Biomarkers of ischemic brain injury in adults with sickle cell disease

项目总结 镰状细胞性贫血(SCA)是一种慢性溶血性贫血，极大地增加了患中枢神经系统疾病的风险。 系统并发症包括无症状性脑梗塞(SCI)、显性中风和颅内狭窄。中风风险 与儿童的筛查程序相比，成人SCA的筛查程序非常不发达 SCA和其他成人人群有中风的风险。然而，脊髓损伤和明显的中风风险仍然存在。 寿命和SCI发生在超过50%的成年SCA患者中，年龄在30岁之前，代表着频繁的 长期残疾的原因。缺乏一种方法来识别有新发或复发脑部疾病风险的成年人 脑梗塞是成人SCA护理的一个主要限制，因为SCA的治疗方法不断改善，寿命延长 越来越多。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的潜在脑组织水平损伤以及我们开发新筛查的必要性 对患有SCA的成年人进行分类以进行适当的中风预防治疗的工具。这项工作的总体目标是 利用新近发现的脑血流动力学代偿机制不足的生物标志物来测试 一项纵向研究中关于成人SCA患者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团队，系统地评估成年人 SCA，使用更新的病理生理指标按顺序评估已知的中风风险因素，包括： (I)氧提取分数(OEF；耗氧量与供氧量之比)，(Ii)脑血流量(CBF； 血液输送到组织的速率)，(Iii)血流速度，和(Iv)脑血管反应性(CVR)；小动脉 对血管活性挑战作出反应)。这项工作导致了以下发现：(1)患有SCA的成年人的OEF升高， 临床损害(既往中风、颅内狭窄或每月输血)，(Ii)OEF在患有以下疾病的成年人中升高 SCA和新的或进展性脑梗塞的证据(回顾数据)，以及(Iii)脑血流对 成人的输血似乎不如患有SCA的儿童强劲。我们已经开发了一些方法来 使用不需要外源性的MRI方法测量这些假想的中风风险生物标记物 造影剂，使其有可能成为脊髓损伤监测和评估治疗反应的工具。这里, 我们建议将这项工作扩展到(目标1)一项纵向的前瞻性研究，以评估新陈代谢和 血流动力学中风危险因素可用于确定哪些患有SCA的成年人将出现新的脑梗塞；(目标2) 量化干细胞移植这一新兴的根治疗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，从而告知他们的 在未来的多点临床试验中集体或单独使用。长期目标是确定潜在的大脑 组织水平损伤，可提供循证生物标记物来评估中风风险、治疗反应、 并指导患有SCA的成年人的治疗决定，目的是减少中风和认知功能障碍 不存在有效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.