Topics in image reconstruction for high resolution positron emission tomography

Les problèmes mal posés représentent un sujet d'intérêt interdisciplinaire qui surgires dans la télédétection et des applications d'imagerie. Cependant, il subsiste des questions cruciales pour l'application réussie de la théorie à une modalité d'imagerie. La tomographie d'émission par positron (TEP) est une technique d'imagerie non-invasive qui permet d'évaluer des processus biochimiques se déroulant à l'intérieur d'organismes in vivo. La TEP est un outil avantageux pour la recherche sur la physiologie normale chez l'humain ou l'animal, pour le diagnostic et le suivi thérapeutique du cancer, et l'étude des pathologies dans le coeur et dans le cerveau. La TEP partage plusieurs similarités avec d'autres modalités d'imagerie tomographiques, mais pour exploiter pleinement sa capacité à extraire le maximum d'information à partir des projections, la TEP doit utiliser des algorithmes de reconstruction d'images à la fois sophistiquée et pratiques. Plusieurs aspects de la reconstruction d'images TEP ont été explorés dans le présent travail. Les contributions suivantes sont d'objet de ce travail: Un modèle viable de la matrice de transition du système a été élaboré, utilisant la fonction de réponse analytique des détecteurs basée sur l'atténuation linéaire des rayons y dans un banc de détecteur. Nous avons aussi démontré que l'utilisation d'un modèle simplifié pour le calcul de la matrice du système conduit à des artefacts dans l'image. (IEEE Trans. Nucl. Sei., 2000) );> La modélisation analytique de la dépendance décrite à l'égard de la statistique des images a simplifié l'utilisation de la règle d'arrêt par contre-vérification (CV) et a permis d'accélérer la reconstruction statistique itérative. Cette règle peut être utilisée au lieu du procédé CV original pour des projections aux taux de comptage élevés, lorsque la règle CV produit des images raisonnablement précises. (IEEE Trans. Nucl. Sei., 2001) Nous avons proposé une méthodologie de régularisation utilisant la décomposition en valeur propre (DVP) de la matrice du système basée sur l'analyse de la résolution spatiale. L'analyse des caractéristiques du spectre de valeurs propres nous a permis d'identifier la relation qui existe entre le niveau optimal de troncation du spectre pour la reconstruction DVP et la résolution optimale dans l'image reconstruite. (IEEE Trans. Nucl. Sei., 2001) Nous avons proposé une nouvelle technique linéaire de reconstruction d'image événement-par-événement basée sur la matrice pseudo-inverse régularisée du système. L'algorithme représente une façon rapide de mettre à jour une image, potentiellement en temps réel, et permet, en principe, la visualisation instantanée de distribution de la radioactivité durant l'acquisition des données tomographiques. L'image ainsi calculée est la solution minimisant les moindres carrés du problème inverse régularisé.Abstract: Ill-posed problems are a topic of an interdisciplinary interest arising in remote sensing and non-invasive imaging. However, there are issues crucial for successful application of the theory to a given imaging modality. Positron emission tomography (PET) is a non-invasive imaging technique that allows assessing biochemical processes taking place in an organism in vivo. PET is a valuable tool in investigation of normal human or animal physiology, diagnosing and staging cancer, heart and brain disorders. PET is similar to other tomographie imaging techniques in many ways, but to reach its full potential and to extract maximum information from projection data, PET has to use accurate, yet practical, image reconstruction algorithms. Several topics related to PET image reconstruction have been explored in the present dissertation. The following contributions have been made: (1) A system matrix model has been developed using an analytic detector response function based on linear attenuation of [gamma]-rays in a detector array. It has been demonstrated that the use of an oversimplified system model for the computation of a system matrix results in image artefacts. (IEEE Trans. Nucl. Sci., 2000); (2) The dependence on total counts modelled analytically was used to simplify utilisation of the cross-validation (CV) stopping rule and accelerate statistical iterative reconstruction. It can be utilised instead of the original CV procedure for high-count projection data, when the CV yields reasonably accurate images. (IEEE Trans. Nucl. Sci., 2001); (3) A regularisation methodology employing singular value decomposition (SVD) of the system matrix was proposed based on the spatial resolution analysis. A characteristic property of the singular value spectrum shape was found that revealed a relationship between the optimal truncation level to be used with the truncated SVD reconstruction and the optimal reconstructed image resolution. (IEEE Trans. Nucl. Sci., 2001); (4) A novel event-by-event linear image reconstruction technique based on a regularised pseudo-inverse of the system matrix was proposed. The algorithm provides a fast way to update an image potentially in real time and allows, in principle, for the instant visualisation of the radioactivity distribution while the object is still being scanned. The computed image estimate is the minimum-norm least-squares solution of the regularised inverse problem

Development of a silicon photomultiplier based innovative and low cost positron emission tomography scanner.

The Silicon Photomultiplier (SiPM) is a state-of-the-art semiconductor photodetector consisting of a high density matrix (up to 104) of independent pixels of micro-metric dimension (from 10 \u3bcm to 100 \u3bcm) which form a macroscopic unit of 1 to 6 mm2 area. Each pixel is a single-photon avalanche diode operated with a bias voltage of a few volts above the breakdown voltage. When a charge carrier is generated in a pixel by an incoming photon or a thermal effect, a Geiger discharge confined to that pixel is initiated and an intrinsic gain of about 106 is obtained. The output signal of a pixel is the same regardless of the number of interacting photons and provide only a binary information. Since the pixels are arranged on a common Silicon substrate and are connected in parallel to the same readout line, the SiPM combined output response corresponds to the sum of all fired pixel currents. As a result, the SiPM as a whole is an analogue detector, which can measure the incoming light intensity. Nowadays a great number of companies are investing increasing efforts in SiPM detector performances and high quality mass production. SiPMs are in rapid evolution and benefit from the tremendous development of the Silicon technology in terms of cost production, design flexibility and performances. They have reached a high single photon detection sensitivity and photon detection efficiency, an excellent time resolution, an extended dynamic range. They require a low bias voltage and have a low power consumption, they are very compact, robust, flexible and cheap. Considering also their intrinsic insensitivity to magnetic field they result to have an extremely high potential in fundamental and applied science (particle and nuclear physics, astrophysics, biology, environmental science and nuclear medicine) and industry. The SiPM performances are influenced by some effects, as saturation, afterpulsing and crosstalk, which lead to an inherent non-proportional response with respect to the number of incident photons. Consequently, it is not trivial to relate the measured electronic signal to the corresponding light intensity. Since for most applications it is desirable to qualify the SiPM response (i.e in order to properly design a detector for a given application, perform corrections on measurements or on energy spectra, calibrate a SiPM for low light measurements, predict detector performance) the implementation of characterization procedures plays a key role. The SiPM field of application that has been considered in this thesis is the Positron Emission Tomography (PET). PET represents the most advanced in-vivo nuclear imaging modality: it provides functional information of the physiological and molecular processes of organs and tissues. Thanks to its diagnostic power, PET has a recognized superiority over all other imaging modalities in oncology, neurology and cardiology. SiPMs are usually successfully employed for the PET scanners because they allow the measurement of the Time Of Flight of the two coincidence photons to improve the signal to noise ratio of the reconstructed images. They also permit to perfectly combine the functional information with the anatomical one by inserting the PET scanner inside the Magnetic Resonance Imaging device. Recently, PET technology has also been applied to preclinical imaging to allow non invasive studies on small animals. The increasing demand for preclinical PET scanner is driven by the fact that small animals host a large number of human diseases. In-vivo imaging has the advantage to enable the measurement of the radiopharmaceutical distribution in the same animal for an extended period of time. As a result, PET represents a powerful research tool as it offers the possibility to study the abnormalities at the origin of a disease, understand its dynamics, evaluate the therapeutic response and develop new drugs and treatments. However, the cost and the complexity of the preclinical scanners are limiting factors for the spread of PET technology: 70-80% of small-animal PET is concentrated in academic or government research laboratories. The EasyPET concept proposed in this Thesis, protected under a patent filed by Aveiro University, aims to achieve a simple and affordable preclinical PET scanner. The innovative concept is based on a single pair of detector kept collinear during the whole data acquisition and a moving mechanism with two degrees of freedom to reproduce the functionalities of an entire PET ring. The main advantages are in terms of the reduction of the complexity and cost of the PET system. In addition the concept is bound to be robust against acollinear photoemission, scatter radiation and parallax error. The sensitivity is expected to represent a fragility due to the reduced geometrical acceptance. This drawback can be partially recovered by the possibility to accept Compton scattering events without introducing image degradation effects, thanks to the sensor alignment. A 2D imaging demonstrator has been realized in order to assess the EasyPET concept and its performance has been analyzed in this Thesis to verify the net balance between competing advantages and drawbacks. The demonstrator had a leading role in the outreach activity to promote the EasyPET concept and a significant outcome is represented by the new partners that recently joined the collaboration. The EasyPET has been licensed to Caen S.p.a. and, thanks to the participation of Nuclear Instruments to the electronic board re-designed, a new prototype has been realized with additional improvements concerning the mechanics and the control software. In this Thesis the prototype functionalities and performances are reported as a result of a commissioning procedure. The EasyPET will be commercialized by Caen S.p.a. as a product for the educational market and it will be addressed to high level didactic laboratories to show the operating principles and technology behind the PET imaging. The topics mentioned above will be examined in depth in the following Chapters according to the subsequent order. In Chapter 1 the Silicon Photomultiplier will be described in detail, from their operating principle to their main application fields passing through the advantages and the drawback effects connected with this type of sensor. Chapter 2 is dedicated to a SiPM standard characterization method based on the staircase and resolving power measurement. A more refined analysis involves the Multi-Photon spectrum, obtained by integrating the SiPM response to a light pulse. It exploits the SiPM single photon sensitivity and its photon number resolving capability to measure some of its properties of general interest for a multitude of potential applications, disentangling the features related to the statistics of the incident light. Chapter 3 reports another SiPM characterization method which implements a post-processing of the digitized SiPM waveforms with the aim of extracting a full picture of the sensor characteristics from a unique data-set. The procedure is very robust, effective and semi-automatic and suitable for sensors of various dimensions and produced by different vendors. Chapter 4 introduces the Positron Emission Tomography imaging: its principle, applications, related issues and state of the art of PET scanner will be explained. Chapter 5 deals with the preclinical PET, reporting the benefits and the technological challenges involved, the performance of the commercially available small animal PET scanners, the main applications and the frontier research in this field. In Chapter 6 the EasyPET concept is introduced. In particular, the basic idea behind the operating principle, the design layout and the image reconstruction will be illustrated and then assessed through the description and the performance analysis of the EasyPET proof of concept and demonstrator. The effect of the use of different sensor to improve the light collection and the coincidence detection efficiency, together with the analysis of the importance of the sensor and the crystal alignment will be reported in Chapter 7. The design, the functionalities and the commissioning of the EasyPET prototype addressed to the educational market will be defined in Chapter 8. Finally, Chapter 9 contains a summary of the conclusions and an outlook of the future research studies

Development of a silicon photomultiplier based innovative and low cost positron emission tomography scanner.

The Silicon Photomultiplier (SiPM) is a state-of-the-art semiconductor photodetector consisting of a high density matrix (up to 104) of independent pixels of micro-metric dimension (from 10 μm to 100 μm) which form a macroscopic unit of 1 to 6 mm2 area. Each pixel is a single-photon avalanche diode operated with a bias voltage of a few volts above the breakdown voltage. When a charge carrier is generated in a pixel by an incoming photon or a thermal effect, a Geiger discharge confined to that pixel is initiated and an intrinsic gain of about 106 is obtained. The output signal of a pixel is the same regardless of the number of interacting photons and provide only a binary information. Since the pixels are arranged on a common Silicon substrate and are connected in parallel to the same readout line, the SiPM combined output response corresponds to the sum of all fired pixel currents. As a result, the SiPM as a whole is an analogue detector, which can measure the incoming light intensity. Nowadays a great number of companies are investing increasing efforts in SiPM detector performances and high quality mass production. SiPMs are in rapid evolution and benefit from the tremendous development of the Silicon technology in terms of cost production, design flexibility and performances. They have reached a high single photon detection sensitivity and photon detection efficiency, an excellent time resolution, an extended dynamic range. They require a low bias voltage and have a low power consumption, they are very compact, robust, flexible and cheap. Considering also their intrinsic insensitivity to magnetic field they result to have an extremely high potential in fundamental and applied science (particle and nuclear physics, astrophysics, biology, environmental science and nuclear medicine) and industry. The SiPM performances are influenced by some effects, as saturation, afterpulsing and crosstalk, which lead to an inherent non-proportional response with respect to the number of incident photons. Consequently, it is not trivial to relate the measured electronic signal to the corresponding light intensity. Since for most applications it is desirable to qualify the SiPM response (i.e in order to properly design a detector for a given application, perform corrections on measurements or on energy spectra, calibrate a SiPM for low light measurements, predict detector performance) the implementation of characterization procedures plays a key role. The SiPM field of application that has been considered in this thesis is the Positron Emission Tomography (PET). PET represents the most advanced in-vivo nuclear imaging modality: it provides functional information of the physiological and molecular processes of organs and tissues. Thanks to its diagnostic power, PET has a recognized superiority over all other imaging modalities in oncology, neurology and cardiology. SiPMs are usually successfully employed for the PET scanners because they allow the measurement of the Time Of Flight of the two coincidence photons to improve the signal to noise ratio of the reconstructed images. They also permit to perfectly combine the functional information with the anatomical one by inserting the PET scanner inside the Magnetic Resonance Imaging device. Recently, PET technology has also been applied to preclinical imaging to allow non invasive studies on small animals. The increasing demand for preclinical PET scanner is driven by the fact that small animals host a large number of human diseases. In-vivo imaging has the advantage to enable the measurement of the radiopharmaceutical distribution in the same animal for an extended period of time. As a result, PET represents a powerful research tool as it offers the possibility to study the abnormalities at the origin of a disease, understand its dynamics, evaluate the therapeutic response and develop new drugs and treatments. However, the cost and the complexity of the preclinical scanners are limiting factors for the spread of PET technology: 70-80% of small-animal PET is concentrated in academic or government research laboratories. The EasyPET concept proposed in this Thesis, protected under a patent filed by Aveiro University, aims to achieve a simple and affordable preclinical PET scanner. The innovative concept is based on a single pair of detector kept collinear during the whole data acquisition and a moving mechanism with two degrees of freedom to reproduce the functionalities of an entire PET ring. The main advantages are in terms of the reduction of the complexity and cost of the PET system. In addition the concept is bound to be robust against acollinear photoemission, scatter radiation and parallax error. The sensitivity is expected to represent a fragility due to the reduced geometrical acceptance. This drawback can be partially recovered by the possibility to accept Compton scattering events without introducing image degradation effects, thanks to the sensor alignment. A 2D imaging demonstrator has been realized in order to assess the EasyPET concept and its performance has been analyzed in this Thesis to verify the net balance between competing advantages and drawbacks. The demonstrator had a leading role in the outreach activity to promote the EasyPET concept and a significant outcome is represented by the new partners that recently joined the collaboration. The EasyPET has been licensed to Caen S.p.a. and, thanks to the participation of Nuclear Instruments to the electronic board re-designed, a new prototype has been realized with additional improvements concerning the mechanics and the control software. In this Thesis the prototype functionalities and performances are reported as a result of a commissioning procedure. The EasyPET will be commercialized by Caen S.p.a. as a product for the educational market and it will be addressed to high level didactic laboratories to show the operating principles and technology behind the PET imaging. The topics mentioned above will be examined in depth in the following Chapters according to the subsequent order. In Chapter 1 the Silicon Photomultiplier will be described in detail, from their operating principle to their main application fields passing through the advantages and the drawback effects connected with this type of sensor. Chapter 2 is dedicated to a SiPM standard characterization method based on the staircase and resolving power measurement. A more refined analysis involves the Multi-Photon spectrum, obtained by integrating the SiPM response to a light pulse. It exploits the SiPM single photon sensitivity and its photon number resolving capability to measure some of its properties of general interest for a multitude of potential applications, disentangling the features related to the statistics of the incident light. Chapter 3 reports another SiPM characterization method which implements a post-processing of the digitized SiPM waveforms with the aim of extracting a full picture of the sensor characteristics from a unique data-set. The procedure is very robust, effective and semi-automatic and suitable for sensors of various dimensions and produced by different vendors. Chapter 4 introduces the Positron Emission Tomography imaging: its principle, applications, related issues and state of the art of PET scanner will be explained. Chapter 5 deals with the preclinical PET, reporting the benefits and the technological challenges involved, the performance of the commercially available small animal PET scanners, the main applications and the frontier research in this field. In Chapter 6 the EasyPET concept is introduced. In particular, the basic idea behind the operating principle, the design layout and the image reconstruction will be illustrated and then assessed through the description and the performance analysis of the EasyPET proof of concept and demonstrator. The effect of the use of different sensor to improve the light collection and the coincidence detection efficiency, together with the analysis of the importance of the sensor and the crystal alignment will be reported in Chapter 7. The design, the functionalities and the commissioning of the EasyPET prototype addressed to the educational market will be defined in Chapter 8. Finally, Chapter 9 contains a summary of the conclusions and an outlook of the future research studies

Metabolic guided vascular analysis of brain tumors using MR/PET

Tese de mestrado integrado, Engenharia Biomédica e Biofísica (Radiações em Diagnóstico e Terapia)Universidade de Lisboa, Faculdade de Ciências, 2016As técnicas de imagiologia são uma mais-valia para a compreensão do corpo humano, constituindo uma ferramenta relevante para a medicina moderna. Estas técnicas permitem não só o diagnóstico, como também a monitorização de doenças, sendo especialmente importantes na área neuro-oncológica. A ressonância magnética e a tomografia por emissão de positrões (MR e PET acrónimo inglês de Magnetic Ressonance e Positron Emission Tomography, respetivamente) são referidas como as técnicas de imagem mais importantes em neuro-oncologia devido à sua capacidade e eficácia na deteção de tumores cerebrais. Estas duas técnicas permitem obter informação relativa à localização, estado e atividade tumoral. No entanto, em ambas, a diferenciação precisa dos tecidos tumorais assim como o acesso a informação referente à heterogeneidade do tumor, através de alterações não especificas dos tecidos é limitada. Neste momento, a análise de imagens de MR em 3 dimensões (3D) é o procedimento mais utlizado no diagnóstico de tumores cerebrais, em particular de gliomas. Desta forma, e devido ao crescente interesse na aquisição de informação adicional relativa à biologia do tumor, técnicas mais avançadas de MR, em particular imagem ponderada por perfusão (PWI, acrónimo inglês de Perfusion-Weighted Imaging), têm vindo a revelar-se uma mais valia para a prática clínica. A dinâmica de contraste suscetível (DSC acrónimo inglês de Dynamic Susceptibility Contrast) é um dos métodos mais utilizados na medição da perfusão sanguínea em tumores cerebrais. O princípio de aquisição de DSC-MR baseia-se na injeção intravenosa de um agente de contraste paramagnético (ex. Gadolinium-Diethylenetriamine Penta-acetic acid (Gd-DTPA)) e na rápida medição das alterações do sinal transmitido durante a passagem do bolus através da circulação cerebral. O volume sanguíneo cerebral (CBV, acrónimo inglês de Cerebral Blood Volume) é um dos parâmetros mais relevantes obtidos por esta técnica. Nos tumores cerebrais, o CBV exibe uma elevada correlação com a densidade dos micro-vasos, pelo que o seu volume é tipicamente mais elevado nas regiões tumorais do que quando comparado com os tecidos saudáveis. Para além de PWI-MR, a introdução de radio-marcadores de aminoácidos na técnica de PET tem demonstrado um bom desempenho no diagnóstico de gliomas. Esta técnica tem por base a medição da magnitude do transporte de aminoácidos e a sua distribuição no tumor. Na região tumoral, a sua incorporação é aumentada quando comparada com o tecido normal, sendo essas diferenças traduzidas em imagem. De entre os radio-marcadores de aminoácidos disponíveis, O(2-[18F] FluoroEthyl)-L-Tyrosine (18F-FET) foi recentemente introduzido e o seu bom desempenho no diagnóstico de gliomas tem vindo a ser comprovado por diversos estudos. Desta forma, esta técnica de imagem permite não só uma delineação precisa da área tumoral como também a subsequente classificação de gliomas. Os principais problemas que afetam o planeamento do tratamento por terapia usando radiação ou biopsia são a precisa delineação do tecido tumoral vital e a falta de informação relativa à heterogeneidade dos vasos nos tecidos tumorais. Deste modo, foi proposta a combinação da informação proveniente da técnica de 18F-FET com a informação proveniente de PWI. Diversos estudos têm sido realizados de forma a comprovar as vantagens da combinação das referidas técnicas em gliomas. Uma boa correlação foi encontrada entre CBV medido através de perfusão e diferentes radio-marcadores de aminoácidos em PET. No entanto, um estudo recente realizado com o objetivo de comparar o desempenho de 18F-FET e CBV na delineação da área tumoral em gliomas, concluiu que a informação proveniente de 18F-FET permite uma delineação tumoral mais precisa. Para além disso, neste estudo foi ainda reportada uma reduzida correlação, fraca congruência espacial e diferentes localizações dos valores máximos na área do tumor entre 18F-FET e CBV. Em consequência destes resultados, bem como do fraco desempenho na delineação tumoral pelos parâmetros de perfusão conhecidos, fluxo sanguíneo cerebral (CBF acrónimo inglês de Cerebral Blood Flow) e CBV, nesta dissertação é proposta um melhoramento na computação dos parâmetros de perfusão e a sua subsequente comparação com a informação proveniente de 18F-FET. Para tal, neste trabalho foi adotada a sequência de PWI-MR desenvolvida no Forschungszentrum Jüllich. Esta sequência adquire múltiplos contrastes, denominado Gradient-Echo-Spin-Echo (GESE), explorando as vantagens da aquisição da técnica de imagem Echo-planar Imaging with keyhole (EPIK). Deste modo, e através da combinação de GE e SE, uma nova metodologia de PWI foi introduzida ,denominada imagiologia do tamanho dos vasos (VSI acrónimo inglês de Vessel Size Imaging). A técnica de VSI fornece informação acerca da vascularização tumoral, através da estimativa do caliber e densidade dos vasos, e da distribuição dos diferentes tipos de vasos (arteríolas, artérias, capilares, vénulas e veias) na área tumoral, o que não seria de outro modo acessível através dos conhecidos parâmetros de perfusão. Para além disso, sendo os tumores cerebrais caracterizados por uma anormal, desorganizada e heterogénea vascularização, alterações do calibre e densidade dos vasos assim como do volume sanguíneo, revelam ser informações importantes numa análise vascular, com particular interesse no diagnóstico de tumores, na sua monitorização e terapia. Assim sendo, e tendo em conta a boa performance mencionada pela técnica de 18F-FET na delineação da área tumoral, o principal objetivo deste trabalho é explorar a informação vascular adquirida através da técnica de VSI na região tumoral obtida pela informação proveniente de 18F-FET. Para este estudo foram recrutados vinte e cinco pacientes com gliomas. Cada paciente foi injetado com uma dose de 0.1 mmol/Kg de Gd-DTPA por peso corporal. As medições foram realizadas no scanner híbrido de MR/PET de 3T. As imagens de perfusão foram adquiridas usando a sequência 5-ecos GESE EPIK, simultaneamente com a aquisição das imagens de 18F-FET. Depois da conversão do sinal de MR na curva de concentração versus tempo (CTC acrónimo inglês de Concentration Time Curve), foi realizado um ajuste da curva na primeira passagem do bolus. As regiões de interesse foram selecionadas tendo em conta áreas saudáveis e tumorais delineadas com base na informação fornecida por 18F-FET. Desta forma, a área saudavél corresponde à região contra-lateral do tumor, respectivamente nos tecidos cerebrais de substância branca (WM acrónimo inglês de White Matter) e substância cinzenta (GM acrónimo inglês de Gray Matter) e a área tumoral, à região onde o rácio entre a região tumoral e a região cerebral saudável (TBR acrónimo do inglês Tumor To Brain Ratio), foi superior ou igual a 1.6. Para o acesso à informação vascular, os parâmetros de VSI: Índice do tamanho dos vasos (Vsi acrónimo inglês de Vessel Size Index), densidade média dos vasos (Q acrónimo inglês de Mean Vessel Density) e CBV foram analisados tanto em regiões saudáveis como tumorais. Subsequentemente, a informação de cada parâmetro foi comparada com a informação fornecida por 18F-FET através do cálculo da distância entre o voxel correspondente á máxima intensidade de 18F-FET e o voxel correspondente ao caliber máximo dos vasos, ao máximo volume sanguíneo e á mínima densidade dos vasos sanguíneos. Para Q foi considerado o mínimo, uma vez que ao contrário dos outros paramêtros é esperado a sua diminução na área tumoral. Por fim, e de forma a obter informação adicional relativa à heterogeneidade tumoral o parâmetro imagiologia da arquitetura dos vasos (VAI acrónimo inglês de Vessel Architecture Imaging) foi analisado na área tumoral delimitada por 18F-FET. A análise dos resultados relativos aos parâmetros de PW (Vsi, CBV e Q) revelou, para todos os pacientes, uma heterogénea variação no caliber e densidade dos vasos, assim como no volume cerebral na região do tumor em comparação com os tecidos cerebrais de aparência normal, WM e GM. Através da análise dos parâmetros de PW, vinte e quatro pacientes de um total de vinte e cinco apresentaram um aumento do caliber dos vasos, dezassete apresentaram um aumento do volume sanguíneo e dez uma redução da densidade dos vasos na área do tumor. Em todos os pacientes, foi verificado uma diferente localização dos parametros de PW nos vóxeis correspondestes ao valor máximo na área do tumor delineada por 18F-FET. Desta forma, como a distância entre o vóxeis de maior intensidade de 18F-FET e dos paramêtros de PW foi diferente de zero é possivél verificar que o voxel correspondente á máxima intensidade por 18F-FET não traduz o máximo de CBV e Vsi e o mínimo de Q. Para além disso, diferentes distâncias foram encontradas para cada um dos parâmetros de PW em cada paciente. Através da combinação dos parâmetros de perfusão, diferente informação relativa á vasculatura cerebral pode ser fornecida a cada paciente e uma variação de sinal foi encontrada entre WM e GM. Ainda, da análise do parâmetro VAI foi possível distinguir os diferentes tipos de vasos (ex. artérias, capilares e veias) no tumor. Em conclusão, a análise metabólica da vasculatura cerebral pela técnica de VSI proporciona novas perspetivas sobre a complexa natureza da vascularização e heterogeneidade tumoral. Adicionalmente, dada a diferente informação encontrada entre a captação de aminoácidos através da técnica de 18F-FET e VSI, a combinação de ambas as informações pode ser bastante importante para os radiologistas, abrindo a possibilidade à obtenção de nova informação, até então disponível apenas aos patologistas e provenientes por biópsia.Introduction: Assessment of vascular information using the Dynamic Susceptibility Contrast Perfusion-Weighted Imaging Magnetic Resonance technique (DSC PWI-MR) has potential benefits in the diagnosis and treatment monitoring of brain tumors. Beyond MR techniques, amino acid Positron Emission Tomography (PET) tracers, particularly O-(2-[18F] FluoroEthyl)-L-Tyrosine (18F-FET), have been demonstrating a good performance in brain tumor diagnosis and treatment monitoring. Previous publications have shown a mismatch between the Cerebral Blood Volume (CBV) defined in PWI and metabolic information from 18F-FET. PWI also allows measuring Vessel Size Imaging (VSI) by combining Gradient-Echo (GE) and Spin-Echo (SE) information with diffusion data. VSI enables the assessment of vessel caliber, density and architecture information, which is not directly accessible using others PWI parameters. The main goal of this work is to explore the tumor vascular information from VSI guided by the metabolic information from 18F-FET. Materials and methods: Twenty-five patients with gliomas were recruited for the study. For each patient, Gd-DTPA was injected with a dose of 0.1 mmol/Kg of body weight. The measurements were performed on a 3T MR-BrainPET scanner. PWI images were acquired using the combined 5-echo GESE echo planar imaging with keyhole (EPIK) sequence simultaneously with 18F-FET PET acquisition. After the conversion of the MR signal to Concentration Time Curve (CTC), the first–bolus passage was fitted using a Gamma Variate Function (GVF). The Regions of Interest (ROIs), in normal and tumor areas were delineated based on 18F-FET information. For the assessment of vascular information VSI parameters (e.g. Vessel Size Index (Vsi), Mean Vessel Density (Q) and Vessel Architecture Imaging (VAI)) and CBV were evaluated. In addition, distance between local hot spots related to 18F-FET PET was also computed. Results: For all the patients, Vsi, CBV and Q revealed a heterogeneous variation in tumor region comparing to brain tissues of normal appearance. Lower values were found in white matter (WM) comparing to grey matter (GM). From the evaluation of Vsi, CBV and Q in tumor area, twenty-four out of twenty-five patients exhibited an increased Vsi, seventeen patients an increased CBV and ten patients a decreased Q. For all the patients, the locations of the local hot spots differed considerably between 18F-FET and PWI metrics. From the evaluation of VAI, different types of vessels were distinguished (arteries, veins and capillaries) in the tumor. Conclusion: VSI metrics present different information when compared to 18F-FET. The metabolic guided analysis of VSI data provides further insights into the complex nature of the tumor vascularity and heterogeneity

Improving Quantification in Lung PET/CT for the Evaluation of Disease Progression and Treatment Effectiveness

Positron Emission Tomography (PET) allows imaging of functional processes in vivo by measuring the distribution of an administered radiotracer. Whilst one of its main uses is directed towards lung cancer, there is an increased interest in diffuse lung diseases, for which the incidences rise every year, mainly due to environmental reasons and population ageing. However, PET acquisitions in the lung are particularly challenging due to several effects, including the inevitable cardiac and respiratory motion and the loss of spatial resolution due to low density, causing increased positron range. This thesis will focus on Idiopathic Pulmonary Fibrosis (IPF), a disease whose aetiology is poorly understood while patient survival is limited to a few years only. Contrary to lung tumours, this diffuse lung disease modifies the lung architecture more globally. The changes result in small structures with varying densities. Previous work has developed data analysis techniques addressing some of the challenges of imaging patients with IPF. However, robust reconstruction techniques are still necessary to obtain quantitative measures for such data, where it should be beneficial to exploit recent advances in PET scanner hardware such as Time of Flight (TOF) and respiratory motion monitoring. Firstly, positron range in the lung will be discussed, evaluating its effect in density-varying media, such as fibrotic lung. Secondly, the general effect of using incorrect attenuation data in lung PET reconstructions will be assessed. The study will compare TOF and non-TOF reconstructions and quantify the local and global artefacts created by data inconsistencies and respiratory motion. Then, motion compensation will be addressed by proposing a method which takes into account the changes of density and activity in the lungs during the respiration, via the estimation of the volume changes using the deformation fields. The method is evaluated on late time frame PET acquisitions using ¹⁸F-FDG where the radiotracer distribution has stabilised. It is then used as the basis for a method for motion compensation of the early time frames (starting with the administration of the radiotracer), leading to a technique that could be used for motion compensation of kinetic measures. Preliminary results are provided for kinetic parameters extracted from short dynamic data using ¹⁸F-FDG

Inverse Problems in data-driven multi-scale Systems Medicine: application to cancer physiology

Systems Medicine is an interdisciplinary framework involving reciprocal feedback between clinical investigation and mathematical modeling/analysis. Its aim is to improve the understanding of complex diseases by integrating knowledge and data across multiple levels of biological organization. This Thesis focuses on three inverse problems, arising from three kinds of data and related to cancer physiology, at different scales: tissues, cells, molecules. The general assumption of this piece of research is that cancer is associated toa path ological glucose consumption and, in fact, its functional behavior can be assessed by nuclear medicine experiments using [18F]-fluorodeoxyglucose (FDG) as a radioactive tracer mimicking the glucose properties. At tissue-scale, this Thesis considers the Positron Emission Tomography (PET) imaging technique, and deals with two distinct issues within compartmental analysis. First, this Thesis presents a compartmental approach, referred to as reference tissue model, for the estimation of FDG kinetics inside cancer tissues when the arterial blood input of the system is unknown. Then, this Thesis proposes an efficient and reliable method for recovering the compartmental kinetic parameters for each PET image pixel in the context of parametric imaging, exploiting information on the tissue physiology. Standard models in compartmental analysis assume that phosphorylation and dephosphorylation of FDG occur in the same intracellular cytosolic volume. Advances in cell biochemistry have shown that the appropriate location of dephosphorylation is the endoplasmic reticulum (ER). Therefore, at cell-scale, this Thesis formalizes a biochemically-driven compartmental model accounting for the specific role played by the ER, and applies it to the analysis of in vitro experiments on FDG uptake by cancer cell cultures obtained with a LigandTracer (LT) device. Finally, at molecule-scale, this Thesis provides a preliminary mathematical investigation of a chemical reaction network (CRN), represented by a huge Molecular Interaction Map (MIM), describing the biochemical interactions occurring between signaling proteins in specific pathways within a cancer cell. The main issue addressed in this case is the network parameterization problem, i.e. how to determine the reaction rate coefficients from protein concentration data

Motion Correction and Pharmacokinetic Analysis in Dynamic Positron Emission Tomography

This thesis will focus on two important aspects of dynamic Positron Emission Tomography (PET): (i) Motion-compensation , and (ii) Pharmacokinetic analysis (also called parametric imaging) of dynamic PET images. Both are required to enable fully quantitative PET imaging which is increasingly finding applications in the clinic. Motion-compensation in Dynamic Brain PET Imaging: Dynamic PET images are degraded by inter-frame and intra-frame motion artifacts that can a ffect the quantitative and qualitative analysis of acquired PET data. We propose a Generalized Inter-frame and Intra-frame Motion Correction (GIIMC) algorithm that uni fies in one framework the inter-frame motion correction capability of Multiple Acquisition Frames and the intra-frame motion correction feature of (MLEM)-type deconvolution methods. GIIMC employs a fairly simple but new approach of using time-weighted average of attenuation sinograms to reconstruct dynamic frames. Extensive validation studies show that GIIMC algorithm outperforms conventional techniques producing images with superior quality and quantitative accuracy. Parametric Myocardial Perfusion PET Imaging: We propose a novel framework of robust kinetic parameter estimation applied to absolute flow quantification in dynamic PET imaging. Kinetic parameter estimation is formulated as nonlinear least squares with spatial constraints problem where the spatial constraints are computed from a physiologically driven clustering of dynamic images, and used to reduce noise contamination. The proposed framework is shown to improve the quantitative accuracy of Myocardial Perfusion (MP) PET imaging, and in turn, has the long-term potential to enhance capabilities of MP PET in the detection, staging and management of coronary artery disease

A Biological Global Positioning System: Considerations for Tracking Stem Cell Behaviors in the Whole Body

Many recent research studies have proposed stem cell therapy as a treatment for cancer, spinal cord injuries, brain damage, cardiovascular disease, and other conditions. Some of these experimental therapies have been tested in small animals and, in rare cases, in humans. Medical researchers anticipate extensive clinical applications of stem cell therapy in the future. The lack of basic knowledge concerning basic stem cell biology-survival, migration, differentiation, integration in a real time manner when transplanted into damaged CNS remains an absolute bottleneck for attempt to design stem cell therapies for CNS diseases. A major challenge to the development of clinical applied stem cell therapy in medical practice remains the lack of efficient stem cell tracking methods. As a result, the fate of the vast majority of stem cells transplanted in the human central nervous system (CNS), particularly in the detrimental effects, remains unknown. The paucity of knowledge concerning basic stem cell biology—survival, migration, differentiation, integration in real-time when transplanted into damaged CNS remains a bottleneck in the attempt to design stem cell therapies for CNS diseases. Even though excellent histological techniques remain as the gold standard, no good in vivo techniques are currently available to assess the transplanted graft for migration, differentiation, or survival. To address these issues, herein we propose strategies to investigate the lineage fate determination of derived human embryonic stem cells (hESC) transplanted in vivo into the CNS. Here, we describe a comprehensive biological Global Positioning System (bGPS) to track transplanted stem cells. But, first, we review, four currently used standard methods for tracking stem cells in vivo: magnetic resonance imaging (MRI), bioluminescence imaging (BLI), positron emission tomography (PET) imaging and fluorescence imaging (FLI) with quantum dots. We summarize these modalities and propose criteria that can be employed to rank the practical usefulness for specific applications. Based on the results of this review, we argue that additional qualities are still needed to advance these modalities toward clinical applications. We then discuss an ideal procedure for labeling and tracking stem cells in vivo, finally, we present a novel imaging system based on our experiments

Perspectives on Nuclear Medicine for Molecular Diagnosis and Integrated Therapy

nuclear medicine; diagnostic radiolog

Fluorescence molecular tomography: Principles and potential for pharmaceutical research

Fluorescence microscopic imaging is widely used in biomedical research to study molecular and cellular processes in cell culture or tissue samples. This is motivated by the high inherent sensitivity of fluorescence techniques, the spatial resolution that compares favorably with cellular dimensions, the stability of the fluorescent labels used and the sophisticated labeling strategies that have been developed for selectively labeling target molecules. More recently, two and three-dimensional optical imaging methods have also been applied to monitor biological processes in intact biological organisms such as animals or even humans. These whole body optical imaging approaches have to cope with the fact that biological tissue is a highly scattering and absorbing medium. As a consequence, light propagation in tissue is well described by a diffusion approximation and accurate reconstruction of spatial information is demanding. While in vivo optical imaging is a highly sensitive method, the signal is strongly surface weighted, i.e., the signal detected from the same light source will become weaker the deeper it is embedded in tissue, and strongly depends on the optical properties of the surrounding tissue. Derivation of quantitative information, therefore, requires tomographic techniques such as fluorescence molecular tomography (FMT), which maps the three-dimensional distribution of a fluorescent probe or protein concentration. The combination of FMT with a structural imaging method such as X-ray computed tomography (CT) or Magnetic Resonance Imaging (MRI) will allow mapping molecular information on a high definition anatomical reference and enable the use of prior information on tissue’s optical properties to enhance both resolution and sensitivity. Today many of the fluorescent assays originally developed for studies in cellular systems have been successfully translated for experimental studies in animals. The opportunity of monitoring molecular processes non-invasively in the intact organism is highly attractive from a diagnostic point of view but even more so for the drug developer, who can use the techniques for proof-of-mechanism and proof-of-efficacy studies. This review shall elucidate the current status and potential of fluorescence tomography including recent advances in multimodality imaging approaches for preclinical and clinical drug development