The extension from Quantitative Magnetic Resonance Imaging to synthetic imaging has the clear advantage of being able to continually image the patient after the exam. MR techniques such as DWI are commonly used but have some clear disadvantages resulting from the use of echoplanar imaging. It should then be asked whether one imaging technique is objectively better. If one technique is better, the incorporation in clinical settings could produce better diagnostic rates, and save valuable time. In order to quantitatively assess the quality of these techniques, the SNR and CNR values of similar tissues were compared. The pre-analysis discussion concentrating on the spatial resolution and artifacts, supports that synthetic images have an advantage over DWI due to higher resolution and absence of artifacts. The SNR and CNR values were calculated for each patient and image type for the comparison, initially assuming that the synthetic images would have a higher mean SNR and CNR. In most cases the differences between scan types was found to not be statistically significant. In conclusion, this analysis could not support the initial theory that the synthetic images had a higher SNR or CNR. The research shows that they are more likely to be comparable. An investigation of the diagnostic power of the synthetic in comparison to standard DWI would give clinical relevance to these results.

Application of Diffusion Tensor Imaging to Brain Gray and White Ma er A In the present work we explore the gray and white ma er applicability of diffusion tensor imaging (DTI). To evaluate effect of ferritin-bound iron on gray ma er contrast in DTI, we created an in vitro model consisting of agarose gel phantoms doped with ferritin, and validated our results in vivo on healthy volunteer subjects - years of age in the basal ganglia. We further explored the application of DTI to amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA); neurodegenerative diseases with gray and white ma er pathophysiological components. In the ALS study, patients and age- and sex-matched controls were recruited, while the MSA study included probable MSA subjects ( MSA-P, MSA-C) and age- and sex-matched controls. We found that ferritin-bound iron may make a signi cant contribution to DTI scalars in gray ma er regions of the brain, mediated by eigenvalue repulsion. is has important implications for DTI studies targeting gray ma er regions, especially in adolescence and in diseases associated with altered brain-iron load. In ALS, we found altered diffusion in the corona radiata and callosal body, and changes in R in the caudate nucleus and frontal white ma er. In MSA, we observed widespread white ma er changes associated...

Biologists and physicians study complex biologic phenomena in which they use advanced imaging methods. They acquire images containing a lot of information which must be extracted in a correct way. This requires computer skills and knowledge in image processing methods which they seldom have. To overcome the problem, this master thesis aimed to develop a routine for artefact correction and information extraction from images acquired in a research project at the Karolinska Institutet in Stockholm. By developing the routine, the thesis showed how software developed for images of human can be applied to images of rats. The routine handles formatting issues and artefact corrections, calculates diffusion metrics, and performs statistical tests on spatially aligned magnetic resonance images of rats acquired with diffusion weighted echo planar imaging. The routine was verified by analysing the images that it had processed and was considered to create reliable images. Future studies within the field should focus on developing atlases of rats and continue the work with identifying how software developed for images of human can be applied to images of rats. / Biologer och läkare studerar komplexa biologiska processer för vilket de använder avancerade bildgivande metoder. De samlar bilder som innehåller mycket information vilken måste extraheras på ett korrekt sätt. Detta kräver god datorvana och kunskaper inom bildprocessning, vilket de sällan har. För att komma runt problemet, syftade den här masteruppsattsen till att utveckla en rutin för artefaktkorrigering och informationsextrahering från bilder tagna i ett forskningsprojekt vid Karolinska Institutet i Stockholm. Genom att utveckla rutinen, visar uppsattsen hur mjukvaror utvecklade för bilder av människa kan appliceras på bilder av råtta. Rutinen hanterar formatteringsproblem och artefaktkorrigering, beräknar diffusionsmått, och utför statistiska tester på spatiellt matchade magnetresonansavbildningar tagna med diffusionsviktade ekoplana metoder. Rutinen verifierades genom att analysera bilder som den processat och det konstaterades att den skapar korrekta bilder. Framtida studier inom området bör fokusera på att utveckla atlaser av råttor och fortsätta identifieringen av hur mjukvaror utvecklade för bilder av människa kan appliceras på bilder av råtta.

Biologists and physicians study complex biologic phenomena in which they use advanced imaging methods. They acquire images containing a lot of information which must be extracted in a correct way. This requires computer skills and knowledge in image processing methods which they seldom have. To overcome the problem, this master thesis aimed to develop a routine for artefact correction and information extraction from images acquired in a research project at the Karolinska Institutet in Stockholm. By developing the routine, the thesis showed how software developed for images of human can be applied to images of rats. The routine handles formatting issues and artefact corrections, calculates diffusion metrics, and performs statistical tests on spatially aligned magnetic resonance images of rats acquired with diffusion weighted echo planar imaging. The routine was verified by analysing the images that it had processed and was considered to create reliable images. Future studies within the field should focus on developing atlases of rats and continue the work with identifying how software developed for images of human can be applied to images of rats. / Biologer och läkare studerar komplexa biologiska processer för vilket de använder avancerade bildgivande metoder. De samlar bilder som innehåller mycket information vilken måste extraheras på ett korrekt sätt. Detta kräver god datorvana och kunskaper inom bildprocessning, vilket de sällan har. För att komma runt problemet, syftade den här masteruppsattsen till att utveckla en rutin för artefaktkorrigering och informationsextrahering från bilder tagna i ett forskningsprojekt vid Karolinska Institutet i Stockholm. Genom att utveckla rutinen, visar uppsattsen hur mjukvaror utvecklade för bilder av människa kan appliceras på bilder av råtta. Rutinen hanterar formatteringsproblem och artefaktkorrigering, beräknar diffusionsmått, och utför statistiska tester på spatiellt matchade magnetresonansavbildningar tagna med diffusionsviktade ekoplana metoder. Rutinen verifierades genom att analysera bilder som den processat och det konstaterades att den skapar korrekta bilder. Framtida studier inom området bör fokusera på att utveckla atlaser av råttor och fortsätta identifieringen av hur mjukvaror utvecklade för bilder av människa kan appliceras på bilder av råtta.

<p>Pancreatic ductal adenocarcinoma is an especially deadly disease having the lowest 5-year survival rate of any major cancer at just 11%. As in many cancers, systemically-delivered chemotherapy forms the backbone of clinical treatment. However, limitations of systemic delivery exacerbated by the unique desmoplastic and avascular microenvironment surrounding the pancreatic tumor cells result in the failed efficacy of current treatments. The high stromal content in the microenvironment, which is especially overabundant in hyaluronic acid, is thought to physically impede drug perfusion into the tissue. Thus, there is clearly a <strong>critical need</strong> to develop novel treatments for pancreatic ductal adenocarcinoma that can overcome these drug delivery barriers. Long-acting injectable implants offer an attractive drug delivery method that can provide <em><strong>sustained</strong></em> drug release directly at the <em><strong>local</strong></em> targeted site, rather than transient, systemic release. Here we use in situ forming implants (ISFIs), which are a low-viscosity solution outside of the body but transition into a solid drug-eluting depot after injection into an aqueous environment. Our <strong>objective</strong> is to develop and characterize an ISFI that can provide sustained release of bioactive hyaluronidase for use as an intratumoral injection to degrade hyaluronic acid in pancreatic tumors. This work was accomplished in four aims. First, a method was developed using diffusion-weighted MRI for noninvasive characterization of the implants. Second, because hyaluronidase is a protein drug, we studied factors affecting protein release from ISFIs, focusing on external factors of the injection site. Third, we showed that basic salt additives can be used to neutralize the acidic environment created by the implants which may improve protein stability. Finally, we formulated an implant to provide sustained release of hyaluronidase and demonstrated retention of its bioactivity both <em>in vitro</em> and <em>ex vivo</em>.</p>

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19403号 / 医博第4054号 / 新制||医||1012(附属図書館) / 32428 / 京都大学大学院医学研究科医学専攻 / (主査)教授 前川 平, 教授 平岡 眞寛, 教授 羽賀 博典 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Objective: Reductions of gray matter volume and cortical thickness in anorexia nervosa (AN) are well documented. However, findings regarding the integrity of white matter (WM) as studied via diffusion weighted imaging (DWI) are remarkably heterogeneous, and WM connectivity has been examined only in small samples using a limited number of regions of interest. The present study investigated whole-brain WM connectivity for the first time in a large sample of acutely underweight patients with AN. Method: DWI data from predominantly adolescent patients with acute AN (n ¼ 96, mean age ¼ 16.3 years) and age-matched healthy control participants (n ¼ 96, mean age ¼ 17.2 years) were analyzed. WM connectivity networks were generated from fiber-tractography-derived streamlines connecting 233 cortical/subcortical regions. To identify group differences, network-based statistic was used while taking head motion, WM, and ventricular volume into account. Results: Patients with AN were characterized by 6 WM subnetworks with abnormal architecture, as indicated by increased fractional anisotropy located primarily in parietal-occipital regions and accompanied by reduced radial diffusivity. Group differences based on number of streamlines reached only nominal significance. Conclusion: Our study reveals pronounced alterations in the WM connectome in young patients with AN. In contrast to known reductions in gray matter in the acutely underweight state of AN, this pattern does not necessarily indicate a deterioration of the WM network. Future studies using advanced MRI sequences will have to clarify interrelations with axonal packing or

Pre-surgical diffusion weighted imaging (DWI) is increasingly important in the context of thyroid cancer for identification of the optimal treatment strategy. It has exemplarily been shown that DWI at 3T can distinguish undifferentiated from well-differentiated thyroid carcinoma, which has decisive implications for the magnitude of surgery. This study used DWI histogram analysis of whole tumor apparent diffusion coefficient (ADC) maps. The primary aim was to discriminate thyroid carcinomas which had already gained the capacity to metastasize lymphatically from those not yet being able to spread via the lymphatic system. The secondary aim was to reflect prognostically important tumor-biological features like cellularity and proliferative activity with ADC histogram analysis. Fifteen patients with follicular-cell derived thyroid cancer were enrolled. Lymph node status, extent of infiltration of surrounding tissue, and Ki-67 and p53 expression were assessed in these patients. DWI was obtained in a 3T system using b values of 0, 400, and 800 s/mm2 . Whole tumor ADC volumes were analyzed using a histogram-based approach. Several ADC parameters showed significant correlations with immunohistopathological parameters. Most importantly, ADC histogram skewness and ADC histogram kurtosis were able to differentiate between nodal negative and nodal positive thyroid carcinoma. Conclusions: histogram analysis of whole ADC tumor volumes has the potential to provide valuable information on tumor biology in thyroid carcinoma. However, further studies are warranted.

Dopamine is an important neurotransmitter that is involved in several human functions such as reward, cognition, emotions and movement. Abnormalities of the neurotransmitter itself, or the dopamine receptors through which it exerts its actions, contribute to a wide range of psychiatric and neurological disorders such as Parkinson’s disease and schizophrenia. Thus far, despite the great interest and extensive research, the exact role of dopamine and the causalities of dopamine related disorders are not fully understood. Here we have developed multimodal imaging methods, to investigate the release of dopamine and the distribution of the dopamine D2-like receptor family in-vivo in healthy humans. We use the [¹¹C]PHNO PET ligand, which enables exploration of dopamine-related parameters in striatal regions, and for the first time in extrastriatal regions, that are known to be associated with distinctive functions and disorders. Our methods involve robust approaches for the manual and automated delineation of these brain regions, in terms of structural and functional organisation, using information from structural and diffusion MRI images. These data have been combined with [¹¹C]PHNO PET data for quantitative dopamine imaging. Our investigation has revealed the distribution and the relative density of the D3R and D2R sites of the dopamine D2-like receptor family, in healthy humans. In addition, we have demonstrated that the release of dopamine has a functional rather than a structural specificity and that the relative densities of the D3R and D2R sites do not drive this specificity. We have also shown that the dopamine D3R receptor is primarily distributed in regions that have a central role in reward and addiction. A finding that supports theories that assigns a primarily limbic role to the D3R.

L'IRM conventionnelle est considérée comme l'outil non invasif de référence pour le diagnostic, le bilan pré-thérapeutique et le suivi post-thérapeutique des tumeurs cérébrales de l'enfant et de l'adulte. Cependant, en raison de son manque de spécificité aussi bien pour certains diagnostics différentiels que pour l'évaluation de la réponse radiologique, différentes modalités d'IRM sont aujourd'hui ajoutées à l'examen conventionnel dans le but d'affiner l'exploration de ces tumeurs. L'utilisation d'une modalité unique n'est malgré tout pas suffisante pour établir une évaluation diagnostique ou pronostique optimale des tumeurs cérébrales. C'est pourquoi nous nous sommes intéressés à la combinaison de données issues des différentes modalités d'IRM dans le but d'obtenir une meilleure caractérisation, en termes de différenciation et d'évolutivité de ces néoplasmes. Dans ce contexte, nous avons investigué par IRM multimodale 1) les tumeurs épileptogènes de l'enfant, pour lesquelles il est crucial de déterminer le diagnostic préopératoire afin d'aider à la prise en charge chirurgicale ; 2) les tumeurs oligodendrogliales de l'adulte, difficilement distinguables et dont les décisions thérapeutiques reposent sur la détermination du grade et du profil moléculaire ; et enfin 3) la réponse des glioblastomes aux traitements anti-angiogéniques. / Conventional MRI is considered as the gold standard method for the non-invasive diagnosis, pretherapeutic assessment and follow-up of brain tumors in adults and in children. However, due to its lack of specificity for both differential diagnosis and evaluation of the response to treatment, several MR modalities are now added to the conventional exam in order to refine the exploration of these tumors. The use of a single modality is however not yet sufficient to establish an accurate diagnosis or prognosis for brain tumors. For this reason, we were interested in the combination of data from different MR modalities in order to obtain a better characterization of these neoplasms. In this context, we used multimodal MRI to investigate 1) pediatric epileptogenic tumors, for which it is crucial to establish a preoperative diagnosis in order to make appropriate surgical and therapeutic decisions; 2) oligodendroglial tumors in adults, hardly distinguishable and which therapeutic decisions are mainly based on the determination of the tumoral grade and molecular profile; and 3) the response of glioblastoma to anti-angiogenic treatments. Through this work, we have shown that the association of different imaging modalities provides a significant contribution to the differential pre-therapeutic diagnosis of epileptogenic brain lesions in children and also of oligodendroglial tumors in adults as well as a support for the early assessment of tumoral response to anti-angiogenic therapies.