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.

项目摘要 而脑氧递送取决于脑血流（CBF； ML血液/100G组织/分钟），而 血氧含量，越来越认识到血毛细管过渡时间本身也可以 即使存在正常或升高的CBF，也会影响组织氧气提取。在有个人 由于血症和 脑自动调节，减少毛细管过渡时间可能导致组织氧的时间减少 卸载。已经提供了令人信服的证据 在多种条件下的氧气递送，包括急性缺血性中风中梗塞的扩展，脑外伤 受伤和阿尔茨海默氏病。在镰状细胞贫血（SCA）中，我们观察到快速的毛细管过境， 在动脉自旋标记（ASL）CBF加权MRI上可见，有50％以上的成人和儿童。 我们已经在来自154名成人和SCA儿童的已发表的工作和初步数据中展示了 脑静脉鼻窦内的高强度ASL信号直接与动脉升高有关 速度，CBF升高和降低氧气萃取馏分（OEF；消耗的氧与氧气的比率 交付），并且这种作用可能会减少在输血疗法后，将氧气递送到 组织。这些发现表明，ASL图像上的静脉高强度信号可能代表 氧气交换效率的毛细管水平干扰。我们最有影响力的发现之一 初步工作是我们已经观察到快速毛细管级动脉 - 河流过渡是相关的 随着氧代谢减少，表明这些运输时间可能会提供生物标志物 SCA患者的脑缺血大于年龄大于50％的脑梗塞风险 30年，但通常缺乏常规的中风风险因素。在这里，我们建议完善神经影像 评估动脉连接的方法，以允许对毛细管转运时间进行稳健的定量测量 非侵入性在体内，随后检验有关脑氧利用的基本假设 在没有梗塞的贫血个体中。目的（1）：应用创新的ASL MRI方法和时间 在健康对照和SCA参与者中，对主要颅内动脉和硬脑膜鼻窦进行了回归分析。 目的（2）：用血液治疗前后的SCA参与者中的脑毛细管过渡时间 输血以了解如何增加血红蛋白的增加，从而改善脑氧提取。 目的（3）：检验以下假设：SCA患者的动脉连过渡时间减少 与没有梗塞的相对于。短期目标是利用非侵入性成像方法来理解 贫血中氧利用和神经血管功能障碍的机制。长期目标是 使用此信息将贫血分类为个性化中风预防疗法，作为 以及客观地量化这些疗法对大脑健康的影响。