White Matter Structural Integrity and Cognition in Children with Sickle Cell Disease

摘要 患有镰状细胞病（SCD）的儿童经历广泛的认知缺陷，沿着许多其他疾病， 医疗后果，包括中风、无症状脑梗死（SCI）、急性胸部综合征、肺 高血压、慢性肾病和过早死亡。镰状细胞内的分子变化 极大地降低了血液的携氧能力，但了解的病理生理， 脑血管疾病，如中风和脊髓损伤是不够的。因此，具体机制由 哪些认知缺陷会发生还没有完全弄清楚。儿童经历的认知缺陷 与SCD相关的日常功能障碍和教育程度降低， 认知是治疗和干预的关键目标。因此，了解认知缺陷是如何 与伴或不伴SCI的SCD儿童的白色物质贫乏相关的研究是下一步努力的关键， 干预和补救认知缺陷。因为患有SCD的儿童经历了广泛的白色物质 我们认为，将他们的大脑组织描述为结构连接体可能有助于 为了解释为什么轴突纤维微结构的变化（例如，脱髓鞘或轴突丢失） 沿着纤维路径的沿着位置可能导致不同儿童的相同认知缺陷。由于这是 第一个研究，以评估结构连接体使用扩散MRI在儿童SCD，我们开始与 一个广泛的目标是确定SCD儿童是否损害了全球结构连接效率， 与对照比较。我们接下来将确定患有SCD和SCI的儿童以及患有SCD的儿童 没有SCI的情况下，使用图论分析计算的网络效率存在差异。另外我们 我将研究富有的俱乐部组织，这是一组高度连接和相互关联的区域， 确定SCD儿童和对照组之间是否存在差异，并调查 在SCD和SCI儿童中存在优先的富俱乐部中断。我们将研究这些图表是否 指标与有和无SCI的SCD中的认知相关。最后，我们将评估孟鲁卡斯特，一个有针对性的 干预，以及孟鲁司特是否提供氧气可用性的改善，从而改善 睡眠障碍儿童的整体结构连接效率和丰富的俱乐部组织 呼吸，一种与SCD相关的常见医学并发症。该提案的目的是获得更多的 对结构连接体的全局效率和丰富的俱乐部组织的复杂理解， 确定与认知缺陷的关联，以及是否可以提高效率和认知缺陷 通过干预改善。这些发现将对功能结果产生重要影响， 并将提供可能影响未来治疗发展的信息 根据这一人群的特定认知和临床需求量身定制的选项。

ABSTRACT Children with sickle cell disease (SCD) experience widespread cognitive deficits along with numerous other medical consequences including stroke, silent cerebral infarction (SCI), acute chest syndrome, pulmonary hypertension, chronic kidney disease, and premature death. Molecular changes within the sickled cell greatly reduces the oxygen-carrying capacity of the blood, but understanding of the pathophysiology of cerebrovascular disease such as stroke and SCI is inadequate. Therefore, the specific mechanisms by which cognitive deficits occur are not yet fully understood. The cognitive deficits experienced by children with SCD are associated with impairments in daily functioning and reduced education attainment, making cognition a critical target for treatment and intervention. Thus, understanding how cognitive deficits are related to poor white matter in children with SCD with and without SCI is a critical next step in efforts to intervene and remediate cognitive deficits. Because children with SCD experience widespread white matter abnormalities, we suggest that characterizing their brain organization as a structural connectome may help to explain why changes in axon fiber microstructure (e.g., demyelination or loss of axons) in diffuse locations along a fiber pathway may lead to the same cognitive deficits in different children. As this is the first study to assess structural connectomes using diffusion MRI in children with SCD, we begin with the broad aim to determine whether children with SCD have impaired global structural connectivity efficiency in comparison to controls. We will next determine whether children with SCD and SCI and children with SCD without SCI have differences in network efficiency calculated using graph theory analyses. Additionally, we will investigate rich club organization, which is a set of highly connected and interconnected regions and determine whether there are differences between children with SCD and controls and investigate whether there is preferential rich club disruption in children with SCD and SCI. We will examine whether these graph metrics correlate with cognition in SCD with and without SCI. Finally, we will assess Montelukast, a targeted intervention, and whether Montelukast provides improvements in oxygen availability and thus improves global structural connectivity efficiency and rich club organization in children with sleep-disordered breathing, a common medical complication associated with SCD. The goal of this proposal is to gain a more complex understanding of the global efficiency and rich club organization of the structural connectome, determine associations with cognitive deficits, and whether efficiency can be improved and cognitive deficits be ameliorated by intervention. The findings will have important implications for functional outcomes for children with SCD and will provide information that could influence the development of future treatment options tailored to the specific cognitive and clinical needs of this population.