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

Significant impact of different oxygen breathing conditions on noninvasive in vivo tumor-hypoxia imaging using [18F]-fluoro-azomycinarabino-furanoside ([18F]FAZA)

<p>Abstract</p> <p>Background</p> <p>[¹⁸F]FAZA is a PET biomarker with great potential for imaging tumor hypoxia. Aim of our study was to compare [¹⁸F]FAZA uptake in mice with subcutaneous exogenous CT26 colon carcinomas and endogenous polyoma middle-T (PyV-mT) mammary carcinomas and to analyze the influence of different breathing protocols in CT26 colon carcinomas as well as the reversibility or irreversibility of [¹⁸F]FAZA uptake.</p> <p>Methods</p> <p>We injected subcutaneous CT26 colon carcinoma or polyomavirus middle-T (PyV-mT) mammary carcinoma-bearing mice intravenously with¹⁸F-FAZA and performed PET scans 1-3 h post injection (<it>p.i.</it>). To analyze the impact of oxygen supply in CT26 carcinomas we used three different breathing protocols: (P0) air; (P1) 100% oxygen 1 h prior injection until 3 h <it>p.i.</it>; (P2) 100% oxygen breathing starting 2 min prior tracer injection until 1 h <it>p.i. </it>and during the PET scans; mice were breathing air between the 2 h and 3 h 10 min static scans. Normalized PET images were analyzed by using defined regions of interest. Finally, some mice were dissected for pimonidazole immunohistochemistry.</p> <p>Results</p> <p>There was no difference in¹⁸F-FAZA uptake 1-3 h <it>p.i. </it>between the two carcinoma types (CT26: 1.58 ± 0.45%ID/cc; PyV-mT: 1.47 ± 0.89%ID/cc, 1 h <it>p.i.</it>, tumor size < 0.5 cm³). We measured a significant tracer clearance, which was more pronounced in muscle tissue (P0). The [¹⁸F]FAZA tumor-to-muscle-ratios in CT26 colon carcinoma-bearing mice 2 h and 3 h, but not 1 h <it>p.i. </it>were significantly higher when the mice breathed air (P0: 3.56 ± 0.55, 3 h) compared to the oxygen breathing protocols (P1: 2.45 ± 0.58; P2: 2.77 ± 0.42, 3 h). Surprisingly, the breathing protocols P1 and P2 showed no significant differences in T/M ratios, thus indicating that the crucial [¹⁸F]FAZA uptake phase is during the first hour after [¹⁸F]FAZA injection. Importantly, the muscle clearance was not affected by the different oxygen breathing conditions while the tumor clearance was lower when mice were breathing air.</p> <p>Conclusion</p> <p>Exogenous CT26 colon carcinomas and endogenous polyoma middle-T (PyV-mT) mammary carcinomas showed no differences in [¹⁸F]FAZA uptake 1-3 h <it>p.i. </it>Our analysis using various breathing protocols with air (P0) and with pure oxygen (P1, P2) clearly indicate that [¹⁸F]FAZA is an appropriate PET biomarker for <it>in vivo </it>analysis of hypoxia revealing an enhanced tracer uptake in tumors with reduced oxygen supply. [¹⁸F]FAZA uptake was independent of tumor-type.</p

A robust coregistration method for in vivo studies using a first generation simultaneous PET/MR scanner

Purpose: Hybrid positron emission tomography (PET)/magnetic resonance (MR) imaging systems have recently been built that allow functional and anatomical information obtained from PET and MR to be acquired simultaneously. The authors have developed a robust coregistration scheme for a first generation small animal PET/MR imaging system and illustrated the potential of this system to study intratumoral heterogeneity in a mouse model. Methods: An alignment strategy to fuse simultaneously acquired PET and MR data, using the MR imaging gradient coordinate system as the reference basis, was developed. The fidelity of the alignment was evaluated over multiple study sessions. In order to explore its robustness in vivo, the alignment strategy was applied to explore the heterogeneity of glucose metabolism in a xenograft tumor model, using ^(18)F-FDG-PET to guide the acquisition of localized ^1H MR spectra within a single imaging session. Results: The alignment method consistently fused the PET/MR data sets with subvoxel accuracy (registration error mean=0.55 voxels, <0.28 mm); this was independent of location within the field of view. When the system was used to study intratumoral heterogeneity within xenograft tumors, a correlation of high ^(18)F-FDG-PET signal with high choline/creatine ratio was observed. Conclusions: The authors present an implementation of an efficient and robust coregistration scheme for multimodal noninvasive imaging using PET and MR. This setup allows time-sensitive, multimodal studies of physiology to be conducted in an efficient manner

A near-infrared probe for non-invasively monitoring cerebrospinal fluid flow by F-18-positron emitting tomography and fluorescence

PURPOSE:Knowing the precise flow of cerebrospinal fluid (CSF) is important in the management of multiple neurological diseases. Technology for non-invasively quantifying CSF flow would allow for precise localization of injury and assist in evaluating the viability of certain devices placed in the central nervous system (CNS). METHODS:We describe a near-infrared fluorescent dye for accurately monitoring CSF flow by positron emission tomography (PET) and fluorescence. IR-783, a commercially available near-infrared dye, was chemically&nbsp;modified and&nbsp;radiolabeled with fluorine-18 to give [18F]-IR783-AMBF3. [18F]-IR783-AMBF3 was intrathecally injected into the rat models with normal and aberrant CSF flow and evaluated by the fluorescence and PET/MRI or PET/CT imaging modes. RESULTS:IR783-AMBF3 was clearly distributed in CSF-containing volumes by PET and fluorescence. We compared IR783-AMBF3 (fluorescent at&nbsp;778/793 nm, ex/em) to a shorter-wavelength, fluorescein equivalent (fluorescent at&nbsp;495/511 nm, ex/em). IR783-AMBF3 was superior for its ability to image through blood (hemorrhage) and for imaging CSF-flow, through-skin, in subdural-run lumboperitoneal shunts. IR783-AMBF3 was safe under the tested dosage both in vitro and in vivo. CONCLUSION:The superior imaging properties of IR783-AMBF3 could lead to enhanced accuracy in the treatment of patients and would assist surgeons in non-invasively diagnosing diseases of the CNS

Feasibility Study of a Small Animal PET Insert Based on a Single LYSO Monolithic Tube

[EN] There are drawbacks with using a Positron Emission Tomography (PET) scanner design employing the traditional arrangement of multiple detectors in an array format. Typically PET systems are constructed with many regular gaps between the detector modules in a ring or box configuration, with additional axial gaps between the rings. Although this has been significantly reduced with the use of the compact high granularity SiPM photodetector technology, such a scanner design leads to a decrease in the number of annihilation photons that are detected causing lower scanner sensitivity. Moreover, the ability to precisely determine the line of response (LOR) along which the positron annihilated is diminished closer to the detector edges because the spatial resolution there is degraded due to edge effects. This happens for both monolithic based designs, caused by the truncation of the scintillation light distribution, but also for detector blocks that use crystal arrays with a number of elements that are larger than the number of photosensors and, therefore, make use of the light sharing principle. In this report we present a design for a small-animal PET scanner based on a single monolithic annulus-like scintillator that can be used as a PET insert in high-field Magnetic Resonance systems. We provide real data showing the performance improvement when edge-less modules are used. We also describe the specific proposed design for a rodent scanner that employs facetted outside faces in a single LYSO tube. In a further step, in order to support and prove the proposed edgeless geometry, simulations of that scanner have been performed and lately reconstructed showing the advantages of the design.This project was funded in part by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No 695536). It has also been supported by the Spanish Ministerio de Economia, Industria y Competitividad under Grant TEC2016-79884-C2-1-R and through PROSPET (DTS15/00152) funded by the Ministerio de Economia y Competitividad. AR is a postdoctoral fellow of the FWO (project 12T7118N). The University of Virginia School of Medicine has provided seed funding for this project.González Martínez, AJ.; Berr, SS.; Cañizares-Ledo, G.; Gonzalez-Montoro, A.; Orero Palomares, A.; Correcher Salvador, C.; Rezaei, A.... (2018). Feasibility Study of a Small Animal PET Insert Based on a Single LYSO Monolithic Tube. Frontiers in Medicine. 5:1-8. https://doi.org/10.3389/fmed.2018.00328S185Kuntner, C., & Stout, D. (2014). Quantitative preclinical PET imaging: opportunities and challenges. Frontiers in Physics, 2. doi:10.3389/fphy.2014.00012Judenhofer, M. S., & Cherry, S. R. (2013). Applications for Preclinical PET/MRI. Seminars in Nuclear Medicine, 43(1), 19-29. doi:10.1053/j.semnuclmed.2012.08.004España, S., Marcinkowski, R., Keereman, V., Vandenberghe, S., & Van Holen, R. (2014). DigiPET: sub-millimeter spatial resolution small-animal PET imaging using thin monolithic scintillators. Physics in Medicine and Biology, 59(13), 3405-3420. doi:10.1088/0031-9155/59/13/3405Yang, Y., Bec, J., Zhou, J., Zhang, M., Judenhofer, M. S., Bai, X., … Cherry, S. R. (2016). A Prototype High-Resolution Small-Animal PET Scanner Dedicated to Mouse Brain Imaging. Journal of Nuclear Medicine, 57(7), 1130-1135. doi:10.2967/jnumed.115.165886Yamamoto, S., Watabe, H., Kanai, Y., Watabe, T., Kato, K., & Hatazawa, J. (2013). Development of an ultrahigh resolution Si-PM based PET system for small animals. Physics in Medicine and Biology, 58(21), 7875-7888. doi:10.1088/0031-9155/58/21/7875Yang, Y., James, S. S., Wu, Y., Du, H., Qi, J., Farrell, R., … Cherry, S. R. (2010). Tapered LSO arrays for small animal PET. Physics in Medicine and Biology, 56(1), 139-153. doi:10.1088/0031-9155/56/1/009Godinez, F., Gong, K., Zhou, J., Judenhofer, M. S., Chaudhari, A. J., & Badawi, R. D. (2018). Development of an Ultra High Resolution PET Scanner for Imaging Rodent Paws: PawPET. IEEE Transactions on Radiation and Plasma Medical Sciences, 2(1), 7-16. doi:10.1109/trpms.2017.2765486Gonzalez, A. J., Aguilar, A., Conde, P., Hernandez, L., Moliner, L., Vidal, L. F., … Benlloch, J. M. (2016). A PET Design Based on SiPM and Monolithic LYSO Crystals: Performance Evaluation. IEEE Transactions on Nuclear Science, 63(5), 2471-2477. doi:10.1109/tns.2016.2522179Moses, W. W. (2011). Fundamental limits of spatial resolution in PET. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 648, S236-S240. doi:10.1016/j.nima.2010.11.092Jones, T., & Townsend, D. (2017). History and future technical innovation in positron emission tomography. Journal of Medical Imaging, 4(1), 011013. doi:10.1117/1.jmi.4.1.011013Lewellen, T. K. (2008). Recent developments in PET detector technology. Physics in Medicine and Biology, 53(17), R287-R317. doi:10.1088/0031-9155/53/17/r01Lee, J. S. (2010). Technical Advances in Current PET and Hybrid Imaging Systems. The Open Nuclear Medicine Journal, 2(1), 192-208. doi:10.2174/1876388x01002010192Ren, S., Yang, Y., & Cherry, S. R. (2014). Effects of reflector and crystal surface on the performance of a depth-encoding PET detector with dual-ended readout. Medical Physics, 41(7), 072503. doi:10.1118/1.4881097Benlloch, J. M., González, A. J., Pani, R., Preziosi, E., Jackson, C., Murphy, J., … Schwaiger, M. (2018). The MINDVIEW project: First results. European Psychiatry, 50, 21-27. doi:10.1016/j.eurpsy.2018.01.002Gonzalez-Montoro, A., Benlloch, J. M., Gonzalez, A. J., Aguilar, A., Canizares, G., Conde, P., … Sanchez, F. (2017). Performance Study of a Large Monolithic LYSO PET Detector With Accurate Photon DOI Using Retroreflector Layers. IEEE Transactions on Radiation and Plasma Medical Sciences, 1(3), 229-237. doi:10.1109/trpms.2017.2692819Moliner, L., González, A. J., Soriano, A., Sánchez, F., Correcher, C., Orero, A., … Benlloch, J. M. (2012). Design and evaluation of the MAMMI dedicated breast PET. Medical Physics, 39(9), 5393-5404. doi:10.1118/1.4742850Morrocchi, M., Ambrosi, G., Bisogni, M. G., Bosi, F., Boretto, M., Cerello, P., … Del Guerra, A. (2017). Depth of interaction determination in monolithic scintillator with double side SiPM readout. EJNMMI Physics, 4(1). doi:10.1186/s40658-017-0180-9Xie, S., Zhao, Z., Yang, M., Weng, F., Huang, Q., Xu, J., & Peng, Q. (2017). LOR-PET: a novel PET camera constructed with a monolithic scintillator ring. 2017 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC). doi:10.1109/nssmic.2017.8532627Stolin, A. V., Martone, P. F., Jaliparthi, G., & Raylman, R. R. (2017). Preclinical positron emission tomography scanner based on a monolithic annulus of scintillator: initial design study. Journal of Medical Imaging, 4(1), 011007. doi:10.1117/1.jmi.4.1.011007Gonzalez, A. J., Aguilar, A., Conde, P., Gonzalez-Montoro, A., Sanchez, S., Moliner, L., … Benlloch, J. M. (2016). Pilot tests of a PET insert based on monolithic crystals in a 7T MR. 2016 IEEE Nuclear Science Symposium, Medical Imaging Conference and Room-Temperature Semiconductor Detector Workshop (NSS/MIC/RTSD). doi:10.1109/nssmic.2016.8069496Jan, S., Santin, G., Strul, D., Staelens, S., Assié, K., Autret, D., … Bloomfield, P. M. (2004). GATE: a simulation toolkit for PET and SPECT. Physics in Medicine and Biology, 49(19), 4543-4561. doi:10.1088/0031-9155/49/19/007Strulab, D., Santin, G., Lazaro, D., Breton, V., & Morel, C. (2003). GATE (geant4 application for tomographic emission): a PET/SPECT general-purpose simulation platform. Nuclear Physics B - Proceedings Supplements, 125, 75-79. doi:10.1016/s0920-5632(03)90969-8Pani, R., Gonzalez, A. J., Bettiol, M., Fabbri, A., Cinti, M. N., Preziosi, E., … Majewski, S. (2015). Preliminary evaluation of a monolithic detector module for integrated PET/MRI scanner with high spatial resolution. Journal of Instrumentation, 10(06), C06006-C06006. doi:10.1088/1748-0221/10/06/c06006Iida, H., Kanno, I., Miura, S., Murakami, M., Takahashi, K., & Uemura, K. (1986). A Simulation Study of a Method to Reduce Positron Annihilation Spread Distributions Using a Strong Magnetic Field in Positron Emission Tomography. IEEE Transactions on Nuclear Science, 33(1), 597-600. doi:10.1109/tns.1986.433717

Monolithic crystals for PET devices: optical coupling optimization

NOTICE: this is the author’s version of a work that was accepted for publication in Nuclear Instruments and Methods in Physics Research Section A. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Nuclear Instruments and Methods in Physics Research Section A [Volume 731, 11 December 2013, Pages 288–294] DOI 10.1016/j.nima.2013.05.049[EN] In this work we present a method to efficiently collect scintillation light when using monolithic scintillator crystals. The acceptance angle of the scintillation light has been reduced by means of optical devices reducing the border effect which typically affects continuous crystals. We have applied this procedure on gamma detectors for PET systems using both position sensitive PMTs and arrays of SiPMs. In the case of using SiPMs, this approach also helps to reduce the photosensor active area. We evaluated the method using PMTs with a variety of different crystals with thicknesses ranging from 10 to 24 mm. We found that our design allows the use of crystal blocks with a thickness of up to 18 mm without degrading the spatial resolution caused by edge effects and without a significant detriment to the energy resolution. These results were compared with simulated data. The first results of monolithic LYSO crystals coupled to an array of 256 SiPMs by means of individual optical light guides are also presented.This work was supported by the Centre for Industrial Technological Development co-funded by FEDER through the Technology Fund (DREAM Project, IDI-20110718), the Spanish Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D +I) under Grant no. FIS2010-21216-CO2-01 and the Valencian Local Government under Grant PROMETEO 2008/114.González Martínez, AJ.; Peiró, A.; Conde, P.; Hernández Hernández, L.; Moliner Martínez, L.; Orero Palomares, A.; Rodríguez-Álvarez, M.... (2013). Monolithic crystals for PET devices: optical coupling optimization. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. 731:288-294. https://doi.org/10.1016/j.nima.2013.05.049S28829473

Magnetic/Silica Nanocomposites as Dual-Mode Contrast Agents for Combined Magnetic Resonance Imaging and Ultrasonography.

A simple and effi cient method for synthesizing a range of hybrid nanocomposites based on a core of silica nanospheres (160, 330, and 660 nm in diameter) covered by an outer shell of superparamagnetic nanoparticles, either iron oxide or heterodimeric FePt-iron oxide nanocrystals, is presented. The magnetic and ultrasound characterization of the resulting nanocomposites shows that they have great potential as contrast agents for dual-mode imaging purposes, combining magnetic resonance imaging (MRI) and ultrasonography (US)

Design of the PET–MR system for head imaging of the DREAM Project

NOTICE: this is the author’s version of a work that was accepted for publication in Nuclear Instruments and Methods in Physics Research Section A. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Nuclear Instruments and Methods in Physics Research Section A, Volume 702, 21 February 2013, Pages 94–97 DOI 10.1016/j.nima.2012.08.028In this paper we describe the overall design of a PET–MR system for head imaging within the framework of the DREAM Project as well as the first detector module tests. The PET system design consists of 4 rings of 16 detector modules each and it is expected to be integrated in a head dedicated radio frequency coil of an MR scanner. The PET modules are based on monolithic LYSO crystals coupled by means of optical devices to an array of 256 Silicon Photomultipliers. These types of crystals allow to preserve the scintillation light distribution and, thus, to recover the exact photon impact position with the proper characterization of such a distribution. Every module contains 4 Application Specific Integrated Circuits (ASICs) which return detailed information of several light statistical momenta. The preliminary tests carried out on this design and controlled by means of ASICs have shown promising results towards the suitability of hybrid PET–MR systems.This work was supported by the Centre for Industrial Technological Development co-funded by FEDER through the Technology Fund (DREAM Project, IDI-20110718), the Spanish Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica (I + D + I) under Grant no. FIS2010-21216-CO2-01 and the Valencian Local Government under Grant PROMETEO 2008/114.González Martínez, AJ.; Conde, P.; Hernández Hernández, L.; Herrero Bosch, V.; Moliner Martínez, L.; Monzó Ferrer, JM.; Orero Palomares, A.... (2013). Design of the PET–MR system for head imaging of the DREAM Project. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. 702:94-97. https://doi.org/10.1016/j.nima.2012.08.028S949770

A 3D MR-acquisition scheme for nonrigid bulk motion correction in simultaneous PET-MR.

PURPOSE: Positron emission tomography (PET) is a highly sensitive medical imaging technique commonly used to detect and assess tumor lesions. Magnetic resonance imaging (MRI) provides high resolution anatomical images with different contrasts and a range of additional information important for cancer diagnosis. Recently, simultaneous PET-MR systems have been released with the promise to provide complementary information from both modalities in a single examination. Due to long scan times, subject nonrigid bulk motion, i.e., changes of the patient's position on the scanner table leading to nonrigid changes of the patient's anatomy, during data acquisition can negatively impair image quality and tracer uptake quantification. A 3D MR-acquisition scheme is proposed to detect and correct for nonrigid bulk motion in simultaneously acquired PET-MR data. METHODS: A respiratory navigated three dimensional (3D) MR-acquisition with Radial Phase Encoding (RPE) is used to obtain T1- and T2-weighted data with an isotropic resolution of 1.5 mm. Healthy volunteers are asked to move the abdomen two to three times during data acquisition resulting in overall 19 movements at arbitrary time points. The acquisition scheme is used to retrospectively reconstruct dynamic 3D MR images with different temporal resolutions. Nonrigid bulk motion is detected and corrected in this image data. A simultaneous PET acquisition is simulated and the effect of motion correction is assessed on image quality and standardized uptake values (SUV) for lesions with different diameters. RESULTS: Six respiratory gated 3D data sets with T1- and T2-weighted contrast have been obtained in healthy volunteers. All bulk motion shifts have successfully been detected and motion fields describing the transformation between the different motion states could be obtained with an accuracy of 1.71 ± 0.29 mm. The PET simulation showed errors of up to 67% in measured SUV due to bulk motion which could be reduced to less than 10% with the proposed motion compensation approach. CONCLUSIONS: A MR acquisition scheme which yields both high resolution 3D anatomical data and highly accurate nonrigid motion information without an increase in scan time is presented. The proposed method leads to a strong improvement in both MR and PET image quality and ensures an accurate assessment of tracer uptake