The aim of this thesis was to assess the efficacy (part 1) and tolerability (part 2) of antiseizure medications (ASMs) in glioma patients with epilepsy. In addition, we aimed to get insight into... Show moreThe aim of this thesis was to assess the efficacy (part 1) and tolerability (part 2) of antiseizure medications (ASMs) in glioma patients with epilepsy. In addition, we aimed to get insight into the ASM prescription behavior and treatment policy in brain tumor-related epilepsy (part 3).First-line levetiracetam seems to be the most efficacious ASM in glioma patients, with favourable tolerability. This is demonstrated in multicenter retrospective observational cohort studies, a systematic review, and is the opinion among the vast majority of European neuro-oncology professionals. Enzyme-inducing AMSs should be avoided in glioma patients due to the high risk of adverse effects. ASM use was not independently associated with neuropsychiatric symptoms in glioma patients, but alternative factors seem to pose a greater risk for developing neuropsychiatric symptoms. If patients experience uncontrolled seizures on ASM monotherapy, levetiracetam combined with valproic acid has better efficacy than other ASM combinations in glioma patients, while toxicity is similar. Subsequently, potential add-on ASMs in glioma patients experiencing uncontrolled seizures on ASM dual therapy include clobazam, lamotrigine, and lacosamide. Show less
This thesis reinforce that children born preterm are at risk for long-term impairments. Being able to predict who is at risk, by neonatal neuroimaging or early assessment, remains difficult,... Show moreThis thesis reinforce that children born preterm are at risk for long-term impairments. Being able to predict who is at risk, by neonatal neuroimaging or early assessment, remains difficult, especially in children who have milder forms of brain injury and/or experience milder difficulties at two years of age. Currently, most follow-up assessments use standardized outcome measures that might not show the full extent of a child’s daily functioning. Additional measurements and/or the implementation of qualitative research can be of great additional value. Show less
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
Because aggressive behavior during early childhood has been related to negative developmental outcomes, a further understanding of the underlying mechanisms of aggression during the first years of... Show moreBecause aggressive behavior during early childhood has been related to negative developmental outcomes, a further understanding of the underlying mechanisms of aggression during the first years of life is essential. Although the factors prenatal risk, parenting behavior, temperament and cognitive functions have consistently been related to externalizing behavior during preschool and school age, research focusing on their interplay in relation to aggressive behavior earlier in life is scarce. The aim of the current dissertation was to gain more insight into these associations during infancy and toddlerhood. Our studies indicated that impairments in children’s early cognitive regulation abilities play a role in the development of aggressive behavior. It can also be concluded that both adverse pre- and postnatal environmental influences have an impact on child aggression: higher prenatal risk and adverse parenting behavior were directly or indirectly (via poor cognitive functioning) related to higher levels of aggression. In addition, it was found that poor cognitive skills increased the risk of aggression in case of high prenatal risk or a highly reactive temperament during early development. These results suggest that early intervention programs to prevent aggression should focus on prenatal risk, parenting behavior and cognitive development during the first years of life. Show less
Patients with Parkinson's Disease may be eligible for Deep Brain Stimulation (DBS) in case of severe motor complications. This thesis provides indications for improving patient selection for DBS,... Show morePatients with Parkinson's Disease may be eligible for Deep Brain Stimulation (DBS) in case of severe motor complications. This thesis provides indications for improving patient selection for DBS, as well as describing new biomarkers based on Electroencephalography (EEG) to aid during the DBS selection process. Show less
We aimed to expand our knowledge about the level of neurocognitive functioning (NCF) and health-related quality of life (HRQoL) in patients with primary and secondary brain tumors during the... Show moreWe aimed to expand our knowledge about the level of neurocognitive functioning (NCF) and health-related quality of life (HRQoL) in patients with primary and secondary brain tumors during the disease course. We found that the tumor itself has the largest negative impact on NCF and HRQoL. At group level, treatment (surgery, radiotherapy and/or chemotherapy) did not seem to have a large extra detrimental effect on the short term. However, subgroups of patients, e.g. patients with tumors in the non-dominant hemisphere and long-term survivors, appeared to be vulnerable for cognitive decline after treatment. At the individual patient level, HRQoL varied to a large degree in the first months after treatment, confirming this is a multidimensional concept and that the impact of treatment differs for the different aspects. With the results from the studies described in this thesis, treatment and individual patient care can be optimized by minimizing the negative impact of treatment, e.g. by intraoperative monitoring of cognition during awake surgery, and by counseling and rehabilitation of patients. Besides, investigators should pay attention to methodological challenges in reporting of neurocognitive outcomes in research, as reporting of these outcomes is currently not sufficient, while evidence can be of value in clinical decision-making. Show less
The number of older people in the population is rising and so is the number of older patients in the Emergency Department (ED). Older patients often have complex problems which leads to an... Show moreThe number of older people in the population is rising and so is the number of older patients in the Emergency Department (ED). Older patients often have complex problems which leads to an increased change of repeat ED visits, longer length of stay, higher chance of hospital admission and higher chance of negative health outcomes. Cognitive impairment is a frequent problem in older ED patients but often remains unrecognized and little is known about the association between cognitive impairment and adverse outcomes in older ED patients. In this thesis we show that cognitive impairment is associated with adverse outcomes in acutely presenting older patients. Secondly, we show that routinely collected parameters in addition to cognitive impairment can be used to screen for high risk of adverse outcomes in older ED patients. We investigated two delirium screeners and showed the CAM-ICU might not be suitable for early detection of delirium in the ED. Finally, vital signs that associate with decreased brain perfusion and oxygenation, such as low systolic blood pressure, were associated with cognitive impairment in older ED patients. Next steps would be to investigate if optimal resuscitation might improve cognition and decrease risk of subsequent delirium and adverse outcomes. Show less
This thesis focused on the evaluation of an eHealth intervention for cognitive stroke rehabilitation and the perspectives of different stakeholders on the uptake of eRehabilitation in general. The... Show moreThis thesis focused on the evaluation of an eHealth intervention for cognitive stroke rehabilitation and the perspectives of different stakeholders on the uptake of eRehabilitation in general. The studies included in this thesis showed that there was no overall effect of an online brain training programme on cognitive functioning of patients with stroke. Only performances on cognitive function tests that were similar to the games included in the intervention improved, no near transfer effect was found. Moreover, usage of the training was suboptimal and not all of the patients were able to complete it. It would appear important to support stroke patients with CBCR training, since training is not well used by all patients. However, regarding patients’ ICT readiness, wishes and requirements it was also found that a relatively large amount of patients in rehabilitation wish to incorporate ICT in their rehabilitation treatment. In addition, developing tailored implementation strategies to implement eHealth in the bachelor curriculum of health professionals, based on the identified barriers and facilitators in this thesis is highly relevant to make sure that future health professionals are able to work with eHealth. Show less
With increasing age, blood pressure (BP) rises as a consequence of arterial stiffness. It has been debated whether it is beneficial to treat hypertension in old age especially in >75-year... Show moreWith increasing age, blood pressure (BP) rises as a consequence of arterial stiffness. It has been debated whether it is beneficial to treat hypertension in old age especially in >75-year-olds when they have multimorbidity, polypharmacy or frailty. Large trials showed that lowering BP in >60-year-olds is beneficial and lowers the risk for myocardial infarction, stroke and all-cause mortality. However, these trials lack generalizability and typically excluded multimorbid patients that are frail. At the same time, observational studies rose concerns about lowering BP too much since there are several cohort studies showing a reverse association of low BP and increased mortality especially in >75-year-olds. The general aim of this thesis is to increase the scientific knowledge about the effects of treating hypertension in >75-year-olds with frailty. This thesis has three aims: 1) to measure the prevalence of polypharmacy in older patients; 2) to test for an association between low SBP and mortality, cognitive function, daily functioning, and QoL in older patients under antihypertensive treatment; and 3) to understand the role that frailty plays in GP decisions about treating hypertension in old age across countries and see if those differences can be explained by country-specific cardiovascular disease burden and life expectancy. Show less
In deze thesis wordt het argument verdedigd dat de manier waarop geometrische patronen als decoraties functioneren precies laat zien hoe representatie werkt. Het argument ontvouwt zich onder... Show moreIn deze thesis wordt het argument verdedigd dat de manier waarop geometrische patronen als decoraties functioneren precies laat zien hoe representatie werkt. Het argument ontvouwt zich onder meer door middel van een uitgebreide analyse van het recente ‘core knowledge’ paradigma uit de cognitieve psychologie. Core knowledge onderzoekers stellen dat culturele fenomenen zoals muziek, taal en visuele patronen, geworteld zijn in aangeboren kennissystemen bijvoorbeeld op het gebied van geometrie en nummer. Hieruit wordt duidelijk dat iedereen over dezelfde mentale bouwstenen beschikt om abstracte patronen te herkennen en te maken. Een analyse van onderzoek uit de antropologie en de semiotiek toont aan dat ook het vermogen om abstracte tekens als representatie van een ander object, lichaam of idee te zien, in elk mens aanwezig moet zijn. Met behulp van theorieën over representatie uit de kunstgeschiedenis, zoals die van Leon Battista Alberti en Gottfried Semper, wordt ten slotte duidelijk hoe het maakproces verloopt door middel waarvan abstracte tekens representaties worden. Geconcludeerd wordt dat als zodanig geometrisch decoratieve patronen op z’n minst en per definitie altijd naar een menselijke maker verwijzen en daarmee naar intentionaliteit. Show less
Children spend most of their days interacting with their social environment. Emotions form a large part of these interactions and vice versa social emotions become meaningful when interacting... Show moreChildren spend most of their days interacting with their social environment. Emotions form a large part of these interactions and vice versa social emotions become meaningful when interacting with others. Understanding the emotion processes that underlie successful social functioning is important, especially in children that experience difficulties in social-emotional functioning such as children with Autism Spectrum Disorders (ASD). These studies used a unique approach towards understanding the complex mechanisms that are involved in emotion processing, incorporating how emotions are perceived, experienced, regulated, and expressed. Sensitive and direct measures of emotion processing such as eyetracking and physiology revealed for the first time on a neurobiological level that children with ASD have difficulties emotionally resonating with others, use less efficient strategies to regulate their emotions, and provided evidence for a possible discordance between the expression and experience of emotions. The preschool years also presented with a possible window of opportunity; children with ASD do feel emotions when it comes to their own experiences and the development of social attention towards others might be prone to improvements during the preschool years. These findings are important to parents and professional and enhance the understanding of emotion processing during these very early years of life. Show less
The locus coeruleus (LC) is a nucleus in the brainstem, and projects widely to the forebrain where it releases norepinephrine (NE). Catecholamines such as NE do not have a unitary effect on their... Show moreThe locus coeruleus (LC) is a nucleus in the brainstem, and projects widely to the forebrain where it releases norepinephrine (NE). Catecholamines such as NE do not have a unitary effect on their target neurons, but instead influence the function of other neurotransmitters, a process that is known known as neuromodulation. By virtue of the LC’s wide projection profile and the neuromodulatory properties of NE, the LC-NE system profoundly influences neural firing characteristics and associated cognitive processes. The work presented in this thesis addresses the role of the LC-NE system in various aspects of human cognition, and the modulation of brain state. Show less
This thesis describes several state-of-the-art challenge methods to study the cholinergic system in humans by measuring the effects of compounds that selectively act upon muscarinic or... Show moreThis thesis describes several state-of-the-art challenge methods to study the cholinergic system in humans by measuring the effects of compounds that selectively act upon muscarinic or nicotinic acetylcholine receptors. The thesis reveals part of the complexity of the cholinergic system, its changes related to aging, its relationship with cognitive function and performance, and its role in inflammation. Additionally, the methodology described in the thesis provides controlled circumstances using repeated measurement of drug concentrations and effects during a pharmacologic cholinergic challenge that can be used in drug development of new compounds with cholinergic activity. Show less
The overriding aim of my thesis was to study the relationship between blood pressure (BP) and cognitive and psychological functioning in older persons. Observational studies indicate that lower BP... Show moreThe overriding aim of my thesis was to study the relationship between blood pressure (BP) and cognitive and psychological functioning in older persons. Observational studies indicate that lower BP increases risk for cognitive decline in older persons. Older persons are at risk for impaired cerebral autoregulation, and lowering their BP may compromise cerebral blood flow and cognitive function. Contradictory to our hypothesis, the Discontinuation of Antihypertensive Treatment in Elderly people (DANTE) Study Leiden, a community-based randomized clinical trial in older persons (aged ≥75 years) with mild cognitive deficits, did not show that discontinuation of antihypertensive treatment improves cognitive functioning. The lack of the effect of this trial may be due to the unintentional inclusion of persons with a relatively intact cerebral autoregulation. Furthermore, we demonstrated that older persons with mild cognitive deficits and with orthostatic hypotension, who discontinued all their antihypertensive medication had an increased probability of being free from orthostatic hypotension 4 months later, compared to persons who continued their medication. Finally, in the DANTE MRI sub study, the relationship between BP and both conventional features of small vessel disease (SVD) and microstructural damage was explored, as well as the relation between microstructural damage and cognitive and psychological dysfunction. Show less
Human ageing is characterized by a gradual decline in cognitive and physical performance strongly determining someone’s functional abilities and quality of life. In this thesis, insights into... Show moreHuman ageing is characterized by a gradual decline in cognitive and physical performance strongly determining someone’s functional abilities and quality of life. In this thesis, insights into these age-related changes and most importantly their interactions are given, which might be suggestive for potential causal mechanisms and is required for the development of preventive and therapeutic paradigms. We focused on global and domain specific measures of cognitive and physical performance and assessed the interactions across different populations of calendar and biological age (range 45 to 90 years). For the assessment of physical performance, instrumented measures were introduced to assess their additional value. Across the entire age range, interactions between cognitive and physical performance were consistently found. The temporal relationship differed across age and domains, suggesting a specific rather than a general relationship. Because age-related changes were already observed from middle age, these results encourage the early and repeated assessment of cognitive and physical performance across different domains and development of age and domain specific interventions. Instrumented measures can be used for the identification of age-related changes and show promising results in providing additional insights into potential underlying determinants. This will enable the development of even more refined and patient specific interventions. Show less
With the increase in life expectancy, the prevalence of cognitive disorders is expected to rise the coming years. In this thesis we studied the association between blood pressure, cardiac... Show moreWith the increase in life expectancy, the prevalence of cognitive disorders is expected to rise the coming years. In this thesis we studied the association between blood pressure, cardiac biomarkers and cognitive function in 5800 people with mean age of 75 years. Furthermore, we investigated the feasibility to use smartphone technology to measure home blood pressure in 151 people during a 6 months follow-up period. We show that higher variability in blood pressure is associated with increased microdamage of the brain and worse cognitive function, independent of average blood pressure and use of blood pressure lowering medication. Furthermore, increased levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT), both markers of cardiac disease, are associated with worse cognitive function and steeper cognitive decline, independent of cardiovascular diseases or risks. Finally, we show that smartphone-based technology is a reliable and promising method with good adherence to measure blood pressure at home. This provides a possibility for implementation in large-scale studies and can potentially contribute to blood pressure reduction, eventually helping to prevent cognitive impairment. Show less
De dissertatie analyseert de aard en structuur van een oud-Egyptisch merktekensysteem en onderzoekt de relatie van deze niet-linguïstische vorm van visuele communicatie tot het... Show more De dissertatie analyseert de aard en structuur van een oud-Egyptisch merktekensysteem en onderzoekt de relatie van deze niet-linguïstische vorm van visuele communicatie tot het linguïstische systeem van schrift. Ook worden merktekensystemen als universeel fenomeen, waar in onze eigen maatschappij nog volop gebruik van wordt gemaakt, geanalyseerd. Show less
With increasing age the prevalence of hypertension rises. High blood pressure at midlife is associated with cognitive impairment. Nevertheless, in older persons a lower rather than a higher... Show more With increasing age the prevalence of hypertension rises. High blood pressure at midlife is associated with cognitive impairment. Nevertheless, in older persons a lower rather than a higher blood pressure is associated with incident dementia. The main purpose of the work in this thesis was to explore the role of blood pressure in relation to cerebral structure, neurocognitive functioning and hemodynamics of the brain in old age. Therefore, we sought to determine whether discontinuation of antihypertensive therapy in persons aged 75 years and over with mild cognitive deficits and using antihypertensive medication (the Discontinuation of ANtihypertensive Treatment in Elderly people [DANTE] population) would improve their cognitive and psychological functioning. The assumption was that the increase in blood pressure after the discontinuation of antihypertensives would lead to a direct increase in cerebral blood flow and, as a consequence, to an improvement in cerebral functioning. An additional objective was to investigate possible underlying mechanisms in the relation between blood pressure and neurocognitive functioning. To enable this, brain MRI was used to determine whether (lower) blood pressure was associated with (micro)structural damage, cerebral small vessel disease and blood flow in the brain, and also whether the presence of cerebral (micro)structural damage was related to neurocognitive functioning. Show less
Current evidence on older adults is derived from population-based cohort studies and randomized controlled trials, which may not include frail individuals. Data are lacking on older outpatients, a... Show moreCurrent evidence on older adults is derived from population-based cohort studies and randomized controlled trials, which may not include frail individuals. Data are lacking on older outpatients, a potentially diverse population. Therefore, we initiated the Milan Geriatrics 75+ Cohort Study, a prospective hospital-based outpatient cohort study. Chapter 1 of this thesis provides a background on the controversies regarding the homeostasis of older adults. Chapter 2, 3 and 4 report findings from the Milan Geriatrics 75+ Cohort Study. Chapter 2 explores the association between blood pressure and cognition, and whether it varies according to age and functional status. Chapter 3 examines the relationship between blood pressure and mortality risk, and whether it varies according to functional and cognitive status. Chapter 4 investigates the association between thyroid status and mortality risk in euthyroid older adults, and whether it differs by sex and age. Chapter 5 and 6 report findings from the PROSPER cohort, which includes older adults at high cardiovascular risk. Chapter 5 presents new evidence on the association of heart rate and heart rate variability with functional decline. Chapter 6 analyses the relationship between blood pressure variability and functional decline. Chapter 7 summarises and discusses the main findings of this thesis. Show less
The use of the electronic medium to compose music entails a variety of cognitive idiosyncrasies which are experienced by both the artist and the audience. Structured around this medium on both... Show moreThe use of the electronic medium to compose music entails a variety of cognitive idiosyncrasies which are experienced by both the artist and the audience. Structured around this medium on both practical and conceptual levels, this study utilizes a tripartite methodology involving artistic practice, cognitive experimentation and theoretical discourse to investigate these idiosyncrasies. All three components of this methodology operate concurrently to address a succession of questions: How do we experience electronic music? How does electronic music operate on perceptual, cognitive and affective levels? What are the common concepts activated in the listener’s mind when listening to electronic music? Why and how are these concepts activated? In this dissertation I argue that our experience of electronic music is guided by a cognitive continuum rooted in our everyday experiences. I describe this continuum as spanning from abstract to representational based on the relationship of gestures in electronic music to events in the environment. Conducting this research has significantly expanded my comprehension of the experiential depth of electronic music. It has also affirmed my belief that we have much more to gain from the electronic medium, and that the cognitive continuum is one of its most remarkable offerings. Show less
