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

项目摘要 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下降 智商下降，未能达到学术里程碑，以及执行功能的缺陷。 然而，认知能力下降的病理生理机制还知之甚少， 这是发展预测性生物标志物和预防性治疗的障碍。菲尔兹博士的长期目标是 了解SCD认知能力下降的病理生理学。她的初步研究表明氧气 SCD患儿的脑组织中的皮质醇含量升高，提示持续的脑代谢应激。她的中心 一种假设是深层白色物质中的局部代谢应激导致功能性代谢紊乱， 特定网络内的连接性，随之而来的是相应认知领域的下降。为了 为了验证她的假设，她将获得脑氧代谢、静息状态、 功能连接和神经认知测试，以完成以下具体目标：1）比较跨- 年龄匹配的SCD儿童和未受影响的健康兄弟姐妹之间的网络内连接 SCD，2）确定代谢应激是否预测SCD中功能网络结构的变化，和3） 评估代谢压力和连接中断作为认知能力下降的预测因素。完成这些 目的是通过创新的MRI方法深入了解SCD对认知发展的影响， 开发神经成像生物标志物，在未来的临床试验中测试干预措施， 旨在改善镰状细胞病的认知影响。候选人：菲尔兹医生是一名儿科医生， 长期目标是成为儿科血液学独立医生-科学家的血液学家 专注于研究镰状细胞病儿童所遭受的认知和神经系统并发症 疾病她的职业发展计划包括正式的课程，机构和国家会议 促进合作和一对一的指导和指导，从博士Jin-Moo李在大脑 代谢，布拉德利Schlaggar博士在采集，处理和应用BOLD成像，艾利森博士 金在神经心理学和镰状细胞病的认知影响和琥珀索尔特博士在 生物统计学该培训计划将使Fields博士能够使用新的成像模式来了解 SCD认知功能下降的病理生理学。环境：华盛顿大学（WU）是世界著名的 用于神经成像研究和资源。用于测量氧提取的专用MR序列 该提案中的分数由该提案的顾问Hongyu An博士在WU开发。正电子 发射断层扫描成像是在WU开发的，许多典型的静息态网络是 在吴发现。除了WU领导的人类连接组项目外，大卫货车博士 埃森和迪安娜巴奇，一些最受尊敬的神经科学家在世界上发现在吴，包括 Drs. Marcus Raichle，Steven Petersen，还有我的导师，Jin-Moo Lee和布拉德利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.