Stephen C. Moore

Clinical Myocardial Perfusion PET/CT

The field of nuclear cardiology is witnessing growing interest in the use of cardiac PET for the evaluation of patients with coronary artery disease (CAD). The available evidence suggests that myocardial perfusion PET provides an accurate means for diagnosing obstructive CAD, which appears superior to SPECT especially in the obese and in those undergoing pharmacologic stress. The ability to record changes in left ventricular function from rest to peak stress and to quantify myocardial perfusion (in mL/min/g of tissue) provides an added advantage over SPECT for evaluating multivessel CAD. There is growing and consistent evidence that gated myocardial perfusion PET also provides clinically useful risk stratification. Although the introduction of hybrid PET/CT technology offers the exciting possibility of assessing the extent of anatomic CAD (CT coronary angiography) and its functional consequences (ischemic burden) in the same setting, there are technical challenges in the implementation of CT-based transmission imaging for attenuation correction. Nonetheless, this integrated platform for assessing anatomy and biology offers a great potential for translating advances in molecularly targeted imaging into humans.

Development and validation of a Monte Carlo simulation of photon transport in an Anger camera

The geometric component of the point spread function (PSF) of a gamma camera collimator can be determined analytically, and the penetration component can be calculated readily by numerical ray-tracing. A Monte Carlo simulation of photon transport which includes collimator scatter is developed. The simulation was implemented with an array processor which propagates up to 1024 photons in parallel, allowing accurate estimates of the total radial PSF in less than a day. The simulation was tested by imaging monoenergetic point sources of Tc-99m, Cr-51, and Sr-85 (140, 320, and 514 keV, respectively) on a General Electric Star Cam with low-energy, general-purpose, and medium-energy collimators. Comparisons of measured and simulated PSFs demonstrate the validity of the model and the significance of collimator scatter in the degradation of image quality.

Quantification of Myocardial Perfusion Reserve Using Dynamic SPECT Imaging in Humans: A Feasibility Study

Myocardial perfusion imaging (MPI) is well established in the diagnosis and workup of patients with known or suspected coronary artery disease (CAD); however, it can underestimate the extent of obstructive CAD. Quantification of myocardial perfusion reserve with PET can assist in the diagnosis of multivessel CAD. We evaluated the feasibility of dynamic tomographic SPECT imaging and quantification of a retention index to describe global and regional myocardial perfusion reserve using a dedicated solid-state cardiac camera. Methods: Ninety-five consecutive patients (64 men and 31 women; median age, 67 y) underwent dynamic SPECT imaging with 99mTc-sestamibi at rest and at peak vasodilator stress, followed by standard gated MPI. The dynamic images were reconstructed into 60–70 frames, 3–6 s/frame, using ordered-subsets expectation maximization with 4 iterations and 32 subsets. Factor analysis was used to estimate blood-pool time–activity curves, used as input functions in a 2-compartment kinetic model. K1 values (99mTc-sestamibi uptake) were calculated for the stress and rest images, and K2 values (99mTc-sestamibi washout) were set to zero. Myocardial perfusion reserve (MPR) index was calculated as the ratio of the stress and rest K1 values. Standard MPI was evaluated semiquantitatively, and total perfusion deficit (TPD) of at least 5% was defined as abnormal. Results: Global MPR index was higher in patients with normal MPI (n = 51) than in patients with abnormal MPI (1.61 [interquartile range (IQR), 1.33–2.03] vs. 1.27 [IQR, 1.12–1.61], P = 0.0002). By multivariable regression analysis, global MPR index was associated with global stress TPD, age, and smoking. Regional MPR index was associated with the same variables and with regional stress TPD. Sixteen patients undergoing invasive coronary angiography had 20 vessels with stenosis of at least 50%. The MPR index was 1.11 (IQR, 1.01–1.21) versus 1.30 (IQR, 1.12–1.67) in territories supplied by obstructed and nonobstructed arteries, respectively (P = 0.02). MPR index showed a stepwise reduction with increasing extent of obstructive CAD (P = 0.02). Conclusion: Dynamic tomographic imaging and quantification of a retention index describing global and regional perfusion reserve are feasible using a solid-state camera. Preliminary results show that the MPR index is lower in patients with perfusion defects and in regions supplied by obstructed coronary arteries. Further studies are needed to establish the clinical role of this technique as an aid to semiquantitative analysis of MPI.

SNMMI/ASNC/SCCT Guideline for Cardiac SPECT/CT and PET/CT 1.0

1Brigham and Women’s Hospital, Boston, Massachusetts; 2Vanderbilt University Medical Center, Nashville, Tennessee; 3Massachusetts General Hospital, Boston, Massachusetts; 4St. Luke’s–Roosevelt Hospital, New York, New York; 5University of Maryland Medical Center, Baltimore, Maryland; 6Baptist Hospital of Miami, Miami, Florida; 7University Hospital Zurich, Zurich, Switzerland; 8Methodist Hospital, Houston, Texas; and 9Advanced Radiology Services, Grand Rapids, Michigan

Mitochondrial iron chelation ameliorates cigarette smoke–induced bronchitis and emphysema in mice

Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element–binding protein 2 (IRP2) as an important COPD susceptibility gene and have shown that IRP2 protein is increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD. By integrating RNA immunoprecipitation followed by sequencing (RIP-seq), RNA sequencing (RNA-seq), and gene expression and functional enrichment clustering analysis, we identified Irp2 as a regulator of mitochondrial function in the lungs of mice. Irp2 increased mitochondrial iron loading and levels of cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice, which had higher mitochondrial iron loading, showed impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas mice deficient in the synthesis of cytochrome c oxidase, which have reduced COX, were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD. Mitochondrial iron chelation also alleviated CS-induced impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD.

Assessment of myocardial perfusion and function with PET and PET/CT.

Over the past decade, there has been a growing interest in cardiac imaging with Positron Emission Tomography (PET). However, PET has been used for more than 35 years as a powerful tool to study cardiac physiology. PET started as an investigative tool used at select academic medical centers equipped with cyclotrons, to probe physiologic processes such as myocardial perfusion, metabolism, neuronal innervation, and receptor function. At the outset, myocardial perfusion imaging (MPI) with PET was primarily used in research applications, or as an adjunct to 18F-fluoro deoxy glucose (FDG) imaging for viability assessment, or to guide clinical management in high-risk patients. Over the past 7-8 years, we have witnessed a paradigm shift in the use of MPI with PET. It is now being increasingly used for routine clinical evaluation of patients with known or suspected coronary artery disease (CAD). Also, it is being used not only at large academic institutions, but also at community hospitals and large private practice groups. There are several factors contributing to this shift in the use of PET MPI, including the exponential growth and availability of combined PET + computed tomography (CT) systems which were driven primarily by oncology applications, FDA approval of an easily available generator produced radiotracer, 82Rubidium (Rb), changes in reimbursement, and the increasing clinical evidence supporting the value of PET/CT MPI. There are several excellent review articles that detail the clinical applications, PET radiotracers,1 quantitative PET,2 viability assessment,3 and utility of hybrid PET MPI applications.3-6 The focus of this article is to discuss the evolution of PET MPI over the course of the years to highlight some of the major achievements in PET that have culminated in the present day applications of PET MPI.

Fast Monte Carlo based joint iterative reconstruction for simultaneous Tc99m∕I123 SPECT imaging

Simultaneous Tc99m∕I123 SPECT allows the assessment of two physiological functions under identical conditions. The separation of these radionuclides is difficult, however, because their energies are close. Most energy-window-based scatter correction methods do not fully model either physical factors or patient-specific activity and attenuation distributions. We have developed a fast Monte Carlo (MC) simulation-based multiple-radionuclide and multiple-energy joint ordered-subset expectation-maximization (JOSEM) iterative reconstruction algorithm, MC-JOSEM. MC-JOSEM simultaneously corrects for scatter and cross talk as well as detector response within the reconstruction algorithm. We evaluated MC-JOSEM for simultaneous brain profusion (Tc99m-HMPAO) and neurotransmission (I123-altropane) SPECT. MC simulations of Tc99m and I123 studies were generated separately and then combined to mimic simultaneous Tc99m∕I123 SPECT. All the details of photon transport through the brain, the collimator, and detector, including Compton and coherent scatter, septal penetration, and backscatter from components behind the crystal, were modeled. We reconstructed images from simultaneous dual-radionuclide projections in three ways. First, we reconstructed the photopeak-energy-window projections (with an asymmetric energy window for I123) using the standard ordered-subsets expectation-maximization algorithm (NSC-OSEM). Second, we used standard OSEM to reconstruct Tc99m photopeak-energy-window projections, while including an estimate of scatter from a Compton-scatter energy window (SC-OSEM). Third, we jointly reconstructed both Tc99m and I123 images using projection data associated with two photopeak energy windows and an intermediate-energy window using MC-JOSEM. For 15 iterations of reconstruction, the bias and standard deviation of Tc99m activity estimates in several brain structures were calculated for NSC-OSEM, SC-OSEM, and MC-JOSEM, using images reconstructed from primary (unscattered) photons as a reference. Similar calculations were performed for I123 images for NSC-OSEM and MC-JOSEM. For I123 images, dopamine binding potential (BP) at equilibrium and its signal-to-noise ratio (SNR) were also calculated. Our results demonstrate that MC-JOSEM performs better than NSC- and SC-OSEM for quantitation tasks. After 15 iterations of reconstruction, the relative bias of Tc99m activity estimates in the thalamus, striata, white matter, and gray matter volumes from MC-JOSEM ranged from -2.4% to 1.2%, while the same estimates for NSC-OSEM (SC-OSEM) ranged from 20.8% to 103.6% (7.2% to 41.9%). Similarly, the relative bias of I123 activity estimates from 15 iterations of MC-JOSEM in the striata and background ranged from -1.4% to 2.9%, while the same estimates for NSC-OSEM ranged from 1.6% to 10.0%. The relative standard deviation of Tc99m activity estimates from MC-JOSEM ranged from 1.1% to 4.8% versus 1.2% to 6.7% (1.2% to 5.9%) for NSC-OSEM (SC-OSEM). The relative standard deviation of I123 activity estimates using MC-JOSEM ranged from 1.1% to 1.9% versus 1.5% to 2.7% for NSC-OSEM. Using the I123 dopamine BP obtained from the reconstruction produced by primary photons as a reference, the result for MC-JOSEM was 50.5% closer to the reference than that of NSC-OSEM after 15 iterations. The SNR for dopamine BP was 23.6 for MC-JOSEM as compared to 18.3 for NSC-OSEM.

Scatter and cross-talk corrections in simultaneous Tc-99m/I-123 brain SPECT using constrained factor analysis and artificial neural networks

Simultaneous imaging of Tc-99m and I-123 would have a high clinical potential in the assessment of brain perfusion (Tc-99m) and neurotransmission (I-123) but is hindered by cross-talk between the two radionuclides. Monte Carlo simulations of 15 different dual-isotope studies were performed using a digital brain phantom. Several physiologic Tc-99m and I-123 uptake patterns were modeled in the brain structures. Two methods were considered to correct for cross-talk from both scattered and unscattered photons: constrained spectral factor analysis (SFA) and artificial neural networks (ANN). The accuracy and precision of reconstructed pixel values within several brain structures were compared to those obtained with an energy windowing method (WSA). In I-123 images, mean bias was close to 10% in all structures for SFA and ANN and between 14% (in the caudate nucleus) and 25% (in the cerebellum) for WSA. Tc-99m activity was overestimated by 35% in the cortex and 53% in the caudate nucleus with WSA, but by less than 9% in all structures with SFA and ANN. SFA and ANN performed well even in the presence of high-energy I-123 photons. The accuracy was greatly improved by incorporating the contamination into the SFA model or in the learning phase for ANN. SFA and ANN are promising approaches to correct for cross-talk in simultaneous Tc-99m/I-123 SPECT.

Collimator optimization for lesion detection incorporating prior information about lesion size

A Bayesian estimator has been developed as a paradigm for human observer performance in detecting lesions of unknown size in a uniform noisy background. The Bayesian observer used knowledge of the range of possible lesion sizes as a prior; its predictions agreed well with the results of a six-observer perceptual study. The average human response to changes in collimator resolution, as measured by the detectability index, dA, was tracked by the Bayesian detectors signal-to-noise ratio (SNR) somewhat better than by two other estimation models based, respectively, on lesser and greater degrees of lesion size uncertainty. As the range of possible lesion sizes increased, the Bayesian detectors SNR decreased and the optimal collimator resolution shifted towards better resolution. An analytic approximation for the variance of lesion activity estimates (which included the same prior) was shown to predict the variance of the Bayesian estimator over a wide range of collimator resolution values. Because the bias of the Bayesian estimator was small (< 1%), the analytic variance estimate permitted a rapid and convenient prediction of the Bayesian detection SNR. This calculation was then used to optimize the geometric parameters of a two-layer tungsten collimator being constructed from crossed grids for a new imaging detector. A Monte Carlo program was first run to estimate all contributions to the radial point-spread function for collimators of differing tungsten contents and spatial resolution values, imaging 140-keV photons emitted from the center of a 15-cm-diameter, water-filled attenuator. The optimal collimator design for detecting lesions with unknown diameters in the range 2.5-7.5 mm yielded a system resolution of approximately 8.5-mm FWHM, a geometric collimator efficiency of 1.21 x 10(-4), and a single-septum penetration probability of 1%.

Quantitation of Perfused Myocardial Mass Using Tl-201 and Emission Computed Tomography

We determined the accuracy with which perfused myocardial mass can be measured using thallium-201 and emission computed tomography in a canine model of acute coronary artery occlusion. Eight dogs underwent permanent coronary artery ligation. Transaxial emission tomography was performed using the Harvard multidetector scanning single photon emission computed tomography system beginning 10 minutes after the intravenous injection of 2 mCi of thallium-201 and 20 minutes after occlusion. After imaging, the animals were killed and the heart sectioned into 1–2-gram specimens for in vitro counting to determine the quantity of myocardium perfused greater than 75% of the maximum concentration in the left ventricle or septum. Perfusion defects were detected in five of the seven animals with perfusion defects ranging in size from 3.7 to 20.3 grams. One dog with a 1.2-g defect at the apex and another with a 6.5-g defect at the base of the left ventricle were not detected. In one of the operated dogs, no perfusion defect was detected by in vitro measurement or by imaging. Correlation between the measurement of perfused myocardial mass by emission tomography and by in vitro measurement was excellent when a variable threshold was used for defining the borders of the myocardium (for myocardium perfused ≥ 75% of maximum, r = 0.83, weight in vitro= 22.6 + 0.69 weight ECT; Sy.x = 7.3). The calculated weight of perfused myocardium was heavily dependent on the threshold when fixed values were used for defining the myocardial borders. Changes in threshold of 5% resulted in a decrease in apparent infarct size by more than 20% for thresholds ranging from 50% to 65%. Emission computed transaxial tomography with thallium-201 can be used to accurately determine the quantity of perfused myocardial mass; the accuracy of the technique is heavily dependent upon the definition of the myocardial border.