Improved Acquisition Methods for Hyperpolarized Carbon-13 Magnetic Resonance Imaging

Magnetic resonance imaging with hyperpolarized 13C-labeled compounds via dynamic nuclear polarization (DNP) has been used to non-invasively study metabolic processes in vivo. This method provides a transient signal enhancement of more than 10,000 fold compared to imaging 13C compounds at thermal equilibrium. However, as soon as the pre-polarized 13C-labeled compound leaves the polarizer, its hyperpolarized state would irreversibly decay to the thermal equilibrium with a decay constant characterized by T1, which is typically less than one minute. The rapid loss of nonrenewable polarization brings challenges in hyperpolarized 13C magnetic resonance imaging. This dissertation presents improved acquisition methods for hyperpolarized 13C imaging with the injection of hyperpolarized [1-13C]pyruvate, which is the most widely studied substrate to date. The improved acquisition methods include a regional bolus tracking sequence for automatic acquisition timing, real-time calibration of frequency and RF power for more robust acquisitions, metabolite specific balanced steady state free precession (bSSFP) sequence and metabolite specific fast spin echo sequence for efficient use of polarization in hyperpolarized [1-13C] imaging. The proposed acquisition methods have been demonstrated in various clinical applications on a MR 3T scanner. Bolus tracking and real-time acquisition methods have been used in imaging human brain, heart, kidney and prostate. Metabolite specific bSSFP sequence has been applied in imaging human kidney. Metabolite specific fast spin echo sequence has been demonstrated in imaging human brain

Quantitative magnetic resonance imaging and high-intensity focused ultrasound treatment of uterine fibroids

Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) treatment is an emerging non-invasive treatment method in which the targeted tissue is heated by high-intensity ultrasound causing coagulative necrosis. Benign muscle tumors of the uterus alias uterine fibroids can be treated with MRgHIFU though treatment outcomes have been varying. Treatment outcomes are affected by different properties of uterine fibroid tissue such as blood flow and histological structure. The blood flow of uterine fibroids can be changed by oxytocin infusion even though oxytocin’s mechanism of action on the blood flow of uterine fibroids is unknown. The present magnetic resonance imaging (MRI) based evaluation methods of uterine fibroids’ suitability for MRgHIFU treatment are not completely satisfactory. Quantitative MRI techniques can be used for measuring the histological properties of tissues in an indirect manner, which could be better for uterine fibroids’ suitability evaluation. This study investigated the feasibility of applying quantitative MRI techniques; diffusion-weighted imaging (DWI) and T2 relaxation time mapping, to predict outcomes of the MRgHIFU treatment of uterine fibroids. Based on these results, new quantitative evaluation methods were developed and compared with currently used MRI-based evaluation methods. In addition, the effect of oxytocin on the blood flow of the uterine fibroid and the myometrium was studied quantitatively using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). The results of this study indicate that DWI and T2 relaxation time mapping are feasible for the evaluation of MRgHIFU treatment outcomes. Evaluation methods based on these techniques also appear to be more reliable than current approaches. When utilizing DCE-MRI, it was observed that oxytocin strongly reduced the blood flow of uterine fibroids without affecting the blood flow in the myometrium, indicating that oxytocin’s effect took place solely in the uterine fibroid. The results of this work are directly applicable to the clinical practice of treating uterine fibroids with MRgHIFU.Myoomien kvantitatiivinen magneettikuvantaminen ja korkea intensiteettinen fokusoitu ultraäänihoito Magneettikuvausohjattu korkeaintensiteettinen kohdennettu ultraäänihoito (magnetic resonance-guided high-intensity focused ultrasound, MRgHIFU) on uudenlainen kajoamaton hoitomenetelmä, jossa kohdekudosta lämmitetään korkeaintensiteettisen ultraäänen avulla, mikä aiheuttaa koagulaationekroosia. Kohdun hyvänlaatuisia lihaskasvaimia eli myoomia voidaan hoitaa MRgHIFUhoidolla, mutta hoitotulokset ovat kuitenkin vaihtelevia. Hoitotuloksiin vaikuttavat myoomakudoksen erilaiset ominaisuudet kuten verenvirtaus ja histologinen rakenne. Myoomien verenvirtausta voidaan muuttaa oksitosiini-infuusiolla, mutta oksitosiinin vaikutusmekanismi myoomien verenvirtaukseen ei ole tunnettu. Nykyiset magneettikuvaukseen perustuvat myoomien soveltuvuuden arviointimenetelmät MRgHIFU-hoitoon eivät ole täysin tyydyttäviä. Kvantitatiivisilla magneettikuvaustekniikoilla voidaan mitata epäsuorasti kudosten histologisia ominaisuuksia ja siten nämä tekniikat voisivat olla parempia myoomien soveltuvuuden arvioinnissa MRgHIFU-hoitoon. Tässä tutkimuksessa arvioitiin kvantitatiivisten magneettikuvaustekniikoiden (diffuusiopainotettu kuvantaminen ja T2-relaksaatioaikakartoitus) soveltuvuutta ennustaa myoomien MRgHIFU-hoitotuloksia. Näiden tulosten perusteella kehitettiin uudet kvantitatiiviset arviointimenetelmät ja verrattiin näitä menetelmiä nykyisiin magneettikuvaukseen perustuviin arviointimenetelmiin. Lisäksi oksitosiinin vaikutusta myooman ja kohdun seinämän verenvirtaukseen tutkittiin kvantitatiivisesti käyttäen dynaamista kontrastiainetehosteista magneettikuvantamista. Tutkimuksen tulokset osoittivat, että diffuusiopainotettu kuvantaminen ja T2-relaksaatioaikakartoitus soveltuvat myoomien MRgHIFU-hoitotulosten arviointiin. Näihin tekniikoihin perustuvat arviointimenetelmät vaikuttavat olevan myös luotettavampia kuin nykyiset arviointimenetelmät. Dynaamisen kontrastitehosteisen magneettikuvantamisen avulla havaittiin, että oksitosiini vähentää voimakkaasti myooman verenvirtausta vaikuttamatta kohdun seinämän verenvirtaukseen viitaten siihen, että oksitosiinin vaikutus tapahtuu vain myoomassa. Tämän työn tulokset ovat suoraan sovellettavissa myoomien MRgHIFU-hoitojen kliinisiin käytäntöihin

Impact of Particle Sizes on MRI Signal Relaxation in Phantoms for Assessment of Hepatic Steatosis and Iron Overload

Magnetic Resonance Imaging (MRI) is emerging as a powerful tool to non-invasively evaluate diffuse liver diseases such as hepatic steatosis and iron overload. To test new MRI techniques, phantom studies are utilized in place of patients but often do not consider the microscopic interactions of particles suspended in the media which may cause a notable difference in the signal. Hence, this study investigates the impact of differing particle sizes on the magnetic resonance signal using phantoms. To accomplish this, steatosis phantoms were created using two different mixing methods to control droplet size and while combination iron-fat phantoms featuring iron particles of differing diameters were used to emulate hepatic iron overload. Signal behavior from both sets of phantoms were resolved using linear calibrations to determine values from two known biomarkers, fat fraction and R2*, for steatosis and iron overload, respectively. Overall, evidence showing that particle size impacts the signal to a significant degree remains inconclusive, but fitting model performance in biomarker quantification varied. This study demonstrates different sequencing and post-processing assessments are critical for the analysis of sensitive biomarkers such as R2* and FF

Temperature Mapping using Mid-Field Magnetic Resonance Imaging

Magnetic Resonance Imaging (MRI) is a non-invasive imaging modality with excellent soft tissue contrast and sensitivity to tissue temperature. MRI use is growing in Canada with expectation that this is expected to continue in the medium term, with more wide adoption of MRI and in particular a renewed focus on MR systems which deviate from the most commonly used 1.5T field strength system. By implementing systems which do not use as strong magnets and instead operate Generally, as the field strength of an MR system decreases, the signal received when imaging also decreases, which makes it difficult to implement some applications which are standard at higher field. One such application is temperature mapping on a these \u3c1T \u3esystems, which can be used to monitor thermal therapies interventionally. This thesis addresses the potentials for implementing temperature mapping at 0.5T, both in the creation of a tissue mimicking phantom which can be used to compare temperature mapping methods and implementing temperature maps both in vivo and in the custom phantom. As well, motivated by the sensitivity that thermal mapping has to external disturbances, the challenges that these accessible MR systems face when being in non-specialized environments is addressed, as this can potentially limit the efficacy of temperature mapping. This work ultimately demonstrates the acceptable capabilities of a 0.5T system to map temperatures with an adequate temporal resolution, along with presenting practical solutions to operating a system in non-traditional locations

Novel approaches for the measurement of tumoral pO2 by magnetic resonance methods

Tesis doctoral inédita realizada en el Instituto de Investigaciones Biomédicas "Alberto Sols" y leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 13 de Diciembre de 2013

Metabolic Signatures of Prostate Cancer and Renal Cell Carcinoma using High-Resolution NMR and Hyperpolarized 13C MRI

Non-invasive techniques to assess metabolic reprogramming during cancer progression can be used to improve therapeutic selection and provide an early assessment of therapeutic response or resistance in individual patients. Prior studies have shown that metabolic reprogramming plays a key role in the development of prostate cancer and renal cell carcinoma (RCC). This dissertation further elucidates the metabolic alterations that occur in treatment-resistant prostate cancer and in patient-derived models of RCC using high-resolution nuclear magnetic resonance (NMR) spectroscopy and hyperpolarized (HP) 13C magnetic resonance imaging (MRI), with the goal of identifying new non-invasive diagnostic imaging tools. Glycolysis, metabolism of pyruvate and glutamate via the tricarboxylic acid (TCA) cycle, glutaminolysis, and glutathione synthesis are upregulated in castration-resistant prostate cancer (CRPC) compared to their androgen-dependent counterparts, using human cell lines as well a treatment-driven transgenic murine model. These metabolic alterations were reversed in castration-resistant murine tumors by treatment with a secondary androgen pathway inhibitor, apalutamide, suggesting that early metabolic responses to treatment can be monitored using non-invasive imaging techniques. Furthermore, treatment-emergent small cell neuroendocrine prostate cancer, a consequence of protracted treatment with primary androgen deprivation therapy and secondary androgen pathway inhibitors, exhibits significantly upregulated glycolysis, TCA cycle metabolism of pyruvate and glutamate, and glutaminolysis, as well as significantly altered redox capacity compared to castration-resistant prostate adenocarcinoma using patient-derived xenograft models. Finally, the metabolic differences associated with the tumor microenvironment were compared between various patient-derived models of RCC, finding that RCC patient-derived xenografts (PDXs) displayed higher redox capacity and were more proliferative than cells and tissue slices derived from the PDXs and maintained ex vivo. The work presented in this dissertation suggests that a combination of HP [1-13C]pyruvate, [2-13C]pyruvate, [5-13C]glutamine, and [1-13C]dehydroascorbate can be used to distinguish advanced prostate cancer and RCC subtypes in future HP 13C MRI of patients for improved treatment selection and monitoring

Toward fast and robust in vivo MR quantification of microvasculature

Department of Biomedical EngineeringMagnetic resonance imaging (MRI) assessments of microvascular anatomy and function in diseases, such as cancer and neurodegenerations are important for detecting abnormal vascular behavior and monitoring therapeutic progress in a noninvasive manner. In MRI, quantitative microvascular biomarkers such as vessel permeability, orientation, blood volume, vessel size index are actively being developed for in vivo applications. Firstly, quantitative vessel permeability information is typically measured by dynamic contrast enhanced (DCE) - MRI, which uses extravasating contrast agent (Gd-DOTA). Following pharmacokinetic modelling is usually applied to dynamical signal change curve after the administration of contrast agent to extract vessel-permeability related parameters. On the other hand, it is generally accepted that there are certain limitations in conventional DCE - MRI acquisitions in terms of its accuracy, and the acquisition speed due to the demanding spatio-temporal tradeoffs for dynamic studies. For example, gradient echo based sequence is typically used for DCE - MRI for high temporal resolution requirements, but induces T2* decay that we often neglect, but becomes significant for high contrast agent concentration regions such as artery or kidney. Tradeoff between spatial and temporal resolution also limits the desired spatial coverage or temporal accuracy of time intensity curves. Secondly, vessel orientation, blood volume, and vessel size index are usually measured by detecting transverse relaxation difference before and after the administration of intravascular T2 contrast agent, such as superparamagnetic iron oxide nanoparticles (SPION). However, transverse relaxation is well known to be affected by unwanted environmental conditions such as air-tissue interface and vessel orientation, which frequently causes severe error in the measurement of blood volume and vessel size index. The subjects and goals of this thesis can be categorized by two sub-sections. In the first section, fast and accurate DCE - MRI was achieved by applying compressed sensing (CS) algorithms, which mitigates the spatio-temporal resolution competition of dynamic acquisitions. Firstly, the optimization for the implementation of compressed sensing to conventional fast low-angle shot (FLASH) sequence which is generally used for DCE - MRI acquisition was performed. After optimization step, temporal or spatial resolution improvements were demonstrated by in vivo experiment, especially in the tumor model. Secondly, compressed sensing was implemented to turbo spin echo (TSE) sequence to minimize transverse artifact by replacing T2* to T2 without reducing temporal resolution and slice coverage. This minimized transverse artifact realized calibration-free T1 estimation from T1-weighted signal intensity. Finally, ultrafast 3D spin echo acquisition was developed by applying compressed sensing to multiple-modulation-multiple-echo (MMME) sequence. Improved enhancement in developed sequence was observed, compared to conventional FLASH sequence with 3D coverage. In the second section, alternative methods to improve accuracy in detecting vessel orientation, blood volume, and vessel size index were developed. Firstly, alternative way to measure blood volume, and vessel size index was suggested and demonstrated by using ultra-short echo time (UTE) sequence. UTE sequence realized the measurement of blood volume with the change of longitudinal relaxation before and after administration of contrast agent, not from that of transverse relaxation. Consequently, accurate blood volume measurement was achieved by longitudinal relaxation which is not sensitive to environmental conditions such as air-tissue interface and vessel orientation. Moreover, alternative vessel size index including longitudinal relaxation showed the potential to reduce the error from environmental conditions. Finally, the new concept of obtaining MR tractography with magnetic field anisotropy was introduced. Compared to the conventional way using susceptibility-induced anisotropic magnetic field inhomogeneity studies, this method doesn???t need re-orientation of the subject utilizing the interference pattern between internal and external field gradients. Developed several methodologies in this thesis for the fast and robust in vivo quantification of microvasculature such as vessel permeability, orientation, blood volume, and vessel size index demonstrated the potentials to improve not only the speed of acquisition but also the accuracy of the in vivo microvascular measurements via efficient sensing and reconstruction MR techniques.ope

Magnetic resonance spectroscopy. Data analysis for clinical applications

This text is taken from the postgraduate thesis, which one of the authors (A.B.) developed for the degree of Medical Physicist in the School on Medical Physics of the University of Florence. The text explores the feasibility of quantitative Magnetic Resonance Spectroscopy as a tool for daily clinical routine use. The results and analysis comes from two types of hyper spectral images: the first set are hyper spectral images coming from a standard phantom (reference images); and hyper spectral images obtained from a group of patients who have undergone MRI examinations at the Santa Maria Nuova Hospital. This interdisciplinary work stems from the IFAC-CNR know how in terms of data analysis and nanomedicine, and the clinical expertise of Radiologists and Medical Physicists. The results reported here, which were the subject of the thesis, are original, unpublished, and represent independent work

Radiation dosimetry by use of radiosensitive hydrogels and polymers : mechanisms, state-of-the-art and perspective from 3D to 4D

Gel dosimetry was developed in the 1990s in response to a growing need for methods to validate the radiation dose distribution delivered to cancer patients receiving high-precision radiotherapy. Three different classes of gel dosimeters were developed and extensively studied. The first class of gel dosimeters is the Fricke gel dosimeters, which consist of a hydrogel with dissolved ferrous ions that oxidize upon exposure to ionizing radiation. The oxidation results in a change in the nuclear magnetic resonance (NMR) relaxation, which makes it possible to read out Fricke gel dosimeters by use of quantitative magnetic resonance imaging (MRI). The radiation-induced oxidation in Fricke gel dosimeters can also be visualized by adding an indicator such as xylenol orange. The second class of gel dosimeters is the radiochromic gel dosimeters, which also exhibit a color change upon irradiation but do not use a metal ion. These radiochromic gel dosimeters do not demonstrate a significant radiation-induced change in NMR properties. The third class is the polymer gel dosimeters, which contain vinyl monomers that polymerize upon irradiation. Polymer gel dosimeters are predominantly read out by quantitative MRI or X-ray CT. The accuracy of the dosimeters depends on both the physico-chemical properties of the gel dosimeters and on the readout technique. Many different gel formulations have been proposed and discussed in the scientific literature in the last three decades, and scanning methods have been optimized to achieve an acceptable accuracy for clinical dosimetry. More recently, with the introduction of the MR-Linac, which combines an MRI-scanner and a clinical linear accelerator in one, it was shown possible to acquire dose maps during radiation, but new challenges arise