Although mortality in old age has significantly decreased over the last fifty years in the developed world, there still remains a large inter-individual variability in ageing trajectories,... Show more Although mortality in old age has significantly decreased over the last fifty years in the developed world, there still remains a large inter-individual variability in ageing trajectories, morbidity and mortality. In the three parts of this thesis, we examined three interacting systems that have been identified as contributing to a slower pace of ageing, namely glucose/insulin metabolism (part I), the thyroid axis (part II), and the autonomic nervous system (part III). We found that familial longevity is associated with a stronger association of insulin parameters with microstructural brain parameters, and by higher TSH secretion, in the absence of differences in basal energy metabolism or differences in heart rate and its variability. Using specialized MRI techniques, we showed that subtle changes in microstructural brain parenchymal homogeneity in relation to insulin can be detected, even in brain tissue that appears normal on conventional MR imaging sequences. Insulin (rather than glucose), seemed to be a stronger indicator of micro- structural brain integrity in normo-glycemic older adults. Furthermore, intranasal application of insulin improved brain perfusion in parietal and occipital gray matter and in the thalamus of older adults. These results deepen our understanding of the physiological mechanisms and processes that underlie the ageing process. 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
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
