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
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
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
The aim of this thesis was to investigate the radiological phenotype of the human brain in familial longevity with regard to brain structure. This study was performed as part of the Leiden... Show moreThe aim of this thesis was to investigate the radiological phenotype of the human brain in familial longevity with regard to brain structure. This study was performed as part of the Leiden Longevity Study __ a study population consisting of offspring of long-lived Dutch people who are genetically predisposed to become long-lived as well and their environmentally and age-matched spouses. Dedicated MR imaging techniques were applied to study the phenotype of the human brain on the macrostructural as well as microstructural level. Both features which are most likely caused by early development and a lower susceptibility to known age-related structural brain changes on the macro- as well as microstructural level are hallmarks of the brain phenotype in longevity. The contributing mechanisms have yet to be identified but may involve homeostatic control and body function. Keeping in mind that there is a gradual transition from healthy brain aging to what is generally accepted as __normal__ brain aging and pathological brain changes as disease correlates, our study results implicate that the brains of offspring of nonagenarian siblings are less susceptible to neurodegenerative brain changes such as (vascular) dementia, Alzheimer__s disease and cerebrovascular disease. Our findings should be considered as starting points for future studies on the functional implications of the presented results and studies on the underlying pathways of brain structure preservation in human longevity. Show less
Alzheimer__s disease (AD) is the predominant form of dementia in the aging population and its increasing incidence represents an important socio-economic and public health concern. The hallmarks of... Show moreAlzheimer__s disease (AD) is the predominant form of dementia in the aging population and its increasing incidence represents an important socio-economic and public health concern. The hallmarks of this disease, amyloid plaques and neurofibrillary tangles, are thought to develop early in the disease pathogenesis, up to decades before first clinical symptoms occur. However, these pathological hallmarks are still difficult to detect in vivo, and therefore a definitive diagnosis can only be made post-mortem. A clinical imaging technique or biomarker capable of visualizing and quantifying amyloid plaques and associated early changes thus may enable an earlier diagnosis, better understanding of the pathophysiology and eventually aid therapy development. The work presented in this thesis aimed to develop innovative diagnostic imaging techniques to detect the histological signatures of AD using emerging ultra-high field MRI technologies (Part I) and molecular imaging strategies (Part II). Show less
While aging remains one of the most significant risk factors for development of Alzheimer disease (AD), increasing evidence strongly points to the potential roles of cerebrovascular and white... Show moreWhile aging remains one of the most significant risk factors for development of Alzheimer disease (AD), increasing evidence strongly points to the potential roles of cerebrovascular and white matter abnormalities in the disease development. A better understanding of the manner in which these abnormalities contribute to disease progression can be achieved by in vivo characterization of AD related pathologies. To this end, MR based techniques serve as effective non-invasive tools to longitudinally monitor changes in AD brain. In this thesis, a variety of MR based techniques were optimized and employed to longitudinally monitor the AD progression in transgenic mouse models of the disease at 9.4T and 17.6T. In Chapter 2, age-dependent blood flow alterations were examined in a Tg2576 mouse model of Alzheimer's disease using MR angiography at 17.6T. AD is linked to abnormalities in the vascular system. In Chapter 3, in vivo T2 changes were longitudinally monitored in the corpus callosum, of the Tg2576 mice. In Chapter 4, age-dependent regional brain T1 and T2 changes in healty mice were established at 17.6T. In vivo imaging of these mouse models at ultra-high magnetic field strengths can permit a better understanding of the underlying cellular mechanism of AD. Show less
The aim of the thesis is to investigate the diagnostic value of MRI performed around term equivalent age in evaluating brain injury and predicting neurodevelopmental outcome at two years corrected... Show moreThe aim of the thesis is to investigate the diagnostic value of MRI performed around term equivalent age in evaluating brain injury and predicting neurodevelopmental outcome at two years corrected age in very preterm infants with a gestational age of less than 32 weeks. MRI is a powerful tool to diagnose all types of white matter injury and is more sensitive than ultrasound in detecting punctate white matter lesions which are associated with developmental delay and cerebral palsy. The positive predictive value of specific MRI findings such as punctate white matter lesions, and also cystic lesions and ventricular dilatation for cognitive and motor delay is low. Advanced DTI techniques are promising and may help predicting clinical outcome. However in combination with findings on conventional MRI sequences, there is only a slight increase in sensitivity and specificity. At this stage a routine clinical MRI in every preterm infant does not seem warranted. In the future, serial MRI and the application of advanced techniques may provide insights into brain development and injury to the preterm infant__s brain, and they may help predicting neurological outcome. Show less
The studies described in this thesis explored the effects of nutritional, exercise and pharmacological interventions on ectopic triglyceride accumulation in obese patients and/or patients with type... Show moreThe studies described in this thesis explored the effects of nutritional, exercise and pharmacological interventions on ectopic triglyceride accumulation in obese patients and/or patients with type 1 or type 2 diabetes mellitus (T2DM). Ectopic fat is defined as triglyceride (TG) storage in tissues, other than adipose tissue, such as the liver, heart and skeletal muscle. The focus of this thesis is on ectopic fat accumulation in two important organs: the liver and the heart. Studies in current thesis indeed have shown that lifestyle and pharmacological interventions can change ectopic triglyceride accumulation in (advanced) T2DM and is associated with changes in function. However, the notion emerges that the different fat compartments have differential regulation in relation to exercise, nutrition and pharmacological interventions. This points to different regulatory mechanisms involved in the accumulation and/or lipolysis of these fat compartments. Alternatively, it is possible that similar mechanisms are involved but with different dose-response relationships. These cannot be derived from the studies described in the current thesis because the aims of these studies were not focussed at these mechanisms underlying the dynamics of the individual fat depots. As patients with obesity and T2DM may have different ectopic fat distribution, this may also affect their (cardiac) risk profile. Manchann et al. already studied the effect of lifestyle intervention versus antidiabetic medication in patients with different fat distribution and found that this could predict intervention failure. More studies in these dynamics will hopefully lead to understanding from which treatments specific patient groups will benefit most. Show less
This thesis focuses on assessing blood supply to brain tissue using MRI. For Dynamic Susceptibility Contrast-MRI a series of images is acquired during the passage of a bolus contrast agent through... Show moreThis thesis focuses on assessing blood supply to brain tissue using MRI. For Dynamic Susceptibility Contrast-MRI a series of images is acquired during the passage of a bolus contrast agent through the brain up to the point that the contrast agent is equally mixed within the total blood pool. The tissue MR signal holds the hemodynamic information and the cerebral blood flow and volume. A reference or Arterial Input Function (AIF) measurement close to the brain tissue is required to enable quantification of perfusion. A special focus of this thesis lies on how to measure a correct AIF. A correct shape of the AIF is crucial for absolute or even relative perfusion values. A correct peak-height is necessary for absolute perfusion quantification, but an erroneous peak-height in combination with a correct shape of the AIF can still produce correct relative values for cerebral blood flow and volume. Therefore, the first objective should be to measure the correct shape of the AIF, whereas the measurement of the peak-height of the AIF should be considered of secondary importance. Show less
Our studies have shown MRI assessed aortic stiffness being an integrated marker of cardiac function, cerebral small vessel disease and atrophy, as well as of renal function in type1 diabetes... Show moreOur studies have shown MRI assessed aortic stiffness being an integrated marker of cardiac function, cerebral small vessel disease and atrophy, as well as of renal function in type1 diabetes mellitus patients. Aortic stiffness already in normal range is related to end-organ damage in type1 diabetes mellitus, suggesting increased organ-susceptibility for vascular alterations in diabetes mellitus. Structural changes in the brain as a manifestation of end-organ damage has shown to be clinical relevant to elderly with diabetes mellitus predicting accelerated cognitive decline. Hypertension is a major contributor to increased aortic stiffness. There is clear effect of aortic stiffness on cardiac and cerebral end-organ damage in hypertensive patients, which is different from type1 diabetes mellitus. The results of our cross-sectional studies suggest that MRI assessment of aortic pulse wave velocity could function as a marker or risk factor for generalized vascular disease and end-organ damage that might potentially be treated. Our findings may therefore have implications for cardiovascular risk stratification and optimization of therapy in diabetes mellitus and hypertensive patients beyond classical risk factors. Finally, this thesis describes the technical implementation and benefits of right coronary artery MRA at high field 7T. This is a promising step towards improved MRI detection of coronary artery disease. 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
The aim of this thesis was to investigate the pathofysiology of neuropsychiatric symptoms in the auto immune disease Systemic Lupus Erythematosus (SLE) using magnetic resonance imaging (MRI) of the... Show moreThe aim of this thesis was to investigate the pathofysiology of neuropsychiatric symptoms in the auto immune disease Systemic Lupus Erythematosus (SLE) using magnetic resonance imaging (MRI) of the brain. To this end MRI abnormalities in SLE patients with neuropsychiatric symptoms were compared with clinical symptoms and serological markers of disease. This thesis shows that immune abnormalities have an influence on the central nervous system in SLE (chapter 3&4). Reversible abnormalities in quantitative brain MRI in NPSLE are associated with clinical symptoms (chapter 2). These abnormalities are associated with neuroimaging features which may be interpreted as reversible axonal and/ or neuronal dysfunction (chapter 5). In line with this, severe ischemia does not appear to play a major role in NPSLE patients without obvious infarction on conventional MRI (chapter 6). Chapter 3 suggests that the influence of auto-immune antibodies is similar to the influence of auto-immune antibodies found in mouse models of NPLSE affecting specific locations of the brain. Using advanced MRI techniques and statistical analysis in chapter 7 suggests that the influence of auto-antibodies in human NPSLE also extends to white matter. Hopefully, these findings will facilitate earlier detection and treatment of neuropsychiatric symptoms in SLE. Show less
Cardiovascular disease is an important problem in the western world and identification of individuals at risk of cardiovascular disease and identification of patients with cardiovascular disease... Show moreCardiovascular disease is an important problem in the western world and identification of individuals at risk of cardiovascular disease and identification of patients with cardiovascular disease who are at risk of complications is important in order to reduce morbidity and mortality. This thesis shows the potential of MRI for risk stratification in cardiovascular disease. MRI enables assessment of morphology and function of the aortic vessel wall, which is important since the thickness and stiffness of the aortic vessel wall are related with coronary artery disease and cardiovascular events. Furthermore, the potential of MRI for visualization of the coronary arteries and assessment of coronary artery flow is explored. Although, this technique is not yet routinely used, ongoing research may in the future make MRI a valuable technique for detection of coronary artery disease. In addition, it is demonstrated that MRI is an excellent technique for detection and quantification of valve regurgitation. MRI also allows for quantification of scar tissue and contractile reserve in patients with ischemic cardiomyopathy enabling assessment of viability, which is important for optimization of treatment and prognosis. Finally, it is demonstrated that infarct size and infarct tissue heterogeneity measured with MRI are important predictors for long-term survival. Show less
The concept of distance is a fundamental notion that forms a basis for the orientation in space. It is related to the scientific measurement process: quantitative measurements result in numerical... Show moreThe concept of distance is a fundamental notion that forms a basis for the orientation in space. It is related to the scientific measurement process: quantitative measurements result in numerical values, and these can be immediately translated into distances. Vice versa, a set of mutual distances defines an abstract Euclidean space. Each system is thereby represented as a point, whose Euclidean distances approximate the original distances as close as possible. If the original distance measures interesting properties, these can be found back as interesting patterns in this space. This idea is applied to complex systems: The act of breathing, the structure and activity of the brain, and dynamical systems and time series in general. In all these situations, optimal transportation distances are used; these measure how much work is needed to transform one probability distribution into another. The reconstructed Euclidean space then permits to apply multivariate statistical methods. In particular, canonical discriminant analysis makes it possible to distinguish between distinct classes of systems, e.g., between healthy and diseased lungs. This offers new diagnostic perspectives in the assessment of lung and brain diseases, and also offers a new approach to numerical bifurcation analysis and to quantify synchronization in dynamical systems. Show less
Embryonic EPDCs are crucial for proper myocardial architecture and coronary vessel formation, both through their physical contribution and their regulatory role in these developmental processes.... Show moreEmbryonic EPDCs are crucial for proper myocardial architecture and coronary vessel formation, both through their physical contribution and their regulatory role in these developmental processes. This thesis reports for the first time on the role of Epicardium-Derived Cells (EPDCs) in the adult ischemic heart. It is demonstrated that transplanted adult EPDCs, isolated from human adult epicardial tissue, improve left ventricular function of the ischemic mouse heart. This is probably instigated by an early paracrine-mediated stimulation of the injected EPDCs on the surrounding host tissue, as indicated by increased wall thickness, augmented vascular density (mouse origin), and enhanced DNA-damage repair activity of the endogenous tissue. Cardiac healing in the EPDC-recipients is further characterized by advanced WT-1 expression, a marker for undifferentiated EPDCs, indicating induction of endogenous epicardial activity. Strikingly, the benefit of EPDC injection can be further enhanced by adding complementary cardiomyocyte progenitor cells to the EPDC transplant, explained by synergistic paracrine actions of the two different cell types. Two different techniques for assessment of left ventricular function in the post-infarct failing mouse heart are evaluated. It is shown that both conductance catheter and magnetic resonance imaging are reliable methods, each having specific unique features which need to be considered during experimental set-up. Show less
Nowadays many advanced MR imaging techniques are available for detection of hypoxic-ischemic brain injury in young infants. In tertiary referral centres and large children__s hospitals, these... Show moreNowadays many advanced MR imaging techniques are available for detection of hypoxic-ischemic brain injury in young infants. In tertiary referral centres and large children__s hospitals, these techniques are used on a regular basis. However, a considerable proportion of young infants with hypoxic-ischemic brain injury are imaged in primary and secondary care centres where experience with these advanced techniques is limited. Consequently, cranial ultrasonography and the conventional MR imaging techniques, such as T1- and T2-weighted imaging remain the mainstay of neonatal neuroimaging today. The purpose of this thesis was to study diagnostic and predictive MR imaging features of hypoxic-ischemic brain injury in young infants. We focused on T1-, T2-, and diffusion-weighted imaging, since these are applied on a large scale in primary and secondary centres. It may be anticipated that in the future, the use of these techniques will increase as experience with these techniques increases and access to MR imaging machines becomes more widespread. To identify all cases of neonatal hypoxic-ischemic brain injury and for optimal outcome prediction, a combination of diagnostic modalities is mandatory. For the diagnosis and outcome prediction of hypoxic-ischemic brain injury in young infants, clinical assessment, neuroimaging (cranial ultrasonography and MR imaging), and EEG are complementary. Show less
The thesis describes the application of several different magnetic resonance (MR) techniques to study the effects of the progression of disease in a transgenic mouse model of Alzheimer's. Using MR... Show moreThe thesis describes the application of several different magnetic resonance (MR) techniques to study the effects of the progression of disease in a transgenic mouse model of Alzheimer's. Using MR imaging, the amyloid plaque deposition was visualized and the plaque load quantified in the same mice as they aged. Concurrently the transverse relaxation time (T2) was measured in affected brain regions and shown to decrease over time as plaque-load increased. To study the neurochemical profile in the mouse brain brain both one- (1D) and two-dimensional (2D) MR spectroscopic techniques were employed. 1D MRS is widely used in similar research, but has limited spectral resolution. To overcome this limitation, a 2D MRS technique was implemented and optimized for use in mouse brain. This technique, L-COSY, allowed the detection of several metabolites which were not visible using standard 1D MRS techniques. This technique was subsequently used to study the effects of Alzheimer's on the neurochemical profile. Observed changes were correlated with plaque deposition. Show less
Osteoarthritis of the knee is a chronic progressive joint disease leading to pain and loss of function in a considerable proportion of patients with great impact and consequences in the ageing... Show moreOsteoarthritis of the knee is a chronic progressive joint disease leading to pain and loss of function in a considerable proportion of patients with great impact and consequences in the ageing population of the industrialized world. Clinical symptoms and radiographs of the knee are normally used to monitor osteoarthritic changes in the knee. However, the correlation between radiographic osteoarthritic findings and clinical features is poor. Does MR imaging of the knee tell us more about the relation between osteoarthritic structural findings and clinical features? According to the present thesis, the answer is “No”. Most of the data presented in this thesis is based on a 1.5T longitudinal MR study called the “Genetica, Artrose & Progressie” (GARP) study. In the GARP study MR imaging findings were associated with clinical features of patients with OA, and it was concluded that there were no strong associations between the most important OA imaging findings and clinical features of patients with OA. These controversial findings are important findings with regards to future clinical trials, as it urges conservatism with regards to the idea of BME being an outcome measure for progression of the disease. Therefore, the current theses also strongly recommend a further quest to identify ideal parameters to quantify the progression of the disease. Show less
Neuropsychiatric systemic lupus erythematosus (NPSLE) is a rheumatologic disorder causing neurologic, psychiatric and/or psychologic symptoms. The most important clinical problems are the aspecific... Show moreNeuropsychiatric systemic lupus erythematosus (NPSLE) is a rheumatologic disorder causing neurologic, psychiatric and/or psychologic symptoms. The most important clinical problems are the aspecific nature of signs and symptoms, the limited knowledge on pathogenesis and the absence of a diagnostic gold standard. Magnetic resonance imaging (MRI) is considered the most important imaging modality of the brain in NPSLE patients. Abnormalities visible on conventional MRI appear anywhere in the brain, and may normalize, stabilize or increase with loss of brain parenchyma. Apart from conventional MRI sequences, in this thesis advanced MRI techniques such as magnetization transfer imaging (MTI) were also applied, which are more sensitive to microscopic brain damage invisible to the human eye. Microscopic brain damage in NPSLE appears mostly in the cortical gray matter and is associated with the presence of anticardiolipin antibodies. The final brain damage, as observed using different MRI techniques, consists of neuronal and axonal damage, atrophy, demyelination and gliosis. Changes in the total amount of microscopic brain damage as detected by MTI correlate with changes in clinical status. This thesis contributes to the knowledge on the pathogenesis of NPSLE, and illustrates that advanced and conventional radiological techniques can be helpful in making diagnostic and therapeutic decisions. Show less
