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

摘要：镰状细胞性贫血(SCA)在世界范围内每1000人中就有一人患病，导致多器官缺血， 长期残疾和过早死亡，预期寿命为42岁。在其并发症中，脑部 脑梗塞和认知障碍很普遍，并且随着年龄的增长而增加，50%的年轻人有沉默 脑梗塞。在儿科SCA中使用神经影像筛查工具选择高危人群取得了很大进展 儿童，但成人仍未得到充分研究。因为大脑比其他人需要更多的氧气 器官占总血供的20%(但只占体重的2%)，动脉血氧含量(CaO2)低，原因是 贫血，使镰状细胞大脑终生处于缺氧的风险中。因此，要尽量满足大脑的氧气需求 (CMRO2)，大脑持续处于血流动力学和代谢“压力”之下，以脑血升高为标志 流量和氧摄取分数(OEF)。我们上一个赠款周期的发现对我们有所帮助 形成对SCA缺血性脑损伤机制的新认识。重要的是，全球范围内 在患者和组织水平上对中风风险进行分层的地区性OEF表明，临床上有很大的希望 这一成像生物标记物的用途。我们现在正在完成后续的核磁共振检查，以确定OEF是否纵向 预测儿童SCA中的脑梗塞。我们的结果中出现了两个意想不到的发现，这证明有必要进一步 调查。首先，我们预计政制事务局局长的CBF和OEF补偿性增长将有助于维持 正常的脑氧代谢需求；然而，我们发现在SCA中静息CMRO2整体升高。 这种需氧量的增加与SCA中全身静息能量消耗的增加同步，这是 推测是由慢性炎症引起的。这一发现很耐人寻味，因为大脑需氧量升高 可能会增加缺血的脆弱性。事实上，镰刀状和高血流速度会损伤血管内皮细胞，导致 各种白细胞与内皮细胞的相互作用。因此，我们假设神经炎症可能促进 脑供氧量增加引起的脑缺血。第二，虽然我们发现全球OEF在患有以下疾病的成年人中升高 与对照组相比，与对照组相比，成人深部白质局部OEF升高不那么明显 对儿童来说，这表明区域OEF随着病程的延长而下降。据推测，毛细管流 毛细血管微结构改变引起的异质性(CFH)导致局部OEF降低。这是 对SCA非常感兴趣，因为由于贫血，毛细血管形态被破坏，转运时间很短。因此， 我们假设，SCA中进行性微血管疾病将扰乱毛细血管血流模式，减少 供氧，作为一种额外的缺血机制。在这次更新中，我们将重点转移到患有SCA的成年人身上，作为 不断增长和未得到充分研究的人口。首先，我们将确定大脑代谢应激是否预示脑缺血 损伤和认知能力下降。接下来，我们将使用新的磁共振方法来研究两种机制(神经- 炎症和CFH)扰乱脑氧代谢生理，以加深我们对 SCA的氧供需不匹配，每一种都可以作为新的治疗靶点。

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.