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
