TOWARDS FURTHER OPTIMIZATION OF RECONSTRUCTION METHODS FOR DUAL-RADIONUCLIDE MYOCARDIAL PERFUSION SPECT

Coronary artery disease (CAD) is the most prevalent type of heart disease and a leading cause of death both in the United States and worldwide. Myocardial perfusion SPECT (MPS) is a well-established and widely-used non-invasive imaging technique to diagnose CAD. MPS images the distribution of radioactive perfusion agent in the myocardium to assess the myocardial perfusion status at rest and stress state and allow diagnosis of CAD and allow differentiation of CAD and previous myocardial infarctions. The overall goal of this dissertation was to optimize the image reconstruction methods for MPS by patient-specific optimization of two advanced iterative reconstruction methods based on simulations of realistic patients population modeling existing hardware and previously optimized dual-isotope simultaneous-acquisition imaging protocols. After optimization, the two algorithms were compared to determine the optimal reconstruction methods for MPS. First, we developed a model observer strategy to evaluate image quality and allow optimization of the reconstruction methods using a population of phantoms modeling the variability seen in human populations. The Hotelling Observer (HO) is widely used to evaluate image quality, often in conjunction with anthropomorphic channels to model human observer performance. However, applying the HO to non- multivariate-normally (MVN) distributed, such as the output from a channel model applied to images with variable signals and background, is not optimal. In this work, we proposed a novel model observer strategy to evaluate the image quality of such data. First, the entire data ensemble is divided into sub-ensembles that are exactly or approximately MVN and homoscedastic. Next, the Linear Discriminant (LD) is applied to estimate test statistics for each sub-ensemble, and a single area under the receiver operating characteristics curve (AUC) is calculated using the pooled test statistics from all the sub-ensembles. The AUC serves as the figure of merit for performance on the defect detection task. The proposed multi-template LD was compared to other model observer strategies and was shown to be a practical, theoretically justified, and produced higher AUC values for non-MVN data such as that arising from the clinically-realistic SKS task used in the remainder of this work. We then optimized two regularized statistical reconstruction algorithms. One is the widely used post-filtered ordered subsets-expectation maximization (OS-EM) algorithm. The other is a maximum a posteriori (MAP) algorithm with dual-tracer prior (DTMAP) that was proposed for dual-isotope MPS study and was expected to outperform the post-filtered OS-EM algorithm. Of importance, we proposed to investigate patient-specific optimization of the reconstruction parameters. To accomplish this, the phantom population was divided into three anatomy groups based on metrics that expected to affect image noise and resolution and thus the optimal reconstruction parameters. In particular, these metrics were the distance from the center of the heart to the face of the collimator, which is directly related to image resolution, heart size, and counts from the myocardium, which is expected to determine image noise. Reconstruction parameters were optimized for each of these groups using the proposed model observer strategy. Parameters for the rest and stress images were optimized separately, and the parameters that achieve the highest AUC were deemed optimal. The results showed that the proposed group-wise optimization method offered slightly better task performance than using a single set of parameters for all the phantoms. For DTMAP, we also applied the group-wise optimization approach. The extra challenges for DTMAP optimization are that it has three parameters to be optimized simultaneously, and it is substantially more computationally expensive than OS-EM. Thus, we adopted optimization strategies to reduce the size of the parameter search space. In particular, we searched in two parameter ranges expected to give result in good image quality. We also reduced the computation burden by exploiting limiting behavior of the penalty function to reduce the number of parameters that need to be optimized. Despite this effort, the optimized DTMAP had poorer task performance compared to the optimized OS-EM algorithm. As a result, we studied the limitations of the DTMAP algorithm and suggest reasons of its worse performance for the task investigated. The results of this study indicate that there is benefit from patient-specific optimization. The methods and optimal patient-specific parameters may be applicable to clinical MPS studies. In addition, the model observer strategy and the group-wise optimization approach may also be applicable both to future work in MPS and to other relevant fields

Doctor of Philosophy

dissertationSingle Photon Emission Computed Tomography (SPECT) myocardial perfusion imaging (MPI), a noninvasive and effective method for diagnosing coronary artery disease (CAD), is the most commonly performed SPECT procedure. Hence, it is not surprising that there is a tremendous market need for dedicated cardiac SPECT scanners. In this dissertation, a novel dedicated stationary cardiac SPECT system that using a segmented-parallel-hole collimator is investigated in detail. This stationary SPECT system can acquire true dynamic SPECT images and is inexpensive to build. A segmented-parallel-hole collimator was designed to fit the existing general-purpose SPECT cameras without any mechanical modifications of the scanner while providing higher detection sensitivity. With a segmented-parallel-hole collimator, each detector was segmented to seven sub-detector regions, providing seven projections simultaneously. Fourteen view-angles over 180 degree were obtained in total with two detectors positioned at 90 degree apart. The whole system was able to provide an approximate 34-fold gain in sensitivity over the conventional single-head SPECT system. The potential drawbacks of the stationary cardiac SPECT system are data truncation from small field of view (FOV) and limited number of view angles. A tailored maximum-likelihood expectation-maximization (ML-EM) algorithm was derived for reconstruction of truncated projections with few view angles. The artifacts caused by truncation and insufficient number of views were suppressed by reducing the image updating step sizes of the pixels outside the FOV. The performance of the tailored ML-EM algorithm was verified by computer simulations and phantom experiments. Compared with the conventional ML-EM algorithm, the tailored ML-EM algorithm successfully suppresses the streak artifacts outside the FOV and reduces the distortion inside the FOV. At 10 views, the tailored ML-EM algorithm has a much lower mean squared error (MSE) and higher relative contrast. In addition, special attention was given to handle the zero-valued projections in the image reconstruction. There are two categories of zero values in the projection data: one is outside the boundary of the object and the other is inside the object region, which is caused by count starvation. A positive weighting factor c was introduced to the ML-EM algorithm. By setting c>1 for zero values outside the projection, the boundary in the image is well preserved even at extremely low iterations. The black lines, caused by the zero values inside the object region, are completely removed by setting 0< c<1. Finally, the segmented-parallel-hole collimator was fabricated and calibrated using a point source. Closed-form explicit expressions for the slant angles and rotation radius were derived from the proposed system geometry. The geometric parameters were estimated independently or jointly. Monte Carlo simulations and real emission data were used to evaluate the proposed calibration method and the stationary cardiac system. The simulation results show that the difference between the estimated and the actual value is less than 0.1 degree for the slant angles and the 5 mm for the rotation radius, which is well below the detector's intrinsic resolution

Perspectives on Nuclear Medicine for Molecular Diagnosis and Integrated Therapy

nuclear medicine; diagnostic radiolog

[¹⁸F]fluorination of biorelevant arylboronic acid pinacol ester scaffolds synthesized by convergence techniques

Aim: The development of small molecules through convergent multicomponent reactions (MCR) has been boosted during the last decade due to the ability to synthesize, virtually without any side-products, numerous small drug-like molecules with several degrees of structural diversity.(1) The association of positron emission tomography (PET) labeling techniques in line with the “one-pot” development of biologically active compounds has the potential to become relevant not only for the evaluation and characterization of those MCR products through molecular imaging, but also to increase the library of radiotracers available. Therefore, since the [18F]fluorination of arylboronic acid pinacol ester derivatives tolerates electron-poor and electro-rich arenes and various functional groups,(2) the main goal of this research work was to achieve the 18F-radiolabeling of several different molecules synthesized through MCR. Materials and Methods: [18F]Fluorination of boronic acid pinacol esters was first extensively optimized using a benzaldehyde derivative in relation to the ideal amount of Cu(II) catalyst and precursor to be used, as well as the reaction solvent. Radiochemical conversion (RCC) yields were assessed by TLC-SG. The optimized radiolabeling conditions were subsequently applied to several structurally different MCR scaffolds comprising biologically relevant pharmacophores (e.g. β-lactam, morpholine, tetrazole, oxazole) that were synthesized to specifically contain a boronic acid pinacol ester group. Results: Radiolabeling with fluorine-18 was achieved with volumes (800 μl) and activities (≤ 2 GBq) compatible with most radiochemistry techniques and modules. In summary, an increase in the quantities of precursor or Cu(II) catalyst lead to higher conversion yields. An optimal amount of precursor (0.06 mmol) and Cu(OTf)2(py)4 (0.04 mmol) was defined for further reactions, with DMA being a preferential solvent over DMF. RCC yields from 15% to 76%, depending on the scaffold, were reproducibly achieved. Interestingly, it was noticed that the structure of the scaffolds, beyond the arylboronic acid, exerts some influence in the final RCC, with electron-withdrawing groups in the para position apparently enhancing the radiolabeling yield. Conclusion: The developed method with high RCC and reproducibility has the potential to be applied in line with MCR and also has a possibility to be incorporated in a later stage of this convergent “one-pot” synthesis strategy. Further studies are currently ongoing to apply this radiolabeling concept to fluorine-containing approved drugs whose boronic acid pinacol ester precursors can be synthesized through MCR (e.g. atorvastatin)

Iterative reconstruction in CT : using mathematical model observers to determine low dose images' trustworthiness

La tomodensitométrie (TDM) est une technique d'imagerie pour laquelle l'intérêt n'a cessé de croitre depuis son apparition au début des années 70. De nos jours, l'utilisation de cette technique est devenue incontournable, grâce entre autres à sa capacité à produire des images diagnostiques de haute qualité. Toutefois, et en dépit d'un bénéfice indiscutable sur la prise en charge des patients, l'augmentation importante du nombre d'examens TDM pratiqués soulève des questions sur l'effet potentiellement dangereux des rayonnements ionisants sur la population. Parmi ces effets néfastes, l'induction de cancers liés à l'exposition aux rayonnements ionisants reste l'un des risques majeurs. Afin que le rapport bénéfice-risques reste favorable au patient il est donc nécessaire de s'assurer que la dose délivrée permette de formuler le bon diagnostic tout en évitant d'avoir recours à des images dont la qualité est inutilement élevée. Ce processus d'optimisation, qui est une préoccupation importante pour les patients adultes, doit même devenir une priorité lorsque l'on examine des enfants ou des adolescents, en particulier lors d'études de suivi requérant plusieurs examens tout au long de leur vie. Enfants et jeunes adultes sont en effet beaucoup plus sensibles aux radiations du fait de leur métabolisme plus rapide que celui des adultes. De plus, les probabilités des évènements auxquels ils s'exposent sont également plus grandes du fait de leur plus longue espérance de vie. L'introduction des algorithmes de reconstruction itératifs, conçus pour réduire l'exposition des patients, est certainement l'une des plus grandes avancées en TDM, mais elle s'accompagne de certaines difficultés en ce qui concerne l'évaluation de la qualité des images produites. Le but de ce travail est de mettre en place une stratégie pour investiguer le potentiel des algorithmes itératifs vis-à-vis de la réduction de dose sans pour autant compromettre la qualité du diagnostic. La difficulté de cette tâche réside principalement dans le fait de disposer d'une méthode visant à évaluer la qualité d'image de façon pertinente d'un point de vue clinique. La première étape a consisté à caractériser la qualité d'image lors d'examen musculo-squelettique. Ce travail a été réalisé en étroite collaboration avec des radiologues pour s'assurer un choix pertinent de critères de qualité d'image. Une attention particulière a été portée au bruit et à la résolution des images reconstruites à l'aide d'algorithmes itératifs. L'analyse de ces paramètres a permis aux radiologues d'adapter leurs protocoles grâce à une possible estimation de la perte de qualité d'image liée à la réduction de dose. Notre travail nous a également permis d'investiguer la diminution de la détectabilité à bas contraste associée à une diminution de la dose ; difficulté majeure lorsque l'on pratique un examen dans la région abdominale. Sachant que des alternatives à la façon standard de caractériser la qualité d'image (métriques de l'espace Fourier) devaient être utilisées, nous nous sommes appuyés sur l'utilisation de modèles d'observateurs mathématiques. Nos paramètres expérimentaux ont ensuite permis de déterminer le type de modèle à utiliser. Les modèles idéaux ont été utilisés pour caractériser la qualité d'image lorsque des paramètres purement physiques concernant la détectabilité du signal devaient être estimés alors que les modèles anthropomorphes ont été utilisés dans des contextes cliniques où les résultats devaient être comparés à ceux d'observateurs humain, tirant profit des propriétés de ce type de modèles. Cette étude a confirmé que l'utilisation de modèles d'observateurs permettait d'évaluer la qualité d'image en utilisant une approche basée sur la tâche à effectuer, permettant ainsi d'établir un lien entre les physiciens médicaux et les radiologues. Nous avons également montré que les reconstructions itératives ont le potentiel de réduire la dose sans altérer la qualité du diagnostic. Parmi les différentes reconstructions itératives, celles de type « model-based » sont celles qui offrent le plus grand potentiel d'optimisation, puisque les images produites grâce à cette modalité conduisent à un diagnostic exact même lors d'acquisitions à très basse dose. Ce travail a également permis de clarifier le rôle du physicien médical en TDM: Les métriques standards restent utiles pour évaluer la conformité d'un appareil aux requis légaux, mais l'utilisation de modèles d'observateurs est inévitable pour optimiser les protocoles d'imagerie. -- Computed tomography (CT) is an imaging technique in which interest has been quickly growing since it began to be used in the 1970s. Today, it has become an extensively used modality because of its ability to produce accurate diagnostic images. However, even if a direct benefit to patient healthcare is attributed to CT, the dramatic increase in the number of CT examinations performed has raised concerns about the potential negative effects of ionising radiation on the population. Among those negative effects, one of the major risks remaining is the development of cancers associated with exposure to diagnostic X-ray procedures. In order to ensure that the benefits-risk ratio still remains in favour of the patient, it is necessary to make sure that the delivered dose leads to the proper diagnosis without producing unnecessarily high-quality images. This optimisation scheme is already an important concern for adult patients, but it must become an even greater priority when examinations are performed on children or young adults, in particular with follow-up studies which require several CT procedures over the patient's life. Indeed, children and young adults are more sensitive to radiation due to their faster metabolism. In addition, harmful consequences have a higher probability to occur because of a younger patient's longer life expectancy. The recent introduction of iterative reconstruction algorithms, which were designed to substantially reduce dose, is certainly a major achievement in CT evolution, but it has also created difficulties in the quality assessment of the images produced using those algorithms. The goal of the present work was to propose a strategy to investigate the potential of iterative reconstructions to reduce dose without compromising the ability to answer the diagnostic questions. The major difficulty entails disposing a clinically relevant way to estimate image quality. To ensure the choice of pertinent image quality criteria this work was continuously performed in close collaboration with radiologists. The work began by tackling the way to characterise image quality when dealing with musculo-skeletal examinations. We focused, in particular, on image noise and spatial resolution behaviours when iterative image reconstruction was used. The analyses of the physical parameters allowed radiologists to adapt their image acquisition and reconstruction protocols while knowing what loss of image quality to expect. This work also dealt with the loss of low-contrast detectability associated with dose reduction, something which is a major concern when dealing with patient dose reduction in abdominal investigations. Knowing that alternative ways had to be used to assess image quality rather than classical Fourier-space metrics, we focused on the use of mathematical model observers. Our experimental parameters determined the type of model to use. Ideal model observers were applied to characterise image quality when purely objective results about the signal detectability were researched, whereas anthropomorphic model observers were used in a more clinical context, when the results had to be compared with the eye of a radiologist thus taking advantage of their incorporation of human visual system elements. This work confirmed that the use of model observers makes it possible to assess image quality using a task-based approach, which, in turn, establishes a bridge between medical physicists and radiologists. It also demonstrated that statistical iterative reconstructions have the potential to reduce the delivered dose without impairing the quality of the diagnosis. Among the different types of iterative reconstructions, model-based ones offer the greatest potential, since images produced using this modality can still lead to an accurate diagnosis even when acquired at very low dose. This work has clarified the role of medical physicists when dealing with CT imaging. The use of the standard metrics used in the field of CT imaging remains quite important when dealing with the assessment of unit compliance to legal requirements, but the use of a model observer is the way to go when dealing with the optimisation of the imaging protocols