With ageing populations, the prevalence of age-related disorders such as dementia is on the rise. As there is currently no curable treatment for dementia, the vascular component of dementia is... Show moreWith ageing populations, the prevalence of age-related disorders such as dementia is on the rise. As there is currently no curable treatment for dementia, the vascular component of dementia is increasingly recognised as a key modifiable cause. This thesis aims to investigate biological pathways between risk factors of cardiometabolic disease and cognitive function, in a population of older adults at increased risk of cardiovascular disease (CVD). We hypothesise that changes in physiological functioning caused by (sub)clinical CVD are possible mediators within the pathway leading to cognitive dysfunction. In the first part of this thesis, we studied electrocardiogram-based intervals and serum cardiac biomarkers (such as troponin) in relation to cognitive function. In the second part of this thesis, we studied the interplay of body mass index and serum leptin, loss of body weight and body weight variability, as well as metabolomics-based health scores in relation to cognitive function. We found that various cardiometabolic risk factors are associated with worse cognitive function. The results of this thesis strongly suggest that subclinical changes in cardiometabolic health may exist before cognitive dysfunction becomes apparent. Treating these cardiometabolic risk factors may be of benefit to future cognitive health. Show less
Persons with dementia may not always be able to set their own goals and expectations. When persons with dementia are no longer able to assess their own Quality of life (QoL), family, friends and... Show morePersons with dementia may not always be able to set their own goals and expectations. When persons with dementia are no longer able to assess their own Quality of life (QoL), family, friends and professional caregivers need to be their voice, as they are most familiar with their values, goals and needs. QoL in persons with advanced dementia is influenced by many factors, such as environment, background and psychological factors such as depression and agitation.The Q-PID study was a 13-week double-blind, randomised, placebo-controlled crossover trial that assessed the effect of paracetamol on QoL, discomfort, pain, neuropsychiatric symptoms, care dependency and daily functioning in 95 persons with moderate to advanced dementia living in long-term care facilities (LTCF).This thesis provides evidence that administration of paracetamol or placebo alone is not effective, i.e., no ‘panacea’, for improving QoL, discomfort, pain, neuropsychiatric symptoms, care dependency and dailyfunctioning in persons with advanced dementia living in LTCF. Personalizing interventions, collaborationbetween different health care workers and family/friends, and combining pharmacological and non-pharmacological interventions are important to maintain the best QoL possible, and we recognize that this will be challenging, but not impossible. 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
The primary aim of this thesis was to investigate the complex relationship between pain, neuropsychiatric symptoms, and ADL functioning in persons with dementia. Furthermore, we studied the... Show moreThe primary aim of this thesis was to investigate the complex relationship between pain, neuropsychiatric symptoms, and ADL functioning in persons with dementia. Furthermore, we studied the psychometric properties of a new and universal observational pain assessment instrument Pain Assessment In Impaired Cognition: PAIC.The results of this thesis show that pain in nursing home residents with dementia is related to a decline in ADL functions, independent of dementia severity. Specifically, a decline in the ADL activities transferring and bathing.Additionally, the psychometric evaluation of the PAIC presented in this thesis not only results in a promising measurement instrument, but also provides useful information for the development and improvement of educational programmes that contribute to the utilization of the PAIC15. Show less
Vitamin D is a hormone produced in the skin via a non-enzymatic process involving ultraviolet light.It is well known that the physiology of aging makes older people particularly susceptible to... Show moreVitamin D is a hormone produced in the skin via a non-enzymatic process involving ultraviolet light.It is well known that the physiology of aging makes older people particularly susceptible to vitamin D deficiency and that, if untreated, it can have serious health consequences. This thesis deliberates on the topics of vitamin D supplementation in older people in light of the current guidelines and on the possible additional effects of ultraviolet light beyond vitamin D synthesis on nursing home residents. We present a cross-sectional study in nursing home residents aged 70 years and over designed to evaluate the efficacy of vitamin D supplementation in achieving vitamin D sufficiency. We also discuss the different supplementation strategies for nursing home residents and community dwelling persons aged 70 years and over based on a survey administered to general practitioners and elderly care physicians in the Netherlands.In the second part we concentrate on additional effects of ultraviolet light beyond vitamin D synthesis. We describe our systematic review of literature on the effect of ultraviolet light, when applied to the skin or eyes, on mood, depression and well-being. We present also our randomized controlled trial on the effect of ultraviolet radiation compared with oral vitamin D supplementation on the well-being of nursing home residents with dementia. Further we use the data of the RCT to carry out a post-hoc analysis to compare the effect of vitamin D alone compared with ultraviolet radiation on the blood pressure of old people with dementia. Show less
As the number of patients suffering from dementia is still growing, most of the patients display behavioral symptoms at some time during the disease and these behavioral symptoms lower the quality... Show moreAs the number of patients suffering from dementia is still growing, most of the patients display behavioral symptoms at some time during the disease and these behavioral symptoms lower the quality of life and increase the burden of caregivers, adequate management of these symptoms is warranted. However, the etiology and management of behavioral symptoms is complex, resulting in (mis)use of pharmacological interventions: a cure which is often worse than the disease. In healthy adults, caffeine is known to influence behavior. Four different studies were conducted to see if caffeine is an easy to adjust cause or a pragmatic intervention for behavioral symptoms in patients with dementia. Based on these studies, we conclude caffeine can influence behavior in persons with dementia, but most likely not in all persons, not in all situations and not all of the time; but it can have an influence. In clinical practice it is advisable to consider caffeine as a possible moderator in the clinical assessment of behavioral symptoms in persons with dementia. Show less
In this thesis, longitudinal analyses have been performed on the PROPARK-Cohort, a hospital-based cohort of 421 patients followed for a period of five years. The main focus of this thesis was... Show moreIn this thesis, longitudinal analyses have been performed on the PROPARK-Cohort, a hospital-based cohort of 421 patients followed for a period of five years. The main focus of this thesis was to determine which predictors and associated factors contributed to the development of certain non-motor symptoms in Parkinson’s disease (PD). Strengths of our cohort study include the length of the follow-up period, broad clinical characterization, limited loss-to-follow-up and the large cohort size. The following non-motor symptoms have been addressed in this thesis: psychosis (hallucinations), dementia, excessive daytime sleepiness (EDS), insomnia, depression and anxiety. We found that while certain non-motor symptoms are inherent components of PD that increase in severity as the disease progresses, others symptoms such as excessive daytime sleepiness are inarguably caused by antiparkinsonian medication. For the future, we hope to see more longitudinal data on the disease progression in PD from large cohorts. Knowledge from longitudinal studies does not only contribute to more insight in the underlying pathobiology of PD, but it could also help the caregiver to monitor patients with particular risk factors more closely and adjust treatment if necessary. 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 aim of this thesis was to work towards pre-clinical proof-of-concept for NOTCH3 cysteine corrective exon skipping as a rational therapeutic approach for CADASIL. To address all aspects required... Show moreThe aim of this thesis was to work towards pre-clinical proof-of-concept for NOTCH3 cysteine corrective exon skipping as a rational therapeutic approach for CADASIL. To address all aspects required for therapeutic development, the work performed for this thesis included not only in vitro testing of NOTCH3 exon skipping in CADASIL patient derived vascular smooth muscle cells and studies into the function of the cysteine corrected proteins, but also the generation of a relevant humanized in vivo model, pre-clinical biomarker development, and studies defining prevalence, spectrum and characteristics of NOTCH3 mutations worldwide. 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
The main objective of this thesis was to clarify the observed reversal of effect of classical risk factors for dementia and mortality with increasing age and to gain better insight in the... Show moreThe main objective of this thesis was to clarify the observed reversal of effect of classical risk factors for dementia and mortality with increasing age and to gain better insight in the biological mechanism behind the relation between both phenotypic and genetic variation in apolipoprotein E (apoE) and cognitive function. Although high cholesterol levels in midlife associate with worse cognitive function and dementia in late-life, this association attenuates and even reverses with increasing age. In memory outpatient clinic patients high blood pressure associated with better cognitive function, only in patients with structural brain damage. In the Leiden 85-Plus Study, a decline in global cognitive function preceded declines in total cholesterol levels, HDL cholesterol levels, and blood pressure, and not vice versa. Moreover, mortality was associated with larger declines in body mass index, total cholesterol levels, HDL cholesterol levels, and blood pressure. High plasma apoE levels associated with worse cognitive function, whereas offspring from Alzheimer__s disease patients had lower plasma apoE levels when measured in midlife compared to offspring from cognitively intact controls. Finally, high serum calcium levels were strongly associated with worse cognitive function in APOE _3_4 carriers, to a lesser extent in _3_3 carriers, but not in _2_3 carriers. Show less
