Sickle cell disease (SCD) is an inherited hemoglobinopathy with an increased risk of neurological complications. Due to anemia and other factors related to the underlying hemoglobinopathy, cerebral blood flow (CBF) increases as compensation; however, the nature of alterations in oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) in SCD remains controversial, largely attributed to the different calibration models. In addition, limited studies have been done to investigate oxygen metabolism in pediatric patients. Thus, this study used a non-invasive T2-based MR oximetry, T2-Relaxation-Under-Spin-Tagging (TRUST) MRI, to measure oxygen homeostasis in pediatric patients with SCD using four different calibration models and examined its relationship to hematological measures. It was found that, compared with controls, SCD patients showed an increased CBF, unchanged total oxygen delivery and increased venous blood T2. The results of OEF and CMRO2 were dependent on the calibration models used. When using sickle-specific, hemoglobin S (HbS) level-dependent calibration, there was a decreased OEF and CMRO2, while the bovine model showed an opposite result. OEF and CMRO2 were also associated with hemoglobin and HbS level; the direction of the relationship was again dependent on the model. Future studies with in vivo calibration are needed to provide more accurate information on the T2-Yv relationship.

Background Blood–brain barrier (BBB) disruption may lead to endothelium dysfunction and inflammation in sickle cell disease (SCD). However, abnormalities of BBB in SCD, especially in pediatric patients for whom contrast agent administration less than optimal, have not been fully characterized. Purpose To examine BBB permeability to water in a group of pediatric SCD participants using a non‐invasive magnetic resonance imaging technique. We hypothesized that SCD participants will have increased BBB permeability. Study Type Prospective cross‐sectional. Population Twenty‐six pediatric participants (10 ± 1 years, 15F/11M) were enrolled, including 21 SCD participants and 5 sickle cell trait (SCT) participants, who were siblings of SCD patients. Field Strength/Sequence 3 T. Water extraction with phase‐contrast arterial spin tagging with echo‐planer imaging, phase‐contrast and T1‐weighted magnetization‐prepared rapid acquisition of gradient echo. Assessment Water extraction fraction (E), BBB permeability‐surface area product (PS), cerebral blood flow, hematological measures (hemoglobin, hematocrit, hemoglobin S), neuropsychological scores (including domains of intellectual ability, attention and executive function, academic achievement and adaptive function, and a composite score). Regions of interest were drawn by Z.L. (6 years of experience). Statistical Tests Wilcoxon rank sum test and chi‐square test for group comparison of demographics. Multiple linear regression analysis of PS with diagnostic category (SCD or SCT), hematological measures, and neuropsychological scores. A two‐tailed P value of 0.05 or less was considered statistically significant. Results Compared with SCT participants, SCD participants had a significantly higher BBB permeability to water (SCD: 207.0 ± 33.3 mL/100 g/minute, SCT: 171.2 ± 27.2 mL/100 g/minute). SCD participants with typically more severe phenotypes also had a significantly leakier BBB than those with typically milder phenotypes (severe: 217.3 ± 31.7 mL/100 g/minute, mild: 193.3 ± 31.8 mL/100 g/minute). Furthermore, more severe BBB disruption was associated with worse hematological symptoms, including lower hemoglobin concentrations (β = −8.84, 95% confidence interval [CI] [−14.69, −3.00]), lower hematocrits (β = −2.96, 95% CI [−4.84, −1.08]), and higher hemoglobin S fraction (β = 0.77, 95% CI [0.014, 1.53]). Data Conclusion These findings support a potential role for BBB dysfunction in SCD pathogenesis of ischemic injury. Level of Evidence 2 Technical Efficacy Stage 2

Introduction: Sickle cell disease (SCD), a common genetic disease involving red blood cell structure and function, is associated with cerebral vasculopathy and increased risk of ischemic events that may also affect the inner ear. Individuals with SCD are at increased risk for hearing loss; however, little is known regarding the effects of SCD on the vestibular system or the relationship between hearing loss and vestibular symptoms in these patients. Vestibular dysfunction affects 15-20% of the general population can lead to significant morbidity through falls, fall-related injuries, missed work, and overall reduction in quality of life. Methods: To assess the burden of vestibular dysfunction amongst individuals with SCD, we surveyed individuals with SCD who answered questions about symptoms of dizziness, imbalance, and hearing loss. The survey also captured demographic information, current symptoms of dizziness/imbalance, symptoms of hearing loss, and history of falls. Fisher's exact test was performed to test for associations between clinical characteristics including SCD genotype, hearing loss, dizziness or imbalance, and headache history. Results: Twenty-six participants, ages 20 to 73 years (median 37.5 years) completed the survey. All participants were Black or African-American. Five participants (19.2%) were male, 15 (58%) had hemoglobin SS, 8 (32%) hemoglobin SC, and 3 (12%) S-β + thalassemia. Three (11.5%) participants reported hearing loss. Twelve (46.2%) participants reported dizziness or imbalance, of which 8 (66%) reported recent falls. Of the 12 participants experiencing dizziness, 9 (75%) reported having dizziness for 1 to 3 days a month, 2 reported having dizziness for 4 to 9 days a month, and 1 reported having dizziness for more than 15 days a month. Three participants reported their dizziness symptoms resolved within seconds, 7 within minutes, and 2 within hours. Eleven (42.3%) participants reported headaches. Self-reported dizziness or imbalance was not associated with hearing loss (X 2=0.57; p=0.45), SCD genotype (X 2=0.75; p=0.68), or sex (X 2=0.09; p=0.76). Headache history was associated with dizziness or imbalance (X 2=9.76; p=0.002). Conclusions: In this small pilot study, 46% of individuals with SCD reported dizziness or imbalance, which is twice the rate reported amongst the general population. Headache history is associated with dizziness and imbalance amongst individuals with SCD. Further investigation is warranted to determine the specific effects of SCD on the vestibular end-organs. Disclosures Lanzkron: Imara: Research Funding; Pfizer: Current holder of individual stocks in a privately-held company; GBT: Research Funding; Shire: Research Funding; Teva: Current holder of individual stocks in a privately-held company; Novartis: Research Funding; Novo Nordisk: Consultancy; Bluebird Bio: Consultancy; CSL Behring: Research Funding. Lance: Novartis: Other: participated in research advisory board in 2020.