京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20257号 / 医博第4216号 / 新制||医||1020(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 宮本 享, 教授 村井 俊哉, 教授 高橋 淳 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

La cartographie du temps de relaxation longitudinale T1 est une technique d'IRM quantitative pour caractériser les tissus myocardiques. Plusieurs études ont déjà montré la corrélation entre la mesure de T1 et la présence de fibrose. Celle-ci est souvent observée dans les pathologies cardiaques telles que les cardiomyopathies ou l'infarctus du myocarde. Cependant, l'acquisition d'une carte T1 du coeur reste techniquement difficile. Actuellement, la quantification T1 du myocarde humain est réalisée en apnée à l'aide de séquences 2D qui sont spécifiques aux constructeurs et donc peu disponibles. Afin de pallier aux limitations de ces séquences, nous proposons une méthode basée sur une séquence 3D clinique. Cette technique, utilisant la variation des angles de bascule avec intégration d'une correction B1, a été adaptée pour une utilisation en imagerie cardiaque. Des essais sur fantôme ont permis de sélectionner les paramètres optimaux et de montrer la reproductibilité de la méthode. Puis, une étude sur volontaires sains a permis de valider la méthode en double synchronisation (cardiaque et respiratoire). Enfin, une méthode de reconstruction intégrant des signaux physiologiques de mouvement a également été utilisée afin de faire de la quantification T1 en respiration libre et de diminuer le temps d'acquisition. Les valeurs de T1 myocardique sur volontaires sont comprises entre 1289 ± 66 ms et 1376 ± 43 ms, correspondant aux valeurs de la littérature. Ces travaux ouvrent la voie à l'utilisation de la cartographie T1 chez les patients avec pour objectifs une meilleure caractérisation des pathologies et une meilleure adaptation des stratégies thérapeutiques / T1 mapping is a useful quantitative MR technique for cardiac tissue characterization. Several studies have shown that T1 measurements are correlated with fibrosis, which is observed in cardiac diseases such as cardiomyopathy or myocardial infarction. However, cardiac T1 mapping remains challenging, mainly because of long acquisition times and interference from cardiac and respiratory motions. T1 quantification on the human myocardium is generally performed on breath-hold with 2D specific sequences. Unfortunately these sequences are scanner specific and poorly available for clinical use. To overcome these limitations, we propose a new method based on a 3D clinical sequence. This technique, using a variable flip angle approach that integrates B1 correction, was adapted in cardiac imaging. Phantom tests were used to select the optimal parameters and to show the method reproducibility. Then, the method was validated with a volunteer study using double synchronization (cardiac and respiratory). Moreover, a reconstruction method integrating physiological signals of motion was also used to perform T1 quantification in free breathing and to reduce the total acquisition time. The myocardial T1 values on volunteers ranged between 1289 ± 66 ms and 1376 ± 43 ms, which was in good agreement with previously published works. These studies allow the use of T1 mapping in patients with better characterization of pathologies and a better adaptation to therapeutic strategies

<p dir="ltr">Manganese (Mn) is an essential trace element for humans that functions primarily as a coenzyme in several biological processes such as nerve and brain development, energy metabolism, bone growth and development, as well as cognitive functioning. However, overexposure to environmental Mn via occupational settings or contaminated drinking water can lead to toxic effects on the central nervous systems and cause a Parkinsonian disorder that features symptoms such as fine motor control deficits, dystonia rigidity, speech and mood disturbances, and cognitive deficits summarized under the term “manganism”. Over time, Mn exposure has shifted from acute, high-level instances leading to manganism, to low-level chronic exposure. Considering that Mn exposure is significantly lower than in the past, it is unlikely to expect manganism from chronic Mn exposure under current working conditions. Therefore, there is a need to develop sensitive methods to aid in updating the clinical diagnostic standards for manganism and Mn neurotoxicity as chronic exposure to Mn leads to more subtle symptoms.</p><p><br></p><p dir="ltr">Historically, magnetic resonance imaging (MRI) has been used as a non-invasive tool for detecting excess brain Mn accumulation. Specifically, T1-weighted images show bilateral hyperintensities of the globus pallidus (GP) due to the paramagnetic properties of Mn which increases the MR relaxation rate R1. Although the GP is considered the hallmark of excess brain Mn, this brain area is not necessarily associated with symptoms, exposure, or neuropsychological outcomes. Thus, the focus should not be on the GP only but on the entire brain. With recent advances in quantitative MRI (qMRI), whole brain mapping techniques allow for the direct measurement of relaxation rate changes due to Mn accumulation. The work in this dissertation uses such quantitative techniques and network science to establish novel computational in vivo imaging methods to a) visualize and quantify excess Mn deposition at the group and individual level, and b) characterize the toxicokinetics of excess brain Mn accumulation and the role of different brain regions in the development of neurotoxicity effects.</p><p><br></p><p dir="ltr">First, we developed a novel method for depicting excess Mn accumulation at the group level using high-resolution R1 relaxation maps to identify regional differences using voxel-based quantification (VBQ) and statistical parametric mapping. Second, we departed from a group analysis and developed subject-specific maps of excess brain Mn to gain a better understanding of the relationship between the spatial distribution of Mn and exposure settings. Third, we developed a novel method that combines network science with MRI relaxometry to characterize the storage and propagation of Mn and Fe in the human brain and the role of different brain regions in the development of neurotoxic effects. Lastly, we explore the application of ultra-short echo (UTE) imaging to map Fe content in the brain and compare it against R2* and quantitative susceptibility mapping (QSM).</p><p><br></p><p dir="ltr">Overall, this dissertation is a successful step towards establishing sensitive neuroimaging screening methods to study the effects of occupational Mn exposure. The individual Mn maps offer great potential for evaluating personal risk assessment for Mn neurotoxicity and allow monitoring of temporal changes in an individual, offering valuable information about the toxicokinetics of Mn. The integration of network science provides a holistic analysis to identify subtle changes in the brain’s mediation mechanisms of excess metal depositions and their associations with health outcomes.</p>

Gadolinium-based contrast agents (GBCAs) are in widespread use to enhance magnetic resonance angiography images for evaluating vascular pathology. However, there are safety concerns and limitations regarding the use of GBCAs. It has been shown that the magnetic resonance imaging (MRI) signal intensity (T1-weighted images) in some of the brain's tissues is higher for patients who had multiple exposures to GBCAs compared to patients who had never had exposure to GBCAs. This implies that GBCAs are not sufficiently removed from body such that GBCAs may potentially have long-term effects on the human body. These potential safety concerns have led to an increased interest in alternative contrast agents. Methemoglobin (metHb) and oxygen-free hemoglobin (HHb) are two forms of hemoglobin with paramagnetic properties. It has been shown that the T1-weighted signal intensity of blood is changed during MRI scans for metHb and HHb, leading to enhanced contrast of MRI images. The ability of metHb and HHb to change the signal intensity has led to the idea that they can be used as effective contrast agents. MetHb can be made by exposing oxyhemoglobin (oxyHb) to nitric oxide (NO) and HHb can be made by removing the oxygen from hemoglobin using nitrogen (N2). In this study, a new gas delivery system was developed to make metHb and HHb. The new gas delivery system was developed to have greater experimental control compared to the PermSelect hollow-fiber module that was used in preliminary studies to make metHb. The same system can be used to make HHb. Initial experiments showed significant amounts of undesired nitrite (NO2-) formation during metHb formation due to the presence of contaminants in the NO gas source. To minimize this problem, flow of NO from the gas source was bubbled in a sodium hydroxide solution in order to reduce the NO2- concentration. Following metHb formation, continuous delivery of NO also led to the formation of ferrous nitrosyl hemoglobin (HbIINO). MRI studies showed that HbIINO can also increase the signal intensity of an MRI image. It is unknown as to whether metHb, HHb, or HbIINO would be a stronger and more appropriate contrast agent and to what extent the T1-weighted signal is affected by the concentration. This study evaluated T1-weighted images of blood samples over a range of metHb and HHb concentrations, as well as HbIINO concentrations. Comparison of T1 values showed that metHb is the strongest contrast agent and that HHb is a relatively weak contrast agent. This study showed for the first time that HbIINO can provide a contrast effect, although not as strong as metHb but stronger than HHb. With metHb providing a viable contrast between 10-20%, metHb has the potential to be a safe and effective contrast agent since it can be naturally converted back to hemoglobin.