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

项目摘要/摘要 这项提议的首要目标是将候选人发展成为一名独立、耐心的- 能够领导旨在保护认知健康的严谨研究的临床调查员 患有镰状细胞病(SCD)的青年。作为一名有认知评估经验的儿科心理学家 和对患有SCD儿童的临床研究，候选人处于独特的地位，可以从NIH受益 导师职业发展奖。SCD是一种未被研究的限制生命的疾病，影响着100,000人 美国的个人和全球每年超过30万新生儿。患有SCD的青少年表现良好 即使与健康的兄弟姐妹相比，他们在认知能力测试中的表现也更差。明显的中风，而实质性的 风险，不影响大多数SCD患者，但有明确的非中风指征， 疾病对中枢神经系统的影响。这些认知缺陷会影响学习成绩， 就业和疾病管理。先前研究的局限性扼杀了翻译 将认知缺陷知识转化为临床应用，以在缺乏认知障碍的情况下保持认知健康 卒中。拟议的研究将通过调查以下具体问题来解决悬而未决的问题 目的：1)测定无明显卒中症状的青少年SCD患者的认知功能轨迹； 探讨无明显症状的青少年SCD患者的静息状态前额叶-纹状体功能连接 卒中。在这项研究中，114名8-17岁的无中风的HbSS青少年将完成计算机化认知 在18个月内每6个月进行一次检查和抽血，并进行经颅多普勒超声 基线和12个月后。年龄在11-17岁之间的子组(n=40)将完成静息状态功能 基线时的磁共振成像。研究结果将推动该领域向预防所有SCD- 通过增强预测模型在没有中风的情况下识别患者的相关认知障碍 未来认知功能下降的风险，并告知认知和疾病修改的战略应用 治疗。候选人组织了一支模范的导师团队，在NIH有显著的记录 资助和指导，致力于推进候选人的职业生涯。导师有专业知识 纵向认知评估(Kristina Hardy博士)、SCD病理生理学(Naomi Luban博士)、 SCD的认知功能(杰弗里·沙茨博士)，功能神经成像(Chanda Vaidya博士)，SCD 严重性测量模型(Julie Panepinto博士)以及研究设计和生物统计学(吉川博士 王)。应聘者将受益于理想的学术环境和广泛的资源 儿童国家健康系统。有条理的培训计划将确保职业生涯的及时进步。 发展目标涉及以下方面的知识：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。 综上所述，拟议的计划将为候选人提供初步数据和指导 他需要成为独立研究资金的有竞争力的候选人，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.