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

翻译后摘要：镰状细胞性贫血（SCA）影响世界各地的1000个人之一，造成多器官缺血， 长期残疾和过早死亡，预期寿命为42岁。在其并发症中，脑 脑梗死和认知障碍是普遍存在的，并随着年龄的增长而增加，其中> 50%的年轻人患有沉默的 梗塞在儿科SCA中，使用神经影像学筛查工具来选择高风险 儿童，但成年人仍然不足。因为大脑比其他器官需要更多的氧气 器官约占总血液供应的20%（但仅占体重的2%），动脉血氧含量（CaO 2）低， 贫血，使镰状细胞脑处于终生缺氧的风险中。因此，为了尽量满足大脑的氧气需求， （CMRO 2），大脑持续处于血液动力学和代谢“应激”下，以脑血流量升高为标志 流量和氧提取分数（OEF）。我们上一个赠款周期的发现有助于 形成对SCA缺血性脑损伤机制的新认识。重要的是，全球 在患者和组织水平上对卒中风险进行分层的区域OEF表明， 这种成像生物标志物的效用。我们现在正在完成随访MRI，以确定OEF是否纵向 预测儿童SCA的梗死。我们的研究结果中出现了两个意想不到的发现， 调查首先，我们预期管制计划协议中的中央预算基金和运营开支基金的补偿性增加， 正常的脑氧代谢需求;然而，我们发现SCA中静息CMRO 2整体升高。 这种需氧量的增加与SCA中全身静息能量消耗的升高平行， 推测是由于慢性炎症。这一发现是有趣的，因为脑需氧量的增加 可能会增加缺血性脆弱性。事实上，镰状化和高血流速度损伤内皮细胞， 各种白细胞-内皮细胞相互作用。因此，我们假设神经炎症可能促进 增加脑需氧量。第二，虽然我们发现成人的总体OEF升高， SCA与对照组相比，成人深层白色物质的区域OEF升高不太明显， 儿童，表明随着疾病持续时间的减少，区域OEF。据推测，毛细流动 由于毛细血管微结构的变化而引起的不均一性（CFH）导致局部OEF降低。这一点 对SCA有很大的兴趣，因为毛细血管形态被破坏，并且由于贫血，通过时间很短。因此，在本发明中， 我们假设SCA中进行性微血管疾病会破坏毛细血管血流模式， 氧气供应，作为额外的缺血机制。在这次更新中，我们将重点转移到患有SCA的成年人， 不断增长的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缺血性脑 损伤和认知能力下降。接下来，我们将采用新的MR方法来研究两种机制（神经- 炎症和CFH）干扰脑氧代谢生理学，以进一步了解 SCA中的氧供需不匹配，每一种都可以被开发为新的治疗靶点。

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.