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 MR 衍生脑氧代谢

基本信息

批准号：
10676097
负责人：
Hongyu An
金额：
$ 67.05万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10676097
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 Disease stratification 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 Polymers Population Predisposition Race Rest Risk Screening procedure Selectins Shapes Sickle Cell Sickle Cell Anemia Specificity Stroke Structure Surface Testing Tissues Tracer Transfusion Unemployment Vascular blood supply Work brain cell brain magnetic resonance imaging brain tissue cerebral ischemic injury clinical predictors cognitive disability cognitive performance cognitive testing cohort comparison control 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

项目摘要

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：镰状细胞贫血（SCA）影响全球1000人，引起多器官缺血，长期残疾和过早死亡，预期寿命为42年。在其并发症中，大脑梗塞和认知障碍是普遍的，随着年龄的增长而增加，> 50％的年轻人保持沉默梗塞。使用神经成像筛查工具选择高危的小儿SCA已取得了出色的进展儿童，但成年人仍被理解。由于大脑的需求比其他氧气不成比例在总血液供应量的约20％（但只有2％的体重），低动脉氧含量（CAO2），因此贫血，将镰状细胞大脑处于终生的缺氧风险。这是为了满足脑氧的需求（cmro2），大脑在血液动力学和代谢“胁迫”下连续不断，标志着脑血液升高流量和氧气提取部分（OEF）。我们以前的赠款周期的发现有所帮助塑造对SCA中缺血性脑损伤机制的新理解。重要的是，全球的特异性在患者和组织水平下，用于分层中风风险的区域OEF为临床表明了很大的希望该成像生物标志物的实用性。我们现在正在完成随访MRI，以确定OEF是否在纵向上预测小儿SCA的梗塞。从我们的结果中得出了两个意外的发现，这些发现还需要进一步调查。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；但是，我们发现在SCA中，静息CMRO2在全球范围内升高。氧气需求的增加与SCA中总体静息能量消耗的高度相似，这是假定是由于慢性炎症。这一发现令人着迷，因为脑氧的需求升高可能会增加缺血性脆弱性。实际上，可恶心和高血速损伤内皮诱导各种白细胞 - 内皮相互作用。因此，我们假设神经炎症可能会促进通过增加脑氧的需求，缺血。第二，我们发现成年人的全球OEF高程与对照组相比，SCA在成年人中与对照组相比，深白质的区域升高不那么突出给儿童，表明随着疾病持续时间的区域OEF减少。张贴毛细血管流由于毛细管微结构变化而引起的异质性（CFH）导致局部OEF的减少。这是对SCA的极大兴趣是因为毛细血管形态受到了破坏，并且由于贫血而导致过境时间很短。那，我们假设SCA中的进行性微血管疾病会破坏毛细血管流动模式，减少氧气供应，作为另一种缺血机制。在这种续约中，我们将重点转移到了SCA的成年人中，成长和理解人口。首先，我们将确定脑代谢应激预测是否缺血大脑伤害和认知能力下降。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）扰动脑氧代谢生理学，以进一步了解我们对 SCA中的氧气供望不匹配，每个供求都可以作为新的治疗靶标开发。