Osteoarthritis develops secondary to the action of hostile biomechanics upon susceptible cartilage. Cam morphology describes a loss of concavity at the femoral head-neck junction resulting in femoral impaction against the acetabular rim within a functional range of movement. This impaction is termed femoroacetabular impingement and can result in pain and cause damage to adjacent articular cartilage that progresses to osteoarthritis. Cam morphology is a target for joint preservation strategies. The first study in this thesis compares hip development in academy football players with controls from local schools. The results provide strong evidence that cam morphology can develop in response to intense sporting activity during adolescence. At present, it is not possible to recommend activity modification as the cardiovascular benefits of exercise are likely to outweigh potentially detrimental effects on hip morphology. Nevertheless, individuals participating in high-level sports during youth may represent a high risk cohort for osteoarthritis warranting surveillance. Diagnostic tools currently available only allow identification of late joint degeneration when disease is irreversible. Advances in the field of disease biomarkers may overcome this challenge. The second study of this thesis explored the prognostic value of compositional MRI. Baseline delayed gadolinium-enhanced MRI of cartilage was able to predict the development of radiographic hip osteoarthritis in asymptomatic individuals within five years. As well as identifying individuals who are likely to benefit from intervention, compositional MRI may allow the evaluation of treatment efficacy within short timeframes. A number of interventions aimed at joint preservation are under investigation for treating cam morphology femoroacetabular impingement. Arthroscopic surgery is increasingly performed to restore the concavity at the femoral head-neck junction and prevent impaction against the acetabular rim. A feasibility study was performed for a proposed randomised controlled study comparing operative and non-operative treatment. The study protocol was developed for the 'Femoroacetabular Impingement Trial' (FAIT).

Abstract Magnetic resonance imaging (MRI) provides important information about structural and biochemical changes in organs. MRI is also an effective imaging method for the evaluation of spinal disorders. However, many of its potential applications - particularly diffusion imaging - have not yet been thoroughly explored. The purpose of this study was to determine the MRI-detectable changes in the intervertebral disc after trauma and to test the feasibility of diffusion-weighted MR imaging of the intervertebral discs. A minipig model was used in the experimental study to determine the MRI changes in the intervertebral disc after peripheral annular lesions in different time frames. Three of eight discs with experimental annular lesions had a normal annular appearance in MRI. Annular lesions, when detectable, were manifested as a bulging of the disc or as a high-intensity zone (HIZ) inside the annulus. Either the signal intensity or the area of bright signal intensity in the nucleus had nearly always decreased after one month, but they were still detectable even in cases where no signs of annular trauma could be seen in the MR images. The histology of HIZ is presented for the first time: clusters of nuclear cells and disorganized granulation tissue with capillaries were detected in the HIZ area. Fourteen patients 8 to 21 years of age with histories of vertebral fracture at least one year previously and 14 asymptomatic healthy control subjects 8 to 22 years of age were studied by MRI. In these young people a vertebral fracture, especially with end-plate injury, proved to be a notable risk factor for initiating disc degeneration. The apparent diffusion coefficients (ADCs) of the thoracolumbar intervertebral discs were determined in three orthogonal directions in 18 healthy young volunteers aged 8-22 years. The ADCs were also determined in 10 young patients with previous vertebral fractures, and clear decreases were found in the ADCx and ADCy directions, but in the ADCz direction values had not changed significantly as compared to the values in the controls. The most marked changes were observed in the degenerated discs, followed by those in the discs with a normal signal intensity adjacent to the primary trauma area. Diffusion-weighted MR imaging affords a useful tool for evaluating disc diseases in the early phases. Additionally, 37 adult volunteers without back symptoms were studied by MRI and by magnetic resonance angiography (MRA) and it was found that the status of the lumbar arteries significantly explained the diffusion values in the lumbar intervertebral discs. The correlation between disc degeneration and diffusion was mostly linear, but not significant.

La prévision du transport et de la rétention des colloïdes représente un enjeu environnemental majeur car ces particules peuvent entraîner des polluants adsorbés ou bien être des polluants eux-mêmes. Les modèles utilisés actuellement pour prédire le devenir des colloïdes dans les sols sont basés sur des mécanismes déduits des courbes de percée (évolution de la concentration en fonction du volume de pore ou du temps) après injection de particules dans une colonne de milieu poreux. Le but de cette thèse est de compléter cette compréhension avec des mesures internes grâce à l’Imagerie par Résonance Magnétique (IRM).L’IRM permet de mesurer la distribution 1D et/ou 2D de particules super-paramagnétiques le long d’un échantillon pendant une expérience de transport dans un milieu poreux. Le couplage de cette technique avec l'étude des courbes de percée donne une approche globale. Nous avons effectué plusieurs expériences de transport dans des colonnes de milieux poreux de complexité de porosité croissante : billes de verre, sable, agrégats de sol, et sol non perturbé.A partir des expériences de transport dans les milieux poreux modèles saturés, nous avons montré que la dispersion est moins importante que la théorie le prévoit et qu’elle est fortement dépendante des effets d’entrée dans la colonne. Cette dépendance est aussi observée pour les mécanismes d’adsorption. Les expériences dans les agrégats de sol ont montré une forte adsorption et un relargage constant, dépendants de la vitesse d’injection. Finalement, des expériences de pluie dans des colonnes de sol non perturbé insaturé ont permis de suivre l’évolution des teneurs en eau et en particules dans le temps / The ability to predict transport and retention of colloidal particles is a major environmental concern as such particles can carry adsorbed pollutants towards the groundwater or be pollutants themselves. The models currently used to predict the fate of colloids in soils are based on mechanisms inferred from breakthrough curves (evolution of concentration as a function of pore volume or time) after injection of particles into a column of porous media. In this thesis we aim to complement this comprehension with internal measurements by Magnetic Resonance Imaging (MRI).MRI provides 1D and/or 2D distribution of contrast agent particles in time along the sample axis during transport experiment through a porous medium. This technique, together with the study of breakthrough curves gives a global approach. We performed several transport experiment in columns of porous media of increasing complexity: glass beads, sand, soil aggregates, and undisturbed soil.From transport experiments in model porous media we show that dispersion is less important than expected and strongly dependent on entrance effects in the column. This dependence is also observed for adsorption. Experiments in soil aggregates showed a strong adsorption but also a constant release, dependent on the flow rate. Finally, rain experiments in undisturbed sol columns allowed following water content and particles as a function of time

L'obésité est associée à une augmentation de la morbidité et de la mortalité liée à de nombreuses maladies, y compris le diabète de type 2, l'hypertension et des pathologies hépatiques menant à une surcharge lipidique d’origine non alcoolique. Récemment, l’imagerie par résonance magnétique (IRM) est devenue la méthode de choix pour la quantification non invasive de la graisse. Dans cette thèse, les méthodes d'IRM ont été étudiées sur un scanner préclinique de 4.7T in vitro (fantômes MR) et in vivo (souris). Deux algorithmes de quantifications de la graisse -la méthode de Dixon et l’algorithme IDEAL- ont été considérés. Les performances de l'algorithme IDEAL ont été analysées en fonction de propriétés des tissus (T2*, fraction de graisse et modèle spectral de la graisse), de paramètres d'acquisition IRM (temps d’écho, nombre d'échos) et de paramètres expérimentaux (SNR et carte de champ). Sur les fantômes, l'approche standard single-T2* IDEAL a montré certaines limites qui pourraient être surmontées en optimisant le nombre d'échos. Une nouvelle méthode, pour déterminer les valeurs de vérité terrain pour T2* de l'eau et pour T2* de la graisse, a été proposée. Pour les mesures in vivo, différentes analyses ont été effectuées en utilisant l'algorithme IDEAL sur le foie et les muscles. L'analyse statistique sur les mesures de ROI a montré que le choix optimal du nombre d'échos est égal à trois pour la quantification de la graisse et six ou plus pour la quantification du T2*. Les valeurs de la fraction de graisse, calculées avec l'algorithme IDEAL, étaient statistiquement comparables aux valeurs obtenues avec la méthode de Dixon. Enfin, un procédé pour générer des signaux de référence mimant les systèmes eau-graisse (Fat Virtual Phantom MRI), sans l'aide d'objets physiques, a été proposé. Ces fantômes virtuels, qui présentent des caractéristiques de bruit réalistes, représentent une alternative intéressante aux fantômes physiques pour fournir un signal de référence dans les mesures IRM. / Obesity is associated with increased morbidity and mortality linked to many diseases, including type 2 diabetes, hypertension and disease nonalcoholic fatty liver. Recently, 1H magnetic resonance imaging (MRI) has emerged as the method of choice for non-invasive fat quantification. In this thesis, MRI methodologies were investigated for in vitro (MR phantoms) and in vivo (mice) measurements on a 4.7T preclinical scanner. Two algorithms of fat quantifications – the Dixon’s method and IDEAL algorithm – were considered. The performances of the IDEAL algorithm were analyzed as a function of tissue properties (T2*, fat fraction and fat spectral model), MRI acquisition parameters (echo times, number of echoes) and experimental parameters (SNR and field map). In phantoms, the standard approach of single-T2* IDEAL showed some limitations that could be overcome by optimizing the number of echoes. A novel method to determine the ground truth values of T2* of water and T2* of fat was here proposed. For in vivo measurements, different analyses were performed using the IDEAL algorithm in liver and muscle. Statistical analysis on ROI measurements showed that the optimal choice of the number of echoes was equal to three for fat quantification and six or more for T2* quantification. The fat fraction values, calculated with IDEAL algorithm, were statistically similar to the values obtained with Dixon’s method. Finally, a method for generating reference signals mimicking fat-water systems (Fat Virtual Phantom MRI), without using physical objects, was proposed. These virtual phantoms, which display realistic noise characteristics, represent an attractive alternative to physical phantoms for providing a reference signal in MRI measurements.

By sensitising the magnetic resonance signal to the diffusion of water molecules in tissue, diffusion-weighted magnetic resonance imaging provides a means of assessing tumour microstructure non-invasively. Such measurements have the potential to provide important information about tumour development and the response of tumours to treatment, but the way in which different tissue properties affect the diffusion-weighted signal remains unclear. Through simulations, in vivo studies and phantom experiments, this thesis investigates the relationship between the diffusion-weighted signal, the pulse sequence parameters used for acquisition, and microstructural properties of tumours. The use of oscillating gradient pulse sequences on a clinical scanner was investigated initially, with theoretical and practical considerations leading subsequent work to focus on pulsed gradient sequences. The forward problem of predicting the diffusion-weighted signal for given combinations of tissue properties and sequence parameters was addressed numerically through Monte Carlo simulations, focussing on how tumour cell size, intracellular volume fraction and membrane permeability affect the signal. These simulations allowed the sensitivity of the signal to changes in these tissue properties to be investigated, revealing how sensitivity depends on sequence parameters as well as the specific microstructural configuration. By repeating the simulations using the specific sequence parameters used in a clinical and preclinical study, the sensitivity of the implemented protocols was assessed, and linked to the experimental findings. The preclinical study illustrated the importance of the diffusion time in determining the sensitivity to treatment-induced changes in tumours, with larger post-treatment signal changes observed at longer diffusion times. These trends were qualitatively reflected in the sensitivity analysis derived from the simulations. Finally, the inverse problem of estimating microstructural properties from the diffusion-weighted signal was addressed using a physical phantom designed as a simple mimic of tumour tissue. By fitting a biophysical model to the diffusion data, the size and volume fraction of the approximately spherical 'cells' were estimated. The radius was slightly underestimated compared with that determined from independent measurements, the fitted volume fraction was plausible, and parameters were found to be estimated with reasonably good precision.

A notable need exists for noninvasive tools to increase our mechanistic understanding of disease progression at a cellular and molecular level. Studying the functions of proteins in their innate in vivo tissue environment can provide useful information about pathology enabling appropriate treatment and early diagnosis. Chemical exchange saturation transfer MRI contrast provides real-time functional characterization of the biological landscape and can be used to detect multiple enzyme biomarker activities. A dual-enzyme catalyCEST contrast agent was developed as a proof-of-concept to demonstrate the potential of using a salicylic acid scaffold and control the CEST signal through enzyme activation. In addition, a straightforward route was designed to synthesize a diamagnetic catalyCEST MRI agent that is a substrate for β-galactosidase and β-glucuronidase enzymes. The synthesized agents generated two peaks in the CEST spectrum, at 4.25 ppm corresponding to a carbamate moiety and at 9.25 ppm corresponding to the salicylic acid moiety. Chemical exchange rates of liable protons were determined from a QUESP Hanes-Woolf plot. In the presence of the corresponding enzymes, the catalyCEST agent was activated via saccharide hydrolysis followed by a spontaneous disassembly to produce 4-aminosalicylic acid. This reaction converted the carbamate moiety into a free primary amine, and caused a loss of CEST signal at 4.25 ppm. The CEST signal at 9.25 ppm was unaffected by the enzyme catalysis, and therefore used as an internal control signal. Michaelis-Menten enzyme kinetics studies were performed with CEST MRI to verify that catalyCEST MRI could truly detect enzyme activity. The Michaelis-Menten kinetics constants from MRI studies were compared to the kinetics constants measured with UVvis results from the same contrast agent, demonstrating the quantitative potential of catalyCEST MRI with both contrast agents. These findings demonstrate that the newly synthesized modular agents have the potential to become reliable catalyCEST MRI imaging probes. In addition, the modular design of these agents facilitates the conjugation of other enzyme substrates to the carbamate spacer, so that this approach constitutes a platform technology for the detection of enzyme activity.

Abstract The association between antipsychotics and brain volume changes in schizophrenia is not clear. Previous imaging studies have not examined benzodiazepine use, though it has been linked to cognitive impairment. The aim of this thesis was to examine the association between long-term antipsychotic and benzodiazepine use and brain structures in schizophrenia. Based on a systematic review and meta-analysis of previous studies on long-term antipsychotic use and brain changes in schizophrenia, a higher antipsychotic exposure associated with parietal lobe decrease and basal ganglia increase. Previous data on the topic is very heterogenous and the overall number of studies is small (N=34). Most reported findings were non-significant. In the Northern Finland Birth Cohort 1966, 38 cases with schizophrenia spectrum disorder participated in the longitudinal study at the ages of 24 and 43. In the cross-sectional study, 44 cases with schizophrenia and 35 cases with affective psychoses participated at the age of 43. Structural brain MRI scans were acquired from all participants an data on antipsychotic and benzodiazepine dose was collected using medical records and interviews. Illness severity and antipsychotic/benzodiazepine dose were included as confounders in the analyses. Higher scan-interval antipsychotic dose associated to volume increase in lateral ventricles and higher benzodiazepine dose associated to volume decrease in the caudate nucleus during the 9-year follow-up. In the 43-year study, higher lifetime antipsychotic dose associated to smaller nucleus accumbens volume in schizophrenia. In comparison, higher lifetime benzodiazepine dose associated to larger volumes of total gray matter, cerebral gray matter, and thalamus in affective psychoses. In analyses without illness severity and other medication as confounders, there were several statistically significant associations. It seems that long-term antipsychotic use may associate to structural brain changes in schizophrenia and some associations may be confounded by symptoms and the use of benzodiazepines. These findings underline the importance of taking benzodiazepine use and other confounding factors into account when studying the effects of antipsychotics on the brain. Further studies should focus on how these findings relate to cognition and functioning. / Tiivistelmä Psykoosilääkityksen yhteys skitsofreniassa tapahtuviin aivomuutoksiin on epäselvä. Aiemmat kuvantamistutkimukset eivät ole tutkineet bentsodiatsepiinien käyttöä, vaikka niiden käyttö on yhdistetty heikompaan kognititioon. Tämän tutkimuksen tarkoituksena oli selvittää pitkäaikaisen psykoosi- ja bentsodiatsepiinlääkityksen yhteyttä aivojen rakenteisiin skitsofreniassa. Systemaattisen katsauksen ja meta-analyysin perusteella suurempi psykoosilääkeannos liittyi päälakilohkon tilavuuden pienenemiseen sekä tyvitumakkeiden koon kasvuun skitsofreniassa pitkäaikaisseurannoissa. Aikaisempi kirjallisuus on erittäin heterogeenistä ja tutkimusten kokonaismäärä on pieni (N=34). Suurin osa löydöksistä ei ollut tilastollisesti merkitseviä. Pohjois-Suomen syntymäkohortti 1966 aineistossa 38 skitsofreniaspektrin psykoosia sairastavaa henkilöä osallistui pitkittäistutkimukseen 34 vuoden ja 43 vuoden iässä. Poikkileikkaustutkimuksessa 44 skitsofreniaa ja 24 mielialapsykoosia sairastavaa henkilöä osallistui tutkimukseen 43 vuoden iässä. Pään rakenteellinen magneettikuvaus tehtiin kaikille osallistujille. Tiedot psykoosilääkkeiden ja bentsodiatsepiinien annoksista kerättiin sairauskertomusmerkinnöistä ja haastatteluista. Taudin vakavuus ja psykoosilääkkeiden/bentosidatsepiinien annos huomioitiin sekoittavina tekijöinä. Korkeampi psykoosilääkeannos liittyi aivokammioiden koon kasvuun ja korkeampi bentsodiatsepiiniannos häntätumakkeen koon pienenemiseen 9 vuoden seurannassa. Poikkileikkaustutkimuksessa korkeampi elinaikainen psykoosilääkeannos liittyi pienempään makaavan tumakkeen tilavuuteen skitsofreniassa. Mielialapsykooseissa korkeampi elinaikainen bentsodiatsepiiniannos liittyi suurempaan koko aivojen harmaan aineen, isoaivojen harmaan aineen ja talamuksen tilavuuteen. Kun sekoittavia tekijöitä ei otettu huomioon, tilastollisesti merkitseviä yhteyksiä löytyi useammilta aivoalueilta Tutkimuksen perusteella psykoosilääkkeiden pitkäaikaiskäyttö saattaa liittyä aivojen rakenteellisiin muutoksiin skitsofreniassa. Bentsodiatsepiinien käyttö ja oireet voivat toimia sekoittavina tekijöinä. Löydökset korostavat sekoittavien tekijöiden huomioimisen tärkeyttä tutkittaessa psykoosilääkkeiden vaikutuksia aivoihin. Tulevaisuudessa tutkimusten tulisi selvittää, miten löydökset liittyvät kognitioon ja toimintakykyyn.

In this thesis a new framework is proposed for obtaining the spongy bone, cortical bone, muscle and adipose tissue from MRI data. The method focuses on the accurate extraction of the edges of the target tissues, which is the main drawback of previous works. In this framework six new methods, as listed in section 1.3, are utilized together for improving the result of the segmentation by detecting the relational position of the tissues, acquiring the best possible contribution from the operator in terms of time and efficiency, forward and backward transfer of the segmented tissues at the seed slice and using the newly proposed Deformable Kernel Fuzzy-C Mean (DKFCM) method for improving the result of segmentation on the edges. This method first limits the searching area for the voxels of the target tissue from the whole data to a small strip around the edges of the target tissue. Then, it applies a very accurate segmentation on the searching area, using a deformable kernel, which is capable of adapting itself with the shape of the edge. Comparing the results of this work with some popular MRI segmentation methods like active contour, watershed, FCM and also some heuristic methods, which are proposed in literature for segmenting the MRI to four tissues, demonstrates the superiority of the proposed method especially on the edges.

Femoro-Acetabular Impingement (FAI) is a hip joint disease which affects and impairs the range of hip motion during performing activities of daily living, jogging, walking, or climbing stairs due to the bony abnormalities of the joint. Ballet dancers and athletes (e.g. gymnasts and hockey players) put their hips at the risk of FAI by extremely moving the hip mainly by excessively rotating the joint. In this research, we introduce a visualization system which helps surgeons to analyze the range of hip motions as well as to have a better communication with patients. These goals are achieved by presenting three dimensional (3D) visualizations of motion envelope by examining the maximum possible rotation of the digital hip bones. Our computer simulation system estimates, analyzes and visualizes the maximum hip range of motion (ROM) for the constructed 3D bone models that are extracted from Magnetic Resonance Images (MRI) after segmenting the bones. These tasks are accomplished by first calculating Hip Joint Center (HJC) which is center of rotation of femoral head on the 3D segmented MRI models followed by simulating hip motions with examining impingement between the femur and the acetabulum using our collision detection system. In our collision detection system, surfaces of femoral head and acetabulum bones are sampled in the spherical coordinates based on rasterization and interpolation. Then, the distance between the femoral head and acetabulum are computed to prevent impingement between them. The maximum motion degree of femur bone within depression of acetabulum in every direction during the digital simulation shows the ROMs of the inputted MRI of the hip joint. Six primary plane motions (flexion/extension, abduction/adduction and internal/external rotation) as well as various combinations of these motions (maximum rotation of the hip between every two rotational movements) and successive movements (maximum rotational movement of the hip per another rotational movement) are simulated and analyzed along with 3D visualization of estimated range of these motions. Generally, the ROM differs by some factors such as age, gender, ethnicity, and geographic location. For instance, newborns up to age two have considerably greater motion in hip flexion and hip abduction than adults. Our system by 3D visualization of motion envelope will provide a platform to understand quicker and better the effect of bony morphology of the hip joint on the possible ROM. We also examine the long-standing question about moving center of rotation related to ROM. We found out the ROM becomes bigger especially when the center moves outward to the direction of acetabulum axis. This thesis does not consider the effect of muscle and other surrounding connective tissue on the hip ROM since they can be altered significantly by physical training to show the potential of maximum ROM. For example a ballerina has a bigger ROM leading a bigger motion envelope compared with non-dancers. Hence we visualize the range of joint motions and their envelopes that are obtained from the osseous anatomy of the hip joint. The osseous anatomy of the joint is the most fundamental and permanent factor of ROM which indicates the maximum motion that the joint can achieve if the muscle and other connective tissues are perfectly trained.

<p>Abstract</p><p>The goal of modern radiotherapy is to precisely deliver a prescribed radiation dose to delineated target volumes that contain a significant amount of tumor cells while sparing the surrounding healthy tissues/organs. Precise delineation of treatment and avoidance volumes is the key for the precision radiation therapy. In recent years, considerable clinical and research efforts have been devoted to integrate MRI into radiotherapy workflow motivated by the superior soft tissue contrast and functional imaging possibility. Dynamic contrast-enhanced MRI (DCE-MRI) is a noninvasive technique that measures properties of tissue microvasculature. Its sensitivity to radiation-induced vascular pharmacokinetic (PK) changes has been preliminary demonstrated. In spite of its great potential, two major challenges have limited DCE-MRI’s clinical application in radiotherapy assessment: the technical limitations of accurate DCE-MRI imaging implementation and the need of novel DCE-MRI data analysis methods for richer functional heterogeneity information. </p><p>This study aims at improving current DCE-MRI techniques and developing new DCE-MRI analysis methods for particular radiotherapy assessment. Thus, the study is naturally divided into two parts. The first part focuses on DCE-MRI temporal resolution as one of the key DCE-MRI technical factors, and some improvements regarding DCE-MRI temporal resolution are proposed; the second part explores the potential value of image heterogeneity analysis and multiple PK model combination for therapeutic response assessment, and several novel DCE-MRI data analysis methods are developed.</p><p>I. Improvement of DCE-MRI temporal resolution. First, the feasibility of improving DCE-MRI temporal resolution via image undersampling was studied. Specifically, a novel MR image iterative reconstruction algorithm was studied for DCE-MRI reconstruction. This algorithm was built on the recently developed compress sensing (CS) theory. By utilizing a limited k-space acquisition with shorter imaging time, images can be reconstructed in an iterative fashion under the regularization of a newly proposed total generalized variation (TGV) penalty term. In the retrospective study of brain radiosurgery patient DCE-MRI scans under IRB-approval, the clinically obtained image data was selected as reference data, and the simulated accelerated k-space acquisition was generated via undersampling the reference image full k-space with designed sampling grids. Two undersampling strategies were proposed: 1) a radial multi-ray grid with a special angular distribution was adopted to sample each slice of the full k-space; 2) a Cartesian random sampling grid series with spatiotemporal constraints from adjacent frames was adopted to sample the dynamic k-space series at a slice location. Two sets of PK parameters’ maps were generated from the undersampled data and from the fully-sampled data, respectively. Multiple quantitative measurements and statistical studies were performed to evaluate the accuracy of PK maps generated from the undersampled data in reference to the PK maps generated from the fully-sampled data. Results showed that at a simulated acceleration factor of four, PK maps could be faithfully calculated from the DCE images that were reconstructed using undersampled data, and no statistically significant differences were found between the regional PK mean values from undersampled and fully-sampled data sets. DCE-MRI acceleration using the investigated image reconstruction method has been suggested as feasible and promising. </p><p>Second, for high temporal resolution DCE-MRI, a new PK model fitting method was developed to solve PK parameters for better calculation accuracy and efficiency. This method is based on a derivative-based deformation of the commonly used Tofts PK model, which is presented as an integrative expression. This method also includes an advanced Kolmogorov-Zurbenko (KZ) filter to remove the potential noise effect in data and solve the PK parameter as a linear problem in matrix format. In the computer simulation study, PK parameters representing typical intracranial values were selected as references to simulated DCE-MRI data for different temporal resolution and different data noise level. Results showed that at both high temporal resolutions (<1s) and clinically feasible temporal resolution (~5s), this new method was able to calculate PK parameters more accurate than the current calculation methods at clinically relevant noise levels; at high temporal resolutions, the calculation efficiency of this new method was superior to current methods in an order of 102. In a retrospective of clinical brain DCE-MRI scans, the PK maps derived from the proposed method were comparable with the results from current methods. Based on these results, it can be concluded that this new method can be used for accurate and efficient PK model fitting for high temporal resolution DCE-MRI. </p><p>II. Development of DCE-MRI analysis methods for therapeutic response assessment. This part aims at methodology developments in two approaches. The first one is to develop model-free analysis method for DCE-MRI functional heterogeneity evaluation. This approach is inspired by the rationale that radiotherapy-induced functional change could be heterogeneous across the treatment area. The first effort was spent on a translational investigation of classic fractal dimension theory for DCE-MRI therapeutic response assessment. In a small-animal anti-angiogenesis drug therapy experiment, the randomly assigned treatment/control groups received multiple fraction treatments with one pre-treatment and multiple post-treatment high spatiotemporal DCE-MRI scans. In the post-treatment scan two weeks after the start, the investigated Rényi dimensions of the classic PK rate constant map demonstrated significant differences between the treatment and the control groups; when Rényi dimensions were adopted for treatment/control group classification, the achieved accuracy was higher than the accuracy from using conventional PK parameter statistics. Following this pilot work, two novel texture analysis methods were proposed. First, a new technique called Gray Level Local Power Matrix (GLLPM) was developed. It intends to solve the lack of temporal information and poor calculation efficiency of the commonly used Gray Level Co-Occurrence Matrix (GLCOM) techniques. In the same small animal experiment, the dynamic curves of Haralick texture features derived from the GLLPM had an overall better performance than the corresponding curves derived from current GLCOM techniques in treatment/control separation and classification. The second developed method is dynamic Fractal Signature Dissimilarity (FSD) analysis. Inspired by the classic fractal dimension theory, this method measures the dynamics of tumor heterogeneity during the contrast agent uptake in a quantitative fashion on DCE images. In the small animal experiment mentioned before, the selected parameters from dynamic FSD analysis showed significant differences between treatment/control groups as early as after 1 treatment fraction; in contrast, metrics from conventional PK analysis showed significant differences only after 3 treatment fractions. When using dynamic FSD parameters, the treatment/control group classification after 1st treatment fraction was improved than using conventional PK statistics. These results suggest the promising application of this novel method for capturing early therapeutic response. </p><p> The second approach of developing novel DCE-MRI methods is to combine PK information from multiple PK models. Currently, the classic Tofts model or its alternative version has been widely adopted for DCE-MRI analysis as a gold-standard approach for therapeutic response assessment. Previously, a shutter-speed (SS) model was proposed to incorporate transcytolemmal water exchange effect into contrast agent concentration quantification. In spite of richer biological assumption, its application in therapeutic response assessment is limited. It might be intriguing to combine the information from the SS model and from the classic Tofts model to explore potential new biological information for treatment assessment. The feasibility of this idea was investigated in the same small animal experiment. The SS model was compared against the Tofts model for therapeutic response assessment using PK parameter regional mean value comparison. Based on the modeled transcytolemmal water exchange rate, a biological subvolume was proposed and was automatically identified using histogram analysis. Within the biological subvolume, the PK rate constant derived from the SS model were proved to be superior to the one from Tofts model in treatment/control separation and classification. Furthermore, novel biomarkers were designed to integrate PK rate constants from these two models. When being evaluated in the biological subvolume, this biomarker was able to reflect significant treatment/control difference in both post-treatment evaluation. These results confirm the potential value of SS model as well as its combination with Tofts model for therapeutic response assessment. </p><p>In summary, this study addressed two problems of DCE-MRI application in radiotherapy assessment. In the first part, a method of accelerating DCE-MRI acquisition for better temporal resolution was investigated, and a novel PK model fitting algorithm was proposed for high temporal resolution DCE-MRI. In the second part, two model-free texture analysis methods and a multiple-model analysis method were developed for DCE-MRI therapeutic response assessment. The presented works could benefit the future DCE-MRI routine clinical application in radiotherapy assessment.</p> / Dissertation