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
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
The focus of this thesis was to evaluate biomarkers of cardiovascular end organ damage in the metabolic syndrome and diabetes mellitus. We performed cross-sectional studies with biochemical and... Show moreThe focus of this thesis was to evaluate biomarkers of cardiovascular end organ damage in the metabolic syndrome and diabetes mellitus. We performed cross-sectional studies with biochemical and magnetic resonance imaging (MRI) techniques. We have demonstrated that insulin resistance is a strong risk predictor for CVD and we provided a novel link between inflammation and angiopoietin-like protein 4 (ANGPTL4) expression by showing that ANGPTL4 levels in humans are related to systemic inflammation and inflammatory stimuli increased ANGPTL4 expression using human macrophages in vitro. The imaging studies described in this thesis extend the knowledge of end organ damage and explored the relation with aortic stiffness. The impact of type 1 diabetes mellitus (T1DM) on regional grey matter was investigated and showed atrophy of all subcortical grey matter structures but the amygdala. By showing an association of aortic stiffness with subtle microstructural deficits in T1DM and kidney function in patients with hypertension the close link between aortic stiffness and the microcirculation is demonstrated. Furthermore regional and individual differences in response to an oral glucose load in MR assessed aortic stiffness were observed, which may open new future research paths possibly linking inter-individual variation in regional vascular response and CVD. Show less
Akintola, A.A.; Berg, A. van den; Altmann-Schneider, I.; Jansen, S.W.; Buchem, M.A. van; Slagboom, P.E.; ... ; Grond, J. van der 2015
The aims of this thesis were to gain insight into specific disease processes in Huntington__s Disease (HD) and to identify biomarkers. To achieve these aims, cognitive functioning, structural brain... Show moreThe aims of this thesis were to gain insight into specific disease processes in Huntington__s Disease (HD) and to identify biomarkers. To achieve these aims, cognitive functioning, structural brain characteristics and intrinstic functional brain connectivity of premanifest and early HD subjects were examined. Cortical, subcortical and the intermediate white matter brain tissue shows evidence of structural and functional decline. We found evidence that disease processes, such as altered metabolism, excessive iron accumulation and cell loss, play a role in the changes. We conclude that changes occur throughout the brain from the earliest disease phase onwards. Hence, both premanifest and manifest HD should not be regarded as a disorder of the basal ganglia, but as a disease affecting the whole brain. Candidate biomarkers that have the potential to objectively reflect the early changes and the progressive nature of the disease are measures of subcortical atrophy, integrity of white matter pathways and of intrinsic functional brain connectivity. Iron, creatine, and N-acetylaspartate concentrations in the caudate nucleus and putamen may prove to be useful as markers of disease state for objectifying transitional disease processes from premanifest to manifest HD. Visuospatial working memory could be applied as a state marker for stage two HD. Show less
The aim of this thesis was to find potential MRI biomarkers for Huntington__s disease (HD). Therefore, after an overview of the current literature on MRI biomarkers, followed by examinations of... Show moreThe aim of this thesis was to find potential MRI biomarkers for Huntington__s disease (HD). Therefore, after an overview of the current literature on MRI biomarkers, followed by examinations of volumetric MRI, magnetization transfer imaging (MTI), diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) were applied in patients in different disease stages of HD. The main conclusions demonstrate that choosing the optimal biomarker for evaluating therapeutic effects is dependent on the disease stage and therapeutic compound. To evaluate the premanifest stages of the disease volumetric MRI and DTI are most suitable. When the transition period is the desired timeframe for evaluation, also MRS can be very useful, especially if the compound in question has a direct potential influence on certain pathogenic pathways which in turn have an impact on specific metabolites. Future research should focus on combining multiple imaging techniques; __multimodal imaging__. A composite MRI biomarker has the potential to distinguish between disease groups more accurately than a single biomarker and in this way improve the evaluation of therapeutic compounds. Show less
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small-vessel disease caused by mutations in the NOTCH3 gene on chromosome 19.... Show moreCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small-vessel disease caused by mutations in the NOTCH3 gene on chromosome 19. Magnetic resonance (MR) imaging plays an important role in the diagnostic work-up of CADASIL patients. In this thesis we describe the presence of microbleeds and a new, highly characteristic radiological finding in CADASIL patients, the so called subcortical lacunar lesions (SLL). We describe the natural history of the various brain lesions that can be observed in CADASIL patients, the microbleeds, SLL, lacunar infarcts, and white matter hyperintensities (WMHs). Also included are the results of a study on the differences of the lesions seen in CADASIL as compared to the lesions that occur in multiple sclerosis, a disease with radiological and clinical similarities to CADASIL. We found that MR lesions develop in a predictable way during the course of the disease and that SLL and WMHs in the anterior temporal lobe are helpful radiological hallmarks for the of detection CADASIL. The WMHs in the anterior lobe especially in combination with one of the other CADASIL MR hallmarks should distinguish CADASIL patients from patients with multiple sclerosis. Show less
