In recent years, approximately 60,000 unruptured intracranial aneurysms (UIAs) were treated in the United States annually, representing nearly a 3-fold increase from 2001 at a conservatively estimated cost of $4 billion. The increase in the number of UIA treatments is likely related to expanded utilization of CT and MR imaging studies leading to the concomitant increase in the detection rate of incidental aneurysms. UIAs are being treated at historically high levels primarily due to dismal outcomes following aneurysmal subarachnoid hemorrhage associated with a 50-60% mortality rate. Unfortunately, UIA treatment presents non-trivial risks to patients, who are typically asymptomatic at presentation with approximately 15% of UIA patients treated with surgical clipping are discharged to long-term care. In-hospital mortality is 1.2% and 0.6% for patients receiving clipping and coiling, respectively. Consequently, there are no clear guidelines for the treatment of UIAs and their management remains controversial. There is strong evidence suggesting that the development of UIA involves several steps, which involves endothelial activation followed by transmigration of leukocytes that interfere with the normal metabolism of supporting (mural) and smooth muscle cells (SMC) in the vascular wall. Although SMC activation may lead to remodeling of the vascular wall resulting in aneurysm stabilization, it can also lead to sustained inflammation and wall weakening. Such gradual destabilization of vascular wall frequently involves adventitial vascularization, which creates additional inside-out pathway for sustained local inflammation. Large numbers of neutrophils carrying primary myeloperoxidase (MPO)-rich granules are the first responders to local endothelial activation resulting in a downstream infiltration of monocytes. We previously developed a strategy for contrast-assisted magnetic resonance imaging (MRI) of MPO activity in vitro and in vivo (Chen JW et al. Radiology 2006 240:473-81) using the effect of enzyme-mediated MR signal amplification (MRamp) (Bogdanov A Jr. et al. Mol Imaging. 2002 1:16-23). In parallel, we used immunohistochemistry to analyze surgically treated human ruptured and unruptured UIAs and discovered the presence of molecular markers of granulocytes in unruptured human aneurysms (treated due to morphological appearance) suggesting the association between MPO in human aneurysms with known risk factors for rupture (Gounis MJ, et al. Stroke 45:1474-7, 2014). During the initial period of exploratory NIH grant-supported research we: 1) developed an interventional strategy for creating local inflammation in rabbit model of UIA and 2) performed testing of the MPO-specific molecular imaging approach for detecting vascular inflammatory lesions (DeLeo MJ et al. Radiology 2009 252:696-703). We used immunohistochemistry and immunofluorescence to analyze samples of surgically treated human ruptured and unruptured UIAs and discovered the presence of molecular markers of granulocytes and macrophages in ruptured as well as unruptured human aneurysms, which were treated due to their high-risk morphology. Therefore, we propose to build on our prior research to optimize a low-molecular weight imaging probe that detects extracellular MPO activity and to perform comprehensive testing of the optimized imaging probes for detecting activated PMNs and SMCs as signatures of the on-going inflammation in the UIA wall. The ultimate goal of this proposal is to develop inroads to identification of aneurysms at risk of rupture and identify through the proposed experiments how specific and sensitive the imaging probes are in tracking active remodeling in aneurysm models.

Public Health Relevance

A large number of people in the USA live with silent brain aneurysms that are being increasingly discovered by imaging procedures. Rupture of brain aneurysms causes about 30,000 people in US to develop hemorrhagic strokes each year, many of whom will die unnecessarily. If there was a procedure to determine with certainty whether the silent aneurysm in the brain can burst, thousands of lives could be saved and thousands could be spared from common and serious complications of unnecessary surgery. In this research we propose to use a model of such brain aneurysm to follow the presence of molecules that can potentially tell whether there is a high chance of aneurysm to burst. This can be done by using brain imaging in patients without the need of opening the skull. Then these patients could be treated before aneurysm bursts and causes a severe stroke.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1)
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Koenig, James I
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University of Massachusetts Medical School Worcester
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