해부학적 유도 PET 재구성: 매끄럽지 않은 사전 함수부터 딥러닝 접근까지

학위논문 (박사) -- 서울대학교 대학원 : 의과대학 의과학과, 2021. 2. 이재성.Advances in simultaneous positron emission tomography/magnetic resonance imaging (PET/MRI) technology have led to an active investigation of the anatomy-guided regularized PET image reconstruction algorithm based on MR images. Among the various priors proposed for anatomy-guided regularized PET image reconstruction, Bowsher’s method based on second-order smoothing priors sometimes suffers from over-smoothing of detailed structures. Therefore, in this study, we propose a Bowsher prior based on the l1 norm and an iteratively reweighting scheme to overcome the limitation of the original Bowsher method. In addition, we have derived a closed solution for iterative image reconstruction based on this non-smooth prior. A comparison study between the original l2 and proposed l1 Bowsher priors were conducted using computer simulation and real human data. In the simulation and real data application, small lesions with abnormal PET uptake were better detected by the proposed l1 Bowsher prior methods than the original Bowsher prior. The original l2 Bowsher leads to a decreased PET intensity in small lesions when there is no clear separation between the lesions and surrounding tissue in the anatomical prior. However, the proposed l1 Bowsher prior methods showed better contrast between the tumors and surrounding tissues owing to the intrinsic edge-preserving property of the prior which is attributed to the sparseness induced by l1 norm, especially in the iterative reweighting scheme. Besides, the proposed methods demonstrated lower bias and less hyper-parameter dependency on PET intensity estimation in the regions with matched anatomical boundaries in PET and MRI. Moreover, based on the formulation of l1 Bowsher prior, the unrolled network containing the conventional maximum-likelihood expectation-maximization (ML-EM) module was also proposed. The convolutional layers successfully learned the distribution of anatomically-guided PET images and the EM module corrected the intermediate outputs by comparing them with sinograms. The proposed unrolled network showed better performance than ordinary U-Net, where the regional uptake is less biased and deviated. Therefore, these methods will help improve the PET image quality based on the anatomical side information.양전자방출단층촬영 / 자기공명영상 (PET/MRI) 동시 획득 기술의 발전으로 MR 영상을 기반으로 한 해부학적 사전 함수로 정규화 된 PET 영상 재구성 알고리즘에 대한 심도있는 평가가 이루어졌다. 해부학 기반으로 정규화 된 PET 이미지 재구성을 위해 제안 된 다양한 사전 중 2차 평활화 사전함수에 기반한 Bowsher의 방법은 때때로 세부 구조의 과도한 평활화로 어려움을 겪는다. 따라서 본 연구에서는 원래 Bowsher 방법의 한계를 극복하기 위해 l1 norm에 기반한 Bowsher 사전 함수와 반복적인 재가중치 기법을 제안한다. 또한, 우리는 이 매끄럽지 않은 사전 함수를 이용한 반복적 이미지 재구성에 대해 닫힌 해를 도출했다. 원래 l2와 제안 된 l1 Bowsher 사전 함수 간의 비교 연구는 컴퓨터 시뮬레이션과 실제 데이터를 사용하여 수행되었다. 시뮬레이션 및 실제 데이터에서 비정상적인 PET 흡수를 가진 작은 병변은 원래 Bowsher 이전보다 제안 된 l1 Bowsher 사전 방법으로 더 잘 감지되었다. 원래의 l2 Bowsher는 해부학적 영상에서 병변과 주변 조직 사이에 명확한 분리가 없을 때 작은 병변에서의 PET 강도를 감소시킨다. 그러나 제안 된 l1 Bowsher 사전 방법은 특히 반복적 재가중치 기법에서 l1 노름에 의해 유도된 희소성에 기인한 특성으로 인해 종양과 주변 조직 사이에 더 나은 대비를 보여주었다. 또한 제안된 방법은 PET과 MRI의 해부학적 경계가 일치하는 영역에서 PET 강도 추정에 대한 편향이 더 낮고 하이퍼 파라미터 종속성이 적음을 보여주었다. 또한, l1Bowsher 사전 함수의 닫힌 해를 기반으로 기존의 ML-EM (maximum-likelihood expectation-maximization) 모듈을 포함하는 펼쳐진 네트워크도 제안되었다. 컨볼루션 레이어는 해부학적으로 유도 재구성된 PET 이미지의 분포를 성공적으로 학습했으며, EM 모듈은 중간 출력들을 사이노그램과 비교하여 결과 이미지가 잘 들어맞게 수정했다. 제안된 펼쳐진 네트워크는 지역의 흡수선량이 덜 편향되고 편차가 적어, 일반 U-Net보다 더 나은 성능을 보여주었다. 따라서 이러한 방법들은 해부학적 정보를 기반으로 PET 이미지 품질을 향상시키는 데 유용할 것이다.Chapter 1. Introduction 1 1.1. Backgrounds 1 1.1.1. Positron Emission Tomography 1 1.1.2. Maximum a Posterior Reconstruction 1 1.1.3. Anatomical Prior 2 1.1.4. Proposed l_1 Bowsher Prior 3 1.1.5. Deep Learning for MR-less Application 4 1.2. Purpose of the Research 4 Chapter 2. Anatomically-guided PET Reconstruction Using Bowsher Prior 6 2.1. Backgrounds 6 2.1.1. PET Data Model 6 2.1.2. Original Bowsher Prior 7 2.2. Methods and Materials 8 2.2.1. Proposed l_1 Bowsher Prior 8 2.2.2. Iterative Reweighting 13 2.2.3. Computer Simulations 15 2.2.4. Human Data 16 2.2.5. Image Analysis 17 2.3. Results 19 2.3.1. Simulation with Brain Phantom 19 2.3.2.Human Data 20 2.4. Discussions 25 Chapter 3. Deep Learning Approach for Anatomically-guided PET Reconstruction 31 3.1. Backgrounds 31 3.2. Methods and Materials 33 3.2.1. Douglas-Rachford Splitting 33 3.2.2. Network Architecture 34 3.2.3. Dataset and Training Details 35 3.2.4. Image Analysis 36 3.3. Results 37 3.4. Discussions 38 Chapter 4. Conclusions 40 Bibliography 41 Abstract in Korean (국문 초록) 52Docto

Faster PET reconstruction with non-smooth priors by randomization and preconditioning

Uncompressed clinical data from modern positron emission tomography (PET) scanners are very large, exceeding 350 million data points (projection bins). The last decades have seen tremendous advancements in mathematical imaging tools many of which lead to non-smooth (i.e. non-differentiable) optimization problems which are much harder to solve than smooth optimization problems. Most of these tools have not been translated to clinical PET data, as the state-of-the-art algorithms for non-smooth problems do not scale well to large data. In this work, inspired by big data machine learning applications, we use advanced randomized optimization algorithms to solve the PET reconstruction problem for a very large class of non-smooth priors which includes for example total variation, total generalized variation, directional total variation and various different physical constraints. The proposed algorithm randomly uses subsets of the data and only updates the variables associated with these. While this idea often leads to divergent algorithms, we show that the proposed algorithm does indeed converge for any proper subset selection. Numerically, we show on real PET data (FDG and florbetapir) from a Siemens Biograph mMR that about ten projections and backprojections are sufficient to solve the MAP optimisation problem related to many popular non-smooth priors; thus showing that the proposed algorithm is fast enough to bring these models into routine clinical practice

Improvements in the registration of multimodal medical imaging : application to intensity inhomogeneity and partial volume corrections

Alignment or registration of medical images has a relevant role on clinical diagnostic and treatment decisions as well as in research settings. With the advent of new technologies for multimodal imaging, robust registration of functional and anatomical information is still a challenge, particular in small-animal imaging given the lesser structural content of certain anatomical parts, such as the brain, than in humans. Besides, patient-dependent and acquisition artefacts affecting the images information content further complicate registration, as is the case of intensity inhomogeneities (IIH) showing in MRI and the partial volume effect (PVE) attached to PET imaging. Reference methods exist for accurate image registration but their performance is severely deteriorated in situations involving little images Overlap. While several approaches to IIH and PVE correction exist these methods still do not guarantee or rely on robust registration. This Thesis focuses on overcoming current limitations af registration to enable novel IIH and PVE correction methods.El registre d'imatges mèdiques té un paper rellevant en les decisions de diagnòstic i tractament clíniques així com en la recerca. Amb el desenvolupament de noves tecnologies d'imatge multimodal, el registre robust d'informació funcional i anatòmica és encara avui un repte, en particular, en imatge de petit animal amb un menor contingut estructural que en humans de certes parts anatòmiques com el cervell. A més, els artefactes induïts pel propi pacient i per la tècnica d'adquisició que afecten el contingut d'informació de les imatges complica encara més el procés de registre. És el cas de les inhomogeneïtats d'intensitat (IIH) que apareixen a les RM i de l'efecte de volum parcial (PVE) característic en PET. Tot i que existeixen mètodes de referència pel registre acurat d'imatges la seva eficàcia es veu greument minvada en casos de poc solapament entre les imatges. De la mateixa manera, també existeixen mètodes per la correcció d'IIH i de PVE però que no garanteixen o que requereixen un registre robust. Aquesta tesi es centra en superar aquestes limitacions sobre el registre per habilitar nous mètodes per la correcció d'IIH i de PVE

Parallel Algorithm and Hybrid Regularization for Dynamic PET Reconstruction

International audienceTo improve the estimation at the voxel level in dynamic Positron Emission Tomography (PET) imaging, we propose to develop a convex optimization approach based on a recently proposed parallel proximal method (PPXA). This class of algorithms was successfully employed for 2D deconvolution in the presence of Poisson noise and it is extended here to (dynamic) space + time PET image reconstruction. Hybrid regularization defined as a sum of a total variation and a sparsity measure is considered in this paper. The total variation is applied to each temporal-frame and a wavelet regularization is considered for the space+time data. Total variation allows us to smooth the wavelet artifacts introduced when the wavelet regularization is used alone. The proposed algorithm was evaluated on simulated dynamic fluorodeoxyglucose (FDG) brain data and compared with a regularized Expectation Maximization (EM) reconstruction. From the reconstructed dynamic images, parametric maps of the cerebral metabolic rate of glucose (CMRglu) were computed. Our approach shows a better reconstruction at the voxel level

Advanced perfusion quantification methods for dynamic PET and MRI data modelling

The functionality of tissues is guaranteed by the capillaries, which supply the microvascular network providing a considerable surface area for exchanges between blood and tissues. Microcirculation is affected by any pathological condition and any change in the blood supply can be used as a biomarker for the diagnosis of lesions and the optimization of the treatment. Nowadays, a number of techniques for the study of perfusion in vivo and in vitro are available. Among the several imaging modalities developed for the study of microcirculation, the analysis of the tissue kinetics of intravenously injected contrast agents or tracers is the most widely used technique. Tissue kinetics can be studied using different modalities: the positive enhancement of the signal in the computed tomography and in the ultrasound dynamic contrast enhancement imaging; T1-weighted MRI or the negative enhancement of T2* weighted MRI signal for the dynamic susceptibility contrast imaging or, finally, the uptake of radiolabelled tracers in dynamic PET imaging. Here we will focus on the perfusion quantification of dynamic PET and MRI data. The kinetics of the contrast agent (or the tracer) can be analysed visually, to define qualitative criteria but, traditionally, quantitative physiological parameters are extracted with the implementation of mathematical models. Serial measurements of the concentration of the tracer (or of the contrast agent) in the tissue of interest, together with the knowledge of an arterial input function, are necessary for the calculation of blood flow or perfusion rates from the wash-in and/or wash-out kinetic rate constants. The results depend on the acquisition conditions (type of imaging device, imaging mode, frequency and total duration of the acquisition), the type of contrast agent or tracer used, the data pre-processing (motion correction, attenuation correction, correction of the signal into concentration) and the data analysis method. As for the MRI, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a non-invasive imaging technique that can be used to measure properties of tissue microvasculature. It is sensitive to differences in blood volume and vascular permeability that can be associated with tumour angiogenesis. DCE-MRI has been investigated for a range of clinical oncologic applications (breast, prostate, cervix, liver, lung, and rectum) including cancer detection, diagnosis, staging, and assessment of treatment response. Tumour microvascular measurements by DCE-MRI have been found to correlate with prognostic factors (such as tumour grade, microvessel density, and vascular endothelial growth factor expression) and with recurrence and survival outcomes. Furthermore, DCE-MRI changes measured during treatment have been shown to correlate with outcome, suggesting a role as a predictive marker. The accuracy of DCE-MRI relies on the ability to model the pharmacokinetics of an injected contrast agent using the signal intensity changes on sequential magnetic resonance images. DCE-MRI data are usually quantified with the application of the pharmacokinetic two-compartment Tofts model (also known as the standard model), which represents the system with the plasma and tissue (extravascular extracellular space) compartments and with the contrast reagent exchange rates between them. This model assumes a negligible contribution from the vascular space and considers the system in, what-is-known as, the fast exchange limit, assuming infinitely fast transcytolemmal water exchange kinetics. In general, the number, as well as any assumption about the compartments, depends on the properties of the contrast agent used (mainly gadolinium) together with the tissue physiology or pathology studied. For this reason, the choice of the model is crucial in the analysis of DCE-MRI data. The value of PET in clinical oncology has been demonstrated with studies in a variety of cancers including colorectal carcinomas, lung tumours, head and neck tumours, primary and metastatic brain tumours, breast carcinoma, lymphoma, melanoma, bone cancers, and other soft-tissue cancers. PET studies of tumours can be performed for several reasons including the quantification of tumour perfusion, the evaluation of tumour metabolism, the tracing of radiolabelled cytostatic agents. In particular, the kinetic analysis of PET imaging has showed, in the past few years, an increasing value in tumour diagnosis, as well as in tumour therapy, through providing additional indicative parameters. Many authors have showed the benefit of kinetic analysis of anticancer drugs after labelling with radionuclide in measuring the specific therapeutic effect bringing to light the feasibility of applying the kinetic analysis to the dynamic acquisition. Quantification methods can involve visual analysis together with compartmental modelling and can be applied to a wide range of different tracers. The increased glycolysis in the most malignancies makes 18F-FDG-PET the most common diagnostic method used in tumour imaging. But, PET metabolic alteration in the target tissue can depend by many other factors. For example, most types of cancer are characterized by increased choline transport and by the overexpression of choline kinase in highly proliferating cells in response to enhanced demand of phosphatidylcholine (prostate, breast, lung, ovarian and colon cancers). This effect can be diagnosed with choline-based tracers as the 18Ffluoromethylcholine (18F-FCH), or the even more stable 18F-D4-Choline. Cellular proliferation is also imaged with 18F-fluorothymidine (FLT), which is trapped within the cytosol after being mono phosphorylated by thymidine kinase-1 (TK1), a principal enzyme in the salvage pathway of DNA synthesis. 18F-FLT has been found to be useful for noninvasive assessment of the proliferation rate of several types of cancer and showed high reproducibility and accuracy in breast and lung cancer tumours. The aim of this thesis is the perfusion quantification of dynamic PET and MRI data of patients with lung, brain, liver, prostate and breast lesions with the application of advanced models. This study covers a wide range of imaging methods and applications, presenting a novel combination of MRI-based perfusion measures with PET kinetic modelling parameters in oncology. It assesses the applicability and stability of perfusion quantification methods, which are not currently used in the routine clinical practice. The main achievements of this work include: 1) the assessment of the stability of perfusion quantification of D4-Choline and 18F-FLT dynamic PET data in lung and liver lesions, respectively (first applications in the literature); 2) the development of a model selection in the analysis of DCE-MRI data of primary brain tumours (first application of the extended shutter speed model); 3) the multiparametric analysis of PET and MRI derived perfusion measurements of primary brain tumour and breast cancer together with the integration of immuohistochemical markers in the prediction of breast cancer subtype (analysis of data acquired on the hybrid PET/MRI scanner). The thesis is structured as follows: - Chapter 1 is an introductive chapter on cancer biology. Basic concepts, including the causes of cancer, cancer hallmarks, available cancer treatments, are described in this first chapter. Furthermore, there are basic concepts of brain, breast, prostate and lung cancers (which are the lesions that have been analysed in this work). - Chapter 2 is about Positron Emission Tomography. After a brief introduction on the basics of PET imaging, together with data acquisition and reconstruction methods, the chapter focuses on PET in the clinical settings. In particular, it shows the quantification techniques of static and dynamic PET data and my results of the application of graphical methods, spectral analysis and compartmental models on dynamic 18F-FDG, 18F-FLT and 18F-D4- Choline PET data of patients with breast, lung cancer and hepatocellular carcinoma. - Chapter 3 is about Magnetic Resonance Imaging. After a brief introduction on the basics of MRI, the chapter focuses on the quantification of perfusion weighted MRI data. In particular, it shows the pharmacokinetic models for the quantification of dynamic contrast enhanced MRI data and my results of the application of the Tofts, the extended Tofts, the shutter speed and the extended shutter speed models on a dataset of patients with brain glioma. - Chapter 4 introduces the multiparametric imaging techniques, in particular the combined PET/CT and the hybrid PET/MRI systems. The last part of the chapter shows the applications of perfusion quantification techniques on a multiparametric study of breast tumour patients, who simultaneously underwent DCE-MRI and 18F-FDG PET on a hybrid PET/MRI scanner. Then the results of a predictive study on the same dataset of breast tumour patients integrated with immunohistochemical markers. Furthermore, the results of a multiparametric study on DCE-MRI and 18F-FCM brain data acquired both on a PET/CT scanner and on an MR scanner, separately. Finally, it will show the application of kinetic analysis in a radiomic study of patients with prostate cancer

PET/MR imaging of hypoxic atherosclerotic plaque using 64Cu-ATSM

ABSTRACT OF THE DISSERTATION PET/MR Imaging of Hypoxic Atherosclerotic Plaque Using 64Cu-ATSM by Xingyu Nie Doctor of Philosophy in Biomedical Engineering Washington University in St. Louis, 2017 Professor Pamela K. Woodard, Chair Professor Suzanne Lapi, Co-Chair It is important to accurately identify the factors involved in the progression of atherosclerosis because advanced atherosclerotic lesions are prone to rupture, leading to disability or death. Hypoxic areas have been known to be present in human atherosclerotic lesions, and lesion progression is associated with the formation of lipid-loaded macrophages and increased local inflammation which are potential major factors in the formation of vulnerable plaque. This dissertation work represents a comprehensive investigation of non-invasive identification of hypoxic atherosclerotic plaque in animal models and human subjects using the PET hypoxia imaging agent 64Cu-ATSM. We first demonstrated the feasibility of 64Cu-ATSM for the identification of hypoxic atherosclerotic plaque and evaluated the relative effects of diet and genetics on hypoxia progression in atherosclerotic plaque in a genetically-altered mouse model. We then fully validated the feasibility of using 64Cu-ATSM to image the extent of hypoxia in a rabbit model with atherosclerotic-like plaque using a simultaneous PET-MR system. We also proceeded with a pilot clinical trial to determine whether 64Cu-ATSM MR/PET scanning is capable of detecting hypoxic carotid atherosclerosis in human subjects. In order to improve the 64Cu-ATSM PET image quality, we investigated the Siemens HD (high-definition) PET software and 4 partial volume correction methods to correct for partial volume effects. In addition, we incorporated the attenuation effect of the carotid surface coil into the MR attenuation correction _-map to correct for photon attention. In the long term, this imaging strategy has the potential to help identify patients at risk for cardiovascular events, guide therapy, and add to the understanding of plaque biology in human patients