Accurate prediction of the unbound drug concentration-time profile at the CNS target site is crucial for the assessment of the right drug concentration-effect relationship. PBPK models have... Show moreAccurate prediction of the unbound drug concentration-time profile at the CNS target site is crucial for the assessment of the right drug concentration-effect relationship. PBPK models have supported the PK prediction of the CNS target sites and the translation of PK data between species and between populations, given their mechanistic, physiology-based structure. In this thesis, we have developed a CNS PBPK model which could predict adequately the brainECF, brainICF, and CSF unbound PK profiles and provide important insights into the brain unbound pharmacokinetics of patients with CNS diseases. Early prediction of the brain target site pharmacokinetics of the right patient population can prioritize drugs with the favored brain PK profiles, which might optimize and accelerate the CNS drug development process. 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
This dissertation examines what network in the human brain is involved in the perception of prosody and whether activity within this network is modulated by the personality trait alexithymia. The... Show moreThis dissertation examines what network in the human brain is involved in the perception of prosody and whether activity within this network is modulated by the personality trait alexithymia. The first four chapters of this dissertation reveal that a bihemispheric network consisting of Heschl__s gyrus, the middle superior temporal gyrus, the posterior superior temporal gyrus and the pars opercularis of the inferior frontal gyrus is involved in the perception of emotional prosody. Furthermore, relative right hemispheric specialization for emotional prosody perception can be demonstrated but no hemispheric specialization can be found for linguistic prosody perception. Moreover, hemispheric specialization for emotional prosody perception seems to be driven by hemispheric specialization for non-prosody-specific acoustic dimensions of the speech signal, and not for abstract emotional processing. Additionally, automaticity of processing can be demonstrated for emotional prosody, particularly for anger, but not for emotional music. Last, alexithymia can indeed be demonstrated to modulate activity within the emotional prosody perception network, particularly at relatively early components of the emotional prosody perception pathway. This dissertation is of interest to neurolinguists, (neuro-)phoneticians, psychologists, cognitive neuroscientists, comparative biologists and neurologists specialized in aphasia Show less
The results in this thesis showed for the first time doublecortin-like (DCL)-specific expression in the adult mouse brain. Besides the expected regions with the capacity to generate new neurons ... Show moreThe results in this thesis showed for the first time doublecortin-like (DCL)-specific expression in the adult mouse brain. Besides the expected regions with the capacity to generate new neurons (hippocampus and olfactory forebrain), DCL expression was found in three novel brain areas namely hypothalamic tanycytes, suprachiasmatic nucleus and Islands of Calleja. A state of the art conditional shRNA expressing mouse model was used to target DCL mRNA. The analysis of these DCL knockdown animals using qPCR and Western blot revealed strong reduction of DCL protein expression. Subsequent stereological analysis using BrdU and several stem cell and neuronal markers revealed increased progenitor proliferation, but impaired neurogenesis in the hippocampus. This impaired neurogenesis was associated, however, with an apparent normal spatial and contextual fear memory formation in circular hole board and in a contextual fear conditioning paradigm. Therefore, DCL-regulated adult neurogenesis seems not crucial for hippocampus-dependent learning. However, more subtle functions like pattern separation and context distinction might be regulated by DCL. DCL knockdown also increased D2 activity within the hypothalamus. Altogether, the DCL-KD mouse seems a good working model to study adult neurogenesis and the role of DCL in this process. Show less
When a child is often scolded or threatened by his parents (emotional abuse) and /or when a child is structurally ignored or isolated by his parents (emotional neglect) we call this childhood... Show moreWhen a child is often scolded or threatened by his parents (emotional abuse) and /or when a child is structurally ignored or isolated by his parents (emotional neglect) we call this childhood emotional maltreatment (CEM). CEM is the most common form of child abuse, however, CEM is also the most hidden, underreported and least studied form of child abuse. An important reason for this may be because that the consequences of CEM are underestimated (e.g. __Sticks and Stones may break bones, but words will never hurt me__). However, this thesis shows that CEM is related with a persistent negative impact on cognition and the brain. We discovered that individuals that report CEM show differential structure and function of a brain area (the medial prefrontal cortex) that is crucial for role in responding to stress and thinking about yourself. Individuals with CEM also showed more activity in an area that signals threat (the amygdala) which may represent a persistent vigilance towards the detection of threat from others. These brain changes may underlie our other findings that individuals with CEM think more negatively about themselves and others. Negative thoughts can evoke negative thoughts and in new situations, which reinforces more negative memories. Due to this process, emotionally abused individuals may be more vulnerable to develop a depressive and/or anxiety disorder. Our findings warrant scientific and policital investments to increase societal awareness about the detrimental impact of CEM on cognition and the brain. Increased societal knowledge will hopefully lead to better awareness, reports, and subsequent interventions for individuals with CEM. Show less
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
Synthetic glucocorticoids such as dexamethasone are frequently used to enhance pulmonary development in preterm ventilator-dependent infants. In contrast to the short-term benefit on survival and... Show moreSynthetic glucocorticoids such as dexamethasone are frequently used to enhance pulmonary development in preterm ventilator-dependent infants. In contrast to the short-term benefit on survival and lung maturation, early glucocorticoid exposure has been shown to adversely affect neurodevelopmental processes. Both human and animal studies have reported acute and long-lasting impairments, including shortening of the lifespan in rodents. Therefore, the objective of the studies described in this thesis was to investigate, using an animal model: 1) the short- and long-term consequences of neonatal dexamethasone treatment and 2) the possibility to prevent these effects using pharmacological and behavioural intervention strategies. We reported that systemic dexamethasone treatment acutely affects brain development by suppressing cell proliferation and glial activity. These acute effects on the brain can be partially prevented by central glucocorticoid receptor antagonist pre-treatment, which might serve as a protective strategy against the adverse effects of dexamethasone treatment on the developing brain. Although neonatal dexamethasone exposure clearly affects the developmental trajectory, we did not observe the frequently described detrimental long-lasting consequences of this treatment. We showed that daily handling of the neonate, which was an inevitable component of our experimental design and leads to enhanced levels of maternal care towards the offspring, may compensate for some of the adverse effects of dexamethasone treatment. We conclude that the impact of neonatal glucocorticoid exposure highly depends on interactions with other components of the early environment and is therefore susceptible to pharmacological and behavioural intervention strategies. Show less
The aim of this thesis was to investigate the pathofysiology of neuropsychiatric symptoms in the auto immune disease Systemic Lupus Erythematosus (SLE) using magnetic resonance imaging (MRI) of the... Show moreThe aim of this thesis was to investigate the pathofysiology of neuropsychiatric symptoms in the auto immune disease Systemic Lupus Erythematosus (SLE) using magnetic resonance imaging (MRI) of the brain. To this end MRI abnormalities in SLE patients with neuropsychiatric symptoms were compared with clinical symptoms and serological markers of disease. This thesis shows that immune abnormalities have an influence on the central nervous system in SLE (chapter 3&4). Reversible abnormalities in quantitative brain MRI in NPSLE are associated with clinical symptoms (chapter 2). These abnormalities are associated with neuroimaging features which may be interpreted as reversible axonal and/ or neuronal dysfunction (chapter 5). In line with this, severe ischemia does not appear to play a major role in NPSLE patients without obvious infarction on conventional MRI (chapter 6). Chapter 3 suggests that the influence of auto-immune antibodies is similar to the influence of auto-immune antibodies found in mouse models of NPLSE affecting specific locations of the brain. Using advanced MRI techniques and statistical analysis in chapter 7 suggests that the influence of auto-antibodies in human NPSLE also extends to white matter. Hopefully, these findings will facilitate earlier detection and treatment of neuropsychiatric symptoms in SLE. Show less
Pronounced ultradian and circadian rhythms in the hormones of the hypothalamic-pituitary-adrenal (HPA) axis (i.e. glucocorticoids), one of the body__s major neuroendocrine axes, were already... Show morePronounced ultradian and circadian rhythms in the hormones of the hypothalamic-pituitary-adrenal (HPA) axis (i.e. glucocorticoids), one of the body__s major neuroendocrine axes, were already demonstrated several decades ago. Until now, the clinical relevance of the pulsatile nature of glucocorticoids was poorly understood or sometimes even regarded as not important. Its evolutionary conservation across many species however implies biological significance. Indeed, glucocorticoids have been proven to be crucial for a plethora of bodily functions, e.g. emotion, cognition and the central mechanism underlying the adaptation to stress. Furthermore, disturbances in the characteristic temporal pattern of glucocorticoid exposure have often been described in stress-related pathology. However, the significance of glucocorticoids secretory patterns for physiology, stress responsiveness and nuclear receptor signalling is still largely unexplored and is accordingly addressed in this thesis. A new concept in the endocrinology of glucocorticoids has evolved from the data presented here showing that pulsatile release of glucocorticoids is a major determinant in __resilience__ of glucocorticoid signalling in neuronal cells and stress responsiveness. Moreover, we show that particularly the glucocorticoid receptor is affected after disrupting glucocorticoid pulsatility and could thus provide an excellent target for therapy to normalise the downstream effects of disturbances in glucocorticoid rhythms in stress-related disease. Show less
Infants born very prematurely (gestational age <32 weeks) are at risk of brain injury and neurodevelopmental problems. Imaging the preterm infant__s brain during the neonatal period, using... Show moreInfants born very prematurely (gestational age <32 weeks) are at risk of brain injury and neurodevelopmental problems. Imaging the preterm infant__s brain during the neonatal period, using cranial ultrasonography (cUS) and magnetic resonance imaging (MRI), is important. Our aim was to study and describe brain findings in very preterm infants using modern, high-quality imaging techniques. Part I reviews brain maturation and injury, and imaging thereof, in very preterm infants. Part II discusses our experience on neonatal cUS (Chapters 2-3) and MRI (Chapter 4), and addresses indications, technical aspects, protocols and safety. Part III gives an overview of findings (incidence and evolution) on frequent, sequential neonatal cUS and term-equivalent MRI (Chapter 5), and their relation with perinatal factors (Chapter 6). Part IV focuses on imaging of white matter (Chapters 7-9), describing both normal maturational phenomena and pathological changes and assessing the accuracy of cUS and MRI for these changes. Part V focuses on imaging of deep grey matter (Chapters 10-12), describing both normal maturational phenomena and pathological changes on cUS and assessing their relation with clinical and MRI findings. Part VI reviews the main findings and conclusions of this thesis, and discusses future perspectives and proposals for further research (Chapter 13). Show less
The thesis describes the application of several different magnetic resonance (MR) techniques to study the effects of the progression of disease in a transgenic mouse model of Alzheimer's. Using MR... Show moreThe thesis describes the application of several different magnetic resonance (MR) techniques to study the effects of the progression of disease in a transgenic mouse model of Alzheimer's. Using MR imaging, the amyloid plaque deposition was visualized and the plaque load quantified in the same mice as they aged. Concurrently the transverse relaxation time (T2) was measured in affected brain regions and shown to decrease over time as plaque-load increased. To study the neurochemical profile in the mouse brain brain both one- (1D) and two-dimensional (2D) MR spectroscopic techniques were employed. 1D MRS is widely used in similar research, but has limited spectral resolution. To overcome this limitation, a 2D MRS technique was implemented and optimized for use in mouse brain. This technique, L-COSY, allowed the detection of several metabolites which were not visible using standard 1D MRS techniques. This technique was subsequently used to study the effects of Alzheimer's on the neurochemical profile. Observed changes were correlated with plaque deposition. Show less
Currently, the raising awareness of the role of glucocorticoids in the onset of numerous (neuro)-pathologies constitutes the increasing necessity of understanding the mechanisms of action of... Show moreCurrently, the raising awareness of the role of glucocorticoids in the onset of numerous (neuro)-pathologies constitutes the increasing necessity of understanding the mechanisms of action of glucocorticoids in bodily processes and brain functioning. Glucocorticoids mediate their effects by binding to intracellular receptors which act as transcription factors. A remarkable and yet unexplained phenomenon described more than two decades ago, is the cell-specific effects glucocorticoids bring about on gene expression in brain. For example, while glucocorticoids suppress corticotrophin-releasing hormone (CRH) synthesis in the hypothalamus, production of CRH in the central nucleus of the amygdala (CeA) is stimulated by increased hormone levels. Inasmuch as the neuroanatomical distribution of the corticosteroid receptors does not satisfactorily explain these effects, it is of interest to decipher the role of recently discovered coregu lator proteins that modulate the direction and the magnitude of steroid receptor-driven transcription. Therefore, in the current thesis the expression and function of central coregulators was studied: the coactivators SRC1a and SRC1e along with the corepressors N-CoR and SMRT were found to be expressed in brain and involved in regulation of CRH gene expression. Finally, a method that allows detection of coregulator recruitment by steroid receptors in brain tissue was developed. Show less
Not everyone who experiments with cocaine acquires compulsive drug use. The mechanism underlying this individual difference in susceptibility to addiction is poorly understood. Recent studies have... Show moreNot everyone who experiments with cocaine acquires compulsive drug use. The mechanism underlying this individual difference in susceptibility to addiction is poorly understood. Recent studies have identified genes and adverse life events (stress) as risk factors. The objective of this thesis is to investigate the contribution of the adrenal stress hormones glucocorticoids and epinephrine to the psychostimulant effects of cocaine in the inbred DBA/2 and C57BL/6 mouse strains. Behavioural sensitisation, measured as an enhanced locomotor response to repeated cocaine exposure, was used as a model for the long-term neural adaptations underlying aspects of drug addiction. The results demonstrate that adrenal hormones play a critical role in cocaine sensitivity, which depends on genetic background because surgical removal of the adrenals (__adrenalectomy__) prevented cocaine sensitisation in DBA/2, but not C57BL/6 mice. The impact of genetic background was further emphasised by strain-specific changes in the midbrain dopamine system that mediates the rewarding effects of drugs. The effects of adrenalectomy could only be fully reversed by co-administration of glucocorticoids and epinephrine. These findings show that, depending on genetic background, adrenal stress hormones are important risk factors for vulnerability to cocaine, suggesting that pharmacological intervention in stress hormone action has therapeutic potential in drug addiction. 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
