Cardiovascular Autonomic Nervous System, Blood Pressure Instability and Brain Health in Older Adults: Population-Based Perspectives

Abstract

The aim of this thesis is to provide new insights into the shared pathways by which the cardiovascular autonomic nervous system underpins optimal regulation of affect and cognitive function in older adults. Ageing is characterised by an increase in sympathetic outflow and a reduction in parasympathetic tone - which may predispose to greater blood pressure instability. Based in two large population-based cohorts of ageing, this thesis presents four quantitative studies which variously employ cross-sectional, longitudinal and life course approaches to investigate associations between indices of blood pressure instability orthostatic blood pressure, baroreflex sensitivity and vasovagal syncope - and markers of brain health in later life: cognition, affect and structural integrity on MRI neuroimaging.

This thesis embraces a continuum approach to the understanding of cognitive decline and affective symptoms in later life - whereby these are overlapping presentations with shared risk factors and neural substrates that progress gradually via subclinical stages towards a clinical diagnostic threshold. In adopting this approach this thesis seeks to identify early/ sub-clinical associations between blood pressure instability and brain health, given that altering the trajectory of decline in brain health may be more successful if intervention is targeted at an early stage. A life course perspective is introduced in the final study to investigate associations between exposure to stress and blood pressure instability across the life span. A life course approach acknowledges that both cardiovascular autonomic function and brain health in older adults are underpinned by biological and environmental/ behavioural exposures occurring earlier in life; and that associations between brain health and blood pressure instability may be bidirectional across the life span.

Study I, based in the Irish Longitudinal Study on Ageing (TILDA), finds that lower orthostatic blood pressure immediately after standing, even when not meeting criteria for orthostatic hypotension, is associated with greater subjective memory impairment - a potential preclinical symptom of dementia. Study II in TILDA finds that lower baroreflex sensitivity is associated with greater affective symptoms in men, and associations are stronger in those on antidepressant treatment. To the best of my knowledge, this is the first study investigating associations between baroreflex sensitivity and both anxiety and depression in a population-based cohort of older adults. Study III, in the US-based Health Aging and Body Composition cohort, reports prospective associations between subclinical orthostatic blood pressure change and poorer brain health (poorer cognitive status and greater grey matter atrophy) up to 15 years later. To my knowledge study III is the first to incorporate MRI structural neuroimaging into the prospective investigation of orthostatic blood pressure and cognitive outcomes at the population level. Study IV investigates life course associations between stress and blood pressure instability and finds that exposure to childhood trauma may contribute to a lifelong vasovagal tendency - and therefore potentially to associations with poorer brain health in later life.

Taken together, Studies I-IV suggest that greater blood pressure instability, even at subclinical levels, and as underpinned by the cardiovascular autonomic nervous system, may be on the pathway to poorer brain health in later life; although associations may differ according to sex and medication status. Furthermore, early life exposure to stress may be a life course determinant of blood pressure instability thus further highlighting central regulation/ integration of the cardiovascular autonomic nervous system. Recognition of an important role for the cardiovascular autonomic nervous system in regulation of affect and cognitive function in later life potentially provides new therapeutic opportunities for promoting better brain health, for longer, in older adults.