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 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
