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

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)

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

Preliminary evidence of increased striatal dopamine in a nonhuman primate model of maternal immune activation.

Women exposed to a variety of viral and bacterial infections during pregnancy have an increased risk of giving birth to a child with autism, schizophrenia or other neurodevelopmental disorders. Preclinical maternal immune activation (MIA) models are powerful translational tools to investigate mechanisms underlying epidemiological links between infection during pregnancy and offspring neurodevelopmental disorders. Our previous studies documenting the emergence of aberrant behavior in rhesus monkey offspring born to MIA-treated dams extends the rodent MIA model into a species more closely related to humans. Here we present novel neuroimaging data from these animals to further explore the translational potential of the nonhuman primate MIA model. Nine male MIA-treated offspring and 4 controls from our original cohort underwent in vivo positron emission tomography (PET) scanning at approximately 3.5-years of age using [18F] fluoro-l-m-tyrosine (FMT) to measure presynaptic dopamine levels in the striatum, which are consistently elevated in individuals with schizophrenia. Analysis of [18F]FMT signal in the striatum of these nonhuman primates showed that MIA animals had significantly higher [18F]FMT index of influx compared to control animals. In spite of the modest sample size, this group difference reflects a large effect size (Cohen's d = 0.998). Nonhuman primates born to MIA-treated dams exhibited increased striatal dopamine in late adolescence-a hallmark molecular biomarker of schizophrenia. These results validate the MIA model in a species more closely related to humans and open up new avenues for understanding the neurodevelopmental biology of schizophrenia and other neurodevelopmental disorders associated with prenatal immune challenge

Quantitative, Simultaneous PET/MRI for Intratumoral Imaging with an MRI-Compatible PET Scanner

Noninvasive methods are needed to explore the heterogeneous tumor microenvironment and its modulation by therapy. Hybrid PET/MRI systems are being developed for small-animal and clinical use. The advantage of these integrated systems depends on their ability to provide MR images that are spatially coincident with simultaneously acquired PET images, allowing combined functional MRI and PET studies of intratissue heterogeneity. Although much effort has been devoted to developing this new technology, the issue of quantitative and spatial fidelity of PET images from hybrid PET/MRI systems to the tissues imaged has received little attention. Here, we evaluated the ability of a first-generation, small-animal MRI-compatible PET scanner to accurately depict heterogeneous patterns of radiotracer uptake in tumors. Methods: Quantitative imaging characteristics of the MRI-compatible PET (PET/MRI) scanner were evaluated with phantoms using calibration coefficients derived from a mouse-sized linearity phantom. PET performance was compared with a commercial small-animal PET system and autoradiography in tumor-bearing mice. Pixel and structure-based similarity metrics were used to evaluate image concordance among modalities. Feasibility of simultaneous PET/MRI functional imaging of tumors was explored by following ^(64)Cu-labeled antibody uptake in relation to diffusion MRI using cooccurrence matrix analysis. Results: The PET/MRI scanner showed stable and linear response. Activity concentration recovery values (measured and true activity concentration) calculated for 4-mm-diameter rods within linearity and uniform activity rod phantoms were near unity (0.97 ± 0.06 and 1.03 ± 0.03, respectively). Intratumoral uptake patterns for both ^(18)F-FDG and a ^(64)Cu-antibody acquired using the PET/MRI scanner and small-animal PET were highly correlated with autoradiography (r > 0.99) and with each other (r = 0.97 ± 0.01). On the basis of these data, we performed a preliminary study comparing diffusion MRI and radiolabeled antibody uptake patterns over time and visualized movement of antibodies from the vascular space into the tumor mass. Conclusion: The MRI-compatible PET scanner provided tumor images that were quantitatively accurate and spatially concordant with autoradiography and the small-animal PET examination. Cooccurrence matrix approaches enabled effective analysis of multimodal image sets. These observations confirm the ability of the current simultaneous PET/MRI system to provide accurate observations of intratumoral function and serve as a benchmark for future evaluations of hybrid instrumentation