Positron Emission Tomography Instrumentation Research Articles

Precise positioning of gamma ray interactions in multiplexed pixelated scintillators using artificial neural networks

Introduction. The positioning of γ ray interactions in positron emission tomography (PET) detectors is commonly made through the evaluation of the Anger logic flood histograms. machine learning techniques, leveraging features extracted from signal waveform, have demonstrated successful applications in addressing various challenges in PET instrumentation. Aim. This paper evaluates the use of artificial neural networks (NN) for γ ray interaction positioning in pixelated scintillators coupled to a multiplexed array of silicon photomultipliers (SiPM). Methods. An array of 16 Cerium doped Lutetium-based (LYSO) crystal pixels (cross-section 2 × 2 mm2) coupled to 16 SiPM (S13360-1350) were used for the experimental setup. Data from each of the 16 LYSO pixels was recorded, a total of 160000 events. The detectors were irradiated by 511 keV annihilation γ rays from a Sodium-22 (22Na) source. Another LYSO crystal was used for electronic collimation. Features extracted from the signal waveform were used to train the model. Two models were tested: i) single multiple-class neural network (mcNN), with 16 possible outputs followed by a softmax and ii) 16 binary classification neural networks (bNN), each one specialized in identifying events occurred in each position. Results. Both NN models showed a mean positioning accuracy above 85% on the evaluation dataset, although the mcNN is faster to train. Discussion The method’s accuracy is affected by the introduction of misclassified events that interacted in the neighbour’s crystals and were misclassified during the dataset acquisition. Electronic collimation reduces this effect, however results could be improved using a more complex acquisition setup, such as a light-sharing configuration. Conclusions The methods comparison showed that mcNN and bNN can surpass the Anger logic, showing the feasibility of using these models in positioning procedures of future multiplexed detector systems in a linear configuration.

Radiolabelling of Polyclonally Expanded Human Regulatory T Cells (Treg) with 89Zr-oxine for Medium-Term In Vivo Cell Tracking.

Regulatory T cells (Tregs) are a promising candidate cell therapy to treat autoimmune diseases and aid the longevity of transplanted solid organs. Despite increasing numbers of clinical trials using human Treg therapy, important questions pertaining to their in vivo fate, distribution, and function remain unanswered. Treg accumulation in relevant tissues was found to be crucial for Treg therapy efficacy, but existing blood-borne biomarkers are unlikely to accurately reflect the tissue state. Non-invasive Treg tracking by whole-body imaging is a promising alternative and can be achieved by direct radiolabelling of Tregs and following the radiolabelled cells with positron emission tomography (PET). Our goal was to evaluate the radiolabelling of polyclonal Tregs with 89Zr to permit their in vivo tracking by PET/CT for longer than one week with current preclinical PET instrumentation. We used [89Zr]Zr(oxinate)4 as the cell-labelling agent and achieved successful radiolabelling efficiency of human Tregs spanning 0.1-11.1 Bq 89Zr/Treg cell, which would be compatible with PET tracking beyond one week. We characterized the 89Zr-Tregs, assessing their phenotypes, and found that they were not tolerating these intracellular 89Zr amounts, as they failed to survive or expand in a 89Zr-dose-dependent manner. Even at 0.1 Bq 89Zr per Treg cell, while 89Zr-Tregs remained functional as determined by a five-day-long effector T cell suppression assay, they failed to expand beyond day 3 in vitro. Moreover, PET imaging revealed signs of 89Zr-Treg death after adoptive transfer in vivo. In summary, 89Zr labelling of Tregs at intracellular radioisotope amounts compatible with cell tracking over several weeks did not achieve the desired outcomes, as 89Zr-Tregs failed to expand and survive. Consequently, we conclude that indirect Treg labelling is likely to be the most effective alternative method to satisfy the requirements of this cell tracking scenario.

A proof-of-concept study of an in-situ partial-ring time-of-flight PET scanner for proton beam verification.

Development of a PET system capable of in-situ imaging requires a design that can accommodate the proton treatment beam nozzle. Among the several PET instrumentation approaches developed thus far, the dual-panel PET scanner is often used as it is simpler to develop and integrate within the proton therapy gantry. Partial-angle coverage of these systems can however lead to limited-angle artefacts in the reconstructed PET image. We have previously demonstrated via simulations that time-of-flight (TOF) reconstruction reduces the artifacts accompanying limited-angle data, and permits proton range measurement with 1-2 mm accuracy and precision. In this work we show measured results from a small proof-of-concept dual-panel PET system that uses TOF information to reconstruct PET data acquired after proton irradiation. The PET scanner comprises of two detector modules, each comprised of an array of 4×4×30 mm3 lanthanum bromide scintillator. Measurements are performed with an oxygen-rich gel-water, an adipose tissue equivalent material, and in vitro tissue phantoms. For each phantom measurement, 2 Gy dose was deposited using 54 - 100 MeV proton beams. For each phantom, a Monte Carlo simulation generating the expected distribution of PET isotope from the corresponding proton irradiation was also performed. Proton range was calculated by drawing multiple depth-profiles over a central region encompassing the proton dose deposition. For each profile, proton range was calculated using two techniques (a) 50% pick-off from the distal edge of the profile, and (b) comparing the measured and Monte Carlo profile to minimize the absolute sum of differences over the entire profile. A 10 min PET acquisition acquired with minimal delay post proton-irradiation is compared with a 10 min PET scan acquired after a 20 min delay. Measurements show that PET acquisition with minimal delay is necessary to collect 15O signal, and maximize 11C signal collection with a short PET acquisition. In comparison with the 50% pick-off technique, the shift technique is more robust and offers better precision in measuring the proton range for the different phantoms. Range measurements from PET images acquired with minimal delay, and the shift technique demonstrate the ability to achieve <1.5 mm accuracy and precision in estimating proton range.

Positron annihilation localization by nanoscale magnetization

In positron emission tomography (PET), the finite range over which positrons travel before annihilating with an electron places a fundamental physical limit on the spatial resolution of PET images. After annihilation, the photon pair detected by the PET instrumentation is emitted from a location that is different from the positron-emitting source, resulting in image blurring. Here, we report on the localization of positron range, and hence annihilation quanta, by strong nanoscale magnetization of superparamagnetic iron oxide nanoparticles (SPIONs) in PET-MRI. We found that positron annihilations localize within a region of interest by up to 60% more when SPIONs are present (with [Fe] = 3 mM) compared to when they are not. The resulting full width at half maximum of the PET scans showed the spatial resolution improved by up to approx 30%. We also found evidence suggesting that the radiolabeled SPIONs produced up to a six-fold increase in ortho-positronium. These results may also have implications for emerging cancer theranostic strategies, where charged particles are used as therapeutic as well as diagnostic agents and improved dose localization within a tumor is a determinant of better treatment outcomes.

Recent Advances in Imaging Inflammation Post-Myocardial Infarction Using Positron Emission Tomography

Despite advances in medical and surgical therapy, some patients after a myocardial infarction still develop heart failure, a devastating disease that has a high rate of morbidity and mortality. Differences in the immune response to the myocardial damage may affect the healing process. Molecular imaging enables the interrogation of immune cell subsets that can aid or impair left ventricular recovery post-myocardial infarction. Visualization of patient-specific differences in the cellular and molecular process among patients post-myocardial infarction may lead to the development of personalized therapy to prevent remodeling and promote myocardial recovery. Positron emission tomography (PET) has emerged as a commonly used modality for imaging myocardial inflammation in both pre-clinical and clinical studies. While 18F-FDG continues to be investigated for its ability to track inflammation in small clinical trials, its relative short half-life and nonspecific uptake have prompted investigation into other PET tracers, including agents that image amino acid metabolism, mitochondrial transport proteins, cell surface receptors, and integrins. Two of the most innovative approaches include the use of reporter gene imaging and nanoparticles. Of these, the latter offers the added advantage of delivering a therapeutic payload. Finally, recent advances in PET instrumentation such as total-body imaging can allow the study of multi-organ dysfunction simultaneously (e.g., cardiac and brain inflammation after a heart attack) with high sensitivity. Moreover, with multi-isotope PET scanners, simultaneous observation of multiple positron emitting isotopes has enabled the examination of different biological processes with distinct molecular probes in a single scan setting. The development of advanced PET tracers for the visualization of the inflammatory cascade post-myocardial infarction may enable the development of immune modulating agents to promote left ventricular recovery.

Advances in PET Diagnostics for Guiding Targeted Cancer Therapy and Studying In Vivo Cancer Biology.

We present an overview of recent advances in positron emission tomography (PET) diagnostics as applied to the study of cancer, specifically as a tool to study in vivo cancer biology and to direct targeted cancer therapy. The review is directed to translational and clinical cancer investigators who may not be familiar with these applications of PET cancer diagnostics, but whose research might benefit from these advancing tools. We highlight recent advances in 3 areas: (1) the translation of PET imaging cancer biomarkers to clinical trials; (2) methods for measuring cancer metabolism in vivo in patients; and (3) advances in PET instrumentation, including total-body PET, that enable new methodologies. We emphasize approaches that have been translated to human studies. PET imaging methodology enables unique in vivo cancer diagnostics that go beyond cancer detection and staging, providing an improved ability to guide cancer treatment and an increased understanding of in vivo human cancer biology.

Brain-Dedicated Emission Tomography Systems: A Perspective on Requirements for Clinical Research and Clinical Needs in Brain Imaging

Research applications of human brain positron emission tomography (PET) imaging have been in place for over 40 years. The unique combination of quantitative PET instrumentation and reconstruction, novel radiotracers, and kinetic modeling has led to the development and application of a huge number of imaging paradigms. These have been applied to the understanding of normal function and pathophysiology, the development of drugs for neuropsychiatric disorders, and the study of drug interactions with the brain. I have had been fortunate to be part of this great endeavor throughout my research career, using brain-dedicated PET scanners, such as the HRRT [item [1] in the Appendix]. Over time, these systems have offered important advantages over whole-body systems. However, due to the limited clinical market for brain PET imaging, scanner manufacturers have focused exclusively on large field-of-view systems for the past two decades [item [2] in the Appendix]. The goal of this perspective is to share a viewpoint on the utility of brain-dedicated PET systems for human research, particularly in the context of novel radiotracers with dynamic studies using kinetic modeling.

Preliminary Results that Assess Metformin Treatment in a Preclinical Model of Pancreatic Cancer Using Simultaneous [18F]FDG PET and acidoCEST MRI.

We sought to determine if the synergy between evaluations of glucose uptake in tumors and extracellular tumor acidosis measured with simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) can improve longitudinal evaluations of the response to metformin treatment. A standard 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET protocol that evaluates glucose uptake in tumors, and a standard acidoCEST MRI protocol that measures extracellular pH (pHe) in tumors, were simultaneously performed to assess eight vehicle-treated (control) mice and eight metformin-treated mice 1day before treatment, 1day after initiating daily treatment with metformin, and 7days after initiating treatment. Longitudinal changes in SUVmax and extracellular pH (pHe) were evaluated for each treatment group, and differences in SUVmax and pHe between metformin-treated and control groups were also evaluated. MRI acquisition protocols had little effect on the PET count rate, and the PET instrumentation had little effect on image contrast during acidoCEST MRI, verifying that [18F]FDG PET and acidoCEST MRI can be performed simultaneously. The average SUVmax of the tumor model had a significant decrease after 7days of treatment with metformin, as expected. The average tumor pHe decreased after 7days of metformin treatment, which reflected the inhibition of the consumption of cytosolic lactic acid caused by metformin. However, the average SUVmax of the tumor model was not significantly different between the metformin-treated and control groups after 7days of treatment, and average pHe was also not significantly different between these groups. For comparison, the combination of average SUVmax and pHe measurements significantly differed between the treatment group and control group on Day 7. [18F]FDG PET and acidoCEST MRI studies can be performed simultaneously. The synergistic combination of assessing glucose uptake and tumor acidosis can improve differentiation of a drug-treated group from a control group during drug treatment of a tumor model.

Advances in PET/MR instrumentation and image reconstruction.

The combination of positron emission tomography (PET) and MRI has attracted the attention of researchers in the past approximately 20 years in small-animal imaging and more recently in clinical research. The combination of PET/MRI allows researchers to explore clinical and research questions in a wide number of fields, some of which are briefly mentioned here. An important number of groups have developed different concepts to tackle the problems that PET instrumentation poses to the exposition of electromagnetic fields. We have described most of these research developments in preclinical and clinical experiments, including the few commercial scanners available. From the software perspective, an important number of algorithms have been developed to address the attenuation correction issue and to exploit the possibility that MRI provides for motion correction and quantitative image reconstruction, especially parametric modelling of radiopharmaceutical kinetics. In this work, we give an overview of some exemplar applications of simultaneous PET/MRI, together with technological hardware and software developments.

Instrumentation for Time-of-Flight Positron Emission Tomography.

Positron emission tomography (PET) is a molecular imaging modality that provides information at the molecular level. This system is composed of radiation detectors to detect incoming coincident annihilation gamma photons emitted from the radiopharmaceutical injected into a patient's body and uses these data to reconstruct images. A major trend in PET instrumentation is the development of time-of-flight positron emission tomography (ToF-PET). In ToF-PET, the time information (the instant the radiation is detected) is incorporated for image reconstruction. Therefore, precise and accurate timing recording is crucial in ToF-PET. ToF-PET leads to better localization of the annihilation event and thus results in overall improvement in the signal-to-noise ratio (SNR) of the reconstructed image. Several factors affect the timing performance of ToF-PET. In this article, the background, early research and recent advances in ToF-PET instrumentation are presented. Emphasis is placed on the various types of scintillators, photodetectors and electronic circuitry for use in ToF-PET, and their impact on timing resolution is discussed.

New prospects for PET in prostate cancer imaging: a physicist's viewpoint.

Prostate cancer is one of the most common forms of cancer among men. Early diagnosis, correct staging, accurate detection of metastasis, and monitoring of the therapy are the key tasks that could greatly benefit from medical imaging. After a review of the main developments in the field of positron emission tomography (PET) tracers for prostate cancer, the impact of improved PET instrumentation with good spatial resolution and high sensitivity is discussed, together with the latest development in PET technology: lutetium oxy-ortho-silicate (LSO) and lutetium-yttrium oxy-ortho-silicate (LYSO) scintillators, resolution recovery, and time-of-flight reconstruction. New directions and multiple approaches in PET instrumentation for prostate cancer are presented and discussed. In particular, improved hardware and noise suppressing reconstruction algorithms allow for higher detectability of small lesions and better spatial resolution in PET/computerized tomography (CT) and PET/magnetic resonance (MR). This can be beneficial for guiding biopsy and surgery and for accurate therapy monitoring.Electronic supplementary materialThe online version of this article (doi:10.1186/2197-7364-1-11) contains supplementary material, which is available to authorized users.

Improving PET spatial resolution and detectability for prostate cancer imaging

Prostate cancer, one of the most common forms of cancer among men, can benefit from recent improvements in positron emission tomography (PET) technology. In particular, better spatial resolution, lower noise and higher detectability of small lesions could be greatly beneficial for early diagnosis and could provide a strong support for guiding biopsy and surgery. In this article, the impact of improved PET instrumentation with superior spatial resolution and high sensitivity are discussed, together with the latest development in PET technology: resolution recovery and time-of-flight reconstruction. Using simulated cancer lesions, inserted in clinical PET images obtained with conventional protocols, we show that visual identification of the lesions and detectability via numerical observers can already be improved using state of the art PET reconstruction methods. This was achieved using both resolution recovery and time-of-flight reconstruction, and a high resolution image with 2 mm pixel size. Channelized Hotelling numerical observers showed an increase in the area under the LROC curve from 0.52 to 0.58. In addition, a relationship between the simulated input activity and the area under the LROC curve showed that the minimum detectable activity was reduced by more than 23%.

Development of a SiPM-based PET imaging system for small animals

Advances in small animal positron emission tomography (PET) imaging have been accelerated by many new technologies such as the successful incorporation of silicon photomultiplier (SiPM). In this paper, we have developed a compact, lightweight PET imaging system that is based on SiPM detectors for small animals imaging, which could be integrated into a multi-modality imaging system. This PET imaging system consists of a stationary detector gantry, a motor-controlled animal bed module, electronics modules, and power supply modules. The PET detector, which was designed as a multi-slice circular ring geometry of 27 discrete block detectors, is composed of a cerium doped lutetium–yttrium oxyorthosilicate (LYSO) scintillation crystal and SiPM arrays. The system has a 60mm transaxial field of view (FOV) and a 26mm axial FOV. Performance tests (e.g. spatial resolution, energy resolution, and sensitivity) and phantom and animal imaging studies were performed to evaluate the imaging performance of the PET imaging system. The performance tests and animal imaging results demonstrate the feasibility of an animal PET system based on SiPM detectors and indicate that SiPM detectors can be promising photodetectors in animal PET instrumentation development.

Tumor Quantification in Clinical Positron Emission Tomography

Positron emission tomography (PET) is used extensively in clinical oncology for tumor detection, staging and therapy response assessment. Quantitative measurements of tumor uptake, usually in the form of standardized uptake values (SUVs), have enhanced or replaced qualitative interpretation. In this paper we review the current status of tumor quantification methods and their applications to clinical oncology. Factors that impede quantitative assessment and limit its accuracy and reproducibility are summarized, with special emphasis on SUV analysis. We describe current efforts to improve the accuracy of tumor uptake measurements, characterize overall metabolic tumor burden and heterogeneity of tumor uptake, and account for the effects of image noise. We also summarize recent developments in PET instrumentation and image reconstruction and their impact on tumor quantification. Finally, we offer our assessment of the current development needs in PET tumor quantification, including practical techniques for fully quantitative, pharmacokinetic measurements.

Overview of Positron Emission Tomography, Hybrid Positron Emission Tomography Instrumentation, and Positron Emission Tomography Quantification

Positron emission tomography (PET) is a powerful quantitative molecular imaging technique that is complementary to structural imaging techniques for purposes of disease detection and characterization. This review article provides a brief overview of PET, hybrid PET instrumentation, and PET quantification.

Nuclear physics detector technology applied to plant biology research

The ability to detect the emissions of radioactive isotopes through radioactive decay (e.g. beta particles, x-rays and gamma-rays) has been used for over 80 years as a tracer method for studying natural phenomena. More recently a positron emitting radioisotope of carbon: 11C has been utilized as a 11CO2 tracer for plant ecophysiology research. Because of its ease of incorporation into the plant via photosynthesis, the 11CO2 radiotracer is a powerful tool for use in plant biology research. Positron emission tomography (PET) imaging has been used to study carbon transport in live plants using 11CO2. Presently there are several groups developing and using new PET instrumentation for plant based studies. Thomas Jefferson National Accelerator Facility (Jefferson Lab) in collaboration with the Duke University Phytotron and the Triangle Universities Nuclear Laboratory (TUNL) is involved in PET detector development for plant imaging utilizing technologies developed for nuclear physics research. The latest developments of the use of a LYSO scintillator based PET detector system for 11CO2 tracer studies in plants will be briefly outlined.

Fundamentals of PET and PET/CT imaging

In this review, the fundamental principles of fluorodeoxyglucose (FDG) positron emission tomography (PET) and FDG PET/computed tomography (CT) imaging have been described. The basic physics of PET instrumentation, radiotracer chemistry, and the artifacts, as well as normal physiological or benign pathological variants, have been described and presented to the readers in a lucid manner to enable them an easy grasp of the fundamentals of the subject. Finally, we have outlined the current developments in quantitative PET imaging, including dual time point and delayed PET imaging, time-of-flight technology in PET imaging and partial volume correction, and global disease assessment with their potential of being incorporated into the assessment of benign and malignant disorders.

Recent development in PET instrumentation.

Positron emission tomography (PET) is used in the clinic and in vivo small animal research to study molecular processes associated with diseases such as cancer, heart disease, and neurological disorders, and to guide the discovery and development of new treatments. This paper reviews current challenges of advancing PET technology and some of newly developed PET detectors and systems. The paper focuses on four aspects of PET instrumentation: high photon detection sensitivity; improved spatial resolution; depth-of-interaction (DOI) resolution and time-of-flight (TOF). Improved system geometry, novel non-scintillator based detectors, and tapered scintillation crystal arrays are able to enhance the photon detection sensitivity of a PET system. Several challenges for achieving high resolution with standard scintillator-based PET detectors are discussed. Novel detectors with 3-D positioning capability have great potential to be deployed in PET for achieving spatial resolution better than 1 mm, such as cadmium-zinc-telluride (CZT) and position-sensitive avalanche photodiodes (PSAPDs). DOI capability enables a PET system to mitigate parallax error and achieve uniform spatial resolution across the field-of-view (FOV). Six common DOI designs, as well as advantages and limitations of each design, are discussed. The availability of fast scintillation crystals such as LaBr(3), and the silicon photomultiplier (SiPM) greatly advances TOF-PET development. Recent instrumentation and initial results of clinical trials are briefly presented. If successful, these technology advances, together with new probe molecules, will substantially enhance the molecular sensitivity of PET and thus increase its role in preclinical and clinical research as well as evaluating and managing disease in the clinic.

Design study of a high-resolution breast-dedicated PET system built from cadmium zinc telluride detectors

We studied the performance of a dual-panel positron emission tomography (PET) camera dedicated to breast cancer imaging using Monte Carlo simulation. The proposed system consists of two 4 cm thick 12 × 15 cm2 area cadmium zinc telluride (CZT) panels with adjustable separation, which can be put in close proximity to the breast and/or axillary nodes. Unique characteristics distinguishing the proposed system from previous efforts in breast-dedicated PET instrumentation are the deployment of CZT detectors with superior spatial and energy resolution, using a cross-strip electrode readout scheme to enable 3D positioning of individual photon interaction coordinates in the CZT, which includes directly measured photon depth-of-interaction (DOI), and arranging the detector slabs edge-on with respect to incoming 511 keV photons for high photon sensitivity. The simulation results show that the proposed CZT dual-panel PET system is able to achieve superior performance in terms of photon sensitivity, noise equivalent count rate, spatial resolution and lesion visualization. The proposed system is expected to achieve ∼32% photon sensitivity for a point source at the center and a 4 cm panel separation. For a simplified breast phantom adjacent to heart and torso compartments, the peak noise equivalent count (NEC) rate is predicted to be ∼94.2 kcts s−1 (breast volume: 720 cm3 and activity concentration: 3.7 kBq cm−3) for a ∼10% energy window around 511 keV and ∼8 ns coincidence time window. The system achieves 1 mm intrinsic spatial resolution anywhere between the two panels with a 4 cm panel separation if the detectors have DOI resolution less than 2 mm. For a 3 mm DOI resolution, the system exhibits excellent sphere resolution uniformity (σrms/mean) ⩽ 10%) across a 4 cm width FOV. Simulation results indicate that the system exhibits superior hot sphere visualization and is expected to visualize 2 mm diameter spheres with a 5:1 activity concentration ratio within roughly 7 min imaging time. Furthermore, we observe that the degree of spatial resolution degradation along the direction orthogonal to the two panels that is typical of a limited angle tomography configuration is mitigated by having high-resolution DOI capabilities that enable more accurate positioning of oblique response lines.

Advances in multimodality molecular imaging

Multimodality molecular imaging using high resolution positron emission tomography (PET) combined with other modalities is now playing a pivotal role in basic and clinical research. The introduction of combined PET/CT systems in clinical setting has revolutionized the practice of diagnostic imaging. The complementarity between the intrinsically aligned anatomic (CT) and functional or metabolic (PET) information provided in a “one-stop shop” and the possibility to use CT images for attenuation correction of the PET data has been the driving force behind the success of this technology. On the other hand, combining PET with Magnetic Resonance Imaging (MRI) in a single gantry is technically more challenging owing to the strong magnetic fields. Nevertheless, significant progress has been made resulting in the design of few preclinical PET systems and one human prototype dedicated for simultaneous PET/MR brain imaging. This paper discusses recent advances in PET instrumentation and the advantages and challenges of multimodality imaging systems. Future opportunities and the challenges facing the adoption of multimodality imaging instrumentation will also be addressed.