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

小儿镰状细胞病的脑氧代谢和功能网络架构

• 批准号: 9295569
• 负责人: Melanie Erin Fields
• 金额: $ 16.04万
• 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: 2017-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295569
• 关键词: Adult; Affect; Age; Algorithms; Amber; Area; Attention; Biometry; Brain; Brain Injuries; Brain region; Cerebrum; Child; Childhood; Clinical Trials; Clinical Trials Design; Cognitive; Cognitive deficits; Collaborations; Complex; Data; Development; Development Plans; Diffuse; Disease; Environment; Episodic memory; Face; Failure; Foundations; Functional disorder; Future; Goals; Human; Image; Impaired cognition; Individual; Instruction; Intervention; Investigation; Linear Models; Magnetic Resonance Imaging; Maps; Measurement; Measures; Mentors; Mentorship; Metabolic stress; Metabolism; Methods; Neurocognitive; Neurologic; Neuronal Injury; Neuropsychology; Oxygen; Pediatric Hematologist; Pediatric Hematology; Physicians; Positron-Emission Tomography; Preventive treatment; Research Project Summaries; Resources; Rest; Risk; Scientist; Severity of illness; Short-Term Memory; Siblings; Sickle Cell Anemia; Signal Transduction; Stroke; Subgroup; Testing; Time; Tissues; Training; Universities; Visual; Washington; axon injury; biomarker development; career development; cognitive development; cognitive testing; cohort; connectome; executive function; gray matter; imaging approach; imaging modality; improved; innovation; insight; network architecture; neurocognitive test; neuroimaging; neuroimaging marker; novel; patient stratification; peer; predictive marker; processing speed; symposium; white matter

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.

项目概要 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能力下降 其表现是智商下降、未能实现学业里程碑以及执行功能缺陷。 然而，人们对认知衰退背后的病理生理机制知之甚少，这提供了 预测性生物标志物和预防性治疗的发展障碍。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 患有 SCD 的儿童的提取率升高，表明持续的脑代谢压力。她的中央 假设是深部白质的区域代谢应激导致功能性破坏 特定网络内的连接性，从而导致相应认知领域的下降。为了 检验她的假设，她将获得脑氧代谢、静息状态的纵向测量 功能连接和神经认知测试，以完成以下具体目标：1）比较 年龄匹配的 SCD 儿童与未受 SCD 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 功能网络结构的变化，以及 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 目标将通过创新的 MRI 方法深入了解 SCD 对认知发展的影响，以及 开发神经影像生物标志物，可以在未来的临床试验测试干预措施中对患者进行风险分层 旨在改善镰状细胞病的认知影响。候选人：Fields 博士是一名儿科医生 血液学家，其长期目标是成为儿科血液学领域的独立医师科学家 专注于研究镰状细胞病儿童所遭受的使人衰弱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课程、机构和国家会议 促进 Jin-Moo Lee 博士在脑科学领域的合作和一对一的指导和指导 新陈代谢，Bradley Schlaggar 博士，BOLD 成像的采集、处理和应用，Allison 博士 King 的神经心理学和镰状细胞病的认知影响以及 Amber Salter 博士的 生物统计学。该培训计划将使菲尔兹博士能够使用新颖的成像方式来了解 SCD 认知能力下降的病理生理学。环境：华盛顿大学（WU）世界知名 用于神经影像研究和资源。用于测量氧气提取量的专用 MR 序列 该提案中的一部分是由该提案的顾问安宏宇博士在 WU 制定的。正电子 发射断层扫描成像是在西弗吉尼亚大学开发的，许多典型的静息态网络是在 在WU发现的。除了 WU 领导的人类连接组项目外，该项目由 Drs. 指导。大卫·范 埃森·巴奇 (Essen Barch) 和迪安娜·巴奇 (Deanna Barch) 是世界上最受尊敬的一些神经科学家，他们都在西弗吉尼亚大学找到了自己的家，其中包括 博士。马库斯·雷克尔 (Marcus Raichle)、史蒂文·彼得森 (Steven Petersen) 和我的导师 Drs.李金茂和布拉德利·施拉格。