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

Monitoring the Function of the P-glycoprotein Transporter at the Blood Brain Barrier

The P-glycoprotein (P-gp) transporter located at the blood-brain barrier (BBB) is an efflux transporter that pumps neurotoxic compounds out of the brain. Its main function is to protect the brain to ensure an appropriate neural function. Decreases in the P-gp function can result in increased accumulation of toxic compounds inside the brain such as beta-amyloid and this may cause the development of Alzheimer´s or other neurological disorders. By contrast, increases in the P-gp function can decrease the therapeutic drug concentration inside the brain and influence the efficacy of the treatment (drug resistance) as occurred in patients with intractable epilepsy. Thus, it is of interest to monitor the P-gp function in vivo to facilitate the early diagnosis of brain disorders and to monitor drug resistance. To this aim, we used Positron Emission Tomography (PET) imaging, a non-invasive technique that allows the quantification of biological processes in vivo, and the novel radiotracer [18F]MC225 which measures the P-gp function. The aim was to study the kinetic properties of the radiotracer in different species and prove its efficacy to measure increases and decrease in the P-gp function before its clinical evaluation. We conclude that the obtained results have broadened the knowledge of the P-gp function at the BBB. Moreover, the results highlight that [18F]MC225 may become the first radiofluorinated P-gp PET tracer able to measure both decreases and increases in the P-gp function in vivo. The radiolabeling with fluorine-18 would allow its distribution to other PET centers and improve the image quality

The evaluation of positron emission tomography to assess pharmacodynamics and pahrmacokinetics of anti cancer drugs

Positron emission tomography (PET) is a non-invasive imaging technique that is emerging as a useful tool in the field of cancer medicine particularly in drug development. The purpose of this thesis has been to perform clinical studies using two different radiotracers, 5-[^V]fIuorouracil (5-['^F]FU) and 2-[''C]thymidine, to assess pharmacokinetic and pharmacodynamic parameters respectively, which were derived from PET imaging and to establish the contribution that PET can add to drug development, in vivo, in man. Aims: 1) Quantify the pharmacodynamic effects of cytotoxic agents in tumour and normal tissue using 2-["C]thymidine 2) Measure changes in tumour and normal tissue pharmacokinetics of 5-Fluorouracil in response to the modulating agents carbogen and nicotinamide or interferon 3) Assessment of blood flow change in tumour and normal tissue to carbogen and nicotinamide or interferon 4) Interpretation of PET data using novel analysis methods with modified Patlak and spectral analysis Methods: In the 5-['^]FU study, patients with metastatic gastrointestinal cancer underwent PET scanning at the start of 2 separate chemotherapy cycles. The 2nd scan was performed after the administration of carbogen and nicotinamide or interferon. In the 2-["C]thymidine study patients receiving chemotherapy were scanned before commencing chemotherapy, and 1 week after the 3''' cycle of chemotherapy. Patients also had conventional imaging before the start of and after 3 cycles of treatment. Findings: After carbogen and nicotinamide administration, 5-['^]FU uptake was increased in tumour, but not in normal tissue. Regional perfusion was elevated in tumours but decreased in kidneys after carbogen and nicotinamide. After interferon administration, there was an increase in 5-['^]FU retention in tumours, but no increase in uptake. Regional perfusion in tumour and normal tissue was unaltered by interferon. Retention of 2-["C]thymidine decreased in tumour in keeping with the results of conventional radiology, suggesting a pathological response, assessed in vivo, to chemotherapy

Developing novel fluorescent probe for peroxynitrite: implication for understanding the roles of peroxynitrite and drug discovery in cerebral ischemia reperfusion injury

Session 7 - Oral PresentationsSTUDY GOAL: Peroxynitrite (ONOO‐) is a cytotoxic factor. As its short lifetime, ONOO‐ is hard to be detected in biological systems. This study aims to develop novel probe for detecting ONOO‐ and understand the roles of ONOO‐ in ischemic brains and drug discovery ABSTRACT: MitoPN‐1 was found to be a ONOO‐ specific probe with no toxicity. With MitoPN‐1, we studied the roles of ONOO‐ in hypoxic neuronal cells in vitro and MCAO …postprin

On the use of image derived input function for quantitative PET imaging with a simultaneous measuring MR-BrainPET

Tese de mestrado integrado em Engenharia Biomédica e Biofísica, apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2012As técnicas de imagiologia são uma mais valia para a compreensão do corpo humano e deste modo constituem uma ferramenta relevante para a medicina moderna. Atualmente, as técnicas de imagiologia que apresentam uma maior especificidade e sensibilidade ao nível molecular são as técnicas de medicina nuclear, onde se destaca a tomografia por emissão de positrões (PET, acrónimo inglês de Positron Emission Tomography). Esta modalidade permite obter, de uma forma não invasiva, informação in vivo sobre a distribuição espácio-temporal de moléculas, que se encontram marcadas com um átomo emissor de positrões, os radio-traçadores. Durante as últimas décadas a PET apresentou um nível de desenvolvimento assinalável, que se refletiu na construção de sistemas de imagem direcionados a imagiologia do cérebro (High-Resolution Research Tomography, resolução espacial de 2.5mm) e de corpo inteiro (ECAT EXACT HR+, resolução espacial de 5 mm). No entanto, uma das limitações desta modalidade de imagem é o facto de apenas permitir obter uma escassa informação anatómica. De forma a potencializar a utilização das imagens de PET na prática clínica, foi proposta a sua fusão com imagens que apresentassem um elevado detalhe anatómico, como é o caso das imagens obtidas por tomografia computorizada (CT, acrónimo inglês de Computed Tomography) ou por ressonância magnética nuclear (MRI, acrónimo inglês de Magnetic Resonance Imaging). Inicialmente, a fusão de imagens médicas teve por base o co-registo de imagens adquiridas de forma não simultânea. Contudo, desta abordagem resultaram erros de co-registo, devido às diferenças existentes no posicionamento do paciente nas várias aquisições, o que não permitiu explorar na sua totalidade as potencialidades de cada técnica de imagiologia. De forma a ultrapassar este problema foi proposto o desenvolvimento de sistemas de imagem híbridos. Durante a década de 90, os sistemas de PET/CT foram os primeiros sistemas de imagem híbridos a serem propostos e serem introduzidos na prática clínica. No entanto, o facto de as técnicas de CT utilizarem radiação ionizante e por as suas imagens apresentarem um reduzido contraste entre os tecidos moles impulsionaram o estudo de sistemas de imagem PET/MRI, onde estes problemas não são verificados. Nestes sistemas o elevado detalhe anatómico da MRI adiciona valor à imagem molecular de PET e vice-versa. No entanto, a utilização de detetores e de eletrónica sensível a campos magnéticos, por parte dos sistemas de PET, dificultou o avanço destes sistemas híbridos de imagem. Em 2006, após o desenvolvimento de detetores e de eletrónica não sensível a campos magnéticos, os fotodíodos de avalanche (APD, acrónimo inglês de Avalanche Photodiode), estes sistemas híbridos de imagem surgiram pela primeira vez. Estes detetores minimizam a interferência entre os sistemas de PET e de MRI, permitindo a aquisição de imagens em simultâneo, a partir de um único sistema. O BrainPET é o primeiro sistema de imagem de PET que permite a aquisição de imagens de PET e de MRI em simultâneo. Trata-se de um dispositivo construído para imagiologia cerebral, que foi desenvolvido pela Siemens Medical Solution Inc1. e que atualmente está instalado em quatro centros de referência em todo o mundo, Tübingen (University Hospital), Boston (Massachusetts Gene ral Hospital), Jülich (Forschungszentrum Jülich) e Atlanta (Emory University). A combinação do sistema de imagem BrainPET de alta resolução (resolução espacial de 3mm) com um sistema de imagem de MRI MAGNETOM Trio de 3 T permite a aquisição em simultâneo de imagens de PET/MRI, onde a informação anatómica, funcional e estrutural da MRI é intersectada com a informação molecular de PET. Um exame PET têm como objetivo principal obter uma imagem da distribuição dos radio-traçadores no organismo. Essa distribuição pode ser analisada visualmente ou de uma forma quantitativa. Pode também ser considerada como uma média ao longo do tempo do exame ou, separando os dados adquiridos, analisada em função do tempo. Desta forma é possível monitorizar as curvas de atividade tempo (TAC, acrónimo inglês de Time Activity Curve) de diferentes estruturas e com base nessa informação aferir sobre a sua fisiologia. Para tal é necessário: 1) imagens corrigidas para os efeitos deteriorantes da imagem e 2) modelos cinéticos. O primeiro ponto é utilizado pois os dados são afetados por diferentes fatores que deterioram a qualidade das imagens, tais como a interação dos fotões com a matéria (atenuação e dispersão) e as características do sistema (eficiência dos detetores e resolução do sistema). A capacidade de modelar ou corrigir estes efeitos sem degradar a relação sinal ruído (SNR, acrónimo inglês de Signal-to-Noise Ratio) das imagens está fortemente relacionado com a precisão das TACs, utilizadas nos modelos cinéticos. É a utilização destes modelos que permite estabelecer uma relação entre as TACs e os parâmetros biológicos que explicam o sistema biológico em estudo. Esta relação é obtida através de modelos compartimentais, que necessitam das TACs e de uma função de entrada (IF, acrónimo inglês de Input Function). Esta IF é normalmente adquirida através da colheita continua de sangue arterial na artéria radial. Contudo, este é um processo moroso, desconfortável e ao qual estão associados riscos de se realizar uma canulação arterial. Para além disso, a IF obtida por este método tem de ser calibrada em relação aos dados de PET e corrigida com um fator de dispersão e de atraso (consequência da distância percorrida pelo sangue desde o local de amostragem (artéria radial) até ao local de interesse (cérebro)). A utilização de exames dinâmicos de PET para extrair TACs referentes às artérias carótidas (CA, acrónimo inglês de Carotid Artery), através da definição de volumes de interesse (VOI, acrónimo inglês de Volume of Interest) em imagens de PET, foi proposta por alguns autores. Esta IF é denominada de função de entrada obtida a partir da imagem (IDIF, acrónimo inglês para Image Derived Input Function). Todavia, a precisão desta abordagem na identificação das CAs é limitada, devido à baixa resolução e à reduzida informação anatómica das imagens de PET. Em alternativa à utilização exclusiva das imagens de PET foi também proposta a utilização de imagens de MRI para definir as CAs, devido à sua elevada resolução e contraste nos tecidos moles. O desenvolvimento do 3 T MR-BrainPET é um excelente pré-requisito para se obter uma IDIF, pois através deste sistema é possível adquirir imagens simultâneas de MRI e de PET de alta resolução. Após a obtenção da IDIF esta necessita de ser corrigida para o efeito do volume parcial (PVE, acrónimo inglês de Partial Volume Effect), que é uma consequência da resolução do sistema e do tamanho das CAs. Este trabalho tem como objetivo investigar métodos não invasivos para estimar a IDIF de dados obtidos com o sistema de imagem híbrido 3 T- MR-BrainPET. Para tal, foram considerados três métodos de correção do efeito do volume parcial (PVC, acrónimo inglês de Partial Volume Correction): 1) Model-based PVC, que utiliza amostras de sangue venoso e 2) Recovery Coefficient e 3) Geometric Transfer Matrix (GTM), que não utilizam amostras de sangue. O método que se encontra descrito na literatura e que originou os melhores resultados foi o model-based PVC. Este método tem por base a estimação de dois coeficientes (PV e SP) utilizando as amostras de sangue venoso nos últimos instantes da TAC das CAs. Assim, o modelo assume que a IDIF é obtida através de uma combinação linear entre a IF corrigida para o PVE e uma TAC dos tecidos do lóbulo temporal adjacente à CA (Bg) (IDIF = IF_ PV + Bg_SP ). Tendo em conta o elevado impacto do ruído nas imagens de PET é de interesse estudar a influência do mesmo nas estimativas de PV e SP. Com este objetivo, utilizaram-se curvas simuladas de [18F]-FDG, às quais foram adicionadas diferentes níveis de ruído. Os resultados mostram que o aumento do ruído resulta numa sobrestimação do PV e numa subestimação do SP. Consequentemente são obtidos erros na área sob a curva (AUC, acrónimo inglês de Area Under the Curve), que é utilizada como input em diferentes modelos cinéticos. Este método apresenta ainda uma dependência do termo SP PV , onde quocientes maiores resultam em maiores erros. Este quociente é aumentado quando num passo de pós-processamento se aplica o filtro Gaussiano, uma vez que este reduz o PV e aumenta o SP (aumenta o PVE e o spillover). Com o objetivo de reduzir a influência do filtro Gaussiano, neste trabalho propomos a utilização de um filtro bilateral, o filtro bilateral híbrido (HBF, acrónimo inglês de Hybrid Bilateral Filter). Este filtro utiliza a informação anatómica das Cas de uma imagem de MRI para controlar a filtragem nos limites das CAs. De forma a avaliar o HBF e os PVC foram geradas imagens dinâmicas de [18F]-FDG PET de um sujeito saudável, com a plataforma de simulação Monte Carlo Geant4 Application for Tomographic Emission (GATE). O impacto da IF foi também estudado na taxa de consumo cerebral de glucose metabolizada (CMRglu acrónimo inglês para Cerebral Metabolic Rate for Glucose). Para se obter a IDIF foram considerados não só a média dos valores no VOI (IDIF-A), mas também a média dos n pixels com valor mais elevado em cada plano no VOI (IDIF-nH) e no VOI (IDIF-nV). O HBF foi avaliado com base nos coeficientes do model-based PVC e na AUC. Os resultados obtidos mostram que os recovery coefficients, denominados de tPV, apresentam valores idênticos aos PV para a IDIF-A e a IDIF-4H a IDIF-10H. Contudo a PVC continua a ser necessária. Após a PVC, as IDIF-4H a IDIF-10H dos dados filtrados com o HBF apresentaram os menores erros em termos de AUC e CMRglu. O HBF aumenta a SNR sem deteriorar a resolução do sistema localmente. Os métodos de PVC foram também avaliados com dados reais de [18F]-FDG, [18F]-FET e [15O]-água adquiridos com o 3 T MR-BrainPET. O co-registo entre as CAs nas imagens de PET e numa imagem Magnetization Prepared Rapid Gradient Echo (MPRAGE) foi validado, o que permite obter uma IDIF através da definição do VOI em imagens de MRI. Para tal, foram analisadas imagens paramétricas de CMRglu e do fluxo sanguíneo cerebral (CBF acrónimo inglês para Cerebral Blood Flow). Os resultados obtidos com os dados de [18F]-FDG mostram que os coeficientes tPV e PV estão de acordo e que o coeficiente SP é aproximadamente constante para a IDIF-A e a IDIF-4H a IDIF-8H. Estes resultados estão de acordo com os dados simulados, o que sugere que pode ser possível utilizar o tPV e um SP constante para corrigir a IDIF com estes parâmetros. Os resultados dos dados de [18F]-FET mostram que ocorreu uma sobrestimação da IDIF, o que sugere que este radio-traçador pode ter propriedades pegajosas. Para os dados de [15O]-água foi também proposto um método de correção da dispersão e do atraso, tendo por base a IDIF, o PVE, a dispersão e o atraso. Cada radio-traçador apresenta características específicas e deste modo, cada método deve ser avaliado para cada radio-traçador. O HBF foi ainda validado com dados de fantomas e de pacientes, onde foram determinados os seus parâmetros ótimos (g _ 6). Estes resultados estão de acordo com os dados de simulação Monte Carlo, onde o HBF aumenta o SNR sem deteriorar a resolução localmente. Em suma, o trabalho desenvolvido nesta dissertação mostra que a integração de um sistema de alta resolução PET (BrainPET) num sistema de imagem MRI de 3 T permite a obtenção de uma IDIF com base em VOIs definidos em imagens de MRI, devido a um co-registo excelente na região das CAs. A IDIF deve ser corrigida para o PVE. Este trabalho propõe e valida o HBF com dados simulados de fantomas e de pacientes. Um novo método de correção da dispersão e do atraso da IF é também proposto tendo em conta a IDIF e o PVE. Assim, a integração de abordagens híbridas PET/MRI abre novos horizontes para a imagiologia cerebral, onde as mais valias de cada modalidade convergem num maior número de oportunidades de conhecimento da funcionalidade cerebral.Introduction: The 3TMR-BrainPET scanner is an excellent tool to obtain an image derived input function (IDIF), due to PET/MRI simultaneous imaging. In this work, we investigated non-invasive methods to estimate an IDIF from volumes of interest (VOI) defined over the carotid arteries (CA) using the MR data. The MR information was used in the hybrid bilateral filter (HBF) and in three MR-based partial volume correction (PVC) methods (blood-free: recovery coefficient (tPV) and geometric transfer matrix (GTM); blood-based: model-based PVC). Material and methods: Synthetic data of a [18F]-FDG patient were used to evaluate the noise impact on the parameter estimation of the model-based PVC (partial volume PV and spillover SP). Monte Carlo GATE simulation data of a [18F]-FDG patient were used to evaluate the HBF and the PVC methods. Real data of a phantom and of five [18F]-FDG and three [18F]-FET scans, with venous blood samples at later times of the curve, and three [15O]-water scans, with arterial blood samples, were also used with the same goal. VOIs were drawn bilaterally over the CAs on an MPRAGE image (MR-VOI) and PET/MRI co-registration was evaluated. To estimate the IDIF, the MR-VOI average (IDIF-A), n hottest pixels per plane (IDIFnH) and n hottest pixels in VOI (IDIF-nV) were considered. Model-based PVC parameters, area under the curve and parametric images (cerebral metabolic rate for glucose and cerebral blood flow) were evaluated against blood samples. Results: An excellent PET/MRI CA co-registration was found. The HBF reduced the noise and partial volume effect (PVE), preserving the edges locally. The IDIF-nH is less influenced by PVE than IDIF-A resulting in a smaller PV, which is in accordance with the tPV. Results obtained with real data were in accordance with simulated data, where the best results (smallest AUC errors) where found with the model-based PVC. Conclusion: With the HBF the PVE and the spillover introduced by Gaussian filtering are reduced and at least the same SNR is achieved without deteriorating the resolution. The integration of a high resolution BrainPET in an MR scanner allows obtaining an IDIF from an MR-based VOI. The IDIF must be corrected for a residual partial volume effect

Neuroreceptor availability and cerebral morphology in human obesity

Obesity is a major challenge to human health worldwide. Little is known about the brain mechanisms that are associated with overeating and obesity in humans. In this project, multimodal neuroimaging techniques were utilized to study brain neurotransmission and anatomy in obesity. Bariatric surgery was used as an experimental method for assessing whether the possible differences between obese and non-obese individuals change following the weight loss. This could indicate whether obesity-related altered neurotransmission and cerebral atrophy are recoverable or whether they represent stable individual characteristics. Morbidly obese subjects (BMI ≥ 35 kg/m2) and non-obese control subjects (mean BMI 23 kg/m2) were studied with positron emission tomography (PET) and magnetic resonance imaging (MRI). In the PET studies, focus was put on dopaminergic and opioidergic systems, both of which are crucial in the reward processing. Brain dopamine D2 receptor (D2R) availability was measured using [11C]raclopride and µ-opioid receptor (MOR) availability using [11C]carfentanil. In the MRI studies, voxel-based morphometry (VBM) of T1-weighted MRI images was used, coupled with diffusion tensor imaging (DTI). Obese subjects underwent bariatric surgery as their standard clinical treatment during the study. Preoperatively, morbidly obese subjects had significantly lower MOR availability but unaltered D2R availability in several brain regions involved in reward processing, including striatum, insula, and thalamus. Moreover, obesity disrupted the interaction between the MOR and D2R systems in ventral striatum. Bariatric surgery and concomitant weight loss normalized MOR availability in the obese, but did not influence D2R availability in any brain region. Morbidly obese subjects had also significantly lower grey and white matter densities globally in the brain, but more focal changes were located in the areas associated with inhibitory control, reward processing, and appetite. DTI revealed also signs of axonal damage in the obese in corticospinal tracts and occipito-frontal fascicles. Surgery-induced weight loss resulted in global recovery of white matter density as well as more focal recovery of grey matter density among obese subjects. Altogether these results show that the endogenous opioid system is fundamentally linked to obesity. Lowered MOR availability is likely a consequence of obesity and may mediate maintenance of excessive energy uptake. In addition, obesity has adverse effects on brain structure. Bariatric surgery however reverses MOR dysfunction and recovers cerebral atrophy. Understanding the opioidergic contribution to overeating and obesity is critical for developing new psychological or pharmacological treatments for obesity. The actual molecular mechanisms behind the positive change in structure and neurotransmitter function still remain unclear and should be addressed in the future research.Neuroreseptorit ja aivojen rakenne lihavuudessa Lihavuudesta on tullut yksi maailman suurimmista terveysongelmista. Lihavuuteen liittyvistä aivojen toiminnan ja rakenteen muutoksista tiedetään kuitenkin toistaiseksi melko vähän. Tässä tutkimuksessa selvitettiin aivojen välittäjäainetoiminnan ja rakenteen eroja lihavien ja normaalipainoisten henkilöiden välillä. Lihavuusleikkauksen ja sitä seuraavan laihtumisen aiheuttamia aivojen välittäjäainetoiminnan ja tiheyden muutoksia arvioimalla voitiin päätellä, ovatko aivomuutokset jo olemassa ennen lihavuuden syntyä vai ovatko ne lihavuuden aiheuttamia. Vaikeasti lihavien henkilöiden (BMI ≥ 35 kg/m2) aivoja verrattiin normaalipainoisten henkilöiden (BMI:n keskiarvo 23 kg/m2) aivoihin käyttämällä positroniemissiotomografiaa (PET) ja magneettiresonanssikuvantamismenetelmiä (MRI). PET-tutkimuksissa käytettiin kahta radioisotoopilla leimattua merkkiainetta, joista [11C]raklopriidi sitoutuu dopamiinin D2-reseptoreihin ja [11C]karfentaniili µ-opioidireseptoreihin. Kummatkin reseptorit ovat keskeisessä asemassa aivojen mielihyväjärjestelmän toiminnassa. MRI-tutkimuksissa käytettiin analyysimenetelminä vokselipohjaista morfometriaa (voxel-based morphometry, VBM) sekä diffuusiotensorikuvantamista (diffusion tensor imaging, DTI). Lihaville tutkittaville tehtiin tutkimuksen aikana lihavuusleikkaus aiemman hoitosuunnitelman mukaisesti. Ennen lihavuusleikkausta lihavilla tutkittavilla oli selvästi vähemmän µ-opioidireseptoreja mielihyväjärjestelmän keskeisissä osissa, kuten tyvitumakkeissa, insulassa ja talamuksessa, mutta dopamiinin D2-reseptorien määrä oli sama kuin normaalipainoisilla tutkittavilla. Lisäksi näiden reseptorijärjestelmien välinen yhteys oli häiriintynyt lihavilla tutkittavilla aivojuovion etuosassa. Lihavuusleikkauksen aiheuttaman laihtumisen jälkeen µ-opioidireseptorien määrä palautui samalle tasolle kuin normaalipainoisilla. Dopamiinireseptorien määrässä ei tapahtunut muutosta. Magneettitutkimuksissa kävi ilmi, että lihavilla tutkittavilla aivojen harmaan ja valkean aineen tiheydet olivat pienemmät kuin normaalipainoisilla tutkittavilla. Eroa löytyi erityisesti mielihyvään ja ruokahaluun liittyvillä alueilla. Myös valkean aineen radastoissa oli vaurion merkkejä. Leikkauksen jälkeen tapahtui palautumista laajasti valkean aineen alueilla mutta myös selvästi pienemmillä harmaan aineen alueilla. Tulokset osoittavat, että opioidijärjestelmä liittyy keskeisesti lihavuuteen ja liikasyömiseen. Opioidijärjestelmän poikkeava toiminta on todennäköisesti lihavuuden aiheuttamaa ja saattaa ylläpitää haitallista syömiskäyttäytymistä. Lisäksi lihavuudella on haitallisia vaikutuksia aivojen rakenteeseen. Lihavuusleikkaus palauttaa opioidijärjestelmän ennalleen ja korjaa lihavuuden aiheuttamaa aivokudoksen harventumaa. Opioidijärjestelmän merkityksen ymmärtäminen on välttämätöntä lihavuuden uusien psykologisten ja farmakologisten hoitomuotojen kehittämisessä. Solutason mekanismit leikkauksen aiheuttamien muutosten taustalla ovat kuitenkin edelleen epäselvät, ja niihin tulisi keskittyä jatkotutkimuksissa.Siirretty Doriast

Extraction de la courbe d'entrée à partir des images TEP du coeur chez le petit animal pour la modélisation pharmacocinétique

Dans cette thèse, nous présentons l'ensemble de nos contributions relatives à la mise en oeuvre et à la validation de techniques d'extraction d'une courbe de l'activité d'un traceur radioactif, dite courbe d'entrée (CE), à partir des images enregistrées par tomographie d'émission par positrons (TEP). Cette courbe est primordiale pour la quantification de paramètres physiologiques et métaboliques comme le métabolisme du glucose au niveau du myocarde chez le petit animal. La modalité d'imagerie TEP sert à déceler, à des phases souvent précoces, le dysfonctionnement d'un organe par un examen médical. L'examen consiste en une injection d'un élément radioactif, émetteur de positrons attachés à une molécule caractérisée par les mêmes propriétés chimiques et biologiques qu'une molécule naturelle, et de suivre son activité temporelle. La quantité du traceur mesurée dans le plasma sanguin en fonction du temps constitue la CE, tandis que la radioactivité mesurée dans les tissus par la TEP constitue la réponse des tissus. La CE et la réponse des tissus sont les fonctions fondamentales d'un modèle mathématique appelé "le modèle pharmacocinétique" qui estime les paramètres physiologiques et métaboliques. Habituellement la CE est obtenue d'une manière invasive par un prélèvement sanguin qui se fait parallèlement à l'acquisition des données. En plus, elle nécessite une chaîne de préparation pour enregistrer la concentration du traceur radioactif dans le plasma et une fréquence d'échantillonnage corrélée avec le découpage de la séquence d'images. Dans le cadre de nos recherches, nous avons développé des techniques d'extraction de la CE directement à partir d'une séquence d'images TEP. Cette approche présente l'avantage d'être non-invasive et permet un contrôle sur la fréquence d'échantillonnage temporel. Néanmoins, la résolution spatiale, les limites physiques, les limites physiologiques et les limites méthodologiques reliées à la reconstruction d'images sont des facteurs qui détériorent la qualité de la courbe. Dans un premier temps, nous avons appliqué un concept probabiliste à l'intérieur de deux régions d'intérêts (Ris) tracées sur la séquence d'images délimitant le ventricule gauche et le myocarde. La méthode estime la fraction du sang dans les deux régions pour déterminer une CE non dégradée par les effets mentionnés précédemment. Cette approche a permis de corriger la courbe en tenant compte des effets causés par la contamination spatiale. Dans un deuxième temps, nous avons travaillé sur la réduction de l'effet du mouvement du coeur et des poumons sur la qualité de la CE. Pour cela, nous avons utilisé une acquisition de données synchronisée par rapport à l'électrocardiogramme (ECG). Cette acquisition nécessite un suivi automatique des RIs sur les différents cadres synchronisés. Pour remédier aux effets de la faible résolution spatiale des images, nous avons développé un modèle particulier d'un contour déformable qui répond aux faiblesses des images TEP. Notre modèle est capable de délimiter le ventricule gauche et le myocarde sur les images d'une façon quasi-automatique. Finalement, nous avons généralisé l'idée de l'extraction de la CE pour différents traceurs tels que le glucose marqué au fluor ([indice supérieur 18]F-FDG), l'ammoniaque marqué à l'azote ([indice supérieur 13]N-ammoniaque), le [indice supérieur 82] rubidium ([indice supérieur 82]Rb) et l'acétate marqué au carbone ([indice supérieur 11]C-acétate). Le modèle que nous avons développé est basé sur l'estimation de la CE par l'analyse en composante indépendante (ACI) et la distribution gaussienne généralisée (DGG). Tous nos résultats pour le traceur [indice supérieur 18]F-FDG sont comparés à la méthode de référence classique, à savoir le prélèvement sanguin. Les résultats de l'extraction de la CE par l'ACI ont été comparés à ceux extraits par la méthode de référence et par la moyenne de l'activité d'une RI segmentée manuellement sur les images. Les résultats montrent l'apport de la méthode sur l'amélioration de la courbe lorsque celle-ci est dégradée par la contamination croisée. Le travail accompli dans cette thèse montre la possibilité de contourner les limites de l'imagerie TEP par l'utilisation d'approches statistiques dans le but d'extraire une CE fiable. Les méthodes développées représentent une alternative à la méthode invasive d'échantillonnage sanguin