The role of metabolic and hemodynamic reserve in age-related brain vulnerability in pediatric sickle cell anemia

代谢和血流动力学储备在儿童镰状细胞性贫血年龄相关大脑脆弱性中的作用

• 批准号: 10427330
• 负责人: Kristin Guilliams
• 金额: $ 47.29万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10427330
• 关键词: Adult; Affect; African American; Age; Anemia; Area; Blood flow; Brain; Brain Injuries; Brain imaging; Cell Death; Cell physiology; Cerebral Infarction; Cerebrum; Child; Childhood; Chronic; Clinical Treatment; Coupled; Data; Data Set; Databases; Dependence; Development; Ensure; Evolution; Goals; Growth; Growth and Development function; Hemoglobin; Hypoxemia; Image; Imaging Techniques; Infarction; Injury; Intervention; Knowledge; Lead; Link; Magnetic Resonance Imaging; Measures; Metabolic; Metabolism; Modeling; Neurological outcome; Only Child; Oxygen; Physiological; Population; Prevention therapy; Resolution; Risk; Role; Sickle Cell; Sickle Cell Anemia; Signal Transduction; Stroke prevention; Technology; Thick; Thinness; Transfusion; age related; age stratification; arteriole; brain dysfunction; brain volume; cellular imaging; cerebrovascular; cohort; cost; experience; follow-up; gray matter; hemodynamics; high risk; hydroxyurea; impaired brain development; improved; innovation; personalized medicine; sex; treatment strategy; white matter

PROJECT ABSTRACT If oxygen supply to the brain does not match its demands, cellular functions are impeded and can lead to cell death. A margin is created between oxygen supply and brain demand by metabolic and hemodynamic reserves. Our preliminary data show that children may have less reserve due to the critical, but costly energy demands of brain growth and maturation. We have shown that lower oxygen supply (hypoxemia) also decreases reserves, and during childhood, may result in impaired brain growth and development. Children with sickle cell anemia (SCA) have chronic hypoxemia due to reduced hemoglobin. Children with SCA have smaller brain volumes and decreased cortical thickness than unaffected children. The intersection of hypoxemia and brain development is poorly understood, impeding our ability to optimize brain development and neurologic outcomes in children with hypoxemia. The goal of this project is to identify physiologic mechanisms of vulnerability and age-dependent consequences of hypoxemia. Our central hypothesis is that the high cerebral metabolic demand in younger children decreases oxygen reserve, resulting in an age-dependent increased risk for impaired brain growth in children with lower oxygen supply. First, we will assess normal developmental changes in metabolic and hemodynamic reserve in 80 healthy children ages 4-21 to determine age-dependence of reserves (Aim 1). Next, we will determine the effects of hypoxemia on metabolic and hemodynamic reserves and the consequence of hypoxemia on brain development. We will compare 40 children with SCA and 40 age and sex-matched controls at baseline and 3 year follow-up imaging, and examine cortical thickness changes in the two cohorts (Aim 2). Finally, we will evaluate whether oxygen reserve increased through hydroxyurea treatment in an SCA cohort impacts long-term brain development. We will utilize a large sickle cell database with 16 years of brain imaging to compare cortical thickness maturation and total brain volumes between treated and untreated children (Aim 3). Determining the age-dependence of hypoxemic vulnerability and its effect on brain development will allow us to personalize treatment strategies for children at high risk for neurodevelopmental injury to be more aggressive during periods of highest vulnerability.

项目摘要 如果大脑的氧气供应与其需求不匹配，细胞功能就会受到阻碍， 会导致细胞死亡氧气供应和大脑需求之间的差额是由 代谢和血液动力学储备。我们的初步数据显示， 由于大脑生长和成熟的关键，但昂贵的能量需求，储备。我们有 显示较低的氧气供应（低氧血症）也会减少储备，在儿童时期， 可能导致大脑生长发育受损。儿童镰状细胞性贫血（SCA） 由于血红蛋白减少而导致慢性低氧血症。患有SCA的儿童大脑较小 体积和减少皮质厚度比未受影响的儿童。交叉口 低氧血症和大脑发育知之甚少，阻碍了我们优化大脑的能力 低氧血症儿童的发育和神经系统结局。该项目的目标是 确定脆弱性的生理机制和 低氧血症。我们的中心假设是，年轻人的高大脑代谢需求 儿童的氧储备减少，导致与年龄相关的受损风险增加。 大脑发育的儿童与较低的氧气供应。首先，我们将评估正常的发育 80名4-21岁健康儿童的代谢和血流动力学储备的变化，以确定 年龄依赖性储备（目标1）。接下来，我们将确定低氧血症对 代谢和血流动力学储备以及低氧血症对脑的影响 发展我们将比较40名SCA儿童和40名年龄和性别匹配的对照组， 基线和3年随访成像，并检查两者的皮质厚度变化 队列（目标2）。最后，我们将评估是否增加氧气储备， 在SCA队列中的羟基脲治疗影响长期脑发育。我们将利用 大型镰状细胞数据库，16年脑成像，比较皮质厚度 治疗和未治疗儿童之间的成熟度和总脑体积（目标3）。确定 低氧血症脆弱性的年龄依赖性及其对大脑发育的影响将使我们能够 针对神经发育损伤高危儿童的个性化治疗策略， 在最脆弱的时期更具侵略性。