Brain Iron Quantification Based on MRI in Intracerebral Hemorrhage

摘要 出血性中风占北美中风病例的20%-30%。它是世界上 世界上导致死亡和神经功能障碍的主要原因。出血性中风是 分为脑出血(ICH)、蛛网膜下腔/脑室出血和 硬膜下出血。在过去的20年里，动物研究取得了长足的进步。 和临床研究以确定继发性脑损伤的机制 大出血。研究开始确认非血红素铁造成的神经毒性是 对于确定神经组织损伤的程度至关重要。 脑出血患者血肿周围非血红素铁的含量增加 显示与血肿的大小和神经元损伤的程度相关。 在脑出血的动物模型中，铁螯合物的作用已被证明是减少脑出血的 血肿大小和对神经元组织的损伤程度减轻。这个想法导致了第一阶段 这种螯合物(去铁沙明)在脑出血患者中的试验表明，它是安全的和 递增剂量的疗效。一项针对脑出血患者的二期试验正在进行中，以确定其益处 在人类人口中。 总的来说，在确定其他组织铁的量化方法方面有了新的活力 身体里的固体器官。这是由于几种铁络合剂的出现 有利于人体生理的药理概况。各种基于MR的协议具有 已被检查以定量组织中的铁与非侵入性成像在组织的其他固体器官 尸体。具有更高磁强度和更高分辨率的磁共振扫描仪已经显示了一些 在这方面的承诺。这项技术可以假想地应用于大脑，以确定 脑出血患者血肿周围脑组织中铁的含量。有一个 脑出血患者存在风险量化机制的临床虚无感和需求未得到满足 根据脑出血后周围组织中测量的铁水平进行分层。一个 目前还没有建立一组可靠的MR序列来帮助铁的定量。这 通过拟议的研究来验证可靠的MRI，可以填补脑出血治疗中的临床差距 协议，以实现脑组织中一致的铁定量。 我们建议对血肿周围脑组织中的铁浓度进行量化，并 能够跟踪脑出血后30天内组织水平的时间变化。这个 我们建议的背景是基于铁精矿模体实验和磁共振R2* 与体模中指定的铁浓度相关的信号计算。我们有 将体模的MRI计算算法应用于大鼠脑出血模型 动物处死后组织铁水平与组织学的相关性。 拟议的研究是创新的，因为它利用了现有的磁化率加权 MRI上的序列，以实际测量组织铁水平，而不仅仅是检测是否存在 铁制的。一旦获得资金，这项研究就有可能建立一种切实的评估方法 基于铁毒性的脑出血的严重程度，也可能是功能结局的替代标志 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.