Cerebral Oxygen Metabolism and Functional Network Architecture in Pediatric Sickle Cell Disease

项目总结 研究：与健康儿童相比，患有镰状细胞病(SCD)的儿童面临进行性认知能力下降 同龄人，表现为智商下降，未能实现学业里程碑，以及执行功能缺陷。 然而，认知衰退背后的病理生理学机制却知之甚少，提供了一种 阻碍了预测性生物标志物和预防性治疗的发展。菲尔兹博士的长期目标是 了解SCD认知功能减退的病理生理学。她的初步研究表明，氧气 SCD儿童的摄取量增加，表明持续的大脑代谢应激。她的中枢 假说是深部白质的局部代谢应激导致功能紊乱。 特定网络内的连通性导致相应认知域的下降。为了 验证她的假设，她将获得脑氧代谢的纵向测量，静息状态 功能连通性和神经认知测试，以完成以下具体目标：1)比较 年龄匹配的SCD儿童与健康兄弟姐妹之间的内部网络连接 SCD，2)确定代谢应激是否预测SCD功能网络结构的变化，以及3) 评估代谢压力和连接性中断作为认知能力下降的预测指标。完成这些工作 AIMS将通过创新的MRI方法深入了解SCD对认知发展的影响，以及 开发神经成像生物标记物，在未来的临床试验中对患者进行风险分层，测试干预措施 目的：改善镰状细胞病的认知功能。候选人：菲尔兹医生是儿科医生 血液学家，他的长期目标是成为儿科血液学领域的独立内科科学家 重点研究患有镰状细胞的儿童所遭受的衰弱认知和神经并发症 疾病。她的职业发展计划包括正式的课程、机构和国家会议。 促进协作和一对一的指导和指导李振武博士在脑部 新陈代谢，Bradley Schlaggar博士在BOLD成像的获取、处理和应用中，Allison博士 金在神经心理学和镰状细胞疾病的认知意义和琥珀·索尔特博士在 生物统计学。这项培训计划将使菲尔兹博士能够使用新的成像方式来了解 SCD认知功能减退的病理生理学研究环境：华盛顿大学(吴)享誉世界 用于神经成像研究和资源。用于测量氧气提取的特殊磁共振序列 这项建议中的分数是由这项建议的顾问安宏宇博士在吴教授那里制定的。正电子 发射断层成像是在吴大学开发的，许多规范的休眠状态网络是 在吴国发现的。除了吴领导的人类连接组项目，由David Van博士执导 埃森和迪安娜·巴奇是世界上最受尊敬的神经科学家，包括 Marcus Raichle博士、Steven Petersen博士以及我的导师李振武博士和Bradley Schlaggar博士。

PROJECT SUMMARY Research: Children with sickle cell disease (SCD) face progressive cognitive decline compared to their healthy peers, evidenced by declining IQ, failure to achieve academic milestones, and deficits in executive function. However, the pathophysiological mechanisms underlying cognitive decline are poorly understood, providing a barrier to the development of predictive biomarkers and preventative treatments. Dr. Fields' long-term goal is to understand the pathophysiology of cognitive decline in SCD. Her preliminary studies have shown that oxygen extraction is elevated in children with SCD, suggesting ongoing cerebral metabolic stress. Her central hypothesis is that regional metabolic stress in the deep white matter results in disruption of functional connectivity within specific networks with consequent decline in corresponding cognitive domains. In order to test her hypothesis, she will obtain longitudinal measures of cerebral oxygen metabolism, resting-state functional connectivity and neurocognitive testing to complete the following specific aims: 1) To compare inter- and intra-network connectivity between age-matched children with SCD and healthy siblings unaffected by SCD, 2) To determine if metabolic stress predicts change in functional network architecture in SCD, and 3) To evaluate metabolic stress and disruption of connectivity as predictors of cognitive decline. Completion of these aims will provide insight into the effects of SCD on cognitive development via innovative MRI methods, and develop neuroimaging biomarkers that can risk stratify patients in future clinical trials testing interventions aimed to ameliorate the cognitive effects of sickle cell disease. Candidate: Dr. Fields is a pediatric hematologist whose long-term goal is to become an independent physician-scientist in pediatric hematology focused on studying the debilitating cognitive and neurologic complications suffered by children with sickle cell disease. Her career development plan encompasses formal coursework, institutional and national conferences to facilitate collaboration and one-on-one mentorship and instruction from Dr. Jin-Moo Lee in cerebral metabolism, Dr. Bradley Schlaggar in acquisition, processing and application of BOLD imaging, Dr. Allison King in neuropsychology and the cognitive implications of sickle cell disease and Dr. Amber Salter in biostatistics. This training plan will enable Dr. Fields to use novel imaging modalities to understand the pathophysiology of cognitive decline in SCD. Environment: Washington University (WU) is world-renowned for neuroimaging research and resources. The specialized MR sequence used to measure oxygen extraction fraction in this proposal was developed at WU by Dr. Hongyu An, a consultant for this proposal. Positron emission tomography imaging was developed at WU, and many of the canonical resting state networks were discovered at WU. In addition to WU leading the Human Connectome Project, directed by Drs. David Van Essen and Deanna Barch, some of the most respected neuroscientists in the world are found at WU, including Drs. Marcus Raichle, Steven Petersen, and my mentors, Drs. Jin-Moo Lee and Bradley Schlaggar.