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:
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.
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| Ronald, John A; Chen, John W; Chen, Yuanxin et al. (2009) Enzyme-sensitive magnetic resonance imaging targeting myeloperoxidase identifies active inflammation in experimental rabbit atherosclerotic plaques. Circulation 120:592-9 |
| DeLeo 3rd, Michael J; Gounis, Matthew J; Hong, Bo et al. (2009) Carotid artery brain aneurysm model: in vivo molecular enzyme-specific MR imaging of active inflammation in a pilot study. Radiology 252:696-703 |
