Molecular Imaging to Determine the Risk of Rupture of Cerebral Aneurysms

描述（由申请人提供）： 在美国，致死性和非致死性动脉瘤破裂的发生率约为每年30，000例。目前蛛网膜下腔出血的病死率为50%，尽管有明显的逐渐改善的趋势，但病死率很高，并且这种疾病经常导致存活患者的毁灭性后果。有强有力的证据表明，从稳定到不稳定的动脉瘤的进展涉及局部炎症。最近证实，破裂动脉瘤的炎症程度明显高于未破裂动脉瘤。我们假设炎症标记物存在的分子成像可以提供一种预测动脉瘤发展不稳定和破裂趋势的策略。这将对诊断的准确性和差异化患者管理产生强烈的积极影响。最近的流行病学证据表明，血液中髓过氧化物酶（MPO）的升高是冠心病和动脉粥样硬化斑块破裂的重要危险因素。鉴于上述情况，我们假设斑块进展中的某些MPO特异性效应也可能导致颅内动脉瘤不稳定。通过在小动物模型中将MRI与MPO特异性顺磁性对比探针的使用相结合，我们最近证明了在人工植入系统以及实验诱导的炎症中，存在稳定的MPO特异性MR信号增加（Chen，JW等人，Radiology 240：473，2006）。本研究的主要目的是建立动物模型并验证MPO特异性探针，该探针可用于颅内动脉瘤潜在不稳定性的无创评估。我们建议通过建立一个由分子成像探针开发的博士PI领导的团队来探索上述概念，该团队将与生物工程师博士、动脉瘤模型专家和MRI科学家博士密切合作，后者将优化兔动脉瘤成像方案。该提案的基本要素是与两名医学博士（神经放射学家和神经外科医生）合作，他们将根据临床方案评估家兔数据并提供人体手术材料。拟定研究的主要目标是进行探索性研究，旨在在3 T MRI装置中使用兔动脉瘤模型中的顺磁性基质测试分子成像方法，最终目标是显著提高区分可能和不可能的候选人进行进一步介入或外科手术的能力。两个主要目标是：目标1。优化兔动脉瘤模型，并将兔动脉瘤中MPO活性与从破裂/未破裂切除的人类动脉瘤中获得的样品中MPO活性相关联。目标二。用MPO特异性顺磁物质对兔动脉瘤内炎性病变的MPO活性进行MR成像。项目叙述：相关性公共卫生相关性声明：在许多人的大脑血管发展缺陷和爆裂。这种疾病（动脉瘤）导致四分之一的患者发生中风和不必要的死亡。如果有一个程序来确定血管是否可能破裂，成千上万的生命可能会被挽救。我们建议使用这种动脉瘤的模型来跟踪一种分子，这种分子可以判断动脉瘤是否有更高的破裂机会。这可以通过在患者体内使用磁共振成像来完成，而无需打开颅骨。然后，这组患者可以在动脉瘤破裂并导致严重中风之前进行治疗。

DESCRIPTION (provided by applicant): The incidence of fatal and non-fatal aneurysm rupture in US is approximately 30,000 annually. Current case fatality rate for aneurysmal subarachnoid hemorrhage is 50%, and though a trend toward gradual improvement is evident, the fatality rate is high and the disease results in frequently devastating consequences in surviving patients. There is strong evidence suggesting that the progression from stable to unstable aneurysm involves local inflammation. As demonstrated recently, the extent of the inflammation is significantly higher in ruptured versus unruptured aneurysms. We hypothesize that molecular imaging of inflammatory marker presence could provide a strategy for predicting the tendency of aneurysm to develop instability and rupture. This would have a strong positive impact on accuracy of diagnosis and for differential patient management. Recent epidemiological evidence suggests that the elevated presence of myeloperoxidase (MPO) in blood is an important risk factor for coronary disease and atherosclerotic plaque rupture. In view of the above, we hypothesize that some of the MPO-specific effects in plaque progression could also contribute to intracranial aneurysm instability. By combining MRI with the use of MPO-specific paramagnetic contrast probe in small animal models we recently demonstrated that in artificial implant systems as well as experimentally induced inflammation there was stable MPO-specific increase of MR signal (Chen, JW et al. Radiology 240:473, 2006). The major objective of the proposed work is to develop animal model and validate the MPO-specific probe which could be used for non-invasive assessment of potential instability of intracranial aneurysms. We propose to explore the above concept by establishing a team lead by PhD PI of molecular imaging probe development who will work closely with PhD bioengineer, an expert in aneurysm models, and PhD MRI scientist who will optimize rabbit aneurysm imaging protocols. The essential element of this proposal is collaboration with two MDs (a neuroradiologist and a neurosurgeon) who will evaluate rabbit data and supply human surgical material under a clinical protocol. The major goal of proposed research is to perform exploratory research directed at the testing of the molecular imaging approach using paramagnetic substrates in rabbit model of aneurysm in a 3T MRI setup with an ultimate goal of dramatically improving the ability to differentiate between likely and unlikely candidates for further interventional or surgical procedures. Two major aims are: Aim 1. Optimize rabbit model of aneurysm and correlate MPO activity in rabbit aneurysm with MPO activity in samples obtained from ruptured/unruptured resected human aneurysms. Aim 2. Perform feasibility MR imaging of MPO activity using MPO-specific paramagnetic susbtrate in experimental inflammatory lesions induced in rabbit aneurysm. PROJECT NARRATIVE: RELEVANCE Public health relevance statement: In many people blood vessels in the brain develop defects and burst. This disease (aneurysm) causes a quarter of patients to develop strokes and die unnecessarily. If there was a procedure to determine whether the vessel can potentially burst, thousands of lives might be saved. We propose to use a model of such aneurysm to follow a molecule that can tell whether there is a higher chance that an aneurysm might burst. This can be done by using magnetic resonance imaging in patients without the need of opening the skull. Then this group of patients could be treated before aneurysm bursts and cause a severe stroke.