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

项目摘要 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 这些并发症中普遍存在的是无症状性脑梗塞，即脑中局部缺血性组织损伤的病灶区域 与认知障碍和学习成绩差有关。尽管有重大后果， 无症状性脑梗死，通常在缺血性损伤发生后才被发现。分类的临床协议 镰状细胞患者利用超声测量大脑动脉中的血流速度， 表明中风风险增加。然而，有相互矛盾的证据表明，高血流速度是否 无症状性脑梗塞的危险因素此外，对高危患者的治疗可能无法保护 对抗无症状性脑梗塞我们需要更好地了解与血管损伤相关的 镰状细胞病中的无症状脑梗死，以更好地预防和治疗这种神经损伤来源。 这项工作提出了MRI测量脑血管反应性作为一种新的来源，血流动力学 与无症状性脑梗死形成相关的信息。脑血管反应性是血液流动对脑缺血的反应。 扩张应激源，并在皮质中的较小血管中测量，使其成为血管健康的更局部指标 比血流速度更快先前的研究表明，成人脑血管反应性受损， 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， 增加缺血的可能性。该提案的目的是：1）评估血液之间的关系 大脑大动脉中的血流速度和大脑皮层中的脑血管反应性，以及2）确定脑血管 在接近无症状脑梗塞的脑区域中反应性改变。目标1是从以前的工作向前迈出的一步， 根据脑血管风险评估的临床标准， 镰状细胞病目标2确定这些额外的信息是否提高了我们对 无症状梗死的空间分布。 这项研究将为镰状儿童的脑血流动力学提供一个全面的评估 并提供了脑血管反应性作为无症状脑血管病血流动力学生物标志物的初步证据。 脑梗死的发生。与无症状性脑梗死相关的血液动力学生物标志物可以告知 治疗镰状细胞病，并帮助开发新的预防性疗法。从长远来看， 本提案中开发的成像技术可作为MRI筛查的替代或补充 更有效地对无症状性脑梗死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.