The aim of this thesis is to develop noise robust electrical properties tomography (EPT) reconstruction methods that are free from tissue transition artifacts to support clinical applications for... Show moreThe aim of this thesis is to develop noise robust electrical properties tomography (EPT) reconstruction methods that are free from tissue transition artifacts to support clinical applications for complex tissue structures such as the brain. In particular the contrast-source inversion approach is pursued. This focus of this thesis is on the reconstruction of the electrical properties from the transmit field of radiofrequency coils most frequently available in magnetic resonance imaging. Show less
The overarching theme throughout this thesis is the exploration of new and the improvement of existing methods of measuring neurovascular pathology using MRI techniques and postprocessing. As... Show moreThe overarching theme throughout this thesis is the exploration of new and the improvement of existing methods of measuring neurovascular pathology using MRI techniques and postprocessing. As cerebrovascular afflictions are not located at a single location, these methods are applied throughout the cerebrovascular tree. This thesis starts with the large (macro) arteries (chapter 2), to the function of (micro) arteries (chapters 3 and 4), to remnants of hemorrhages in brain tissue (chapter 5), to finally the venous compartment (chapter 6), and takes into account both structure and function of selected parts of the cerebrovascular tree. Show less
Dit proefschrift richt zich op het symptomatische voorstadium van reumatoïde artritis, clinically suspect arthalgia, met de volgende doelstellingen: beter begrijpen van de symptomen en de hieraan... Show moreDit proefschrift richt zich op het symptomatische voorstadium van reumatoïde artritis, clinically suspect arthalgia, met de volgende doelstellingen: beter begrijpen van de symptomen en de hieraan onderliggende mechanismen (deel I), met MRI in de CSA-fase meerleren over het ontstaan van RA en identificeren van mensen met een verhoogd risico op RA (deel II), onderzoeken of medicamenteuze behandeling in de CSA-fase zin heeft en hoe deze behandeling eruit zou moeten zien (deel III). Show less
In this thesis two main aims were addressed. It has long been established that early treatment of rheumatoid arthritis (RA) improves disease outcomes. In Part I of this thesis we therefore further... Show moreIn this thesis two main aims were addressed. It has long been established that early treatment of rheumatoid arthritis (RA) improves disease outcomes. In Part I of this thesis we therefore further investigated the early detection of at-risk individuals by studying a large cohort of patients with clinically suspect arthralgia (CSA). We explored the value of two easy clinical tests, their potential to detect underlying inflammatory processes and to predict disease progression. In addition we investigated the presence of subclinical synovitis on imaging as starting point for treatment with disease modifying anti-rheumatic drugs (DMARDs) and the value of magnetic resonance imaging (MRI) detected erosions as new predictor for RA-development. In Part II of this thesis we aimed to determine which disease processes are involved in the different phases of RA-development. Knowledge on disease pathogenesis and timing of influencing factors can help to better target treatment during RA-development. We therefore evaluated whether autoantibody-response maturation occurred during the phase of CSA, and investigated the timing of genetic risk factor human leukocyte antigen-shared epitope (HLA-SE) and environmental risk factor smoking during the development of autoantibody-positive disease. Show less
In this thesis I investigate new ways to use MRI (magnetic resonance imaging) for the diagnosis, treatment and follow-up of uveal melanoma (UM) patients, mainly in relation to the planning of... Show moreIn this thesis I investigate new ways to use MRI (magnetic resonance imaging) for the diagnosis, treatment and follow-up of uveal melanoma (UM) patients, mainly in relation to the planning of proton beam therapy. Proton beam therapy is performed while sitting whereas MRI scans are scanned in prone position. In chapter 2 I have shown that the shape of the eye and tumor are not affected by the change in position. During treatment planning the tumor shape needs to be determined. This can be done by drawing the tumor on MRI. In chapter 3 I have shown that the variance between segmentations performed by different doctors are on average smaller then 0.4mm. As MRI based planning is not yet available for UM patients we have developed an MRI protocol to support the current model based treatment planning software with MRI based measurements. In chapter 4 I compare these MRI based measurements with conventional measurements and show that MRI measurements are comparable and sometimes even better. A common side effect of UM is retinal detachment. This is sometimes treated with silicon oil. Unfortunately ultrasound imaging is not possible in these patients. In chapter 5 I describe and evaluate a MRI protocol to imaging these tumors with MRI. Finally, MRI can also provide information about tissue and functional characteristics. In chapter 6 I present a method to overcome eye specific challenges in the quantitative analysis of perfusion weighted MRI. Show less
This thesis shows the potential utility of imaging biomarkers of the heart, kidneys, and visceral adiposity in the clinical management of cardiorenal syndrome and type 2 diabetes. We explored the... Show moreThis thesis shows the potential utility of imaging biomarkers of the heart, kidneys, and visceral adiposity in the clinical management of cardiorenal syndrome and type 2 diabetes. We explored the methods to quantify visceral fat, and demonstrated the potential clinical implications of a special compartment of visceral fat, renal sinus fat. We summarized the current role of imaging techniques in the clinical management of cardiorenal syndrome, and evaluated the preclinical MRI-derived imaging biomarkers in a group of patients with type 4 cardiorenal syndrome. Our findings could potentially benefit the clinical care for patients with metabolic disorders and/or cardiorenal syndrome. Continuous technical developments in quantitative imaging will increase the potential for applying imaging biomarkers in the management of reno-cardiometabolic diseases, and contribute to achieving the goals of personalized medicine. Show less
This thesis describes several studies on migraine and cluster headache which associate these primary headache syndromes with macrostructural and microstructural changes. Some of these brain changes... Show moreThis thesis describes several studies on migraine and cluster headache which associate these primary headache syndromes with macrostructural and microstructural changes. Some of these brain changes may be congenital, some may represent reversible or irreversible neuroplastic changes as a response of the brain to adapt to external stimuli and others should be considered as brain damage associated with these primary headache syndromes. Cluster headache patients have larger anterior hypothalamic volumes and wider skulls, observations that oppose previous neuroimaging findings and pathophysiological theories. Migraine is associated with microstructural changes in particularly visual processing areas in both cortical and subcortical grey matter and in white matter tracts connecting these structures. These changes might in part be irreversible or mSome migraineurs are also at increased risk of visually detectable changes on MRI, such as infratentorial microbleeds, and in male migraineurs, infratentorial hypertensities. Some migraineurs are also at increased risk of visually detectable changes on MRI, such as infratentorial microbleeds and, in male migraineurs, infratentorial hyperintensities. The underlying etiology of these types of cerebrovascular damage remains elusive and is probably the consequence of a multifactorial process. Show less
One of the pathological hallmarks of Alzheimer's disease is amyloid‑β accumulation in the parenchymal brain tissue. Amyloid‑β is also found in the vessel wall of patients with cerebral amyloid... Show moreOne of the pathological hallmarks of Alzheimer's disease is amyloid‑β accumulation in the parenchymal brain tissue. Amyloid‑β is also found in the vessel wall of patients with cerebral amyloid angiopathy (CAA). These pathological accumulations of the amyloid‑β peptide are referred to as amyloidosis. Both patients with AD and CAA also commonly show cerebrovascular dysfunction. The aim of this thesis was to improve our understanding of the relation between cerebrovascular dysfunction and amyloidosis. To that end, cerebrovascular function measurements were designed and carried out in mouse models of cerebral amyloidosis. Chapter 2 and 3 show improvements of the current techniques to measure cerebrovascular function in mice. Surprisingly however, no difference was found in cerebrovascular function in two different models of amyloidosis, as shown in chapter 4 and 5. Possible explanations of the negative findings are further discussed in chapter 6. Despite the negative connotation of the outcome this thesis, this work is another small step towards a better understanding of the exact relationship between cerebrovascular dysfunction and amyloid‑β deposition in AD and CAA patients. Ultimately, this will help in the design of highly needed novel therapies for AD and CAA. Show less
In this thesis we have pursued innovative analytical solutions for some of the most challenging questions in the field of SpA. We have gained better insights into the concept of axSpA by studying... Show moreIn this thesis we have pursued innovative analytical solutions for some of the most challenging questions in the field of SpA. We have gained better insights into the concept of axSpA by studying it independently of the rheumatologist’s opinion. Our findings likely add knowledge to what axSpA really is. Future studies will learn us how much of these insights will translate into a better recognition of the disease in clinical practice and in better classifying them for research purposes. Since SpA is a slowly progressing disease, several years are needed to see meaningful changes in imaging abnormalities of the axial skeleton, which poses methodological challenges. We have shown that thoughtful analytical approaches, that make best use of imaging data, are helpful in better estimating progression, in unravelling its determinants and in clarify which outcomes are best to monitor disease. Efforts are made to further improve outcome measurement in axSpA, including the development of new imaging techniques, which can benefit from our proposed solutions to long-term imaging scoring. Show less
This thesis is about the role of spreading depolarization (SD) in subarachnoid hemorrhage (SAH) as explained in Chapter 1.Chapters 2 and 3 use a rat model of SAH, SD induction and SD-inhibitor... Show moreThis thesis is about the role of spreading depolarization (SD) in subarachnoid hemorrhage (SAH) as explained in Chapter 1.Chapters 2 and 3 use a rat model of SAH, SD induction and SD-inhibitor valproate. They suggest a direct association between SD and lesion growth after experimental SAH, which can be counteracted by valproate.Chapter 4 explores the application of MRI techniques to monitor SD induced in rats. Balanced-steady-state-free-precession (b-SSFP) captures more detail than gradient-echo MRI. Diffusion-weighted multi-spin-echo (DT2) scans allowed for simultaneous recording of hemodynamic and diffusion changes.Chapter 5 describes a trend towards less DCI in SAH patients using SD-inhibiting drugs, but that did not result in a better clinical outcome. This suggests a possible protective effect of SD-inhibition on DCI but an unclear possible detrimental effect on other factors that affect clinical outcome.Chapter 6 found, in an ischemic stroke cohort, no statistically significant differences in the percentage of incomplete circles of Willis between migraine and non-migraine patients.Chapter 7 provides a general discussion of the findings from chapter 2-6. Show less
Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disease characterised by the progressive degeneration of the frontal and temporal lobes, which results in behavioural (behavioural... Show moreFrontotemporal dementia (FTD) is a heterogeneous neurodegenerative disease characterised by the progressive degeneration of the frontal and temporal lobes, which results in behavioural (behavioural variant FTD) and language (primary progressive aphasia) disorders. No effective therapies currently exist to cure FTD or slow disease progression. However, efforts are being made to develop disease modifying treatments, which aim to reverse or inhibit pathological processes leading up to neuronal cell death. Therefore, the ability to diagnose FTD before brain atrophy (i.e., irreversible brain damage) is crucial. Approximately 10–30% of all FTD patients have a familial form, often caused by mutations in the genes MAPT, GRN or a repeat expansion in the gene C9orf72. These families offer the unique opportunity to study mutation carriers in the presymptomatic stage, where early pathological changes may already occur, but subjects are cognitively healthy. In this dissertation, we used multimodal MRI and machine learning to investigate whether MRI biomarkers for FTD have diagnostic value on the single-subject level to detect FTD-related differences in the presymptomatic disease stage. Furthermore, we aimed to advance the combination of resting-state functional MRI data between scanners. Lastly, we studied potential biomarkers for the differentiation between early stages of FTD and Alzheimer’s disease. Show less
A large part of this thesis focussed on the additional value of MRI in the early detectionof RA. In contrast to showing its additional value, we also found that MRI can alsobe too sensitive and... Show moreA large part of this thesis focussed on the additional value of MRI in the early detectionof RA. In contrast to showing its additional value, we also found that MRI can alsobe too sensitive and appoint patients with MRI-detected inflammation that never willgo on to develop imminent, chronic RA. In clinical practise the exact role of imagingfor the early detection of RA still needs to be established further. Also the causes ofinflammation at MRI in patients with CSA or early IA are not fully understood yet. Itneeds to be specified in which individual patients, MRI has the most beneficial effectsand in combination with which clinical characteristics. In addition to this, also its costeffectiveness needs to be determined. The second part of this thesis focused more on subjective components of the disease, which is highly valuable for patients’ themselves.But next to this, a patients’ perspective is increasingly being taken into account fordecisions on treatment options. Although current treatment strategies have resulted inimproved disease outcomes and chronic damage can be prevented in a large amount ofpatients, patients still experience problems in daily life and at work. As we observed thatdespite improved therapies, many important outcomes remain present, like fatigue andpain, these should also be incorporated in future treatment aims as they pose a burdenon patients’ wellbeing as well as on society. Show less
The aim of this thesis was to investigate the feasibility of multimodal visualization techniques to observe adult stem cells, in particular HFBSCs, in the living animal. Due to the novelty of... Show moreThe aim of this thesis was to investigate the feasibility of multimodal visualization techniques to observe adult stem cells, in particular HFBSCs, in the living animal. Due to the novelty of HFBSCs in the field of inner ear research, a series of proof-of-principle experiments have been undertaken to investigate if these cells can undergo neuronal differentiation, tolerate genetic modification with lentiviral constructs containing the genes coding for reporter proteins, and tolerate subsequent loading with nanoparticles in vitro. In addition, it was of importance to examine if HFBSCs do integrate into modiolar tissue and if they can be visualized in the cochlea of the guinea pig. Lastly, we performed in vivo studies to investigate the ototoxic effect of ouabain in guinea pigs and the behavior of HFBSCs in mice with traumatic brain injury. Show less
For many cerebrovascular diseases, visualization of blood flow through the large vasculature, as well as quantitative information on tissue perfusion, is very important. Arterial Spin labelling ... Show moreFor many cerebrovascular diseases, visualization of blood flow through the large vasculature, as well as quantitative information on tissue perfusion, is very important. Arterial Spin labelling (ASL) magnetic resonance (MR) imaging enables the visualization of arterial flow by labelling the magnetization of arterial blood using radiofrequency pulses. The labelled arterial blood acts as an endogenous tracer and allows, which can avoid the reliance on the use of contrast agents. In this doctoral thesis, several new techniques for dynamic MR angiography and perfusion imaging were developed based on ASL techniques, which include pulsed ASL, pseudo-continuous ASL (pCASL), vessel-encoded pCASL, time-encoded pCASL as well as simultaneous multi-slice pCASL. The underlying motivation of these development is to reduce the burden on patients by employing non-invasive ASL techniques as potential alternatives to X-ray digital subtraction angiography, contrast-enhanced MR angiography and perfusion imaging. In each study, the optimum ASL techniques was carefully chosen by considering the pros and cons of the technique to achieve better clinical usability, while improving robustness against potential artifacts. Show less
The studies described in this thesis were all centred around the same aim: the early recognitionof axial spondyloarthritis (axSpA) and a minimization of the diagnostic delay. An importantstep in... Show moreThe studies described in this thesis were all centred around the same aim: the early recognitionof axial spondyloarthritis (axSpA) and a minimization of the diagnostic delay. An importantstep in tackling these issues was that experts in the field have designed prospective cohortstudies in which consecutive patients with either chronic or inflammatory back pain (thelatter being the most common first symptom) of short duration are included and followed upin a standardized manner with imaging performed at certain pre-set times. This allows us toobtain information on who will develop axSpA and who will not. Those cohort studies providevaluable information on the early detection and disease course of axSpA and form the basisof the research presented in this thesis. Show less
The primary aim of the project “Go with the flow: the heart-brain axis” was to elucidate the interaction between heart and the brain, across the lifespan. This was done by integration of... Show moreThe primary aim of the project “Go with the flow: the heart-brain axis” was to elucidate the interaction between heart and the brain, across the lifespan. This was done by integration of physiological concepts into the MRI-environment and by monitoring brain perfusion at both the macrovascular level (using transcranial Doppler; TCD) and the tissue level (using arterial spin labeling MRI; ASL). This thesis focused on the comparison and validation of these two modalities used in this project. We found that high levels of end-tidal CO2, blood pressure and handgrip all influence the middle cerebral artery (MCA) diameter, challenging the long-held assumption of diameter constancy. Furthermore, we found that during rhythmic handgrip the flow velocity (TCD) increased, whereas no change in the MCA flow territory (ASL) could be observed. Therefore, whole-brain CBF-measurements by ASL do not support the claim that a change in flow velocity measured by TCD can be used as a proxy for regional CBF during rhythmic handgrip exercise. Finally, we found in simulations and in-vivo experiments only modest influence of the cardiac cycle on the end-of-labeling. Therefore, cardiac triggering at the start or the end of labeling has little benefit to pseudo-Continuous ASL signal stability. Show less
Cardiovascular magnetic resonance imaging is an important noninvasive imaging modality for the diagnosis, clinical work‐up and treatment planning in patients suspected for a wide range of... Show moreCardiovascular magnetic resonance imaging is an important noninvasive imaging modality for the diagnosis, clinical work‐up and treatment planning in patients suspected for a wide range of cardiovascular pathology. CMR imaging is accurate and reliable, and provides invaluable information to evaluate the cardiovascular system without the need of ionizing radiation. The studies described in this thesis evaluate new CMR imaging techniques in clinical practice and explore the prognostic value of new CMR imaging biomarkers in patients with symptomatic peripheral arterial occlusive disease. New advances and innovations in MR imaging technology improve and further expand the clinical applications of cardiovascular imaging in daily clinical practice. In this thesis, a new, fast free‐breathing 2D delayed‐enhancement MRI sequence is validated and demonstrated to be a reliable tool for detecting myocardial infarction. Furthermore, new technical developments allow single‐injection, three‐station, moving‐table MRA protocol at 3Tesla with similar diagnostic performance when compared to 1.5Tesla. Additionally, submillimeter isotropic voxel acquisition in the lower legs at 1.5Tesla improves the diagnostic accuracy and depicts more open infragenual arterial segments.Additionally, it is demonstrated that new MRI biomarkers as distal aortic pulse wave velocity statistically significantly correlate with stenosis severity in symptomatic patients with peripheral arterial occlusive disease. Finally, we showed that CMR derived biomarkers relating to stenosis severity, aortic stiffness and left ventricular function play a role in prognosis of outcome in patients with symptomatic PAOD. In the future, incorporation of the described new MRI biomarkers in the clinical workup of peripheral arterial occlusive disease may play an important role for full vascular risk assessment and ultimately, patients may benefit in clinical practice. Show less
The human body is inherently designed to be able to adapt to challenging situations. However, some experiences are so severe that they can lead to substantial and longerlasting disturbances in an... Show moreThe human body is inherently designed to be able to adapt to challenging situations. However, some experiences are so severe that they can lead to substantial and longerlasting disturbances in an individuals’ behavioral, psychological and physiological functioning. Importantly, there is a degree of inter-individual variation, as not all individuals show similar reactions to severe stress. Neuroimaging techniques can help to unravel the brain characteristics related to vulnerability and resilience to severe stress. In the research for this dissertation several neuroimaging modalities were used to further explore the brain characteristics related to (dys)function after exposure to severe stress and after exposure to hypercortisolism, such as voxel-based morphometry and diffusion tensor imaging to study the structure of gray and white matter in the brain, and resting-state fMRI to study functional connectivity patterns. We studied brain characteristics in several groups consisting of: patients in long-term remission of Cushing’s disease, and individuals with a history of childhood emotional maltreatment to examine the effects of hypercortisolism and severe stress on the brain. In addition, we studied a group of police officers and a group of individuals with a history of childhood maltreatment to investigate the brain characteristics related to resilience to stress. Show less
Measuring biomechanics of the knee with an acceptable degree of accuracy is difficult. When the in vivo knee joint motion is analyzed in all its six degrees-of-freedom without compromising on... Show moreMeasuring biomechanics of the knee with an acceptable degree of accuracy is difficult. When the in vivo knee joint motion is analyzed in all its six degrees-of-freedom without compromising on physiological loading conditions, the task becomes even more challenging. This thesis offers a brief overview of the development, validation and application of a non-invasive imaging methodology to capture the in vivo biomechanics of anterior cruciate ligament (ACL) deficient and posterior cruciate ligament (PCL) deficient knees. By combining dual fluoroscopy to capture the in vivo joint motion and magnetic resonance imaging to reconstruct the joint anatomy, we obtained a comprehensive insight in both tibiofemoral as well as patellofemoral kinematics and cartilage biomechanics of healthy knees under various loading conditions. These baseline measurements helped us comprehend the alterations in biomechanics seen in knees after injury of either ACL or PCL, which in turn generated clinically useful data for the improvement of our surgical reconstruction techniques. Show less
This thesis focuses on the assessment and monitoring of health and imaging outcomes in axial spondyloarthritis (SpA) and the relationship between these outcomes. Four major contributions to... Show more This thesis focuses on the assessment and monitoring of health and imaging outcomes in axial spondyloarthritis (SpA) and the relationship between these outcomes. Four major contributions to the understanding and management of axial SpA were made: 1) the improvement and facilitation of the assessment of disease activity using the Ankylosing Spondylitis Disease Activity Score (ASDAS), for which we defined disease activity cut-offs and response criteria and provided guidance about the calculation of the score; 2) the increase in the knowledge about the mutual relationships between health outcomes in axial SpA, namely health related quality of life, physical function, clinical disease activity, spinal mobility, structural damage and magnetic resonance imaging (MRI) of the spine; 3) the increase in the knowledge about the factors that influence phenotypic variability in axial SpA, namely Human Leukocyte Antigen B27 (HLA-B27) positivity (a genetic factor), smoking (an environmental factor) and the presence of psoriasis (an extra-articular manifestation); and 4) the insight into the processes that drive structural progression in axial SpA and into the link between inflammation and structural damage, by specifically looking at the relationship between MRI inflammation, MRI fat deposition and new bone formation in axial SpA. Show less
