Molecular Imaging to Determine the Risk of Rupture of Cerebral Aneurysms

描述(由申请人提供)：在美国，致命性和非致命性动脉瘤破裂的发生率每年约为30,000。目前动脉瘤性蛛网膜下腔出血的病死率为50%，虽然有明显的逐渐改善的趋势，但病死率很高，而且这种疾病经常会对存活的患者造成毁灭性的后果。有强有力的证据表明，从稳定的动脉瘤到不稳定的动脉瘤的进展涉及局部炎症。最近证实，破裂的动脉瘤的炎症程度明显高于未破裂的动脉瘤。我们假设，炎症标志物存在的分子成像可以为预测动脉瘤发展不稳定和破裂的趋势提供一种策略。这将对诊断的准确性和患者的差异化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)的升高是冠状动脉疾病和动脉粥样硬化斑块破裂的重要危险因素。有鉴于此，我们推测，斑块进展过程中MPO的某些特异性效应也可能导致颅内动脉瘤的不稳定性。通过在小动物模型中结合MRI和MPO特异性顺磁对比探针的使用，我们最近证明了在人工种植系统和实验诱导的炎症中，MPO特异性MR信号稳定增加(Chen，JW等人)。放射学240：473,2006)。这项工作的主要目的是建立动物模型并验证MPO特异性探针，该探针可用于无创性评估颅内动脉瘤的潜在不稳定性。我们建议通过建立一个由PhD Pi领导的分子成像探针开发团队来探索上述概念，该团队将与动脉瘤模型专家PhD生物工程师和将优化兔动脉瘤成像方案的PhD MRI科学家密切合作。这项建议的基本要素是与两名医学博士(一名神经放射科医生和一名神经外科医生)合作，他们将根据临床方案评估兔子的数据并提供人类手术材料。拟议研究的主要目标是在3T MRI设备中使用顺磁底物在兔动脉瘤模型中进行探索性研究，旨在测试分子成像方法，最终目标是显著提高区分进一步介入或外科手术的可能和不可能的候选对象的能力。目的：1.优化兔动脉瘤模型，并将兔动脉瘤中MPO活性与破裂/未破裂切除的人动脉瘤标本中的MPO活性进行关联。目的2.用MPO特异性顺磁悬浮液对实验性兔动脉瘤炎性病变进行MPO活性的磁共振成像。项目简介：相关公共卫生相关声明：在许多人中，大脑中的血管会出现缺陷和破裂。这种疾病(动脉瘤)会导致四分之一的患者发生中风并不必要地死亡。如果有一种程序来确定血管是否有可能破裂，可能会拯救数千人的生命。我们建议使用这种动脉瘤的模型来跟踪一种分子，该分子可以判断动脉瘤破裂的可能性是否更高。这可以通过在患者身上使用磁共振成像来实现，而不需要打开头骨。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.