Seasonal nitrogen remobilization and the role of auxin transport in poplar trees.

Seasonal nitrogen (N) cycling in Populus, involves bark storage proteins (BSPs) that accumulate in bark phloem parenchyma in the autumn and decline when shoot growth resumes in the spring. Little is known about the contribution of BSPs to growth or the signals regulating N remobilization from BSPs. Knockdown of BSP accumulation via RNAi and N sink manipulations were used to understand how BSP storage influences shoot growth. Reduced accumulation of BSPs delayed bud break and reduced shoot growth following dormancy. Further, 13N tracer studies also showed that BSP accumulation is an important factor in N partitioning from senescing leaves to bark. Thus, BSP accumulation has a role in N remobilization during N partitioning both from senescing leaves to bark and from bark to expanding shoots once growth commences following dormancy. The bark transcriptome during BSP catabolism and N remobilization was enriched in genes associated with auxin transport and signaling, and manipulation of the source of auxin or auxin transport revealed a role for auxin in regulating BSP catabolism and N remobilization. Therefore, N remobilization appears to be regulated by auxin produced in expanding buds and shoots that is transported to bark where it regulates protease gene expression and BSP catabolism.

Focused Ultrasound Enabled Trans-Blood Brain Barrier Delivery of Gold Nanoclusters: Effect of Surface Charges and Quantification Using Positron Emission Tomography.

Focused ultrasound (FUS) technology is reported to enhance the delivery of 64 Cu-integrated ultrasmall gold nanoclusters (64 Cu-AuNCs) across the blood-brain barrier (BBB) as measured by positron emission tomography (PET). To better define the optimal physical properties for brain delivery, 64 Cu-AuNCs with different surface charges are synthesized and characterized. In vivo biodistribution studies are performed to compare the individual organ uptake of each type of 64 Cu-AuNCs. Quantitative PET imaging post-FUS treatment shows site-targeted brain penetration, retention, and diffusion of the negative, neutral, and positive 64 Cu-AuNCs. Autoradiography is performed to compare the intrabrain distribution of these nanoclusters. PET Imaging demonstrates the effective BBB opening and successful delivery of 64 Cu-AuNCs into the brain. Of the three 64 Cu-AuNCs investigated, the neutrally charged nanostructure performs the best and is the candidate platform for future theranostic applications in neuro-oncology.

High-resolution Imaging Using Virtual-Pinhole PET Concept.

Organ-specific PET scanners continues to draw interest for their high-resolution imaging capability that is unmatched by whole-body PET/computed tomography (CT) scanners. The virtual-pinhole PET concept offers new opportunities in PET system design, allowing one to mix and match detectors of different characteristics to achieve the highest performance such as high image resolution, high system sensitivity, and large imaging field-of-view. This novel approach delivers high-resolution PET images previously available only through organ-specific PET scanner while maintaining the imaging field-of-view of a clinical PET/CT scanner to see the entire body.

Beyond Average: α-Particle Distribution and Dose Heterogeneity in Bone Metastatic Prostate Cancer.

α-particle emitters are emerging as a potent modality for disseminated cancer therapy because of their high linear energy transfer and localized absorbed dose profile. Despite great interest and pharmaceutical development, there is scant information on the distribution of these agents at the scale of the α-particle pathlength. We sought to determine the distribution of clinically approved [223Ra]RaCl2 in bone metastatic castration-resistant prostate cancer at this resolution, for the first time to our knowledge, to inform activity distribution and dose at the near-cell scale. Methods: Biopsy specimens and blood were collected from 7 patients 24 h after administration. 223Ra activity in each sample was recorded, and the microstructure of biopsy specimens was analyzed by micro-CT. Quantitative autoradiography and histopathology were segmented and registered with an automated procedure. Activity distributions by tissue compartment and dosimetry calculations based on the MIRD formalism were performed. Results: We revealed the activity distribution differences across and within patient samples at the macro- and microscopic scales. Microdistribution analysis confirmed localized high-activity regions in a background of low-activity tissue. We evaluated heterogeneous α-particle emission distribution concentrated at bone-tissue interfaces and calculated spatially nonuniform absorbed-dose profiles. Conclusion: Primary patient data of radiopharmaceutical therapy distribution at the small scale revealed that 223Ra uptake is nonuniform. Dose estimates present both opportunities and challenges to enhance patient outcomes and are a first step toward personalized treatment approaches and improved understanding of α-particle radiopharmaceutical therapies.

3-D Spatial Resolution of 350 µm Pitch Pixelated CdZnTe Detectors for Imaging Applications.

We are currently investigating the feasibility of using highly pixelated Cadmium Zinc Telluride (CdZnTe) detectors for sub-500 µm resolution PET imaging applications. A 20 mm × 20 mm × 5 mm CdZnTe substrate was fabricated with 350 µm pitch pixels (250 µm anode pixels with 100 µm gap) and coplanar cathode. Charge sharing among the pixels of a 350 µm pitch detector was studied using collimated 122 keV and 511 keV gamma ray sources. For a 350 µm pitch CdZnTe detector, scatter plots of the charge signal of two neighboring pixels clearly show more charge sharing when the collimated beam hits the gap between adjacent pixels. Using collimated Co-57 and Ge-68 sources, we measured the count profiles and estimated the intrinsic spatial resolution of 350 µm pitch detector biased at -1000 V. Depth of interaction was analyzed based on two methods, i.e., cathode/anode ratio and electron drift time, in both 122 keV and 511 keV measurements. For single-pixel photopeak events, a linear correlation between cathode/anode ratio and electron drift time was shown, which would be useful for estimating the DOI information and preserving image resolution in CdZnTe PET imaging applications.

A virtual-pinhole PET device for improving contrast recovery and enhancing lesion detectability of a one-meter-long PET scanner: a simulation study.

This paper presents a simulation study to demonstrate that the contrast recovery coefficients (CRC) and detectability of small lesions of a one-meter-long positron emission tomography (PET) scanner can be further enhanced by the integration of high resolution virtual-pinhole (VP) PET devices. The scanner under investigation is a Siemens Biograph Vision Quadra which has an axial field-of-view (FOV) of 106 cm. The VP-PET devices contain two high-resolution flat panel detectors, each composed of 2 × 8 detector modules each of which consists of 32 × 64 lutetium-oxyorthosilicate crystals (1.0 × 1.0 × 10.0 mm3each). Two configurations for the VP-PET device placement were evaluated: (1) place the two flat-panel detectors at the center of the scanner's axial FOV below the patient bed; (2) place one flat-panel detector at the center of the first and the last quarter of the scanner's axial FOV below the patient bed. Sensitivity profiles were measured by moving a point22Na source stepwise across the scanner's FOV axially at different locations. To assess the improvement in CRC and lesion detectability by the VP-PET devices, an elliptical torso phantom (31.6 × 22.8 × 106 cm3) was first imaged by the native scanner then subsequently by the two VP-PET geometry configurations. Spherical lesions (4 mm in diameter) having 5:1 lesion-to-background radioactivity concentration ratio were grouped and placed at nine regions in the phantom to analyze the dependence of the improvement in plane. Average CRCs and their standard deviations of the 7 tumors in each group were computed and the receiver operating characteristic (ROC) curves were drawn to evaluate the improvement in lesion detectability by the VP-PET device over the native long axial PET scanner. The fraction of coincidence events between the inserts and the scanner detectors was 13%-16% (out of the total number of coincidences) for VP-PET configuration 1 and 2, respectively. The VP-PET systems provide higher CRCs for lesions in all regions in the torso, with more significant enhancement at regions closer to the inserts, than the native scanner does. For any given false positive fraction, the VP-PET systems offer higher true positive fraction compared to the native scanner. This work provides a potential solution to further enhance the image resolution of a long axial FOV PET scanner to maximize its lesion detectability afforded by its super high effective sensitivity.

Positron Emission Tomography (PET) for Molecular Plant Imaging.

Positron emission tomography (PET) is an imaging technology that measures 3D spatial distribution and kinetics of radio-tagged biomolecules in a living subject quantitatively and nondestructively. Commonly used positron-emitting radionuclides include 11C, 13N, and 15O, which are essential elements for plant growth. Combining radiotracer techniques with PET, this in vivo molecular imaging capability offers plant biologists a powerful tool for molecular phenotyping research. While PET is widely used clinically for cancer diagnosis and pre-clinically for drug development, it is an unfamiliar imaging tool for plant biologists. This chapter introduces the basic principles of PET, factors that affect the quantitative accuracy of PET when imaging plants, and techniques for administering radiotracers to plants for a variety of molecular plant imaging applications.

Parallel Beam Approximation for Calculation of Detection Efficiency of Crystals in PET Detector Arrays.

In this work we propose a parallel beam approximation for the computation of the detection efficiency of crystals in a PET detector array. In this approximation the detection efficiency of a crystal is estimated using the distance between source and the crystal and the pre-calculated detection cross section of the crystal in a crystal array which is calculated for a uniform parallel beam of gammas. The pre-calculated detection cross sections for a few representative incident angles and gamma energies can be used to create a look-up table to be used in simulation studies or practical implementation of scatter or random correction algorithms. Utilizing the symmetries of the square crystal array, the pre-calculated look-up tables can be relatively small. The detection cross sections can be measured experimentally, calculated analytically or simulated using a Monte Carlo (MC) approach. In this work we used a MC simulation that takes into account the energy windowing, Compton scattering and factors in the "block effect". The parallel beam approximation was validated by a separate MC simulation using point sources located at different positions around a crystal array. Experimentally measured detection efficiencies were compared with Monte Carlo simulated detection efficiencies. Results suggest that the parallel beam approximation provides an efficient and accurate way to compute the crystal detection efficiency, which can be used for estimation of random and scatter coincidences for PET data corrections.

Performance comparison of a dedicated total breast PET system with a clinical whole-body PET system: a simulation study.

This paper presents a novel PET geometry for breast cancer imaging. The scanner consists of a 'stadium' (a rectangle with two semi-circles on opposite sides) shaped ring, along with anterior and posterior panels to provide high sensitivity and high spatial resolution for an imaging field-of-view (FOV) that include both breasts, mediastinum and axilla. We simulated this total-breast PET system using GATE and reconstructed the coincidence events using a GPU-based list-mode image reconstruction implementing maximum likelihood expectation-maximization (ML-EM) algorithm. The rear-panel is made up of a single layer of LSO crystals (3.2 × 3.2 × 20 mm3each), while the 'stadium'-shaped elongated ring and the anterior panel are made with dual-layered LSO crystals (1.6 × 1.6 × 6 mm3each). The energy resolution and coincidence resolving time of all detectors are assumed to be 12% and 250 ps full-width-at-half-maximum, respectively. Various sized simulated lesions (4, 5, 6 mm) having 4:1, 5:1, and 6:1 lesion-to-background radioactivity concentration ratios, mimicking different biological uptakes, were strategically located throughout a volumetric torso phantom. We compared system sensitivity and lesion detectability of the dedicated total-breast PET system to a state-of-the-art clinical whole-body PET scanner. The mean sensitivity of the total-breast PET system is 3.21 times greater than that of a whole-body PET scanner in the breast regions. The total-breast PET system also provides better contrast-recovery coefficients for lesions of all sizes and lesion-to-background ratios in the breast when compared to a reference clinical whole-body PET scanner. Receiver operating characteristics (ROC) study shows the area under the ROC curve is 0.948 and 0.924 for the total-breast system and the whole-body PET scanner, respectively, in the detection of 4 mm diameter lesions with 4:1 lesion-to-background ratio. This study demonstrates our novel geometry can provide an imaging FOV larger than conventional PEM systems to simultaneously image both breasts, chest wall and axillae with significantly improved lesion detectability in the breasts when compared to a whole-body PET scanner.

Compton Scattering in Clinical PET/CT With High Resolution Half Ring PET Insert Device.

The integration of a high resolution PET insert into a conventional PET system can significantly improve the resolution and the contrast of its images within a reduced imaging field of view. For the rest of the scanner imaging field of view, the insert is a highly attenuating and scattering media. In order to use all available coincidence events (including coincidences between 2 detectors in the original scanner, namely the scanner-scanner coincidences), appropriate scatter and attenuation corrections have to be implemented. In this work, we conducted a series of Monte Carlo simulations to estimate the composition of the scattering background and the importance of the scatter correction. We implemented and tested the Single Scatter Simulation (SSS) algorithm for a hypothetical system and show good agreement between the estimated scatter using SSS and Monte Carlo simulated scatter contribution. We further applied the SSS to estimate scatter contribution from an existing prototype PET insert for a clinical PET/CT scanner. The results demonstrated the applicability of SSS to estimate the scatter contribution within a clinical PET/CT system even when there is a high resolution half ring PET insert device in its imaging field of view.

Augmented Whole-Body Scanning via Magnifying PET.

A novel technique, called augmented whole-body scanning via magnifying PET (AWSM-PET), that improves the sensitivity and lesion detectability of a PET scanner for whole-body imaging is proposed and evaluated. A Siemens Biograph Vision PET/CT scanner equipped with one or two high-resolution panel-detectors was simulated to study the effectiveness of AWSM-PET technology. The detector panels are located immediately outside the scanner's axial field-of-view (FOV). A detector panel contains 2 ×8 detector modules each consisting of 32 ×64 LSO crystals ( 1.0 ×1.0 ×10.0 mm3 each). A 22Na point source was stepped across the scanner's FOV axially to measure sensitivity profiles at different locations. An elliptical torso phantom containing 7×9 spherical lesions was imaged at different axial locations to mimic a multi-bed-position whole-body imaging protocol. Receiver operating characteristic (ROC) curves were analyzed to evaluate the improvement in lesion detectability by the AWSM-PET technology. Experimental validation was conducted using an existing flat-panel detector integrated with a Siemens Biograph 40 PET/CT scanner to image a torso phantom containing spherical lesions with diameters ranging from 3.3 to 11.4 mm. The contrast-recovery-coefficient (CRC) of the lesions was evaluated for the scanner with or without the AWSM-PET technology. Monte Carlo simulation shows 36%-42% improvement in system sensitivity by a dual-panel AWSM-PET device. The area under the ROC curve is 0.962 by a native scanner for the detection of 4 mm diameter lesions with 5:1 tumor-to-background activity concentration. It was improved to 0.977 and 0.991 with a single- and dual-panel AWSM-PET system, respectively. Experimental studies showed that the average CRC of 3.3 mm and 4.3 mm diameter tumors were improved from 2.8% and 4.2% to 7.9% and 11.0%, respectively, by a single-panel AWSM-PET device. With a high-sensitivity dual-panel device, the corresponding CRC can be further improved to 11.0% and 15.9%, respectively. The principle of the AWSM-PET technology has been developed and validated. Enhanced system sensitivity, CRC and tumor detectability were demonstrated by Monte Carlo simulations and imaging experiments. This technology may offer a cost-effective path to realize high-resolution whole-body PET imaging clinically.

Magnetic Resonance Imaging-Guided Focused Ultrasound-Based Delivery of Radiolabeled Copper Nanoclusters to Diffuse Intrinsic Pontine Glioma.

Diffuse intrinsic pontine glioma (DIPG) is an invasive pediatric brainstem malignancy exclusively in children without effective treatment due to the often-intact blood-brain tumor barrier (BBTB), an impediment to the delivery of therapeutics. Herein, we used focused ultrasound (FUS) to transiently open BBTB and delivered radiolabeled nanoclusters (64Cu-CuNCs) to tumors for positron emission tomography (PET) imaging and quantification in a mouse DIPG model. First, we optimized FUS acoustic pressure to open the blood-brain barrier (BBB) for effective delivery of 64Cu-CuNCs to pons in wildtype mice. Then the optimized FUS pressure was used to deliver radiolabeled agents in DIPG mouse. Magnetic resonance imaging (MRI)-guided FUS-induced BBTB opening was demonstrated using a low molecular weight, short-lived 68Ga-DOTA-ECL1i radiotracer and PET/CT before and after treatment. We then compared the delivery efficiency of 64Cu-CuNCs to DIPG tumor with and without FUS treatment and demonstrated the FUS-enhanced delivery and time-dependent diffusion of 64Cu-CuNCs within the tumor.

Cherenkov luminescence imaging of shallow sources in semitransparent media.

We experimentally investigated the Cherenkov luminescence imaging (CLI) of the isotopes with different beta particles energies (Cu64, F18, Au198, P32, and Br76) in semitransparent biological equivalent media. The main focus of this work is to characterize the CLI when the sources are at the depth comparable with the range of beta particles. The experimental results were compared with Monte Carlo (MC) simulation results to fine tune the simulation parameters to better model the phantom materials. This approach can be applied to estimate the CLI performance for different phantom materials and isotopes. This work also demonstrates some unique properties of high energy beta particles that can be beneficial for CLI, including the possibility to utilize the betas escaped from the object for imaging purposes.

Feasibility study of a point-of-care positron emission tomography system with interactive imaging capability.

PURPOSE: We investigated the feasibility of a novel positron emission tomography (PET) system that provides near real-time feedback to an operator who can interactively scan a patient to optimize image quality. The system should be compact and mobile to support point-of-care (POC) molecular imaging applications. In this study, we present the key technologies required and discuss the potential benefits of such new capability. METHODS: The core of this novel PET technology includes trackable PET detectors and a fully three-dimensional, fast image reconstruction engine implemented on multiple graphics processing units (GPUs) to support dynamically changing geometry by calculating the system matrix on-the-fly using a tube-of-response approach. With near real-time image reconstruction capability, a POC-PET system may comprise a maneuverable front PET detector and a second detector panel which can be stationary or moved synchronously with the front detector such that both panels face the region-of-interest (ROI) with the detector trajectory contoured around a patient's body. We built a proof-of-concept prototype using two planar detectors each consisting of a photomultiplier tube (PMT) optically coupled to an array of 48 × 48 lutetium-yttrium oxyorthosilicate (LYSO) crystals (1.0 × 1.0 × 10.0 mm3 each). Only 38 × 38 crystals in each arrays can be clearly re-solved and used for coincidence detection. One detector was mounted to a robotic arm which can position it at arbitrary locations, and the other detector was mounted on a rotational stage. A cylindrical phantom (102 mm in diameter, 150 mm long) with nine spherical lesions (8:1 tumor-to-background activity concentration ratio) was imaged from 27 sampling angles. List-mode events were reconstructed to form images without or with time-of-flight (TOF) information. We conducted two Monte Carlo simulations using two POC-PET systems. The first one uses the same phantom and detector setup as our experiment, with the detector coincidence re-solving time (CRT) ranging from 100 to 700 ps full-width-at-half-maximum (FWHM). The second study simulates a body-size phantom (316 × 228 × 160 mm3 ) imaged by a larger POC-PET system that has 4 × 6 modules (32 × 32 LYSO crystals/module, four in axial and six in transaxial directions) in the front panel and 3 × 8 modules (16 × 16 LYSO crystals/module, three in axial and eight in transaxial directions) in the back panel. We also evaluated an interactive scanning strategy by progressively increasing the number of data sets used for image reconstruction. The updated images were analyzed based on the number of data sets and the detector CRT. RESULTS: The proof-of-concept prototype re-solves most of the spherical lesions despite a limited number of coincidence events and incomplete sampling. TOF information reduces artifacts in the reconstructed images. Systems with better timing resolution exhibit improved image quality and reduced artifacts. We observed a reconstruction speed of 0.96 × 106 events/s/iteration for 600 × 600 × 224 voxel rectilinear space using four GPUs. A POC-PET system with significantly higher sensitivity can interactively image a body-size object from four angles in less than 7 min. CONCLUSIONS: We have developed GPU-based fast image reconstruction capability to support a PET system with arbitrary and dynamically changing geometry. Using TOF PET detectors, we demonstrated the feasibility of a PET system that can provide timely visual feedback to an operator who can scan a patient interactively to support POC imaging applications.

A second-generation virtual-pinhole PET device for enhancing contrast recovery and improving lesion detectability of a whole-body PET/CT scanner.

PURPOSE: We have developed a second-generation virtual-pinhole (VP) positron emission tomography (PET) device that can position a flat-panel PET detector around a patient's body using a robotic arm to enhance the contrast recovery coefficient (CRC) and detectability of lesions in any region-of-interest using a whole-body PET/computed tomography (CT) scanner. METHODS: We constructed a flat-panel VP-PET device using 32 high-resolution detectors, each containing a 4  ×  4 MPPC array and 16  ×  16 LYSO crystals of 1.0  ×  1.0  ×  3.0 mm3 each. The flat-panel detectors can be positioned around a patient's body anywhere in the imaging field-of-view (FOV) of a Siemens Biograph 40 PET/CT scanner by a robotic arm. New hardware, firmware and software have been developed to support the additional detector signals without compromising a scanner's native functions. We stepped a 22 Na point source across the axial FOV of the scanner to measure the sensitivity profile of the VP-PET device. We also recorded the coincidence events measured by the scanner detectors and by the VP-PET detectors when imaging phantoms of different sizes. To assess the improvement in the CRC of small lesions, we imaged an elliptical torso phantom measuring 316  ×  228  ×  162 mm3 that contains spherical tumors with diameters ranging from 3.3 to 11.4 mm with and without the VP-PET device. Images were reconstructed using a list mode Maximum-Likelihood Estimation-Maximization algorithm implemented on multiple graphics processing units (GPUs) to support the unconventional geometries enabled by a VP-PET system. The mean and standard deviation of the CRC were calculated for tumors of different sizes. Monte Carlo simulation was also conducted to image clusters of lesions in a torso phantom using a PET/CT scanner alone or the same scanner equipped with VP-PET devices. Receiver operating characteristic (ROC) curves were analyzed for three system configurations to evaluate the improvement in lesion detectability by the VP-PET device over the native PET/CT scanner. RESULTS: The repeatability in positioning the flat-panel detectors using a robotic arm is better than 0.15 mm in all three directions. Experimental results show that the average CRC of 3.3, 4.3, and 6.0 mm diameter tumors was 0.82%, 2.90%, and 5.25%, respectively, when measured by the native scanner. The corresponding CRC was 2.73%, 6.21% and 10.13% when imaged by the VP-PET insert device with the flat-panel detector under the torso phantom. These values may be further improved to 4.31%, 9.65% and 18.01% by a future dual-panel VP-PET insert device if DOI detectors are employed to triple its detector efficiency. Monte Carlo simulation results show that the tumor detectability can be improved by a VP-PET device that has a single flat-panel detector. The improvement is greater if the VP-PET device employs a dual-panel design. CONCLUSIONS: We have developed a prototype flat-panel VP-PET device and integrated it with a clinical PET/CT scanner. It significantly enhances the contrast of lesions, especially for those that are borderline detectable by the native scanner, within regions-of-interest specified by users. Simulation demonstrated the enhancement in lesion detectability with the VP-PET device. This technology may become a cost-effective solution for organ-specific imaging tasks.

A feasibility study of a prototype PET insert device to convert a general-purpose animal PET scanner to higher resolution.

UNLABELLED: We developed a prototype system to evaluate the feasibility of using a PET insert device to achieve higher resolution from a general-purpose animal PET scanner. METHODS: The system consists of a high-resolution PET detector, a computer-controlled rotation stage, and a custom mounting plate. The detector consists of a cerium-doped lutetium oxyorthosilicate array (12 x 12 crystals, 0.8 x 1.66 x 3.75 mm(3) each) directly coupled to a position-sensitive photomultiplier tube (PS-PMT). The detector signals were fed into the scanner electronics to establish coincidences between the 2 systems. The detector was mounted to a rotation stage that is attached to the scanner via the custom mounting plate after removing the transmission source holder. The rotation stage was concentric with the center of the scanner. The angular offset of the insert detector was calibrated via optimizing point-source images. In all imaging experiments, coincidence data were collected from 9 angles to provide 180 degrees sampling. A (22)Na point source was imaged at different offsets from the center to characterize the in-plane resolution of the insert system. A (68)Ge point source was stepped across the axial field of view to measure the sensitivity of the system. A 23.2-g mouse was injected with 38.5 MBq of (18)F-fluoride and imaged at 3 h after injection for 2 h. RESULTS: The transverse image resolution of the PET insert device ranges from 1.1- to 1.4-mm full width at half maximum (FWHM) without correction for the point-source dimension. This corresponds to approximately 33% improvement over the resolution of the original scanner (1.7- to 1.8-mm FWHM) in 2 of the 3 directions. The sensitivity of the device is 0.064% at the center of the field, 46-fold lower than the sensitivity of an existing animal PET scanner. The mouse bone scan had improved image resolution using the PET insert device over that of the existing animal PET scanner alone. CONCLUSION: We have demonstrated the feasibility of using a high-resolution insert device in an existing PET scanner to provide high-resolution PET. A PET insert device with more detector modules will improve sensitivity and may become an alternative to special-purpose PET systems for high-resolution PET.

Virtual-pinhole PET.

UNLABELLED: We proposed and tested a novel geometry for PET system design analogous to pinhole SPECT called the virtual-pinhole PET (VP-PET) geometry to determine whether it could provide high-resolution images. METHODS: We analyzed the effects of photon acolinearity and detector sizes on system resolution and extended the empiric formula for reconstructed image resolution of conventional PET proposed earlier to predict the resolutions of VP-PET. To measure the system resolution of VP-PET, we recorded coincidence events as a (22)Na point source was stepped across the coincidence line of response between 2 detectors made from identical arrays of 12 x 12 lutetium oxyorthosilicate crystals (each measuring 1.51 x 1.51 x 10 mm(3)) separated by 565 mm. To measure reconstructed image resolution, we built 4 VP-PET systems using 4 types of detectors (width, 1.51-6.4 mm) and imaged 4 point sources of (64)Cu (half-life = 12.7 h to allow a long acquisition time). Tangential and radial resolutions were measured and averaged for each source and each system. We then imaged a polystyrene plastic phantom representing a 2.5-cm-thick cross-section of isolated breast volume. The phantom was filled with an aqueous solution of (64)Cu (713 kBq/mL) in which the following were imbedded: 4 spheric tumors ranging from 1.8 to 12.6 mm in inner diameter (ID), 6 micropipettes (0.7- or 1.1-mm ID filled with (64)Cu at 5x, 20x, or 50x background), and a 10.0-mm outer-diameter cold lesion. RESULTS: The shape and measured full width at half maximum of the line spread functions agree well with the predicted values. Measured reconstructed image resolution (2.40-3.24 mm) was +/-6% of the predicted value for 3 of the 4 systems. In one case, the difference was 12.6%, possibly due to underestimation of the block effect from the low-resolution detector. In phantom experiments, all spheric tumors were detected. Small line sources were detected if the activity concentration is at least 20x background. CONCLUSION: We have developed and characterized a novel geometry for PET. A PET system following the VP-PET geometry provides high-resolution images for objects near the system's high-resolution detectors. This geometry may lead to the development of special-purpose PET systems or resolution-enhancing insert devices for conventional PET scanners.

Micro insert: a prototype full-ring PET device for improving the image resolution of a small-animal PET scanner.

UNLABELLED: A full-ring PET insert device should be able to enhance the image resolution of existing small-animal PET scanners. METHODS: The device consists of 18 high-resolution PET detectors in a cylindric enclosure. Each detector contains a cerium-doped lutetium oxyorthosilicate array (12 x 12 crystals, 0.72 x 1.51 x 3.75 mm each) coupled to a position-sensitive photomultiplier tube via an optical fiber bundle made of 8 x 16 square multiclad fibers. Signals from the insert detectors are connected to the scanner through the electronics of the disabled first ring of detectors, which permits coincidence detection between the 2 systems. Energy resolution of a detector was measured using a (68)Ge point source, and a calibrated (68)Ge point source stepped across the axial field of view (FOV) provided the sensitivity profile of the system. A (22)Na point source imaged at different offsets from the center characterized the in-plane resolution of the insert system. Imaging was then performed with a Derenzo phantom filled with 19.5 MBq of (18)F-fluoride and imaged for 2 h; a 24.3-g mouse injected with 129.5 MBq of (18)F-fluoride and imaged in 5 bed positions at 3.5 h after injection; and a 22.8-g mouse injected with 14.3 MBq of (18)F-FDG and imaged for 2 h with electrocardiogram gating. RESULTS: The energy resolution of a typical detector module at 511 keV is 19.0% +/- 3.1%. The peak sensitivity of the system is approximately 2.67%. The image resolution of the system ranges from 1.0- to 1.8-mm full width at half maximum near the center of the FOV, depending on the type of coincidence events used for image reconstruction. Derenzo phantom and mouse bone images showed significant improvement in transaxial image resolution using the insert device. Mouse heart images demonstrated the gated imaging capability of the device. CONCLUSION: We have built a prototype full-ring insert device for a small-animal PET scanner to provide higher-resolution PET images within a reduced imaging FOV. Development of additional correction techniques are needed to achieve quantitative imaging with such an insert.

Focused ultrasound combined with microbubble-mediated intranasal delivery of gold nanoclusters to the brain.

Focused ultrasound combined with microbubble-mediated intranasal delivery (FUSIN) is a new brain drug delivery technique. FUSIN utilizes the nasal route for direct nose-to-brain drug administration, thereby bypassing the blood-brain barrier (BBB) and minimizing systemic exposure. It also uses FUS-induced microbubble cavitation to enhance transport of intranasally (IN) administered agents to the FUS-targeted brain location. Previous studies have provided proof-of-concept data showing the feasibility of FUSIN to deliver dextran and the brain-derived neurotrophic factor to the caudate putamen of mouse brains. The objective of this study was to evaluate the biodistribution of IN administered gold nanoclusters (AuNCs) and assess the feasibility and short-term safety of FUSIN for the delivery of AuNCs to the brainstem. Three experiments were performed. First, the whole-body biodistribution of IN administered 64Cu-alloyed AuNCs (64Cu-AuNCs) was assessed using in vivo positron emission tomography/computed tomography (PET/CT) and verified with ex vivo gamma counting. Control mice were intravenously (IV) injected with the 64Cu-AuNCs. Second, 64Cu-AuNCs and Texas red-labeled AuNCs (TR-AuNCs) were used separately to evaluate FUSIN delivery outcome in the brain. 64Cu-AuNCs or TR-AuNCs were administered to mice through the nasal route, followed by FUS sonication at the brainstem in the presence of systemically injected microbubbles. The spatial distribution of 64Cu-AuNCs and TR-AuNCs were examined by autoradiography and fluorescence microscopy of ex vivo brain slices, respectively. Third, histological analysis was performed to evaluate any potential histological damage to the nose and brain after FUSIN treatment. The experimental results revealed that IN administration induced significantly lower 64Cu-AuNCs accumulation in the blood, lungs, liver, spleen, kidney, and heart compared with IV injection. FUSIN enhanced the delivery of 64Cu-AuNCs and TR-AuNCs at the FUS-targeted brain region compared with IN delivery alone. No histological-level tissue damage was detected in the nose, trigeminal nerve, and brain. These results suggest that FUSIN is a promising technique for noninvasive, spatially targeted, and safe delivery of nanoparticles to the brain with minimal systemic exposure.

Focused ultrasound-enabled delivery of radiolabeled nanoclusters to the pons.

The goal of this study was to establish the feasibility of integrating focused ultrasound (FUS)-mediated delivery of 64Cu-integrated gold nanoclusters (64Cu-AuNCs) to the pons for in vivo quantification of the nanocluster brain uptake using positron emission tomography (PET) imaging. FUS was targeted at the pons for the blood-brain barrier (BBB) disruption in the presence of systemically injected microbubbles, followed by the intravenous injection of 64Cu-AuNCs. The spatiotemporal distribution of the 64Cu-AuNCs in the brain was quantified using in vivo microPET/CT imaging at different time points post injection. Following PET imaging, the accumulation of radioactivity in the pons was further confirmed using autoradiography and gamma counting, and the gold concentration was quantified using inductively coupled plasma-mass spectrometry (ICP-MS). We found that the noninvasive and localized BBB opening by the FUS successfully delivered the 64Cu-AuNCs to the pons. We also demonstrated that in vivo real-time microPET/CT imaging was a reliable method for monitoring and quantifying the brain uptake of 64Cu-AuNCs delivered by the FUS. This drug delivery platform that integrates FUS, radiolabeled nanoclusters, and PET imaging provides a new strategy for noninvasive and localized nanoparticle delivery to the pons with concurrent in vivo quantitative imaging to evaluate delivery efficiency. The long-term goal is to apply this drug delivery platform to the treatment of pontine gliomas.