Trajectory of Cognitive Functioning in Youth with Sickle Cell Disease without Cerebral Infarction

项目总结/摘要 该提案的总体目标是将候选人发展成为一个独立的，耐心的- 面向临床研究者能够领导严格的研究，旨在保持认知健康， 患有镰状细胞病（SCD）的年轻人。作为一个有认知评估经验的儿科心理学家 和临床研究与儿童SCD，候选人是唯一的定位，受益于这个国家卫生研究院 职业发展奖。SCD是一种未充分研究的限制生命的疾病，影响10万人， 美国和全球每年超过30万新生儿。青年与SCD表演 在认知能力测试中，甚至与健康的兄弟姐妹相比也是如此。明显的中风， 风险，不影响大多数SCD患者，但有明确的非卒中指征， 疾病对中枢神经系统的影响。这些认知缺陷会影响学业成绩， 就业和疾病管理。以往研究的局限性阻碍了 将认知缺陷的知识应用于临床，以在缺乏认知缺陷的情况下保持认知健康。 中风拟议的研究将通过调查以下具体问题来解决尚未回答的问题 目的：1）确定无明显卒中的SCD青年患者的认知功能轨迹; 2） 探索无明显症状的SCD青年亚组静息状态前额叶-纹状体功能连接 中风在这项研究中，114名年龄在8-17岁之间患有HbSS但没有中风的青少年将完成计算机认知 每6个月进行一次检查和抽血，持续18个月，以及经颅多普勒超声检查， 基线和12个月后。年龄在11-17岁之间的一个子集（n=40）将完成静息状态功能 磁共振成像基线。结果将推动该领域朝着预防所有SCD的方向发展- 通过增强预测模型，在没有中风的情况下识别患者， 未来认知能力下降的风险，并为认知和疾病改善的战略应用提供信息 治疗。候选人组织了一个模范导师团队，具有NIH的显著记录 资金和指导谁致力于推进候选人的职业生涯。导师有专业知识 在纵向认知评估（Kristina哈代博士）、SCD病理生理学（Naomi Luban博士） SCD认知功能（Jeffrey Schatz博士），功能性神经影像学（Chandan Vaidya博士），SCD 严重性测量模型（Julie Panepinto博士），研究设计和生物统计学（Jichuan博士 Wang）。候选人将受益于理想的学术环境和广泛的资源， 国家儿童保健系统。结构化的培训计划将确保职业生涯的及时进展 发展目标包括获得以下知识：1）SCD病理生理学和疾病 严重程度测量; 2）功能磁共振成像设计和解释; 3）先进的临床研究方法。 总的来说，拟议的计划将为候选人提供初步的数据和指导 需要他成为独立研究资金的竞争力候选人，同时也定位 他是SCD认知结果领域的领导者。

PROJECT SUMMARY/ABSTRACT The overarching goal of this proposal is the development of the candidate into an independent, patient- oriented clinical investigator capable of leading rigorous research aimed at preserving cognitive health in youth with sickle cell disease (SCD). As a pediatric psychologist with experience in cognitive assessment and clinical research with children with SCD, the candidate is uniquely positioned to benefit from this NIH Mentored Career Development Award. SCD is an understudied, life-limiting disease affecting 100,000 individuals in the United States and over 300,000 newborns globally every year. Youth with SCD perform lower on tests of cognitive ability, even compared to healthy siblings. Overt stroke, while a substantial risk, does not affect the majority of patients with SCD yet there are clear indications of non-stroke, disease effects on the central nervous system. These cognitive deficits impact school achievement, employment, and disease management. Limitations of previous research have stifled translation of knowledge about cognitive deficits into clinical applications to preserve cognitive health in the absence of stroke. The proposed study will address unanswered questions by investigating the following specific aims: 1) determine the trajectory of cognitive functioning in youth with SCD without overt stroke; and 2) explore resting-state prefrontal-striatal functional connectivity in a subset of youth with SCD without overt stroke. In this study, 114 youth ages 8-17 with HbSS without stroke will complete computerized cognitive tests and blood draws every 6 months for 18 months, as well as transcranial Doppler ultrasonography at baseline and 12 months later. A subset (n=40) between ages 11-17 will complete resting-state functional magnetic resonance imaging at baseline. Results will advance the field toward prevention of all SCD- related cognitive deficits in the absence of stroke by enhancing predictive models that identify patients at risk for future cognitive declines and informing strategic application of cognitive and disease-modifying treatments. The candidate has organized an exemplary mentorship team with notable records of NIH funding and mentorship who are committed to advancing the candidate's career. Mentors have expertise in longitudinal cognitive assessment (Dr. Kristina Hardy), SCD pathophysiology (Dr. Naomi Luban), cognitive functioning in SCD (Dr. Jeffrey Schatz), functional neuroimaging (Dr. Chandan Vaidya), SCD severity measurement models (Dr. Julie Panepinto), and research design and biostatistics (Dr. Jichuan Wang). The candidate will benefit from an ideal academic environment and extensive resources in Children's National Health System. A structured training plan will ensure timely progress toward career development goals involving acquisition of knowledge about: 1) SCD pathophysiology and disease severity measurement; 2) fMRI design and interpretation; and 3) advanced clinical research methods. Taken together, the proposed plan will provide the candidate with the preliminary data and mentorship needed for him to be a competitive candidate for independent research funding, while also positioning him as a leader in the field of cognitive outcomes in SCD.