB (r= -0.63, P=0.04) while SO 2 increased with HgB (r= 0.63, P=0.04). HbT and cerebral blood volume (CBV) were also significantly lower than the reference values (mean difference of -24.8 μM and -0.75 ml/100g, P<0.001 and P<0.02, respectively) and positively correlated with age (r=0.51 and 0.57, P=0.04). CBF did not correlate with either age or HgB. Hemodynamic variables did not differ between groups with and without hydroxyurea, except for HbT and CBV likely secondary to the cohort age difference. Taken together, this suggests that CBF compensatory mechanisms were insufficient to prevent elevated oxygen extraction. Summary: These preliminary results suggest that inadequate oxygen transport to the brain secondary to SCD evokes a compensatory increase in cFTOE starting in early infancy. The progressive hemodynamic stress to brain health during the period of the brain's greatest growth and metabolic demand for oxygen is concerning because of the potential for injury as compensatory mechanisms become exhausted. Hydroxyurea did not reduce this stress, but may have prevented further declines. Recruitment is ongoing to increase the size of the cohort and to continue following patients' trajectories with age. We demonstrated the potential of qNIRS as biomarkers of cerebral hemodynamic compensation to determine when intervention is necessary and evaluate the effectiveness of a chosen intervention in individual patients. 1. Franceschini, M. A. et al. Assessment of infant brain development with frequency-domain near-infrared spectroscopy. Pediatr Res 61, 546-551, 2007.