R. Glenn Wells

Half-Time SPECT Myocardial Perfusion Imaging with Attenuation Correction

Reducing acquisition time may improve patient throughput, increase camera efficiency, and reduce costs; reducing acquisition time also increases image noise. Newly available software controls the effects of noise by maximum a posteriori reconstruction while maintaining resolution with resolution-recovery methods. This study compares half-time (HT) gated myocardial SPECT images processed with ordered-subset expectation maximization with resolution recovery (OSEM-RR) (with and without CT-based attenuation correction [AC]) with full-time (FT) images obtained with a standard clinical protocol and reconstructed with filtered backprojection (FBP) and OSEM (with and without AC). Methods: A total of 212 patients (mean age, 57 y; age range, 27–86 y) underwent 1-d rest/stress 99mTc-tetrofosmin gated SPECT. FT (12.5 min, both rest and stress) and HT (rest, 7.5 min; stress, 6.0 min) images were acquired with low-dose CT for AC in 112 patients. HT acquisitions were processed with OSEM-RR (with and without AC) using software, and FT acquisitions were processed with FBP and OSEM (with and without AC). In another 100 patients, test–retest repeatability was assessed using 2 sets of FT images (FBP reconstruction) that were acquired one immediately after the other. Radiologists unaware of the acquisition and reconstruction protocols visually assessed all reconstructed images for summed stress, summed rest, and summed difference scores and regional wall motion using a 17-segment model. Automated analysis on gated SPECT was used to determine left ventricular volumes, ejection fraction, and dilation (end-diastolic volume, end-systolic volume, left ventricular ejection fraction, and transient ischemic dilation [TID]). A clinical diagnosis was also determined. Results: All measurements resulted in significant correlations (P < 0.01) between the HT and FT images. The only significant difference in mean values was for OSEM-RR plus AC; this method led to an increase in TID by 4% over FT imaging. The concordance in the clinical diagnosis for HT versus FT was 106 to 112 (κ = 0.88) for no AC and 102 to 106 (κ = 0.91) for AC, similar to the repeatability of FT versus FT (98/100, κ = 0.95). Conclusion: HT images processed with the new algorithm provided a clinical diagnosis in concordance with that from FT images in 95% (no AC) to 96% (AC) of cases. This concordance is similar to the test–retest repeatability of FT imaging.

Single-Phase CT Aligned to Gated PET for Respiratory Motion Correction in Cardiac PET/CT

Respiratory motion can induce artifacts in cardiac PET/CT because of the misregistration of the CT attenuation map and emission data. Some solutions to the respiratory motion problem use 4-dimensional CT, but this increases patient radiation exposure. Realignment of 3-dimensional CT and PET images can remove apparent uptake defects caused by mispositioning of the PET emission data into the lung regions on the CT scan. This realignment is typically done as part of regular clinical quality assurance. We evaluated a method to improve on this standard approach, without increasing the radiation exposure to the patient, by acquiring a respiration-gated PET scan and separately aligning the 3-dimensional CT scan to each phase of the PET study. Methods: Three hundred ten clinical PET perfusion scans (82Rb [n = 187] and 13N-ammonia [n = 123]) were retrospectively assessed. Studies were respiration-gated, and motion was measured between inspiration and expiration phases. Those studies with motion ≥ 8 mm were evaluated for significant differences between inspiration and expiration. Studies with significant differences were reprocessed with the phase-alignment approach. The observed motion with 82Rb and 13N-ammonia for rest and stress imaging was also compared. Results: Twenty-three scans (7.41%) had motion ≥ 8 mm, and 9 of these had significant differences between inspiration and expiration, suggesting the presence of respiratory artifacts. Phase-aligned respiratory motion compensation reduced this difference in 8 of 9 cases (89%). No significant differences were observed between 82Rb and 13N-ammonia, and motion during stress imaging was correlated with motion at rest (r = 0.61, P < 0.001). Conclusion: Phase-aligned correction improves the consistency of PET/CT perfusion images by reducing discrepancies caused by respiratory motion. This new approach to CT-based attenuation correction has no additional patient radiation exposure and may improve the specificity of PET perfusion imaging.

In Vivo SPECT Quantification of Transplanted Cell Survival After Engraftment Using 111In-Tropolone in Infarcted Canine Myocardium

Current investigations of cell transplant therapies in damaged myocardium are limited by the inability to quantify cell transplant survival in vivo. We describe how the labeling of cells with 111In can be used to monitor transplanted cell viability in a canine infarction model. Methods: We experimentally determined the contribution of the 111In signal associated with transplanted cell (TC) death and radiolabel leakage to the measured SPECT signal when 111In-labeled cells were transplanted into the myocardium. Three groups of experiments were performed in dogs. Radiolabel leakage was derived by labeling canine myocardium in situ with free 111In-tropolone (n = 4). To understand the contribution of extracellular 111In (e.g., after cell death), we developed a debris impulse response function (DIRF) by injecting lysed 111In-labeled cells within reperfused (n = 3) and nonreperfused (n = 5) myocardial infarcts and within normal (n = 3) canine myocardium. To assess the application of the modeling derived from these experiments, 111In-labeled cells were transplanted into infarcted myocardium (n = 4; 3.1 × 107 ± 5.4 × 106 cells). Serial SPECT images were acquired after direct epicardial injection to determine the time-dependent radiolabel clearance. Clearance kinetics were used to correct for 111In associated with viable TCs. Results: 111In clearance followed a biphasic response and was modeled as a biexponential with a short (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{T}_{1/2}^{\mathrm{s}}\) \end{document}) and long (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{T}_{1/2}^{\mathrm{l}}\) \end{document}) biologic half-life. The \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{T}_{1/2}^{\mathrm{s}}\) \end{document} was not significantly different between experimental groups, suggesting that initial losses were due to transplantation methodology, whereas the \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{T}_{1/2}^{\mathrm{l}}\) \end{document} reflected the clearance of retained 111In. DIRF had an average \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{T}_{1/2}^{\mathrm{l}}\) \end{document} of 19.4 ± 4.1 h, and the \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{T}_{1/2}^{\mathrm{l}}\) \end{document} calculated from free 111In-tropolone injected in situ was 882.7 ± 242.8 h. The measured \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{T}_{1/2}^{\mathrm{l}}\) \end{document} for TCs was 74.3 h and was 71.2 h when corrections were applied. Conclusion: A new quantitative method to assess TC survival in myocardium using SPECT and 111In has been introduced. At the limits, method accuracy is improved if appropriate corrections are applied. In vivo 111In imaging most accurately describes cell viability half-life if \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{T}_{1/2}^{\mathrm{l}}\) \end{document} is between 20 h and 37 d.

Imaging of Gene Expression in Live Pancreatic Islet Cell Lines Using Dual-Isotope SPECT

We are combining nuclear medicine with molecular biology to establish a sensitive, quantitative, and tomographic method with which to detect gene expression in pancreatic islet cells in vivo. Dual-isotope SPECT can be used to image multiple molecular events simultaneously, and coregistration of SPECT and CT images enables visualization of reporter gene expression in the correct anatomic context. We have engineered pancreatic islet cell lines for imaging with SPECT/CT after transplantation under the kidney capsule. Methods: INS-1 832/13 and αTC1-6 cells were stably transfected with a herpes simplex virus type 1−thymidine kinase−green fluoresecent protein (HSV1-thymidine kinase-GFP) fusion construct (tkgfp). After clonal selection, radiolabel uptake was determined by incubation with 5-131I-iodo-1-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)uracil (131I-FIAU) (αTC1-6 cells) or 123I-FIAU (INS-1 832/13 cells). For the first set of in vivo experiments, SPECT was conducted after αTC1-6/tkgfp cells had been labeled with either 131I-FIAU or 111In-tropolone and transplanted under the left kidney capsule of CD1 mice. Reconstructed SPECT images were coregistered to CT. In a second study using simultaneous acquisition dual-isotope SPECT, INS-1 832/13 clone 9 cells were labeled with 111In-tropolone before transplantation. Mice were then systemically administered 123I-FIAU and data for both 131I and 111In were acquired simultaneously. Results: αTC1-6/tkgfp cells showed a 15-fold greater uptake of 131I-FIAU, and INS-1/tkgfp cells showed a 12-fold greater uptake of 123I-FIAU, compared with that of wild-type cells. After transplantation under the kidney capsule, both reporter gene expression and location of cells could be visualized in vivo with dual-isotope SPECT. Immunohistochemistry confirmed the presence of glucagon- and insulin-positive cells at the site of transplantation. Conclusion: Dual-isotope SPECT is a promising method to detect gene expression in and location of transplanted pancreatic cells in vivo.

Advances in Cardiac SPECT and PET Imaging: Overcoming the Challenges to Reduce Radiation Exposure and Improve Accuracy

Nuclear cardiology came of age in the 1970s and subsequently has expanded so that more than 9 million single-photon emission computed tomography (SPECT) studies are performed annually in North America. Coronary artery disease management has demanded a reliable technique that will detect, risk stratify, and assist with revascularization decisions. Using cardiac SPECT and positron-emission tomography (PET), researchers and clinicians have sought to achieve excellence in coronary artery disease diagnosis and risk stratification, and strive to achieve higher standards in these areas. Developments in other cardiac imaging modalities, however, such as cardiac computed tomography, cardiac magnetic resonance, and echocardiography, have raised expectations in terms of diagnostic accuracy and achieving high quality images with little or no ionizing radiation exposure. The challenge facing nuclear cardiology as it embarks upon a fifth decade of clinical use is whether high quality images can be obtained at lower radiation exposures. In this review we consider current practice in SPECT and PET perfusion imaging. We discuss emerging advances in techniques, technologies, and radiotracers that focus specifically on improvements in image quality that enhance diagnostic accuracy while reducing radiation exposure. We provide a perspective as to the future roles of cardiac SPECT and PET in ischemic heart disease, and consider emerging novel applications beyond perfusion imaging. Although for a number of years nuclear cardiology has shone brightly as a leading light for the imaging of ischemic heart disease, its half-life has not yet been reached. Instead, even with the pressure to reduce radiation exposure, the future continues to look bright for cardiac SPECT and PET.

New SPECT and PET radiopharmaceuticals for imaging cardiovascular disease

Nuclear cardiology has experienced exponential growth within the past four decades with converging capacity to diagnose and influence management of a variety of cardiovascular diseases. Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) with technetium-99m radiotracers or thallium-201 has dominated the field; however new hardware and software designs that optimize image quality with reduced radiation exposure are fuelling a resurgence of interest at the preclinical and clinical levels to expand beyond MPI. Other imaging modalities including positron emission tomography (PET) and magnetic resonance imaging (MRI) continue to emerge as powerful players with an expanded capacity to diagnose a variety of cardiac conditions. At the forefront of this resurgence is the development of novel target vectors based on an enhanced understanding of the underlying pathophysiological process in the subcellular domain. Molecular imaging with novel radiopharmaceuticals engineered to target a specific subcellular process has the capacity to improve diagnostic accuracy and deliver enhanced prognostic information to alter management. This paper, while not comprehensive, will review the recent advancements in radiotracer development for SPECT and PET MPI, autonomic dysfunction, apoptosis, atherosclerotic plaques, metabolism, and viability. The relevant radiochemistry and preclinical and clinical development in addition to molecular imaging with emerging modalities such as cardiac MRI and PET-MR will be discussed.

Clinical Interpretation Standards and Quality Assurance for the Multicenter PET/CT Trial Rubidium-ARMI

Rubidium-ARMI (82Rb as an Alternative Radiopharmaceutical for Myocardial Imaging) is a multicenter trial to evaluate the accuracy, outcomes, and cost-effectiveness of low-dose 82Rb perfusion imaging using 3-dimensional (3D) PET/CT technology. Standardized imaging protocols are essential to ensure consistent interpretation. Methods: Cardiac phantom qualifying scans were obtained at 7 recruiting centers. Low-dose (10 MBq/kg) rest and pharmacologic stress 82Rb PET scans were obtained in 25 patients at each site. Summed stress scores, summed rest scores, and summed difference scores (SSS, SRS, and SDS [respectively] = SSS–SRS) were evaluated using 17-segment visual interpretation with a discretized color map. All scans were coread at the core lab (University of Ottawa Heart Institute) to assess agreement of scoring, clinical diagnosis, and image quality. Scoring differences greater than 3 underwent a third review to improve consensus. Scoring agreement was evaluated with intraclass correlation coefficient (ICC-r), concordance of clinical interpretation, and image quality using κ coefficient and percentage agreement. Patient 99mTc and 201Tl SPECT scans (n = 25) from 2 centers were analyzed similarly for comparison to 82Rb. Results: Qualifying scores of SSS = 2, SDS = 2, were achieved uniformly at all imaging sites on 9 different 3D PET/CT scanners. Patient scores showed good agreement between core and recruiting sites: ICC-r = 0.92, 0.77 for SSS, SDS. Eighty-five and eighty-seven percent of SSS and SDS scores, respectively, had site–core differences of 3 or less. After consensus review, scoring agreement improved to ICC-r = 0.97, 0.96 for SSS, SDS (P < 0.05). The agreement of normal versus abnormal (SSS ≥ 4) and nonischemic versus ischemic (SDS ≥ 2) studies was excellent: ICC-r = 0.90 and 0.88. Overall interpretation showed excellent agreement, with a κ = 0.94. Image quality was perceived differently by the site versus core reviewers (90% vs. 76% good or better; P < 0.05). By comparison, scoring agreement of the SPECT scans was ICC-r = 0.82, 0.72 for SSS, SDS. Seventy-six and eighty-eight percent of SSS and SDS scores, respectively, had site–core differences of 3 or less. Consensus review again improved scoring agreement to ICC-r = 0.97, 0.90 for SSS, SDS (P < 0.05). Conclusion: 82Rb myocardial perfusion imaging protocols were implemented with highly repeatable interpretation in centers using 3D PET/CT technology, through an effective standardization and quality assurance program. Site scoring of 82Rb PET myocardial perfusion imaging scans was found to be in good agreement with core lab standards, suggesting that the data from these centers may be combined for analysis of the rubidium-ARMI endpoints.

Respiratory phase alignment improves blood‐flow quantification in Rb82 PET myocardial perfusion imaging

PURPOSE Positron emission tomography (PET) is considered the gold standard for measuring myocardial blood flow in vivo but it is known that respiratory motion can lead to misalignment of the PET and computed tomography (CT) data sets and introduce artifacts in the CT-based attenuation correction (AC) of images. In addition, respiratory motion blurs the PET image and degrades spatial resolution. The purpose of this study is to evaluate the combined effect of respiratory motion compensation (MC) and accurate attenuation correction on relative and absolute blood flow imaging of the heart. METHODS Dynamic (82)Rb-PET acquisitions were generated for a homogeneous tracer distribution in the heart using an anthropomorphic computer phantom and a Monte Carlo simulator. Attenuation correction was done using three different approaches in which the PET data were corrected by: (1) a respiratory-gated CT map with each respiratory phase of the PET scan corrected by its corresponding CT phase (matched); (2) a time-averaged attenuation map (avg); or (3) an attenuation map generated from the maximum CT-number of every voxel over the respiratory cycle (max). Motion compensated was done using an automated rigid-body registration algorithm that aligned all of the phases of the respiratory-gated PET data after AC. The corrected dynamic PET data were then processed by inhouse kinetic analysis software to generate 3D maps of blood flow. Polar maps of the blood-flow for each CT-AC method with and without MC were compared to the truth using a 17-segment model. The same comparison was performed on data from a pig study. RESULTS Motion compensation significantly reduced the segmental mean percentage error (sMPE) in all cases (p < 0.01 for matched CTAC and avg CTAC and p = 0.03 for max CTAC). MC significantly increased image uniformity in the case of matched and avg CTAC (p < 0.01, p = 0.04, respectively) with the best improvement coming for matched CTAC. Without MC, there were no significant differences between the three CTAC approaches. With MC, matched CTAC had significantly smaller mean absolute sMPE (p < 0.01 vs avg CTAC; p < 0.01 vs max CTAC) and improved uniformity (p = 0.05 vs avg CTAC; p < 0.01 vs max CTAC). The results were supported with a pig study. CONCLUSIONS Without MC, there was no significant difference between the three CTAC methods for measuring blood flow. With MC, the matched CTAC approach was significantly better, reducing the mean difference from truth by 6% in the simulated data and improving uniformity by 5%.

Optimization of SPECT Measurement of Myocardial Blood Flow with Corrections for Attenuation, Motion, and Blood-Binding Compared to PET

Myocardial blood flow (MBF) and myocardial flow reserve (MFR) measured with PET have clinical value. SPECT cameras with solid-state detectors can obtain dynamic images for measurement of MBF and MFR. In this study, SPECT measurements of MBF made using 99mTc-tetrofosmin were compared with PET in the same patients. Methods: Thirty-one patients underwent PET MBF rest–stress studies performed with 82Rb or 13N-ammonia within 1 mo of their SPECT study. Dynamic rest–stress measurements were made using a SPECT camera. Kinetic parameters were calculated using a 1-tissue-compartment model and converted to MBF and MFR. Processing with and without corrections for attenuation (+AC and −AC), patient body motion (+MC and −MC), and binding of the tracer to red blood cells (+BB and −BB) was evaluated. Results: Both +BB and +MC improved the accuracy and precision of global SPECT MBF compared with PET MBF, resulting in an average difference of 0.06 ± 0.37 mL/min/g. Global MBF and detection of abnormal MFR were not significantly improved with +AC. Global SPECT MFR with +MC and +BB had an area under the receiver-operating curve of 0.90 (+AC) to 0.95 (−AC) for detecting abnormal PET MFR less than 2.0. Regional analysis produced similar results with an area under the receiver-operating curve of 0.84 (+AC) to 0.87 (−AC). Conclusion: Solid-state SPECT provides global MBF and MFR measurements that differ from PET by 2% ± 32% (MBF) and 2% ± 28% (MFR).

Patient position alters attenuation effects in multipinhole cardiac SPECT

PURPOSE Dedicated cardiac cameras offer improved sensitivity over conventional SPECT cameras. Sensitivity gains are obtained by large numbers of detectors and novel collimator arrangements such as an array of multiple pinholes that focus on the heart. Pinholes lead to variable amounts of attenuation as a source is moved within the camera field of view. This study evaluated the effects of this variable attenuation on myocardial SPECT images. METHODS Computer simulations were performed for a set of nine point sources distributed in the left ventricular wall (LV). Sources were placed at the location of the heart in both an anthropomorphic and a water-cylinder computer phantom. Sources were translated in x, y, and z by up to 5 cm from the center. Projections were simulated with and without attenuation and the changes in attenuation were compared. A LV with an inferior wall defect was also simulated in both phantoms over the same range of positions. Real camera data were acquired on a Discovery NM530c camera (GE Healthcare, Haifa, Israel) for five min in list-mode using an anthropomorphic phantom (DataSpectrum, Durham, NC) with 100 MBq of Tc-99m in the LV. Images were taken over the same range of positions as the simulations and were compared based on the summed perfusion score (SPS), defect width, and apparent defect uptake for each position. RESULTS Point sources in the water phantom showed absolute changes in attenuation of ≤8% over the range of positions and relative changes of ≤5% compared to the apex. In the anthropomorphic computer simulations, absolute change increased to 20%. The changes in relative attenuation caused a change in SPS of <1.5 for the water phantom but up to 4.2 in the anthropomorphic phantom. Changes were larger for axial than for transverse translations. These results were supported by SPS changes of up to six seen in the physical anthropomorphic phantom for axial translations. Defect width was also seen to significantly increase. The position-dependent changes were removed with attenuation correction. CONCLUSIONS Translation of a source relative to a multipinhole camera caused only small changes in homogeneous phantoms with SPS changing <1.5. Inhomogeneous attenuating media cause much larger changes to occur when the source is translated. Changes in SPS of up to six were seen in an anthropomorphic phantom for axial translations. Attenuation correction removes the position-dependent changes in attenuation.