Zielsetzung: Die Chronisch-Rekurrierende Multifokale Osteomyelitis/Chronische Nicht-bakterielle Osteitis (CRMO/CNO) ist eine seltene auto-inflammatorische Erkrankung, deren typische Symptome starke Knochenschmerzen und lokale Schwellungen sind. Da die Ursachen muskuloskelettaler Beschwerden bei Kindern und Heranwachsenden vielfältig sein können, ist die differentialdiagnostische Unterscheidung einer CRMO/CNO von anderen Erkrankungen, unspezifischen Schmerzen oder einer malignen Grunderkrankung als Quelle der Symptome schwierig. Neue Techniken wie die diffusionsgewichtete Bildgebung (DWI) in der Magnetresonanztomographie (MRT) erlauben Rückschlüsse auf die Gewebestruktur und können in bestimmten Fällen eine Unterscheidung zwischen entzündlichen und malignen Prozessen vereinfachen. Ziel dieser Studie war es daher, die Sichtbarkeit von CRMO-/CNO-Läsionen mittels der DWI-Ganzkörperbildgebung zu evaluieren und den potentiellen klinischen Wert zu untersuchen. Material und Methoden: Sechzehn Patienten mit bekannter CRMO/CNO wurden bei 3 Tesla untersucht. Das Untersuchungsprotokoll beinhaltete u. a. 2D Short Tau Inversion Recovery (STIR) und diffusionsgewichtete Sequenzen in axialer Schichtführung. Die Sichtbarkeit von Läsionen in der DWI und der STIR wurde von 2 Auswertern im Konsensus evaluiert. Für alle Läsionen und in der korrespondierenden Referenzlokalisation wurden der Apparent Diffusion Coefficient (ADC) ermittelt. Ergebnisse: Insgesamt wurden 33 Läsionen eingeschlossen (durchschnittlich 2 Läsionen pro Patient), die sowohl in der STIR als auch in der DWI sichtbar waren. Diese waren vornehmlich in den langen Röhrenknochen lokalisiert. Der mittlere ADC-Wert in Läsionen betrug 1283 mm2/s und war somit signifikant höher als in der Referenzregion, hier betrug der mittlere ADC 782 mm2/s. Im ADCVerhältnis (Läsion vs. Referenzregion) zeigten 82 % der Läsionen eine relative Signalintensitätssteigerung um mehr als 10 %, und 76 % (25 Läsionen) zeigten eine Intensitätssteigerung von mehr als 15 %. Der mittlere relative Signalintensitätsanstieg betrug 69 %. Schlussfolgerung: Diese Studie zeigt, dass die diffusionsgewichtete Ganzkörperbildgebung bei 3 Tesla zuverlässig bei Kindern durchgeführt werden kann. Die ADC-Werte waren in CRMO-/CNO-Läsionen im Vergleich zur Referenzregion signifikant erhöht. Daher wird die Ganzkörperbildgebung in Kombination mit klinischen Angaben von uns als vielversprechende Methode angesehen, um benigne inflammatorische Prozesse anhand der ADC-Werte von bestimmten Malignitäten zu unterscheiden.

<p>Hyperpolarized (HP) 129Xe MRI has emerged as a viable tool for evaluating lung function without ionizing radiation. HP 129Xe has already been used to image ventilation and quantify ventilation defects. However, this thesis aims to further develop imaging techniques that are capable of imaging, not just ventilation, but also gas transfer within the lung. This ability to image gas transfer directly is enabled by the solubility and chemical shifts of 129Xe that provide separate MR signatures in the airspaces, barrier tissue, and red blood cells (RBCs). </p><p>While 129Xe in the airspace (referred to as gas-phase 129Xe) can be readily imaged with standard vendor-provided imaging sequences, 129Xe in the barrier and RBC compartments (collectively referred to as dissolved-phase 129Xe) has such a rapid T2* (<2 msec at 2T) that even simple gradient recalled echo (GRE) sequences are ineffective at imaging the limited signal before it decays. To minimize these losses from T2* decay, the 3D radial sequence offers much shorter TEs that can image the dissolved-phase 129Xe. Despite their ability to image dissolved-phase signal, however, 3D radial sequences have not yet been widely adopted within the hyperpolarized gas community. In order to demonstrate the potential of the 3D radial pulse sequence, chapter 3 uses standard 129Xe ventilation imaging to compare 3D radial image quality and defect conspicuity with that of the conventional GRE. Since the 3D radial sequence offered comparable performance in ventilation imaging, and also provided the ability to image dissolved-phase 129Xe, chapter 3 establishes that the 3D radial sequence is well-suited for imaging 129Xe in humans.</p><p>Though 3D radial acquisition offers clear advantages for functional 129Xe lung imaging, its non-Cartesian sampling of k-space complicates image reconstruction. Chapter 4 carefully explains the process of gridding-based reconstruction, and describes how problems arising from non-selective RF pulses and undersampling, both of which are commonly employed in hyperpolarized 129Xe imaging, can be avoided by using appropriate reconstruction techniques. Furthermore, we detail a generalized procedure to optimize reconstruction parameters, then demonstrate the benefits of our improved reconstruction methods across both 1H anatomical imaging as well as functional imaging of 129Xe in the gas- and dissolved-phases. </p><p>These dissolved-phase images are particularly interesting because they consist of separate contributions from 129Xe in the RBCs and barrier tissue. Once these two resonances are disentangled from one another, they provide a noninvasive means to measure gas exchange regionally. However, such decomposition of these two resonances is predicated on prior knowledge of their spectroscopic properties. To that end, chapter 5 describes a non-linear spectroscopic curve fitting toolbox that we developed to more accurately characterize the 129Xe spectrum in vivo. Though previously, only two dissolved-phase resonances have ever been described within the lung, our fitting tools were able to identify a third dissolved-phase resonance in both healthy volunteers and healthy controls. Furthermore, we describe several spectroscopic features that differ statistically between our healthy volunteers and IPF subjects to demonstrate that this technique is sensitive to even subtle functional changes within the lung. These spectroscopic measurements provide the basis for imaging gas transfer. </p><p>Describing lung function regionally requires phase-sensitive imaging techniques that can decompose the dissolved-phase signal into images that represent the contribution from the RBC and barrier resonances. To date, only two implementations have been demonstrated, and both suffered from poor SNR and challenges in quantifying gas transfer. Chapter 6 adds quantitative processing techniques that improve phase sensitive imaging of 129Xe gas transfer. These methods 1) normalize both the RBC and barrier uptake images by gas-phase magnetization so that intensities can be compared across subjects, 2) compress the dynamic range of these functional images to enhance their perceived SNR, and 3) derive colormap thresholds from a healthy reference population to give intensities meaningful context.</p><p>To show the value of our quantitative gas transfer imaging, chapter 7 applies these techniques to a cohort of healthy volunteers and another of IPF patients. Since patients with IPF exhibit a progressive thickening and hardening of the pulmonary interstitium that severely restricts the transport of gases between the lungs and blood, they represent an ideal population to prove out our methods. This analysis identifies several patterns to the RBC and barrier distributions which could potentially represent different stages of disease. Furthermore, we demonstrate that our MRI-based findings correlate well with DLCO and FVC, and to a lesser extent with the structural cues seen in CT. This suggests that 129Xe imaging offers complimentary functional information that can’t be derived from CT, while also describing its spatial distribution unlike PFTs. </p><p>The work in this thesis has transitioned our HP 129Xe gas transfer studies from a proof of concept to an optimized and quantitative imaging protocol with robust processing pipelines. Using these MRI methods, we have shown that we can directly and quantitatively probe pulmonary ventilation and gas transfer within a single breath hold. In IPF, such noninvasive imaging methods are desperately needed to monitor the efficacy of these new treatments to ensure that the associated medical expense is justified with positive changes in outcomes. Finally, these new functional contrasts will be useful in studying other cardiopulmonary diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary arterial hypertension.</p> / Dissertation

Tumors have several important hallmarks; anomalous and heterogeneous behaviors of their vascular structures, and high angiogenesis and neovascularization. Tumor tissue presents high blood flow (F) and extraction ratio (E) of contrast molecules. Consequently there is growing interest in non invasive methods for characterizing changes in tumor vasculature. Toft's model has been extensively used in the past in order to calculate Ktrans maps which take into consideration both F and E. However, in this thesis we argue that for accurate tumor characterization we need a model able to compute both F and E in tissue plasma. This project has been developed as part of a larger project, working toward building a Clinical Decision Support System (CDSS): an interactive expert computer software, that helps doctors and other health professionals make decisions regarding patient treatment progress. Using the Gamma Capillary Transit Time (GCTT) pharmacokinetic model we calculate F and E separately in a more realistic framework; unlike other models it takes into account the heterogeneity of the tumor, which depends on parameter a-1. a-1 is the width of the distribution of the capillary transit times within a tissue voxel. In more detail, a-1 expresses the heterogeneity of tissue microcirculation and microvasculature. We studied 9 patients pathologically diagnosed with glioblastoma multiforme (GBM), a common malignant type of brain tumor. Several physiological parameters including the blood flow and extraction ratio distributions were calculated for each patient. Then we investigated if these parameters can characterize early the patients' responsiveness to current treatment; we assessed the classification potential based on the actual therapy outcome. To this end, we present a novel analysis framework which exploits the new parameter a-1 and organizes each voxel into four sub-region. Our results indicate that early characterization of response based on GCCT can be significantly improved by focusing on tumor voxels from a specific sub-region.

Title: MRI Contrast Agents Based on Saturation Transfer Author: Bc. Tereza Krchová Department: Department of Inorganic Chemistry, Faculty of Science, Charles University in Prague Supervisor: doc. RNDr. Jan Kotek, Ph.D. Supervisor's email: modrej@natur.cuni.cz Abstract: The aim of this thesis was to synthesize macrocyclic ligands (based on the DO3A and DO2A framework) with exchangeable protons on the aminic coordinating groups that could be (after the complexation with suitable paramagnetic metal ions) potential contrast agents based on saturation transfer, so called CEST contrast agents (Chemical Exchange Saturation Transfer). Two ligands H3L1 and H2L2 with one and two aminoethyl groups have been synthesized. The structurally similar ligands H3L1 Me and H3L1 2Me with one exchangeable proton and without it have been also prepared. The protonation constants of the ligands H3L1 and H2L2 have been determined by pH 1 H NMR and potentiometric titrations. The stability constants of metal ion complexes with H3L1 and H2L2 have been also determined by potentiometry. The CEST effect of Eu3+ and Yb3+ complexes with H3L1 , H3L1 Me and H3L1 2Me in solution have been studied. The residence lifetime of the inner-sphere water molecule has been determined for Gd-L1 complex. Keywords: CEST, MRI, aminoethyl, DO3A, DO2A, 17 O...

Magnetic resonance imaging (MRI) methods thought to assess myelin and axon integrity are improving the understanding of white matter diseases like multiple sclerosis (MS). This thesis improved the understanding of how microstructural tissue changes caused by various pathologies influence MRI metrics by developing and applying MRI methods in a longitudinal study using the cuprizone mouse model of MS. In vivo and ex vivo MRI measurments (T1 and T2 relaxometry, diffusion tensor imaging, and quantitative magnetization transfer imaging) were correlated with tissue measurements taken from electron microscopy images of control and cuprizone fed mice at weeks 2 and 3 of cuprizone feeding. Significant Spearman correlations included mean diffusivity vs. myelinated axon fraction (ρ=0.84), ex vivo T2 vs. myelinated axon fraction (ρ=0.68), and normalized T2-weighted signal vs. myelinated axon fraction (ρ =-0.80). Multiparametric MRI studies show promise in bridging the gap between damage detected in images and clinical status associated with MS. / May 2016

Due to the complex anatomy of the heart, heart valves and aorta, blood flow in the aorta is known to be complex and can exhibit a swirling, or helical, flow pattern. The purpose of this thesis is to implement methods to quantify and visualize both the speed of helicity, referred to as the helicity density, and the direction of helicity, which is measured by the localized normalized helicity. Furthermore, the relationship between helicity and geometrical aorta parameters were studied in young and old healthy volunteers. Helicity and geometrical parameters were quantified for 22 healthy volunteers (12 old, 10 young) that were examined using 4D Flow MRI. The relation between helicity and the geometry of the aorta was explored, and the results showed that the tortuosity and the diameter of the aorta are related to the helicity, but the jet angle and flow displacement do not appear to play an important role. This suggests that in healthy volunteers the helical flow is primarily affected by the geometry of the aorta, although further trials should be performed to fully characterize the effects of aortic geometry. The results also show that the helicity changes with age between the two age groups and some of the geometrical parameters also has a significant difference between the age groups.

Mon travail de thèse se place dans le cadre du projet ANR TUCCIRM de développement d’un système de thérapie par ultrasons focalisés de haute intensité (HIFU) dédié au cerveau implantable dans un IRM clinique 1,5 T. Les développements IRM ont été l’objet de mon travail. Dans un premier temps, l’IRM a été utilisée pour suivre l’évolution en température des tissus en cours de traitement. Pour cela, nous avons tout d’abord réalisé une étude d’optimisation et de comparaison de séquences de thermométrie basées sur le principe du décalage chimique (PRFS). Puis, nous avons optimisé le rapport signal sur bruit pour améliorer la qualité des images ainsi que la précision en température. Ces développements ont été appliqués au cours de tests HIFU suivi par IRM de têtes de cadavres humains.Dans un deuxième temps, l’IRM a été utilisée pour caractériser la viscoélasticité des tissus cérébraux par la technique d’élastograhie par résonance magnétique. Ces propriétés changeant avec la température, cette méthode permettrait de suivre l’état des tissus pendant le traitement HIFU pour en déterminer l’effet thermique. Dans ce contexte, nous avons développé un nouveau concept de générateur d’onde, testé ensuite sur six rats in vivo. / My Ph.D. work is a part of the ANR TUCCIRM project, which consist in developing a treatment system dedicated to the brain using High Intensity Focalized Ultrasound (HIFU) usable with clinical 1.5T MRI. My work was mainly focus to MRI development.During the first part of my work, we used the MRI to observe the evolution of the temperature of tissue inside the brain during the ultrasound treatment. Firstly, based on the chemical shift principle, we perform an optimization study and thermometric sequence comparison. Then an optimization of the signal-to-noise ratio has been realized to improve the image quality and then the temperature measurement precision. This development has been used during HIFU test on human head corpse following the evolution of the temperature with MRI. In a second part, MRI was used to characterize the viscoelasticity of brain tissue using elastography by magnetic resonances. These properties are evolving with the temperature, so this method should allow following tissue state during HIFU treatment to determine temperature effect on brain tissue. For that purposes we develop a new concept of wave generator, witch has been tested on 6 rats in vivo.

<div> <p> Essential tremor (ET) is one of the most common movement disorders, characterized by kinetic tremor in the upper extremities with additional cranial tremor often present in the neck or jaw. While it is well established that ET is primarily a cerebellar disorder, recent investigations have shown more widespread pathological effects throughout the brain. Furthermore, the neurodegenerative nature of ET is still disputed and requires additional investigation. Additionally, the link between ET and Parkinson’s disease (PD) is of special interest, as it can be challenging to clinically differentiate these diseases.</p> <p> While post-mortem studies have helped to further the pathological understanding of these diseases, non-invasive in-vivo techniques allow for more accurate diagnosis in the clinic. With a more accurate diagnosis comes a more targeted treatment, and hopefully an improved remediation of the disease. My thesis seeks to further investigate the neurodegenerative hypothesis of ET as well as explore magnetic resonance imaging (MRI) biomarkers for potential differences in ET and PD. </p> <p>These aims will be accomplished in three steps. First, gray matter volume loss in the cerebellum was investigated using voxel-based morphometry and the Spatially Unbiased Infra-Tentorial Template (SUIT) atlas on a lobule level. High resolution 3D T1-weighted MRI images were acquired on 47 ET cases and 36 controls. The cerebellum was segmented into 34 lobules using the SUIT atlas. Percent gray matter was calculated as the ratio of lobule gray matter volume divided by total lobule volume. No significant differences were identified between ET cases and controls in any of the 34 lobules. However, nine lobules had significantly decreased percent gray matter in ET cases with head or jaw tremor (n = 27) compared to controls. Also, 11 lobules had significantly decreased percent gray matter in ET cases with voice tremor (n = 22) compared to controls. This result confirms, with increased regional accuracy, gray matter volume loss in the cerebellum of ET cases.</p> <p>Second, gray matter volume loss beyond the cerebellum, in the cerebrum, was investigated using voxel-based morphometry. High resolution 3D T1-weighted MRI images were acquired on 47 ET cases and 36 controls for processing in SPM12. The processing steps of SPM12 were updated to include a higher resolution atlas and set of tissue probability maps to optimize the segmentation and normalization of each subject image. After segmentation, normalization, and smoothing, a voxel-wise statistical analysis was performed to identify clusters of gray matter volume in ET cases compared to controls. ET cases showed decreased gray matter volume in the bilateral superior temporal region and the anterior and posterior cingulate cortex. These results, in combination with previous work provide support of wide-spread neurodegeneration in ET using optimized methodology.</p> <p>Third, we applied T2* mapping to determine relative iron concentrations in the substantia nigra (SN) and globus pallidus (GP) in ET and PD cases. Three separate studies were independently investigated to validate the reproducibility and detectability of group differences using T2* mapping. The first study (ET study) acquired T2* maps on 21 ET cases and 12 matched controls, the second study (PD study 1) acquired T2* maps on 10 PD cases and 7 controls, and the third study (PD study 2) acquired T2* maps on 21 PD cases and 17 controls. Regions of interest (ROIs) were manually placed in the SN and GP for each subject and group differences were calculated independently for each study using a linear regression model with age and sex as covariates. A significant decrease in T2* was found in PD study 1 and PD study 2 in the right SN in PD cases compared to their respective controls, indicating increased iron deposition. No significant difference was found in the ET group compared to their respective controls in the SN. No significant differences were found in any of the three studies in the GP. These results provide evidence for a difference in brain iron regulation in the pathology of ET and PD.</p> <p>Together, these thesis aims provide additional evidence in support of the neurodegenerative hypothesis of ET using updated methodology and present a quantitative imaging difference between groups of ET and PD cases. </p> </div> <br>

Introduction: Preterm birth is increasing worldwide and is a major cause of neonatal death. Survivors are at increased risk of neurodisability, cognitive, social and psychiatric disorders in later life. Alterations to the white matter can be assessed using diffusion tensor imaging (DTI) MRI and are associated with poor neurodevelopmental outcome. The pathogenesis of white matter injury is multifactorial and several clinical risk and resilience factors have been identified. DNA methylation (DNAm) is an epigenetic process which links stressful early life experience to later life disease and is associated with normal brain development, neuronal processes and neurological disease. Several studies have shown DNAm is altered by the perinatal environment, however its role in preterm white mater injury is yet to be investigated. Aims: 1. To examine the relationship between preterm birth and white matter integrity 2. To investigate the effect of neuroprotective treatments and deleterious clinical states on white matter integrity in preterm infants 3. To assess the best DTI method of quantifying white matter integrity in a neonatal population 4. To investigate the effect of preterm birth on DNA methylation and 5. To determine the clinical and imaging factors that contribute to the variance in DNA Methylation caused by preterm birth Methods: DTI data was acquired from preterm infants (< 32 weeks' gestation or < 1500 grams at birth) at term equivalent age (TEA) and term controls (> 37 weeks' gestation at birth). Region-of-interests (ROI) and tract-averaged methods of DTI analysis were performed to obtain measurements of fractional anisotropy (FA) and mean diffusivity (MD) in the genu of corpus callosum, posterior limb of internal capsule and centrum semiovale. Clinical data was collected for all infants and the effect of prematurity, neuroprotective agents and clinical risk factors on white matter integrity were analysed. 8 major white matter tracts were segmented using probabilistic neighbourhood tractography (PNT), a tract-averaged technique which also allowed the calculation of tract shape. The two DTI techniques were compared to evaluate agreement between results. DNA was collected from preterm infants and term controls at TEA, and a genome-wide analysis of DNAm was performed. DTI parameters from probabilistic neighborhood tractography (PNT) methodology and clinical risk and resilience factors were used to inform a principal components analysis to investigate the contribution of white matter integrity and clinical variables to variance in DNAm. Results: FA and MD were significantly affected by preterm birth on ROI analysis. In addition, DTI parameters were affected by clinical factors that included antenatal magnesium sulphate, histological chorioamnionitis and bronchopulmonary dysplasia. Evaluation of DTI methodology revealed good accuracy in repeated ROI measurements but limited agreement with tract-averaged values. Differential methylation was found within 25 gene bodies and 58 promoters of protein-coding genes in preterm infants, compared with controls. 10 of these genes have a documented association with neural function or neurological disease. Differences detected in the array were validated with pyrosequencing which captured additional differentially methylated CpGs. Ninety-five percent of the variance in DNAm in preterm infants was explained by 23 principal components (PC); corticospinal tract shape associated with 6th PC, and gender and early nutritional exposure associated with the 7th PC. Conclusions: Preterm birth is associated with alterations in white matter integrity which is modifiable by clinical risk factors and neuroprotective agents. ROI analysis may not provide sufficient representation of white matter tracts in their entirety. Prematurity is related to alterations in the methylome at sites that influence neural development and function. Differential methylation analysis has identified several promising candidate genes for future work and contributed to the understanding of the pathogenesis of preterm brain injury.

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