The Integration of Positron Emission Tomography With Magnetic Resonance Imaging

A number of laboratories and companies are currently exploring the development of integrated imaging systems for magnetic resonance imaging (MRI) and positron emission tomography (PET). Scanners for both preclinical and human research applications are being pursued. In contrast to the widely distributed and now quite mature PET/computed tomography technology, most PET/MRI designs allow for simultaneous rather than sequential acquisition of PET and MRI data. While this offers the possibility of novel imaging strategies, it also creates considerable challenges for acquiring artifact-free images from both modalities. This paper discusses the motivation for developing combined PET/MRI technology, outlines the obstacles in realizing such an integrated instrument, and presents recent progress in the development of both the instrumentation and of novel imaging agents for combined PET/MRI studies. The performance of the first-generation PET/MRI systems is described. Finally, a range of possible biomedical applications for PET/MRI are outlined

Radiolabeling human peripheral blood stem cells for positron emission tomography (PET) imaging in young rhesus monkeys.

These studies focused on a new radiolabeling technique with copper ((64)Cu) and zirconium ((89)Zr) for positron emission tomography (PET) imaging using a CD45 antibody. Synthesis of (64)Cu-CD45 and (89)Zr-CD45 immunoconjugates was performed and the evaluation of the potential toxicity of radiolabeling human peripheral blood stem cells (hPBSC) was assessed in vitro (viability, population doubling times, colony forming units). hPBSC viability was maintained as the dose of (64)Cu-TETA-CD45 increased from 0 (92%) to 160 µCi/mL (76%, p>0.05). Radiolabeling efficiency was not significantly increased with concentrations of (64)Cu-TETA-CD45 >20 µCi/mL (p>0.50). Toxicity affecting both growth and colony formation was observed with hPBSC radiolabeled with ≥40 µCi/mL (p<0.05). For (89)Zr, there were no significant differences in viability (p>0.05), and a trend towards increased radiolabeling efficiency was noted as the dose of (89)Zr-Df-CD45 increased, with a greater level of radiolabeling with 160 µCi/mL compared to 0-40 µCi/mL (p<0.05). A greater than 2,000 fold-increase in the level of (89)Zr-Df-CD45 labeling efficiency was observed when compared to (64)Cu-TETA-CD45. Similar to (64)Cu-TETA-CD45, toxicity was noted when hPBSC were radiolabeled with ≥40 µCi/mL (p<0.05) (growth, colony formation). Taken together, 20 µCi/mL resulted in the highest level of radiolabeling efficiency without altering cell function. Young rhesus monkeys that had been transplanted prenatally with 25×10(6) hPBSC expressing firefly luciferase were assessed with bioluminescence imaging (BLI), then 0.3 mCi of (89)Zr-Df-CD45, which showed the best radiolabeling efficiency, was injected intravenously for PET imaging. Results suggest that (89)Zr-Df-CD45 was able to identify engrafted hPBSC in the same locations identified by BLI, although the background was high

Subsecond total-body imaging using ultrasensitive positron emission tomography.

A 194-cm-long total-body positron emission tomography/computed tomography (PET/CT) scanner (uEXPLORER), has been constructed to offer a transformative platform for human radiotracer imaging in clinical research and healthcare. Its total-body coverage and exceptional sensitivity provide opportunities for innovative studies of physiology, biochemistry, and pharmacology. The objective of this study is to develop a method to perform ultrahigh (100 ms) temporal resolution dynamic PET imaging by combining advanced dynamic image reconstruction paradigms with the uEXPLORER scanner. We aim to capture the fast dynamics of initial radiotracer distribution, as well as cardiac motion, in the human body. The results show that we can visualize radiotracer transport in the body on timescales of 100 ms and obtain motion-frozen images with superior image quality compared to conventional methods. The proposed method has applications in studying fast tracer dynamics, such as blood flow and the dynamic response to neural modulation, as well as performing real-time motion tracking (e.g., cardiac and respiratory motion, and gross body motion) without any external monitoring device (e.g., electrocardiogram, breathing belt, or optical trackers)

Colored reflectors to improve coincidence timing resolution of BGO-based time-of-flight PET detectors

Time-of-flight (TOF) positron emission tomography (PET) detectors improve the signal-to-noise ratio of PET images by limiting the position of the generation of two 511 keV gamma-rays in space using the arrival time difference between the two photons. Unfortunately, bismuth germanate (BGO), widely used in conventional PET detectors, was limited as a TOF PET scintillator due to the relatively slow decay time of the scintillation photons. However, prompt Cerenkov light in BGO has been identified in addition to scintillation photons. Using Cerenkov photons for timing has significantly improved the coincidence timing resolution (CTR) of BGO. Based on this, further research on improving the CTR for a BGO-based TOF PET system is being actively conducted. Wrapping materials for BGO pixels have primarily employed white reflectors to most efficiently collect scintillation light. White reflectors have customarily been used as reflectors for BGO pixels even after Cerenkov light began to be utilized for timing calculations in pixel-level experiments. However, when the arrival-time differences of the two 511 keV annihilations photons were measured with pure Cerenkov radiators, painting the lateral sides of the radiators black can improve CTR by suppressing the reflection of Cerenkov photons. The use of BGO for TOF PET detectors requires simultaneously minimizing scintillation loss for good energy information and suppressing reflected Cerenkov photons for better timing performance. Thus, reflectors for BGO pixels should be optimized for better timing and energy performance. In this study, colored polytetrafluoroethylene (PTFE) tapes with discontinuous reflectance values at specific wavelengths were applied as a BGO reflector. We hypothesized that CTR could be enhanced by selectively suppressing reflected Cerenkov photons with an optimum colored reflector on the BGO pixel while minimizing scintillation photon loss. CTRs were investigated utilizing white and three colors (yellow, red, and green) PTFE tapes as a reflector. In addition, black-painted PTFE tape and enhanced specular reflector film were investigated as reference reflector materials. When 3 × 3 × 20 mm3BGO pixels were wrapped with the yellow PTFE reflector, the CTR was significantly improved to 365 ± 5 ps from 403 ± 14 ps measured with the conventional white PTFE reflector. Adequate energy information was still obtained with only 4.1% degradation in light collection compared to the white reflector. Colored reflectors show the possibility to further improve CTR for BGO pixels with optimum reflectance design

High Resolution PET with 250 micrometer LSO Detectors and Adaptive Zoom

There have been impressive improvements in the performance of small-animal positron emission tomography (PET) systems since their first development in the mid 1990s, both in terms of spatial resolution and sensitivity, which have directly contributed to the increasing adoption of this technology for a wide range of biomedical applications. Nonetheless, current systems still are largely dominated by the size of the scintillator elements used in the detector. Our research predicts that developing scintillator arrays with an element size of 250 {micro}m or smaller will lead to an image resolution of 500 {micro}m when using 18F- or 64Cu-labeled radiotracers, giving a factor of 4-8 improvement in volumetric resolution over the highest resolution research systems currently in existence. This proposal had two main objectives: (i) To develop and evaluate much higher resolution and efficiency scintillator arrays that can be used in the future as the basis for detectors in a small-animal PET scanner where the spatial resolution is dominated by decay and interaction physics rather than detector size. (ii) To optimize one such high resolution, high sensitivity detector and adaptively integrate it into the existing microPET II small animal PET scanner as a 'zoom-in' detector that provides higher spatial resolution and sensitivity in a limited region close to the detector face. The knowledge gained from this project will provide valuable information for building future PET systems with a complete ring of very high-resolution detector arrays and also lay the foundations for utilizing high-resolution detectors in combination with existing PET systems for localized high-resolution imaging

Simultaneous in vivo positron emission tomography and magnetic resonance imaging

Positron emission tomography (PET) and magnetic resonance imaging (MRI) are widely used in vivo imaging technologies with both clinical and biomedical research applications. The strengths of MRI include high-resolution, high-contrast morphologic imaging of soft tissues; the ability to image physiologic parameters such as diffusion and changes in oxygenation level resulting from neuronal stimulation; and the measurement of metabolites using chemical shift imaging. PET images the distribution of biologically targeted radiotracers with high sensitivity, but images generally lack anatomic context and are of lower spatial resolution. Integration of these technologies permits the acquisition of temporally correlated data showing the distribution of PET radiotracers and MRI contrast agents or MR-detectable metabolites, with registration to the underlying anatomy. An MRI-compatible PET scanner has been built for biomedical research applications that allows data from both modalities to be acquired simultaneously. Experiments demonstrate no effect of the MRI system on the spatial resolution of the PET system and <10% reduction in the fraction of radioactive decay events detected by the PET scanner inside the MRI. The signal-to-noise ratio and uniformity of the MR images, with the exception of one particular pulse sequence, were little affected by the presence of the PET scanner. In vivo simultaneous PET and MRI studies were performed in mice. Proof-of-principle in vivo MR spectroscopy and functional MRI experiments were also demonstrated with the combined scanner

Establishment of Clonal MIN-O Transplant Lines for Molecular Imaging via Lentiviral Transduction & In Vitro Culture

As the field of molecular imaging evolves and increasingly is asked to fill the discovery and validation space between basic science and clinical applications, careful consideration should be given to the models in which studies are conducted. The MIN-O mouse model series is an established in vivo model of human mammary precancer ductal carcinoma in situ with progression to invasive carcinoma. This series of transplant lines is propagated in vivo and experiments utilizing this model can be completed in non-engineered immune intact FVB/n wild type mice thereby modeling the tumor microenvironment with biological relevance superior to traditional tumor cell xenografts. Unfortunately, the same qualities that make this and many other transplant lines more biologically relevant than standard cell lines for molecular imaging studies present a significant obstacle as somatic genetic re-engineering modifications common to many imaging applications can be technically challenging. Here, we describe a protocol for the efficient lentiviral transduction of cell slurries derived from precancerous MIN-O lesions, in vitro culture of “MIN-O-spheres” derived from single cell clones, and the subsequent transplantation of these spheres to produce transduced sublines suitable for optical imaging applications. These lines retain the physiologic and pathologic properties, including multilineage differentiation, and complex microanatomic interaction with the host stroma characteristic of the MIN-O model. We also present the in vivo imaging and immunohistochemical analysis of serial transplantation of one such subline and detail the progressive multifocal loss of the transgene in successive generations

Cherenkov luminescence measurements with digital silicon photomultipliers: a feasibility study.

BackgroundA feasibility study was done to assess the capability of digital silicon photomultipliers to measure the Cherenkov luminescence emitted by a β source. Cherenkov luminescence imaging (CLI) is possible with a charge coupled device (CCD) based technology, but a stand-alone technique for quantitative activity measurements based on Cherenkov luminescence has not yet been developed. Silicon photomultipliers (SiPMs) are photon counting devices with a fast impulse response and can potentially be used to quantify β-emitting radiotracer distributions by CLI.MethodsIn this study, a Philips digital photon counting (PDPC) silicon photomultiplier detector was evaluated for measuring Cherenkov luminescence. The PDPC detector is a matrix of avalanche photodiodes, which were read one at a time in a dark count map (DCM) measurement mode (much like a CCD). This reduces the device active area but allows the information from a single avalanche photodiode to be preserved, which is not possible with analog SiPMs. An algorithm to reject the noisiest photodiodes and to correct the measured count rate for the dark current was developed.ResultsThe results show that, in DCM mode and at (10-13) °C, the PDPC has a dynamic response to different levels of Cherenkov luminescence emitted by a β source and transmitted through an opaque medium. This suggests the potential for this approach to provide quantitative activity measurements. Interestingly, the potential use of the PDPC in DCM mode for direct imaging of Cherenkov luminescence, as a opposed to a scalar measurement device, was also apparent.ConclusionsWe showed that a PDPC tile in DCM mode is able to detect and image a β source through its Cherenkov radiation emission. The detector's dynamic response to different levels of radiation suggests its potential quantitative capabilities, and the DCM mode allows imaging with a better spatial resolution than the conventional event-triggered mode. Finally, the same acquisition procedure and data processing could be employed also for other low light levels applications, such as bioluminescence

Effects of neonatal amygdala or hippocampus lesions on resting brain metabolism in the macaque monkey: A microPET imaging study

Longitudinal analysis of animals with neonatal brain lesions enables the evaluation of behavioral changes during multiple stages of development. Interpretation of such changes, however, carries the caveat that permanent neural injury also yields morphological and neurochemical reorganization elsewhere in the brain that may lead either to functional compensation or to exacerbation of behavioral alterations. We have measured the long-term effects of selective neonatal brain damage on resting cerebral glucose metabolism in nonhuman primates. Sixteen rhesus monkeys (Macaca mulatta) received neurotoxic lesions of either the amygdala (n = 8) or hippocampus (n = 8) when they were two weeks old. Four years later, these animals, along with age- and experience-matched sham-operated control animals (n = 8), were studied with high-resolution positron emission tomography (microPET) and 2-deoxy-2[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) to detect areas of altered metabolism. The groups were compared using an anatomically-based region of interest analysis. Relative to controls, amygdala-lesioned animals displayed hypometabolism in three frontal lobe regions, as well as in the neostriatum and hippocampus. Hypermetabolism was also evident in the cerebellum of amygdala-lesioned animals. Hippocampal-lesioned animals only showed hypometabolism in the retrosplenial cortex. These results indicate that neonatal amygdala and hippocampus lesions induce very different patterns of long-lasting metabolic changes in distant brain regions. These observations raise the possibility that behavioral alterations in animals with neonatal lesions may be due to the intended damage, to consequent brain reorganization or to a combination of both factors