MR-Derived Cerebral Oxygen Metabolism underlying Ischemic Vulnerability in Sickle Cell Disease

镰状细胞病缺血性脆弱性背后的磁共振衍生脑氧代谢

• 批准号: 10454118
• 负责人: Hongyu An
• 金额: $ 67.39万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454118
• 关键词: Adhesions; Adult; Affect; Age; Aging; Anemia; Binding; Biological Markers; Blood; Blood Vessels; Blood capillaries; Body Weight; Bone Marrow Transplantation; Brain; Cell Adhesion Molecules; Cerebral Hypoxia; Cerebral Infarction; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrum; Cessation of life; Child; Childhood; Chronic; Clinical; Clinical Trials; Core-Binding Factor; Cytokine Activation; Data; Diffusion; Disease; Employment; Endothelium; Energy Metabolism; Erythrocytes; Erythropoiesis; Failure; Grant; Growth; Hemolytic Anemia; Heterogeneity; Hypoxia; Impaired cognition; Individual; Infarction; Inflammation; Investigation; Ischemia; Ischemic Brain Injury; Kinetics; Leukocytes; Life Expectancy; Magnetic Resonance Imaging; Measures; Metabolic; Metabolic stress; Metabolism; Methods; Microvascular Dysfunction; Morphology; Neonatal Screening; Neurocognitive; Neurologic; Organ; Oxygen; P-Selectin; Patients; Pattern; Physiology; Plasma Proteins; Population; Predisposition; Race; Rest; Risk; Screening procedure; Selectins; Shapes; Sickle Cell; Sickle Cell Anemia; Specificity; Stroke; Surface; Testing; Time; Tissues; Tracer; Transfusion; Unemployment; Vascular blood supply; Work; base; brain cell; brain magnetic resonance imaging; brain tissue; cerebral ischemic injury; clinical predictors; cognitive disability; cognitive performance; cognitive testing; cohort; cytokine; density; disability; disorder risk; experience; follow-up; hemodynamics; high risk; hydroxyurea; illness length; imaging biomarker; inhibitor; interest; ischemic injury; neuroimaging; neuroinflammation; neuroprotection; new therapeutic target; novel; polymerization; predictive signature; premature; sickling; spectrograph; stroke risk; systemic inflammatory response; vaso-occlusive crisis; white matter; young adult

Abstract: Sickle cell anemia (SCA) affects one in 1000 individuals worldwide, causing multi-organ ischemia, long-term disability, and premature death, with a life expectancy of 42 years. Among its complications, cerebral infarction and cognitive disability are prevalent and increase with age, with > 50% of young adults having silent infarcts. Great headway has been made in pediatric SCA using neuroimaging screening tools to select high-risk children, yet adults remain understudied. As the brain demands disproportionately more oxygen than other organs at ~20% of total blood supply (but only 2% of body weight), low arterial oxygen content (CaO2) due to anemia, places the sickle cell brain at lifelong risk of hypoxia. Thus, to try to meet cerebral oxygen demand (CMRO2), the brain is continually under hemodynamic and metabolic “stress”, marked by elevated cerebral blood flow and oxygen extraction fraction (OEF), respectively. Findings from our previous grant cycle have helped shape a new understanding of ischemic brain injury mechanisms in SCA. Importantly, specificity of both global and regional OEF for stratifying stroke risk, at patient and tissue levels, suggests great promise for the clinical utility of this imaging biomarker. We are now completing follow-up MRIs to determine if OEF longitudinally predicts infarction in pediatric SCA. Two unexpected findings emerged from our results which warrant further investigation. First, we expected that compensatory increases in CBF and OEF in SCA would serve to maintain a normal cerebral oxygen metabolic demand; however, we found that resting CMRO2 is globally elevated in SCA. This increase in oxygen demand parallels an elevation in total body resting energy expenditure in SCA, which is postulated to be due to chronic inflammation. The finding is intriguing as an elevated cerebral oxygen demand may increase ischemic vulnerability. Indeed, sickling and high blood velocity injure the endothelium inducing a variety of leukocyte-endothelial interactions. Therefore, we hypothesize that neuroinflammation may promote ischemia by increasing cerebral oxygen demand. Second, while we find global OEF elevation in adults with SCA compared to controls, regional OEF elevation in the deep white matter is less prominent in adults compared to children, suggesting a decrease in regional OEF with disease duration. It is postulated that capillary flow heterogeneity (CFH) due to change in capillary microarchitecture leads to a reduction in local OEF. This is of great interest in SCA because capillary morphology is disrupted and transit times are short due to anemia. Thus, we hypothesize that progressive microvascular disease in SCA will disrupt capillary flow patterns, decreasing oxygen supply, as an additional ischemic mechanism. In this renewal, we shift focus to adults with SCA, as a growing and understudied population. First, we will determine if cerebral metabolic stress predicts ischemic brain injury and cognitive decline. Next, we will employ novel MR approaches to investigate two mechanisms (neuro- inflammation and CFH) which perturb cerebral oxygen metabolic physiology, to further our understanding of oxygen supply-demand mismatch in SCA, each which can be developed as a novel therapeutic target.

摘要：镰状细胞性贫血（SCA）影响全世界千分之一的人，导致多器官缺血， 长期残疾，过早死亡，预期寿命42岁。在其并发症中，脑 梗死和认知障碍很普遍，并且随着年龄的增长而增加，> 50% 的年轻人患有沉默症 梗塞。使用神经影像筛查工具选择高风险儿童 SCA 已取得巨大进展 儿童，但成人仍未得到充分研究。由于大脑比其他部位需要更多的氧气 器官的血液供应量约为 20%（但仅占体重的 2%），由于以下因素导致动脉氧含量 (CaO2) 较低 贫血使镰状细胞脑终生面临缺氧的风险。因此，要尽量满足脑氧需求 (CMRO2)，大脑持续处于血流动力学和代谢“压力”之下，其特点是脑血流量升高 分别是流量和氧提取分数（OEF）。我们之前的资助周期的调查结果有所帮助 形成对 SCA 缺血性脑损伤机制的新​​认识。重要的是，全球的特殊性 和区域 OEF 在患者和组织水平上对中风风险进行分层，为临床提供了巨大的希望 该成像生物标志物的效用。我们现在正在完成后续 MRI 以确定 OEF 是否纵向 预测小儿 SCA 中的梗塞。我们的结果中出现了两个意想不到的发现，值得进一步研究 调查。首先，我们预计 SCA 中 CBF 和 OEF 的补偿性增加将有助于维持 正常的脑氧代谢需求；然而，我们发现 SCA 中静息 CMRO2 总体升高。 需氧量的增加与 SCA 中全身静息能量消耗的增加平行，即 推测是由于慢性炎症引起的。这一发现很有趣，因为大脑需氧量升高 可能会增加缺血性脆弱性。事实上，镰状细胞和高血流速度会损伤内皮细胞，从而导致 多种白细胞-内皮相互作用。因此，我们推测神经炎症可能促进 通过增加脑需氧量来缓解缺血。其次，虽然我们发现患有以下疾病的成年人的整体 OEF 升高 与对照组相比，SCA 中深部白质的局部 OEF 升高在成人中不太明显 对儿童来说，这表明局部 OEF 随着疾病持续时间而下降。假设毛细管​​流动 毛细血管微结构变化导致的异质性 (CFH) 会导致局部 OEF 降低。这是属于 人们对 SCA 非常感兴趣，因为贫血导致毛细血管形态受到破坏并且转运时间很短。因此， 我们假设 SCA 中的进行性微血管疾病会扰乱毛细血管流动模式，从而减少 氧气供应，作为额外的缺血机制。在本次更新中，我们将重点转向患有 SCA 的成年人，作为 不断增长且未被充分研究的人口。首先，我们将确定脑代谢应激是否预示着脑缺血 损伤和认知能力下降。接下来，我们将采用新颖的 MR 方法来研究两种机制（神经- 炎症和CFH）扰乱脑氧代谢生理学，以进一步我们的理解 SCA 中的氧供需失配，每一种都可以开发为新的治疗靶点。