Level-Set Based Artery-Vein Separation in Blood Pool Agent CE-MR Angiograms

Blood pool agents (BPAs) for contrast-enhanced (CE) magnetic-resonance angiography (MRA) allow prolonged imaging times for higher contrast and resolution. Imaging is performed during the steady state when the contrast agent is distributed through the complete vascular system. However, simultaneous venous and arterial enhancement in this steady state hampers interpretation. In order to improve visualization of the arteries and veins from steady-state BPA data, a semiautomated method for artery-vein separation is presented. In this method, the central arterial axis and central venous axis are used as initializations for two surfaces that simultaneously evolve in order to capture the arterial and venous parts of the vasculature using the level-set framework. Since arteries and veins can be in close proximity of each other, leakage from the evolving arterial (venous) surface into the venous (arterial) part of the vasculature is inevitable. In these situations, voxels are labeled arterial or venous based on the arrival time of the respective surface. The evolution is steered by external forces related to feature images derived from the image data and by internal forces related to the geometry of the level sets. In this paper, the robustness and accuracy of three external forces (based on image intensity, image gradient, and vessel-enhancement filtering) and combinations of them are investigated and tested on seven patient datasets. To this end, results with the level-set-based segmentation are compared to the reference-standard manually obtained segmentations. Best results are achieved by applying a combination of intensity- and gradient-based forces and a smoothness constraint based on the curvature of the surface. By applying this combination to the seven datasets, it is shown that, with minimal user interaction, artery-vein separation for improved arterial and venous visualization in BPA CE-MRA can be achieved

Contrast-enhanced magnetic resonance angiography.

Contrast-enhanced magnetic resonance angiography (CE-MRA) is a diagnostic method for imaging of vascular structures based on nuclear magnetic resonance. Vascular enhancement is achieved by injection of a contrast medium (CM). Studies were performed using two different types of CM: conventional paramagnetic CM, and a new type of CM based on hyperpolarized (HP) nuclei. The effects of varying CM concentration with time during image acquisition were studied by means of computer simulations using two different models. It was shown that a rapid concentration variation during encoding of the central parts of k-space could result in signal loss and severe image artifacts. The results were confirmed qualitatively with phantom experiments. A postprocessing method was developed to address problems with simultaneous enhancement of arteries and veins in CE-MRA of the lower extremities. The method was based on the difference in flow-induced phase in the two vessel types. Evaluation of the method was performed with flow phantom measurements and with CE-MRA in two volunteers using standard pulse sequences. The flow-induced phase in the vessels of interest was sufficient to distinguish arteries from veins in the superior-inferior direction. Using this method, the venous enhancement could be extinguished. The possibility of using HP nuclei as CM for CE-MRA was evaluated. Signal expressions for a flow of HP CM imaged with a gradient echo sequence were derived. These signal expressions were confirmed in phantom experiments using HP 129Xe dissolved in ethanol. Studies were also performed with a new CM based on HP 13C. The CM had very long relaxation times (T1,in vivo/T2,in vivo≈ 38/1.3 s). The long relaxation times were utilized in imaging with a fully balanced steady-state free precession pulse sequence (trueFISP), where the optimal flip angle was found to be 180°. CE-MRA with the 13C-based CM in rats resulted in images with high vascular SNR (~500). CE-MRA is a useful clinical tool for diagnosing vascular disease. With the development of new contrast media, based on hyperpolarized nuclei for example, there is a potential for further improvement in the signal levels that can be achieved, enabling a standard of imaging of vessels that is not possible today

Acceleration of Subtractive Non-contrast-enhanced Magnetic Resonance Angiography

Although contrast-enhanced magnetic resonance angiography (CE-MRA) is widely established as a clinical examination for the diagnosis of human vascular diseases, non-contrast-enhanced MRA (NCE-MRA) techniques have drawn increasing attention in recent years. NCE-MRA is based on the intrinsic physical properties of blood and does not require the injection of any exogenous contrast agents. Subtractive NCE-MRA is a class of techniques that acquires two image sets with different vascular signal intensity, which are later subtracted to generate angiograms. The long acquisition time is an important drawback of NCE-MRA techniques, which not only limits the clinical acceptance of these techniques but also renders them sensitive to artefacts from patient motion. Another problem for subtractive NCE-MRA is the unwanted residual background signal caused by different static background signal levels on the two raw image sets. This thesis aims at improving subtractive NCE-MRA techniques by addressing both these limitations, with a particular focus on three-dimensional (3D) femoral artery fresh blood imaging (FBI). The structure of the thesis is as follows: Chapter 1 describes the anatomy and physiology of the vascular system, including the characteristics of arteries and veins, and the MR properties and flow characteristics of blood. These characteristics are the foundation of NCE-MRA technique development. Chapter 2 introduces commonly used diagnostic angiographic methods, particularly CE-MRA and NCE-MRA. Current NCE-MRA techniques are reviewed and categorised into different types. Their principles, implementations and limitations are summarised. Chapter 3 describes imaging acceleration theories including compressed sensing (CS), parallel imaging (PI) and partial Fourier (PF). The Split Bregman algorithm is described as an efficient CS reconstruction method. The SPIRiT reconstruction for PI and homodyne detection for PF are also introduced and combined with Split Bregman to form the basis of the reconstruction strategy for undersampled MR datasets. Four image quality metrics are presented for evaluating the quality of reconstructed images. In Chapter 4, an intensity correction method is proposed to improve background suppression for subtractive NCE-MRA techniques. Residual signals of background tissues are removed by performing a weighted subtraction, in which the weighting factor is obtained by a robust regression method. Image sparsity can also be increased and thereby potentially benefit CS reconstruction in the following chapters. Chapter 5 investigates the optimal k-space sampling patterns for the 3D accelerated femoral artery FBI sequence. A variable density Poisson-disk with a fully sampled centre region and missing partial Fourier fractions is employed for k-space undersampling in the ky-kz plane. Several key parameters in sampling pattern design, such as partial Fourier sampling ratios, fully sampled centre region size and density decay factor, are evaluated and optimised. Chapter 6 introduces several reconstruction strategies for accelerated subtractive NCE-MRA. A new reconstruction method, k-space subtraction with phase and intensity correction (KSPIC), is developed. By performing subtraction in k-space, KSPIC can exploit the sparsity of subtracted angiogram data and potentially improve the reconstruction performance. A phase correction procedure is used to restore the polarity of negative signals caused by subtraction. The intensity correction method proposed in Chapter 4 is also incorporated in KSPIC as it improves background suppression and thereby sparsity. The highly accelerated technique can be used not only to reduce the acquisition time, but also to enable imaging with increased resolution with no time penalty. A time-efficient high-resolution FBI technique is proposed in Chapter 7. By employing KSPIC and modifying the flow-compensation/spoiled gradients, the image matrix size can be increased from 256×256 to up to 512×512 without prolonging the acquisition time. Chapter 8 summarises the overall achievements and limitations of this thesis, as well as outlines potential future research directions.Cambridge Trust China Scholarship Council Addenbrooke’s Charitable Trust National Institute of Health Research, Cambridge Biomedical Research Cente

New MRI Techniques for Nanoparticle Based Functional and Molecular Imaging

Although in clinical use for several decades, magnetic resonance imaging: MRI) is undergoing a transition from a qualitative anatomical imaging tool to a quantitative technique for evaluating myriad diseases. Furthermore, MRI has made great strides as a potential tool for molecular imaging of cellular and tissue biomarkers. Of the candidate contrast agents for molecular MRI, the excellent bio-compatibility and adaptability of perfluorocarbon nanoparticles: PFC NP) has established these agents as a potent targeted imaging agent and as a functional platform for non-invasive oxygen tension sensing. Direct readout and quantification of PFC NP can be achieved with fluorine: 19F) MRI because of the unique 19F signal emanating from the core PFC molecules. However, the signal is usually limited by the modest accumulated concentrations as well as several special NMR considerations for PFC NP, which renders 19F MRI technically challenging in terms of detection sensitivity, scan time, and image reconstruction. In the present dissertation, some of the pertinent NMR properties of PFC NP are investigated and new 19F MRI techniques developed to enhance their performance and expand the biomedical applications of 19F MRI with PFC NP. With the use of both theoretical and experimental methods, we evaluated J-coupling modulation, chemical shift and paramagnetic relaxation enhancement of PFC molecules in PFC NP. Our unique contribution to the technical improvement of 19F MRI of small animal involves:: 1) development of general strategies for RF 1H/19F coil design;: 2) design of novel MR pulse sequences for 19F T1 quantification; and: 3) optimization of imaging protocols for distinguishing and visualizing multiple PFC components: multi-chromatic 19F MRI). The first pre-clinical application of our novel 19F MRI techniques is blood vessel imaging and rapid blood oxygen tension measurement in vivo. Blood vessel anatomy and blood oxygen tension provide pivotal physiological information for routine diagnosis of cardiovascular disease. Using our novel Blood: flow)-Enhanced-Saturation-Recovery: BESR) sequence, we successfully visualized reduced flow caused by thrombosis in carotid arteries and jugular veins, and we quantified the oxygen tension in the cardiac ventricles of the mouse. The BESR sequence depicted the expected oxygenation difference between arterial and venous blood and accurately registered the response of blood oxygen tension to high oxygen concentration in 100% oxygen gas. This study demonstrated the potential application of PFC NP as a blood oxygen tension sensor and blood pool MR contrast agent for angiography. Another pre-clinical application investigated was functional kidney imaging with 19F MRI of circulating PFC NP. Conventional functional kidney imaging typically calls for the injection of small molecule contrast agents that may be nephrotoxic, which raises concerns for their clinical applications in patients with renal insufficiency. We demonstrated that our 19F MRI technique offers a promising alternative functional renal imaging approach that generates quantitative measurement of renal blood volume and intrarenal oxygenation. We successfully mapped the expected heterogeneous distribution of renal blood volume and confirmed the presence of an oxygenation gradient in healthy kidneys. We validated the diagnostic capability of 19F MRI in a mouse model of acute ischemia/reperfusion kidney injury. We also employed 19F MRI as a tool to test the therapeutic efficacy of a new nanoparticle-based drug, i. e. PPACK: D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone) PFC NP, which was postulated to inhibit microvascular coagulation during acute kidney injury. Based on our preliminary 19F MRI findings, we observed that PPACK PFC NP effectively reduced coagulation in our animal model, as evidenced by lesser accumulation of particles trapped by the clotting process. This finding suggests the potential for 19F MRI to be used as a drug monitoring tool as well in common medical emergencies such as acute kidney failure

Non-contrast Magnetic Resonance Angiography for Evaluation of Peripheral Arterial Disease

Peripheral arterial disease (PAD) is a major cause of morbidity and mortality in the USA with an estimated prevalence of up to 20% in those over 75 years. Vascular disease and kidney impairment frequently coexist; prevalence of moderate to severe renal dysfunction in PAD patients is estimated at 27-36%. Knowledge of location, severity, and extent of PAD is imperative for accurate diagnosis and treatment planning. However, all established imaging modalities that are routinely used for treatment planning are contra-indicated in kidney disease patients. Contrast-enhanced x-ray and CT angiography are unsafe due to exposure to nephrotoxic contrast material and ionizing radiation. Recently, the FDA has also warned against the use of gadolinium-enhanced MRA (Gd-MRA) due to evidence that gadolinium could trigger a life-threatening condition known as nephrogenic systemic fibrosis (NSF) in patients with moderate to severe kidney dysfunction. There is a clinical need to develop vascular imaging techniques that are safe in patients with coexisting PAD and renal insufficiency. The focus of this thesis was the development of a non-contrast alternative to Gd-MRA for imaging of peripheral vessels from renal to pedal arteries with MRI. A new imaging sequence for non-contrast visualization of the abdominal and pelvic arteries was designed, implemented, and validated in a small cohort of PAD patients against Gd-MRA. In addition, an existing fast spin-echo based technique for unenhanced imaging of the lower extremities was optimized for improved performance in a clinical setting

Vessel Axis Tracking Using Topology Constrained Surface Evolution

An approach to three-dimensional vessel axis tracking based on surface evolution is presented. The main idea is to guide the evolution of the surface by analyzing its skeleton topology during evolution, and imposing shape constraints on the topology. For example, the intermediate topology can be processed such that it represents a single vessel segment, a bifurcation, or a more complex vascular topology. The evolving surface is then re-initialized with the newly found topology. Re-initialization is a crucial step since it creates probing behavior of the evolving front, encourages the segmentation process to extract the vascular structure of interest and reduces the risk on leaking of the curve into the background. The method was evaluated in two computed tomography angiography applications: (i) extracting the internal carotid arteries including the region in which they traverse through the skull base, which is challenging due to the proximity of bone structures and overlap in intensity values, and (ii) extracting the carotid bifurcations including many cases in which they are severely stenosed and contain calcifications. The vessel axis was found in 90% (18/20 internal carotids in ten patients) and 70% (14/20 carotid bifurcations in a different set of ten patients) of the cases

Cardiovascular Magnetic Resonance Myocardial Perfusion Mapping for the Assessment of Coronary Artery Disease

Pixelwise myocardial perfusion mapping is a novel cardiovascular magnetic resonance (CMR) technique enables quantitative measurement of myocardial blood flow (MBF) at a pixel level. This could improve the accuracy of detection of obstructive coronary artery disease (CAD) and may also have a role in the diagnosis and assessment of coronary microvascular dysfunction (CMD). In this thesis, I explore the use of this novel technique in cohorts of clinical patients and controls with suspected CAD or CMD. Firstly, I demonstrate that stress MBF measured using perfusion mapping is accurate for the detection of CAD using invasive fractional flow reserve (FFR) as the reference standard, and that global stress MBF can be used as a marker of CMD using invasive index of microcirculatory resistance (IMR) as the reference standard. One limitation of adenosine stress testing is the confirmation of adequate hyperaemia with lack of gold standard non-invasive marker. Here, I demonstrate that regional stress MBF can be utilised as a non-invasive marker of adequate stress response. Another limitation of stress MBF is the relatively poor performance for the detection of multivessel disease. In a cohort of patients with confirmed two- and three-vessel disease I demonstrate that perfusion mapping is superior to visual analysis for the correct identification of disease severity. Perfusion mapping provides a host of options for quantitative image analysis. I show that the most reliable method for detection of coronary disease at a patient level is the presence of reduced MBF in two adjacent myocardial segments. In summary, in this thesis I performed a series of studies investigating the clinical utilisation of CMR perfusion mapping that can be translated to clinical practice to enhance the performance of stress perfusion CMR