Under-Sampled Reconstruction Techniques for Accelerated Magnetic Resonance Imaging

Due to physical and biological constraints and requirements on the minimum resolution and SNR, the acquisition time is relatively long in magnetic resonance imaging (MRI). Consequently, a limited number of pulse sequences can be run in a clinical MRI session because of constraints on the total acquisition time due to patient comfort and cost considerations. Therefore, it is strongly desired to reduce the acquisition time without compromising the reconstruction quality. This thesis concerns under-sampled reconstruction techniques for acceleration of MRI acquisitions, i.e., parallel imaging and compressed sensing. While compressed sensing MRI reconstructions are commonly regularized by penalizing the decimated wavelet transform coefficients, it is shown in this thesis that the visual artifacts, associated with the lack of translation-invariance of the wavelet basis in the decimated form, can be avoided by penalizing the undecimated wavelet transform coefficients, i.e., the stationary wavelet transform (SWT). An iterative SWT thresholding algorithm for combined SWT-regularized compressed sensing and parallel imaging reconstruction is presented. Additionally, it is shown that in MRI applications involving multiple sequential acquisitions, e.g., quantitative T1/T2 mapping, the correlation between the successive acquisitions can be incorporated as an additional constraint for joint under-sampled reconstruction, resulting in improved reconstruction performance. While quantitative measures of quality, e.g., reconstruction error with respect to the fully-sampled reference, are commonly used for performance evaluation and comparison of under-sampled reconstructions, this thesis shows that such quantitative measures do not necessarily correlate with the subjective quality of reconstruction as perceived by radiologists and other expert end users. Therefore, unless accompanied by subjective evaluations, quantitative quality measurements/comparisons will be of limited clinical impact. The results of experiments aimed at subjective evaluation/comparison of different under-sampled reconstructions for specific clinical neuroimaging MRI applications are presented in this thesis. One motivation behind the current work was to reduce the acquisition time for relaxation mapping techniques DESPOT1 and DESPOT2. This work also includes a modification to the Driven Equilibrium Single Pulse Observation of T1 with high-speed incorporation of RF field inhomogeneities (DESPOT1-HIFI), resulting in more accurate estimation of T1 values at high strength (3T and higher) magnetic fields

Novel strategies for mouse cardiac MRI : better, faster, stronger

Mouse models of cardiac disease are an important tool to gain understanding of the pathophysiological processes related to the heart, as well as for the development of new treatment strategies. In this respect, Magnetic Resonance Imaging (MRI) has become the gold standard imaging modality, because it combines high spatial resolution imaging with a large variety of soft tissue contrast weightings that can be related to the presence of diseased tissue. In addition, (targeted) MRI contrast agents can be employed to visualize different processes on the molecular level, for example in relation to myocardial infarction and the subsequent cardiac remodeling process. The specificity to discriminate healthy from diseased tissue as well as the sensitivity for detection of MR contrast agents is strongly affected by the specific MRI protocol design. Moreover, the challenging physiology of the mouse heart, especially with respect to its small size and high heart rate, often limits the direct translation of imaging protocols already available from clinical studies. Finally, the growing knowledge on cardiac pathology continuously pushes the development of sophisticated mouse cardiac MRI protocols that allow more detailed measurements of a variety of physiologically relevant cardiac parameters. The overall goal of this thesis was therefore to design and investigate novel imaging strategies in the field of mouse cardiac MRI and their application in models of cardiac disease. Chapter 2 of this thesis contains an extensive overview of currently available protocols for mouse cardiac MRI and more specifically those related to contrast enhanced imaging of myocardial infarction. The remainder of the thesis contains the experimental chapters describing all details on our newly developed mouse cardiac MRI techniques. This chapter shortly summarizes the aims and results with respect to each of these techniques, categorized based on the parameter of interest for which each measurement was specifically designed. Diastolic function Measurement of murine diastolic function requires Cine imaging with an extremely high frame rate ¿ more than 60 frames within a cardiac cycle of 100-120 ms ¿ to be able to discriminate between the two separate filling phases of the heart. In chapter 3, it was shown that using a retrospectively triggered MRI sequence, reconstruction of 80 Cine images was feasible, corresponding to a temporal resolution of around 1.5 ms. This was achieved without using any form of data interpolation. With retrospective triggering, the MRI measurements are not synchronized with the ECG, thereby in theory sampling an infinite number of time points during the cardiac cycle. Correct assignment of each k-line to a specific cardiac frame could be done retrospectively by measuring an additional navigator signal prior to image acquisition, whose signal amplitude varies with cardiac as well as respiratory movements. Because in this case, filling of k-space for each cardiac frame is a stochastic process, simulations were performed to investigate the efficiency of the method with respect to signal averaging, which was found to be almost equal compared to regular prospective triggering. Diabetic cardiomyopathy has a high prevalence in type 2 diabetes patients and is characterized by diastolic dysfunction. With the current technique, we were indeed able to measure a subtle reduction is several diastolic function parameters, which are the E/A-ratio and the E-contribution to total left ventricular filling. Therefore, this technique is a promising tool in experimental studies of diabetic cardiomyopathy and for evaluation of emerging treatment strategies for diastolic dysfunction. Myocardial perfusion Chapter 4 describes the application of first-pass perfusion measurements in a mouse model of myocardial infarction to allow the assessment of the myocardial perfusion status. A first-pass perfusion measurement is performed by venous injection of an MRI contrast agent and monitoring its passage through the left ventricle and myocardial wall. From the signal intensity changes upon passage of the contrast agent, myocardial perfusion values can be determined. The application of this technique in mice requires ultra-fast MRI sequences that can sample the signal intensity-time curves with sufficient temporal resolution. Because this concerns imaging of non-periodic signal changes this is a much different problem compared to the diastolic function experiments described in chapter 3. We showed that using a saturation recovery MRI sequence with segmented k-space read-out in combination with parallel imaging acceleration techniques, a time-series of images could be acquired with a temporal resolution of 1 image for each 3 heart beats. The use of parallel imaging was crucial, since this requires less k-lines for image reconstruction compared to conventional imaging. Furthermore, the use of saturation pulses enhanced the contrast between contrast-enhanced and non-enhanced blood and myocardium. Using this technique, semi-quantitative perfusion values could be determined based on the upslope of the signal intensity-time curves. Experiments in mice with permanent occlusion of the LAD showed a significant decrease of perfusion values in the infarcted myocardium as compared to remote myocardium. In future experiments, this technique will be extended to provide quantitative perfusion values (in mg/l/min), requiring determination of the true arterial input function from a pre-bolus measurement with a smaller contrast agent bolus volume. T1 and T2 relaxation times Pathology is often accompanied by a change in the magnetic properties of the tissue, in particular the T1 and T2 relaxation times. This directly affects the signal intensity on the MR image. Diseased and healthy tissue can therefore be discriminated on MR images, which is one of the main applications of MRI in clinical diagnostics. However, there is much interest in quantitative assesment of T1 and T2 relaxation times, as this improves repeatibility of results in longitudinal studies and reproducibility between research groups. In this thesis, we aimed at developing protocols for both T1 and T2 mapping of the complete mouse heart for application in mouse models of myocardial infarction. Whole-heart coverage is important considering that a priori, the extent of the infarct is unknown. Currently available protocols for T1 mapping are relatvively time-consuming. In chapter 5, a 3D T1 mapping sequence is presented which allows myocardial T1 quantification of the mouse heart within 20 minutes. The retrospective triggering sequence used in chapter 3 proved also useful in this study, because it allows steady-state acqusition with very short repetition times, enabling whole heart coverage. T1 values were derived from measuring a variable flip angle data set and using available MRI signal models. Variable flip angle data showed excellent agreement in cardiac anatomy, allowing pixel-wise determination of T1. In healthy mice, no substantial differences in T1 were found for different heart regions in the 3D volume. Coefficents of repeatibility were determined from measurements at different days, which varied as function of the number of flip angles used in data analysis. In contrast to T1, T2 values could not be acquired using 3D acquisitons or retrospective triggering. Alternatively, chapter 6 describes a multi-slice T2 mapping protocol for the mouse heart based on a ECG-triggered T2 magnetization preparation module with variable TE. Because the preparation module consisted of many consecutive RF pulses, the effect of these pulses on T2 relxation had to be taken into account. Additionally, simulations were used to calculate the effect of T1 relaxation on T2 estimation, which was small as long as the repetition time was kept sufficiently long. Homogeneous T2 maps of healthy mouse heart were obtained, with no substantial differences between different heart regions or slices. In a ischemia/reperfusion model, elevated T2 values were found in the infarcted area, probably as result of edema formation. The extent of the infarction was also measured using late gadolinium enhanced imaging. The degree of correlation of T2 and LGE enhanced regions strongly depended on the signal intensity thresholds derived from remote tissue. Contrast agent accumulation Another application of quantitative T1 and T2¬ mapping is the assessment of the concentration of a contrast agent, which has been targeted to a specific disease site. This is especially valuable in molecular imaging applications where contrast agents report on the presence of specific disease markers related to various cardiac remodeling processes after myocardial infarction. Chapter 7 describes the application of the T1 mapping protocol from chapter 5 to quantify the accumulation of a Gd-based liposomal contrast agent in a model of myocardial infarction. Functional imaging and assessment of wall thickening values were used to determine which regions could be identified as being infarcted. Statistical analysis showed that before contrast agent administration, T¬1¬ values were already elevated in the infarcted regions as compared to remote myocardium, however, a more pronounced change in T1 values was found 24h post-contrast, with significantly lower T1 values in the infarcted areas. Pre-contrast T1 values in control mice were very similar to the study described in chapter 5, proving good reproducibility of T1 quantification using our methods. After the MRI measurement, the hearts were cut into slices, from which the Gd-content was determined in different sections of the heart using inductively coupled plasma mass spectrometry. T1 changes measured using in vivo MRI correlated well with ex vivo measurements of Gd concentration. These are promising results for quantification of contrast agent concentrations in contrast-enhanced MRI of mouse models of cardiac disease. More research has to be performed with regard to changes in contrast agent efficiency as a result of different cellular environments. Our results already indicate that the relaxivity values of liposomal contrast agents are significantly lower in vivo as compared to values obtained from measurements in phantom solutions. Conclusion This thesis has shown that mouse cardiac MRI is capable of assessing a large variety of parameters related to cardiac physiology in the in vivo mouse heart in a non-invasive way. This makes this technique an attractive platform for experimental studies on cardiac disease, as well as developing new treatment strategies

Model-based multi-parameter mapping

Quantitative MR imaging is increasingly favoured for its richer information content and standardised measures. However, computing quantitative parameter maps, such as those encoding longitudinal relaxation rate (R1), apparent transverse relaxation rate (R2*) or magnetisation-transfer saturation (MTsat), involves inverting a highly non-linear function. Many methods for deriving parameter maps assume perfect measurements and do not consider how noise is propagated through the estimation procedure, resulting in needlessly noisy maps. Instead, we propose a probabilistic generative (forward) model of the entire dataset, which is formulated and inverted to jointly recover (log) parameter maps with a well-defined probabilistic interpretation (e.g., maximum likelihood or maximum a posteriori). The second order optimisation we propose for model fitting achieves rapid and stable convergence thanks to a novel approximate Hessian. We demonstrate the utility of our flexible framework in the context of recovering more accurate maps from data acquired using the popular multi-parameter mapping protocol. We also show how to incorporate a joint total variation prior to further decrease the noise in the maps, noting that the probabilistic formulation allows the uncertainty on the recovered parameter maps to be estimated. Our implementation uses a PyTorch backend and benefits from GPU acceleration. It is available at https://github.com/balbasty/nitorch.Comment: 20 pages, 6 figures, accepted at Medical Image Analysi

Doctor of Philosophy

dissertationThis dissertation presents original research that improves the ability of magnetic resonance imaging (MRI) to measure temperature in aqueous tissue using the proton resonance frequency (PRF) shift and T1 measurements in fat tissue in order to monitor focused ultrasound (FUS) treatments. The inherent errors involved in measuring the longitudinal relaxation time T1 using the variable flip angle method with a two-dimensional (2D) acquisition are presented. The edges of the slice profile can contribute a significant amount of signal for large flip angles at steady state, which causes significant errors in the T1 estimate. Only a narrow range of flip angle combinations provided accurate T1 estimates. Respiration motion causes phase artifacts, which lead to errors when measuring temperature changes using the PRF method. A respiration correction method for 3D imaging temperature of the breast is presented. Free induction decay (FID) navigators were used to measure and correct phase offsets induced by respiration. The precision of PRF temperature measurements within the breast was improved by an average factor of 2.1 with final temperature precision of approximately 1 °C. Locating the position of the ultrasound focus in MR coordinates of an ultrasound transducer with multiple degrees of freedom can be difficult. A rapid method for predicting the position using 3 tracker coils with a special MRI pulse iv sequence is presented. The Euclidean transformation of the coil's current positions to their calibration positions was used to predict the current focus position. The focus position was predicted to within approximately 2.1 mm in less than 1 s. MRI typically has tradeoffs between imaging field of view and spatial and temporal resolution. A method for acquiring a large field of view with high spatial and temporal resolution is presented. This method used a multiecho pseudo-golden angle stack of stars imaging sequence to acquire the large field of view with high spatial resolution and k-space weighted image contrast (KWIC) to increase the temporal resolution. The pseudo-golden angle allowed for removal of artifacts introduced by the KWIC reconstruction algorithm. The multiple echoes allowed for high readout bandwidth to reduce blurring due to off resonance and chemical shift as well as provide separate water/fat images, estimates of the initial signal magnitude M(0), T2 * time constant, and combination of echo phases. The combined echo phases provided significant improvement to the PRF temperature precision, and ranged from ~0.3-1.0 °C within human breast. M(0) and T2 * values can possibly be used as a measure of temperature in fat

Use of High Resolution 3D Diffusion Tensor Imaging to Study Brain White Matter Development in Live Neonatal Rats

High resolution diffusion tensor imaging (DTI) can provide important information on brain development, yet it is challenging in live neonatal rats due to the small size of neonatal brain and motion-sensitive nature of DTI. Imaging in live neonatal rats has clear advantages over fixed brain scans, as longitudinal and functional studies would be feasible to understand neuro-developmental abnormalities. In this study, we developed imaging strategies that can be used to obtain high resolution 3D DTI images in live neonatal rats at postnatal day 5 (PND5) and PND14, using only 3 h of imaging acquisition time. An optimized 3D DTI pulse sequence and appropriate animal setup to minimize physiological motion artifacts are the keys to successful high resolution 3D DTI imaging. Thus, a 3D rapid acquisition relaxation enhancement DTI sequence with twin navigator echoes was implemented to accelerate imaging acquisition time and minimize motion artifacts. It has been suggested that neonatal mammals possess a unique ability to tolerate mild-to-moderate hypothermia and hypoxia without long term impact. Thus, we additionally utilized this ability to minimize motion artifacts in magnetic resonance images by carefully suppressing the respiratory rate to around 15/min for PND5 and 30/min for PND14 using mild-to-moderate hypothermia. These imaging strategies have been successfully implemented to study how the effect of cocaine exposure in dams might affect brain development in their rat pups. Image quality resulting from this in vivo DTI study was comparable to ex vivo scans. fractional anisotropy values were also similar between the live and fixed brain scans. The capability of acquiring high quality in vivo DTI imaging offers a valuable opportunity to study many neurological disorders in brain development in an authentic living environment

Microstructural imaging of the human brain with a 'super-scanner': 10 key advantages of ultra-strong gradients for diffusion MRI

The key component of a microstructural diffusion MRI 'super-scanner' is a dedicated high-strength gradient system that enables stronger diffusion weightings per unit time compared to conventional gradient designs. This can, in turn, drastically shorten the time needed for diffusion encoding, increase the signal-to-noise ratio, and facilitate measurements at shorter diffusion times. This review, written from the perspective of the UK National Facility for In Vivo MR Imaging of Human Tissue Microstructure, an initiative to establish a shared 300 mT/m-gradient facility amongst the microstructural imaging community, describes ten advantages of ultra-strong gradients for microstructural imaging. Specifically, we will discuss how the increase of the accessible measurement space compared to a lower-gradient systems (in terms of Δ, b-value, and TE) can accelerate developments in the areas of 1) axon diameter distribution mapping; 2) microstructural parameter estimation; 3) mapping micro-vs macroscopic anisotropy features with gradient waveforms beyond a single pair of pulsed-gradients; 4) multi-contrast experiments, e.g. diffusion-relaxometry; 5) tractography and high-resolution imaging in vivo and 6) post mortem; 7) diffusion-weighted spectroscopy of metabolites other than water; 8) tumour characterisation; 9) functional diffusion MRI; and 10) quality enhancement of images acquired on lower-gradient systems. We finally discuss practical barriers in the use of ultra-strong gradients, and provide an outlook on the next generation of 'super-scanners'

QUANTITATIVE MAPPING IN MAGNETIC RESONANCE IMAGING

Magnetic Resonance Imaging (MRI) produces superior soft tissue contrast that is mostly determined by the tissue relaxation times (T1 and T2) and spin density (PD). This dissertation introduces novel methods to quantify T1, T2 and PD, and explored their value for disease classification, and tracking delivery of cell therapies. First, a novel T2 measurement (Dual-τ) method that employs adiabatic pulses is proposed, that exploits the property that the spins undergo T2 decay during excitation by long adiabatic pulses. The new method is relatively immune to MR static and excitation field inhomogeneity, and has a higher efficiency than the conventional methods. The adiabatic excitation pulse can also serve as a preparation pulse that introduces T2 contrast into the MRI, and can be combined with T1 quantification methods to produce T1 and T2 simultaneously. The method is shown to be most accurate at short T2s. The T2 measurements were validated in phantoms and in vivo in human studies. Second, three methods of mapping T1, T2, and PD simultaneously with the least possible number of acquisitions are presented, also utilizing adiabatic pulses. The first, Dual-τ-Dual-FA method, encodes T1 by varying excitation flip-angle (FA). The second, Dual-τ-Dual-TR method, encodes T1 using the variations in the sequence repetition time (TR). The third method incorporates the FA self-correction to eliminate T1 errors caused by field inhomogeneities, and is called the Four-FA method. All three methods were validated in phantom studies, and the Dual-τ-Dual-FA and Four-FA methods were validated in human brain studies as well. The Four-FA method is demonstrated to have the best overall accuracy compared to the existing methods, such as DESPOT1/2, IR TrueFISP, etc. Combining the multi-parametric mapping methods with intravascular (IV) MRI potentially offers a means of reducing the scan time and increasing the local SNR. For the first time, multi-parametric high-resolution (<200μm) T1, T2, PD and fat images of human vessels are obtained. These maps were used to train a machine-learning based classifier to automatically distinguish early- and advanced-stage vessel disease from healthy and smooth muscle. This application enables differentiation of vessel wall disease types with high sensitivity and specificity compared with histology as the standard. The contrast of cells delivered as therapeutic agents in MRI can be enhanced using capsules impregnated with MRI-sensitive contrast agents. At the end of the dissertation, we explore quantitative cell tracking using 19F-labeled capsules that provide dual modality contrast for both computed tomography (CT) and MRI. The method was validated in rabbit diseased models using clinical imaging systems. Compared with CT, 19F MRI was able to accurately track cells non-invasively in vivo, without the use of ionizing radiation. Two weeks after the cell administration, no significant changes in the volume or concentration of the capsules were observed, and the cells preserved high viability according to histology

MRI of myocardial infarction using lipid-based contrast agents

Ischemic heart disease is the leading cause of death worldwide. Occlusion of a coronary artery results in cardiac ischemia downstream, which leads to irreversible myocardial cell death. If patients survive the ischemic event, infarct healing and global cardiac remodeling take place. A dynamic cascade of events is initiated, which is characterized by four distinct phases: cell death, inflammation, the formation of granulation tissue and finally fibrosis (chapter 1). The main goal of this thesis was to develop and in vivo apply paramagnetic lipid-based contrast agents for contrast-enhanced MRI of murine myocardial infarction. The visualization of specific processes in myocardial infarction could give insight in pathophysiological mechanisms, predict outcome and provide readout of therapy efficacy. Furthermore, the nanoparticulate contrast materials are very promising as theranostics agents. Previously, several (targeted) contrast agents for the visualization of cell death, inflammation, angiogenesis and fibrosis have been developed. However, these are still not routinely applied. Moreover, MRI measurement protocols and sequences specifically aimed at contrast-enhanced MRI of the mouse heart have been developed. The current status of contrast-enhanced MRI of murine myocardial infarction is extensively reviewed in chapters 2 and 3. In chapter 4 the distribution and accumulation kinetics of paramagnetic micelles and liposomes in a mouse model of cardiac ischemia reperfusion (IR) injury was studied. In vivo T1-weighted MRI and high-resolution ex vivo fluorescence microscopy revealed that both types of nanoparticles accumulated specifically in the infarcted myocardium in both acute (day 1) and chronic (week 1 and 2) IR injury. Micelles displayed faster accumulation kinetics compared to liposomes, which is most probably related to their smaller size. Furthermore, liposomes sometimes co-localized with vessels and inflammatory cells, whereas this was not observed for micelles. Due to the specific accumulation in infarcted myocardium, the presented lipid-based nanoparticles are a promising platform for drug delivery to infarcted myocardium. Although reperfusion therapy limits infarct size, it also promotes apoptosis, resulting in adverse secondary IR injury. Visualization of apoptotic cells could aid in the detection of IR injury and the indication of potentially salvageable tissue. For this purpose, the potential of annexin A5 (anxA5)-functionalized liposomes was explored (chapter 5). AnxA5 is a protein that specifically binds to phosphatidylserine expressed by apoptotic cells. AnxA5-liposmes were injected in mice with IR injury and T1-weighted and cine MRI were performed 24 h later. Both anxA5-liposomes and non-functionalized liposomes accumulated in the infarcted myocardium, leading to similar signal intensities in the remote and infarct regions and a comparable distribution of enhanced pixels. Careful comparison of cine MR measurements and T1-weighted MR images revealed that anxA5-liposomes accumulated to a higher degree in less severely infarcted myocardium, whereas non-functionalized liposomes preferentially accumulated in severely infarcted myocardium. Ex vivo high-resolution microscopy confirmed these in vivo results. Therefore, anxA5-liposomes might be useful for drug delivery to potentially salvageable myocardial tissue. Inflammatory cells are key regulators in myocardial infarct healing and in adverse left ventricular remodeling. Therefore, a non-invasive method for imaging of inflammatory cells could provide information on infarct status and outcome. To this end paramagnetic phosphatidylserine (PS)-containing liposomes were developed. Inflammatory cells recognize PS expressed by apoptotic cells and subsequently engulf the dying cells. The association of liposomes to murine macrophages was determined in vitro (chapter 6). Liposomes containing 6 mol% of PS showed a higher association with macrophages compared to control-liposomes without PS. Furthermore, this association was Ca2+- and Mg2+-dependent and PS-containing liposomes were predominantly internalized by macrophages, whereas control-liposomes only bound to the macrophage cell membrane. Due to the enhanced in vitro uptake by macrophages, PS-containing liposomes might be suitable for in vivo visualization of macrophage content. Therefore, these liposomes were applied in a mouse model of IR injury (chapter 7). When PS-liposomes circulated for 2.5 h, the signal change on T1-weighted MR images was lower compared to mice injected with liposomes without PS. This is explained by the shorter blood-circulation half-life of PS-containing liposomes. Nevertheless, high-resolution ex vivo fluorescence microscopy revealed some co-localization of PS-liposomes and macrophages, while this was not observed for liposomes without PS. After 24 h of circulation both types of liposomes accumulated in the infarcted myocardium resulting in similar signal changes. These findings were confirmed by in vivo T1 mapping as well. Due to the specific association of PS-containing liposomes and inflammatory cells 2.5 h after administration, these nanoparticles might be suitable for drug delivery to inflammatory cells in the infarcted myocardium. Finally, chapter 8 concludes with a general discussion on the preceding chapters and some future perspective in the field of contrast-enhanced MRI of myocardial infarction

MRI of mouse heart failure

Heart failure (HF) is the inability of the heart to pump blood at a rate that satisfies the peripheral needs and is a final consequence of many pathologies. Left ventricular (LV) pressure overload and myocardial infarction are amongst the most important causes of HF. Common and important hallmarks of HF are myocardial hypertrophy, fibrosis, vascular adaptation and metabolic remodeling. The role of cardiac magnetic resonance (CMR) as a diagnostic tool for HF is rapidly increasing. The prognostic value of important measures of LV function such as ejection fraction, however, is limited. To improve diagnostic relevance and risk stratification additional MR imaging and spectroscopy techniques are therefore highly desired. For that, preclinical research in mouse models plays an important role. This goal of this thesis was to apply multiple, novel MR imaging methods and phosphorous 31PMR spectroscopy for the evaluation of mouse HF, with a focus on myocardial hypertrophy, fibrosis, perfusion and LV energy status. These techniques are part of an ever extending toolbox for mouse CMR that allows the researcher to perform a multi-parametric assessment of myocardial tissue status. Preferably, a time-efficient protocol is constructed from all these tools, which is tailored for a particular HF phenotype and yields the relevant, decisive features of the stage of development towards HF. After successful proof-of-concept studies in mice, these techniques could be translated for clinical use. Ultimately, these techniques might then contribute to improved diagnostic accuracy and a better characterization of the tissue status, new (surrogate) end-points to evaluate the success of therapies and interventions, and perhaps may even provide better prognostic markers for the disease course. The transverse aortic constriction (TAC) mouse model was used throughout this thesis as it is an important model of pressure overload induced hypertrophy and HF. Since the TAC model was first described, it has been extensively used to study various facets of pressure overload induced LV adaptation. In Chapter 2 we characterized cardiac function and morphology in a mild and severe TAC model. Mice underwent repeated measurements to evaluate the progression of cardiac parameters over time. The mild TAC mice developed a stage of compensated LV hypertrophy and mildly impaired LV function. No progressive deterioration of myocardial function was observed over time and LV maladaptation did not result in pulmonary remodeling and RV failure. LV function and morphology in severe TAC mice, on the other hand, progressively deteriorated over time resulting in overt decompensated hypertrophy, which was also indicated by profound pulmonary remodeling and impaired RV function. A repeatable method for quantitative, first-pass perfusion MRI of the mouse heart based on a dual-bolus approach was described in Chapter3. A non-saturated arterial input function was acquired from a low-dose containing Gd(DTPA)2- prebolus. The myocardial tissue response was measured from a separate high-dose full-bolus infusion. Perfusion (ml min-1 g-1) was quantified using a Fermi constrained deconvolution of the myocardial tissue response with the arterial input function. This calculation critically depends on linearity of the measured MR signal intensity with Gd(DTPA)2- concentration in the LV lumen during the prebolus and in the myocardial wall during the full-bolus. In separate experiments these assumptions were proven to be valid for our experimental conditions. Interestingly, this assumption was to the best of our knowledge never demonstrated in vivo, although Weber et al. confirmed the appropriateness of this assumption for quantitative first-pass perfusion measurements in the human heart using phantom experiments. The first-pass perfusion method was used in Chapter 4 to study myocardial perfusion in TAC mice, which was considerably decreased as compared to perfusion in control mice. Importantly, the relationship between perfusion and LV morphology and function was studied. Clear correlations were obtained between a decreased perfusion in TAC mice and the indices of LV function and morphology, e.g., LV ejection fraction, volumes as well as LV mass. Although group-averaged perfusion values in TAC mice did not change between measurements in the longitudinal study, these results revealed that with an ensuing hypertrophic growth and concomitantly declining LV function (Chapter 2) perfusion gradually diminishes. Current MRI techniques for the quantification of diffuse myocardial fibrosis suffer from severe limitations. In Chapter 5 ultra short echo time (UTE) MRI was used to study replacement and diffuse fibrosis in the ex vivo and in vivo mouse heart. Here, the MI mouse model was also used as it results in the formation of a spatially confined, collagenous scar providing an ideal model for proof-of-principle purposes. Subtraction of short- and long-TE images resulted in images highlighting tissue with short T2*, such as collagen. Indeed, a good correlation was obtained between the relative infarct volume as determined from histology and ex vivo UTE MRI. UTE MRI also resulted in signal differences between control and TAC hearts, which were related to the amount of collagen present in the hearts. Cardiovascular UTE MRI may thus provide a means for the assessment of diffuse fibrosis based on endogenous tissue contrast. Impaired myocardial energetics are thought to play an important role in HF. Chapter 6 describes 3D Image Selected In vivo Spectroscopy (ISIS) for single-voxel localized 31P-MRS of the in vivo mouse heart. From the resulting spectra the phosphocreatine-to-ATP (PCr/¿-ATP) ratio was quantified as a measure for myocardial energy status. When mice showed a markedly impaired LV systolic function and myocardial hypertrophy 7 weeks after TAC, PCr/ATP was approximately 25% lower 7 weeks as compared to control mice. Multiple studies have pointed to the possible predictive value of PCr/ATP, an important measure for myocardial energy status, for subsequent maladaptive ventricular remodeling. It is unclear though if PCr/ATP measured during the first stage of the remodeling process also predicts consecutive maladaptation. In Chapter 7 the hypothesis was therefore tested that PCr/ATP measured at the day of TAC or four days thereafter predicts subsequent remodeling. Such a relation could, however, not be established. Clear relations were obtained, on the other hand, between LV function and morphology four days after TAC and seven weeks, pointing to the importance of the severity of the initial pressure overload for maladaptive cardiac remodeling. In addition, these experiments showed an apparent decrease of PCr/ATP already at the day of TAC, whereas PCr/ATP four days after TAC was significantly decreased, pointing to the first signs of an impaired myocardial energy status

Quantitative methods in high field MRI

The increased signal-to-noise ratio available at high magnetic field makes possible the acquisition of clinically useful MR images either at higher resolution or for quantitative methods. The work in this thesis is focused on the development of quantitative imaging methods used to overcome difficulties due to high field MRI systems (> 3T). The protocols developed and presented here have been tested on various studies aiming at discriminating tissues based on their NMR properties. The quantities of interest in this thesis are the longitudinal relaxation time T1, as well as the magnetization transfer process, particularly the chemical exchange phenomenon involving amide protons which is highlighted particularly well at 7T under specific conditions. Both quantities (T1 and amide proton transfer) are related to the underlying structure of the tissues in-vivo, especially inside the white matter of the brain. While a standard weighted image at high resolution can provide indices of the extent of the pathology, a robust measure of the NMR properties of brain tissues can detect earlier abnormalities. A method based on a 3D Turbo FLASH readout and measuring reliably the T1 in-vivo for clinical studies at 7T is first presented. The other major part of this thesis presents magnetization transfer and chemical exchange phenomena. First a quantitative method is investigated at 7T, leading to a new model for exchange as well as contrast optimization possibility for imaging. Results using those methods are presented and applied in clinical setting, the main focus being to image reliably the brain of both healthy subjects and Multiple Sclerosis patients to look at myelin structures