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Introduction: Low-grade gliomas are a sub-group of primary brain tumours that typically affect young adults and which present specific challenges to conventional diagnostic imaging. They demonstrate a pattern of growth whereby tumour cells infiltrate healthy brain tissue without distortion of the surrounding brain or blood-brain barrier integrity. These features limit the capacity of conventional neuro-imaging strategies to effectively delineate the tumour extent or characterise the degree of 'malignancy'. One solution is to apply multiple imaging modalities to image different aspects of the tumour behaviour, analogous to histological classification based upon changes in mitotic activity, cellular atypia, microvascular proliferation and necrosis. Published information regarding how imaging techniques that address these parameters correlate within the tumour volume is limited. This reflects the technical challenges in acquiring and processing data at an adequate spatial resolution to characterise small but heterogenous tumours. In this thesis, following a series of experiments seeking to optimise the sensitivity and reproducibility of PET analysis in gliomas, a prospective multi-modal neuro-imaging study is presented addressing this need. Methods: Retrospective [11C]-methionine PET (MET PET) data made available through a collaboration with the Max-Planck Institute for Neurological Research in Cologne was carried out first to address the optimal method of analysis of PET data in gliomas. A normal methionine uptake map was created and its use in the analysis of patient scans validated against a conventional approach. Automated methods for delineating the extent of abnormal methionine uptake and identifying the region of peak uptake were developed and evaluated to optimise the reproducibility of the approach. High-resolution MET PET and a comprehensive MRI brain tumour protocol were then acquired prospectively in 20 subjects in Manchester. Detailed analysis of the peak uptake and extent of abnormal tissue defined using PET and MRI modalities including structural, diffusion- and perfusion-weighted techniques was performed. Results: Evaluation of methionine uptake with respect to population normal data, the 'RatioMap' technique, yielded peak uptake measurements that correlated closely with a conventional approach (r = 0.97) but with improved reproducibility. The constrained 3D region-growing algorithm designed to delineate the abnormal region was shown to be reproducible and to generate volumes that correlated with tumour grade. High-resolution multi-modal data in suspected low-grade gliomas demonstrated consistent correlation between peak methionine uptake ratio and peak regional cerebral blood volume (r = 0.85) but with disparity between the location of the maximal uptake regions (mean distance = 11.2mm). Significant correlation was seen between multi-modal MRI and PET ‘tumour’ volumes (r = 0.91) but with substantially larger MRI defined abnormal volumes (ratio = 2.0) including small regions identified as abnormal by multiple MRI parameters but normal on PET imaging. Conclusion: A novel method to enhance the reproducibility of analysis of MET PET images in gliomas has been presented and validated but there remains no single imaging modality capable of fully characterising glioma extent and 'malignancy' non-invasively. Considerable correlation between PET and MRI tumour biomarkers has been demonstrated but there are significant differences between the regions identified as the 'most malignant' for biopsy targeting and the extent of potentially tumour bearing tissue. Combined use of diffusion- and perfusion-weighted MRI parameters can provide results very closely correlated to the PET findings but cannot yet completely replace the use of nuclear medicine techniques. The use of multi-modal approaches to tumour characterisation as demonstrated in this study provides the most effective currently available approach to fully characterise a suspected glioma.

Positron Emission Tomography (PET) images reconstructed without adequate scatter corrections introduce noise and degrade image contrast. In commercial imaging systems, misalignment between computed tomography (CT) and PET images can introduce biases in the activity distribution. Recently, several reconstruction algorithms have been proposed, which made direct use of single scattered photons in the activity reconstruction. However, the realistic dataset contains single and higher order scattered photons, and current scatter reconstruction methods do not distinguish them. In this study, a novel reconstruction algorithm that is capable of processing higher order scattered photons was developed. A restricted attenuation correction method was created to avoid overcorrecting for scattered photons. The simulation outcomes have shown that the proposed methods can, under ideal energy resolution, reconstruct images that are qualitatively and quantitatively better than those obtained using existing algorithms, and that the methods show promise for use under more realistic clinical conditions. / October 2016

Orientador: Cesar Fabiano Fioriti / Resumo: O crescimento da população e do seu poder aquisitivo mudaram a geração de resíduos. Atualmente se produz resíduos diferentes em qualidade e volume diferentes daqueles produzidos por gerações passadas. Entre os resíduos gerados atualmente se encontram os resíduos de PET, oriundos de embalagens descartáveis, que acarretam problemas ambientais devido ao descarte incorreto. Este trabalho se propõe em estudar a aplicação destes resíduos para a produção de pavers de concreto, observando suas características de desempenho em relação aos pavers produzidos com concreto convencional, ambos produzidos por procedimentos manuais. Para atingir o objetivo proposto foram realizados ensaios de trabalhabilidade, ensaios de massa específica em estado fresco e endurecido, ensaios de absorção de água, medição da incorporação de ar, ensaios de resistência à compressão, tração e impacto e microscopia eletrônica de varredura para os traços produzidos com 5%, 10%, 15% e 20% de substituição em volume dos agregados miúdos e graúdos. Dessa maneira, foi possível buscar informações a respeito do comportamento obtido por meio da substituição parcial dos agregados pelos resíduos de PET produzindo peças com características semelhantes àquelas proporcionadas pelos pavers convencionais, atingindo a resistência à compressão de 35 MPa, definida em norma, em 4 traços produzidos, mesmo com valores de absorção superiores aos 6% estipulados em norma. / Abstract: Population growth and purchasing power changed waste generation. Currently the wastes produced differs in quality and volume than that produced by past generations. Amongst the waste currently produced are the PET waste, originating from disposable packaging, which generate environmental problems due to incorrect disposal. The purpose of this work is to study the application of these residues in concrete pavers production, observing the performance characteristics in comparison to those produced with conventional concrete, both produced by manual procedures. To achieve the proposed goal were performed workability tests, specific weight in both fresh and hardened conditions, water absorption tests, air content tests, compressive strength, splitting tensile strength and impact tests and scanning electron microscopy for the concrete designs containing 5%, 10%, 15% and 20% by volume of both fine and coarse aggregate. Thus, it was possible to achieve information about the concrete behavior produced with partial substitution of the aggregates by the PET waste, producing pavers with similar characteristics of those provided by pavers produced with conventional concrete, achieving the compressive strength of 35 MPa, required by standard, in 4 mixtures with substitution, although the absorption values were above the 6% required by standard. / Mestre

La dysplasie cérébelleuse est une anomalie du développement tissulaire intéressant principalement le cervelet et résultant en une anomalie focale ou diffuse de son architecture macroscopique et microscopique. Plusieurs travaux antérieurs ont bien documenté sa caractérisation morphologique à l'imagerie par résonance magnétique (IRM). Cependant, le retentissement de cette malformation, parfois associée à d'autres anomalies développementales du système nerveux central (SNC), sur le développement et le fonctionnement cognitifs est mal connu et peu documenté. Dans le but d'étudier les corrélations anatomo-fonctionnelles de cette pathologie constitutionnelle du cervelet, par le biais de l'approche des altérations neuropsychologiques, génétiques et, fonctionnelles associées, ainsi que par l'approche neuroanatomique, nous avons dirigé nos travaux dans quatre axes principaux et sur trois types de population distinctes. Le premier axe a concerné l'évaluation du profil neuropsychologique et du suivi chez dix enfants porteurs d'une dysplasie cérébelleuse isolée (DCI). Nous avons pu observer chez ces enfants une grande diversité de l'expression neuropsychologique de la DCI, depuis l'efficience normale jusqu'au retard mental sévère, sans corrélation avec le degré de dysplasie. D'autre part, au cours du suivi de ces enfants, nous avons observé une hétérogénéité d'évolution à caractère imprédictible, avec l'émergence des certaines fonctions dans l'axe du langage notamment. Le deuxième axe a porté sur l'investigation fonctionnelle du SNC par l'étude de la consommation cérébrale du fluorodeoxyglucose par Tomographie à émission de positons (TEP-FDG) chez six enfants porteurs d'une DCI. Les résultats ont montré, au sein du cervelet, un aspect normal dans les dysplasies mineures (limitées au vermis), un hypométabolisme des zones dysplasiques (corrélé à l'extension anatomique), et un isométabolisme au cortex dans les hétérotopies. Toutefois, ces anomalies de captation du glucose n'étaient pas corrélées au dysfonctionnement cognitif. Le troisième axe était d'approcher les corrélations génétiques, dans l'hypothèse d'un lien physiopathologique embryologique entre le cerveau et le cervelet, dans les dysplasies cérébelleuses associées (DCA) aux Lissencéphalies (cerveaux lisses). La caractérisation génétique relativement bien définie des Lissencéphalies nous a permis d'identifier des gènes de la migration neuronale et axonale (RELN et VLDRL) comme étant significativement associés aux dysplasies cérébelleuses, en dehors des dystrophies musculaires congénitales impliquant les gènes de la O-glycosylation. Le quatrième axe a été de rechercher chez des volontaires sains les marqueurs neuroanatomiques potentiels des altérations cognitives dans les dysplasies cérébelleuses, partant de l'hypothèse selon laquelle, une malformation isolée du cervelet induirait des anomalies anatomiques détectables en imagerie par tenseur de diffusion (DTI), sur les voies de projections cérébello-corticales, vraisemblablement impliquées dans la contribution du cervelet au développement et à l'exécution des fonctions supérieures. Ce travail nous a permis d'individualiser et de quantifier les projections cérébello-corticales préfrontales et pariétales chez tous les sujets sains. Ainsi, nos travaux nous ont permis: (i) de mieux établir les anomalies neuropsychologiques propres aux DCI et leur caractère hétérogène, tant au diagnostic qu'à l'évolution, (ii) de corréler la dysplasie cérébelleuse à des anomalies de la consommation cérébrale du glucose et par conséquent de son fonctionnement, (iii) de suggérer d'axer chez ces patients la recherche d'anomalies génétiques sous-jacentes vers les gènes impliqués dans la migration neuronale et axonale, et enfin, (iv) d'obtenir des marqueurs neuroanatomiques que nous pourrons appliquer aux patients pour étudier la possibilité de l'altération des vois de projections cérébello-corticales. De nombreuses perspectives d'imagerie avancée anatomique et fonctionnelle du SNC appliquées aux dysplasies cérébelleuses ont été ainsi ouvertes. / Cerebellar dysplasia is a developmental anomaly involving mainly the cerebellum, resulting in a focal or diffuse macroscopic and microscopic disruption of the tissue architecture. Previous studies have well documented the magnetic resonance imaging (MRI) features of this malformation. However, the impact of cerebellar dysplasia, which may be associated with other developmental anomalies of the central nervous system (CNS), on the cognitive development and function, is ill known and poorly documented. We aimed to study the structural functional correlations in this cerebellar malformation, by investigating the neuropsychological, genetic and, functional disturbances associated as well as the neuroanatomical approach. Our work was conducted in 4 directions including 3 different populations. First, we assessed the neuropsychological profile and the follow-up of children with isolated cerebellar dysplasia (ICD). We observed I this population a wide range of neuropsychological expression of ICD, from normal efficiency to severe mental retardation, without no correlation with the degree of dysplasia. Moreover, during the follow-up of these children, we noticed the unpredictable heterogeneity of the cognitive evolution with the emergence in some cases of certain function such as language. Secondly, we investigated the CNS function using fluorodeoxyglucose positron emission tomography (FDG-PET) in six children with ICD. The results showed within the cerebellum a normal aspect in patients with minor dysplasia (restricted to the vermis), a hypometabolism in dysplastic zones (correlating with the anatomical extent), and a metabolism similar to that of the cortex in heterotopias. Nevertheless, these functional disturbances were not correlated with neuropsychological impairement. Thirdly, we attempted to investigate the genetic abnormalities leading to the embryology physiopathology basis of cerebellar dysplasias associated (CDA) with Lissencephalies (smooth brain). The quite well characterized genetics of human brain lissencephalies have allowed us to identify some genes involved in the neuronal and axonal migration process (RELN and VLDLR) to be significantly associated with cerebellar dysplasia, not including CDA in muscular dystrophy syndromes related to O-glycosylation defects. Fourthly, we aimed to find in normal volunteers the neuroanatomical potential markers of cognitive disturbances associated with cerebellar dysplasia, on the hypothesis that an isolated cerebellar malformation could induce some anomalies on the pathways of cerebello-cortical projections, detectable by diffusion tensor imaging (DTI). These pathways are presumably involved in the cerebellar implication in higher functions. This work has allowed us to visualize and quantify selectively the cerebello-cortical projections to the prefrontal and parietal cortices in the normal human brain. Thus, our overall results have permitted: (i) to clearly assess the neuropsychological disturbances associated with ICD and their heterogeneity, both at the time of diagnosis and at the follow-up, (ii) to correlate the cerebellar dysplasia to brain glucose uptake differences and subsequently to brain dysfunction, (iii) to suggest some precise genetic analyses in neuronal and axonal migration pathways, and eventually, (iv) to obtain some anatomical markers which we can apply to dysplastic patients in order to assess the putative disruption of cerebello-cortical projections. Thereby, our results have opened numerous perspectives in applying advanced anatomical and functional neuroimaging techniques to the cerebellar dysplastic patients.

Notre recherche a pour objectif la biocompatibilisation active de polymères de synthèse. La stratégie utilisée consiste à greffer de manière covalente en surface du polymère des signaux synthétiques. Parmi les nombreuses applications de cette stratégie, nous nous sommes intéressés à la promotion de l'adhésion cellulaire sur le poly(éthylènetéréphtalate) (PET). Ce matériau possède des propriétés déjà amplement exploitées dans des application biomédicales. Durant cette thèse, nous avons abordé plusieurs aspects dans le contrôle et l'évaluation du substrat modifié. Afin de réaliser un greffage efficace, nous avons étudié les sites réactifs du PET (fonctions acides vs fonctions alcools) ainsi que les méthodes de couplage via la chimie organique appliquées à l'interface solide-liquide (surface wet chemistry). En relation avec cette étude, nous avons synthétisé et évalué différents bras d'espacements afin d'établir les plus performants lors d'un greffage en surface. L'adhésion cellulaire est un phénomène s'établissant via des récepteurs cellulaires. Par le greffage de motifs de reconnaissance de ces récepteurs, nous envisageons d'accroître le taux d'adhésion cellulaire. Pour cela, nous avons réalisé le design et la synthèse de peptidomimétiques de la séquence RGD, motif universellement reconnu par les intégrines. Ces dernières sont une des grandes familles de récepteurs cellulaires, très étudiés en chimie médicinale. Finalement, notre évaluation biologique se scinde en 2 parties. D'une part, greffés en surface, nos peptidomimétiques ont pour effet recherché, la promotion de l'adhésion cellulaire. D'autre part, la saturation des récepteurs cellulaires par les ligands en solution inhibe l'adhésion cellulaire via ces récepteurs. Ce dernier point est un aspect développé par de nombreux groupes pharmaceutiques dans le traitement de certaines maladies. Un test plus poussé de binding moléculaire a pu être effectué nous apportant des informations quand au phénomène de reconnaissance. A partir des premiers résultats obtenus, nous avons pu optimiser le design selon un protocole itératif basé sur une analyse théorique par modélisation plus poussée.

PET (positron emission tomography) scans are still in the experimental phase, as one of the newest breast cancer diagnostic techniques. It is becoming the new standard in neurology, oncology and cardiology. PET, like other nuclear medicine diagnostic and treatment techniques, involves the use of radiation. Because of the negative impact of radioactivity to our bodies the radiation doses in PET should be small. The existing computing algorithms for calculating PET images can be divided into two broad categories: analytical and iterative methods. In the analytical approach the relation between the picture and its projections is expressed by a set of integral equations which are then solved analytically. The Fourier backprojection (FBP) algorithm is a numerical approximation of this analytical solution. Iterative approaches use deterministic (ART = Algebraic Reconstructed Technique) or stochastic (EM = Expectation Maximization) algorithms. My proposed kernel density estimation (KDE) algorithm also falls also into the category of iterative methods. However, in this approach each coincidence event is considered individually. The estimate location of the annihilation event that caused each coincidence event is based on the previously assigned location of events processed earlier. To accomplish this, we construct a probability distribution along each coincidence line. This is generated from previous annihilation points by density estimation. It is shown that this density estimation approach to PET can reconstruct an image of an existing tumor using significantly less data than the standard CT algorithms, such as FBP. Therefore, it might be very promising technique allowing reduced radiation dose for patients, while retaining or improving image quality. / October 2007

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Accurate constitutive modeling of polymeric fibers presents a difficult and distinct challenge. While significant progress has been made in constructing models applicable for small strains and limited strain-rate and temperature regimes, much less has been made for more general conditions. This is due in part to the complexity of polymeric behavior. In this work, experimental results of uniaxial extension tests on Polyethylene terephthalate (PET) were obtained from Dr. S.Bechtel, were analyzed, and were formulated into a new model which explains the behavior of PET at different temperatures and strains. The biggest impediment in the determining the behavior of polymeric was the difference in the behavior of PET above and below its glass transition temperature. Consequently, well established (from microstructural considerations) constitutive models and concepts for rubber elasticity and plasticity were not directly transferable to modeling PET fibers. In the model, the PET fibers were assumed to be constituted by amorphous and crystallization segments and the response of the material during stretching was the combined response of simultaneous stretching of the amorphous and the crystalline segments. The strengthening mechanism is due to orientation of the amorphous segments during stretching. The model involves a friction element which took account of the plastic behavior below the glass transition temperature. The model was used to predict the response of PET at different temperatures and the results from the model showed good agreement with the experimental data. The results from the research will be further used to increase the overall efficiency of the fiber drawing process.

This thesis has contributed to the achievement of in-beam PET as a promising clinical monitoring technique. In response to a pressing medical demand, this work has provided a tool for quantification of local dose deviations in case of observed discrepancies between the measured and expected PET images. The implemented interactive approach described in chapter 3 is in clinical use since 2001. It provides the radio-oncologist with a valuable feedback which may allow a prompt reaction in the strategy of the therapy prior to the delivery of the successive treatment fraction in case of significant deviations between planned and actually applied dose. ...