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.

由于氧气供应不足以达到高能量，可能会发生小儿中风 对发展大脑的需求。大脑经历了巨大的增长和发展 到童年。脑组织消耗血液传递的氧气，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。 如果大脑的区域没有足够的氧气，则是因为血液不携带 足够的氧气，或者由于血液未到达组织，可能会发生中风。大脑 反映大脑能量需求的氧代谢率（CMRO2）是一个 血液中可用的氧气量的产物，血液流量率（脑血流， 或CBF）以及脑组织占用的氧气百分比（氧气提取 分数或OEF）。 CBF和OEF是动态的过程，能够补偿次要 扰动或根据需要增加需求，以维持稳定的能耗率。在 成年人增加的OEF表现出高代谢补偿，并表示高 中风风险。因为儿童的氧气需求高于成年人，并且变化 在整个童年时期，尚不清楚CBF是否增加了OEF和增加的CBF 高程风险。这是未知的原因之一是因为以前OEF需要辐射 用于组织水平的测量；因此，对小儿的OEF测量不道德 研究。我们的团队开发了新颖的MR序列来测量组织级的OEF。孩子们 由于镰状细胞疾病（SCD）的血液中有较低的氧气量 贫血。患有SCD的孩子也有很高的中风事件，有3个孩子中有1个 在成年之前在MRI上证明中风。这个项目试图了解 OEF和CBF的年龄依赖性是否会预测SCD儿童的中风。我 假设该年龄和氧代谢可以预测SCD儿童的中风风险。长期 该项目的术语目标是开发这些方法来评估中风风险和机制 跨小儿中风种群。目标1：确定年龄和SCD对氧气的影响 代谢。我将研究年龄，血液计数以及SCD对CBF和OEF的贡献。 目标2：确定年龄和氧代谢是否预测患有受试者的单个中风风险 scd。我将关注SCD的受试者4年，以确定全球的预测价值 年龄和氧代谢，会计血数和疾病的区域量度 严重程度。目标3：确定氧代谢对热干预的反应是否年龄 依赖。我将研究全球和区域代谢如何随输血而变化。