Probing silent cerebral infarct pathogenesis in sickle cell disease with cerebrovascular MRI

项目总结 患有镰状细胞病的儿童患严重脑血管并发症的风险增加。最多的 这些并发症中最常见的是无症状脑梗塞，即脑内缺血组织损伤的局部区域。 与认知障碍和学习成绩不佳有关。尽管存在严重后果， 静止性脑梗塞，通常在缺血性损害发生后才被发现。分诊的临床方案 镰状细胞患者使用超声测量大脑大动脉的血流速度，并伴有高血 速度表明中风的风险增加。然而，有相互矛盾的证据表明，高血流速度是否 无症状脑梗塞的危险因素。此外，给高危患者开的疗法可能不会起到保护作用。 对抗静止性脑梗塞。我们需要更好地了解与之相关的血管损伤 镰状细胞病中的静止性脑梗塞，以更好地预防和治疗这种神经损伤的来源。 这项工作提出了脑血管反应性的MRI测量作为血流动力学的新来源。 与无症状脑梗塞形成相关的信息。脑血管反应性是血流对 扩张性应激源，在皮质中较小的血管中测量，使其成为血管健康的更局部性指标 而不是血流速度。以前的研究表明，成年人的脑血管反应性受损， 患有镰状细胞病的儿童，表明增加血流量以满足氧气需求的能力降低 增加了发生缺血的可能性。这项建议的目的是：1)评估血液和血液之间的关系 大脑大动脉的血流速度和皮质的脑血管反应性，以及2)决定脑血管是否 在接近无症状脑梗塞的大脑区域，反应性会发生改变。目标1比以前的工作向前迈进了一步， 脑血管反应性与脑血管风险评估临床标准的相关性 镰状细胞病。目标2确定这些附加信息是否提高了我们对 静止性脑梗塞的空间分布。 这项拟议的研究将提供对镰刀儿童脑血流动力学的全面评估。 细胞疾病，并提供脑血管反应性作为沉默的血流动力学生物标志物的初步证据 脑梗塞的发生。一种与无症状脑梗塞相结合的血液动力学生物标记物可以告知 治疗镰状细胞病，并协助开发新的预防性疗法。从长远来看， 这项建议中开发的成像技术可以作为MRI筛查的替代或补充 更有效地对无症状脑梗塞风险进行分层的工具。

PROJECT SUMMARY Children with sickle cell disease are at increased risk for serious cerebrovascular complications. The most prevalent of these complications are silent cerebral infarcts, focal areas of ischemic tissue damage in the brain associated with cognitive impairment and poor school performance. Despite the significant consequences of silent cerebral infarcts, they are often detected after ischemic damage has occurred. Clinical protocols to triage sickle cell patients utilize ultrasound measurements of blood velocity in large cerebral arteries, with high blood velocity indicating increased risk for stroke. However, there is conflicting evidence whether high blood velocity is a risk factor for silent cerebral infarcts. Additionally, therapies prescribed to high-risk patients may not protect against silent cerebral infarcts. We need improved understanding of the vascular impairments associated with silent cerebral infarcts in sickle cell disease to better prevent and treat this source of neurological injury. This work proposes MRI measurements of cerebrovascular reactivity as a novel source of hemodynamic information related to silent cerebral infarct formation. Cerebrovascular reactivity is the blood flow response to a dilatory stressor and is measured in smaller vessels in the cortex, making it a more local metric of vascular health than blood velocity. Previous studies have demonstrated impaired cerebrovascular reactivity in adults and children with sickle cell disease, indicating reduced ability to increase blood flow to meet oxygen demands and increased likelihood for ischemia. The aims of this proposal are to: 1) evaluate the relationship between blood velocity in large cerebral arteries and cerebrovascular reactivity in the cortex, and 2) determine if cerebrovascular reactivity is altered in brain regions close to silent cerebral infarcts. Aim 1 is a step forward from previous work, contextualizing cerebrovascular reactivity against the clinical standard for cerebrovascular risk assessment in sickle cell disease. Aim 2 determines whether this additional information improves our understanding of the spatial distribution of silent infarcts. The proposed study will provide a comprehensive assessment of cerebral hemodynamics in children with sickle cell disease and offer preliminary evidence for cerebrovascular reactivity as a hemodynamic biomarker for silent cerebral infarct occurrence. A hemodynamic biomarker that is coupled to silent cerebral infarcts could inform the treatment of sickle cell disease and aid in the development of new preventative therapies. In the long term, the imaging techniques developed in this proposal could serve as an alternative or complementary MRI screening tool to stratify for silent cerebral infarct risk more effectively.