This thesis examines the utility of USPIO-MRI to provide a tool of tracking macrophage recruitment to sites of neuroinflammation within the CNS. Recruited macrophages and microglia resident in CNS tissue play a key role in the pathophysiology of a number of neuroinflammatory diseases such as neuropathic pain and multiple sclerosis. Under activated conditions, microglia and macrophages will phagocytose invading cells and CNS debris. It has been shown that ultrasmall superparamagnetic particles of iron oxide (USPIO), such as Sinerem, injected systemically, are engulfed by macrophages, which in turn migrate to sites of tissue injury. USPIOs can be visualised as a distinct reduction in signal intensity on T2* weighted MR images. However, there are still some issues regarding the distinction between iron-laden recruited macrophages and the entry of free iron across a permeable blood brain barrier (BBB) in disease cases. Hence, it was shown that intravenously injected Sinerem is cleared from the peripheral circulation within 24 hours, indentifying this as a time point as suitable for MCP-1 injection. Data showed that free USPIO can be visualised in the brain and that there is a linear relationship between Sinerem concentration and T2* signal intensity changes. MCP-1 induces macrophage recruitment to the site of microinjection and causes BBB breakdown at between 3 and 4 hours. In particular it was shown that T2* signal intensity changes are seen, in the presence of an intact BBB, as a result of Sinerem laden macrophages. This finding was verified by the co-localisation of ED-1 positive cells and Prussian blue positive regions. It was demonstrated that there is a strong correlation between T2* signal changes and the number of macrophages. This demonstrates that USPIO-MRI can be used to characterise macrophage infiltration in neuroinflammation in the presence of an intact BBB.

This thesis presents an investigation on multiphase reactor hydrodynamics using magnetic resonance imaging (MRI). The study demonstrates experimental techniques by which computational and quasi-analytical fluid models may be validated. Three types of industrially-important multiphase reaction vessels are considered: a co-current upflow gas-liquid-solid bed, a co-current downward trickle bed (gas, liquid, solid), and a gas-solid fluidised bed. These reactors were selected as they commonly demonstrate local hydrodynamic anisotropy which affects the global performance of industrial units. MRI was used to obtain 2D velocity images of the gas and liquid phases in the packed beds, and of the gas and the solid phases in the fluidised bed. This study reports the first spatially resolved velocity measurements of both the gas and liquid phases in a co-current upflow bed, and the gas and solid phases of an isolated bubble in a fluidised bed. The experimental vessels were: 52 mm in diameter using 5 mm glass spheres in the upflow bed at 8 bara, 27 mm with 5 mm glass spheres in the trickle bed at 6.75 bara, and 52 mm using 1.2 mm poppy seeds as the fluidised particles at 8.5 bara. The experiments were conducted at a laboratory temperature of 25.0 ± 3.0 °C. In the upflow bed, time-averaged velocity images were acquired over a 2.5 h experimental time. This was done to capture the steady state behaviour of the vessel operating in the pulsing flow regime. The temporally-stable trickle flow state in the trickle bed was imaged over 15-100 minutes. In both packed beds, severe spatial anisotropy in the distribution of flow between pores was revealed. Furthermore, the data were used to determine classical design features such as catalyst wetting and liquid holdup which compared well with literature models. The trickle bed data were further analysed using a morphological algorithm which unambiguously identified the gas-liquid and liquid-solid interfaces. The interfacial flow fields were found to be similar to the bulk flow, with most voxels exhibiting static behaviour. The amount of interaction between the phases was found to be minimal, which is typical of the low interaction regime. A single bubble injection system was employed in the fluidised bed which allowed the injection of isolated bubbles into the incipiently fluidised bed. It also enabled the triggered acquisition of NMR data at precise time intervals. The bubble was found to be an indented ellipsoidal shape, which rose with atypical behaviour which caused it to collapse. Rise velocity was found to be consistent with theory, and the injected bubbles were sufficiently spatially reproducible to acquire 2D velocity images using single-point imaging. These velocity images showed flow behaviour characteristic of a 'fast' rising bubble, with a gas recirculation cloud 37 mm in diameter. The particle field was shown to have very high flow in the bubble wake, revealing the mechanism of bubble collapse. The flow data were compared to classical two-phase fluidisation theory, which revealed noteworthy differences in the division of flow between the particulate and bubbling regions.

L’utilisation d’antennes miniatures à haute sensibilité basées sur le principe des lignes de transmission a permis, lors de l’étude de pathologies chez l’Homme ou le petit animal , une amélioration significative de la qualité des images obtenues en micro Imagerie par Résonance Magnétique (IRM). Les performances élevées de ces antennes et leurs dimensions réduites entrainent cependant des difficultés critiques pour traiter et conditionner le signal de Résonance Magnétique Nucléaire (RMN) détecté. Plus particulièrement, le réajustement de la fréquence de résonance de l’antenne de détection, au cours d’une expérience d’IRM, ne peut être réalisé à l’aide de composants rapportés, comme c’est le cas avec les antennes d’IRM conventionnelles, ceci afin de ne pas dégrader leurs performances.Notre étude a consisté à développer deux techniques d’accord originales et dédiées aux antennes miniatures à lignes de transmission. Ces techniques sont basées sur le déplacement micrométrique d’un élément d’accord à proximité de l’antenne entrainant une variation de l’environnement électromagnétique de celle-ci, et donc de la fréquence de résonance, par couplage (diélectrique ou inductif). L’ensemble des résultats obtenus (par des caractérisations expérimentales, des simulations numériques et des modélisations analytiques) a servi de base à la conception et la réalisation d’un dispositif de micro-déplacement chargé d’assurer le réglage fin de la fréquence de résonance à travers le déplacement de l’élément d’accord.La mise en œuvre d’une antenne accordée à l’aide du dispositif a été réalisée au sein d’un imageur à 4,7 T. Des images de démonstration sur fantôme ont été obtenues et validées, montrant ainsi la pertinence d’un tel dispositif et la faisabilité de systèmes résonants auto-accordés dédiés à l’IRM haute sensibilité. / The use of miniature transmission lines coils, in the study of diseases in humans or small animals, has allowed for significant improvements in Micro Magnetic Resonance Imaging (MRI). The high sensitivity of such coils combined with their small size, however, leads to critical problems in treating and conditioning the detected Nuclear Magnetic Resonance (NMR) signal. In particular, the adjustment of the resonant frequency of these detection coils, during a MRI experiment, cannot be achieved using reported components, as is the case of conventional MRI coils, in order not to degrade their performances.We have developed two original tuning techniques for such coils. These techniques are based on the micrometric displacement of a tuning element near the coil surface, which modifies the electromagnetic environment of the coil by coupling, resulting in a change of the resonant frequency. The obtained results have enabled the design and construction of a micro-displacement device responsible for the fine tuning of the coil, through the displacement of a tuning element.The tuned coil and micro-device have been implemented in a 4.7 T MRI. Sample images were obtained and validated, showing the relevance and feasibility of using an auto-tuning resonant system, dedicated to high sensitivity MRI.

This work explores if combining information from multiple Magnetic Resonance Imaging (MRI) modalities provides improved interpretation of brain biological architecture as each MR modality can reveal different characteristics of underlying anatomical structures. Structural MRI provides a means for high-resolution quantitative study of brain morphometry. Diffusion-weighted MR imaging (DWI) allows for low-resolution modeling of diffusivity properties of water molecules. Structural and diffusion-weighted MRI modalities are commonly used for monitoring the biological architecture of the brain in normal development or neurodegenerative disease processes. Structural MRI provides an overall map of brain tissue organization that is useful for identifying distinct anatomical boundaries that define gross organization of the brain. DWI models provide a reflection of the micro-structure of white matter (WM), thereby providing insightful information for measuring localized tissue properties or for generating maps of brain connectivity. Multispectral information from different structural MR modalities can lead to better delineation of anatomical boundaries, but careful considerations should be taken to deal with increased partial volume effects (PVE) when input modalities are provided in different spatial resolutions. Interpretation of diffusion-weighted MRI is strongly limited by its relatively low spatial resolution. PVE's are an inherent consequence of the limited spatial resolution in low-resolution images like DWI. This work develops novel methods to enhance tissue classification by addressing challenges of partial volume effects encountered from multi-modal data that are provided in different spatial resolutions. Additionally, this project addresses PVE in low-resolution DWI scans by introducing a novel super-resolution reconstruction approach that uses prior information from multi-modal structural MR images provided in higher spatial resolution. The major contributions of this work include: 1) Enhancing multi-modal tissue classification by addressing increased PVE when multispectral information come from different spatial resolutions. A novel method was introduced to find pure spatial samples that are not affected by partial volume composition. Once detecting pure samples, we can safely integrate multi-modal information in training/initialization of the classifier for an enhanced segmentation quality. Our method operates in physical spatial domain and is not limited by the constraints of voxel lattice spaces of different input modalities. 2) Enhancing the spatial resolution of DWI scans by introducing a novel method for super-resolution reconstruction of diffusion-weighted imaging data using high biological-resolution information provided by structural MRI data such that the voxel values at tissue boundaries of the reconstructed DWI image will be in agreement with the actual anatomical definitions of morphological data. We used 2D phantom data and 3D simulated multi-modal MR scans for quantitative evaluation of introduced tissue classification approach. The phantom study result demonstrates that the segmentation error rate is reduced when training samples were selected only from the pure samples. Quantitative results using Dice index from 3D simulated MR scans proves that the multi-modal segmentation quality with low-resolution second modality can approach the accuracy of high-resolution multi-modal segmentation when pure samples are incorporated in the training of classifier. We used high-resolution DWI from Human Connectome Project (HCP) as a gold standard for super-resolution reconstruction evaluation to measure the effectiveness of our method to recover high-resolution extrapolations from low-resolution DWI data using three evaluation approaches consisting of brain tractography, rotationally invariant scalars and tensor properties. Our validation demonstrates a significant improvement in the performance of developed approach in providing accurate assessment of brain connectivity and recovering the high-resolution rotationally invariant scalars (RIS) and tensor property measurements when our approach was compared with two common methods in the literature. The novel methods of this work provide important improvements in tools that assist with improving interpretation of brain biological architecture. We demonstrate an increased sensitivity for volumetric and diffusion measures commonly used in clinical trials to advance our understanding of both normal development and disease induced degeneration. The improved sensitivity may lead to a substantial decrease in the necessary sample size required to demonstrate statistical significance and thereby may reduce the cost of future studies or may allow more clinical and observational trials to be performed in parallel.

In this work, gadolinium-based carbon nanocapsules are developed as a novel nanotechnology that addresses the shortcomings of current diagnostic and therapeutic methods of stem cell-based cardiomyoplasty. With cardiovascular disease (CVD) responsible for approximately 30% of deaths worldwide, the growing need for improved cardiomyoplasty has spurred efforts in nanomedicine to develop innovative techniques to enhance the therapeutic retention and diagnostic tracking of transplanted cells. Having previously been demonstrated as a high-performance T1-weighted magnetic resonance imaging (MRI) contrast agent, Gadonanotubes (GNTs) are shown for the first time to intracellularly label pig bone marrow-derived mesenchymal stem cells (MSCs). Without the use of a transfection agent, micromolar concentrations of GNTs deliver up to 10^9 Gd(III) ions per cell, allowing for MSCs to be visualized in a 1.5 T clinical MRI scanner. The cellular response to the intracellular incorporation of GNTs is also assessed, revealing that GNTs do not compromise the viability, differentiation potential, or phenotype characteristics of the MSCs. However, it is also found that GNT-labeled MSCs exhibit a decreased response to select cell adhesion proteins and experience a non-apoptotic, non-proliferative cell cycle arrest, from which the cells recover 48 h after GNT internalization. In tandem with developing GNTs as a new stem cell diagnostic agent, this current work also explores for the first time the therapeutic application of the magnetically-active GNTs as a magnetic facilitator to increase the retention of transplanted stem cells during cardiomyoplasty. In vitro flow chamber assays, ex vivo perfusion experiments, and in vivo porcine injection procedures all demonstrate the increased magnetic-assisted retention of GNT-labeled MSCs in the presence of an external magnetic field. These studies prove that GNTs are a powerful ‘theranostic’ agent that provides a novel platform to simultaneously monitor and improve the therapeutic nature of stem cells for the treatment of CVD. It is expected that this new nanotechnology will further catalyze the development of cellular cardiomyoplasty and other stem cell-based therapies for the prevention, detection, and treatment of human diseases.

Magnetic resonance imaging (MRI) is a very versatile imaging modality which can be used to acquire several different types of images. Some examples include anatomical images, images showing local brain activation and images depicting different types of pathologies. Brain activation is detected by means of functional magnetic resonance imaging (fMRI). This is useful e.g. in planning of neurosurgical procedures and in neurological research. To find the activated regions, a sequence of images of the brain is collected while a patient or subject alters between resting and performing a task. The variations in image intensity over time are then compared to a model of the variations expected to be found in active parts of the brain. Locations with high correlation between the intensity variations and the model are considered to be activated by the task. Since the images are very noisy, spatial filtering is needed before the activation can be detected. If adaptive filtering is used, i.e. if the filter at each location is adapted to the local neighborhood, very good detection performance can be obtained. This thesis presents two methods for adaptive spatial filtering of fMRI data. One of these is a modification of a previously proposed method, which at each position maximizes the similarity between the filter response and the model. A novel feature of the presented method is rotational invariance, i.e. equal sensitivity to activated regions in different orientations. The other method is based on bilateral filtering. At each position, this method averages pixels which are located in the same type of brain tissue and have similar intensity variation over time. A method for robust correlation estimation is also presented. This method automatically detects local bursts of noise in a signal and disregards the corresponding signal segments when the correlation is estimated. Hence, the correlation estimate is not affected by the noise bursts. This method is useful not only in analysis of fMRI data, but also in other applications where correlation is used to determine the similarity between signals. Finally, a method for correcting artifacts in complex MR images is presented. Complex images are used e.g. in the Dixon technique for separate imaging of water and fat. The phase of these images is often affected by artifacts and therefore need correction before the actual water and fat images can be calculated. The presented method for phase correction is based on an image integration technique known as the inverse gradient. The method is shown to provide good results even when applied to images with severe artifacts.

The number of patients who have undergone some kind of internal fixation or joint replacement is increasing thanks to the development of technology and orthopaedics. All these patients carry metal implants. Magnetic resonance imaging has an advantage over other imaging methods, due to its superior soft tissue contrast and to its sensitivity in detecting the inflammation which is present at infections and malignancies. However metal implants usually deteriorate the image quality and as a result affect the accuracy of the diagnostic procedure. This is the case when the region of interest is in the proximal vicinity of the implant, or the implant is large enough. A number of MRI sequences have been proposed in order to overcome the artifact that comes from metal implants, more formally known as susceptibility artifact. However the most effective of them, are not widely available. The need for optimization of MR imaging at the presence of metal implants presupposes the development of methods capable of quantifying the artifact under various imaging sequences and conditions. Most artifact quantification techniques proposed until now, are usually based on the visual observation (experienced radiologists) or at image segmentation methods. These segmentation methods, segment the image based on arbitrary selected gray values (thresholds). A more objective and precise quantification method relies on the subtraction of images of a zero artifact replica (test object) from those of the real metal implant. The copy is constructed from material with similar values of magnetic susceptibility with its environment (usually water). The images deriving from the copy if we take in consideration the noise differences, have no susceptibility artifact. In this method artifact is quantified as energy differences between the two images [Kolind S et al, 2004]. Since the acquisition conditions are identical except the presence of susceptibility artifact in the image depicting the real metal object, the energy difference is used to quantify the artifact. While the method quantifies the artifact, giving precise values, it does not inform us for its position in space At this thesis we proposed a new, to our knowledge, method of artifact quantification. It is based in the physical cause of the artifact, which are the gradients of the magnetic field, which derive from the presence of the metal implant. The gradients of the magnetic field create corresponding gradients at the gray scale values of the image. These gradients may be detected if we apply suitable filter which detects the amplitude of the gradient. In this way we detect both regions with signal void (low signal intensity) and signal pill ups (high signal intensity). That means that we do not have to apply two different operators to segment two regions of the artifact with so different signal intensity values. Then the image is thresholded using a fully automated algorithm, proposed by [Li & Lee 1993]. This algorithm is available in image analysis environment ImageJ. At the first part of this thesis there are presented the basic principles of nuclear magnetic imaging image formation. The interaction of the most common materials with the magnetic field is also presented. All these are considered necessary to explain the generation of magnetic susceptibility artifact at the image acquired. The theory beyond the magnetic susceptibility artifact generation is then explained in detail. At the experimental part of this thesis, the proposed algorithm is applied to the imaging of two implants (made of titanium and antimagnetic stainless steel) at the sequences which are most commonly used to musculoskeletal MRI. The proposed algorithm is compared with a variation of the method of the image energy differences proposed by [Kolind Sh, 2004]. This method quantifies the artifact as energy difference of image of the real implant from the image of a replica with zero susceptibility artifact (reference image). In the present thesis the image of lower susceptibility artifact (obtained at higher bandwidth) is considered as reference image. In our case it is assumed that the energy difference among different bandwidth acquisitions is negligible in relation to the susceptibility artifact amplitude. This assumption allows as to use instead of energy differences, the differences in the gray scale values of the image instead. Statistical analysis showed moderate to strong positive correlation between the two methods. Possible reasons of not obtaining strong correlation at all measurements is due to the regions of the image that the proposed algorithm quantifies. By segmenting regions of high gradient, we focus mainly at regions where there is high variation at the gray scale values. However, in many cases nearly homogeneous regions of an image, with little or no alteration in gray scale values, may also be considered as artifact. These areas are not segmented as artifact when the proposed algorithm is applied. More over the assumption of considering negligible the noise contribution between the different acquisitions may be an oversimplification. Nevertheless, the proposed algorithm, is an objective repeatable and observer independent method. Moreover it is capable of determining the boundaries of the artifact in image space. It is not intended to be used as a method of absolute quantification of the susceptibility artifact. It should be used as means of comparison of acquisitions concerning the same sequence. Its combination with an additional algorithmic step, such as one which detects image features may result in a powerful tool of image artifact quantification. This more sophisticated version of this proposed algorithm should be adequate enough to quantify the artifact not only at phantom models but even at the everyday clinical practice. / H εξέλιξη της ιατρικής και ειδικότερα της ορθοπαιδικής έχει κάνει ολοένα και περισσότερο συχνή την ύπαρξη ασθενών που φέρουν μεταλλικά εμφυτεύματα. Η απεικόνιση με μαγνητικό συντονισμό πλεονεκτεί σε σχέση με άλλες απεικονιστικές μεθόδους εξαιτίας της καλύτερης αντίθεσης που προσφέρει στους μαλακούς ιστούς και στην ευαισθησία στην ανάδειξη της φλεγμονής που συνοδεύει τις μολύνσεις και τις κακοήθειες. Η ύπαρξη μεταλλικών εμφυτευμάτων συνήθως υποβαθμίζει την ποιότητα της εικόνας και την καθιστά πολλές φορές μη διαγνωστική, ειδικά αν η περιοχή ενδιαφέροντος είναι κοντά στο μεταλλικό εμφύτευμα ή στην περίπτωση που αυτό είναι αρκετά μεγάλο. Μια σειρά από μεθόδους ή ακόμη και ειδικές ακολουθίες έχει προταθεί κατά καιρούς για να αντιμετωπιστεί η ύπαρξη των τεχνημάτων επιδεκτικότητας, όπως ονομάζονται τα artifact που έχουν σαν αιτία τους τις τοπικές στρεβλώσεις στο μαγνητικό πεδίο εξαιτίας μεταλλικών προθέσεων. Οι πιο αποτελεσματικές από αυτές παραμένουν μη διαθέσιμες για το ευρύ κοινό. Η ανάγκη για βελτιστοποίηση των συνθηκών απεικόνισης κάνει επιτακτική την ανάγκη για ποσοτικοποίηση του artifact στις διαφορετικές συνθήκες λήψεις. Οι τεχνικές ποσοτικοποίησης του artifact που έχουν προταθεί μέχρι σήμερα βασίζονται στην ποιοτική ακτινολογική εκτίμηση (οπτική παρατήρηση) είτε σε μεθόδους τμηματοποίησης της περιοχής εικόνας του artifact που συνήθως στηρίζονται στην επιλογή αυθαίρετων τιμών κατωφλίου τόνων του γκρι. Μια πιο αντικειμενική και ακριβής μέθοδος αφορά στην αφαίρεση εικόνων γεωμετρικού αναλόγου (αντικείμενο ελέγχου- ομοίωμα) του εμφυτεύματος από την εικόνα που απεικονίζει το ίδιο το εμφύτευμα. Το ανάλογο είναι κατασκευασμένο από υλικό με παρόμοια μαγνητική επιδεκτικότητα προς το περιβάλλον του εμφυτεύματος. Η απεικόνιση ενός τέτοιου ομοιώματος, λαμβανομένης υπόψη και της συνεισφοράς του θορύβου, παρουσιάζει μηδενικό artifact επιδεκτικότητας σε σχέση με το πραγματικό εμφύτευμα. Το artifact στην περίπτωση αυτή ποσοτικοποιείται ως διαφορά ενέργειας εικόνας στην περιοχή του περιβάλλοντος υλικού [Kolind S et al,2004]. Η τελευταία αυτή μέθοδος ενώ ποσοτικοποιεί με ακρίβεια το artifact δεν παρέχει πληροφορίες για τη θέση του στο χώρο. Στην παρούσα μεταπτυχιακή εργασία, προτείνεται μία νέα, με βάση τα όσα γνωρίζουμε, μέθοδος ποσοτικοποίησης του artifact. Η μέθοδος αυτή βασίζεται στη γενεσιουργό αιτία του artifact, που είναι οι στρεβλώσεις του μαγνητικού πεδίου από την παρουσία του μεταλλικού αντικειμένου. Οι στρεβλώσεις αυτές εκφράζονται ως βαθμιδώσεις του μαγνητικού πεδίου. Οι βαθμιδώσεις του Μ.Π προκαλούν αντίστοιχες βαθμιδώσεις στην ένταση των τόνων του γκρι στην εικόνα. Αυτές οι βαθμιδώσεις μπορούν να αναδειχθούν αν εφαρμόσουμε κατάλληλο φίλτρο στην εικόνα που ανιχνεύει το μέγεθος/ πλάτος της βαθμίδωσης. Με αυτό τον τρόπο θα ανιχνευτούν τόσο περιοχές με υψηλό όσο και περιοχές με χαμηλό σήμα, απλοποιώντας έτσι τη διαδικασία, αφού δε χρειάζεται να ανιχνευτούν με ξεχωριστό αλγόριθμο περιοχές του artifact με πολύ διαφορετικές τιμές τόνων του γκρι. Στη συνέχεια η εικόνα που προκύπτει κατωφλιώνεται με αυτόματή μέθοδο που έχει προταθεί [Li & Lee 1993] και είναι διαθέσιμη στο περιβάλλον ανάλυσης εικόνας Image J. Στο πρώτο τμήμα της παρούσας εργασίας αναπτύσσονται, συνοπτικά βασικές αρχές του πυρηνικού μαγνητικού συντονισμού και του τρόπου με τον οποίο δημιουργείται η δισδιάστατη εικόνα στο MRI. Ακολουθεί επίσης μια σύντομη περιγραφή του τρόπου με τον οποίο συμπεριφέρονται τα πιο κοινά υλικά όταν βρεθούν εντός του μαγνητικού πεδίου. Όλα αυτά είναι αναγκαία για γίνει κατανοητός ο τρόπος που δημιουργείται το artifact μαγνητικής επιδεκτικότητας στην εικόνα που λαμβάνουμε. Στη συνέχεια αναπτύσσεται με λεπτομέρεια ο μηχανισμός και η φυσική που εμπλέκεται στη δημιουργία των artifact μαγνητικής επιδεκτικότητας. Στο πειραματικό μέρος, εφαρμόζεται ο προτεινόμενος αλγόριθμος σε απεικονίσεις δύο εμφυτευμάτων (τιτανίου και αντιμαγνητικού χάλυβα) στις πιο κοινά χρησιμοποιούμενες ακολουθίες του μυοσκελετικού. Ο προτεινόμενος αλγόριθμος ελέγχεται ως προς την ικανότητα του να ποσοτικοποιεί το artifact με μία παραλλαγή της μεθόδου διαφοράς ενεργειών εικόνων [Kolind Sh,2004]. H μέθοδος αυτή ποσοτικοποιεί το artifact ως διαφορά ενέργειας της εικόνας του πραγματικού εμφυτεύματος από εικόνα γεωμετρικού αναλόγου με μηδενικό artifact (εικόνα αναφοράς). Στην περίπτωση μας χρησιμοποιήσαμε ως εικόνα αναφοράς την εικόνα με το ελάχιστο artifact (η οποία βάσει θεωρίας αντιστοιχεί στη λήψη με το υψηλότερο bandwindth). Επίσης θεωρήσαμε τη διαφορά θορύβου των διαφορετικών λήψεων αμελητέα ως προς τις τιμές έντασης (τόνοι του γκρι) του artifact, ώστε να μπορούμε να αξιοποιήσουμε το πεδίο των τιμών των τόνων του γκρι και όχι αυτό της ενέργειας της εικόνας. Η στατιστική επεξεργασία αναδεικνύει μέτρια ως ισχυρή θετική συσχέτιση των 2 αλγορίθμων. Πιθανοί λόγοι που δεν έχουμε σε όλες τις μετρήσεις ισχυρή ή πολύ ισχυρή συσχέτιση αποδίδονται πρωτίστως στην περιοχή της εικόνας που ποσοτικοποιεί η προτεινόμενη μέθοδος. Τμηματοποιώντας τις βαθμιδώσεις της εικόνας εστιάζουμε σε περιοχές που υπάρχει έντονη μεταβολή των τιμών του γκρι. Παρόλα αυτά το artifact μπορεί κατά περιπτώσεις να περιλαμβάνει και ομοιογενείς περιοχές εικόνας με παραπλήσιες τιμές του γκρι. Αυτές είναι περιοχές που δεν τμηματοποιεί (ανιχνεύει) η προτεινόμενη προσέγγιση. Μια ακόμη αιτία θα μπορούσε να είναι η μη αξιολογήση της συνεισφοράς του θορύβου στις διαφορετικές λήψεις (bandwidths). Η απώλεια τέτοιων περιοχών δεν μειώνει την αξία του αλγορίθμου, αφού αποτελεί μια αντικειμενική μέθοδο, ανεξάρτητη από τον παρατηρητή, επαναλήψιμη και ικανή να οριοθετήσει το artifact στο χώρο. Δεν της επιτρέπει παρόλα αυτά να χρησιμοποιηθεί σαν μέθοδος απόλυτης ποσοτικοποίησης του artifact. Μπορεί να χρησιμοποιηθεί για την πραγματοποίηση συγκρίσεων ιδανικά σε συνθήκες λήψεις που αφορούν την ίδια ακολουθία. Ο συνδυασμός της με ένα επιπλέον αλγοριθμικό βήμα, όπως ένα βήμα που θα ανιχνεύονται χαρακτηριστικά της εικόνας σε συνδυασμό με την οριοθέτηση του artifact που έχει προηγηθεί, μπορεί να δώσει ένα ισχυρό εργαλείο τμηματοποίησης της εικόνας με εφαρμογές που θα μπορούν να επεκταθούν από τη χρήση σε ομοιωμάτων ως εργαλείων για την ποσοτικοποίηση του artifact και στην καθημερινή κλινική πρακτική.

Background Although abdominal aortic aneurysm (AAA) growth is non-linear, serial measurements of aneurysm diameter are the mainstay of aneurysm surveillance and contribute to decisions on timing of intervention. Aneurysm biology plays a key part in disease evolution but is not currently routinely assessed in clinical practice. Magnetic Resonance Imaging (MRI) and Positron Emission Tomography-Computed Tomography (PET-CT) provide insight into disease processes on a cellular or molecular level, and represent exciting new imaging biomarkers of disease activity. Macrophage-mediated inflammation may be assessed using ultrasmall superparamagnetic particles of iron oxide (USPIO) MRI and the PET radiotracer 18FSodium Fluoride (18F-NaF) identifies microcalcification which is a response to underlying necrotic inflammation. The central aim of this thesis was to investigate these imaging modalities in patients with AAA. Methods and Results USPIO MRI: MULTI-CENTRE STUDY In a prospective multi-centre observational cohort study, 342 patients (85.4% male, mean age 73.1±7.2 years, mean AAA diameter 49.6±7.7mm) with asymptomatic AAA ≥4 cm anteroposterior diameter underwent MRI before and 24-36 hours after intravenous administration of USPIO. Colour maps (depicting the change in T2* caused by USPIO) were used to classify aneurysms on the basis of the presence of USPIO uptake in the aneurysm wall, representing mural inflammation. Intra- and inter-observer agreement were found to be very good, with proportional agreement of 0.91 (kappa 0.82) and 0.83 (kappa 0.66), respectively. At 1 year, there was 29.3% discordant classification of aneurysms on repeated USPIO MRI and at 2 years, discordance was 65%, suggesting that inflammation evolves over time. In the observational study, after a mean of 1005±280 days of follow up, there were 126 (36.8%) aneurysm repairs and 17 (5.0%) ruptures. Participants with USPIO enhancement (42.7%) had increased aneurysm expansion rates (3·1±2·5 versus 2·5±2·4 mm/year; difference 0·6 [95% confidence intervals (CI), 0·02 to 1·2] mm/year, p=0·0424) and had higher rates of aneurysm rupture or repair (69/146=47·3% versus 68/191=35·6%; difference 11·7%, 95% CI 1·1 to 22·2%, p=0·0308). USPIO MRI was therefore shown to predict AAA expansion and the composite of rupture or repair, however this was not independent of aneurysm diameter (c-statistic, 0·7924 to 0·7926; unconditional net reclassification -13·5%, 95% confidence intervals -36·4% to 9·3%). 18F-NaF PET-CT: SINGLE-CENTRE STUDY A sub-group of 76 patients also underwent 18F-NaF PET-CT, which was evaluated using the maximum tissue-to-background ratio (TBRmax) in the most diseased segment (MDS), a technique that showed very good intra- (ICC 0.70-0.89) and inter-observer (ICC 0.637-0.856) agreement. Aneurysm tracer uptake was compared firstly in a case-control study, with 20 patients matched to 20 control patients for age, sex and smoking status. 18F-NaF uptake was higher in aneurysm when compared to control aorta (log2TBRmax 1.712±0.560 vs. 1.314±0.489; difference 0.398 (95% CI 0.057, 0.739), p=0.023), or to non-aneurysmal aorta in patients with AAA (log2TBRmax 1.647±0.537 vs. 1.332±0.497; difference 0.314 (95% CI 0.0685, 0.560), p=0.004). An ex vivo study was performed on aneurysm and control tissue, which demonstrated that 18F-NaF uptake on microPET-CT was higher in the aneurysm hotspots and higher in aneurysm tissue compared to control tissue. Histological analysis suggested that 18F-NaF was highest in areas of focal calcification and necrosis. In an observational cohort study, aneurysms were stratified by tertiles of TBRmax in the MDS and followed up for 510±196 days, with 6 monthly serial ultrasound measurements of diameter. Those in the highest tertile of tracer uptake expanded more than 2.5 times more rapidly than those in the lowest tertile (3.10 [3.58] mm/year vs. 1.24 [2.41] mm/year, p=0.008) and were also more likely to experience repair or rupture (15.3% vs. 5.6%, log-rank p=0.043). In multivariable analyses, 18F-NaF uptake on PET-CT emerged as an independent predictor of AAA expansion (p=0.042) and rupture or repair (HR 2.49, 95% CI1.07, 5.78; p=0.034), even when adjusted for age, sex, body mass index, systolic blood pressure, current smoking and, crucially, aneurysm diameter. Conclusion These are the largest USPIO MRI and PET-CT studies in AAA disease to date and the first to investigate 18F-NaF. Both USPIO MRI and 18F-NaF PET-CT are able to predict AAA expansion and the composite of rupture and repair, with 18F-NaF PETCT emerging as the first imaging biomarker that independently predicts expansion and AAA events, even after adjustment for aneurysm diameter. This represents an exciting new predictor of disease progression that adds incremental value to standard clinical assessments. Feasibility and randomised clinical trials are now required to assess the potential of this technique to change the management and outcome of patients with AAA.

Les anévrismes intracrâniens présentent des risques importants en raison de leur taux de rupture élevé et des conséquences qui peuvent être fatales comme lors d’hémorragies méningées. Afin d’effectuer une recherche hémodynamique sur l’anévrisme intracrânien in vitro, un fantôme est indispensable. Jusqu’à présent, des fantômes rigides ou simplifiés sont utilisés dans littérature, peu d’entre eux sont suffisamment fidèle à la réalité. Le travail de cette thèse se concentre sur la méthodologie de fabrication des fantômes patient-spécifiques d’anévrismes intracrâniens ainsi que leur mise en œuvre pour différentes utilisations. Ces fantômes possèdent la forme anatomique de l’artère du patient et une paroi élastique. Ils sont fabriqués en appliquant une technique originale de prototypage rapide. Les fantômes sont vérifiés selon plusieurs aspects. Pour effectuer des recherches hémodynamiques sur les fantômes, un banc d’essai compatible avec différentes modalités d’imagerie a été conçu. L’angiographie par résonance magnétique 2D par contraste de phase a été utilisée pour étudier l’hémodynamique des fantômes. Le comportement dynamique de paroi, les trajectoires 3D du flux et son champ de vélocité sont analysés. L’application potentielle dans domaine clinique du fantôme patient-spécifique a été aussi testée dans cette thèse, des simulations d’intervention sur des anévrismes intracrâniens ont été effectuées sur le banc d’essai et les fantômes, les résultats de différentes méthodes ont été analysés et comparés. / Intracranial aneurysms are a hazard to human health because of their high rupture rate and fatal subsequence, such as subarachnoid hemorrhage. In order to carry out a hemodynamic research in vitro on the intracranial aneurysm, a phantom is indispensable. Until now, rigid or simplified phantoms are mainly used in the literature, few among them possess sufficient properties compared with reality. The work of this thesis focuses on the methodology of manufacturing patient-specific phantoms of intracranial aneurysms as well as their implementation for different uses. The phantoms have an anatomical shape of patient’s artery and an elastic wall. They are manufactured by applying an original rapid prototyping technique. The phantoms are examined and verified in different ways. In order to perform a hemodynamic research of the phantoms, a testing platform compatible with different imaging modalities has been designed and established. 2D phase-contrast magnetic resonance angiography was applied in the hemodynamic study of the phantoms. The dynamic behavior of the artery wall, the 3D path-line of flow and the velocity field of flow were analyzed. The potential application in the clinical domain of the patient-specific phantoms was also tested in this thesis, simulations of intervention on intracranial aneurysms were carried out with the testing platform and the phantoms, the results of different treatment strategies were analyzed and compared.

OBJECTIVES: Models for the development of new treatment options in vestibular schwannoma (VS) treatment are lacking. The purpose of this study is to establish a quantifiable human VS xenograft model in mice. STUDY DESIGN AND METHODS: Both rat malignant schwannoma cells (KE-F11 and RT4) and human malignant schwannoma (HMS-97) cells were implanted near the sciatic nerve in the thigh of severe combined immunodeficiency (SCID) mice. Additionally, human benign VS specimens were implanted in another set of SCID mice. Three-dimensional tumor volumes were calculated from magnetic resonance images over the next 6 months. RESULTS: Mice implanted with malignant schwannoma cells developed visible tumors within 2 weeks. Imaging using a 4.7-tesla magnetic resonance imaging and immunohistopathologic examination identified solid tumors in all KE-F11 and HMS-97 xenografts, whereas RT4 xenografts consistently developed cystic schwannomas. VS xenografts demonstrated variability in their growth rates similar to human VS. The majority of VS xenografts did not grow but persisted throughout the study, whereas two of 15 xenografts grew significantly. Histopathologic examination and immunohistochemistry confirmed that VS xenografts retained their original microscopic and immunohistochemical characteristics after prolonged implantation. CONCLUSIONS: This study describes the first animal model for cystic schwannomas. Also, we demonstrate the use of high-field magnetic resonance imaging to quantify VS xenograft growth over time. The VS xenografts represent a model complimentary to Nf2 transgenic and knockout mice for translational VS research.