The Impact of Cerebral Metabolic Stress on the Development of the Structural and Functional Connectome in Pediatric Sickle Cell Anemia

脑代谢应激对小儿镰状细胞贫血症结构和功能连接体发育的影响

• 批准号: 10179749
• 负责人: Melanie Erin Fields
• 金额: $ 64.97万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-05 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10179749
• 关键词: Accounting; Acute; Age; Algorithms; Anatomy; Attenuated; Biological Markers; Brain; Brain Injuries; Brain region; Cerebrum; Child; Childhood; Chronic; Clinical; Cognitive; Data; Development; Erythrocyte Transfusion; Evaluation; Executive Dysfunction; Exposure to; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Impaired cognition; Infarction; Injury; Intervention; Investigative Techniques; Link; MRI Scans; Magnetic Resonance Imaging; Measures; Mediating; Mentored Patient-Oriented Research Career Development Award; Metabolic; Metabolic stress; Metabolism; Nervous System Trauma; Outcome; Oxygen; Participant; Patient Care; Patients; Primary Prevention; Rest; Screening procedure; Sickle Cell Anemia; Stroke; Structure; Techniques; Testing; Time; Transcranial Doppler Ultrasonography; Transfusion; Treatment Efficacy; Vulnerable Populations; biomarker development; cognitive function; cognitive testing; cohort; connectome; disability; executive function; experience; improved; improved outcome; innovation; insight; neuroimaging; neuroimaging marker; novel; patient population; prediction algorithm; predictive marker; prevent; prospective; recruit; risk prediction; risk stratification; stroke risk; treatment effect; white matter

PROJECT SUMMARY Children with sickle cell anemia (SCA) suffer from cognitive decline, even when unaffected by stroke. The pathophysiology of cognitive dysfunction in SCA is poorly understood. Understanding the mechanism and trajectory of injury and degree of reversibility is necessary to prevent lifelong disability in this vulnerable population. Furthermore, current screening tools are inadequate as transcranial Doppler ultrasound and structural brain MRI only screen for risk of stroke and evaluate for presence of irreversible infarction. The long- term goal of this proposal is to determine the mechanism of brain injury with MR measures of oxygen metabolism, structural connectivity, and functional connectivity, and develop neuroimaging biomarkers for cognitive dysfunction in SCA. Children with SCA experience cerebral metabolic stress, as measured by increased oxygen extraction fraction (OEF). OEF peaks within the deep white matter, co-localizing with the brain region at greatest risk for stroke in SCA. Increased metabolic stress is associated with disrupted connectivity within specific functional brain networks, and the nodes of networks with diminished functional connectivity in SCA are anatomically- contiguous, clustered and aligned with the region of elevated OEF in the white matter. However, OEF decreases and executive function abilities improve with a single red blood cell transfusion in children with SCA, suggesting some aspects of cognitive dysfunction, potentially driven by alterations in FC, are acutely reversible as metabolic stress is attenuated in SCA. The central hypothesis of this proposal is that isolated disruption of functional connectivity caused by increased metabolic stress will be acutely reversible; however, disruption of functional connectivity mediated by structural connectivity will be irreversible. Treatment of the former may improve cognitive function, while treatment of the latter may mitigate progressive cognitive decline. In order to test her hypothesis, Dr. Fields will obtain longitudinal measures, separated by three years, of cognitive testing and brain MRIs to measure OEF, structural connectivity and functional connectivity in control, non-transfused SCA, and transfused SCA participants. The transfused participants will undergo cognitive testing and brain MRI before and after red blood cell transfusion at study entrance. Using this data, she will test her central hypothesis by completing the following specific aims: 1) Determine if disruption of the structural and functional connectome is reversible with transfusion of RBCs in SCA, 2) Determine the impact of increased OEF on the development of the structural and functional connectome, and 3) Determine if MR metrics of metabolic stress, SC and FC predict aberrant cognitive trajectories. Completion of these aims will provide insight into the pathophysiology of cognitive dysfunction in SCA, and allow the definition and development of biomarkers for reversible neurologic injury, which can potentially guide treatment effect, and improve outcomes in this vulnerable population.

项目概要 患有镰状细胞性贫血 (SCA) 的儿童即使未受中风影响，也会出现认知能力下降。 SCA 认知功能障碍的病理生理学尚不清楚。了解机制和 伤害轨迹和可逆性程度对于防止这一弱势群体终身残疾是必要的 人口。此外，目前的筛查工具还不够充分，如经颅多普勒超声和 结构性脑部 MRI 仅筛查中风风险并评估是否存在不可逆梗塞。长- 该提案的长期目标是通过氧的 MR 测量来确定脑损伤的机制 代谢、结构连接和功能连接，并开发神经影像生物标志物 SCA 中的认知功能障碍。 患有 SCA 的儿童会经历脑代谢应激（通过吸氧量增加来衡量） 分数（OEF）。 OEF 在深层白质内达到峰值，与最有风险的大脑区域共定位 SCA 中风。代谢压力增加与特定功能内的连接中断有关 大脑网络，以及 SCA 中功能连接减弱的网络节点在解剖学上是 与白质中 OEF 升高的区域相邻、聚集并对齐。然而，OEF 患有 SCA 的儿童通过单次红细胞输注可减少执行功能， 表明认知功能障碍的某些方面可能是由 FC 的改变引起的，并且是可急剧逆转的 因为 SCA 中的代谢应激得到了缓解。该提案的中心假设是孤立的破坏 由代谢压力增加引起的功能连接将是可急剧逆转的；然而，破坏 由结构连接介导的功能连接将是不可逆转的。前者的治疗可 改善认知功能，而后者的治疗可能会减轻进行性认知衰退。为了 为了验证她的假设，菲尔兹博士将获得认知测试的纵向测量，间隔三年 和脑部 MRI，用于测量对照、非输血的 OEF、结构连接和功能连接 SCA 和输血的 SCA 参与者。输血的参与者将接受认知测试和大脑测试 研究入口处红细胞输注前后的 MRI。使用这些数据，她将测试她的中央 通过完成以下具体目标来提出假设： 1）确定结构和功能是否受到破坏 通过在 SCA 中输注红细胞，连接组是可逆的，2) 确定增加的 OEF 对 结构和功能连接体的发育，以及 3) 确定代谢应激的 MR 指标， SC 和 FC 预测异常的认知轨迹。完成这些目标将有助于深入了解 SCA 认知功能障碍的病理生理学，并允许定义和开发生物标志物 可逆性神经损伤，可以潜在地指导治疗效果，并改善这种情况的结果 弱势群体。