A CNN-based four-layer DOI encoding detector using LYSO and BGO scintillators for small animal PET imaging.

Objective. We propose a novel four-layer depth-of-interaction (DOI) encoding phoswich detector using lutetium-yttrium oxyothosilicate (LYSO) and bismuth germanate (BGO) scintillator crystal arrays for high sensitivity and high spatial resolution small animal PET imaging.Approach. The detector was comprised of a stack of four alternating LYSO and BGO scintillator crystal arrays coupled to an 8 × 8 multi-pixel photon counter (MPPC) array and read out by a PETsys TOFPET2 application specific integrated circuit. The four layers from the top (gamma ray entrance) to the bottom (facing the MPPC) consisted of a 24 × 24 array of 0.99 × 0.99 × 6 mm3LYSO crystals, a 24 × 24 array of 0.99 × 0.99 × 6 mm3BGO crystals, a 16 × 16 array of 1.53 × 1.53 × 6 mm3LYSO crystals and a 16 × 16 array of 1.53 × 1.53 × 6 mm3BGO crystals.Main results. Events that occurred in the LYSO and BGO layers were first separated by measuring the pulse energy (integrated charge) and duration (time over threshold (ToT)) from the scintillation pulses. Convolutional neural networks (CNNs) were then used to distinguish between the top and lower LYSO layers and between the upper and bottom BGO layers. Measurements with the prototype detector showed that our proposed method successfully identified events from all four layers. The CNN models achieved a classification accuracy of 91% for distinguishing the two LYSO layers and 81% for distinguishing the two BGO layers. The measured average energy resolution was 13.1% ± 1.7% for the top LYSO layer, 34.0% ± 6.3% for the upper BGO layer, 12.3% ± 1.3% for the lower LYSO layer, and 33.9% ± 6.9% for the bottom BGO layer. The timing resolution between each individual layer (from the top to the bottom) and a single crystal reference detector was 350 ps, 2.8 ns, 328 ps, and 2.1 ns respectively.Significance. In conclusion, the proposed four-layer DOI encoding detector achieved high performance and is an attractive choice for next-generation high sensitivity and high spatial resolution small animal positron emission tomography systems.

Cerenkov Luminescence Imaging in the Development and Production of Radiopharmaceuticals.

Over the past several years there has been an explosion of interest in exploiting Cerenkov radiation to enable in vivo and intraoperative optical imaging of subjects injected with trace amounts of radiopharmaceuticals. At the same time, Cerenkov luminescence imaging (CLI) also has been serving as a critical tool in radiochemistry, especially for the development of novel microfluidic devices for producing radiopharmaceuticals. By enabling microfluidic processes to be monitored non-destructively in situ, CLI has made it possible to literally watch the activity distribution as the synthesis occurs, and to quantitatively measure activity propagation and losses at each step of synthesis, paving the way for significant strides forward in performance and robustness of those devices. In some cases, CLI has enabled detection and resolution of unexpected problems not observable via standard optical methods. CLI is also being used in analytical radiochemistry to increase the reliability of radio-thin layer chromatography (radio-TLC) assays. Rapid and high-resolution Cerenkov imaging of radio-TLC plates enables detection of issues in the spotting or separation process, improves chromatographic resolution (and/or allows reduced separation distance and time), and enables increased throughput by allowing multiple samples to be spotted side-by-side on a single TLC plate for parallel separation and readout. In combination with new multi-reaction microfluidic chips, this is creating a new possibility for high-throughput optimization in radiochemistry. In this mini review, we provide an overview of the role that CLI has played to date in the radiochemistry side of radiopharmaceuticals.

A digital phoswich detector using time-over-threshold for depth of interaction in PET.

We present the performance of a digital phoswich positron emission tomography (PET) detector, composed by layers of pixilated scintillator arrays, read out by solid state light detectors and an application specific integrated circuit (ASIC). We investigated the use of integrated charge from the scintillation pulses along with time-over-threshold (ToT) to determine the layer of interaction (DOI) in the scintillator. Simulations were performed to assess the effectiveness of the ToT measurements for separating the scintillator events and identifying cross-layer-crystal-scatter (CLCS) events. These simulations indicate that ToT and charge integration from such a detector provide sufficient information to determine the layer of interaction. To demonstrate this in practice, we used a pair of prototype LYSO/BGO detectors. One detector consisted of a 19 × 19 array of 7 mm long LYSO crystals (1.36 mm pitch) coupled to a 16 × 16 array of 8 mm long BGO crystals (1.63 mm pitch). The other detector was similar except the LYSO crystal pitch was 1.63 mm. These detectors were coupled to an 8 × 8 multi-pixel photon counter mounted on a PETsys TOFPET2 ASIC. This high performance ASIC provided digital readout of the integrated charge and ToT from these detectors. We present a method to separate the events from the two scintillator layers using the ToT, and also investigate the performance of this detector. All the crystals within the proposed detector were clearly resolved, and the peak to valley ratio was 11.8 ± 4.0 and 10.1 ± 2.9 for the LYSO and BGO flood images. The measured energy resolution was 9.9% ± 1.3% and 28.5% ± 5.0% respectively for the LYSO and BGO crystals in the phoswich layers. The timing resolution between the LYSO-LYSO, LYSO-BGO and BGO-BGO coincidences was 468 ps, 1.33 ns and 2.14 ns respectively. Results show ToT can be used to identify the crystal layer where events occurred and also identify and reject the majority of CLCS events between layers.

Integration of High-Resolution Radiation Detector for Hybrid Microchip Electrophoresis.

For decades, there has been immense progress in miniaturizing analytical methods based on electrophoresis to improve sensitivity and to reduce sample volumes, separation times, and/or equipment cost and space requirements, in applications ranging from analysis of biological samples to environmental analysis to forensics. In the field of radiochemistry, where radiation-shielded laboratory space is limited, there has been great interest in harnessing the compactness, high efficiency, and speed of microfluidics to synthesize short-lived radiolabeled compounds. We recently proposed that analysis of these compounds could also benefit from miniaturization and have been investigating capillary electrophoresis (CE) and hybrid microchip electrophoresis (hybrid-MCE) as alternatives to the typically used high-performance liquid chromatography (HPLC). We previously showed separation of the positron-emission tomography (PET) imaging tracer 3'-deoxy-3'-fluorothymidine (FLT) from its impurities in a hybrid-MCE device with UV detection, with similar separation performance to HPLC, but with improved speed and lower sample volumes. In this paper, we have developed an integrated radiation detector to enable measurement of the emitted radiation from radiolabeled compounds. Though conventional radiation detectors have been incorporated into CE systems in the past, these approaches cannot be readily integrated into a compact hybrid-MCE device. We instead employed a solid-state avalanche photodiode (APD)-based detector for real-time, high-sensitivity ß particle detection. The integrated system can reliably separate [18F]FLT from its impurities and perform chemical identification via coinjection with nonradioactive reference standard. This system can quantitate samples with radioactivity concentrations as low as 114 MBq/mL (3.1 mCi/mL), which is sufficient for analysis of radiochemical purity of radiopharmaceuticals.

Performance evaluation of HiPET, a high sensitivity and high resolution preclinical PET tomograph.

HiPET is a recently developed prototype preclinical PET scanner dedicated to high sensitivity and high resolution molecular imaging. The HiPET system employs a phoswich depth of interaction (DOI) detector design, which also allows identification of the large majority of the cross layer crystal scatter (CLCS) events. This work evaluates its performance characteristics following the National Electrical Manufacturers Association (NEMA) NU4-2008 protocol. The HiPET consists of twenty flat panel type detectors arranged in two rings. The inner diameter is 160 mm and the axial field of view (FOV) is 104 mm. Each detector is comprised of two layers of phoswich scintillator crystal arrays, a tapered, pixelated glass lightguide and a multi anode photomultiplier tube (MAPMT). The front (gamma ray entrance) layer is a 48 × 48 pixelated cerium doped lutetium yttrium orthosilicate (LYSO) scintillator array with individual crystals measuring 1.01 × 1.01 × 6.1 mm. The back (towards the PMT) layer is a 32 × 32 pixelated bismuth germanate (BGO) scintillator array with individual crystals measuring 1.55 × 1.55 × 8.9 mm. For energy windows of 250-650 keV and 350-650 keV, the peak absolute sensitivity at the center of the FOV was 13.5% and 10.4% including CLCS events, and 11.8% and 8.9% excluding CLCS events, respectively. The average detector energy resolution derived by averaging the individual crystal spectra was 11.7% ± 1.4% for LYSO and 17.0% ± 1.4% for BGO. The 3D ordered-subsets expectation maximization (OSEM) reconstructed image of a point source in air, ranged from 0.73 mm to 1.19 mm, with an average value of 0.93 ± 0.09 mm at all measured locations. The peak noise equivalent count rate (NECR) and scatter fraction were 179 kcps at 12.4 MBq and 6.9% for the mouse-sized phantom, and 63 kcps at 11.3 MBq and 18.3% for the rat-sized phantom. For the NEMA image quality phantom, the uniformity was 5.8%, and the spillover ratios measured in the water- and air-filled cold region chambers were 0.047 and 0.044, respectively. The recovery coefficients (RC) ranged from 0.31 to 0.92. These results and in vivo evaluation demonstrate that the HiPET can achieve high quality molecular imaging for biomedical applications.

High-throughput radio-TLC analysis.

INTRODUCTION: Radio thin layer chromatography (radio-TLC) is commonly used to analyze purity of radiopharmaceuticals or to determine the reaction conversion when optimizing radiosynthesis processes. In applications where there are few radioactive species, radio-TLC is preferred over radio-high-performance liquid chromatography due to its simplicity and relatively quick analysis time. However, with current radio-TLC methods, it remains cumbersome to analyze a large number of samples during reaction optimization. In a couple of studies, Cerenkov luminescence imaging (CLI) has been used for reading radio-TLC plates spotted with a variety of isotopes. We show that this approach can be extended to develop a high-throughput approach for radio-TLC analysis of many samples. METHODS: The high-throughput radio-TLC analysis was carried out by performing parallel development of multiple radioactive samples spotted on a single TLC plate, followed by simultaneous readout of the separated samples using Cerenkov imaging. Using custom-written MATLAB software, images were processed and regions of interest (ROIs) were drawn to enclose the radioactive regions/spots. For each sample, the proportion of integrated signal in each ROI was computed. Various crude samples of [18F]fallypride, [18F]FET and [177Lu]Lu-PSMA-617 were prepared for demonstration of this new method. RESULTS: Benefiting from a parallel developing process and high resolution of CLI-based readout, total analysis time for eight [18F]fallypride samples was 7.5 min (2.5 min for parallel developing, 5 min for parallel readout), which was significantly shorter than the 48 min needed using conventional approaches (24 min for sequential developing, 24 min for sequential readout on a radio-TLC scanner). The greater separation resolution of CLI enabled the discovery of a low-abundance side product from a crude [18F]FET sample that was not discernable using the radio-TLC scanner. Using the CLI-based readout method, we also observed that high labeling efficiency (99%) of [177Lu]Lu-PSMA-617 can be achieved in just 10 min, rather than the typical 30 min timeframe used. CONCLUSIONS: Cerenkov imaging in combination with parallel developing of multiple samples on a single TLC plate proved to be a practical method for rapid, high-throughput radio-TLC analysis.

Prediction of major torso organs in low-contrast micro-CT images of mice using a two-stage deeply supervised fully convolutional network.

Delineation of major torso organs is a key step of mouse micro-CT image analysis. This task is challenging due to low soft tissue contrast and high image noise, therefore anatomical prior knowledge is needed for accurate prediction of organ regions. In this work, we develop a deeply supervised fully convolutional network which uses the organ anatomy prior learned from independently acquired contrast-enhanced micro-CT images to assist the segmentation of non-enhanced images. The network is designed with a two-stage workflow which firstly predicts the rough regions of multiple organs and then refines the accuracy of each organ in local regions. The network is trained and evaluated with 40 mouse micro-CT images. The volumetric prediction accuracy (Dice score) varies from 0.57 for the spleen to 0.95 for the heart. Compared to a conventional atlas registration method, our method dramatically improves the Dice of the abdominal organs by 18%-26%. Moreover, the incorporation of anatomical prior leads to more accurate results for small-sized low-contrast organs (e.g. the spleen and kidneys). We also find that the localized stage of the network has better accuracy than the global stage, indicating that localized single organ prediction is more accurate than global multiple organ prediction. With this work, the accuracy and efficiency of mouse micro-CT image analysis are greatly improved and the need for using contrast agent and high x-ray dose is potentially reduced.

Performance Evaluation of G8, a High-Sensitivity Benchtop Preclinical PET/CT Tomograph.

G8 is a benchtop integrated PET/CT scanner dedicated to high-sensitivity and high-resolution imaging of mice. This work characterizes its National Electrical Manufacturers Association NU 4-2008 performance where applicable and also assesses the basic imaging performance of the CT subsystem. Methods: The PET subsystem in G8 consists of 4 flat-panel detectors arranged in a boxlike geometry. Each panel consists of 2 modules of a 26 × 26 pixelated bismuth germanate scintillator array with individual crystals measuring 1.75 × 1.75 × 7.2 mm. The crystal arrays are coupled to multichannel photomultiplier tubes via a tapered, pixelated glass lightguide. A cone-beam CT scanner consisting of a MicroFocus x-ray source and a complementary metal oxide semiconductor detector provides anatomic information. Sensitivity, spatial resolution, energy resolution, scatter fraction, count-rate performance, and the capability of performing phantom and mouse imaging were evaluated for the PET subsystem. Noise, dose level, contrast, and resolution were evaluated for the CT subsystem. Results: With an energy window of 350-650 keV, the peak sensitivity was 9.0% near the center of the field of view. The crystal energy resolution ranged from 15.0% to 69.6% in full width at half maximum (FWHM), with a mean of 19.3% ± 3.7%. The average intrinsic spatial resolution was 1.30 and 1.38 mm FWHM in the transverse and axial directions, respectively. The maximum-likelihood expectation maximization reconstructed image of a point source in air averaged 0.81 ± 0.11 mm FWHM. The peak noise-equivalent count rate for the mouse-sized phantom was 44 kcps for a total activity of 2.9 MBq (78 µCi), and the scatter fraction was 11%. For the CT subsystem, the value of the modulation transfer function at 10% was 2.05 cycles/mm. Conclusion: The overall performance demonstrates that the G8 can produce high-quality images for molecular imaging-based biomedical research.

Immuno-PET in Inflammatory Bowel Disease: Imaging CD4-Positive T Cells in a Murine Model of Colitis.

Inflammatory bowel diseases (IBDs) in humans are characterized in part by aberrant CD4-positive (CD4+) T-cell responses. Currently, identification of foci of inflammation within the gut requires invasive procedures such as colonoscopy and biopsy. Molecular imaging with antibody fragment probes could be used to noninvasively monitor cell subsets causing intestinal inflammation. Here, GK1.5 cys-diabody (cDb), an antimouse CD4 antibody fragment derived from the GK1.5 hybridoma, was used as a PET probe for CD4+ T cells in the dextran sulfate sodium (DSS) mouse model of IBD. Methods: The DSS mouse model of IBD was validated by assessing changes in CD4+ T cells in the spleen and mesenteric lymph nodes (MLNs) using flow cytometry. Furthermore, CD4+ T cell infiltration in the colons of colitic mice was evaluated using immunohistochemistry. 89Zr-labeled GK1.5 cDb was used to image distribution of CD4+ T cells in the abdominal region and lymphoid organs of mice with DSS-induced colitis. Region-of-interest analysis was performed on specific regions of the gut to quantify probe uptake. Colons, ceca, and MLNs were removed and imaged ex vivo by PET. Imaging results were confirmed by ex vivo biodistribution analysis. Results: An increased number of CD4+ T cells in the colons of colitic mice was confirmed by anti-CD4 immunohistochemistry. Increased uptake of 89Zr-maleimide-deferoxamine (malDFO)-GK1.5 cDb in the distal colon of colitic mice was visible in vivo in PET scans, and region-of-interest analysis of the distal colon confirmed increased activity in DSS mice. MLNs from colitic mice were enlarged and visible in PET images. Ex vivo scans and biodistribution confirmed higher uptake in DSS-treated colons (DSS, 1.8 ± 0.40; control, 0.45 ± 0.12 percentage injected dose [%ID] per organ, respectively), ceca (DSS, 1.1 ± 0.38; control, 0.35 ± 0.09 %ID per organ), and MLNs (DSS, 1.1 ± 0.58; control, 0.37 ± 0.25 %ID per organ). Conclusion:89Zr-malDFO-GK1.5 cDb detected CD4+ T cells in the colons, ceca, and MLNs of colitic mice and may prove useful for further investigations of CD4+ T cells in preclinical models of IBD, with potential to guide development of antibody-based imaging in human IBD.

ARAS: an automated radioactivity aliquoting system for dispensing solutions containing positron-emitting radioisotopes.

BACKGROUND: Automated protocols for measuring and dispensing solutions containing radioisotopes are essential not only for providing a safe environment for radiation workers but also to ensure accuracy of dispensed radioactivity and an efficient workflow. For this purpose, we have designed ARAS, an automated radioactivity aliquoting system for dispensing solutions containing positron-emitting radioisotopes with particular focus on fluorine-18 ((18)F). METHODS: The key to the system is the combination of a radiation detector measuring radioactivity concentration, in line with a peristaltic pump dispensing known volumes. RESULTS: The combined system demonstrates volume variation to be within 5 % for dispensing volumes of 20 µL or greater. When considering volumes of 20 µL or greater, the delivered radioactivity is in agreement with the requested amount as measured independently with a dose calibrator to within 2 % on average. CONCLUSIONS: The integration of the detector and pump in an in-line system leads to a flexible and compact approach that can accurately dispense solutions containing radioactivity concentrations ranging from the high values typical of [(18)F]fluoride directly produced from a cyclotron (~0.1-1 mCi µL(-1)) to the low values typical of batches of [(18)F]fluoride-labeled radiotracers intended for preclinical mouse scans (~1-10 µCi µL(-1)).

A deformable atlas of the laboratory mouse.

PURPOSE: This paper presents a deformable mouse atlas of the laboratory mouse anatomy. This atlas is fully articulated and can be positioned into arbitrary body poses. The atlas can also adapt body weight by changing body length and fat amount. PROCEDURES: A training set of 103 micro-CT images was used to construct the atlas. A cage-based deformation method was applied to realize the articulated pose change. The weight-related body deformation was learned from the training set using a linear regression method. A conditional Gaussian model and thin-plate spline mapping were used to deform the internal organs following the changes of pose and weight. RESULTS: The atlas was deformed into different body poses and weights, and the deformation results were more realistic compared to the results achieved with other mouse atlases. The organ weights of this atlas matched well with the measurements of real mouse organ weights. This atlas can also be converted into voxelized images with labeled organs, pseudo CT images and tetrahedral mesh for phantom studies. CONCLUSIONS: With the unique ability of articulated pose and weight changes, the deformable laboratory mouse atlas can become a valuable tool for preclinical image analysis.

Quantitative assessments of glycolysis from single cells.

The most common positron emission tomography (PET) radio-labeled probe for molecular diagnostics in patient care and research is the glucose analog, 2-deoxy-2-[F-18]fluoro-D-glucose (18F-FDG). We report on an integrated microfluidics-chip/beta particle imaging system for in vitro18F-FDG radioassays of glycolysis with single cell resolution. We investigated the kinetic responses of single glioblastoma cancer cells to targeted inhibitors of receptor tyrosine kinase signaling. Further, we find a weak positive correlation between cell size and rate of glycolysis.

The hidden cost of housing practices: using noninvasive imaging to quantify the metabolic demands of chronic cold stress of laboratory mice.

Laboratory mice routinely are housed at 20 to 22 °C-well below the murine thermoneutral zone of 29 to 34 °C. Chronic cold stress requires greater energy expenditure to maintain core body temperature and can lead to the failure of mouse models to emulate human physiology. We hypothesized that mice housed at ambient temperatures of 20 to 22 °C are chronically cold-stressed, have greater energy expenditure, and have high glucose utilization in brown adipose tissue. To test our hypotheses, we used indirect calorimetry to measure energy expenditure and substrate utilization in C57BL/6J and Crl:NU-Foxn1(nu) nude mice at routine vivarium (21 °C), intermediate (26 °C), and heated (31 °C) housing temperatures. We also examined the activation of interscapular brown adipose tissue, the primary site of nonshivering thermogenesis, via thermography and glucose uptake in this region by using positron emission tomography. Energy expenditure of mice was significantly higher at routine vivarium temperatures compared with intermediate and heated temperatures and was associated with a shift in metabolism toward glucose utilization. Brown adipose tissue showed significant activation at routine vivarium and intermediate temperatures in both hirsuite and nude mice. Crl:NU-Foxn1(nu) mice experienced greater cold stress than did C57BL/6J mice. Our data indicate mice housed under routine vivarium conditions are chronically cold stress. This novel use of thermography can measure cold stress in laboratory mice housed in vivaria, a key advantage over classic metabolic measurement tools. Therefore, thermography is an ideal tool to evaluate novel husbandry practices designed to alleviate murine cold stress.

Fast metabolic response to drug intervention through analysis on a miniaturized, highly integrated molecular imaging system.

UNLABELLED: We report on a radiopharmaceutical imaging platform designed to capture the kinetics of cellular responses to drugs. METHODS: A portable in vitro molecular imaging system comprising a microchip and a ß-particle imaging camera permitted routine cell-based radioassays of small numbers of either suspended or adherent cells. We investigated the kinetics of responses of model lymphoma and glioblastoma cancer cell lines to (18)F-FDG uptake after drug exposure. Those responses were correlated with kinetic changes in the cell cycle or with changes in receptor tyrosine kinase signaling. RESULTS: The platform enabled direct radioassays of multiple cell types and yielded results comparable to those from conventional approaches; however, the platform used smaller sample sizes, permitted a higher level of quantitation, and did not require cell lysis. CONCLUSION: The kinetic analysis enabled by the platform provided a rapid (≈ 1 h) drug screening assay.

Optimization of microfluidic PET tracer synthesis with Cerenkov imaging.

Microfluidic technologies provide an attractive platform for the synthesis of radiolabeled compounds. Visualization of radioisotopes on chip is critical for synthesis optimization and technological development. With Cerenkov imaging, beta particle emitting isotopes can be localized with a sensitive CCD camera. In order for Cerenkov imaging to also serve as a quantitative tool, it is necessary to understand how material properties relevant to Cerenkov emission, namely, index of refraction and beta particle stopping power, affect Cerenkov light output. In this report, we investigate the fundamental physical characteristics of Cerenkov photon yield at different stages of [(18)F]FDG synthesis on the electrowetting on dielectric (EWOD) microfluidic platform. We also demonstrate how Cerenkov imaging has enabled synthesis optimization. Geant4, a Monte Carlo program applied extensively in high energy physics, is used to simulate Cerenkov photon yield from (18)F beta particles traversing materials of interest during [(18)F]FDG synthesis on chip. Our simulations show that the majority (approximately two-thirds) of the (18)F beta particle energy available to produce Cerenkov photons is deposited on the glass plates of the EWOD chip. This result suggests the possibility of using a single calibration factor to convert Cerenkov signal to radioactivity, independent of droplet composition. We validate our simulations with a controlled measurement examining varying ratios of [(18)O]H2O, dimethyl sulfoxide (DMSO), and acetonitrile (MeCN), and find a consistent calibration independent of solvent composition. However, the calibration factor may underestimate the radioactivity in actual synthesis due to discoloration of the droplet during certain steps of probe synthesis. In addition to the attractive quantitative potential of Cerenkov imaging, this imaging strategy provides indispensable qualitative data to guide synthesis optimization. We are able to use this imaging technique to optimize the mixing protocol as well as identify and correct for loss of radioactivity due to the migration of radioactive vapor outside of the EWOD heater, enabling an overall increase in the crude radiochemical yield from 50 ± 3% (n = 3) to 72 ± 13% (n = 5).

A method of 2D/3D registration of a statistical mouse atlas with a planar X-ray projection and an optical photo.

The development of sophisticated and high throughput whole body small animal imaging technologies has created a need for improved image analysis and increased automation. The registration of a digital mouse atlas to individual images is a prerequisite for automated organ segmentation and uptake quantification. This paper presents a fully-automatic method for registering a statistical mouse atlas with individual subjects based on an anterior-posterior X-ray projection and a lateral optical photo of the mouse silhouette. The mouse atlas was trained as a statistical shape model based on 83 organ-segmented micro-CT images. For registration, a hierarchical approach is applied which first registers high contrast organs, and then estimates low contrast organs based on the registered high contrast organs. To register the high contrast organs, a 2D-registration-back-projection strategy is used that deforms the 3D atlas based on the 2D registrations of the atlas projections. For validation, this method was evaluated using 55 subjects of preclinical mouse studies. The results showed that this method can compensate for moderate variations of animal postures and organ anatomy. Two different metrics, the Dice coefficient and the average surface distance, were used to assess the registration accuracy of major organs. The Dice coefficients vary from 0.31 ± 0.16 for the spleen to 0.88 ± 0.03 for the whole body, and the average surface distance varies from 0.54 ± 0.06 mm for the lungs to 0.85 ± 0.10mm for the skin. The method was compared with a direct 3D deformation optimization (without 2D-registration-back-projection) and a single-subject atlas registration (instead of using the statistical atlas). The comparison revealed that the 2D-registration-back-projection strategy significantly improved the registration accuracy, and the use of the statistical mouse atlas led to more plausible organ shapes than the single-subject atlas. This method was also tested with shoulder xenograft tumor-bearing mice, and the results showed that the registration accuracy of most organs was not significantly affected by the presence of shoulder tumors, except for the lungs and the spleen.

MARS: a mouse atlas registration system based on a planar x-ray projector and an optical camera.

This paper introduces a mouse atlas registration system (MARS), composed of a stationary top-view x-ray projector and a side-view optical camera, coupled to a mouse atlas registration algorithm. This system uses the x-ray and optical images to guide a fully automatic co-registration of a mouse atlas with each subject, in order to provide anatomical reference for small animal molecular imaging systems such as positron emission tomography (PET). To facilitate the registration, a statistical atlas that accounts for inter-subject anatomical variations was constructed based on 83 organ-labeled mouse micro-computed tomography (CT) images. The statistical shape model and conditional Gaussian model techniques were used to register the atlas with the x-ray image and optical photo. The accuracy of the atlas registration was evaluated by comparing the registered atlas with the organ-labeled micro-CT images of the test subjects. The results showed excellent registration accuracy of the whole-body region, and good accuracy for the brain, liver, heart, lungs and kidneys. In its implementation, the MARS was integrated with a preclinical PET scanner to deliver combined PET/MARS imaging, and to facilitate atlas-assisted analysis of the preclinical PET images.

NEMA NU 4-2008 comparison of preclinical PET imaging systems.

UNLABELLED: The National Electrical Manufacturers Association (NEMA) standard NU 4-2008 for performance measurements of small-animal tomographs was recently published. Before this standard, there were no standard testing procedures for preclinical PET systems, and manufacturers could not provide clear specifications similar to those available for clinical systems under NEMA NU 2-1994 and 2-2001. Consequently, performance evaluation papers used methods that were modified ad hoc from the clinical PET NEMA standard, thus making comparisons between systems difficult. METHODS: We acquired NEMA NU 4-2008 performance data for a collection of commercial animal PET systems manufactured since 2000: microPET P4, microPET R4, microPET Focus 120, microPET Focus 220, Inveon, ClearPET, Mosaic HP, Argus (formerly eXplore Vista), VrPET, LabPET 8, and LabPET 12. The data included spatial resolution, counting-rate performance, scatter fraction, sensitivity, and image quality and were acquired using settings for routine PET. RESULTS: The data showed a steady improvement in system performance for newer systems as compared with first-generation systems, with notable improvements in spatial resolution and sensitivity. CONCLUSION: Variation in system design makes direct comparisons between systems from different vendors difficult. When considering the results from NEMA testing, one must also consider the suitability of the PET system for the specific imaging task at hand.

Micro-chemical synthesis of molecular probes on an electronic microfluidic device.

We have developed an all-electronic digital microfluidic device for microscale chemical synthesis in organic solvents, operated by electrowetting-on-dielectric (EWOD). As an example of the principles, we demonstrate the multistep synthesis of [(18)F]FDG, the most common radiotracer for positron emission tomography (PET), with high and reliable radio-fluorination efficiency of [(18)F]FTAG (88 ± 7%, n = 11) and quantitative hydrolysis to [(18)F]FDG (> 95%, n = 11). We furthermore show that batches of purified [(18)F]FDG can successfully be used for PET imaging in mice and that they pass typical quality control requirements for human use (including radiochemical purity, residual solvents, Kryptofix, chemical purity, and pH). We report statistical repeatability of the radiosynthesis rather than best-case results, demonstrating the robustness of the EWOD microfluidic platform. Exhibiting high compatibility with organic solvents and the ability to carry out sophisticated actuation and sensing of reaction droplets, EWOD is a unique platform for performing diverse microscale chemical syntheses in small volumes, including multistep processes with intermediate solvent-exchange steps.

Mouse atlas registration with non-tomographic imaging modalities-a pilot study based on simulation.

PURPOSE: This study investigates methodologies for the estimation of small animal anatomy from non-tomographic modalities, such as planar X-ray projections, optical cameras, and surface scanners. The key goal is to register a digital mouse atlas to a combination of non-tomographic modalities, in order to provide organ-level anatomical references of small animals in 3D. PROCEDURES: A 2D/3D registration method was developed to register the 3D atlas to the combination of non-tomographic imaging modalities. Eleven combinations of three non-tomographic imaging modalities were simulated, and the registration accuracy of each combination was evaluated. RESULTS: Comparing the 11 combinations, the top-view X-ray projection combined with the side-view optical camera yielded the best overall registration accuracy of all organs. The use of a surface scanner improved the registration accuracy of skin, spleen, and kidneys. CONCLUSIONS: The methodologies and evaluation presented in this study should provide helpful information for designing preclinical atlas-based anatomical data acquisition systems.