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In Dynamic Contrast Enhanced MRI there are several steps from the initial signal to obtaining the pharmacokinetic parameters for tumor characterization. The aim of this work was to validate the steps in the flow of data focusing on T1-mapping, Contrast Agent (CA)-quantification and the pharmacokinetical (PK) model, using a digital phantom of a head. In the Digital Phantom tissues are assigned necessary values to obtain both a regular and contrast enhanced (using Parker AIF) representation and simulating an SPGR signal. The data analysis was performed in a software called MICE, as well as the Digital Phantom developed at the department of Radiation Sciences at Umeå University. The method of variable flip angles for the T1-mapping was analyzed with respect to SNR and number of flip angles, finding that the median value in each tissue is correct and stable. A "two point" inversion recovery sequence was tested with optimal combination of inversion times for white matter and CSF and obtaining correct T1-values when the inversion times were close to the tissue T1, otherwise with large deviations seen. Three different methods for CA-quantification were analyzed and a large underestimation was found assuming a linearity between signal and CA-concentration mainly for vessels at about 60%, but also for other tissue such as white matter at about 15%, improving when the assumption was removed. Still there was a noticeable underestimation of 30% and 10% and the quantification was improved further, achieving a near perfect agreement with the reference concentration, taking the T2*-effect into account. Applying Kety-model, discarding the vp-term, Ktrans was found to be stable with respect to noise in the tumor rim but ve noticeably underestimated with about 50%. The effect of different bolus arrival time, shifting the AIF required in the PK-model with respect to the CA-concentration, was tested with values up to 5 s, obtaining up to about 5% difference in Ktrans as well as the effect of a vascular transport function obtained by the means of an effective mean transit time up to 5 s and up to about 5% difference in Ktrans.

Diffusion weighted imaging (DWI) and dynamic susceptibility contrast-enhanced (DSC) perfusion-weighted imaging (PWI) are commonly employed in clinical practice and in research to give pathophysiological information for patients with acute ischemic stroke. DWI is thought to roughly reflect the severely damaged infarct core, while DSC-PWI reflects the area of hypoperfusion. The volumetric difference between DWI and DSC-PWI is termed the PWI/DWI-mismatch, and has been suggested as an MRI surrogate of the ischemic penumbra. However, due to the application of a contrast agent, which has potentially severe side-effects (e.g., nephrogenic systemic fibrosis), the DSC-PWI precludes repetitive examinations for monitoring purposes. New approaches are being sought to overcome this shortcoming. BOLD (blood oxygen-level dependent) signal can reflect the metabolism of blood oxygen in the brain and hemodynamics can be assessed with resting-state fMRI. The aim of this thesis was to use resting-state fMRI as a new approach to give similar information as DSC-PWI. This thesis comprises two studies: In the first study (see Chapter 2), two resting-state fMRI methods, local methods which compare low frequency amplitudes between two hemispheres and a k-means clustering approach, were applied to investigate the functional damage of patients with acute ischemic stroke both in the time domain and frequency domain. We found that the lesion areas had lower amplitudes than contralateral homotopic healthy tissues. We also differentiated the lesion areas from healthy tissues using a k-means clustering approach. In the second study (see Chapter 3), time-shift analysis (TSA), which assesses time delays of the spontaneous low frequency fluctuations of the resting-state BOLD signal, was applied to give similar pathophysiological information as DSC-PWI in the acute phase of stroke. We found that areas which showed a pronounced time delay to the respective mean time course were very similar to the hypoperfusion area. In summary, we suggest that the resting-state fMRI methods, especially the time-shift analysis (TSA), may provide comparable information to DSC-PWI and thus serve as a useful diagnostic tool for stroke MRI without the need for the application of a contrast agent.

Magnetic resonance imaging (MRI) of the liver is an important non-invasive tool for diagnosing liver disease. A key application is dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). With the use of the hepatocyte specific contrast agent (CA) Gd-EOB-DTPA it is now possible to evaluate the liver function. Beyond traditional qualitative evaluation of the DCE-MRI images, parametric quantitative techniques are on the rise which yields more objective evaluations. Systems biology is a gradually expanding field using mathematical modeling to gain deeper mechanistic understanding in complex biological systems. The aim of this thesis to combine these two fields in order to derive a physiologically accurate minimal whole body model that can be used to quantitatively evaluate liver function using clinical DCE-MRI examinations.  The work is based on two previously published sources of data using Gd-EOB-DTPA in healthy humans; i) a region of interest analysis of the liver using DCE-MRI ii) a pre-clinical evaluation of the contrast agent using blood sampling.  The modeling framework consists of a system of ordinary differential equations for the contrast agent dynamics and non-linear models for conversion of contrast agent concentrations to relaxivity values in the DCE-MRI image volumes. Using a χ2-test I have shown that the model, with high probability, can fit the experimental data for doses up to twenty times the clinically used one, using the same parameters for all doses. The results also show that some of the parameters governing the hepatocyte flux of CA can be numerically identifiable. Future applications with the model might be as a basis for regional liver function assessment. This can lead to disease diagnosis and progression evaluation for physicians as well as support for surgeons planning liver resection.

Tato dizertační práce představuje metodu zobrazování perfúze magnetickou rezonancí, jež je výkonným nástrojem v diagnostice, především v onkologii. Po ukončení sběru časové sekvence T1-váhovaných obrazů zaznamenávajících distribuci kontrastní látky v těle začíná fáze zpracování dat, která je předmětem této dizertace. Je zde představen teoretický základ fyziologických modelů a modelů akvizice pomocí magnetické rezonance a celý řetězec potřebný k vytvoření obrazů odhadu parametrů perfúze a mikrocirkulace v tkáni. Tato dizertační práce je souborem uveřejněných prací autora přispívajícím k rozvoji metodologie perfúzního zobrazování a zmíněného potřebného teoretického rozboru.

Le cancer de la prostate est le cancer le plus fréquent chez les hommes. Son développement entraine une néo-angiogénèse qui modifie le réseau capillaire. Il est reconnu que l'IRM dynamique (DCE-MRI) est capable de distinguer ces modifications de la microcirculation physiologique. Cependant, ces images restent difficiles à analyser et à interpréter en routine clinique. Dans cette thèse, nous nous sommes intéressés à la mise en place de méthodes robustes pour l'analyse de ces images. Dans un premier temps, nous traitons les méthodes de quantifications des paramètres pharmacocinétiques. Ainsi, une plateforme logicielle a été construite autour du modèle multi-étapes de Tofts. La validation technique a été conduite en utilisant des images simulées avec connaissance de la vérité de terrain de la distribution des lésions. La validation clinique est en cours dans le service de Radiologie de l'Hôpital Claude Huriez du CHRU de Lille. Parallèlement, nous avons exploré l'application des techniques de traitement des données pour l'analyse non paramétrique et non supervisée des courbes temps-intensités. Nous avons développé une approche originale basée sur la classification spectrale. Cette méthode, basée sur la théorie des graphes, permet le regroupement des signaux après transformation de l'espace de représentation. Par la suite, ces groupes de données peuvent être étiquetés par comparaison avec un signal artériel qui sert de référence. Les expérimentations préliminaires conduites sur les données simulées ainsi que sur des données cliniques montre la faisabilité de l'approche. Les deux approches développées sont complémentaires, l'une donnant des paramètres quantitatifs et l'autre permettant de segmenter les zones cancéreuses. / Prostate cancer is the most common cancer among men. Its developments leads to a neo-angiogenesis that changes the capillary network. It is recognized that the DCE-MRI is able to distinguish these physiological changes in microcirculation. However, the images are difficult to analyze and interpret. In this thesis, we were interested by the development of robust methods for the analysis of these images. Initially, we were focused on pharmacokinetic parameters quantification methods. A software platform was constructed to implement the multi-step Tofts model. Technical validation was performed using simulated images with knowledge of the ground truth. Clinical validation is in progress in the Radiology department of Lille University Hospital. In parallel, we have explored the application of nonparametric and unsupervised techniques of data processing for time-intensity curve analysis. We have developed an original approach based on spectral classification. This method, based on graph theory, allows the grouping of signals after transformation of the space of representation. Subsequently, these groups of data can be labeled by comparison to the arterial signal serving as reference. Preliminary experiments conducted on simulated data as well as clinical data show the feasibility of the approach. The two approaches are complementary, one giving quantitative parameters and the other segmenting the cancerous areas.

<p> </p><p>Acquired data from dynamic contrast enhanced MRI measurements can be used to non-invasively assess tumour vascular characteristics through pharmacokinetic modelling. The modelling requires an arterial input function which is the concentration of contrast agent in the blood reaching the volume of interest as a function of time. The aim of this work is testing and optimizing a turboFLASH sequence to appraise its suitability for measuring the arterial input function by measuring phase.</p><p>Contrast concentration measurements in a phantom were done with both phase and relaxivity techniques. The results were compared to simulations of the experiment conditions to compare the conformance. The results using the phase technique were promising, and the method was carried on to in-vivo testing. The in-vivo data displayed a large signal loss which motivated a new phantom experiment to examine the cause of this signal reduction. Dynamic measurements were made in a phantom with pulsatile flow to mimic a blood vessel with a somewhat modified turboFLASH sequence. The conclusions drawn from analyzing the data were used to further improve the sequence and this modified turboFLASH sequence was tested in an in-vivo experiment. The obtained concentration curve showed significant improvement and was deemed to be a good representation of the true blood concentration.</p><p>The conclusion is that phase measurements can be recommended over relaxivity based measurements. This recommendation holds for using a slice selective saturation recovery turboFLASH sequence and measuring the arterial input function in the neck. Other areas of application need more thorough testing.</p><p> </p>

Contrast-enhanced mammography (CEM) relies on visualizing the growth of new blood vessels (i.e. tumor angiogenesis) to provide sufficient materials for cell proliferation during the development of cancer. Since cancers will accumulate an injected contrast agent more than other tissues, it is possible to use one of several methods to enhance the area of lesions in the x-ray image and remove the contrast of normal tissue. Large area flat panel detectors may be used for CEM wherein the subtraction of two acquired images is used to create the resulting enhanced image. There exist several methods to acquire the images to be subtracted, which include temporal subtraction (pre- and post-contrast images) and dual-energy subtraction (low- and high-energy images), however these methods suffer from artifacts due to patient motion between image acquisitions. In this research the use of a multilayer flat panel detector is examined for CEM that is designed to acquire both (low- and high-energy) images simultaneously, thus avoiding motion artifacts in the resulting subtracted image. For comparison, a dual-energy technique prone to motion artifacts that uses a single-layer detector is also investigated. Both detectors are evaluated and optimized using amorphous selenium as the x-ray to charge conversion material, however the theoretical analysis could be extended to other conversion materials. Experimental results of single pixel prototypes of both multilayer and single-layer detectors are also discussed and compared to theoretical results. For a more comprehensive analysis, the motion artifacts present in dual-exposure techniques are modeled and the performance degradation due to motion artifacts is estimated. The effects of noise reduction techniques are also evaluated to determine potential image quality improvements in CEM images.

During cardiac ischemia, intracellular calcium (Ca²⁺) overload occurs which can result in cell death. MRI T₁ shortening contrast agent manganese (Mn²⁺) acts as a surrogate marker for Ca²⁺. Cardiac T₁-mapping manganese-enhanced MRI (MEMRI) techniques were applied to study the efflux of Mn²⁺ from both healthy mice and mice post-myocardial infarction (MI) surgery. Temporal changes in the myocardial relaxation rate, ∆R₁, post-MnCl₂ infusion were shown to be linearly correlated to the absolute Mn content. The relative importance of individual efflux mechanisms in healthy mice was investigated by inhibiting the sodium-calcium exchanger (NCX) with SEA0400, following infusion of MnCl₂, with SEA0400 reducing the rate of Mn²⁺ efflux. Regional alterations in Mn²⁺ uptake and efflux were also studied post-myocardial infarction, allowing for the identification of potentially salvageable myocardium in the peri-infarcted zone surrounding the necrosed tissue. Application of pharmacokinetic models to in vivo and elemental analysis data from both the healthy and MI mice groups suggested that the NCX was more active in Mn²⁺ efflux than for Ca²⁺ and that there was an increase in Mn²⁺ uptake due to the disease condition, consistent with Ca²⁺ overloading. Studying Mn²⁺ efflux using these protocols could provide a pre-clinical model for examining alterations in relative Ca²⁺ fluxes and to potentially monitor disease progression.