High-resolution Positron Emission Tomography Research Articles

Synaptic loss and its association with symptom severity in Parkinson’s disease

Parkinson’s disease (PD) is the fastest growing neurodegenerative disease, but at present there is no cure, nor any disease-modifying treatments. Synaptic biomarkers from in vivo imaging have shown promise in imaging loss of synapses in PD and other neurodegenerative disorders. Here, we provide new clinical insights from a cross-sectional, high-resolution positron emission tomography (PET) study of 30 PD individuals and 30 age- and sex-matched healthy controls (HC) with the radiotracer [11C]UCB-J, which binds to synaptic vesicle glycoprotein 2A (SV2A), and is therefore, a biomarker of synaptic density in the living brain. We also examined a measure of relative brain perfusion from the early part of the same PET scan. Our results provide evidence for synaptic density loss in the substantia nigra that had been previously reported, but also extend this to other early-Braak stage regions known to be affected in PD (brainstem, caudate, olfactory cortex). Importantly, we also found a direct association between synaptic density loss in the nigra and severity of symptoms in patients. A greater extent and wider distribution of synaptic density loss in PD patients with longer illness duration suggests that [11C]UCB-J PET can be used to measure synapse loss with disease progression. We also demonstrate lower brain perfusion in PD vs. HC groups, with a greater extent of abnormalities in those with longer duration of illness, suggesting that [11C]UCB-J PET can simultaneously provide information on changes in brain perfusion. These results implicate synaptic imaging as a useful PD biomarker for future disease-modifying interventions.

A finely segmented semi-monolithic detector tailored for high-resolution PET.

Preclinical research and organ-dedicated applications use and require high (spatial-)resolution positron emission tomography (PET) detectors to visualize small structures (early) and understand biological processes at a finer level of detail. Researchers seeking to improve detector and image spatial resolution have explored various detector designs. Current commercial high-resolution systems often employ finely pixelated or monolithic scintillators, each with its limitations. We present a semi-monolithic detector, tailored for high-resolution PET applications with a spatial resolution in the range of 1mm or better, merging concepts of monolithic and pixelated crystals. The detector features LYSO slabs measuring (24×10×1)mm3, coupled to a 12×12 readout channel photosensor with 4mm pitch. The slabs are grouped in two arrays of 44 slabs each to achieve a higher optical photon density despite the fine segmentation. We employ a fan beam collimator for fast calibration to train machine-learning-based positioning models for all three dimensions, including slab identification and depth-of-interaction (DOI), utilizing gradient tree boosting (GTB). The data for all dimensions was acquired in less than 2h. Energy calculation was based on a position-dependent energy calibration. Using an analytical timing calibration, time skews were corrected for coincidence timing resolution (CTR) estimation. Leveraging machine-learning-based calibration in all three dimensions, we achieved high detector spatial resolution: down to 1.18mm full width at half maximum (FWHM) detector spatial resolution and 0.75mm mean absolute error (MAE) in the planar-monolithic direction, and 2.14mm FWHM and 1.03mm MAE for DOI at an energy window of (435-585)keV. Correct slab interaction identification in planar-segmented direction exceeded 80%, alongside an energy resolution of 12.7% and a CTR of 450ps FWHM. The introduced finely segmented, high-resolution slab detector demonstrates appealing performance characteristics suitable for high-resolution PET applications. The current benchtop-based detector calibration routine allows these detectors to be used in PET systems.

Effect of depth of interaction resolution on the spatial resolution of SIAT aPET

Objective. Spatial resolution is a crucial parameter for a positron emission tomography (PET) scanner. The spatial resolution of a high-resolution small animal PET scanner is significantly influenced by the effect of depth of interaction (DOI) uncertainty. The aim of this work is to investigate the impact of DOI resolution on the spatial resolution of a small animal PET scanner called SIAT aPET and determine the required DOI resolution to achieve nearly uniform spatial resolution within the field of view (FOV). Approach. The SIAT aPET detectors utilize 1.0 × 1.0 × 20 mm3 crystals, with an average DOI resolution of ∼2 mm. A default number of 16 DOI bins are used during data acquisition. First, a Na-22 point source was scanned in the center of the axial FOV with different radial offsets. Then, a Derenzo phantom was scanned at radial offsets of 0 and 15 mm in the center axial FOV. The measured DOI information was rebinned to 1, 2, 4 and 8 DOI bins to mimic different DOI resolutions of the detectors during image reconstruction. Main results. Significant artifacts were observed in images obtained from both the point source and Derenzo phantom when using only one DOI bin. When accurate measurement of DOI is not achieved, degradation in spatial resolution is more pronounced in the radial direction compared to tangential and axial directions for large radial offsets. The radial spatial resolutions at a 30 mm radial offset are 5.05, 2.62, 1.24, 0.86 and 0.78 mm when using 1, 2, 4, 8, or 16 DOI bins, respectively. The axial spatial resolution improved from ∼1.3 to 0.7 mm as the number of DOI bins increased from 1 to 16 at radial offsets from 0 to 25 mm. Two DOI bins are required to obtain images without significant artifacts. The required DOI resolution is about three times the crystal width of SIAT aPET to achieve a uniform submillimeter spatial resolution within the central 60 mm FOV and resolve the 1 mm rods of the Derenzo phantom at both positions.

Left atrial glucose metabolism by 18F-FDG PET/CT in persistent atrial fibrillation and after return to sinus rhythm

Abstract Background Atrial Fibrillation (AF) is strongly associated with the development of Left Atrial (LA) remodeling. Animal studies pointed to an important role of metabolic deregulation in AF, yet few studies have assessed LA myocardial metabolism in vivo in patients with AF. 18-fluorodeoxyglucose (FDG) Positron Emission tomography (PET) has been widely used for evaluation of left ventricular (LV) metabolism, but its application to study metabolism of LA has not yet been explored. Purpose The aim of this study was to evaluate LA glucose metabolism and contractile efficiency in patients with persistent AF, following our successful implementation of a protocol enabling the acquisition of high-resolution PET images of the LA. Methods 36 nondiabetic patients (64±7 years, 29 men) with persistent non valvular AF (peAF) undergoing a first AF ablation and 5 healthy age matched volunteers (69±5 years, 3 men, p=0.114) without AF underwent FDG PET, speckle tracking echocardiography (STE) and cardiac MRI (cMR). PET was performed after overnight fasting and after administration of a nicotinic acid derivative (Acipimox 250 mg) to maximally stimulate myocardial glucose uptake. The 3 tests were repeated 3 months later in 26 patients in whom return to permanent sinus rhythm (SR) could be obtained after the ablation procedure. PET images were registered with cMR LA angiography, and the mean partial volume and spillover corrected standardized FDG uptake (SUV) in the whole LA, the left atrial appendage (LAA), and the left ventricle (LV) were computed. Measurements were compared to global Peak Atrial Longitudinal Strain (GPALS) and to left atrial ejection fraction (LAEF) measured by STE and LA contractile efficiency was computed as the ratio of LA SUV to LAEF. Results Hemodynamics (syst. BP mmHg: 128±11 vs 129±5 mmHg, p=0.663) and metabolic parameters (glycemia: 99±14 vs 96±7 mg/dl, p=0.480) were similar in peAF patients and healthy controls. While 18F-FDG SUV in the LV was comparable between pEAF patients and healthy controls, patients in peAF exhibited significantly increased SUV in LA and LAA compared to controls. Following a return to SR, LA-SUVmean and LAA-SUVmean in patients peAF decreased significantly after 3 months (20.3%, p<0.002 and 34.1%, p<0.001), whereas the LV-SUVmean remained unchanged (p=0.847). The Global Peak Atrial Longitudinal Strain (GPALS) increased by 54.2%(p<0.001), and the Left Atrial Ejection Fraction (LAEF) by 39.2% (p<0.001), post-restoration of SR. (Figure 1). Accordingly contractile efficiency of LA SUV/LAEF in peAF patients improved significantly upon their return to SR (47%, p<0.001). Conclusion LA glucose metabolism is significantly increased in peAF and return after restoration of SR. This could indicate oxygen wasting and reduced contractile efficiency of AF or metabolic shift towards preferred glucose metabolism in AF. These findings support the notion that LA glucose metabolism plays a role in the pathophysiology of AF.Figure 1Figure 2

Multi-scale dissolution dynamics for carbon sequestration in carbonate rock samples

Carbon dioxide (CO2) sequestration in porous, sedimentary reservoirs is a key technology to mitigate emissions of anthropogenic CO2 and curb irreversible climate change. The abundance of carbonate formations, both as saline aquifers and hydrocarbon reservoirs, makes future CO2 storage in carbonate formations highly likely. The weak carbonic acid that forms when CO2 dissolves in water will, however, interact with highly reactive carbonate. Preferential flow paths may form during dissolution or calcite precipitation may reduce injectivity - both processes significantly impacting reservoir sweep efficiency. Hence, understanding the dynamics of the dissolution processes and their influence on flow properties is necessary to safely store CO2 in carbonate formations. Darcy and sub-Darcy scale dissolution kinetics were here assessed in carbonate core plugs with and without pre-existing highly permeable pathways, during multiphase flow and under relevant storage conditions.Darcy-scale dissolution and precipitation data (injectivity changes, effluent analysis and mass loss) confirmed that CO2 and brine co-injections altered the carbonate rock structure on Darcy scale, but could not determine the cause of change. Multi-modal imaging was applied to independently quantify structural changes with computed tomography (CT) and aqueous flow characteristics with positron emission tomography (PET), thereby determining injectivity dependence on local flow patterns. Formation of high permeability pathways, which was expected due to rock dissolution, was only observed in cores with pre-existing open fractures, where reactive flow was limited to the fracture plane. A good correlation between the two imaging modules was found: areas of higher porosity yielded a low-density CT signal (i.e. high number of voids present) and a high PET signal density (i.e. large volume of traced fluid present). Loss of injectivity suggested local changes in the flow pattern due to blocking of pore throats by moving particles or secondary precipitation or mineralization of dissolved ions. High-resolution PET imaging revealed cementation, that was also visible using micro-CT, hence determining sub-Darcy local flow obstructions that led to decreased Darcy scale injectivity. Multi-modal imaging, where core characteristics, such as large vugs and cementation, can be independently determined by complementary modalities, may therefore be a useful tool to quantify reactive flow and resulting dissolution in rock samples.

Development of a Novel [11C]CO-Labeled Positron Emission Tomography Radioligand [11C]BIO-1819578 for the Detection of O-GlcNAcase Enzyme Activity.

Imaging O-GlcNAcase OGA by positron emission tomography (PET) could provide information on the pathophysiological pathway of neurodegenerative diseases and important information on drug-target engagement and be helpful in dose selection of therapeutic drugs. Our aim was to develop an efficient synthetic method for labeling BIO-1819578 with carbon-11 using 11CO for evaluation of its potential to measure levels of OGA enzyme in non-human primate (NHP) brain using PET. Radiolabeling was achieved in one-pot via a carbon-11 carbonylation reaction using [11C]CO. The detailed regional brain distribution of [11C]BIO-1819578 binding was evaluated using PET measurements in NHPs. Brain radioactivity was measured for 93 min using a high-resolution PET system, and radiometabolites were measured in monkey plasma using gradient radio HPLC. Radiolabeling of [11C]BIO-1819578 was successfully accomplished, and the product was found to be stable at 1 h after formulation. [11C]BIO-1819578 was characterized in the cynomolgus monkey brain where a high brain uptake was found (7 SUV at 4 min). A pronounced pretreatment effect was found, indicating specific binding to OGA enzyme. Radiolabeling of [11C]BIO-1819578 with [11C]CO was successfully accomplished. [11C]BIO-1819578 binds specifically to OGA enzyme. The results suggest that [11C]BIO-1819578 is a potential radioligand for imaging and for measuring target engagement of OGA in the human brain.

Neural correlates of PTSD in women with childhood sexual abuse with and without PTSD and response to paroxetine treatment: A placebo-controlled, double-blind trial

ObjectiveChildhood sexual abuse is the leading cause of posttraumatic stress disorder (PTSD) in women, and is a prominent cause of morbidity and loss of function for which limited treatments are available. Understanding the neurobiology of treatment response is important for developing new treatments. The purpose of this study was to assess neural correlates of personalized traumatic memories in women with childhood sexual abuse with and without PTSD, and to assess response to treatment. MethodsWomen with childhood sexual abuse with (N = 28) and without (N = 17) PTSD underwent brain imaging with High-Resolution Positron Emission Tomography scanning with radiolabeled water for brain blood flow measurements during exposure to personalized traumatic scripts and memory encoding tasks. Women with PTSD were randomized to paroxetine or placebo followed by three months of double-blind treatment and repeat imaging with the same protocol. ResultsWomen with PTSD showed decreases in areas involved in the Default Mode Network (DMN), a network of brain areas usually active when the brain is at rest, hippocampus and visual processing areas with exposure to traumatic scripts at baseline while women without PTSD showed increased activation in superior frontal gyrus and other areas (p < 0.005). Treatment of women with PTSD with paroxetine resulted in increased anterior cingulate activation and brain areas involved in the DMN and visual processing with scripts compared to placebo (p < 0.005). ConclusionPTSD related to childhood sexual abuse in women is associated with alterations in brain areas involved in memory and the stress response and treatment with paroxetine results in modulation of these areas.

Acute psychological stress-induced progenitor cell mobilization and cardiovascular events

ObjectiveCertain brain activation responses to psychological stress are associated with worse outcomes in CVD patients. We hypothesized that elevated acute psychological stress, manifesting as greater activity within neural centers for emotional regulation, mobilizes CPC from the bone marrow to the peripheral blood and predicts future cardiovascular events. MethodsIn 427 patients with stable CAD undergoing a laboratory-based mental stress (MS) test, CPCs were enumerated using flow cytometry as CD34-expressing mononuclear cells (CD34+) before and 45 min after stress. Changes in brain regional blood flow with MS were measured using high resolution-positron emission tomography (HR-PET). Association between the change in CPC with MS and the risk of cardiovascular death or myocardial infarction (MI) during a 5-year follow-up period was analyzed. ResultsMS increased CPC counts by a mean of 150 [630] cells/mL (15%), P < 0.001. Greater limbic lobe activity, indicative of activation of emotion-regulating centers, was associated with greater CPC mobilization (P < 0.005). Using Fine and Gray models after adjustment for demographioc, clinical risk factors and medications use, greater CPC mobilization was associated with a higher adjusted risk of adverse events; a rise of 1000 cells/mL was associated with a 50% higher risk of cardiovascular death/MI [hazards ratio, 1.5, 95% confidence interval, 1.1–2.2). ConclusionGreater limbic lobe activity, brain areas involved in emotional regulation, is associated with MS-induced CPC mobilization. This mobilization isindependently associated with cardiovascular events. These findings provide novel insights into mechanisms through which psychological stressors modulate cardiovascular risk.

Evaluation of a modular all-in-one high-resolution PET detector and readout electronics setup

Objective. The all-in-one solution and modularity of the C13500 series TOF-PET detector modules (Hamamatsu Photonics K.K., Hamamatsu, Japan) make them a highly attractive candidate for the development of positron emission tomography (PET) systems. However, the commercially available portfolio targets clinical whole-body PET systems with a scintillation crystal cross area of 3.1 × 3.1 mm2. To extend the modules for high resolution (preclinical or organ specific) systems, the support for smaller scintillation crystals is required. Approach. In this work, a PET detector was developed based on the TOF-PET modules using a light sharing approach, 16 × 16 lutetium oxyorthosilicate (LSO) scintillation crystals with a size of 1.51 × 1.51 × 10.00 mm3 readout with 8 × 8 photosensor channels of size 3.0 × 3.0 mm2. In addition to hardware and software development, the optimized parameter settings for the adapted configuration were evaluated. Main Results. A factor of two in amplification of the analog signal compared to the minimum gain setting was necessary for an accurate crystal identification (peak-to-valley ratio 14.9 ± 5.9). A further increase to a factor of three was not determined as optimum as the time over threshold duration, thus pile-up probability, increased from 1032.1 ± 109.5 to 1789.5 ± 218.5 ns (photopeak position). With this amplification a full width at half maximum (FWHM) energy resolution of 14.1 ± 2.0% and a high linearity of the energy detection was obtained. A FWHM coincidence resolving time (CRT) of 313 ps was achieved by using a low timing threshold, increasing the bandwidth of the front-end circuit and using a narrow ± 1σ energy window. To approximately double the sensitivity and reduce the power consumption, the timing parameters were adjusted resulting in a FWHM CRT of 354 ps (±2σ). Significance. Based on the results obtained with the proof-of-concept detector setup, we confirm the modularity and flexibility of the all-in-one TOF-PET detector modules for the future development of application-specific high-resolution PET systems.

SPARSE REPRESENTATION IN THE RECONSTRUCTION OF ULTRA-HIGH-RESOLUTION PET IMAGES

Reconstructed pictures in positron emission tomography (PET) research are frequently noisy and low quality. The low-count issue is the main source of these issues. Sparse prediction is more likely to be chosen as the solution as sparse technology is employed more frequently. I suggest a brand-new sparse prior technique in this research to process low quality PET reconstructed pictures. Two dictionaries (D1 for low-resolution PET images and D2 for high-resolution PET images) are trained from plenty of actual PET image patches in the proposed approach. The sparse representation for each patch of the input PET picture is then obtained using D1. Finally, D2 is used to create a high-resolution PET image from this sparse representation. The results of the studies show that the suggested strategy has superior effects that improve image resolution and detail recovery that are stable. In terms of root mean square error, this technique performs better quantitatively than older methods (RMSE). The suggested method offers a fresh and effective way to enhance the image quality of PET reconstructions. The back projection technique was created for magnetic resonance imaging (MRI) picture reconstruction of under sampled data and has been used to denoise dynamic PET images. Keywords: PET imaging, data acquisition, artifacts, resolution, information technologies.

Experimental evaluation of convolutional neural network-based inter-crystal scattering recovery for high-resolution PET detectors

Objective. One major limiting factor for achieving high resolution of positron emission tomography (PET) is a Compton scattering of the photon within the crystal, also known as inter-crystal scattering (ICS). We proposed and evaluated a convolutional neural network (CNN) named ICS-Net to recover ICS in light-sharing detectors for real implementations preceded by simulations. ICS-Net was designed to estimate the first-interacted row or column individually from the 8 × 8 photosensor amplitudes. Approach. We tested 8 × 8, 12 × 12, and 21 × 21 Lu2SiO5 arrays with pitches of 3.2, 2.1, and 1.2 mm, respectively. We first performed simulations to measure the accuracies and error distances, comparing the results to previously studied pencil-beam-based CNN to investigate the rationality of implementing fan-beam-based ICS-Net. For experimental implementation, the training dataset was prepared by obtaining coincidences between the targeted row or column of the detector and a slab crystal on a reference detector. ICS-Net was applied to the detector pair measurements with moving a point source from the edge to center using automated stage to evaluate their intrinsic resolutions. We finally assessed the spatial resolution of the PET ring. Main results. The simulation results showed that ICS-Net improved the accuracy compared with the case without recovery, reducing the error distance. ICS-Net outperformed a pencil-beam CNN, which provided a rationale to implement a simplified fan-beam irradiation. With the experimentally trained ICS-Net, the degree of improvements in intrinsic resolutions were 20%, 31%, and 62% for the 8 × 8, 12 × 12, and 21 × 21 arrays, respectively. The impact was also shown in the ring acquisitions, achieving improvements of 11%–46%, 33%–50%, and 47%–64% (values differed from the radial offset) in volume resolutions of 8 × 8, 12 × 12, and 21 × 21 arrays, respectively. Significance. The experimental results demonstrate that ICS-Net can effectively improve the image quality of high-resolution PET using a small crystal pitch, requiring a simplified setup for training dataset acquisition.

Depth-of-interaction positron emission tomography detector with 45° tilted silicon photomultipliers using dual-ended signal readout.

Small-animal positron emission tomography (PET) systems are widely used in molecular imaging research and drug development. There is also growing interest in organ-dedicated clinical PET systems. In these small-diameter PET systems, the measurement of the depth-of-interaction (DOI) of annihilation photons in scintillation crystals allows for the correction of parallax error in PET system, leading to an improvement on the spatial resolution uniformity. The DOI information is also useful for improving the timing resolution of PET system as it enables the correction of DOI-dependent time walk in the arrival time difference measurement of annihilation photon pairs. The dual-ended readout scheme is one of the most widely investigated DOI measurement methods, which collects visible photons using a pair of photosensors located at both ends of the scintillation crystal. Although the dual-ended readout allows for simple and accurate DOI estimation, it requires twice the number of photosensors compared to the single-ended readout scheme. To effectively reduce the number of photosensors in a dual-ended readout scheme, we propose a novel PET detector configuration that employs 45° tilted and sparsely arranged silicon photomultipliers (SiPMs). In this configuration, the angle between the scintillation crystal and SiPM is 45°. Therefore, and thus, the diagonal of the scintillation crystal matches one of the lateral sides of the SiPM. Accordingly, it allows for the use of SiPM device larger than the scintillation crystal, thereby improving light collection efficiency with a higher fill factor and reducing SiPM quantity. In addition, all scintillation crystals can achieve more uniform performance than other dual-ended readout methods with a sparse SiPM arrangement because 50% of the scintillation crystal cross section is commonly in contact with the SiPM. To demonstrate the feasibility of our proposed concept, we implemented a PET detector that employs a 4 4 LSO block with a single crystal dimension of 3.03 × 3.03 × 20 mm3 and a 45° tilted SiPM array. The 45° tilted SiPM array consists of 2 × 3 SiPM elements at the top ("Top SiPM") and 3 × 2 SiPM elements at the bottom ("Bottom SiPM"). Each crystal element of the 4 × 4 LSO block is optically coupled with each quarter section of the Top SiPM and Bottom SiPM pair. To characterize the performance of the PET detector, the energy, DOI, and timing resolution were measured for all 16 crystals. The energy data was obtained by summing all the charges from the Top SiPMs and Bottom SiPMs, and the DOI resolution was measured by irradiating the side of the crystal block at five different depths (2, 6, 10, 14, and 18mm). The timing was estimated by averaging the arrival time of the annihilation photons measured at the Top SiPMs and Bottom SiPMs (Method 1). The DOI-dependent time-walk effect was further corrected by using DOI information and statistical variations in the trigger times at the Top SiPMs and Bottom SiPMs (Method 2). The average DOI resolution of the proposed PET detector was 2.5mm, thereby resolving the DOI at five different depths, and the average energy resolution was 16% full width at half maximum (FWHM). When Methods 1 and 2 were applied, the coincidence timing resolutions were 448 and 411ps FWHM, respectively. We expect that our novel low-cost PET detector design with 45° tilted SiPMs and a dual-ended readout scheme would be a suitable solution for constructing a high-resolution PET system with DOI encoding capability.

Edge effect reduction of high-resolution PET detectors using LYSO and GAGG phoswich crystals

Objective. Small-animal positron emission tomography (PET) is a powerful preclinical imaging tool in animal model studies. The spatial resolution and sensitivity of current PET scanners developed for small-animal imaging need to be improved to increase the quantitative accuracy of preclinical animal studies. This study aimed to improve the identification capability of edge scintillator crystals of a PET detector which will enable to apply a crystal array with the same cross-section area as the active area of a photodetector for improving the detection area and thus reducing or eliminating the inter-detector gaps. Approach. PET detectors using crystal arrays with mixed lutetium yttrium orthosilicate (LYSO) and gadolinium aluminum gallium garnet (GAGG) crystals were developed and evaluated. The crystal arrays consisted of 31 × 31 array of 0.49 × 0.49 × 20 mm3 crystals; they were read out by two silicon photomultiplier arrays with pixel sizes of 2 × 2 mm2 that were placed at both ends of the crystal arrays. The second or first outermost layer of the LYSO crystals was replaced by GAGG crystals in the two crystal arrays. The two crystal types were identified using a pulse-shape discrimination technique to provide better edge crystal identification. Main results. Using the pulse shape discrimination technique, almost all (except for a few edge) crystals were resolved in the two detectors; high sensitivity was achieved by using the scintillator array and the photodetector with the same areas and achieved high resolution by using crystals with sizes equal to 0.49 × 0.49 × 20 mm3. Energy resolutions of 19.3 ± 1.8% and 18.9 ± 1.5%, depth-of-interaction resolutions of 2.02 ± 0.17 mm and 2.04 ± 0.18 mm, and timing resolutions of 1.6 ± 0.2 ns and 1.5 ± 0.2 ns were achieved by the two detectors, respectively. Significance. In summary, novel three-dimensional high-resolution PET detectors consisting of a mixture of LYSO and GAGG crystals were developed. The detectors significantly improve the detection area with the same photodetectors and thus improve the detection efficiency.

Towards high sensitivity and high-resolution PET scanners: imaging-guided proton therapy and total body imaging

Abstract Quantitative imaging (i.e., providing not just an image but also the related data) guidance in proton radiation therapy to achieve and monitor the precision of planned radiation energy deposition field in-vivo (a.k.a. proton range verification) is one of the most under-invested aspects of radiation cancer treatment despite that it may dramatically enhance the treatment accuracy and lower the exposure related toxicity improving the entire outcome of cancer therapy. In this article, we briefly describe the effort of the TPPT Consortium (a collaborative effort of groups from the University of Texas and Portugal) on building a time-of-flight positron-emission-tomography (PET) scanner to be used in pre-clinical studies for proton therapy at MD Anderson Proton Center in Houston. We also discuss some related ideas towards improving and expanding the use of PET detectors, including the total body imaging.

Immuno-PET Imaging and Radioimmunotherapy of Lymphomas.

Monoclonal antibodies (Ab) have revolutionized the management of lymphomas, the most common hematologic malignancy in adults. Indeed, incorporation of rituximab into the regimen for indolent non-Hodgkin's lymphomas (NHLs) has dramatically improved treatment response and disease outcome. Yet, newer Ab therapeutics against promising antigen targets need to be developed to treat refractory or relapsed patients. Treatment efficacy can be further enhanced by conjugating toxic molecules to the Abs. Radioimmunotherapy (RIT) harnesses Abs as vehicles for targeted delivery of therapeutic radionuclide payloads for direct killing of targeted tumor cells. Positron emission tomography (PET) with radiolabeled Abs (called immuno-PET) can facilitate the development of new Ab therapeutics and RIT by providing pharmacokinetic and pharmacodynamic information and by quantifying tumor antigen level relevant for treatment decision. Immuno-PET has recently gravitated toward labeling Abs with 89Zr, a radiometal with a 3.3 day half-life that is trapped following Ab internalization and thus provides high-resolution PET images with excellent contrast. Immuno-PET methods against major lymphoma antigens including CD20 and other promising targets are currently under development. With continued improvements, immuno-PET has the potential to be used in lymphoma management as an imaging biomarker for patient selection and assessment of treatment response.

Brain partial volume correction with point spreading function reconstruction in high-resolution digital PET: comparison with an MR-based method in FDG imaging

ObjectiveIn quantitative positron emission tomography (PET) of the brain, partial volume effect due mainly to the finite spatial resolution of the PET scanner (> 3 mm full width at half maximum [FWHM]) is a primary source of error in the measurement of tracer uptake, especially in small structures such as the cerebral cortex (typically < 3 mm thickness). The aim of this study was to evaluate the partial volume correction (PVC) performance of point spread function-incorporated reconstruction (PSF reconstruction) in combination with the latest digital PET scanner. This evaluation was performed through direct comparisons with magnetic resonance imaging (MR)-based PVC (used as a reference method) in a human brain study.MethodsTen healthy subjects underwent brain 18F-FDG PET (30-min acquisition) on a digital PET/CT system (Siemens Biograph Vision, 3.5-mm FWHM scanner resolution at the center of the field of view) and anatomical T1-weighted MR imaging for MR-based PVC. PSF reconstruction was applied with a wide range of iterations (4 to 256; 5 subsets). FDG uptake in the cerebral cortex was evaluated using the standardized uptake value ratio (SUVR) and compared between PSF reconstruction and MR-based PVC.ResultsCortical structures were visualized by PSF reconstruction with several tens of iterations and were anatomically well matched with the MR-derived cortical segments. Higher numbers of iterations resulted in higher cortical SUVRs, which approached those of MR-based PVC (1.76), although even with the maximum number of iterations they were still smaller by 16% (1.47), corresponding to approximately 1.5-mm FWHM of the effective spatial resolution.ConclusionWith the latest digital PET scanner, PSF reconstruction can be used as a PVC technique in brain PET, albeit with suboptimal resolution recovery. A relative advantage of PSF reconstruction is that it can be applied not only to cerebral cortical regions, but also to various small structures such as small brain nuclei that are hardly visualized on anatomical T1-weighted imaging, and thus hardly recovered by MR-based PVC.

High-resolution and high-sensitivity PET for quantitative molecular imaging of the monoaminergic nuclei: A GATE simulation study.

Quantitative in vivo molecular imaging of fine brain structures requires high-spatial resolution and high-sensitivity. Positron emission tomography (PET) is an attractive candidate to introduce molecular imaging into standard clinical care due to its highly targeted and versatile imaging capabilities based on the radiotracer being used. However, PET suffers from relatively poor spatial resolution compared to other clinical imaging modalities, which limits its ability to accurately quantify radiotracer uptake in brain regions and nuclei smaller than 3 mm in diameter. Here we introduce a new practical and cost-effective high-resolution and high-sensitivity brain-dedicated PET scanner, using our depth-encoding Prism-PET detector modules arranged in a conformal decagon geometry, to substantially reduce the partial volume effect and enable accurate radiotracer uptake quantification in small subcortical nuclei. Two Prism-PET brain scanner setups were proposed based on our 4-to-1 and 9-to-1 coupling of scintillators to readout pixels using mm3 and mm3 crystal columns, respectively. Monte Carlo simulations of our Prism-PET scanners, Siemens Biograph Vision, and United Imaging EXPLORER were performed using Geant4 application for tomographic emission (GATE). National Electrical Manufacturers Association (NEMA) standard was followed for the evaluation of spatial resolution, sensitivity, and count-rate performance. An ultra-micro hot spot phantom was simulated for assessing image quality. A modified Zubal brain phantom was utilized for radiotracer imaging simulations of 5-HT1A receptors, which are abundant in the raphe nuclei (RN), and norepinephrine transporters, which are highly concentrated in the bilateral locus coeruleus (LC). The Prism-PET brain scanner with 1.5 mm crystals is superior to that with 1 mm crystals as the former offers better depth-of-interaction (DOI) resolution, which is key to realizing compact and conformal PET scanner geometries. We achieved uniform 1.3 mm full-width-at-half-maximum (FWHM) spatial resolutions across the entire transaxial field-of-view (FOV), a NEMA sensitivity of 52.1 kcps/MBq, and a peak noise equivalent count rate (NECR) of 957.8 kcps at 25.2 kBq/mL using 450-650 keV energy window. Hot spot phantom results demonstrate that our scanner can resolve regions as small as 1.35 mm in diameter at both center and 10 cm away from the center of the transaixal FOV. Both 5-HT1A receptor and norepinephrine transporter brain simulations prove that our Prism-PET scanner enables accurate quantification of radiotracer uptake in small brain regions, with a 1.8-fold and 2.6-fold improvement in the dorsal RN as well as a 3.2-fold and 4.4-fold improvement in the bilateral LC compared to the Biograph Vision and EXPLORER, respectively. Based on our simulation results, the proposed high-resolution and high-sensitivity Prism-PET brain scanner is a promising cost-effective candidate to achieve quantitative molecular neuroimaging of small but important brain regions with PET clinicallyviable.

Future Prospects of Positron Emission Tomography-Magnetic Resonance Imaging Hybrid Systems and Applications in Psychiatric Disorders.

A positron emission tomography (PET)–magnetic resonance imaging (MRI) hybrid system has been developed to improve the accuracy of molecular imaging with structural imaging. However, the mismatch in spatial resolution between the two systems hinders the use of the hybrid system. As the magnetic field of the MRI increased up to 7.0 tesla in the commercial system, the performance of the MRI system largely improved. Several technical attempts in terms of the detector and the software used with the PET were made to improve the performance. As a result, the high resolution of the PET–MRI fusion system enables quantitation of metabolism and molecular information in the small substructures of the brainstem, hippocampus, and thalamus. Many studies on psychiatric disorders, which are difficult to diagnose with medical imaging, have been accomplished using various radioligands, but only a few studies have been conducted using the PET–MRI fusion system. To increase the clinical usefulness of medical imaging in psychiatric disorders, a high-resolution PET–MRI fusion system can play a key role by providing important information on both molecular and structural aspects in the fine structures of the brain. The development of high-resolution PET–MR systems and their potential roles in clinical studies of psychiatric disorders were reviewed as prospective views in future diagnostics.

Neural correlates of stress and leucocyte telomere length in patients with coronary artery disease

BackgroundAccelerated biological aging, as indicated by telomere shortening, is associated with CAD pathogenesis. In a cross-sectional study, we investigated neural correlates of acute psychological stress and short telomeres in patients with CAD. MethodsIndividuals with CAD (N = 168) underwent a validated mental stress protocol including public speaking and mental arithmetic. Imaging of the brain with [O-15] water and high-resolution positron emission tomography (HR-PET) was performed during mental stress and control conditions. Blood flow during stressful tasks (average of speech and arithmetic) and control tasks were assessed. Telomere length in peripheral leucocytes was measured by quantitative polymerase chain reaction and expressed as Telomere/Single Copy Gene (T/S) ratio. Voxel-wise regression models were constructed to assess the association between brain areas and activity during rest and mental stress after adjustments for demographic factors and clinical characteristics. ResultsThe mean (SD) age of the sample was 62 (8) years, and 69% were men. Increased activation with mental stress in the lingual gyrus, cerebellum and superior and inferior frontal gyri were associated with reduced telomere length; 1.6 higher voxel activation of these areas was associated with 0.1 T/S-units reduction in telomere length (P < 0.005). Additionally, during neutral counting and speaking tasks, brain activity in the precentral, middle and superior frontal and middle temporal gyri was inversely associated with telomere length. Results remained consistent after adjustment for demographic and clinical risk factors. ConclusionIncreased stress-induced activity in brain areas mediating the stress response was associated with shortened telomere length in CAD patients.

Design and modeling of a high resolution and high sensitivity PET brain scanner with double-ended readout

In the wake of recent advancements in scintillator, photodetector, and low-noise fast electronics technologies, as well as in fast reconstruction software, positron emission tomography (PET) scanners have seen considerable improvements in spatial resolution, time resolution, and absolute sensitivity. To continue this trend, we present a helmet type PET brain scanner design that combines high solid angle coverage and double-ended readout of 30 mm-thick scintillator crystals to achieve excellent absolute sensitivity, depth of interaction resolution, and time resolution. This scanner comprises 598 detector arrays, each with 8 × 8 Lu1.8Y0.2SiO5:Ce (LYSO:Ce) crystals with dimensions 3.005 × 3.005 × 30 mm3 one-to-one coupled on either end to silicon photomultipliers (SiPMs). Our Monte Carlo simulations based in the platform Geant4 predict that this scanner would attain an absolute sensitivity to a 35 cm line source placed at the center of the radial field of view of (17.1 ± 0.1)%, a depth of interaction resolution of (3.99 ± 0.05) mm, and a coincidence time resolution of (198 ± 5) ps. Our simulations also predict radial, tangential, and axial spatial resolutions at the center of the field of view of 3.3 mm, 3.1 mm, and 3.3 mm, respectively. As this set of simultaneous parameters compares favorably to today’s most advanced clinical PET scanners and other proposed designs, this scanner has a good chance of becoming a preferred tool for high quality brain imaging.