The field of rheumatoid arthritis (RA) is moving into identification of patients as early as possible and the ultimate aim is to prevent RA becoming a chronic disease. To this end, we studied the... Show moreThe field of rheumatoid arthritis (RA) is moving into identification of patients as early as possible and the ultimate aim is to prevent RA becoming a chronic disease. To this end, we studied the phase of Clinically Suspect Arthralgia (CSA). Patients with arthralgia that were considered by the rheumatologist to have an increased risk to progress to RA (CSA) had indeed an increased risk of RA. In addition, subclinical MRI-inflammation preceded clinical arthritis with a few months. Future research will shed more light on processes underlying progression from CSA to RA and effectiveness of treatment initiation in the CSA phase. The severity of the course of RA is variable between patients and this cannot be yet accurately predicted. In this thesis, we performed studies that contributed to the understanding of these differences in severity. Three genetic risk factors for more severe joint damage progression (two non-HLA and one HLA variation) and one for arthritis persistence were identified. Further research on functional implications of the identified variants and whether they might be useful as biomarkers to guide treatment decisions is needed. Show less
This work is focussed on the precolonial Mesoamerican codices. Less than twenty of these rare books still exist today. The main questions are how were these objects made, and for what were... Show more This work is focussed on the precolonial Mesoamerican codices. Less than twenty of these rare books still exist today. The main questions are how were these objects made, and for what were they used. The author also looked at why so few of these books remain today and how they have been reproduced in more recent times. One special aspect of this research was the investigation of one specific book, the codex Añute, held at the Bodleian Libraries of the University of Oxford. This book is a known palimpsest. By understanding its physical composition, new techniques could be developed to investigate this palimpsest and recover new pictographic texts from underneath the surfaces. 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
De belangrijkste resultaten van dit proefschrift: de ASAS classificatie criteria voor axSpA blijken robuust en zijn goed toepasbaar in een setting waarbij de waarschijnlijkheid op axSpA lager is... Show moreDe belangrijkste resultaten van dit proefschrift: de ASAS classificatie criteria voor axSpA blijken robuust en zijn goed toepasbaar in een setting waarbij de waarschijnlijkheid op axSpA lager is dan waarin de criteria ontwikkeld zijn. Daarnaast is er op basis van bevindingen in dit proefschrift een belangrijke aanpassing doorgevoerd in een hulpmiddel dat reumatologen begeleidt in het diagnostische proces van (vroege) axSpA. Tevens is het MRI protocol van het SPACE cohort aangepast nadat de toegevoegde waarde van het toedienen van een contrastvloeistof bij het maken van MRI’s nihil bleek te zijn, met als resultaat dat er sinds april 2012 geen MRI’s meer worden gemaakt met de toediening van gadolinium. Dit proefschrift biedt ook adequate handvatten voor verder onderzoek naar de optimale definitie van een positieve MRI. Bovendien worden discrepanties aangaande de beoordeling door verschillende soorten lezers van afwijkingen in de rug (op röntgenfoto’s en MRI’s) aan het licht gebracht waardoor de vraag naar voren komt of training in het onderscheiden van axSpA afwijkingen en afwijkingen die niet gerelateerd zijn aan axSpA van potentiële belang is op de betrouwbaarheid van het beoordelen van afwijkingen in de rug. De onderzoeken in dit proefschrift leveren een bijdrage aan betere herkenning en behandeling van axSpA. Show less
Over the last decade, there has been an exponential development in cardiac imaging technology. Currently, cardiac imaging plays a central role in clinical management and decision making in the... Show moreOver the last decade, there has been an exponential development in cardiac imaging technology. Currently, cardiac imaging plays a central role in clinical management and decision making in the diverse and growing population of patients encountered in daily cardiology practice. Important outcome-related parameters can be derived from these techniques, allowing better risk stratification of patients with ischemic heart disease. Still, the large amount of information provided by the different imaging modalities can be overwhelming and it can be challenging for the cardiologist to make optimal use of all information that is provided by the different modalities. The purpose of this thesis was to optimize the clinical usefulness of specific cardiac imaging modalities for particular patient categories, with the purpose of improving risk estimation in patients with suspected coronary artery disease, patients who suffered from STEMI and heart failure patients. Show less
In the past decade, advances in structure determination with electron microscopy of organic, beam sensitive, materials have been significant. The newly developed techniques, triggered by new... Show moreIn the past decade, advances in structure determination with electron microscopy of organic, beam sensitive, materials have been significant. The newly developed techniques, triggered by new microscope systems and new cameras, made it possible to acquire 3D structural information from these samples to a resolution which was impossible to achieve before. Knowledge is required to improve structure solution and every aspect of the process involved, from treatment of radiation sensitive materials, sample preparation, TEM imaging and diffraction systems all the way to how data must be interpreted. In this thesis I explained multiple new techniques and methods developed by us, using both new microscopes as well as a new type of detector: Timepix. I describe how these tools can help to overcome (what were) the most important problems and bottlenecks in detection of very low dose electron diffraction. Show less
The main objective of this thesis is to compare bony decompression with implantation of interspinous process devices (IPDs) in patients with intermittent neurogenic claudication (INC) caused by... Show moreThe main objective of this thesis is to compare bony decompression with implantation of interspinous process devices (IPDs) in patients with intermittent neurogenic claudication (INC) caused by lumbar spinal stenosis (LSS). A national survey among Dutch spine surgeons is presented about the usual care of patients with intermittent neurogenic claudication caused by lumbar spinal stenosis. Surgeons' expectations of different treatment options are presented. The existing evidence on interspinous implant surgery will be systematically reviewed. Results of treatment with IPDs are compared with other (conservative) treatment options. The Foraminal Enlargement Lumbar Interspinosus distraXion (FELIX) trial is described. This double-blind, multicenter, randomized (cost)effectiveness study was designed to answer the question whether treatment with IPDs would be more (cost) effective compared with conventional bony decompression. Short-term results (eight weeks), long-term results (one and two year) and results in different subgroups are described in this thesis. The analysis based on total direct and indirect costs of both procedures (treatment with IPD and bony decompression) are also presented. INC suitable for surgical treatment. The compression on MR images was evaluated and correlated with baseline complaints and long-term clinical outcome. Show less
Cardiovascular risk assessment in patients with diabetes mellitus (DM) remains challenging. Risk scores to predict cardiovascular risk are widely used, but are developed in the general population... Show moreCardiovascular risk assessment in patients with diabetes mellitus (DM) remains challenging. Risk scores to predict cardiovascular risk are widely used, but are developed in the general population and tend to underestimate the cardiovascular risk of DM patients. Risk scores developed in diabetic populations to estimate cardiovascular risk have demonstrated good calibration and discriminations indices. However, external validation is still needed. A recent meta-analysis showed that the predictive ability of these scores developed in diabetic populations is not superior to those scores developed in general population. Accordingly, the additional use of other biomarkers or imaging tools seems a good alternative to better risk stratify diabetic patients. This thesis evaluates the application and performance of non-invasive cardiac imaging tests for cardiovascular risk assessment and management of DM patients. Identification of new markers of CAD derived from non-invasive cardiac imaging might result in a broader applicability of cardiovascular risk assessment. Non-invasive cardiac imaging tests might evaluate target organ damage as well as the presence, severity and extent of subclinical atherosclerosis preceding overt clinical CAD. Thus, high-risk patients for CAD can be identified and further decision making of each DM patient can be tailored in order to improve the clinical outcomes at long-term follow-up Show less
The general objective of this thesis was to investigate new (quantitative) MR techniques and MR markers in the light of both AD and cerebral aging. The quantitative MR techniques that we used were... Show moreThe general objective of this thesis was to investigate new (quantitative) MR techniques and MR markers in the light of both AD and cerebral aging. The quantitative MR techniques that we used were MTI, tCBF and WSS measurements. The new markers we studied were cerebral microbleeds and iron accumulation in the basal ganglia. In chapter 2 we investigated whether MTI changes could be detected in the GM, WM or both in patients suffering from MCI or AD. Using MTI we found evidence for structural brain changes in both GM and WM of patients with MCI and AD. Furthermore, these MTI changes were related to cognitive impairment as expressed by the mini mental state examination (MMSE) score. These findings imply that cerebral changes can be detected in both GM and WM even before patients are clinically demented. The finding of MTI changes in the GM might relate to classical AD type pathology, whereas WM MTI changes could indicate concomitant vascular pathology. The findings in chapter 2 raised the question of how the MTI changes found in this study are distributed over the GM and WM. This was investigated in chapter 3. In this study we showed that brain damage, as detected by MTI, is widespread over the lobes in both AD and MCI patients whereas GM damage is more focally present in the temporal and frontal lobe of MCI patients. These findings are compatible with the knowledge that GM damage originates from the temporal lobe in AD. This interpretation is further supported by the observed independent association between temporal GM peak height and cognitive decline. MTI changes were found in all four lobes of the MCI patients investigated in this study and show the involvement of a diffuse process affecting the WM even before patients are clinically demented, a finding potentially explained by the presence of diffuse vascular pathology. Chapter 4 shows that the tCBF is strongly associated with parenchymal volume rather than age and, although much weaker, with the severity of WMHs. Although the association between tCBF and parenchyma volume seems straightforward, this finding has important implications for future studies. Volume flow measurements should be corrected for parenchymal volume ratherthan age in all future studies in which flow measurements are being used as a diagnostic tool. In addition, studies including elderly patients or patients with a pathological increase of WMHs, such as diabetic type II subjects, should also correct their tCBF measurements for WMH volumes. Chapter 5 shows that hemodynamic conditions of the carotid and basilar arteries, as expressed in lower WSS parameters, are worse in both MCI and AD compared to controls. In addition, the WSS parameters were found to correlate strongly with cognition. Again, this study is additional evidence for an important role of vascular pathology in the development of AD. In chapter 6, we found a high prevalence of microbleeds in a population of patients suffering from vascular disease or at high risk of developing this condition. Age, hypertension and WMH were the most important risk factors for microbleeds, especially when located in the cortico-subcortical junction and basal ganglia. Regarding the associations between the presence and location of microbleeds on the one hand and parameters of cognitive functioning on the other, chapter 7 shows that microbleeds located infratentorially are associated with impaired cognitive functioning in the aging population with increased vascular risk factors. This suggests that in elderly individuals microbleeds in the posterior fossa should be considered a sign of small vessel disease with potential functional consequences. The semi-quantative scale for scoring basal ganglia hypo-intensity on T2*- weighted imaging presented in chapter 8 was associated with markers of neurodegeneration. This study showed that low signal intensity of the caudate nucleus T2*-weighted MR is a frequent finding which is associated with more cerebral atrophy, a higher load of WMH and a higher load of invisible changes in both cortical GM and NAWM non-demented elderly. Furthermore, hypo- intensity limited to the globus pallidus and putamen was not associated with any of these parameters of neurodegeneration. In chapter 9 we present a method for automated detection and classification of hypo-intense regions on T2-weighted MR images of the basal ganglia. In this chapter we not only show an association between basal ganglia hypo-intensity and cardiovascular risk factors but also with measures of cognitive functioning. From this we conclude that hypo-intensity of the basal ganglia on T2-weighted MR is not only a radiological finding accompanying cerebral aging but also an independent marker of neurodegeneration. Show less
In this thesis the prospects of electron diffraction and imaging techniques are discussed to solve the structure of three dimensional nano-crystals. These crystals are beyond the scope of current X... Show moreIn this thesis the prospects of electron diffraction and imaging techniques are discussed to solve the structure of three dimensional nano-crystals. These crystals are beyond the scope of current X-ray techniques. Show less
During gastrulation, the cells, and consequently the organ anlagen, are repositioned according to their future arrangement along the anterio- posterior axis. The movements responsible, the... Show moreDuring gastrulation, the cells, and consequently the organ anlagen, are repositioned according to their future arrangement along the anterio- posterior axis. The movements responsible, the convergence and extension (CE) cell movements, are crucial for normal development and defects in their mechanism underlie human pathologies like spina bifida and Noonan syndrome. Collective polarization of the cells is essential for these morphogenetic. The coordination and regulation are governed by intricate signaling mechanisms. Tyrosine phosphorylation is one of such mechanisms. By either phosphorylation by protein-tyrosine kinases or dephosphorylation by protein-tyrosine phosphatases (PTPs) of tyrosine residues, many signaling proteins can be switched from active to inactive states. In this thesis, we focus on the role of ‘classical’ PTPs. We identified PTP-BL, Ptpn20, RPTPα and RPTPε as components of a system regulating cell polarity. Additionally, we identified via screening one additional PTP, ptprda, as essential for CE movements. Quantitative analysis and clear representation of the data is essential to modern day biology. Studying collective cell migrations requires the analysis of the net effect of cell polarization and/or displacements of a large number of cells within a tissue rather than measurements of a few individuals. An automated cell tracing algorithm was developed and an algorithm for the detection of cell membranes. Additionally, a novel method of graphical data representation is introduced. Show less
The general introduction of this thesis gives an overview of the epidemiology of ST-segment elevation myocardial infarction (STEMI) and the current focus of the guidelines concerning the management... Show moreThe general introduction of this thesis gives an overview of the epidemiology of ST-segment elevation myocardial infarction (STEMI) and the current focus of the guidelines concerning the management of these patients. In the past decades changes in the treatment and outcome of STEMI patients have influenced the risk stratification of this population and the focus has been shifted to the evaluation of infarct size. Furthermore, the role of echocardiography in the risk stratification after STEMI is addressed including the evolving echocardiographic techniques. The aim of the current thesis was to evaluate the clinical characteristics of this contemporary population of STEMI patients and to assess the value of echocardiography for the improvement of the risk stratification of these patients. First, the current population of STEMI patients treated with primary percutaneous coronary intervention is described in Part I, where clinical parameters are being evaluated in relation to short- and long-term outcome. In Part II, the role of conventional and novel echocardiographic techniques is being evaluated for the assessment of left ventricular (LV) systolic function and the importance of LV diastolic function is addressed in Part III. Finally, the role of echocardiography in patients with chronic ischemic heart disease is studied in Part IV. Show less
Brain function has long been the realm of philosophy, psychology and psychiatry and since the mid 1800s, of histopathology. Through the advent of magnetic imaging in the end of the last century, an... Show moreBrain function has long been the realm of philosophy, psychology and psychiatry and since the mid 1800s, of histopathology. Through the advent of magnetic imaging in the end of the last century, an in vivo visualization of the human brain became available. This thesis describes the development of two unique techniques, imaging of diffusion of water protons and manganese enhanced imaging, that both allow for the depiction of white matter tracts. The reported studies show, that these techniques can be used for a three-dimensional depiction of fiber bundles and that quantitative measures reflecting fiber integrity and neuronal function can be extracted from such data. In clinical applications, the potential use of the developed methods is illustrated in human gliomas, as measure for fiber infiltration, and in spinal cord injury, to monitor potential neuroprotective and __regenerative medication. Show less
In this thesis, several strategies are presented that aim to facilitate the analysis and visualization of whole-body in vivo data of small animals. Based on the particular challenges for image... Show moreIn this thesis, several strategies are presented that aim to facilitate the analysis and visualization of whole-body in vivo data of small animals. Based on the particular challenges for image processing, when dealing with whole-body follow-up data, we addressed several aspects in this thesis. The developed methods are tailored to handle data of subjects with significantly varying posture and address the large tissue heterogeneity of entire animals. In addition, we aim to compensate for lacking tissue contrast by relying on approximation of organs based on an animal atlas. Beyond that, we provide a solution to automate the combination of multimodality, multidimensional data. Show less
In this research heavy chain antibody fragments (VHHs) are developed as potential tools for non-invasive in vivo imaging of Alzheimer__s disease (AD) and Cerebral Amyloid Angiopathy (CAA). First... Show moreIn this research heavy chain antibody fragments (VHHs) are developed as potential tools for non-invasive in vivo imaging of Alzheimer__s disease (AD) and Cerebral Amyloid Angiopathy (CAA). First the generation of antibody fragments, directed against A_ is described. VHHs that were selected from different libraries showed differential affinity for different A_ epitopes when used for immunohistochemistry. These observations indicate that the VHHs are the first immunologic probes with the capacity to differentiate between parenchymal and vascular beta amyloid aggregates. Next, in chapter three the VHH are assessed on their ability to cross the blood-brain barrier using an established in vitro blood brain barrier co-culture system. VHH ni3A showed the highest transmigration efficiency of all tested VHHs. This transport is, in part, facilitated by a 3 amino acid substitution in its N-terminal domain. Additional studies indicated that the mechanism of transcellular passage of ni3A is by active transport. The data described in chapter four provides preliminary proof that these VHHs have the capacity to target A_ depositions in vivo. Consequently, the VHHs are promising tools for further development as imaging agents for the differential diagnosis of A_-related neurodegenerative diseases like CAA and AD. Show less
Non-invasive imaging plays an increasingly important role in the diagnosis and risk stratification of coronary artery disease. Several techniques such as stress echocardiography and myocardial... Show moreNon-invasive imaging plays an increasingly important role in the diagnosis and risk stratification of coronary artery disease. Several techniques such as stress echocardiography and myocardial perfusion imaging have become available to assess cardiac function and myocardial perfusion. With the arrival of multi-slice computed tomography coronary angiography (CTA), non-invasive imaging of coronary anatomy has also become possible. CTA is a relatively new imaging technique; the objective of the thesis is therefore to explore the value of CTA for diagnosis and risk stratification of CAD in patients presenting with suspected and known CAD, in order to further define its role in clinical practice. The results of this thesis show that CTA provides important diagnostic information relative to existing non-invasive imaging strategies. In addition the detailed anatomic information obtained using CTA was shown to provide important prognostic information. CTA supplies complementary information to existing non-invasive imaging techniques, and has the potential to provide a more patient tailored approach to patient management. What remains to be determined is how CTA and non-invasive functional imaging should be integrated into clinical practice. Show less
The presence of a decreased left ventricular (LV) function after myocardial infarction has demonstrated to be of considerable clinical importance. In this thesis, the role of 2D echocardiography to... Show moreThe presence of a decreased left ventricular (LV) function after myocardial infarction has demonstrated to be of considerable clinical importance. In this thesis, the role of 2D echocardiography to evaluate LV function in ischemic heart disease was investigated. In the first part of the thesis, recently introduced echocardiographic parameters to describe LV function were studied and their importance for prognosis after myocardial infarction was evaluated. In addition, in the second part of the thesis, the role for echocardiography in the decision making around advanced treatment options in heart failure such as cardiac resynchronization therapy (CRT) and cardiac surgery was explored. Show less
Cochlear implants (CIs) are a well accepted treatment for hearing impaired people. In pre- and postoperative assessment of CI-candidates imaging plays an important role to analyze anatomy, rule out... Show moreCochlear implants (CIs) are a well accepted treatment for hearing impaired people. In pre- and postoperative assessment of CI-candidates imaging plays an important role to analyze anatomy, rule out pathology and determine intracochlear positioning and integrity of the implant. Developments in CI-design, differences in surgical approach and broadening of treatment indications have raised new questions to radiologists, which were the subject of several studies described in this thesis. For optimal, a-traumatic positioning of a CI precise information about the inner ear anatomy is mandatory. We describe the development, validation and application of a method for 3-dimensional medical image exploration of the inner ear. This renders a tool to obtain cochlear dimensions on clinical computer tomography (CT) images. This will be useful for patientspecific implantplanning. It also shows an anatomical substrate for cochlear trauma during insertion. For postoperative imaging we studied the value of multislice-CT for optimal visualization of the implant within the cochlea. Its role to evaluate operation technique and electrode design, to study frequency mapping and to assess cochlear trauma is discussed. Moreover an international consensus for an objective cochlear framework is presented, forming a common ground for clear and easy exchange of findings in scientific and clinical studies. Show less
Current non-invasive detection of coronary artery disease (CAD) is based on demonstration of ischemia using stress-rest imaging: this is an indirect way of identifying CAD by demonstration of the... Show moreCurrent non-invasive detection of coronary artery disease (CAD) is based on demonstration of ischemia using stress-rest imaging: this is an indirect way of identifying CAD by demonstration of the hemodynamic consequences rather than direct visualization of the obstructive lesions in the coronary arteries. Multi-slice computed tomography (MSCT) has recently emerged as an extremely rapidly developing non-invasive imaging modality, which allows anatomical imaging of the coronary arteries, or non-invasive coronary angiography. In addition, total plaque burden, plaque morphology and (to some extent) plaque constitution can be assessed by MSCT. The technique also provides information on resting left ventricular systolic function, and possibly resting perfusion. Ideally, stress function and perfusion should also be evaluated, since this would allow detection of ischemia and would complete the picture on CAD. However, this is not routinely performed, since sequential acquisitions are associated with high radiation doses and thus pose a limitation for cardiovascular applications of MSCT. It is anticipated that, with reduction in radiation, MSCT may become an important player in the diagnostic and prognostic workup of patients with known or suspected CAD. Show less
Various modalities are available in the diagnostic and prognostic evaluation of patients presenting with known or suspected coronary artery disease (CAD). A rapidly expanding technique is... Show moreVarious modalities are available in the diagnostic and prognostic evaluation of patients presenting with known or suspected coronary artery disease (CAD). A rapidly expanding technique is noninvasive coronary angiography with Multi-Slice Computed Tomography (MSCT), which allows accurate detection of significant stenoses. The main value of the technique lies in the noninvasive exclusion of CAD in patients with intermediate pre-test likelihood. Although imaging in populations such as patients with previous stent placement appears to be more challenging, promising results have been obtained in these populations as well. However, it remains important to realize that the presence of coronary atherosclerosis with luminal obstruction does not invariably imply the presence of ischemia. Accordingly, a noninvasive angiographic imaging technique as MSCT cannot be used to predict the hemodynamical importance of lesions. In patients with borderline stenosis, therefore, functional testing (which can be performed by nuclear imaging, stress echocardiography or MRI) will remain necessary to determine management. Nonetheless, detection of CAD at a far earlier stage than functional imaging is an important advantage of MSCT. Initial investigations suggest that MSCT may distinguish different plaque characteristics between various presentations. Potentially, this information could be useful for risk stratification. Finally, additional non-coronary information can be derived as well. LV function can be evaluated with high accuracy while also information on the cardiac venous system can be obtained. Show less
