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Angiogenesis is a fundamental driver of tumor biology and many other important aspect of human health. Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) has been shown to be a valuable biomarker for the indirect assessment of angiogenesis. However, DCE-MRI is very specialized technique that has limitations. In this dissertation new models and contrast agents to address some of these limitations are presented. Chapter 1 presents an introduction to DCE-MRI, the rationale to asses tumor biology with this technique, the MRI pulses sequences and the standard pharmacokinetic modeling used for the analysis of DCE- MRI data. Chapter 2 describes the application of DCE-MRI to asses the response to the hypoxia-activated drug TH-302. It is shown that DCE-MRI can detect a response after only 24 hours of initiating therapy. In Chapter 3, a new model for the analysis of DCE-MRI is presented, the so-called Linear Reference Region Model (LRRM). This new model improves upon existing models and it was demonstrated that it is ~620 faster than current algorithms and 5 times less sensitive to noise, and more importantly less sensitive to temporal resolution which enables the analysis of DCE-MRI data obtained in the clinical setting, which opens a new area of study in clinical MRI. Chapter 4 describes the extension of the LRRM to estimate the absolute permeability of two fluorinated contrast agents; we call this approach the Reference Agent Model (RAM). In order to make this new model an experimental reality, a novel pulse sequence and contrast agents (CA) for ¹⁹F MRI were developed. Two contributions to the field of DCE-MRI are presented in this chapter, the first simultaneous ¹⁹F-DCE-MRI detection of two fluorinated CA in a mouse model of breast cancer, and the estimation of their relative permeability. RAM eliminates some of the physiological variables that affect DCE-MRI, which may improve its sensitivity and specificity. Finally, new potential applications of LRRM and RAM are discussed in Chapter 5.

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The study of brain temperature is important for a number of clinical conditions such as stroke, traumatic brain injury, schizophrenia and birth asphyxia (for neonates). A direct method to estimate brain temperature non-invasively will allow assessment of brain thermoregulation and its variation in clinical conditions. Magnetic resonance imaging is a powerful technique widely used for diagnosis of a range of neurological conditions. All magnetic resonance procedures involve manipulation of the hydrogen nuclei in the water molecules of the human body. The resonance frequency of the water molecules is temperature dependent, thus MR thermometry is a powerful tool for non-invasive temperature measurement. Using internal reference MR spectroscopic imaging (MRSI), absolute brain temperature maps can be estimated. However a number of temperature independent factors influence MRSI data acquisition, thus a thorough validation is necessary and is the focus of this PhD study. In this PhD study using phantom (test object) studies it was shown that optimization of the MRSI pulse sequence is necessary to reduce systematic error in temperature maps and extensive in-vitro validation of MRSI temperature mapping was performed. A custom made temperature-controlled phantom was designed for this purpose and is presented in this thesis. MRSI data acquired from healthy (young and elderly) volunteers was employed to assess regional brain temperature variations and repeatability. Finally, the feasibility of employing fast echo planar spectroscopic imaging for volumetric MRSI temperature mapping will be presented in this thesis.

Les anévrysmes de l'aorte abdominale sont retrouvés chez 5 à 9 % de la population après l'âge de 65 ans, et la rupture de ces anévrysmes cause chaque année au moins 15000 décès. Bien que la plupart soient petits et asymptomatiques, typiquement leur diamètre s'accroît avec le temps et environ 60% finissent par nécessiter une réparation chirurgicale. A ce jour, aucune thérapeutique ne permet de ralentir ou de stopper la croissance des petits anévrysmes. La paroi anévrysmale est caractérisée par une inflammation chronique et un remodelage du tissu conjonctif associant synthèse et destruction qui conduisent à l'appauvrissement de la paroi en élastine. Tous ces éléments sont présents dans le modèle d'anévrysme à l'élastase chez la souris. Alors que de nombreuses données ont été accumulées sur l'implication des metalloprotéinases dans la dégradation de la matrice extracellulaire, le rôle des serines protéases a reçu beaucoup moins d'intérêt. En utilisant le modèle d'anévrysme à l'élastase chez les souris cathepsine S et cathepsine C knockout, nous avons montré que leur présence était indispensable au développement anévrysmal. Nous avons également montré qu'il était possible de bloquer le modèle au moyen d'un inhibiteur des cathepsines, l'E64. L'ensemble de nos travaux semblent montrer que les cathepsines jouent un rôle prépondérant dans la phase d'initiation de la réaction inflammatoire et que les cathepsines sont une voie de recherche potentielle pour le développement de traitements médicamenteux pouvant ralentir la croissance des AAAs. / Abdominal aortic aneurysms occur in 5-9% of the population over the age of 65, and rupture of these aneurysms cause every year at least 15,000 deaths. Although most AAAs are small and asymptomatic, their diameter typically increases over time and about 60% eventually require surgical repair. To date, no therapy can slow or stop the growth of small aneurysms. The aneurysmal wall is characterized by chronic inflammation and tissue remodeling involving synthesis and destruction that leads to the loss of elastin. All these elements are present in the elastase model of aneurysm in mice. While many data have been accumulated on the involvement of metalloproteinases in the degradation of the extracellular matrix, the role of serine proteases has received much less interest. Using this model in mice cathepsin S and cathepsin C knockout, we have shown that their presence was essential for aneurysmal development. We also showed that it was possible to block the model using E64, an inhibitor of cathepsins. Taken together these data suggest that cathepsins play a role in the initiation of the inflammatory reaction and that cathepsins are a potential way of research for the development of medication which could slow down the AAAs growth. In order to block by pharmacological means the model, we developed the possibility to infuse doxycyline directly on the aneurysm. These studies showed that it was possible to block the model with an infusion of local doxycycline without blood levels of doxycycline. This experimental work opens the way for the development of drug-eluting stent graft, i.e. a stent graft able to infuse an active product which can stabilize the wall of the aneurysm.

The goal of this work was to evaluate the performance of a classical method for predicting vocal tract cross-sectional areas from cross-distances, to be implemented in speaker-specific articulatory modelling. The data forming the basis of the evaluation were magnetic resonance images from the vocal tract combined with simultaneous audio and video recordings. These data were collected from one female and one male speaker. The speech materials consisted of extended articulation of each of the nine Swedish long vowels together with two short allophonic qualities. The data acquisition and processing involved, among other things, the development of a method for dental integration in the MR image, and a refined sound recording technique required for the particular experimental conditions. Articulatory measurements were made of cross-distances and cross-sectional areas from the speakers’ larynx, pharynx, oral cavity and lip section, together with estimations on the vocal tract termination points. Acoustic and auditory analyses were made of the sound recordings, including an evaluation of the influence of the noise from the MR machine on the vowel productions. Cross-distance to cross-sectional area conversion rules were established from the articulatory measurements. The evaluation of these rules involved quantitative as well as qualitative dimensions. The articulatory evaluation gave rise to a vowel-dependent extension of the method under investigation, allowing more geometrical freedom for articulatory configurations along the vocal tract. The extended method proved to be more successful in predicting cross-sectional areas, particularly in the velar region. The acoustic evaluation, based on area functions derived from the proposed rules, did however not show significant differences in formant patterns between the classical and the extended method. This was interpreted as evidence for the classic method having higher acoustic than physiological validity on the present materials. For application and extrapolation in articulatory modelling, it is however possible that the extended method will perform better in articulation and acoustics, given its physiologically more fine-tuned foundation. Research funded by the NIH (R01 DC02014) and Stockholm University (SU 617-0230-01). / <p>För att köpa boken skicka en beställning till exp@ling.su.se/ To order the book send an e-mail to exp@ling.su.se</p>