Age-Dependence of Cerebral Oxygen Metabolism and Stroke Risk in Pediatric Sickle Cell Disease

儿童镰状细胞病脑氧代谢和中风风险的年龄依赖性

• 批准号: 9224435
• 负责人: Kristin Guilliams
• 金额: $ 17.52万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9224435
• 关键词: 9 year old; Accounting; Acute; Adolescence; Adult; Age; Age-Years; Anemia; Award; Blood; Blood Transfusion; Brain; Brain region; Cell physiology; Cerebrovascular Circulation; Cerebrum; Child; Childhood; Childhood stroke; Consumption; Data; Dependence; Development; Financial compensation; Functional disorder; Goals; Growth and Development function; Hemoglobin; Human; Image; Incidence; Individual; Injury; Knowledge; Life; Magnetic Resonance Imaging; Measurement; Measures; Metabolic; Metabolic stress; Metabolism; Methods; Minor; Modeling; Morbidity - disease rate; Oxygen; Pediatric Research; Population; Positron-Emission Tomography; Predictive Value; Process; Radiation; Radiation exposure; Research; Research Personnel; Risk; Scanning; Severity of illness; Sickle Cell Anemia; Stress; Stroke; Structure; Techniques; Testing; Therapeutic Intervention; Tissues; Transfusion; Variant; Vascular Diseases; age effect; age related; base; brain tissue; career development; congenital heart disorder; experimental study; follow-up; high risk; high risk population; indexing; innovation; metabolic abnormality assessment; metabolic rate; mortality; novel; predictive modeling; response; risk mitigation; stroke therapy; white matter

Pediatric stroke may occur because of an inadequate oxygen supply to meet the high energy demands of a developing brain. The brain undergoes tremendous growth and development throughout childhood. Brain tissues consume oxygen delivered by the blood, providing energy for cellular processes. The brain’s demand for oxygen appears to peak between ages 5-9. If regions of the brain do not get enough oxygen, either because the blood does not carry enough oxygen, or because blood does not reach the tissue, a stroke can occur. The cerebral metabolic rate of oxygen utilization (CMRO2), reflecting the energy demands of the brain, is a product of amount of oxygen available in the blood, rate of blood delivery (cerebral blood flow, or CBF) and the percentage of oxygen delivered taken up by the brain tissue (oxygen extraction fraction, or OEF). CBF and OEF are dynamic processes, able to compensate for minor perturbations or increased demand as needed to maintain a steady energy consumption rate. In adults, an increased OEF demonstrates high metabolic compensation and signifies a high stroke risk. Because the oxygen demand is higher in children than adults and changes throughout childhood, it is unclear whether increased OEF and increased CBF also denote a high stroke risk. One reason this is unknown is because previously OEF has required radiation for tissue-level measurements; thus rendering OEF measurements unethical for pediatric research. Our team has developed novel MR sequences to measure tissue-level OEF. Children with sickle cell disease (SCD) have lower amounts of oxygen available in their blood due to anemia. Children with SCD also have a high incidence of stroke, with 1 of 3 children demonstrating stroke on MRI before reaching adulthood. This project seeks to understand whether or not age-dependent increases in OEF and CBF predict stroke in children with SCD. I hypothesize that age and oxygen metabolism predict stroke risk in children with SCD. The long- term goal of this project is to develop these methods to assess stroke risk and mechanism across pediatric stroke populations. Aim 1: To determine effects of age and SCD on oxygen metabolism. I will examine the contribution of age, blood counts, and SCD on CBF and OEF. Aim 2: To determine if age and oxygen metabolism predict individual stroke risk in subjects with SCD. I will follow subjects with SCD for 4 years to determine the predictive value of global and regional measures of age and oxygen metabolism, accounting blood counts, and disease severity. Aim 3: To determine if oxygen metabolism response to therapeutic intervention is age- dependent. I will examine how global and regional metabolism changes with transfusion.

儿童中风可能是因为氧气供应不足，无法满足高能 对大脑发育的要求。大脑经历了巨大的生长和发展 贯穿整个童年。脑组织消耗血液输送的氧气，提供能量 用于细胞过程。大脑对氧气的需求似乎在5-9岁之间达到顶峰。 如果大脑的某些区域没有获得足够的氧气，要么是因为血液不能携带 足够的氧气，或者因为血液不能到达组织，可能会发生中风。大脑皮层 反映大脑能量需求的氧利用代谢率(CMRO2)是一种 血液中可利用的氧气量、输血率(脑血流量、 或CBF)和脑组织所输送的氧气的百分比(氧气提取 分数，或OEF)。CBF和OEF是动态的过程，能够补偿次要的 根据需要进行扰动或增加需求，以保持稳定的能源消耗率。在……里面 成年人，OEF增加表明高代谢代偿性，并意味着高 中风风险。因为儿童的需氧量比成年人高，所以会改变 在整个童年时期，还不清楚OEF增加和CBF增加是否也意味着 中风风险很高。这是未知的原因之一是因为之前OEF需要辐射 用于组织水平测量；因此使OEF测量对儿科医生来说是不道德的 研究。我们的团队已经开发出新的磁共振序列来测量组织水平的OEF。儿童 患有镰状细胞病(SCD)的患者由于以下原因，其血液中的可用氧量较低 贫血。患有SCD的儿童中风的发病率也很高，每3个孩子中就有1个 成年前在核磁共振上显示中风。这个项目试图理解 SCD儿童的OEF和CBF是否与年龄相关可预测卒中。我 假设年龄和氧代谢预测SCD儿童的中风风险。长的- 本项目的长期目标是开发这些方法来评估中风的风险和机制 在儿童中风人群中。目的1：确定年龄和SCD对氧的影响 新陈代谢。我将研究年龄、血细胞计数和SCD对CBF和OEF的贡献。 目的2：确定年龄和氧代谢是否预测中风的个体风险 SCD。我将对患有SCD的受试者进行为期4年的跟踪调查，以确定全球和 年龄和氧代谢的区域性测量，计算血细胞计数和疾病 严肃性。目的3：确定氧代谢对治疗干预的反应是否与年龄有关。 依附的。我将研究全球和区域新陈代谢如何随着输血而变化。