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 primary aim of this thesis is to investigate vascular and structural neuroimaging findings in migraine to ultimately identify possible causes for the well-known increased risk of structural... Show moreThe primary aim of this thesis is to investigate vascular and structural neuroimaging findings in migraine to ultimately identify possible causes for the well-known increased risk of structural brain lesions. To this purpose, we used advanced MRI techniques in migraine patients, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) patients and controls to evaluate vascular function. Moreover, we evaluated structural brain changes in repetitive hemiplegic migraine attacks. Secondary aim of this thesis is to describe the neuroimaging findings in a large Dutch cohort of RVCL-S patients of different ages. Show less
Placebo and nocebo effects, positive and negative effects experienced after both real and sham interventions, putatively due to positive or negative outcome expectancies, can shape our sensory... Show morePlacebo and nocebo effects, positive and negative effects experienced after both real and sham interventions, putatively due to positive or negative outcome expectancies, can shape our sensory experience. Although placebo and nocebo effects are known to occur reliably in many individuals for sensations like pain and itch, our understanding of psychological learning processes and methodological factors that influence these effects remains limited. Chapters 2, 3, and 4 investigate this topic with meta-analysis, narrative review, and a behavioral study. Similarly, our characterization of the neural markers of nocebo effects is incomplete. A better grasp of how these effects form is necessary to contextualize them within the larger framework of bottom-up and top-down integration. Chapters 5, 6, and 7 investigate this topic in a series of EEG and fMRI studies. Advancing both psychological and neural accounts of placebo and nocebo effects will aid in applying findings from this field of study to everyday life; particularly in clinical settings, and potentially any setting in which expectations regarding one’s future experiences come into play. Show less
The primary aim of this thesis was to improve the overall methodology for assessing supraclavicular brown adipose tissue (scBAT) activity in human adults to enable evaluation of therapies (in... Show moreThe primary aim of this thesis was to improve the overall methodology for assessing supraclavicular brown adipose tissue (scBAT) activity in human adults to enable evaluation of therapies (in)directly targeting BAT. The studies in this thesis have improved the feasibility of using non-invasive methods such as infrared thermography and magnetic resonance imaging for the assessment of scBAT activity in human adults and have led to a better understanding of the physiological mechanisms that influence the cold tolerance capacity in human adults. We showed the amount of activated BAT could vary among indi viduals with different body types and that cooling protocols should be carefully selected, especially in heterogenous study populations. With regards to imaging, we strongly recommend to use motion-correcting methods such as non-rigid image registration to correct for motion-induced variability, and to reduce the analysis time. Finally, due to the heterogenous nature of the scBAT depot in human adults, the use of FF thresholds for analysis should be carefully considered. Show less
Duchenne and Becker muscular dystrophy (DMD and BMD, respectively) are characterized by progressive loss of muscle function combined with an increase in fat tissue in muscle. In some muscles this... Show moreDuchenne and Becker muscular dystrophy (DMD and BMD, respectively) are characterized by progressive loss of muscle function combined with an increase in fat tissue in muscle. In some muscles this process of ‘fat replacement’ starts earlier or progresses faster than in others and this occurs in a consistent temporal pattern. In addition, even within muscles fat replacement seems to progress heterogeneously. Evidently there are factors that vary between and within muscles which cause differential fat replacement of muscle tissue, but these are currently unknown. The identification of factors that influence this process of muscle degeneration could support the selection of current, and the development of future, therapies.The aim of part 1 of this thesis was to identify differences between muscles that are related to muscle fat replacement over time. These can provide therapeutical targets for, and support the design of, future clinical trials in DMD and BMD. Part 2 aimed to develop new approaches to study intramuscular differences in muscle physiology and mechanics in healthy muscle. These can be applied in neuromuscular disease in the future, and can be related to intramuscular differences in disease progression. Show less
The general aim of this thesis was to study the frequency, causes and consequences of pathologic brain aging specifically focusing on sub-clinical and clinical MRI manifestations of vascular (small... Show moreThe general aim of this thesis was to study the frequency, causes and consequences of pathologic brain aging specifically focusing on sub-clinical and clinical MRI manifestations of vascular (small vessel disease) and neurodegenerative (brain atrophy) disease. A second aim was to improve the accuracy of the tools to quantify brain tissue so to better reflect the imaging characteristics of older people. All data presented in this thesis are from the AGES-Reykjavik Study including 5764 elderly men and women. The data is based on cross-sectional and longitudinal assessments of the brain with MRI measures. Show less
Alzheimer’s disease (AD) is the most common cause of dementia and quickly becoming one of the most burdening diseases of the century. Effective treatments are still missing, partially because its... Show moreAlzheimer’s disease (AD) is the most common cause of dementia and quickly becoming one of the most burdening diseases of the century. Effective treatments are still missing, partially because its pathogenesis is still incompletely understood. This thesis explores the role of iron in AD, how it interacts with the immune system to influence disease pathogenesis and whether it could serve as potential biomarker. The first part of this thesis describes the importance of translational MRI, and how it can be used to increase our understanding of neurological diseases and help identify biomarkers. Subsequently, we used translational MRI to characterize the differences in iron accumulation in the brain between patients with AD and healthy elderly. The second part of this thesis investigated how the immune cells of the brain, microglia, interact with the accumulated iron. Using a combination of advanced multispectral immunofluorescence on brain tissue from AD patients and a human stem-cell derived microglia model, we studied the activation pattern of iron-accumulating microglia in human brains and emulated microglial iron accumulation in vitro. This enabled us to study the effect of iron on the gene expression patterns and function of the brain’s immune cells. Show less
Venous thromboembolism (VTE) encompasses pulmonary embolism (PE) and deep vein thrombosis (DVT). DVT most commonly occurs in the deep veins of the lower extremity but can also occur in the veins of... Show moreVenous thromboembolism (VTE) encompasses pulmonary embolism (PE) and deep vein thrombosis (DVT). DVT most commonly occurs in the deep veins of the lower extremity but can also occur in the veins of upper extremity, abdomen and cerebrum. As symptoms of VTE are nonspecific, the diagnosis of VTE is based on diagnostic tests, including clinical decision rules (CDR), D-dimer tests and imaging. Although the diagnostic management of VTE has greatly advanced in recent years with the introduction of novel CDRs and high-sensitive D-dimer tests, the diagnosis may still be challenging in certain settings. The latter is mainly caused by the indirect way of thrombus visualisation by current imaging tests, such as by showing incompressibility with compression ultrasonography (CUS) or a filling defect on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI).This thesis focuses on challenging settings for diagnosing VTE, including suspected recurrent ipsilateral DVT, upper extremity DVT, cerebral vein thrombosis and portal vein thrombosis. We studied a novel imaging technique called Magnetic Resonance Non-Contrast Thrombus Imaging (MR-NCTI) and its application in these different VTE settings. Show less
The life expectancy of individuals has been almost doubled in the past century. The aging population brings challenges to the economic and medical burden of care-needed dependent older people... Show moreThe life expectancy of individuals has been almost doubled in the past century. The aging population brings challenges to the economic and medical burden of care-needed dependent older people limited by age-associated cognitive impairment. Age-associated cognitive decline is a meaningful experience that occurs over the lifespan.This thesis aimed to evaluate the association of cognitive performance with the risk of cardiovascular events and various causes of mortality in elderly populations. The lower cognitive function performance might be an early manifestation of clinically unrecognized cerebral and systemic vascular pathologies, which signals the future risk of cardiovascular events and mortality.In the present research, we included two longitudinal studies, the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) prospective randomized controlled trial in the elderly population of Scotland, Ireland, and the Netherlands that aimed to evaluate whether treatment with pravastatin decreases the risk of cardiovascular events, and Leiden 85-Plus Study which is a prospective population-based study of 85-year-old inhabitants of Leiden district, the Netherlands. Based on our findings and also considering results from other studies, we concluded that cognitive impairment associates with cardiovascular events and several causes of mortality in elderly individuals. Show less
This thesis aimed to gain more insight into the role of iron in neurodegenerative diseases using high-field MRI. I investigated the pathological correlates of susceptibility-based contrasts on MRI,... Show moreThis thesis aimed to gain more insight into the role of iron in neurodegenerative diseases using high-field MRI. I investigated the pathological correlates of susceptibility-based contrasts on MRI, and how iron accumulation is associated with disease progression both ex vivo and in vivo. Show less
The research described in this thesis was aimed at identifying and understanding biological mechanisms and molecular pathways involved in the pathophysiology of stroke and migraine, including the... Show moreThe research described in this thesis was aimed at identifying and understanding biological mechanisms and molecular pathways involved in the pathophysiology of stroke and migraine, including the detrimental connection between them. The thesis consists of two parts. Part 1 describes multiple experimental stroke research projects in mice in which we set out to: (I) improve the methodology of stroke research, and (II) unravel the stroke-migraine connection using diff erent research strategies, methods, and transgenic mouse models. The mouse models express human pathogenic mutations found in CADASIL, RVCL-S and FHM1 and represent the clinical spectrum of monogenic disorders linking ischemic stroke and migraine. Part 2 includes multiple clinical projects in which we set out to study a large cohort of ischemic stroke patients with and without migraine in search for means to investigate stroke characteristics and vascular pathology. Show less
Cervical motion preservation prostheses are considered a developing technology, with widespread clinical use beginning in the early 2000s. They are developed to reduce adjacent segment degeneration... Show moreCervical motion preservation prostheses are considered a developing technology, with widespread clinical use beginning in the early 2000s. They are developed to reduce adjacent segment degeneration (ASD) in the postsurgical follow-up by maintaining range of motion (ROM). However, it is still a controversial issue. The main objective of this thesis was to uncover the relationship between preserved motion and radiological ASD in patients with single-level cervical radiculopathy. Other factors which may be correlated to ASD were studied as well. Show less
Patients with social anxiety disorder (SAD) are 'extremely shy': they are afraid of a negative evaluation by others and avoid social situations as much as possible, with negative influence on... Show morePatients with social anxiety disorder (SAD) are 'extremely shy': they are afraid of a negative evaluation by others and avoid social situations as much as possible, with negative influence on their lives. It is therefore important to gain insight in the factors that make children and adolescents vulnerable to develop SAD.SAD often runs in families: being ‘genetically close’ to a patient with SAD substantially increases the risk to develop the disorder. The studies summarized in this thesis aim to broaden our knowledge of this genetic vulnerability to SAD, by focusing on neurobiological endophenotypes as measured with structural and functional magnetic resonance imaging. We used data from the unique Leiden Family Lab study on Social Anxiety Disorder and demonstrated that several structural and functional brain alterations were genetically linked to the disorder. These results offer novel insights in the neurobiological pathways leading to SAD, and provide clues for prevention and intervention. Show less
Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder with a broad spectrum of clinical features. The disease is caused by a mutation in the Huntingtin gene (HTT... Show moreHuntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder with a broad spectrum of clinical features. The disease is caused by a mutation in the Huntingtin gene (HTT) on the short arm of chromosome 4. In September 2015, the first-in-human study looking into the safety of an intrathecally administered antisense oligonucleotide therapy to reduce mutant HTT (mHTT) protein was launched in HD patients, where the drug proved to be safe and the intended mHTT lowering was demonstrated. The aim of this thesis is to find biomarkers corresponding with disease state and measuring progression in different stages of HD, which in turn can be used as suitable objective surrogate clinical trial endpoints. We put special emphasis on longitudinal study designs, as these provide the most useful clinical progression and parameter change associations. Although previous neuroimaging studies have shown potential markers, findings remain inconsistent or lacking association with disease state. As such, further exploration of neuroimaging techniques is of great relevance. Using different approaches to evaluate the potential usefulness of specific markers, we demonstrate biomarkers that may assist in the objective assessment of a potential disease-modifying intervention. Show less
Huntington’s disease (HD) is a progressive autosomal dominant inherited neurodegenerative disorder.The primary aim of this thesis is to examine alterations in the cerebral cortex in HD gene... Show moreHuntington’s disease (HD) is a progressive autosomal dominant inherited neurodegenerative disorder.The primary aim of this thesis is to examine alterations in the cerebral cortex in HD gene carriers. Different image modalities and approaches will be used to extent the knowledge on both structural and functional cortical brain changes in early disease. Although striatal atrophy is more extensively present in HD, changes in the cerebral cortex can also be detected in the pre-symptomatic stage. Different methodological approaches used in our studies all showed a consistent pattern of cortical atrophy making volumetric MRI a reliable and effective tool to assess early in-vivo cortical brain changes, even in a rare neurodegenerative disorder such as HD. The influence of cortical changes on other clinical signs that occur in HD should not be overlooked. Our results demonstrate that volume loss and thinning of the cerebral cortex, especially the posterior brain regions, is detectable in early stages and contributes to the presence of specific motor signs and cognitive impairments. We believe that intervention trials could benefit from using cortical volumes as outcome measures, instead of using striatal volumes alone. Show less
Studies in this thesis were performed in a secondary care cohort of patients with hand osteoarthritis. Several factors were investigated for their association with disease status and disease... Show moreStudies in this thesis were performed in a secondary care cohort of patients with hand osteoarthritis. Several factors were investigated for their association with disease status and disease progression after two years. These factors included comorbidity, illness perceptions and MRI-defined inflammatory features such as bone marrow lesions, synovitis and joint effusion. In the MRI studies we found that these MRI-features have a clinically relevant role for their association with pain (at the same moment and after two years) and progression of radiographic damage after two years. In the second part of this thesis we evaluated the clinimetric properties of two new instruments: self-reported painful joint count and semi-automatic joint space width measurements. Show less
In this thesis we have analyzed an important number of laboratory, radiological, clinical and patient´s reported outcomes in systemic lupus erythematosus (SLE) patients presenting with... Show moreIn this thesis we have analyzed an important number of laboratory, radiological, clinical and patient´s reported outcomes in systemic lupus erythematosus (SLE) patients presenting with neuropsychiatric (NP) manifestations. Our studies are among the most robust to date in this field due to the large number of patients included, the prospective character and the standard assessment followed by a multidisciplinary expert consensus.Furthermore our studies include the novelty of a phenotypic characterization of all NP manifestations according to the suspected underlying pathophysiological mechanism (inflammation or immune-mediated vs. ischemic or thrombotic). These studies give more light to the understanding of the underlying pathophysiological mechanisms of nervous involvement in SLE. Show less
This thesis provides insight in the impact of congenital and acquired heart diseases on electrophysiology and hemodynamics in the heart, that could help understand the often complex... Show moreThis thesis provides insight in the impact of congenital and acquired heart diseases on electrophysiology and hemodynamics in the heart, that could help understand the often complex pathophysiological mechanisms involved in cardiovascular diseases and might aid in the early detection of patients prone to cardiovascular deterioration. The first part of this thesis shows the value of the electrocardiogram and vectorcardiogram in the assessment of patients with right-sided acquired and congenital heart defects. The 3D vectorcardiographic VG and SA could be valuable in the assessment of patients with right ventricular volume or pressure overload. The second part of this thesis shows significant steps towards clinical utility of 4D flow MRI. Valvular flow quantification with 4D flow MRI, especially in combination with automated valve tracking, has great potential as a future clinical standard. The third part of this thesis provides important insights in intraventricular hemodynamics in Fontan patients. In time to come, knowledge on intraventricular hemodynamics could aid in determining follow-up frequency and the ideal timing of initiation of heart failure management, perhaps even on an individual patient’s level. Moreover, these findings can create a platform for further research in the field of intraventricular hemodynamics in healthy subjects and different patient groups. Show less
This thesis evaluates two total hip implant designs used in the younger aged patient population; (1) a cementless THR with a conventional cobalt on polyethylene (CoP) bearing and (2) a THR with a... Show moreThis thesis evaluates two total hip implant designs used in the younger aged patient population; (1) a cementless THR with a conventional cobalt on polyethylene (CoP) bearing and (2) a THR with a MoM bearing. An analysis into outcome and failure mechanisms on both designs was performed with focus on: The clinical outcome and survival of a conventional MoP THA cohort with the 24-year follow-up and an analysis into factors associated with clinical and radiographic outcome. The clinical evaluation of a large head MoM THA cohort. Analysis of failure of the MoM THA in relation to anatomical reconstruction of the hip. The failure mechanisms of the MoM THA as visualised at MRI images. The reproducibility of the histological scoring system of peri-articulair tissue reactions of failed MoM THA. Show less
In this thesis we determined the added value of MR imaging in primary care for patients with knee complaints. We conducted a randomised controlled trial including patients with knee complaints... Show moreIn this thesis we determined the added value of MR imaging in primary care for patients with knee complaints. We conducted a randomised controlled trial including patients with knee complaints after trauma, aged 18-45 year. Patients were randomised between usual care (no MR scan) or an MR scan within 2 weeks. MR imaging was bot non-inferior but also not superior to usual care. On the 1-year follow-up, patients in the MR group more often perceived themselves to be recovered and more often reported to be satisfied during the 1-year follow-up. However, the MR scan requested by the GP neither improved health outcomes, nor saved costs. Furthermore, in the MR group there was no reduction in the orthopaedic referral rate and a non-significantly higher proportion of patients underwent an arthroscopy. We also evaluated the added value of MR imaging for patients suspected to develop knee osteoarthritis. We combined early MR osteoarthritis features into a prediction model, resulting in moderate sensitivity and specificity rates for the development of radiographic knee osteoarthritis. We concluded that for the entire population seeking medical attention of the GP for knee complains, MR imaging does not contribute to an improved clinical outcome nor to cost containment. Show less
