Performance evaluation of resolution and sensitivity of C-SPECT's variable slat-stack collimator.

BACKGROUND: Myocardial perfusion imaging is commonly performed using SPECT, where both general-purpose and dedicated scanners are available. A limitation with general-purpose systems has been the inability to image dynamically since different projections are obtained far apart in time due to scanner rotation. Dedicated systems can have this capability since they acquire completely sampled projections (i.e., those with enough angular views for reconstruction) with short time frames. C-SPECT, does not need any scanner or patient motion to obtain complete projections, allowing fast dynamics. When imaging fast dynamics, the optimal collimator settings are not necessarily the same as for static imaging, where longer acquisitions can be utilized. Thus, C-SPECT offers adaptive collimation in the transverse and axial directions. PURPOSE: The performance of adaptation in the axial direction was characterized herein. METHODS: The ratio of the resolution metric in high-sensitivity mode to that in the high-resolution mode, termed resolution boost factor, was determined. Analogously, the sensitivity boost factor was also determined. Comparisons were made with theory and simulations. RESULTS: The boost factors for resolution and sensitivity, averaged over the 14 modules of the system, were determined to be 1.72 and 1.75, respectively. CONCLUSIONS: The boost factors, which ideally would be two, were between 10% and 15% below optimal values and tracked each other, suggesting mechanical challenges in the apparatus, such as incomplete closure of adjacent slats, but show reasonably successful adaptation between modes.

Quantification of defect contrast in microSPECT imaging of a myocardial phantom.

Ischemic heart disease remains a significant public health concern, accentuating the importance of basic research and therapeutic studies of small animals in which myocardial changes can be reproducibly detected and quantified. Few or no studies have investigated the performance of microSPECT in quantifying myocardial lesions. We utilized three versions of a multi-compartment phantom containing two left ventricular myocardial compartments (one uniform and one with a transmural 'cold' defect), a ventricular blood pool, and a background compartment, where each version had a different myocardial wall thickness (0.75, 1.0 and 1.25 mm). Each compartment was imaged separately while acquiring list-mode data. The separate compartment data were manipulated into a single data set with a known defect contrast, blood-pool and background activity. Data were processed with background-free defect-contrast values of 0 (no defect), -0.25, -0.5, -0.75, and -1.0 (all defect), three ratios of blood-pool to myocardial activity, 0 (no blood pool activity), 0.1, and 0.2 (20% of the activity in the healthy myocardial compartment), and three ratios of uniform background 0 (no background activity), 0.1 and 0.2, relative to the healthy myocardial compartment. For each wall thickness, defect contrast, blood-pool, and background activity combination, 25 list-mode noise realizations were generated and reconstructed. Volumes of interest were drawn and used to determine mean contrast recovery coefficients (CRCs) over the noise ensembles. We developed a slope-analysis procedure to estimate a single CRC over all contrast levels, with resulting CRC values (for no blood-pool and no background) of 0.848, 0.946, and 0.834 for the 0.75, 1.0, and 1.25 mm wall thicknesses, respectively. We also determined and validated a reprocessing method to calculate an ideal CRC. This work demonstrates the quantitative abilities of microSPECT for myocardial-defect imaging utilizing CRC and establishes a framework for evaluating defect-imaging capabilities in other systems.

Quantification of myocardial uptake rate constants in dynamic small-animal SPECT using a cardiac phantom.

Myocardial blood flow and myocardial blood flow reserve (MBFR) measurements are often used clinically to quantify coronary microvascular function. Developing imaging-based methods to measure MBFR for research in mice would be advantageous for evaluating new treatment methods for coronary microvascular disease (CMVD), yet this is more challenging in mice than in humans. This work investigates microSPECT's quantitative capabilities of cardiac imaging by utilizing a multi-part cardiac phantom and applying a known kinetic model to synthesize kinetic data from static data, allowing for assessment of kinetic modeling accuracy. The phantom was designed with four main components: two left-ventricular (LV) myocardial sections and two LV blood-pool sections, sized for end-systole (ES) and end-diastole (ED). Each section of the phantom was imaged separately while acquiring list-mode data. These static, separate-compartment data were manipulated into synthetic dynamic data using a kinetic model representing the myocardium and blood-pool activity concentrations over time and then combined into a set of dynamic image frames and reconstructed. Regions of interest were drawn on the resulting images, and kinetic parameters were estimated. This process was performed for three tracer uptake values (K 1), three myocardial wall thicknesses, ten filter parameters, and 20 iterations for 25 noise ensembles. The degree of filtering and iteration number were optimized to minimize the root mean-squared error (RMSE) of K 1 values, with the largest number of iterations and minimal filtering yielding the lowest error. Using the optimized parameters, K 1 was determined with reasonable error (~3% RMSE) over all wall thicknesses and K 1 input values. This work demonstrates that accurate and precise measurements of K 1 are possible for the U-SPECT+ system used in this study, for several different uptake rates and LV dimensions. Additionally, it allows for future investigation utilizing other imaging systems, including PET studies with any radiotracer, as well as with additional phantom parts containing lesions.

Task-based design of a synthetic-collimator SPECT system used for small animal imaging.

PURPOSE: In traditional multipinhole SPECT systems, image multiplexing - the overlapping of pinhole projection images - may occur on the detector, which can inhibit quality image reconstructions due to photon-origin uncertainty. One proposed system to mitigate the effects of multiplexing is the synthetic-collimator SPECT system. In this system, two detectors, a silicon detector and a germanium detector, are placed at different distances behind the multipinhole aperture, allowing for image detection to occur at different magnifications and photon energies, resulting in higher overall sensitivity while maintaining high resolution. The unwanted effects of multiplexing are reduced by utilizing the additional data collected from the front silicon detector. However, determining optimal system configurations for a given imaging task requires efficient parsing of the complex parameter space, to understand how pinhole spacings and the two detector distances influence system performance. METHODS: In our simulation studies, we use the ensemble mean-squared error of the Wiener estimator (EMSEW ) as the figure of merit to determine optimum system parameters for the task of estimating the uptake of an 123 I-labeled radiotracer in three different regions of a computer-generated mouse brain phantom. The segmented phantom map is constructed by using data from the MRM NeAt database and allows for the reduction in dimensionality of the system matrix which improves the computational efficiency of scanning the system's parameter space. To contextualize our results, the Wiener estimator is also compared against a region of interest estimator using maximum-likelihood reconstructed data. RESULTS: Our results show that the synthetic-collimator SPECT system outperforms traditional multipinhole SPECT systems in this estimation task. We also find that image multiplexing plays an important role in the system design of the synthetic-collimator SPECT system, with optimal germanium detector distances occurring at maxima in the derivative of the percent multiplexing function. Furthermore, we report that improved task performance can be achieved by using an adaptive system design in which the germanium detector distance may vary with projection angle. Finally, in our comparative study, we find that the Wiener estimator outperforms the conventional region of interest estimator. CONCLUSIONS: Our work demonstrates how this optimization method has the potential to quickly and efficiently explore vast parameter spaces, providing insight into the behavior of competing factors, which are otherwise very difficult to calculate and study using other existing means.

Design of a dual-resolution collimator for preclinical cardiac SPECT with a stationary triple-detector system.

PURPOSE: One approach to preclinical single-photon emission computed tomography (SPECT) imaging that provides both high resolution and high sensitivity is based on imaging a mouse inside a collimating tube; many magnified pinhole projection images from a small target region, e.g., the heart, can be recorded simultaneously on multiple detectors with little multiplexing since each pinhole aperture's opening angle is restricted to view mostly the target organ. However, to obtain complete data for reconstruction, it may be necessary to scan the mouse through the target region of the tube. The authors are developing a different approach based on acquisition and reconstruction of both low-resolution and high-resolution projection data acquired sequentially through many pinholes embedded in two tungsten tube sections of different diameters, a "scout" section and a high-resolution section, placed end-to-end along the axis of a triple-head clinical SPECT scanner. This paper describes the design procedures used to determine the geometric parameters of two new collimator-tube sections, as well as one approach for joint reconstruction of data acquired from both sections. METHODS: The high-resolution section was designed by projecting as many pinhole views of a simulated mouse heart as possible over each detector's camera, with no overlapping of heart projections and minimal overlapping between adjacent "hot" organ and cardiac projections. The authors then jointly optimized the geometric design of the scout section for a triple-detector camera system, as well as the number of maximum-likelihood expectation maximization (MLEM) iterations required to provide minimum mean-squared error of reconstructed voxel counts throughout a 7-cm axial range, with the constraints of fixed, 2.4-mm scout system resolution at the tube center for all apertures, limited multiplexing, and no detector motion. Simulated mouse projection data from both tube sections were then reconstructed to illustrate a simple approach for using high-resolution data to improve the whole-body scout images within a cylindrical region surrounding the heart. RESULTS: The 2-cm-inner-radius high-resolution tube section accommodated 87 platinum-iridium pinhole inserts, each with a 0.3-mm square aperture; their radial distances from the centerline of the system ranged from 2.2 to 3.0 cm. The optimal radial distance to the closest scout pinhole and optimal number of MLEM iterations were 4.4 cm and 35 iterations, respectively, and the radial distances of the 39 scout pinholes ranged from 4.4 to 4.8 cm; aperture sizes ranged from 1.1 to 1.7 mm transaxially and 0.9-1.5 mm axially. After including data from the high-resolution section viewing the heart region into whole-body mouse reconstructions from scout data, the authors obtained high-resolution images of the heart, embedded within lower resolution images of the body, with minimal artifacts. CONCLUSIONS: The authors have optimized a dual-resolution collimator tube that provides both whole-body projections of a mouse and more targeted projections centered on the heart that can be jointly reconstructed to obtain high-resolution images of the heart embedded within lower-resolution whole-body images.

Development of a Germanium Small-Animal SPECT System.

Advances in fabrication techniques, electronics, and mechanical cooling systems have given rise to germanium detectors suitable for biomedical imaging. We are developing a small-animal SPECT system that uses a double-sided Ge strip detector. The detector's excellent energy resolution may help to reduce scatter and simplify processing of multi-isotope imaging, while its ability to measure depth of interaction has the potential to mitigate parallax error in pinhole imaging. The detector's energy resolution is <1% FWHM at 140 keV and its spatial resolution is approximately 1.5 mm FWHM. The prototype system described has a single-pinhole collimator with a 1-mm diameter and a 70-degree opening angle with a focal length variable between 4.5 and 9 cm. Phantom images from the gantry-mounted system are presented, including the NEMA NU-2008 phantom and a hot-rod phantom. Additionally, the benefit of energy resolution is demonstrated by imaging a dual-isotope phantom with 99mTc and 123I without cross-talk correction.

Reducing multiplexing artifacts in multi-pinhole SPECT with a stacked silicon-germanium system: a simulation study.

In pinhole single photon emission computed tomography (SPECT), multi-pinhole collimators can increase sensitivity but may lead to projection overlap, or multiplexing, which can cause image artifacts. In this work, we explore whether a stacked-detector configuration with a germanium and a silicon detector, used with 123I (27-32, 159 keV), where little multiplexing occurs in the Si projections, can reduce image artifacts caused by highly-multiplexed Ge projections. Simulations are first used to determine a reconstruction method that combines the Si and Ge projections to maximize image quality. Next, simulations of different pinhole configurations (varying projection multiplexing) in conjunction with digital phantoms are used to examine whether additional Si projections mitigate artifacts from the multiplexing in the Ge projections. Reconstructed images using both Si and Ge data are compared to those using Ge data alone. Normalized mean-square error and normalized standard deviation provide a quantitative evaluation of reconstructed images' error and noise, respectively, and are used to evaluate the impact of the additional nonmultiplexed data on image quality. For a qualitative comparison, the differential point response function is used to examine multiplexing artifacts. Results show that in cases of highly-multiplexed Ge projections, the addition of low-multiplexed Si projections helps to reduce image artifacts both quantitatively and qualitatively.

Characterization of a high-purity germanium detector for small-animal SPECT.

We present an initial evaluation of a mechanically cooled, high-purity germanium double-sided strip detector as a potential gamma camera for small-animal SPECT. It is 90 mm in diameter and 10 mm thick with two sets of 16 orthogonal strips that have a 4.5 mm width with a 5 mm pitch. We found an energy resolution of 0.96% at 140 keV, an intrinsic efficiency of 43.3% at 122 keV and a FWHM spatial resolution of approximately 1.5 mm. We demonstrated depth-of-interaction estimation capability through comparison of pinhole acquisitions with a point source on and off axes. Finally, a flood-corrected flood image exhibited a strip-level uniformity of less than 1%. This high-purity germanium offers many desirable properties for small-animal SPECT.

Longitudinal live animal micro-CT allows for quantitative analysis of tumor-induced bone destruction.

The majority of breast cancer and prostate cancer patients with metastatic disease will go on to develop bone metastases, which contribute largely to the patient's morbidity and mortality. Numerous small animal models of cancer metastasis to bone have been developed to study tumor-induced bone destruction, but the advancement of imaging modalities utilized for these models has lagged significantly behind clinical imaging. Therefore, there is a significant need for improvements to live small animal imaging, particularly when obtaining high-resolution images for longitudinal quantitative analyses. Recently, live animal micro-computed tomography (µCT) has gained popularity due to its ability to obtain high-resolution 3-dimensional images. However, the utility of µCT in bone metastasis models has been limited to end-point analyses due to off-target radiation effects on tumor cells. We hypothesized that live animal in vivo µCT can be utilized to perform reproducible and quantitative longitudinal analyses of bone volume in tumor-bearing mice, particularly in a drug treatment model of breast cancer metastasis to bone. To test this hypothesis, we utilized the MDA-MB-231 osteolytic breast cancer model in which the tumor cells are inoculated directly into the tibia of athymic nude mice and imaged mice weekly by Faxitron (radiography), Imtek µCT (in vivo), and Maestro (GFP-imaging). Exvivo µCT and histology were performed at end point for validation. After establishing a high-resolution scanning protocol for the Imtek CT, we determined whether clear, measurable differences in bone volume were detectable in mice undergoing bisphosphonate drug treatments. We found that in vivo µCT could be used to obtain quantifiable and longitudinal images of the progression of bone destruction over time without altering tumor cell growth. In addition, we found that we could detect lesions as early as week 1 and that this approach could be used to monitor the effect of drug treatment on bone. Taken together, these data indicate that in vivo µCT is an effective and reproducible method for longitudinal monitoring of tumor-associated bone destruction in mouse models of tumor-induced bone disease.

Osteoclast-derived matrix metalloproteinase-9 directly affects angiogenesis in the prostate tumor-bone microenvironment.

In human prostate to bone metastases and in a novel rodent model that recapitulates prostate tumor-induced osteolytic and osteogenic responses, we found that osteoclasts are a major source of the proteinase, matrix metalloproteinase (MMP)-9. Because MMPs are important mediators of tumor-host communication, we tested the effect of host-derived MMP-9 on prostate tumor progression in the bone. To this end, immunocompromised mice that were wild-type or null for MMP-9 received transplants of osteolytic/osteogenic-inducing prostate adenocarcinoma tumor tissue to the calvaria. Surprisingly, we found that that host MMP-9 significantly contributed to prostate tumor growth without affecting prostate tumor-induced osteolytic or osteogenic change as determined by microcomputed tomography, microsingle-photon emission computed tomography, and histomorphometry. Subsequent studies aimed at delineating the mechanism of MMP-9 action on tumor growth focused on angiogenesis because MMP-9 and osteoclasts have been implicated in this process. We observed (a) significantly fewer and smaller blood vessels in the MMP-9 null group by CD-31 immunohistochemistry; (b) MMP-9 null osteoclasts had significantly lower levels of bioavailable vascular endothelial growth factor-A(164); and (c) using an aorta sprouting assay, conditioned media derived from wild-type osteoclasts was significantly more angiogenic than conditioned media derived from MMP-9 null osteoclasts. In conclusion, these studies show that osteoclast-derived MMP-9 affects prostate tumor growth in the bone microenvironment by contributing to angiogenesis without altering prostate tumor-induced osteolytic or osteogenic changes.