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: 9610744
• 负责人: Anna Hood
• 金额: $ 4.84万
• 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/9610744
• 关键词: 18 year old; Adolescent and Young Adult; Adult; Age; Anti-inflammatory; 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; Imagery; 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; 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; 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.

摘要 患有镰状细胞病(SCD)的儿童与许多其他疾病一起经历了广泛的认知缺陷 医疗后果包括中风、无症状性脑梗塞(SCI)、急性胸部综合征、肺部疾病 高血压、慢性肾脏疾病和过早死亡。镰状细胞内的分子变化 极大地降低了血液的携氧能力，但对 中风和脊髓损伤等脑血管疾病是不够的。因此，具体的机制是 发生了哪些认知缺陷还没有完全弄清楚。儿童经历的认知缺陷 SCD与日常功能障碍和受教育程度降低有关，使 认知是治疗和干预的关键目标。因此，理解认知缺陷是如何 与患有和不伴有脊髓损伤的SCD儿童的脑白质贫乏有关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，我们认为，将他们的大脑组织描述为结构连接体可能会有所帮助 为了解释弥漫性轴突纤维微结构变化(例如，脱髓鞘或轴突丢失)的原因 纤维通路上的位置可能会导致不同儿童的相同认知缺陷。因为这是 第一项使用弥散磁共振成像评估儿童SCD的结构连接的研究，我们从 广泛的目标是确定SCD儿童是否损害了全球结构连接效率 与控件进行比较。接下来我们将确定SCD儿童和SCI儿童以及SCD儿童 用图论分析方法计算了无SCI时网络效率的差异。此外，我们 将调查富豪俱乐部组织，这是一组高度联系和相互联系的地区和 确定SCD儿童和对照组之间是否存在差异，并调查是否 在SCD和SCI儿童中，存在优先的丰富俱乐部破坏。我们将检查这些图表是否 SCD伴和不伴SCI的量表与认知相关。最后，我们将评估Montelukast，一个有针对性的 干预，以及孟鲁司特是否改善了氧气的可获得性从而改善了 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，与SCD相关的常见医学并发症。这项提议的目标是获得更多的 对结构连接体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 通过干预得到改善。这一发现将对患者的功能结局产生重要影响 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做的选项。