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January 2010 | Vol 7 | N.º 1 | CNIC-16 [ PDF (900 KB) ]
Future Perspectives In Cardiovascular Imaging.
Simultaneous PET/MRI Technology In Biomedical Research
Carlos Zaragoza1, Borja Ibañez1, Luis Jesus Jimenez Borreguero1, Volkmar Schulz3, Zahi Fayad2, and Valentín Fuster1,2.
About the authors
Correspondence: Carlos Zaragoza. Laboratory of Vascular Wall Remodeling and Cardiovascular Disease. Department of Atherothrombosis and Cardiovascular Imaging, Fundación Centro Nacional de Investigaciones Cardiovasculares CNIC. Melchor Fernández Almagro 3, Madrid, 28029, Spain. Tel: 34-91-453-1200
Email czaragoza@cnic.es.
Abstract
In recent years, advances in biomedical sciences have been boosted by the introduction of new non-invasive imaging technologies. Magnetic resonance imaging (MRI), positron emission tomography (PET) and computerized tomography (CT) are now widely used to diagnose the development and progression of several pathologies, including cardiovascular diseases and cancer.
The integration of anatomic imaging, such as CT, and the most sensitive imaging modality, PET, provides an anatomical reference for diagnosis and lesion localization. Compared to MRI, however, PET/CT requires radiation and provides reduced soft tissue contrast. To overcome these shortcomings and thanks to recent advances in the field, MRI has the potential to be considered as an alternative to CT, and in combination with PET, provides excellent human anatomical information, superior soft tissue characterization and temporal resolution.
Recently, a European consortium of eight partners (HYPERImage project, including CNIC) from six countries was established to address new areas for concurrent PET/MRI. This consortium is focused on cardiovascular disease and cancer, the two most frequent causes of death in the world, and is developing a new technique based on the simultaneous acquisition of time-of-flight PET and MRI data for biomedical and clinical research. The advantages of simultaneous acquisition of PET/MRI images compared to other imaging modalities in biomedical research are discussed below.
Two decades ago the primary challenge in clinical practice was the combination of different imaging technologies at the same time to improve the sensitivity and accuracy of diagnosis 1-4. Today, multimodal imaging is well established, and the combination of PET and CT offers unique sensitivity and anatomical information combined in one multimodal assay. Significant limitations of PET/CT, however, exist related to non-simultaneous data acquisition 5,6. In fact, even though patients are scanned in the same session, the CT scan is the first step, followed by PET acquisition. Given that CT scans take seconds while PET images are acquired during more extended periods of time, organ motion and different respiratory cycles may lead to significant artefacts 7,8 . Additionally, the radiation risk associated with CT scans and reduced soft tissue contrast compared with MRI also constitute key limitations of this multimodal imaging technology.
PET/CT scans are used in clinical and pre-clinical cardiovascular research; however, investigations to overcome the primary limitations of PET/CT are becoming a central focus in the field. The combination of PET and MRI technologies constitutes the primary alternative as combined PET/MRI scans should provide simultaneous data acquisition together with the best combination of anatomical information and sensitivity and lower radiation exposure to the patient 6,7,9.
Combination of PET and MRI platforms: technical challenges
Three main challenges to combining both platforms still remain to be overcome. The first involves avoiding performance degradation as a result of building a single piece of equipment in which the photomultiplier tubes (PMTs) required for PET scanners 10,11 are not operative in the presence of the magnetic fields generated by MRI scanners. Second, there is a reduction in the quality of MRI images as result of the gradient degradation and radiofrequency disturbance generated by the PET insert 12,13. Third, attenuation correction algorithms must be developed as they are required for working simultaneously with MR 14.
Attenuation correction for PET/CT is an established technology, and values are collected from the same CT images in which attenuation coefficients corresponding to bone apart from the rest of the tissues are separated. This is not a valid approach for PET/MRI, however, because the magnetic resonance of bone is very similar to that of air. This is not a limiting factor for small animal evaluation, but human whole-body PET/MRI requires the use of efficient algorithms. This currently constitutes a bottleneck for the use of this promising platform in clinical practice.
Potential applications of PET/MRI
The use of imaging technology has greatly contributed to advancements in the field of pre-clinical cardiovascular research 15-26. Gadolinium contrast-enhanced MRI alone or in combination with PET has made it possible to identify atherosclerosis, plaque composition and plaque burden, 18,26-31 in addition to different cardiac alterations such as myocardial infarction, in different animal models of disease 15,32. We expect that simultaneous acquisition of PET and MRI images will lead to the next generation of research because excellent sensitivity in the detection of radiotracers will be combined with unprecedented anatomical information to provide exact localization of signals.
Hybrid PET/MRI systems have the potential to yield much more than the combination of anatomic MRI and PET. As depicted below, new advances in multimodal probe design are now becoming a reality in pre-clinical investigation 33. The transition towards clinical practice, however, is still in progress. We are currently investigating ways to overcome technical issues (e.g., attenuation correction, radiofrequency effect on MRI, magnetic field effect on PET nanotubes), and multimodal imaging protocols are still preliminary in human assays.
Recent advancements in the design of specific nanoprobes for multimodal detection on different platforms permit the localization of signals in a region of interest. Furthermore, it is possible to quantify the amount of specific particles associated with particular pathophysiological events at the molecular level, including atherosclerosis, aneurysm formation and progression, vascular remodelling, cardiac remodelling and left ventricular dysfunction, with the possibility to noninvasively monitor the efficiency of drug therapy and treatment. In this regard, early atherosclerosis has been efficiently targeted by the combination of PET and MRI using specific nanoparticles containing gadolinium-loaded micelles conjugated to anti-CD68 macrophage-specific antibodies (indicative of macrophage infiltration), anti-VCAM-1 (indicative of inflammatory atherosclerosis) and [18F]-FDG (a radiotracer specific for glucose uptake and a marker of glucose metabolism) in PET scans, which correlate to macrophage detection in atherosclerotic plaques 34,35.
Intraplaque angiogenesis via the proliferation of medial vasa vasorum has been implicated in rapid plaque growth, intraplaque haemorrhage and plaque rupture and is currently being targeted using specific nanoparticles to detect the expression of avb3 integrin, which is indicative of angiogenesis 36. Recent advances in the field have provided new nanoprobes for the simultaneous detection of avb3 integrin by PET and MRI, increasing the strength of detection and improving the accuracy of diagnosis 37.
The use of simultaneous PET/MRI in combination with specific nanoprobes may have a great impact on the early diagnosis of ischemic heart disease associated with myocardial infarction, acute coronary syndrome and acute and chronic myocarditis. PET tracers used for ischemic imaging include [18F]fluoromisonidazole ([18F]FMISO) and [64Cu]diacetyl-bis(N4-methylthiosemicarbazone) ([64Cu]ATSM) 38. In combination with the use of antibodies against P-selectin conjugated to micron-sized iron oxide nanoparticles 39, which have been successfully evaluated in animal models, hybrid PET/MRI may represent the best method to analyze these pathologies.
Clinical benefits of PET/MRI
As mentioned previously, the generation of a whole-body PET/MRI system has the potential benefit of simultaneous acquisition, combining excellent anatomical information and higher soft tissue contrast with the high sensitivity of PET, together with the future capacity to obtain multimodal and functional parameters due to great advances in the emerging field of nanotechnology and the generation of multimodal nanoprobes. Many diagnostic benefits can be expected from combining the functional information of PET with the anatomical data of MRI. Concurrent imaging protocols for both platforms are now in development, and initial data collected in animal models of brain disease, cardiovascular disease and cancer with the first prototypes are very promising 40. Thus, multifunctional imaging scans could be implemented in the near future in the clinic. Taken together with the ability to obtain metabolic and functional data, the use of PET/MRI will create a new era in cardiovascular practice. Therefore, different entities are actively involved in the development of this technological platform, and CNIC is part of an international consortium participating in a project (HYPERImage Project) with the ultimate goal of advancing the accuracy of diagnostic imaging in cardiovascular disease and cancer. The HYPERImage project is a collaborative research project financed by the European Commission in the context of the 7th Framework Programme. The project is driving the development of a brand new system for simultaneous whole-body PET/MRI for preclinical research (Figs. 1 and 2) and human studies. The goal is not only to improve existing diagnostic applications but also to open new approaches to therapy guidance and therapy response monitoring. The consortium behind HYPERImage comprises a leading medical company (Philips, coordinator of the project) and a total of five academic partners and public research organizations (one of which is CNIC) from six EU state members.
Figure 1
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Figure 1. Mechanical design of a pre-clinical scanner (cross-section)
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The HYPERImage project is divided into three major research areas: instrumentation development, correction technologies for quantitative imaging and preclinical and clinical validation. The ultimate goals include the development of an MRI-compatible detector technology with ultra-high time resolution; concurrent PET/MR test systems; 4D PET/MR motion, attenuation and functional data acquisition techniques; and a PET/MRI test for validation of cancer and cardiovascular diseases.
Figure 2
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Figure 2. Pre-clinical PET/MRI test system (mechanics only). The central inner tube covers the RF transmit/receive coil, while the outer ring covers 10 PET-modules (not shown here) each with a detector area of 6 x 32.7 x 32.7 mm2.
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Despite all of the potential benefits, the use of these techniques in clinical practice is still pending the development of MRI-compatible PET detectors and the standardization of a protocol to account for PET attenuation correction. In this regard, a critical milestone was reached in the HYPERImage project with the development of a functional gamma-ray detector that meets the performance requirements of the latest time-of-flight PET scanners. New gamma-ray detectors have been designed to be compatible with the strong static and dynamic magnetic fields present in a combined PET/MRI scanner (Fig. 3). Furthermore, the team has achieved major progress with respect to MRI-based static and dynamic PET attenuation correction. Details of the latest advancements were recently presented at the IEEE Nuclear Science Symposium and Medical Imaging Conference, October 25-31 in Orlando, FL, USA (www.nss-mic.org/2009).
Figure 3
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Figure 3. A PET module with an SPU board and one (out of six total) complete detector stack (SiPM-, ASIC- and Interface-tile). The square SiPM-Tile has 8 x 8 SiPMs with a linear extension of L= 32.7 mm. The LYSO array and the RF-screen are not shown here.
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Conclusions
Preclinical investigations into the implementation of a simultaneous whole-body PET/MRI scanner are now becoming a reality. In the next few years, great progress will be made in biomedical research thanks to different groups working around the world, including the HYPERImage consortium, together with the great advancements in nanoparticle research and multimodal probe design for use in combination with this hybrid system. Here we have outlined the vast potential of this new technology in cardiovascular research. The coming years may represent a new era for the implementation of PET/MRI in biomedical and clinical practice.
Financial Source
FP7-Health-2007-201651 “HYPERImage. Hybrid PET-MR system for concurrent ultra-sensitive imaging”.
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Authors
1.- Department of Atherothrombosis and Cardiovascular Imaging, Fundación Centro Nacional de Investigaciones Cardiovasculares CNIC. Melchor Fernández Almagro 3, Madrid, 28029, Spain.
2.- Mount Sinai School of Medicine, New York
3.- Philips Research Europe, Germany, Weissausstrasse 2, 52066 Aachen, Germany
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