Thomas C. Rust

Estimating myocardial perfusion from dynamic contrast-enhanced CMR with a model-independent deconvolution method

BackgroundModel-independent analysis with B-spline regularization has been used to quantify myocardial blood flow (perfusion) in dynamic contrast-enhanced cardiovascular magnetic resonance (CMR) studies. However, the model-independent approach has not been extensively evaluated to determine how the contrast-to-noise ratio between blood and tissue enhancement affects estimates of myocardial perfusion and the degree to which the regularization is dependent on the noise in the measured enhancement data. We investigated these questions with a model-independent analysis method that uses iterative minimization and a temporal smoothness regularizer. Perfusion estimates using this method were compared to results from dynamic 13N-ammonia PET.ResultsAn iterative model-independent analysis method was developed and tested to estimate regional and pixelwise myocardial perfusion in five normal subjects imaged with a saturation recovery turboFLASH sequence at 3 T CMR. Estimates of myocardial perfusion using model-independent analysis are dependent on the choice of the regularization weight parameter, which increases nonlinearly to handle large decreases in the contrast-to-noise ratio of the measured tissue enhancement data. Quantitative perfusion estimates in five subjects imaged with 3 T CMR were 1.1 ± 0.8 ml/min/g at rest and 3.1 ± 1.7 ml/min/g at adenosine stress. The perfusion estimates correlated with dynamic 13N-ammonia PET (y = 0.90x + 0.24, r = 0.85) and were similar to results from other validated CMR studies.ConclusionThis work shows that a model-independent analysis method that uses iterative minimization and temporal regularization can be used to quantify myocardial perfusion with dynamic contrast-enhanced perfusion CMR. Results from this method are robust to choices in the regularization weight parameter over relatively large ranges in the contrast-to-noise ratio of the tissue enhancement data.

Rapid dual-tracer PTSM+ATSM PET imaging of tumour blood flow and hypoxia: a simulation study

Blood flow and hypoxia are interrelated aspects of physiology that affect cancer treatment and response. Cu-PTSM and Cu-ATSM are related PET tracers for blood flow and hypoxia, and the ability to rapidly image both tracers in a single scan would bring several advantages over conventional single-tracer techniques. Using dynamic imaging with staggered injections, overlapping signals for multiple PET tracers may be recovered utilizing information from kinetics and radioactive decay. In this work, rapid dual-tracer PTSM+ATSM PET was simulated and tested as a function of injection delay, order and relative dose for several copper isotopes, and the results were compared relative to separate single-tracer data. Time-activity curves representing a broad range of tumour blood flow and hypoxia levels were simulated, and parallel dual-tracer compartment modelling was used to recover the signals for each tracer. The main results were tested further using a torso phantom simulation of PET tumour imaging. Using scans as short as 30 minutes, the dual-tracer method provided measures of blood flow and hypoxia similar to single-tracer imaging. The best performance was obtained by injecting PTSM first and using a somewhat higher dose for ATSM. Comparable results for different copper isotopes suggest that tracer kinetics with staggered injections play a more important role than radioactive decay in the signal separation process. Rapid PTSM+ATSM PET has excellent potential for characterizing both tumour blood flow and hypoxia in a single, fast scan, provided that technological hurdles related to algorithm development and routine use can be overcome.

Feasibility of rapid multitracer PET tumor imaging

Positron emission tomography (PET) can characterize different aspects of tumor physiology using various tracers. PET scans are usually performed using only one tracer since there is no explicit signal for distinguishing multiple tracers. We tested the feasibility of rapidly imaging multiple PET tracers using dynamic imaging techniques, where the signals from each tracer are separated based upon differences in tracer half-life, kinetics, and distribution. Time-activity curve populations for FDG, acetate, ATSM, and PTSM were simulated using appropriate compartment models, and noisy dual-tracer curves were computed by shifting and adding the single-tracer curves. Single-tracer components were then estimated from dual-tracer data using two methods: principal component analysis (PCA)-based fits of single-tracer components to multitracer data, and parallel multitracer compartment models estimating single-tracer rate parameters from multitracer time-activity curves. The PCA analysis found that there is information content present for separating multitracer data, and that tracer separability depends upon tracer kinetics, injection order and timing. Multitracer compartment modeling recovered rate parameters for individual tracers with good accuracy but somewhat higher statistical uncertainty than single-tracer results when the injection delay was >10 min. These approaches to processing rapid multitracer PET data may potentially provide a new tool for characterizing multiple aspects of tumor physiology in vivo.

Rapid dual-injection single-scan 13N-ammonia PET for quantification of rest and stress myocardial blood flows.

Quantification of myocardial blood flows at rest and stress using 13N-ammonia PET is an established method; however, current techniques require a waiting period of about 1 h between scans. The objective of this study was to test a rapid dual-injection single-scan approach, where 13N-ammonia injections are administered 10 min apart during rest and adenosine stress. Dynamic PET data were acquired in six human subjects using imaging protocols that provided separate single-injection scans as gold standards. Rest and stress data were combined to emulate rapid dual-injection data so that the underlying activity from each injection was known exactly. Regional blood flow estimates were computed from the dual-injection data using two methods: background subtraction and combined modelling. The rapid dual-injection approach provided blood flow estimates very similar to the conventional single-injection standards. Rest blood flow estimates were affected very little by the dual-injection approach, and stress estimates correlated strongly with separate single-injection values (r=0.998, mean absolute difference=0.06 ml min-1 g-1). An actual rapid dual-injection scan was successfully acquired in one subject and further demonstrates feasibility of the method. This study with a limited dataset demonstrates that blood flow quantification can be obtained in only 20 min by the rapid dual-injection approach with accuracy similar to that of conventional separate rest and stress scans. The rapid dual-injection approach merits further development and additional evaluation for potential clinical use.

Evaluation of rapid dual-tracer 62Cu-PTSM + 62Cu-ATSM PET in dogs with spontaneously occurring tumors

We are developing methods for imaging multiple PET tracers in a single scan with staggered injections, where imaging measures for each tracer are separated and recovered using differences in tracer kinetics and radioactive decay. In this work, signal separation performance for rapid dual-tracer (62)Cu-PTSM (blood flow) + (62)Cu-ATSM (hypoxia) tumor imaging was evaluated in a large animal model. Four dogs with pre-existing tumors received a series of dynamic PET scans with (62)Cu-PTSM and (62)Cu-ATSM, permitting evaluation of a rapid dual-tracer protocol designed by previous simulation work. Several imaging measures were computed from the dual-tracer data and compared with those from separate, single-tracer imaging. Static imaging measures (e.g. SUV) for each tracer were accurately recovered from dual-tracer data. The wash-in (k(1)) and wash-out (k(2)) rate parameters for both tracers were likewise well recovered (r = 0.87-0.99), but k(3) was not accurately recovered for PTSM (r = 0.19) and moderately well recovered for ATSM (r = 0.70). Some degree of bias was noted, however, which may potentially be overcome through further refinement of the signal separation algorithms. This work demonstrates that complementary information regarding tumor blood flow and hypoxia can be acquired by a single dual-tracer PET scan, and also that the signal separation procedure works effectively for real physiologic data with realistic levels of kinetic model mismatch. Rapid multi-tracer PET has the potential to improve tumor assessment for image-guide therapy and monitoring, and further investigation with these and other tracers is warranted.

Single-scan dual-tracer FLT+FDG PET tumor characterization.

Rapid multi-tracer PET aims to image two or more tracers in a single scan, simultaneously characterizing multiple aspects of physiology and function without the need for repeat imaging visits. Using dynamic imaging with staggered injections, constraints on the kinetic behavior of each tracer are applied to recover individual-tracer measures from the multi-tracer PET signal. The ability to rapidly and reliably image both (18)F-fluorodeoxyglucose (FDG) and (18)F-fluorothymidine (FLT) would provide complementary measures of tumor metabolism and proliferative activity, with important applications in guiding oncologic treatment decisions and assessing response. However, this tracer combination presents one of the most challenging dual-tracer signal-separation problems--both tracers have the same radioactive half-life, and the injection delay is short relative to the half-life and tracer kinetics. This work investigates techniques for single-scan dual-tracer FLT+FDG PET tumor imaging, characterizing the performance of recovering static and dynamic imaging measures for each tracer from dual-tracer datasets. Simulation studies were performed to characterize dual-tracer signal-separation performance for imaging protocols with both injection orders and injection delays of 10-60 min. Better performance was observed when FLT was administered first, and longer delays before administration of FDG provided more robust signal-separation and recovery of the single-tracer imaging measures. An injection delay of 30 min led to good recovery (R > 0.96) of static image values (e.g. SUV), K(net), and K(1) as compared to values from separate, single-tracer time-activity curves. Recovery of higher order rate parameters (k(2), k(3)) was less robust, indicating that information regarding these parameters was harder to recover in the presence of statistical noise and dual-tracer effects. Performance of the dual-tracer FLT(0 min)+FDG(32 min) technique was further evaluated using PET/CT imaging studies in five patients with primary brain tumors where the data from separate scans of each tracer were combined to synthesize dual-tracer scans with known single-tracer components; results demonstrated similar dual-tracer signal recovery performance. We conclude that rapid dual-tracer FLT+FDG tumor imaging is feasible and can provide quantitative tumor imaging measures comparable to those from conventional separate-scan imaging.

Feasibility of rapid multi-tracer PET tumor imaging

Positron emission tomography (PET) can characterize different aspects of tumor physiology using various tracers. PET scans are usually performed using only one tracer since there is no explicit signal for distinguishing multiple tracers. We tested the feasibility of rapidly imaging multiple PET tracers using dynamic imaging techniques, where the signals from each tracer are separated based upon differences in tracer half-life, kinetics, and distribution. Time-activity curve populations for FDG, acetate, ATSM, and PTSM were simulated using appropriate compartment models, and noisy dual-tracer curves were computed by shifting and adding the single-tracer curves. Single-tracer components were then estimated from dual-tracer data using two methods: principal component analysis (PCA)-based fits of single-tracer components to multitracer data, and parallel multitracer compartment models estimating single-tracer rate parameters from multitracer time-activity curves. The PCA analysis found that there is information content present for separating multitracer data, and that tracer separability depends upon tracer kinetics, injection order and timing. Multitracer compartment modeling recovered rate parameters for individual tracers with good accuracy but somewhat higher statistical uncertainty than single-tracer results when the injection delay was >10 min. These approaches to processing rapid multitracer PET data may potentially provide a new tool for characterizing multiple aspects of tumor physiology in vivo.

Survey of parallel slat collimator designs for hybrid PET imaging

Hybrid PET gamma cameras with coincidence detection electronics are commonly equipped with parallel slat collimators in order to reduce detection of singles and scattered photons, and create a pseudo-2D imaging geometry. The objective of this work was to survey a broad range of parallel slat collimator designs using a series of Monte Carlo simulated PET acquisitions. Collimator properties including septal height, septal thickness and pitch were independently examined over a wide range of values. Simulations were performed for hybrid PET imaging of a long cylindrical phantom uniformly filled with water and radioactivity. The performance for each collimator design was evaluated in terms of the trues-to-singles ratio, scatter fraction, and noise equivalent count rate for a wide range of camera trigger rates. Results indicate that increasing septal height offers the biggest performance gain. Septal thickness should be at least 0.5 mm, and should be optimized in conjunction with pitch to obtain the best performance. This survey provides the groundwork necessary for optimizing slat collimators, and provides a starting point for investigating new slat collimator designs.

Converging slat collimators for PET imaging with large-area detectors

Parallel slat collimators are often employed in hybrid positron emission tomography (PET) to reduce the scatter fraction, decrease singles rates, and create a pseudo 2-D imaging geometry. Similar collimators or inter-slice septa may be used with newer classes of large-area dedicated PET cameras. While conventional parallel slat collimators are adequate for some applications, other collimator designs which produce pseudo 3-D imaging geometries have the potential to greatly improve performance for targeted volume-of-interest (VOI) imaging applications. We have investigated three types of converging slat collimators which may improve shielding of out-of-field-of-view (FOV) photons while greatly increasing sensitivity to the central FOV. Such collimators create a pseudo 3-D imaging geometry and maintain good shielding of scattered events. A series of Monte Carlo simulations were performed for 2-, 3-, 4-, 6-, and 8-head class systems equipped with parallel slat collimators, no collimators (fully 3-D), and the new converging slat designs. Collimator performance was measured in terms of trues sensitivity, singles rejection, scatter fraction, and noise-equivalent counts. The axially-focused slat collimators were found to provide greatly increased sensitivity to the central FOV while also providing better shielding of out-of-FOV events. Whole-body noise equivalent count (NEC) performance for fan slat collimators was nearly identical to that for conventional parallel slat collimators, and VOI NEC was nearly doubled using fan slat collimators. These results suggest that converging slat collimators may provide greatly improved VOI imaging while maintaining good whole-body imaging performance.

Characterization of multiple aspects of tumor physiology by multitracer positron emission tomography

Publisher Summary Noninvasive medical imaging procedures play a central and increasingly important role in cancer diagnosis, staging, re-staging, assessment of prognosis, treatment planning, therapy monitoring, and evaluation for recurrence. The dominant modality for imaging tumor physiology in vivo is positron emission tomography (PET). In PET, a pharmaceutical or compound that traces a specific molecular function or pathway is labeled with a positron-emitting radioisotope. The vast majority of clinical PET experience to date has been with 18F-fluorodeoxyglucose (FDG), which is a marker for hexokinase activity. Most cancerous cells exhibit markedly increased FDG uptake as compared to normal cells. FDG PET is a fairly general-use tool for cancer imaging and is routinely used for evaluating indeterminate pulmonary nodules, staging, detecting distant metastases through whole-body imaging, and evaluating recurrent or residual disease following therapy. Moreover, since different PET tracers assess different aspects of tumor function, the complementary use of multiple PET tracers can provide greater insight into disease status. Such information may potentially offer improved methods for evaluating the grade and extent of disease, making an individualized prognosis and characterization of the malignancy, selecting the most effective therapy, monitoring tumor response to therapy, and evaluating residual/recurrent disease. Multiple PET tracers can provide significantly improved characterization of tumor status in vivo and may offer improved treatment selection and monitoring, but they are not widely used because of the technical and logistical challenges involved in imaging multiple PET tracers.