Biomarkers of ischemic brain injury in adults with sickle cell disease

项目摘要 镰状细胞性贫血（SCA）是一种慢性溶血性贫血， 系统并发症，包括无症状脑梗死（SCI）、显性卒中和颅内狭窄。中风风险 与儿童筛查程序相比，成人SCA筛查程序相当落后 SCA和其他有中风风险的成年人群。然而，SCI和明显的中风风险持续存在， 超过50%的SCA成人在30岁时发生SCI，这代表了一种常见的 长期残疾的原因。缺乏一种方法来识别有新发或复发性脑卒中风险的成年人， 梗死是成人SCA护理的主要限制，因为SCA的治疗不断改善， 增加。解决成人中风风险和预防的关键障碍在于我们无法识别 作为常规医疗护理的一部分，我们需要开发新的筛查方法 工具来对患有SCA的成年人进行分类，以进行适当的卒中预防治疗。这项工作的总体目标是 利用最近发现的脑血流动力学代偿机制不足的生物标志物， 在一项纵向研究中，关于SCA成人卒中风险和治疗反应的基本假设。 在过去的七年里，我们建立了一个多学科的团队，系统地评估成年人， SCA，使用更多新的病理生理学指标依次评估已知的卒中风险因素，包括： (i)氧摄取分数（OEF;氧消耗与氧递送的比率）;（ii）脑血流量（CBF; 血液输送到组织的速率），（iii）流速，和（iv）脑血管反应性（CVR;小动脉的 对血管活性激发作出反应）。这项工作导致了以下发现：（i）SCA成人的OEF升高， 临床损害（既往卒中、颅内狭窄或每月输血），（ii）OEF在成人中升高， SCA和新发或进展性梗死的证据（回顾性数据），和（iii）CBF对用 与SCA儿童相比，成人的输血似乎不那么稳健。我们已经开发出方法， 使用MRI方法测量这些假设的卒中风险生物标志物， 造影剂，使其成为SCI监测和评估治疗反应的可能工具。在这里， 我们建议将这项工作扩展到（目标1）一项纵向前瞻性研究，以评估代谢和 血流动力学卒中危险因素可用于确定哪些SCA成人患者将发生新的梗死;（目的2） 量化干细胞移植（一种新兴的治疗方法）对脑组织健康的影响;以及（目标3） 比较从两种最流行的非侵入性MRI方法获得的OEF值，从而告知其 在未来的多中心临床试验中集体或单独使用。长期的目标是确定潜在的大脑 组织水平的损伤，可以提供循证生物标志物，以评估中风风险，治疗反应， 并指导SCA成人患者的治疗决策，目的是减少这一人群中的中风和认知功能障碍。 不存在经验证的中风筛查工具的高危人群。

PROJECT SUMMARY Sickle cell anemia (SCA) is a chronic hemolytic anemia that dramatically increases the risk of central nervous system complications including silent cerebral infarcts (SCI), overt strokes, and intracranial stenosis. Stroke risk screening procedures for adults with SCA are considerably underdeveloped compared to procedures for children with SCA and other populations of adults at risk for stroke. However, SCI and overt stroke risk persists across the lifespan, and SCIs occur in more than 50% of adults with SCA by age 30 years, representing a frequent cause of long-term disability. The absence of an approach to identify adults at risk for new or recurrent cerebral infarcts is a major limitation in adult SCA care, as treatments for SCA continue to improve and lifespan is increasing. The critical barrier to addressing stroke risk and prevention in adults rests with our inability to identify underlying brain tissue-level impairment as a part of routine medical care and our need to develop new screening tools to triage adults with SCA for appropriate stroke prevention therapies. The overall goal of this work is to utilize recently identified biomarkers of inadequate cerebral hemodynamic compensatory mechanisms to test fundamental hypotheses about stroke risk and treatment response in adults with SCA in a longitudinal study. Over the past seven years, we have established a multidisciplinary team to systematically evaluate adults with SCA, assessing known stroke risk factors in sequence with more novel pathophysiological indicators including: (i) oxygen extraction fraction (OEF; ratio of oxygen consumed to oxygen delivered), (ii) cerebral blood flow (CBF; rate of blood delivery to tissue), (iii) flow velocity, and (iv) cerebrovascular reactivity (CVR; ability of arterioles to respond to a vasoactive challenge). This work led to the findings that (i) OEF is elevated in adults with SCA and clinical impairment (prior stroke, intracranial stenosis, or monthly transfusions), (ii) OEF is elevated in adults with SCA and evidence of new or progressive infarcts (retrospective data), and (iii) CBF response to treatment with blood transfusion appears to be less robust in adults than children with SCA. We have developed methods to measure these hypothesized stroke risk biomarkers using MRI approaches that do not require exogenous contrast agents, making them a possible tool for SCI surveillance and for evaluating treatment response. Here, we propose to extend this work to (Aim 1) a longitudinal, prospective study, to evaluate how metabolic and hemodynamic stroke risk factors can be used to identify which adults with SCA will have new infarcts; (Aim 2) to quantify the impact of stem cell transplant, an emerging curative treatment, on brain tissue health; and (Aim 3) to compare OEF values obtained from the two most popular non-invasive MRI methods thereby informing their collective or individual use in future multi-site clinical trials. The long-term goal is to identify underlying brain tissue-level impairment that may provide evidence-based biomarkers to assess stroke risk, treatment response, and guide therapy decisions in adults with SCA, with the goal of reducing stroke and cognitive dysfunction in this high-risk population for which validated stroke screening tools do not exist.