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

项目总结 患有镰状细胞性贫血(SCA)的儿童即使没有受到中风的影响，也会出现认知能力下降。 SCA患者认知功能障碍的病理生理学机制尚不清楚。了解机制和 损伤的轨迹和可逆性程度是预防这种脆弱的终生残疾所必需的 人口。此外，目前的筛查工具是不够的，如经颅多普勒超声和 结构脑MRI只筛查中风的风险，并评估是否存在不可逆转的脑梗塞。长的- 这项建议的长期目标是通过磁共振氧气测量来确定脑损伤的机制。 代谢、结构连接和功能连接，并开发神经成像生物标记物 SCA的认知功能障碍。 SCA儿童经历大脑代谢应激，通过增加氧摄取量来衡量 分数(OEF)。OEF峰值位于深部白质内，与大脑区域共同定位，风险最大 SCA中的中风。代谢应激增加与特定功能内的连接中断有关 大脑网络，以及SCA中功能连接性减弱的网络节点在解剖学上- 与白质中OEF升高的区域相邻、聚集并对齐。然而，OEF 单次输注红细胞可降低SCA儿童的执行功能并改善其执行功能， 这表明，认知功能障碍的某些方面，可能是由FC的改变所驱动的，是非常可逆的 因为新陈代谢应激在SCA中减弱。这一提议的中心假设是，孤立地破坏 由增加的代谢应激引起的功能连接将是可逆的；然而， 以结构联通为中介的功能联通将是不可逆转的。对前者的处理可能 改善认知功能，而治疗后者可能会缓解进行性认知功能下降。为了 验证她的假设，菲尔兹博士将获得相隔三年的认知测试的纵向测量 和脑磁共振成像测量OEF，结构连接和功能连接在对照组，非输血 SCA，并输注SCA参与者。被输血的参与者将接受认知测试和大脑 入选时进行红细胞输注前后的核磁共振检查。使用这些数据，她将测试她的中央 假设通过完成以下具体目标：1)确定是否结构和功能的破坏 通过在SCA中输注红细胞，连接体是可逆的，2)确定OEF增加对 结构和功能连接体的发展，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。完成这些目标将提供对 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，这可能会指导治疗效果，并改善预后 弱势群体。

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.