Brain Iron Quantification Based on MRI in Intracerebral Hemorrhage

摘要 出血性卒中占北美卒中病例的20 - 30%。之一 世界上导致死亡和神经残疾的主要原因。出血性中风是 分为脑内出血（ICH）、蛛网膜下腔/脑室内出血和 硬膜下出血在过去的20年里，动物 和临床研究，以确定脑内继发性脑损伤的机制， 出血研究开始确定非血红素铁引起的神经毒性是 这对确定神经组织损伤的程度至关重要。 ICH血肿周围非血红素铁含量增加， 显示与血肿的大小以及神经元损伤的程度相关。 在ICH的动物模型中，铁螯合物的作用已被证明是减少了脑出血的发生。 血肿大小和神经元组织损伤程度降低。这个想法导致了第一阶段 这种螯合物（去铁胺）在脑出血患者中的试验已经显示了安全性， 剂量递增的功效。一项在ICH患者中进行的II期试验正在进行中， 在人类中。 总的来说，在确定其他组织铁的定量方法方面有新的活力。 身体里的实体器官。这是由于几种铁螯合剂的出现， 对人体生理学有利的药理学特征。各种基于MR的协议具有 已经检查了在其他实体器官中用非侵入性成像定量组织中的铁， 身体具有更高磁体强度和更好分辨率的MR扫描仪已经证明了一些 在这方面的承诺。这项技术可以假设应用于大脑，以确定 脑出血患者血肿周围脑组织中的铁含量。有一个 ICH患者的临床无效和未满足的风险定量机制需求 基于ICH后周围组织中测量的铁水平进行分层。一 一套可靠的磁共振序列尚未建立，以帮助铁定量。这 ICH管理中的临床差距可以通过拟议的研究来验证可靠的MRI 方案，以实现脑组织中一致的铁定量。 我们建议量化血肿周围脑组织中的铁浓度， 能够跟踪ICH后30天内组织水平的时间变化。的 我们建议的背景是基于铁浓度体模实验和MRI R2* 与体模中指定铁浓度相关的信号计算。我们有 在大鼠ICH模型中应用来自体模的MRI计算算法， 与动物处死后组织学上组织铁水平的相关性。 拟议的研究是创新的，因为它利用现有的敏感性加权 在MRI上的序列，实际测量组织铁水平，而不仅仅是检测存在 铁。一旦获得资助，这项研究就有可能建立一种切实可行的评估方法。 基于铁毒性的ICH严重程度，也可能是功能结局的替代标志物 在未来

Abstract Hemorrhagic stroke constitutes 20 -30% of stroke cases in North America. It is one of the leading causes of death and neurological disability in the world. Hemorrhagic stroke is divided into Intra - cerebral hemorrhage (ICH), subarachnoid/intraventricular hemorrhage and subdural hemorrhage. There has been considerable progress over the past 20 years in animal and clinical studies to identify mechanisms of brain injury secondary to intracerebral hemorrhage. Studies are starting to identify that neurotoxicity contributed by Non-Heme iron is critical in determining the extent of neurological tissue damage. Increased amount of non heme iron surrounding the hematoma in an ICH has been shown to correlate with the size of the hematoma and also with the extent of neuronal damage. In animal models of ICH the effect of iron chelates has been demonstrated as reduction in the hematoma size and reduced extent of damage to neuronal tissue. This idea has led to phase I trial of such a chelate (Desferroxamine) in patients with ICH which has shown the safety and efficacy of an escalating dose. A phase II trial in ICH patients is underway to define the benefit in the human population. In general there is renewed vigor in identifying ways of quantifying tissue iron in other solid organs in the body. This is due to emergence of several iron chelate agents with a pharmacological profile favorable to the human physiology. Various MR based protocols have been examined to quantify iron in tissue with non-invasive imaging in other solid organs of the body. MR scanners with higher magnet strength and better resolution have demonstrated some promise in this regard. This technology can be hypothetically applied to the brain to ascertain the amount of iron in the brain tissue surrounding the hematoma in ICH patients. There is a clinical void and unmet need in the ICH patients of having a quantitative mechanism of risk stratification based on measured iron levels in the surrounding tissue following an ICH. A reliable set of MR sequences have not yet been established to help with iron quantification. This clinical gap in ICH management can be fulfilled by the proposed study to validate a reliable MRI protocol to enable consistent iron quantification in the brain tissue. We propose to quantify the iron concentration in the perihematomal brain tissue and be able to track the temporal variation in tissue levels over a period of 30 days following ICH. The background to our proposal is based on iron concentration phantom experiments and MRI R2* signal calculation correlating with the specified iron concentrations in the phantom. We have applied the MRI calculation algorithm from the phantom in a rat ICH model showing excellent correlation with tissue iron levels on histology following sacrifice of the animal. The proposed study is innovative because it utilizes existing susceptibility weighted sequence on MRI to actually measure tissue iron levels rather than merely detect the presence of iron. Once funded this study has the potential of establishing a tangible way of assessing severity of ICH based on iron toxicity and also may be a surrogate marker of functional outcome in the future.