Mechanisms of cerebral infarcts and brain oxygen utilization in anemia

脑梗死机制及贫血中脑氧利用

• 批准号: 10437155
• 负责人: Manus J Donahue
• 金额: $ 44.49万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10437155
• 关键词: Acute; Adult; Affect; Aftercare; Age; Age-Years; Alzheimer' s Disease; Anemia; Benefits and Risks; Biological Markers; Blood; Blood Transfusion; Blood Vessels; Blood capillaries; Brain; Brain imaging; Cerebral Infarction; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrum; Child; Clinical; Data; Disease; Enrollment; Functional disorder; Genetic; Goals; Health; Hemoglobin; Hemoglobin concentration result; Homeostasis; Hyperemia; Hypertension; Image; Imaging Techniques; Individual; Infarction; Ischemic Stroke; Lead; Magnetic Resonance Imaging; Measures; Metabolic; Metabolism; Methods; Migraine; Nervous System Trauma; Outcome; Oxygen; Oxygen Consumption; Participant; Patients; Physiologic arteriovenous anastomosis; Physiology; Prevention therapy; Procedures; Publishing; Race; Regression Analysis; Reporting; Reproducibility; Risk; Risk Factors; Scanning; Severity of illness; Sickle Cell Anemia; Signal Transduction; Sinus; Stroke; Stroke prevention; Testing; Therapeutic Trials; Time; Tissues; Transfusion; Traumatic Brain Injury; Triage; Vascular Diseases; Venous; Work; arterial spin labeling; biomarker development; brain health; cerebral capillary; clinically relevant; cohort; early childhood; hemodynamics; high risk; imaging approach; improved; in vivo; innovation; intracranial artery; neuroimaging; neurovascular; non-invasive imaging; novel; novel therapeutics; public health relevance; sex; stem cell therapy; stroke risk; tool; treatment response; venous sinus

PROJECT SUMMARY While cerebral oxygen delivery depends on the cerebral blood flow (CBF; ml blood/100g tissue/minute) and blood oxygen content, it is becoming increasingly recognized that blood capillary transit time itself can also influence tissue oxygen extraction, even in the presence of normal or elevated CBF. In individuals with anemia where accelerated capillary flow velocities may be present as a result of hyperemia and cerebral autoregulation, reduced capillary transit time can lead to reduced times for tissue oxygen offloading. Compelling evidence has been provided for heterogeneous capillary flow underlying abnormal oxygen delivery in multiple conditions including expansion of infarcts in acute ischemic stroke, traumatic brain injury, and Alzheimer's disease. In sickle cell anemia (SCA), we have observed that rapid capillary transit, visible on arterial spin labeling (ASL) CBF-weighted MRI, is present in more than 50% of adults and children. We have shown in published work and preliminary data from 154 adults and children with SCA that hyperintense ASL signal within cerebral dural venous sinuses is directly associated with elevated arterial velocities, elevated CBF, and reduced oxygen extraction fraction (OEF; ratio of oxygen consumed to oxygen delivered), and that this effect may reduce following transfusion therapies that improve oxygen delivery to tissue. These findings indicate that venous hyperintense signal on ASL images may represent a marker of capillary-level disturbances in oxygen exchange efficiency. One of the most impactful findings of our preliminary work is that we have observed that rapid capillary-level arterio-venous transit is associated with reduced oxygen metabolism, suggesting that these transit times may provide a biomarker of cerebral ischemia in individuals with SCA who have greater than a 50% risk of cerebral infarcts by age 30 years, yet often lack conventional stroke risk factors. Here, we propose to refine neuroimaging methods for evaluating arterio-venous transit to allow for robust, quantitative measures of capillary transit time non-invasively in vivo, and subsequently to test fundamental hypotheses regarding cerebral oxygen utilization in anemic individuals with vs. without infarcts. Aim (1): To apply innovative ASL MRI methods and time regression analyses over major intracranial arteries and dural sinuses in healthy control and SCA participants. Aim (2): To quantify cerebral capillary transit time in SCA participants before and after treatment with blood transfusion to understand how increases in hemoglobin parallel an improvement in brain oxygen extraction. Aim (3): To test the hypothesis that arterio-venous transit times are reduced in individuals with SCA with versus without infarcts. The short-term goal is to utilize non-invasive imaging approaches to understand mechanisms of oxygen utilization and neurovascular dysfunction in anemia. The long-term goal is to use this information to triage individuals with anemia for personalized stroke prevention therapies, as well as to objectively quantify the impact of these therapies on brain health.

项目概要 而脑氧输送取决于脑血流量（CBF；ml血液/100g组织/分钟）和 人们越来越认识到，毛细血管通过时间本身也可以影响血氧含量 影响组织氧提取，即使存在正常或升高的 CBF。在个体中 贫血，由于充血和毛细血管流速可能加快 大脑自动调节，毛细血管传输时间减少会导致组织供氧时间减少 卸载。已经为异常毛细血管流动的不均匀性提供了令人信服的证据 多种情况下的氧气输送，包括急性缺血性中风、脑外伤中梗塞的扩大 损伤和阿尔茨海默病。在镰状细胞性贫血（SCA）中，我们观察到快速毛细血管运输， 动脉自旋标记 (ASL) CBF 加权 MRI 上可见，超过 50% 的成人和儿童存在这种现象。 我们已发表的研究成果和来自 154 名患有 SCA 的成人和儿童的初步数据显示， 脑硬膜静脉窦内的高信号 ASL 信号与动脉血压升高直接相关 速度、CBF 升高和氧提取分数降低 (OEF；消耗的氧气与氧气的比率 ），并且这种效应可能会在改善氧气输送的输血治疗后减少 组织。这些发现表明 ASL 图像上的静脉高信号可能代表了 毛细血管水平对氧交换效率的干扰。我们最有影响力的发现之一 初步工作是我们观察到快速毛细血管水平动静脉转运与 氧代谢减少，表明这些转运时间可能提供生物标志物 患有 SCA 的患者发生脑缺血，按年龄计算，其脑梗塞风险大于 50% 30 年，但往往缺乏常规的中风危险因素。在这里，我们建议完善神经影像学 评估动静脉转运的方法，以便对毛细血管转运时间进行稳健、定量的测量 无创体内，随后测试有关脑氧利用的基本假设 在有梗塞和无梗塞的贫血个体中。目标 (1)：应用创新的 ASL MRI 方法和时间 对健康对照组和 SCA 参与者的主要颅内动脉和硬脑膜窦进行回归分析。 目标 (2)：量化 SCA 参与者在血液治疗前后的脑毛细血管传输时间 输血以了解血红蛋白的增加如何与脑氧提取的改善同时发生。 目标 (3)：检验以下假设：SCA 患者的动静脉转运时间缩短 与没有梗塞的情况相比。短期目标是利用非侵入性成像方法来了解 贫血中氧利用和神经血管功能障碍的机制。长期目标是 使用此信息对贫血患者进行分类以进行个性化中风预防治疗，例如 以及客观地量化这些疗法对大脑健康的影响。