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满足高能量，可能会发生小儿中风 大脑发育的需求。 在整个童年时期，脑组织消耗血液输送的氧气，提供能量。 大脑对氧气的需求似乎在 5 至 9 岁之间达到峰值。 如果大脑区域没有获得足够的氧气，或者是因为血液不携带 足够的氧气，或者由于血液没有到达组织，可能会发生中风。 氧利用率代谢率（CMRO2）反映了大脑的能量需求，是一个 血液中可用氧量、血液输送速率（脑血流量、 或 CBF）和脑组织吸收的氧气百分比（氧提取 分数，或 OEF）。 CBF 和 OEF 是动态过程，能够补偿微小的变化。 根据需要进行扰动或增加需求，以维持稳定的能源消耗率。 对于成年人来说，OEF 增加表明代谢补偿较高，并意味着高 因为儿童的需氧量比成人高并且发生变化。 在整个童年时期，尚不清楚增加的 OEF 和增加的 CBF 是否也表示 中风风险较高的原因之一是因为以前 OEF 需要放射治疗。 用于组织水平测量；因此 OEF 测量对于儿科来说是不道德的 我们的团队开发了新的 MR 序列来测量儿童组织水平的 OEF。 镰状细胞病 (SCD) 患者血液中的可用氧气量较低，原因是 患有 SCD 的儿童中风的发病率也很高，每 3 名儿童中就有 1 名发生中风。 该项目旨在在成年之前通过 MRI 展示中风。 OEF 和 CBF 的年龄依赖性增加是否可以预测 SCD I 儿童的中风。 坚持认为年龄和氧代谢可以预测 SCD 儿童的中风风险。 该项目的长期目标是开发这些方法来评估中风风险和机制 目标 1：确定年龄和 SCD 对氧气的影响。 我将研究年龄、血细胞计数和 SCD 对 CBF 和 OEF 的影响。 目标 2：确定年龄和氧代谢是否可以预测患有以下疾病的受试者的个体中风风险 我将对患有 SCD 的受试者进行为期 4 年的跟踪，以确定总体和预测的价值。 年龄和氧代谢、血细胞计数和疾病的区域测量 目标 3：确定氧代谢对治疗干预的反应是否与年龄相关。 我将研究全球和区域新陈代谢如何随着输血而变化。