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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

基本信息

批准号：
10624274
负责人：
Kristin Guilliams
金额：
$ 44.76万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10624274
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 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 metabolic imaging personalized medicine sex structural imaging treatment strategy white matter

项目摘要

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