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

镰状细胞病儿童的白质结构完整性和认知

• 批准号: 9906051
• 负责人: Anna Hood
• 金额: $ 5.31万
• 依托单位: UNIVERSITY COLLEGE LONDON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-31 至 2022-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906051
• 关键词: 18 year old; Adolescent and Young Adult; Adult; Age; Anti-Inflammatory Agents; Attention; Axon; Blood; Brain; Brain region; Carrying Capacities; Cerebral Infarction; Cerebrovascular Disorders; Cessation of life; Child; Childhood; Childhood Asthma; Chronic; Chronic Kidney Failure; Classification; Clinical; Cognition; Cognitive; Cognitive deficits; Complex; Demyelinations; Development; Diffuse; Diffusion Magnetic Resonance Imaging; Disease; Dorsal; Education; Face; Fiber; Functional disorder; Funding; Future; Goals; Graph; HIV; Hemoglobin; Impairment; Individual; Infarction; Inflammation; Intervention; Knowledge; Lead; Leukotriene Antagonists; Location; Magnetic Resonance Imaging; Medical; Medical Research; Methods; Microvascular Dysfunction; Molecular; Morbidity - disease rate; Neurologic; Nociception; Oral; Outcome; Oxygen; Pathway interactions; Patients; Placebos; Population; Prevalence; Pulmonary Hypertension; Randomized; Research; Rest; Sickle Cell; Sickle Cell Anemia; Sleep Apnea Syndromes; Stroke; Structure; Therapeutic; Time; Transfusion; United States National Institutes of Health; Visualization; White Matter Hyperintensity; acute chest syndrome; base; chronic pain; cingulate cortex; connectome; daily functioning; disorder control; executive function; experience; fetal; functional outcomes; graph theory; high risk; hydroxyurea; improved; medical complication; montelukast; mortality; neuroimaging; organizational structure; premature; primary endpoint; processing speed; white matter

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.

抽象的 患有镰状细胞病 (SCD) 的儿童会经历广泛的认知缺陷以及许多其他疾病 医疗后果包括中风、无症状脑梗塞 (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 大大降低了血液的携氧能力，但了解其病理生理学 中风、SCI等脑血管疾病的治疗力度不够。因此，具体机制 哪些认知缺陷会发生，目前尚不完全清楚。儿童经历的认知缺陷 SCD 与日常功能障碍和教育程度降低有关， 认知是治疗和干预的关键目标。因此，了解认知缺陷是如何发生的 与伴有或不伴有 SCI 的 SCD 儿童白质不良相关的问题是下一步努力的关键 干预和纠正认知缺陷。因为患有 SCD 的儿童会经历广泛的白质 异常，我们建议将他们的大脑组织描述为结构连接组可能会有所帮助 解释为什么轴突纤维微观结构发生变化（例如脱髓鞘或轴突损失） 纤维通路上的位置可能会导致不同儿童出现相同的认知缺陷。由于这是 第一项使用扩散 MRI 评估 SCD 儿童结构连接体的研究，我们从 确定患有 SCD 的儿童是否损害了全球结构连接效率的广泛目标 与对照的比较。接下来我们将确定是否患有 SCD 和 SCI 的儿童以及患有 SCD 的儿童 没有 SCI 的情况下，使用图论分析计算出的网络效率存在差异。此外，我们 将调查丰富的俱乐部组织，这是一组高度连接和相互关联的区域和 确定 SCD 儿童与对照儿童之间是否存在差异，并调查是否存在差异 患有 SCD 和 SCI 的儿童有优先丰富的俱乐部干扰。我们将检查这些图是否 指标与有或没有 SCI 的 SCD 认知相关。最后，我们将评估孟鲁司特，一种有针对性的药物 干预，以及孟鲁司特是否能改善氧气利用率，从而改善 睡眠障碍儿童的全球结构连接效率和丰富的俱乐部组织 呼吸，一种与 SCD 相关的常见并发症。该提案的目标是获得更多 对结构连接组的全球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 可以通过干预来改善。研究结果将对功能结果产生重要影响 患有 SCD 的儿童，并将提供可能影响未来治疗发展的信息 针对该人群的特定认知和临床需求量身定制的选项。