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This review outlines recent preclinical and clinical advances in molecular imaging of abdominal aortic aneurysms (AAA) with a focus on molecular magnetic resonance imaging (MRI) of the extracellular matrix (ECM). In addition, developments in pharmacologic treatment of AAA targeting the ECM will be discussed and results from animal studies will be contrasted with clinical trials. Abdominal aortic aneurysm (AAA) is an often fatal disease without non-invasive pharmacologic treatment options. The ECM, with collagen type I and elastin as major components, is the key structural component of the aortic wall and is recognized as a target tissue for both initiation and the progression of AAA. Molecular imaging allows in vivo measurement and characterization of biological processes at the cellular and molecular level and sets forth to visualize molecular abnormalities at an early stage of disease, facilitating novel diagnostic and therapeutic pathways. By providing surrogate criteria for the in vivo evaluation of the effects of pharmacological therapies, molecular imaging techniques targeting the ECM can facilitate pharmacological drug development. In addition, molecular targets can also be used in theranostic approaches that have the potential for timely diagnosis and concurrent medical therapy. Recent successes in preclinical studies suggest future opportunities for clinical translation. However, further clinical studies are needed to validate the most promising molecular targets for human application.

Magnetic particle imaging (MPI) is a non-invasive, non-ionizing imaging technique for the visualization and quantification of magnetic nanoparticles (MNPs). The technique is especially suitable for cell imaging as it offers zero background contribution from the surrounding tissue, high sensitivity, and good spatial and temporal resolutions. Previous studies have demonstrated that the dynamic magnetic behaviour of MNPs changes during cellular binding and internalization. In this study, we demonstrate how this information is encoded in the MPI imaging signal. Through MPI imaging we are able to discriminate between free and cell-bound MNPs in reconstructed images. This technique was used to image and quantify the changes that occur in-vitro when free MNPs come into contact with cells and undergo cellular-uptake over time. The quantitative MPI results were verified by colorimetric measurements of the iron content. The results showed a mean relative difference between the MPI results and the reference method of 23.8% for the quantification of cell-bound MNPs. With this technique, the uptake of MNPs in cells can be imaged and quantified directly from the first MNP cell contact, providing information on the dynamics of cellular uptake.

Background: Molecular magnetic resonance imaging is a promising modality for the characterization of abdominal aortic aneurysms (AAAs). The combination of different molecular imaging biomarkers may improve the assessment of the risk of rupture. This study investigates the feasibility of imaging inflammatory activity and extracellular matrix degradation by concurrent dual-probe molecular magnetic resonance imaging in an AAA mouse model., Methods: Osmotic minipumps with a continuous infusion of Ang II (angiotensin II; 1000 ng/[kg·min]) to induce AAAs were implanted in apolipoprotein-deficient mice (N=58). Animals were assigned to 2 groups. In group 1 (longitudinal group, n=13), imaging was performed once after 1 week with a clinical dose of a macrophage-specific iron oxide-based probe (ferumoxytol, 4 mgFe/kg, surrogate marker for inflammatory activity) and an elastin-specific gadolinium-based probe (0.2 mmol/kg, surrogate marker for extracellular matrix degradation). Animals were then monitored with death as end point. In group 2 (week-by-week-group), imaging with both probes was performed after 1, 2, 3, and 4 weeks (n=9 per group). Both probes were evaluated in 1 magnetic resonance session., Results: The combined assessment of inflammatory activity and extracellular matrix degradation was the strongest predictor of AAA rupture (sensitivity 100%; specificity 89%; area under the curve, 0.99). Information from each single probe alone resulted in lower predictive accuracy. In vivo measurements for the elastin- and iron oxide-probe were in good agreement with ex vivo histopathology (Prussian blue-stain: R 2 =0.96, P<0.001; Elastica van Giesson stain: R 2 =0.79, P<0.001). Contrast-to-noise ratio measurements for the iron oxide and elastin-probe were in good agreement with inductively coupled mass spectroscopy ( R 2 =0.88, R 2 =0.75, P<0.001) and laser ablation coupled to inductively coupled plasma-mass spectrometry., Conclusions: This study demonstrates the potential of the concurrent assessment of inflammatory activity and extracellular matrix degradation by dual-probe molecular magnetic resonance imaging in an AAA mouse model. Based on the combined information from both molecular probes, the rupture of AAAs could reliably be predicted.

Background: The incidence of abdominal aortic aneurysms (AAAs) will significantly increase during the next decade. Novel biomarkers, besides diameter, are needed for a better characterization of aneurysms and the estimation of the risk of rupture. Fibrin is a key protein in the formation of focal hematoma associated with the dissection of the aortic wall and the development of larger thrombi during the progression of AAAs. This study evaluated the potential of a fibrin-specific magnetic resonance (MR) probe for the in vivo characterization of the different stages of AAAs., Methods and Results: AAAs spontaneously developed in ApoE -/- mice following the infusion of angiotensin-II (Ang-II, 1 μg/kg -1 ·per minute). An established fibrin-specific molecular MR probe (EP2104R, 10 μmol/kg -1 ) was administered after 1 to 4 weeks following Ang-II infusion (n=8 per group). All imaging experiments were performed on a clinical 3T Achieva MR system with a microscopy coil (Philips Healthcare, Netherlands). The development of AAA-associated fibrin-rich hematoma and thrombi was assessed. The high signal generated by the fibrin probe enabled high-resolution MR imaging for an accurate assessment and quantification of the relative fibrin composition of focal hematoma and thrombi. Contrast-to-noise-ratios (CNRs) and R1-relaxation rates following the administration of the fibrin probe were in good agreement with ex vivo immunohistomorphometry ( R 2 =0.83 and 0.85) and gadolinium concentrations determined by inductively coupled plasma mass spectroscopy ( R 2 =0.78 and 0.72)., Conclusions: The fibrin-specific molecular MR probe allowed the delineation and quantification of changes in fibrin content in early and advanced AAAs. Fibrin MRI could provide a novel in vivo biomarker to improve the risk stratification of patients with aortic aneurysms., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

This review summarizes the current status of molecular imaging of the extracellular matrix (ECM) in the context of atherosclerosis. Apart from cellular components, the ECM of the atherosclerotic plaque plays a relevant role during the initiation of atherosclerosis and its' subsequent progression. Important structural and signaling components of the ECM include elastin, collagen and fibrin. However, the ECM not only plays a structural role in the arterial wall but also interacts with different cell types and has important biological signaling functions. Molecular imaging of the ECM has emerged as a new diagnostic tool to characterize biological aspects of atherosclerotic plaques, which cannot be characterized by current clinically established imaging techniques, such as X-ray angiography. Different types of molecular probes can be detected in vivo by imaging modalities such as magnetic resonance imaging (MRI), positron emission tomography (PET) and single photon emission computed tomography (SPECT). The modality specific signaling component of the molecular probe provides information about its spatial location and local concentration. The successful introduction of molecular imaging into clinical practice and guidelines could open new pathways for an earlier detection of disease processes and a better understanding of the disease state on a biological level. Quantitative in vivo molecular parameters could also contribute to the development and evaluation of novel cardiovascular therapeutic interventions and the assessment of response to treatment., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In the Western world and developing countries, the number one causes of mortality and morbidity result from cardiovascular diseases. Cardiovascular diseases represent a wide range of pathologies, including myocardial infarction, peripheral vascular disease, and cerebrovascular disease, which are all linked by a common cause - atherosclerosis. Currently, the diagnosis of atherosclerosis is in most cases established at the end stage of the disease, when patients are administered to the emergency room due to a myocardial infarction or stroke. Even though cardiovascular diseases have an enormous impact on society, there are still limitations in the early diagnosis and the prevention of the disease. Current imaging methods mainly focus on morphological changes that occur at an advanced disease stage, e.g., degree of stenosis. Cardiovascular magnetic resonance imaging and specifically molecular cardiovascular magnetic resonance imaging are capable to reveal pathophysiological changes already occurring during early atherosclerotic plaque formation. This allows for the assessment of cardiovascular disease on a level, which goes beyond morphological or anatomical criteria. In this review, we will introduce promising MR-based molecular imaging strategies for the non-invasive assessment of cardiovascular disease.

Background: The incidence of abdominal aortic aneurysms (AAAs) has increased during the last decades. However, there is still controversy about the management of medium-sized AAAs. Therefore, novel biomarkers, besides aneurysmal diameter, are needed to assess aortic wall integrity and risk of rupture. Elastin is the key protein for maintaining aortic wall tensile strength and stability. The progressive breakdown of structural proteins, in particular, medial elastin, is responsible for the inability of the aortic wall to withstand intraluminal hemodynamic forces. Here, we evaluate the usefulness of elastin-specific molecular MRI for the in vivo characterization of AAAs., Methods and Results: To induce AAAs, ApoE(-/-) mice were infused with angiotensin-II. An elastin-specific magnetic resonance molecular imaging agent (ESMA) was administered after 1, 2, 3, and 4 weeks of angiotensin-II infusion to assess elastin composition of the aorta (n=8 per group). The high signal provided by ESMA allowed for imaging with high spatial resolution, resulting in an accurate assessment of ruptured elastic laminae and the compensatory expression of elastic fibers. In vivo contrast-to-noise ratios and R1-relaxation rates after ESMA administration were in good agreement with ex vivo histomorphometry (Elastica van Gieson stain) and gadolinium concentrations determined by inductively coupled plasma mass spectroscopy. Electron microscopy confirmed colocalization of ESMA with elastic fibers., Conclusions: Changes in elastin content could be readily delineated and quantified at different stages of AAAs by elastin-specific molecular magnetic resonance imaging. ESMA-MRI offers potential for the noninvasive detection of the aortic rupture site prior to dilation of the aorta and the subsequent in vivo monitoring of compensatory repair processes during the progression of AAAs., (© 2014 American Heart Association, Inc.)

Cardiovascular diseases remain the leading cause of morbidity and mortality in the Western world and developing countries. In clinical practice, in vivo characterization of atherosclerotic lesions causing myocardial infarction, ischemic stroke, and other complications remains challenging. Imaging methods, limited to the assessment luminal stenosis, are the current reference standard for the assessment of clinically significant coronary and carotid artery disease and the guidance of treatment. These techniques do not allow distinction between stable and potentially vulnerable atherosclerotic plaque. Magnetic resonance (MR) imaging is a modality well suited for visualization and characterization of the relatively thin arterial vessel wall, because it allows imaging with high spatial resolution and excellent soft-tissue contrast. In clinical practice, atherosclerotic plaque components of the carotid artery and aorta may be differentiated and characterized by using unenhanced vessel wall MR imaging. Additional information can be gained by using clinically approved nonspecific contrast agents. With the advent of targeted MR contrast agents, which enhance specific molecules or cells, pathologic processes can be visualized at a molecular level with high spatial resolution. In this article, the pathophysiologic changes of the arterial vessel wall underlying the development of atherosclerosis will be first reviewed. Then basic principles and properties of molecular MR imaging contrast agents will be introduced. Additionally, recent advances in preclinical molecular vessel wall imaging will be reviewed. Finally, the clinical feasibility of arterial vessel wall imaging at unenhanced and contrast material-enhanced MR imaging of the aortic, carotid, and coronary vessel wall will be discussed., (© RSNA, 2013.)

Molecular imaging with targeted contrast agents by magnetic resonance imaging (MRI) allows for the noninvasive detection and characterization of biological changes on a molecular level. In this article, the principles of molecular MRI and its applications in cardiovascular diseases are reviewed. First, basic properties of positive and negative contrast agents are introduced and their effect on signal generation in a magnetic field is described. In the next part, different types of MRI scanners and the influence of field strength on signal properties of contrast agents for molecular imaging are discussed. Additionally, the assessment, analysis, and quantification of the changes in T1 and T2* relaxation time induced by the different molecular contrast agents are reviewed. Finally, the basic mechanisms of targeting of imaging probes on a molecular level and recent applications of molecular MRI in cardiovascular disease are reviewed.

Constant interactions between tumor cells and the extracellular matrix (ECM) influence the progression of prostate cancer (PCa). One of the key components of the ECM are collagen fibers, since they are responsible for the tissue stiffness, growth, adhesion, proliferation, migration, invasion/metastasis, cell signaling, and immune recruitment of tumor cells. To explore this molecular marker in the content of PCa, we investigated two different tumor volumes (500 mm3 and 1000 mm3) of a xenograft mouse model of PCa with molecular magnetic resonance imaging (MRI) using a collagen-specific probe. For in vivo MRI evaluation, T1-weighted sequences before and after probe administration were analyzed. No significant signal difference between the two tumor volumes could be found. However, we detected a significant difference between the signal intensity of the peripheral tumor area and the central area of the tumor, at both 500 mm3 (p < 0.01, n = 16) and at 1000 mm3 (p < 0.01, n = 16). The results of our histologic analyses confirmed the in vivo studies: There was no significant difference in the amount of collagen between the two tumor volumes (p > 0.05), but within the tumor, higher collagen expression was observed in the peripheral area compared with the central area of the tumor. Laser ablation with inductively coupled plasma mass spectrometry further confirmed these results. The 1000 mm3 tumors contained 2.8 ± 1.0% collagen and the 500 mm3 tumors contained 3.2 ± 1.2% (n = 16). There was a strong correlation between the in vivo MRI data and the ex vivo histological data (y = −0.068x + 1.1; R2 = 0.74) (n = 16). The results of elemental analysis by inductively coupled plasma mass spectrometry supported the MRI data (y = 3.82x + 0.56; R2 = 0.79; n = 7). MRI with the collagen-specific probe in PCa enables differentiation between different tumor areas. This may help to differentiate tumor from healthy tissue, potentially identifying tumor areas with a specific tumor biology. [ABSTRACT FROM AUTHOR]

Simple Summary: Magnetic resonance imaging (MRI) is a non-invasive method and can be used to diagnose prostate cancer (PCa). Due to their high biological safety, iron oxide nanoparticles are becoming increasingly important as contrast agents for MRI. Macrophages are able to take up these iron particles, which leads to a loss of signal in T2- and T2*-weighted images during MRI. Macrophages play an important role in the development and progression of prostate cancer. In this article, ferumoxytol is visualized at two different PCa volumes on MRI in a xenograft mouse model. Ferumoxytol is a superparamagnetic iron oxide probe and was used here as a contrast agent. The in vivo data were correlated with histological data. When using ferumoxytol, we found that small tumors took up more ferumoxytol than larger tumor volumes. These results were obtained in vivo as well as ex vivo. Prostate cancer (PCa) is one of the most common cancers in men. For detection and diagnosis of PCa, non-invasive methods, including magnetic resonance imaging (MRI), can reduce the risk potential of surgical intervention. To explore the molecular characteristics of the tumor, we investigated the applicability of ferumoxytol in PCa in a xenograft mouse model in two different tumor volumes, 500 mm3 and 1000 mm3. Macrophages play a key role in tumor progression, and they are able to internalize iron-oxide particles, such as ferumoxytol. When evaluating T2*-weighted sequences on MRI, a significant decrease of signal intensity between pre- and post-contrast images for each tumor volume (n = 14; p < 0.001) was measured. We, furthermore, observed a higher signal loss for a tumor volume of 500 mm3 than for 1000 mm3. These findings were confirmed by histological examinations and laser ablation inductively coupled plasma-mass spectrometry. The 500 mm3 tumors had 1.5% iron content (n = 14; σ = 1.1), while the 1000 mm3 tumors contained only 0.4% iron (n = 14; σ = 0.2). In vivo MRI data demonstrated a correlation with the ex vivo data (R2 = 0.75). The results of elemental analysis by inductively coupled plasma-mass spectrometry correlated strongly with the MRI data (R2 = 0.83) (n = 4). Due to its long retention time in the blood, biodegradability, and low toxicity to patients, ferumoxytol has great potential as a contrast agent for visualization PCa. [ABSTRACT FROM AUTHOR]

Abstract Objectives This study sought to investigate the potential of the noninvasive albumin-binding probe gadofosveset-enhanced cardiac magnetic resonance (GE-CMR) for detection of coronary plaques that can cause acute coronary syndromes (ACS). Background ACS are frequently caused by rupture or erosion of coronary plaques that initially do not cause hemodynamically significant stenosis and are therefore not detected by invasive x-ray coronary angiography (XCA). Methods A total of 25 patients with ACS or symptoms of stable coronary artery disease underwent GE-CMR, clinically indicated XCA, and optical coherence tomography (OCT) within 24 h. GE-CMR was performed approximately 24 h following a 1-time application of gadofosveset-trisodium. Contrast-to-noise ratio (CNR) was quantified within coronary segments in comparison with blood signal. Results A total of 207 coronary segments were analyzed on GE-CMR. Segments containing a culprit lesion in ACS patients (n = 11) showed significant higher signal enhancement (CNR) following gadofosveset-trisodium application than segments without culprit lesions (n = 196; 6.1 [3.9 to 16.5] vs. 2.1 [0.5 to 3.5]; p < 0.001). GE-CMR was able to correctly identify culprit coronary lesions in 9 of 11 segments (sensitivity 82%) and correctly excluded culprit coronary lesions in 162 of 195 segments (specificity 83%). Additionally, segmented areas of thin-cap fibroatheroma (n = 22) as seen on OCT demonstrated significantly higher CNR than segments without coronary plaque or segments containing early atherosclerotic lesions (n = 185; 9.2 [3.3 to 13.7] vs. 2.1 [0.5 to 3.4]; p = 0.001). Conclusions In this study, we demonstrated for the first time the noninvasive detection of culprit coronary lesions and thin-cap fibroatheroma of the coronary arteries in vivo by using GE-CMR. This method may represent a novel approach for noninvasive cardiovascular risk prediction. Graphical abstract [ABSTRACT FROM AUTHOR]

Despite advances in prevention, risk assessment and treatment, coronary artery disease (CAD) remains the leading cause of morbidity and mortality in Western countries. The lion's share is due to acute coronary syndromes (ACS), which are predominantly triggered by plaque rupture or erosion and subsequent coronary thrombosis. As the majority of vulnerable plaques does not cause a significant stenosis, due to expansive remodeling, and are rather defined by their composition and biological activity, detection of vulnerable plaques with x-ray angiography has shown little success. Non-invasive vulnerable plaque detection by identifying biological features that have been associated with plaque progression, destabilization and rupture may therefore be more appropriate and may allow earlier detection, more aggressive treatment and monitoring of treatment response. MR molecular imaging with target specific molecular probes has shown great promise for the noninvasive in vivo visualization of biological processes at the molecular and cellular level in animals and humans. Compared to other imaging modalities; MRI can provide excellent spatial resolution; high soft tissue contrast and has the ability to simultaneously image anatomy; function as well as biological tissue composition and activity. [ABSTRACT FROM AUTHOR]

Simple Summary: One of the most commonly diagnosed cancers in men is prostate cancer (PCa). Understanding tumor progression can help diagnose and treat the disease at an early stage. Components of the extracellular matrix (ECM) play a key role in the development and progression of PCa. Elastin is an essential component of the ECM and constantly changes during tumor development. This article visualizes and quantifies elastin in magnetic resonance imaging (MRI) using a small molecule probe. Results were correlated with histological examinations. Using an elastin-specific molecular probe, we were able to make predictions about the cellular structure in relation to elastin and thus draw conclusions about the size of the tumor, with smaller tumors having a higher elastin content than larger tumors. Human prostate cancer (PCa) is a type of malignancy and one of the most frequently diagnosed cancers in men. Elastin is an important component of the extracellular matrix and is involved in the structure and organization of prostate tissue. The present study examined prostate cancer in a xenograft mouse model using an elastin-specific molecular probe for magnetic resonance molecular imaging. Two different tumor sizes (500 mm3 and 1000 mm3) were compared and analyzed by MRI in vivo and histologically and analytically ex vivo. The T1-weighted sequence was used in a clinical 3-T scanner to calculate the relative contrast enhancement before and after probe administration. Our results show that the use of an elastin-specific probe enables better discrimination between tumors and surrounding healthy tissue. Furthermore, specific binding of the probe to elastin fibers was confirmed by histological examination and laser ablation–inductively coupled plasma–mass spectrometry (LA-ICP-MS). Smaller tumors showed significantly higher signal intensity (p > 0.001), which correlates with the higher proportion of elastin fibers in the histological evaluation than in larger tumors. A strong correlation was seen between relative enhancement (RE) and Elastica–van Gieson staining (R2 = 0.88). RE was related to inductively coupled plasma–mass spectrometry data for Gd and showed a correlation (R2 = 0.78). Thus, molecular MRI could become a novel quantitative tool for the early evaluation and detection of PCa. [ABSTRACT FROM AUTHOR]

This review summarizes recent developments regarding molecular imaging markers for magnetic resonance imaging (MRI) of prostate cancer (PCa). Currently, the clinical standard includes MR imaging using unspecific gadolinium-based contrast agents. Specific molecular probes for the diagnosis of PCa could improve the molecular characterization of the tumor in a non-invasive examination. Furthermore, molecular probes could enable targeted therapies to suppress tumor growth or reduce the tumor size. [ABSTRACT FROM AUTHOR]

Simple Summary: The newest Prostate Imaging Reporting and Data System (PI-RADS) version 2.1, was published in 2019. There are a few variations of the new standard, which will change prostate lesions' classification rules. Our study aims to analyze the pattern change of lesion positron emission tomography (PET) standardized uptake values maximum (SUVmax) distribution under PI-RADS V2.1, compared with PI-RADS V2.0. Moreover, we studied the correlation between prostate-specific membrane antigen (PSMA) SUVmax and magnetic resonance imaging (MRI) PI-RADS. So far, there is no article reporting the effect of the newest PI-RADS on [68Ga]Ga-PSMA-11 PET/MRI. We did a thorough analysis, including two subgroups, peripheral zone, transitional zone, and 215 lesions. We analyzed the impact of each variation of PI-RADS one by one. Purpose: We aimed to evaluate the correlation between PSMA uptake and magnetic resonance imaging (MRI) PI-RADS of simultaneous [68Ga]Ga-PSMA-11 PET/MRI regarding PI-RADS version 2.0 and 2.1 respectively and compared the difference between these two versions. Materials and Methods: We retrospectively analyzed a total of forty-six patients with biopsy-proven prostate cancer who underwent simultaneous [68Ga]Ga-PSMA-11 PET/MRI. We classified the lesions regarding PI-RADS version 2.0 and 2.1, peripheral zone (PZ), and transitional zone (TZ), respectively. Based on regions of interest (ROI), standardized uptake values maximum (SUVmax), and corresponding lesion-to-background ratios (LBR) of SUVmax of each category, PI-RADS score 1 to 5, were measured. A comparison between PI-RADS version 2.0 and PI-RADS version 2.1 was performed. Results: A total of 215 focal prostate lesions were analyzed, including two subgroups, 125 TZ and 90 PZ. Data are reported as median and interquartile range (IQR). Regarding PI-RADS version 2.1, TZ SUVmax of each category were 1.5 (0.5, 1.9), 1.9 (0.8, 2.3), 3.3 (2.1, 4.6), 4.2 (3.1, 5.7), 7.3 (5.2, 9.7). PZ SUVmax of each category were 1.0 (0.8, 1.6), 2.5 (1.5, 3.2), 3.3 (1.9, 4.5), 4.3 (3.0, 5.4), 7.4 (5.0, 9.3). Regarding the inter-reader agreement of the overall PI-RADS assessment category, the kappa value was 0.723 for version 2.0 and 0.853 for version 2.1. Conclusion: Revisions of PI-RADS version 2.1 results in variations in lesions classification. Lesions with the PI-RADS category of 3, 4, and 5 present relatively higher intraprostatic PSMA uptake, while lesions with the PI-RADS category of 1 and 2 present relatively lower and similar uptake. Version 2.1 has higher inter-reader reproducibility than version 2.0. [ABSTRACT FROM AUTHOR]

Abdominal aortic aneurysms (AAAs) represent a vascular disease with severe complications. AAAs are currently the overall 10th leading cause of death in western countries and their incidence is rising. Although different diagnostic techniques are currently available in clinical practice, including ultrasound (US), magnetic resonance imaging (MRI), and computed tomography (CT), imaging-based prediction of life-threatening complications such as aneurysm-rupture remains challenging. Molecular imaging provides a novel diagnostic approach for in vivo visualization of biological processes and pathological alterations at a cellular and molecular level. Its overall aim is to improve our understanding of disease pathogenesis and to facilitate novel diagnostic pathways. This review outlines recent preclinical and clinical developments in molecular MRI, positron emission tomography (PET), and single-photon emission computed tomography (SPECT) for imaging of AAAs. [ABSTRACT FROM AUTHOR]