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
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
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 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
The main aim of this thesis is to determine the role of magnetic resonance imaging (MRI) in early rheumatoid arthritis (RA). We set out to improve the MRI protocol and sequences used in arthritis... Show moreThe main aim of this thesis is to determine the role of magnetic resonance imaging (MRI) in early rheumatoid arthritis (RA). We set out to improve the MRI protocol and sequences used in arthritis patients, to detect subclinical inflammation in various patient groups and to describe the clinical implications of MRI. Chapter 1 provides a general introduction to this thesis, in chapter 2 the earliest disease stages of rheumatoid arthritis and the concept of pre-rheumatoid arthritis are further explored. In chapters 3-5 various ways are described to optimize the scanning protocol for arthritis patients. In chapters 6-8 we looked at the presence of inflammation on MRI when no inflammation can be detected at physical examination, i.e. subclinical inflammation. In chapters 9 and 10 we explore some of the clinical implications of the MRI findings. Chapter 11 provides a summary of the thesis and a discussion of the main findings. Show less
Newborn infants requiring intensive care treatment are at risk of cerebellar injury. This can have important consequences for long-term neurodevelopmental outcome. The aim of this thesis was to... Show moreNewborn infants requiring intensive care treatment are at risk of cerebellar injury. This can have important consequences for long-term neurodevelopmental outcome. The aim of this thesis was to study the incidence and characteristics of cerebellar injury, and to investigate the role of different neuroimaging techniques (cranial ultrasound (CUS) with additional mastoid fontanelle (MF) views and MRI) for its detection in both preterm and high-risk term infants. Part I describes the standard CUS procedure and supplementary imaging techniques to optimize its performance, including the use of additional acoustic windows. Part II focuses on the detection, risk factors and prognostic implications of cerebellar injury in preterm infants. Part III focuses on CUS and MRI findings of posterior fossa abnormalities in full-term infants with various neonatal disorders. Part VI reviews the main findings and conclusions of this thesis, and discusses future perspectives and proposals for further research. Based on the findings of this thesis, we conclude that in both preterm and critically ill full-term infants CUS protocols should include MF views. This enables early detection of most major and clinically relevant posterior fossa abnormalities. Routine MRI for the detection of small hemorrhagic lesions is not warranted, as these lesions have a favorable prognosis Show less
The general objective of this thesis was to investigate new (quantitative) MR techniques and MR markers in the light of both AD and cerebral aging. The quantitative MR techniques that we used were... Show moreThe general objective of this thesis was to investigate new (quantitative) MR techniques and MR markers in the light of both AD and cerebral aging. The quantitative MR techniques that we used were MTI, tCBF and WSS measurements. The new markers we studied were cerebral microbleeds and iron accumulation in the basal ganglia. In chapter 2 we investigated whether MTI changes could be detected in the GM, WM or both in patients suffering from MCI or AD. Using MTI we found evidence for structural brain changes in both GM and WM of patients with MCI and AD. Furthermore, these MTI changes were related to cognitive impairment as expressed by the mini mental state examination (MMSE) score. These findings imply that cerebral changes can be detected in both GM and WM even before patients are clinically demented. The finding of MTI changes in the GM might relate to classical AD type pathology, whereas WM MTI changes could indicate concomitant vascular pathology. The findings in chapter 2 raised the question of how the MTI changes found in this study are distributed over the GM and WM. This was investigated in chapter 3. In this study we showed that brain damage, as detected by MTI, is widespread over the lobes in both AD and MCI patients whereas GM damage is more focally present in the temporal and frontal lobe of MCI patients. These findings are compatible with the knowledge that GM damage originates from the temporal lobe in AD. This interpretation is further supported by the observed independent association between temporal GM peak height and cognitive decline. MTI changes were found in all four lobes of the MCI patients investigated in this study and show the involvement of a diffuse process affecting the WM even before patients are clinically demented, a finding potentially explained by the presence of diffuse vascular pathology. Chapter 4 shows that the tCBF is strongly associated with parenchymal volume rather than age and, although much weaker, with the severity of WMHs. Although the association between tCBF and parenchyma volume seems straightforward, this finding has important implications for future studies. Volume flow measurements should be corrected for parenchymal volume ratherthan age in all future studies in which flow measurements are being used as a diagnostic tool. In addition, studies including elderly patients or patients with a pathological increase of WMHs, such as diabetic type II subjects, should also correct their tCBF measurements for WMH volumes. Chapter 5 shows that hemodynamic conditions of the carotid and basilar arteries, as expressed in lower WSS parameters, are worse in both MCI and AD compared to controls. In addition, the WSS parameters were found to correlate strongly with cognition. Again, this study is additional evidence for an important role of vascular pathology in the development of AD. In chapter 6, we found a high prevalence of microbleeds in a population of patients suffering from vascular disease or at high risk of developing this condition. Age, hypertension and WMH were the most important risk factors for microbleeds, especially when located in the cortico-subcortical junction and basal ganglia. Regarding the associations between the presence and location of microbleeds on the one hand and parameters of cognitive functioning on the other, chapter 7 shows that microbleeds located infratentorially are associated with impaired cognitive functioning in the aging population with increased vascular risk factors. This suggests that in elderly individuals microbleeds in the posterior fossa should be considered a sign of small vessel disease with potential functional consequences. The semi-quantative scale for scoring basal ganglia hypo-intensity on T2*- weighted imaging presented in chapter 8 was associated with markers of neurodegeneration. This study showed that low signal intensity of the caudate nucleus T2*-weighted MR is a frequent finding which is associated with more cerebral atrophy, a higher load of WMH and a higher load of invisible changes in both cortical GM and NAWM non-demented elderly. Furthermore, hypo- intensity limited to the globus pallidus and putamen was not associated with any of these parameters of neurodegeneration. In chapter 9 we present a method for automated detection and classification of hypo-intense regions on T2-weighted MR images of the basal ganglia. In this chapter we not only show an association between basal ganglia hypo-intensity and cardiovascular risk factors but also with measures of cognitive functioning. From this we conclude that hypo-intensity of the basal ganglia on T2-weighted MR is not only a radiological finding accompanying cerebral aging but also an independent marker of neurodegeneration. Show less
CADASIL is a hereditary cerebral small vessel disease, caused by a mutation in the NOTCH3 gene, leading to migraine with aura, cerebrovascular accidents and cognitive decline at young to middle... Show moreCADASIL is a hereditary cerebral small vessel disease, caused by a mutation in the NOTCH3 gene, leading to migraine with aura, cerebrovascular accidents and cognitive decline at young to middle adult age. MRI scans of the brain may show lacunar infarcts, white matter lesions and microbleeds. In this thesis MRI scans of the brains are used to investigate the disease course in CADASIL. It is shown that lacunar infarcts, white matter lesions and microbleeds are progressive in CADASIL patients. Vascular risk factors are not associated with rate of progression of these MRI abnormalities. However, the rate of disease progression can be predicted by measuring the amount of MRI abnormalities at baseline. Lacunar infarcts, microbleeds and increased white ventricular volume are strongly associated with cognitive decline in CADASIL. Progression of white matter hyperintensities can be predicted by measurements of cerebrovascular reactivity. Using high-field MRI we demonstrated that luminal diameters of lenticulostriate arteries are normal in CADASIL, and that lacunar infarcts in CADASIL are not the result of luminal narrowing of these vessels. High-field MRI also showed that CADASIL patients have an increased diffuse iron deposition in the putamen and caudate nucleus of the brain. Show less
This thesis evaluates the relationship between structural and functional aortic vessel wall alterations and end-organ damage in cross-sectional patient studies with use of MRI. These studies show... Show moreThis thesis evaluates the relationship between structural and functional aortic vessel wall alterations and end-organ damage in cross-sectional patient studies with use of MRI. These studies show that aortic pulse wave velocity (PWV) in DM1 patients is mainly determined by hypertension, whereas the effect of DM1 itself on aortic PWV is marginal. Increased aortic PWV in patients with hypertension is associated with aortic and carotid vessel wall alterations. Also, increased aortic PWV is associated with cardiac as well as cerebral damage both in hypertensive and DM1 patients. Furthermore, this thesis describes and evaluates the ability of more optimized cardiac MRI-techniques for assessment of cardiovascular disease. Right coronary artery flow can be accurately and reproducibly assessed using 3T VE MRI in healthy control subjects. Furthermore, the use of standardized 7T MRI protocols for assessment of LV volumes, function and flow provides similar quantitative results when compared to 1.5T MRI. Finally, 3D three-directional VE MRI better describes LV diastolic function as compared to 2D one-directional VE MRI in patients with ischemic heart failure. Show less
The general objective of this thesis was to investigate whether early clinical alterations and structural and functional brain markers could be detected in carriers of the Huntington__s disease... Show moreThe general objective of this thesis was to investigate whether early clinical alterations and structural and functional brain markers could be detected in carriers of the Huntington__s disease gene (referred to as carriers) who are still without manifest motor signs. We aimed to detect brain deficits using MRI and found smaller basal ganglia volumes in carriers compared to non carriers. Also, we demonstrated an increased amount of hypointensities in basal ganglia of carriers and suggested this may reflect excessive iron deposition. Furthermore, we showed strong associations between MRI characteristics and clinical variables suggesting that a combination of these measures may shed more light on the contribution of different kinds of pathological processes to the changing phenotype. When using memory activation during EEG registration early funcional brain changes, reflected in reduced alpha power, could be demonstrated in carriers. Furthermore, remarkably strong associations were found between the P3 Event-Related Potential and basal ganglia volumes. Subtle clinical abnormalities in motor function, executive function and memory could be demonstrated in carriers, especially over time. This study showed that several biomarkers provide new and important information on premanifest HD. The mulitfactorial approach offers new insights into the relation between clinical phenomena and abnormalities in the neural substrate Show less
Onderzocht werd of het mogelijk was om met MRI de maagfysiologie op non-invasieve wijze te onderzoeken. Allereerst werd de MRI gevalideerd met de barostatmethode, waarna de fysiologie van de maag... Show moreOnderzocht werd of het mogelijk was om met MRI de maagfysiologie op non-invasieve wijze te onderzoeken. Allereerst werd de MRI gevalideerd met de barostatmethode, waarna de fysiologie van de maag werd onderzocht bij gezonde proefpersonen. Dit bleek betrouwbare resultaten op te leveren. Hierna is een groep gezonden vergeleken met een groep pati_nten met functionele dyspepsie. Met MRI bleken verschillen tussen deze twee groepen duidelijk waarneembaar te zijn. In het laatste deel werd de werking van somatostatine op de maagfysiologie bij gezonden en bij patienten met functionele dyspepsie onderzocht. Met MRI bleek ook hier een effect van somatostatine aantoonbaar te zijn. Er werd geconcludeerd, dat het MRI goed mogelijk is om de maagfysiologie en het effect van medicamenten op de maagfysiologie op non-invasieve wijze te onderzoeken. Show less
The objective of this thesis was to elucidate whether migraine is a true and independent risk factor for brain lesions. We summarized migraine symptoms, diagnostic criteria, epidemiologic data, and... Show moreThe objective of this thesis was to elucidate whether migraine is a true and independent risk factor for brain lesions. We summarized migraine symptoms, diagnostic criteria, epidemiologic data, and assumed pathophysiology. We described the existing literature on the relationship between migraine and ischemic stroke and cerebral white matter lesions (WML). The findings of the population-based CAMERA MRI-study are reported. Posterior circulation (cerebellar) infarcts occurred in 8% of migraineurs with aura (adjusted-OR 13.7). Female migraineurs were at increased risk of high-deep-WML-load (OR 2.0). Risks increased with attack frequency, suggestive of a causal relationship. We detailed on the infarcts and other infratentorial lesions. Findings of higher iron-concentration in deep brain nuclei in younger migraineurs suggest that repeated migraine attacks are associated with changes in regions known to be involved in central pain processing and migraine pathophysiology. In addition, we showed that migraineurs had more syncope-related autonomic-nervous-system symptoms, and we identified frequent syncope and orthostatic insufficiency as independent risk factors for high-DWML-load. With these data, there is now strong evidence that migraine is indeed an independent risk factor for silent brain lesions. The real extent of brain injury in migraine patients in the general population is likely underestimated. Show less
Early dementias are difficult to distinguish from normal age-related memory decline. In the preclinical stages of Alzheimer’s disease and Huntington’s disease, brain functions are already changing... Show moreEarly dementias are difficult to distinguish from normal age-related memory decline. In the preclinical stages of Alzheimer’s disease and Huntington’s disease, brain functions are already changing, but this is not directly visible from the outside. Many research is aimed at discovering early disease markers. However, research using EEG registration during conventional eyes closed conditions revealed little additional information. The yield of EEG research can be improved by probing the weakest spot, which, in case of dementia, is memory. Karin van der Hiele introduced memory tests during EEG registration and found that early abnormalities in brain functioning can then be observed in Alzheimer’s disease and Huntington’s disease. An interesting finding came to light: the EEG in dementia displays a lot of muscle activity which is normally filtered out. However, the researchers decided not to throw this activity away but to measure it. Interestingly, they found that the amount of muscle activity was related to cognition and to the number of depressive complaints. It may pay to keep an open mind regarding the nature of the parameter to be measured. Show less
Aging of the brain was studied by comparing follow-up MRI scans in 554 persons aged 70-82 years. Mean interval time between these scans was three years and scans were looked for changes in cerebral... Show moreAging of the brain was studied by comparing follow-up MRI scans in 554 persons aged 70-82 years. Mean interval time between these scans was three years and scans were looked for changes in cerebral infarcts, white matter lesions, cerebral blood flow, and brain volume. Besides this, the preventive effect of pravastatin on these changes was studied. During the study time there was progression of cerebral infarcts, white matter lesions and there was decline of cerebral blood flow and progression of brain atrophy. Treatment with pravastatin 40 mg/daily did not have a protective effect on these changes. Show less
Ischemic heart disease remains the leading cause of morbidity and mortality in the Western world. Ischemic cardiomyopathy is a frequent cause of chronic heart failure and has become a major problem... Show moreIschemic heart disease remains the leading cause of morbidity and mortality in the Western world. Ischemic cardiomyopathy is a frequent cause of chronic heart failure and has become a major problem in clinical cardiology. In recent years, magnetic resonance imaging (MRI) has been applied increasingly, in the evaluation of patients with CAD. A comprehensive cardiac MRI study including assessment of myocardial perfusion, myocardial function, both at rest and under stress, and delayed contrast-enhancement for myocardial viability imaging, and coronary magnetic resonance angiography for detecting stenosis can now be performed in a relatively short time. Therefore, MRI can be used to evaluate most aspects of the ischemic cascade. Moreover, MRI provides additional information for the surgeon needed to select the optimal surgical strategy, for instance including information on left and right ventricular function, the presence of aneurysms and ischemic mitral regurgitation. The aim of this thesis was to evaluate magnetic resonance imaging (MRI) techniques for the assessment of myocardial viability in patients with acute and chronic myocardial infarction. In addition, remodeling of the ventricles was investigated and evaluated. Show less
