Cognitive functioning and microvascular disease

Cognitive impairment and dementia form a major health issue, affecting a considerable proportion of the aging population. Cerebral vascular damage is increasingly recognized as one of the main causes of cognitive decline in aging and dementia. Another main cause of cognitive deterioration in older people are neurodegenerative processes, resulting in Alzheimer’s disease (AD) type pathologies. Evidence is growing for a crucial role of vascular damage in AD. A current challenge is to explore the role of vascular disease in causing cognitive impairment, by itself or in interaction with AD. Besides the cerebral large vessels, the cerebral microvasculature is fundamentally important for brain functioning. Microvascular damage is important for the entire range of cognitive functioning, from subtle decrements in normal aging to frank dementia. The research in this thesis aimed to investigate the relation between biomarkers of microvascular disease and cognitive functioning. In the first part of this thesis, we investigated measures of microvascular disease in parts of the body outside the brain and the relation with cognitive functioning. We show in that retinal microvascular changes, microalbuminuria, and low-grade inflammation and endothelial dysfunction were related to subtle cognitive decrements in non-demented older individuals. Despite consistency of the findings, in all studies associations between markers of microvascular disease and cognitive functioning were rather weak. Thus, these biomarkers of systemic microvascular disease are of limited value as markers of reduced cognitive performance in the population. In the second part of this thesis, measures of microvascular disease in the brain were investigated, in patients with amnestic mild cognitive impairment (aMCI) or early AD. Multiple microbleeds were associated with disruptions of the microstructure and organization of the cerebral network as measured with diffusion tensor imaging (DTI), independent of other measures of small vessel disease or atrophy. We used 7 Tesla MRI to investigate the presence of microbleeds in detail and to image cortical microinfarcts. We showed that the majority of patients with aMCI or early AD exhibit cerebral microbleeds. Microinfarct numbers were not significantly increased in patients relative to controls. They did appear to be related to cerebral microbleed numbers and to other, larger, cortical infarcts. We showed that cerebral microvascular lesions are associated with (end-stage) dementia presence, but not so much with cognitive functioning in patients with AD. In the third part of this thesis, we investigated spatial navigation, a cognitive function that is often affected in patients with aMCI or early AD, which has high clinical relevance. On three fundamental aspects of spatial navigation, patients performed worse than controls, and patients with aMCI were at an intermediate level between controls and patients with AD. In conclusion, microvascular disease is important for cognition. A consistent, but rather weak, association between markers of microvascular disease and cognitive functioning is present in people without cognitive complaints. In patients with aMCI or early AD, cerebral markers of microvascular disease are prevalent and are related to other vascular brain damage. Our findings contribute to a better understanding of vascular-related cognitive impairment.