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Koemans, E.A. 2024

Staging cerebral amyloid angiopathy: from marker to model

Doctoral Thesis

some documents under embargo until 2025-11-29

Cerebral Amyloid Angiopathy (CAA) is one of the main causes of intracerebral hemorrhage (ICH) in the elderly, and affects millions of people worldwide. CAA is caused by the deposition of the... Show moreCerebral Amyloid Angiopathy (CAA) is one of the main causes of intracerebral hemorrhage (ICH) in the elderly, and affects millions of people worldwide. CAA is caused by the deposition of the protein Amyloid-β in the walls of the cerebral and leptomeningeal vessels, which leads to vessel fragility and eventually rupture. CAA has a variable disease course and can present with a spectrum of symptoms. There is currently no cure for CAA, and certain diagnosis during life remains challenging.This thesis has used data from patients with hereditary and non-hereditary (sporadic) CAA to investigate novel clinical and radiological (MRI) markers of CAA, and has used them to formulate a pathophysiologic framework for the temporal ordering of disease processes in CAA. Our results provide new insights in the disease cascade, can aid in diagnosing the disease and have important implications for future clinical trial design, aiding in the identification and timing of candidates for disease-modifying treatments and the choice for the appropriate biomarkers to monitor treatment effect. CAA is a disease with a complex disease cascade and a large variety in disease course, both clinically and radiologically. However, it is just this variety that gives hope for the future: if we find what drives variability in CAA we might find ways for disease modification, prevention and treatment, and identification of in vivo biomarkers with specificity for CAA are a vital part of this search. Show less

Leijsen, R.L. 2024

Electrical property mapping using MRI: analytical methods and implementations

Doctoral Thesis

open access

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

Hoogeveen, E.S. 2024

Vascular and structural neuroimaging findings in migraine and RVCL-S

Doctoral Thesis

some documents under embargo until 2025-08-13

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

Matthijssen, X.M.E. 2022

Differences and similarities of autoantibody-positive and autoantibody-negative rheumatoid arthritis during the disease course: on our way to personalized medicine

Doctoral Thesis

open access

This thesis aims to assess the differences and similarities between autoantibody-positive and autoantibody-negative RA from the start of complaints to the end of the disease. The described research... Show moreThis thesis aims to assess the differences and similarities between autoantibody-positive and autoantibody-negative RA from the start of complaints to the end of the disease. The described research was performed with the ultimate goal to clarify whether autoantibody-negative and autoantibody-positive RA are distinct diseases that require different diagnoses and treatment. Show less

Kenkhuis, B. 2022

Iron-immune interactions in Alzheimer's disease

Doctoral Thesis

open access

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

Dam, L.F. van 2022

Novel imaging strategies in venous thromboembolism

Doctoral Thesis

open access

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

Rostamian, S. 2021

Cognitive function, vascular events, and mortality in old age

Doctoral Thesis

open access

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

Bulk, M. 2021

The iron brain: Post-mortem and in vivo imaging of iron in brain diseases

Doctoral Thesis

open access

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

Dakkak, Y.J. 2020

The forefoot in early rheumatoid arthritis: Anatomy, imaging and clinical aspects

Doctoral Thesis

open access

Rheumatoid arthritis (RA) is a disease of the synovium that involves the small joints of hands and feet. The focus in RA-research, however, has primarily been on involvement of the hands. In this... Show moreRheumatoid arthritis (RA) is a disease of the synovium that involves the small joints of hands and feet. The focus in RA-research, however, has primarily been on involvement of the hands. In this thesis we studied involvement of the forefoot. Throughout this thesis we found that synovitis in the rheumatoid foot affects more than just the joints. In an anatomic study we revealed that the tendon-sheaths in the forefoot also possess a synovial layer. Inflammation of this, detected by MRI that is referred to as tenosynovitis, was an important aspect of RA involvement in the forefoot. In addition, intermetatarsal bursae also detected by MRI are also often inflamed due to disease-involvement. These extra-articular involvements of the synovium that are found in RA importantly contribute to joint swelling and walking disability, and are therefore clinically relevant. Therefore we believe that it is essential for the clinician to pay attention to the forefeet of patients with RA to have a complete idea of disease activity Show less

Mulder, I.A. 2020

Stroke and migraine: Translational studies into a complex relationship

Doctoral Thesis

open access

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

Boeters, D.M. 2020

Early identification and resolution of rheumatoid arthritis

Doctoral Thesis

open access

overzicht van verschillende voorspellers voor het ontwikkelen van RA binnen patiënten met artralgie

rol van nieuwe autoantistoffen en MRI in vroege diagnostiek RA

onderzoek naar behalen van DMARD...

overzicht van verschillende voorspellers voor het ontwikkelen van RA binnen patiënten met artralgie

rol van nieuwe autoantistoffen en MRI in vroege diagnostiek RA

onderzoek naar behalen van DMARD-vrije remissie: voorkomen van immunologische remissie en identificatie van subgroep van RA-patiënten met verhoogde kans op remissie

Show less

Yang, X. 2020

Motion preservation in cervical prosthesis surgery: Implications for adjacent segment degeneration

Doctoral Thesis

open access

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

Bas, J.M. 2020

Extremely shy & genetically close : investigating neurobiological endophenotypes of social anxiety disorder

Doctoral Thesis

some documents under embargo

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

Odish, O.F.F. 2019

Functional and structural neuroimaging in Huntington’s disease

Doctoral Thesis

open access

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

Coppen, E.M. 2019

Structure and function of the cerebral cortex in Huntington's disease

Doctoral Thesis

open access

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

Damman, W. 2019

Lessons learnt about two-year follow-up in hand osteoarthritis: the HOSTAS study.

Doctoral Thesis

some documents under embargo

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

Magro Checa, C. 2019

On cerebral lupus: from pathogenesis to clinical outcomes

Doctoral Thesis

open access

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

Aizenberg, E. 2019

Computer-aided techniques for assessment of MRI-detected inflammation for early identification of inflammatory arthritis

Doctoral Thesis

open access

Inflammatory arthritis comprises a group of diseases in which the immune system attacks the body’s own tissues. Two prevalent types of inflammatory arthritis are rheumatoid arthritis (RA) and... Show moreInflammatory arthritis comprises a group of diseases in which the immune system attacks the body’s own tissues. Two prevalent types of inflammatory arthritis are rheumatoid arthritis (RA) and spondyloarthritis (SpA). Clinical research points to the importance of early diagnosis, as treatment in early disease stages increases chances of better outcome and improved quality of life for patients. To this end, the diagnostic potential of imaging modalities sensitive to local inflammation, such as magnetic resonance imaging (MRI), is of great interest. The goal of this thesis was to develop computer-aided methods for assessment of MRI-detected inflammation with the aim of aiding early diagnosis of inflammatory arthritis. In particular, we focused on the tasks of comparative visualization, automatic quantification, and feature selection. The presented studies showcase the potential of comparative visualization and automatic quantification to overcome the limitations of visual scoring and lay out a fertile ground for future improvements. Additionally, the understanding of the diagnostic role of individual inflammatory features in prediction of RA development is further advanced. Collectively, these findings can help facilitate the use of MRI for early diagnosis of inflammatory arthritis and potentially increase chances of better outcome and quality of life for patients. Show less

Kamphuis, V.P. 2019

Multidimensional evaluation of cardiac hemodynamics and electrophysiology in patients with congenital and acquired heart disease

Doctoral Thesis

open access

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

Smeekes, C. 2018

Uncemented total hip arthroplasty. Wear is the problem

Doctoral Thesis

open access

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

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