This thesis describes studies of individuals with systemic lupus erythematosus (SLE) presenting with neuropsychiatric (NP) symptoms at the Leiden NPSLE clinic. A diverse range of studies, including... Show moreThis thesis describes studies of individuals with systemic lupus erythematosus (SLE) presenting with neuropsychiatric (NP) symptoms at the Leiden NPSLE clinic. A diverse range of studies, including laboratory, radiological, clinical and patient´s reported outcomes are presented.The Leiden NPSLE clinic is a tertiary referral center for patients with SLE and neuropsychiatric (NP) symptoms. In the NPSLE clinic, patients are assessed by a multidisciplinary team. Thereafter, clinical, radiological and laboratory measures are weighed in a consensus meeting to correctly attribute the NP symptoms: related to lupus activity (NPSLE) or not. This extensive and standardized assessment of NPSLE, a rare and heterogenous disease lacking a gold standard, is unique and creates the opportunity to explore many aspects of NPSLE in well-defined phenotypes.In the first part of this thesis, we evaluate both classification and treatment of patients withSLE and NP symptoms. The second part of this thesis focuses on a diverse range of clinicaloutcomes of NPSLE, including both morbidity and mortality. The last part of this thesisassesses potential biomarkers for (specific manifestations of) NPSLE. 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
More than 45 years of research on the effects of glucocorticoids on brain function has yielded many insights, but also left a number of longstanding questions. One conundrum has been how activation... Show moreMore than 45 years of research on the effects of glucocorticoids on brain function has yielded many insights, but also left a number of longstanding questions. One conundrum has been how activation of the structurally comparable mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) can lead to very different, or even opposite effects. It also remained unclear how the consequence of activation of a single receptor, GR, can differ from cell to cell and from situation to situation. In this thesis we have investigated two aspects of transcriptional regulation in response to glucocorticoids: the cause of MR/GR specificity, and the role of crosstalk with other transcription factors. Within the hippocampus, we found NeuroD factors to drive the specificity in corticosteroid receptor DNA binding and subsequent gene regulation, i.e. by stimulating MR signaling. We identified Jun dimerization protein 2 (Jdp2) as a stress-responsive MR-specific target gene. In a stress hormone relevant memory task, GR was suggested to act context-dependently and several novel GR target genes were detected. Further elucidation of distinct MR/GR downstream pathways will enable us to better understand the stress physiology and more specifically target aspects of glucocorticoid signaling for treatment of stress-related disorders. 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 describes the longitudinal population-based CAMERA-study on the association between migraine and brain changes (e.g. white matter hyperintensities, infarct-like and other lesions) and... Show moreThis thesis describes the longitudinal population-based CAMERA-study on the association between migraine and brain changes (e.g. white matter hyperintensities, infarct-like and other lesions) and possible causes and consequences of those brain changes. Women with migraine showed higher incidence of deep white matter hyperintensities after nine years of follow-up. Infratentorial hyperintensities were also found more often among migraine women compared to controls. Migraine severity characteristics were not associated with progression of lesions. By using voxel based morphometry region-of-interest analyses, migraineurs showed decreased grey matter volume in visual areas of the right occipital cortex compared to controls. The occurrence of ischemia during attacks seems a logical explanation for the development of lesions. One other possible explanation for brain lesions is recurrent paradoxical (micro-)emboli as a result of right-to-left shunting (RLS). In our study, RLS are also more prevalent among migraineurs than among controls. As for the possible consequences: migraine patients and controls showed similar performance on all cerebellar functioning tests. In addition, cognitive functioning was similar for migraine patients and controls, deep white matter hyperintensities were not related to impaired cognitive performance, and migraine had no influence on this association. Our findings are reassuring for migraine patients and their doctors. Show less
The prevalence of obesity, defined as a body mass index (BMI) > 30 kg/m2, is increasing to epidemic proportions. In 2014, 11% of men and 15% of women worldwide were obese. Thus, more than... Show moreThe prevalence of obesity, defined as a body mass index (BMI) > 30 kg/m2, is increasing to epidemic proportions. In 2014, 11% of men and 15% of women worldwide were obese. Thus, more than half a billion adults worldwide are classed as obese. The fundamental cause of obesity is an imbalance between energy intake (excessive intake of energy-dense foods) and energy expenditure (reduced physical activity). People with obesity are at risk for a range of chronic conditions including cardiovascular disease (CVD) and nonalcoholic fatty liver disease (NAFLD). Furthermore, obesity is a major risk factor for the development of type 2 diabetes, which is one of the most common chronic diseases in nearly all countries. According to the World Health Organization, the global prevalence of diabetes in 2014 was estimated to be 9%, of which 90% was comprised of type 2 diabetes. This thesis focuses on cardiovascular and cerebral dimensions and function in people with obesity and type 2 diabetes. State-of-the-art imaging techniques are used to investigate links between the heart, liver, abdominal fat, and brain to elucidate parts of the complex relationships between these organs. Show less
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness caused by DMD gene mutations leading to absence of the full-length dystrophin protein in muscle. Multiple... Show moreDuchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness caused by DMD gene mutations leading to absence of the full-length dystrophin protein in muscle. Multiple dystrophin isoforms are expressed in brain, but little is known about their function. DMD is associated with specific learning and behavioral disabilities which are more prominent in patients with mutations in the distal part of the DMD gene, predicted to affect expression of shorter protein isoforms. The aim of this thesis was to provide a detailed description of the structural, perfusion and metabolic differences in the brain between patients with DMD and healthy age-matched controls and to assess the role of dystrophin isoforms. Show less
In this thesis I have described the introduction and validation of a new spatially non-selective arterial spin labeling (SNS-ASL) method in healthy subjects. Acceleration selective ASL (AccASL... Show moreIn this thesis I have described the introduction and validation of a new spatially non-selective arterial spin labeling (SNS-ASL) method in healthy subjects. Acceleration selective ASL (AccASL) was compared with pseudo continuous ASL (pCASL), a traditional ASL method, as well as other spatially non-selective ASL methods (velocity selective ASL, as introduced by Wong et al with two velocity-selective blocks, and using only a single labeling module), and with [15O]-H2O PET as the gold standard for brain perfusion imaging. By combining an AccASL with VSASL labeling module, the location of label origin in the vascular tree was assessed. Furthermore, time-encoded pCASL was explored in combination with SNS-ASL labeling modules to obtain insight into labeling at multiple post labeling delays (PLD). Finally, te-pCASL was combined with T2-Relaxation-under-Spin-Tagging (TRUST) to provide a time efficient method to distinguish spin compartments based on their T2-values. Show less
