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

项目摘要 如果大脑的氧气供应与其需求不匹配，细胞功能就会受阻， 会导致细胞死亡。氧气供应和大脑需求之间的差距是由 代谢和血流动力学储备。我们的初步数据显示，儿童可能会有更少的 由于大脑发育和成熟的关键但昂贵的能量需求而储备。我们有 研究表明，较低的氧气供应(低氧血症)也会减少储备，在儿童时期， 可能会导致大脑生长和发育受损。儿童镰状细胞性贫血(SCA) 由于血红蛋白减少而出现慢性低氧血症。患有SCA的儿童大脑较小 与未受影响的儿童相比，体积和皮质厚度减少。的交集 人们对低氧血症和大脑发育知之甚少，这阻碍了我们优化大脑的能力 低氧血症儿童的发育和神经学结局。这个项目的目标是 确定易损性的生理机制和年龄相关性后果 低氧血症。我们的中心假设是，年轻人对大脑代谢的高需求 儿童减少氧气储备，导致与年龄相关的受损风险增加 氧气供应不足的儿童的大脑发育。首先，我们将评估正常发育 80例4~21岁健康儿童代谢和血流动力学储备的变化 储量与年龄的关系(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及低氧血症对脑的影响 发展。我们将对40名患有SCA的儿童和40名年龄和性别匹配的对照组进行比较 基线和3年随访，并检测两组皮质厚度的变化 队列(目标2)。最后，我们将评估氧气储备是否通过 SCA队列中的羟基脲治疗影响长期大脑发育。我们将利用一个 大型镰状细胞数据库与16年的脑成像比较皮质厚度 治疗和未治疗儿童的成熟度和总脑体积(目标3)。确定 低氧脆弱性的年龄相关性及其对大脑发育的影响将使我们能够 为神经发育损伤的高危儿童制定个性化治疗策略 在最脆弱的时期更具攻击性。

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.