Combined Visualization of Nigrosome-1 and Neuromelanin in the Substantia Nigra Using 3T MRI for the Differential Diagnosis of Essential Tremor and de novo Parkinson's Disease

Differentiating early-stage Parkinson's disease (PD) from essential tremor (ET) remains challenging. In the current study, we aimed to evaluate whether visual analyses of neuromelanin-sensitive magnetic resonance imaging (NM-MRI) combined with nigrosome-1 (N1) imaging using quantitative susceptibility mapping (QSM) in the substantia nigra (SN) are of diagnostic value in the differentiation of de novo PD from untreated ET. Sixty-eight patients with de novo PD, 25 patients with untreated ET, and 34 control participants underwent NM-MRI and QSM. NM and N1 signals in the SN on MR images were visually evaluated using a 3-point ordinal scale. Receiver operating characteristic (ROC) analyses were performed to determine the diagnostic values of the visual ratings of NM and N1. The diagnostic values of the predicted probabilities were calculated via logistic regression analysis using the combination of NM and N1 visual ratings, as well as their quadratic items. The proportions of invisible NM and invisible N1 were significantly higher in the PD group than those in the ET and control groups (p < 0.001). The sensitivity/specificity for differentiating PD from ET was 0.882/0.800 for NM and 0.794/0.920 for N1, respectively. Combining the two biomarkers, the area under the curve (AUC) of the predicted probabilities was 0.935, and the sensitivity/specificity was 0.853/0.920 when the cutoff value was set to 0.704. Our findings demonstrate that visual analyses combing NM and N1 imaging in the SN may aid in differential diagnosis of PD and ET. Furthermore, our results suggest that patients with PD exhibit larger iron deposits in the SN than those with ET

Fast quantitative susceptibility mapping with L1-regularization and automatic parameter selection

Purpose To enable fast reconstruction of quantitative susceptibility maps with total variation penalty and automatic regularization parameter selection. Methods ℓ[subscript 1]-Regularized susceptibility mapping is accelerated by variable splitting, which allows closed-form evaluation of each iteration of the algorithm by soft thresholding and fast Fourier transforms. This fast algorithm also renders automatic regularization parameter estimation practical. A weighting mask derived from the magnitude signal can be incorporated to allow edge-aware regularization. Results Compared with the nonlinear conjugate gradient (CG) solver, the proposed method is 20 times faster. A complete pipeline including Laplacian phase unwrapping, background phase removal with SHARP filtering, and ℓ[subscript 1]-regularized dipole inversion at 0.6 mm isotropic resolution is completed in 1.2 min using MATLAB on a standard workstation compared with 22 min using the CG solver. This fast reconstruction allows estimation of regularization parameters with the L-curve method in 13 min, which would have taken 4 h with the CG algorithm. The proposed method also permits magnitude-weighted regularization, which prevents smoothing across edges identified on the magnitude signal. This more complicated optimization problem is solved 5 times faster than the nonlinear CG approach. Utility of the proposed method is also demonstrated in functional blood oxygen level–dependent susceptibility mapping, where processing of the massive time series dataset would otherwise be prohibitive with the CG solver. Conclusion Online reconstruction of regularized susceptibility maps may become feasible with the proposed dipole inversion

Quantitative Susceptibility Mapping in Cognitive Decline: A Review of Technical Aspects and Applications

In the human brain, essential iron molecules for proper neurological functioning exist in transferrin (tf) and ferritin (Fe3) forms. However, its unusual increment manifests iron overload, which reacts with hydrogen peroxide. This reaction will generate hydroxyl radicals, and irons higher oxidation states. Further, this reaction causes tissue damage or cognitive decline in the brain and also leads to neurodegenerative diseases. The susceptibility difference due to iron overload within the volume of interest (VOI) responsible for field perturbation of MRI and can benefit in estimating the neural disorder. The quantitative susceptibility mapping (QSM) technique can estimate susceptibility alteration and assist in quantifying the local tissue susceptibility differences. It has attracted many researchers and clinicians to diagnose and detect neural disorders such as Parkinsons, Alzheimers, Multiple Sclerosis, and aging. The paper presents a systematic review illustrating QSM fundamentals and its processing steps, including phase unwrapping, background field removal, and susceptibility inversion. Using QSM, the present work delivers novel predictive biomarkers for various neural disorders. It can strengthen new researchers fundamental knowledge and provides insight into its applicability for cognitive decline disclosure. The paper discusses the future scope of QSM processing stages and their applications in identifying new biomarkers for neural disorders

Otimização de sequências e ferramentas de processamento para quantificação do ferro (QSM)

As doenças neurodegenerativas, como o caso das doenças de Parkinson, Huntington e Tremor Essencial não possuem, atualmente, terapias de cura, mas sim tratamentos que prolongam a vida e melhoram a qualidade de vida dos pacientes. Todavia, têm vindo a ser feitos esforços por parte de investigadores para descobrir os mecanismos da génese destas patologias de modo a tornar possível o seu diagnóstico precoce e com isso estudar estratégias de implementação de novas soluções. Assim, esta dissertação surge no seguimento de uma serie de trabalhos que se focaram particularmente na caracterização destas doenças. Especificamente, este estudo utilizou dados de pacientes do Hospital Santa Maria (Lisboa) submetidos a protocolos de sequências de aquisição de imagens multi-eco de ressonância magnética de 3T em 2D e 3D ponderadas em T2 e T2* para diagnóstico da doença de Parkinson tendo-se concentrado na otimização destes, na otimização de ferramentas e mecanismos para o seu pós-processamento. Focou-se também na quantificação do ferro como um biomarcador relevante nas regiões normalmente afetadas, como é o caso dos núcleos da base (globo pálido, putamen, núcleo caudado, substantia nigra e núcleo rubro). Nestes núcleos ocorre acumulação anómala de ferro ligada à progressão da neurodegeneração, segundo estudos recentes. Nesta tese foi utilizada uma técnica conhecida como mapeamento quantitativo de suscetibilidade magnética (QSM – Quantitative Susceptibility Mapping), que avalia a diferença de suscetibilidades magnéticas entre tecidos, que por sua vez indicam o balanço entre paramagnetismo e diamagnetismo das espécies moleculares presentes. Utilizando software designado para este fim, criado por investigadores de Cornell MRI Research Lab, que se baseia no algoritmo MEDI (Morphology Enabled Dipole Inversion) geraram-se, depois de algumas adaptações ao código original, os mapas das suscetibilidades, cujos volumes de interesse foram em seguida segmentados de forma automática e manual, de modo a se estimarem os valores de suscetibilidade (médias e desvios padrão) das estruturas segmentadas. Compararam-se os resultados obtidos das suscetibilidades entre os vários ecos, as várias estruturas, entre as aquisições 2D e 3D e entre pacientes considerados como controlo e aqueles com sinais de neurodegeneração, tendo sido demonstrada a viabilidade dos parâmetros de aquisição, métodos de processamento e ferramentas de mapeamento e segmentação utilizadas e comprovada a acumulação de ferro nos volumes de interesse, proporcional aos valores de suscetibilidade obtidos

Identification of Intracranial Lesions with Dual-Energy Computed Tomography and Magnetic Resonance Phase Imaging

On conventional Single-energy Computed Tomography (SECT), lesions with an attenuation greater than 100 Hounsfield Units (HU) can be definitively diagnosed as calcification. However, low-density calcifications and hemorrhage may have overlapping attenuation ranges between 40 and 100 HU and, therefore, cannot be differentiated with SECT alone. On T2*-weighted Gradient Recalled Echo (GRE) MRI, these lesions appear as “foci of susceptibility” in which their signal is hypointense due to the magnetic susceptibility of the lesions differing from that of the background tissue. Dual-energy Computed Tomography (DECT) and Phase-Sensitive Magnetic Resonance Imaging (PS-MRI) represent two new imaging paradigms which both have the potential to more accurately identify intracranial calcification and hemorrhage. In DECT, x-ray tomography is acquired at two tube voltages; because x-ray attenuation is energy- and material-dependent, the data can be used to differentiate between materials that may have the same signal level on SECT. PS-MRI utilizes the phase data from T2*-weighted MRI acquisitions to determine how the local magnetic field varies across the image. By applying post-processing algorithms such as Quantitative Susceptibility Mapping (QSM), the phase can be used to calculate the magnetic susceptibility of a lesion. Since calcifications are diamagnetic and hemorrhage paramagnetic, we can make inferences about a lesion’s composition from these algorithms. The objective of this dissertation work was to characterize brain lesions, discovered with traditional imaging methods, as either hemorrhagic or calcific by using Dual-Energy Computed Tomography (DECT) and Phase-Sensitive Magnetic Resonance Imaging (PS-MRI). To this end, MRI-compatible phantoms featuring models of both calcific and hemorrhagic lesions were developed and validated. This resulted in two phantoms with biologically similar lesion models that were then used to test the feasibility of differentiating calcific and hemorrhagic lesions with PS-MRI post-processing methods, in which QSM was able to accurately differentiate calcific and hemorrhagic lesion models. Finally, we undertook a patient trial testing the feasibility of identifying calcification and chronic hemorrhage in humans using both DECT and QSM in which the two modalities had accuracies of 99.7% (327/328) and 99.4% (326/328), respectively. The two modalities were concordant for 99.3% (148/149) lesions with SECT attenuation under 100 HU

Magnetic Resonance Imaging of Susceptibility Effects in Carotid Atherosclerosis

This thesis explores the use of susceptibility-weighted imaging (SWI) and quantitative susceptibility mapping (QSM), to characterize carotid artery plaques with and without the use of ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle contrast agents. The overall hypothesis is that QSM can serve to differentiate carotid artery plaque features of different susceptibility and provide a positive contrast mechanism for imaging the uptake of USPIOs. Chapter 1 describes the pathophysiology of carotid atherosclerosis. Vulnerable plaques, i.e. those at risk of rupture, can be characterized by the presence of a lipid rich necrotic core (LRNC), intraplaque haemorrhage (IPH), and inflammation. In addition, plaques may develop calcifications that may be protective of rupture. The chapter describes the established multi-contrast imaging protocols used for characterizing plaques. Furthermore, the use of USPIO-contrast agents to image inflammation is described. Chapter 2 describes the physical principles of MR image generation including the sensitivity to magnetic susceptibility. The principles of T2*w imaging, and susceptibility weighted imaging (SWI) are explained. Chapter 3 reviews the principles and post-processing steps involved in commonly used algorithms for QSM in terms of the underlying physical and mathematical principles which are then demonstrated in the form of numerical simulations. Chapter 4 presents the application of SWI to a group of patients who underwent USPIO enhanced MRI on a 1.5T MRI system. Images were acquired prior to infusion and 48 hours post infusion. SWI and gradient echo phase images were used to depict the field inhomogeneities generated by diamagnetic and paramagnetic materials within the plaques, calcification and USPIO-uptake. These results were then compared to a conventional carotid multi-contrast protocol, which includes R2*-mapping and T2*w imaging, and, where available, CT and histology. In chapter 5 QSM is performed in the carotid artery wall of a cohort of normal volunteers on a 1.5T MRI system. Unlike the brain, the neck contains fat which can cause severe errors in the field estimate, which propagate into the susceptibility map. Therefore, QSM was combined with water-fat separation for application in the neck to correct for these artifacts. This correctly estimated a high fat-fraction in fatty tissue in the neck and allowed for a detailed depiction of the anatomy of healthy volunteers. The susceptibility value measured in fatty tissue agreed with literature values. Chapter 6 applies QSM with water-fat separation to a subset of the patient group on a 1.5T MRI system. On pre-contrast scans QSM successfully identified calcification as diamagnetic tissue and the water-fat separation identified a lipid core. On the post-contrast susceptibility maps, USPIO-uptake was identified as hyperintense signal. This allows QSM to provide quantitative contrast in carotid imaging that can identify multiple features simultaneously and to simplify the imaging of USPIO-contrast. The results were confirmed using the multi-contrast carotid MRI protocol and, where available, histology and CT. Chapter 7 discusses the limitations of the current studies and the potential future improvements of the current methodology in terms of MR acquisition, post-processing algorithms and MR protocols. Future studies could serve to further evaluate the potential of QSM in carotid imaging and use it as a novel tool to quantify USPIO uptake in atherosclerotic carotid arteries

The implementation and application of quantitative susceptibility mapping in the pre-clinical liver

Quantitative Susceptibility Mapping (QSM) is a relatively new Magnetic Resonance Imaging (MRI) technique that gives information about the relative quantities of magnetically active constituents of a biological system. Using phase data, not normally utilised in standard MRI, measurements are made of local variations in the main magnetic field, B0. This data is then processed to calculate a map of local magnetic susceptibility within an organ of interest. This map yields relatively quantitative information, and compositional inferences can be made regarding the organ. Thus far, the body of literature on QSM has focussed almost exclusively on the brain, and has been performed on clinical data. This will be a preclinical project, and will focus primarily on the liver. The first two chapters of this thesis will establish the context of the research, as well as the background theory of QSM, including a detailed discussion of the set of algorithms selected to calculate the susceptibility maps for this body of work. The implementation of QSM in the preclinical liver has not been performed previously, and the novelty of the technique and the experimental work performed necessitated optimising both data acquisition and processing protocols. This was done on an empirical basis, and comprises the experimental work detailed in chapter 3. Chapters 4 – 6 describe the application of QSM to a number of hepatic conditions. It was established in chapter 4 that QSM is sensitive to changes in the oxygen saturation of blood in large branches of the major hepatic blood vessels in healthy mice. Chapter 5 discusses the application of QSM to a preclinical model of colorectal liver metastases, and also examines the ability of QSM to assess the efficacy of a Vascular Disrupting Agent (VDA), a novel chemotherapeutic drug. Finally, chapter 6 details the application of QSM to a model of liver cirrhosis

Quantitative Susceptibility Mapping in the Human Brain

Magnetic resonance imaging (MRI) offers a good tissue contrast and the ability to visualize many disease related morphologies. The work presented in this thesis investigates the study of underlying structure of the brain using quantitative methods with a special emphasis on quantitative susceptibility mapping (QSM). Magnetic susceptibility reflects the interaction of a material to the magnetic field and measures in biological tissues the magnetic susceptibility of inclusions. The reconstruction of QSM requires further processing steps as the magnetic field produced by the sources needs to be disentangled from the orders of magnitude bigger background field. The produced field also depends not only on the shape and the orientation, but also on the anisotropy of susceptibility and the microstructural compartmentalization of the biological source. For this reason, reconstruction methods need to be capable to calculate accurate values for different brain regions as well as applicable in the everyday clinical diagnosis. Within the framework of the thesis a data acquisition protocol based on a multiple-echo gradient echo sequence as well as a post-processing protocol was implemented. One of the processing steps, the background removal method, was applied to preserve the brain regions close to the cerebrospinal fluid (CSF). This method outperforms state of the art methods in this regions but is computationally intensive. Different brain regions were studied using quantitative methods with special emphasis on the QSM. A new method, modulated closed form solution, with extremely fast computational time is proposed. The comparison with other single orientation methods revealed similar results and the highest correlation to the state-of-the-art method (COSMOS) in the deep gray matter. The R2* maps calculated from the same dataset are also able to distinguish the deep gray matter structures with a similar quality. However, QSM shows a higher sensitivity in early stage multiple sclerosis lesions as well as white matter-gray matter structures. In the human cortex the obtained cortical maps show enhancement of primary sensory cortex, which is known to be highly myelinated, on three evaluated quantitative contrasts R1,R2* and susceptibility. The contrasts based on the relaxation rates, R1 and R2*, show a monotonically decrease from the white matter to the CSF imitating the decrease in iron and myelin. The susceptibility behaviour is more complex as iron and myelin content introduce an opposing sensitivity, allowing to study iron and myelin content when combining the three contrasts. The microstructural organization of white matter influences the R2*, R2 as well as field map from which QSM is calculated. This structure leads to an orientation dependence of the studied contrasts and for QSM the spherical assumption is not valid anymore. Therefore a new QSM method is introduced, which includes the Lorentzian correction in white matter. Main fibres such as forceps major and minor were analysed for the three different quantitative contrasts. The anisotropic component associated with susceptibility is similar for the relaxation rates whereas the isotropic component of R2* shows a higher variability. The resulting deep gray matter structure of the new QSM method remained similar to the state-of-the-art method when comparing the isotropic component but calculates physically meaningful susceptibility maps with improved contrast between known fibre bundles