Medicine and Radiology - Theses
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ItemThe effect of midlife cardiovascular risk factors on late life brain structure and cognitive function in normal ageing women( 2017)Cardiovascular disease and dementia are amongst the major threats to heath and quality of life for Australian women. Since neurodegenerative pathologies develop before the onset of dementia, a life course prospective study is needed to clarify the risk factors. The link between cardiovascular risk factors and dementia is supported by common neurological findings of brain atrophy and cerebrovascular dysfunction. Despite the growing literature reporting the effect of midlife cardiovascular risk factors on late life brain structure and cognitive functional changes, there are still several unanswered questions regarding underlying mechanisms and the best imaging methods for detecting neurological effects of vascular risk factors. The main aim of this thesis is to determine the effects of mid to late life cardiovascular risk burden over two decades on brain volume changes and cognitive function in elderly women. The findings of this thesis identify brain regions and cognitive domains where structural and cerebrovascular deficits are associated with presence of cardiovascular risk factors in midlife and may influence late life cognitive function. The present thesis utilizes the wealth of structural Magnetic Resonance Imaging (MRI) data collected from the Women’s Healthy Ageing Project (WHAP). This Australian population-based study contains data on cardiovascular risk factors and cognitive function from midlife until two decades later. The Framingham Cardiovascular Risk Profile (FCRP) is a validated tool for estimating the 10-year risk of cardiovascular disease based on a midlife profile incorporating several vascular risk factors. This risk score is used to indicate whether the cardiovascular risk burden has any relationship to structural neuroimaging findings and late life cognitive performance. This thesis focuses on the effects of individual cardiovascular risk factors and measured risk score at midlife on late life brain structural changes, evaluated by MRI, and domain-specific cognitive function. The studies herein used a number of methods for brain structural analysis, providing information on both neurodegenerative and cerebrovascular pathologies in elderly women. The first chapter reviews relevant literature in the context of midlife cardiovascular risk factors, brain structure and cognitive function. This chapter also explains the basic principle of MRI physics and brain structural biomarkers for the normal ageing brain. The second chapter covers the general methodology of the thesis, including cardiovascular risk assessments, cognitive measures, MRI acquisition protocols and image processing tools. This thesis included 4 sub-studies: Chapter 3, Study I investigated the influence of midlife cardiovascular risk score on the burden of White Matter Hyperintensity (WMH) lesions in late life and whether this volume of WMH lesions mediated the association between midlife FCRP and cognitive function two decades later. The results show that an increase in FCRP score at midlife is associated with greater WMH volume two decades later, and this is predominantly driven by the impact of High Density Lipoprotein (HDL) cholesterol level, controlling for age, education and APOE ε4 status. This study also demonstrates that the relationship between midlife FCRP score and late life executive function is mediated by WMH volume. Chapter 4, study II examined the role of midlife cardiovascular risk burden on late life grey matter volumes and domain-specific cognitive function in the WHAP-MRI cohort. We found that higher midlife cardiovascular risk burden, as assessed by the FCRP score, is associated with smaller total cortical grey matter volumes, mainly in frontal and temporal lobes, two decades later. Of the FCRP components, age and midlife systolic blood pressure (SBP) are significantly correlated with cortical grey matter volume loss. After adjusting for age, education and APOE ε4 status, SBP assessed 10-years prior to the MRI scans, remained significantly correlated with grey matter volume loss in temporal lobe. This smaller grey matter volume in temporal lobe and increase in whole brain WMH lesions are largely mediated the relationship between midlife FCRP score and late life executive function performance. In addition, lower performance in verbal episodic memory in elderly women is indirectly associated with increase in cardiovascular risk burden at midlife, as measured by FCRP score, through decrease in total brain volumes, particularly in frontal and temporal lobes and in the hippocampus. Stratifying our study by APOE ε4 status shows that an increase in cardiovascular risk burden at midlife is associated with lower performance in executive function two decades later, whereas a decline in verbal episodic memory performance is linked with a decrease in total brain and hippocampal volumes. Chapter 5, study III explored the longitudinal changes in brain volume and cognition over a 10-year period. This study shows that baseline measurements of frontal and temporal grey matter volumes predict changes in verbal episodic memory performance, whereas hippocampal volume at baseline is associated with changes in executive function performance over a 10-year period of follow-ups. In addition, higher whole brain and hippocampal atrophy rates are correlated with a decline in verbal episodic memory. Chapter 6, Study IV explored the impact of hippocampal segmentation methods on correlations with midlife cardiovascular risk factors and late life verbal episodic function. In this study, a combination of manual and automated segmentation methods was applied to measure total and regional hippocampal volumes and their relationship with midlife clinical data and late life verbal episodic memory performance. We found a high correlation between manual tracing of hippocampal volume and automated Freesurfer output segmentations. Midlife FCRP score is not associated with late life hippocampal volumes, adjusted for intracranial volume, age, education and APOE ε4 status. Anterior hippocampal volume segmented either with manual tracing or automated Freesurfer software is sensitive to changes in midlife HDL cholesterol level, while posterior hippocampal volume is linked with verbal episodic memory performance in elderly women. The last chapter, Chapter 7, concludes this work and discusses potential study limitations and future directions. Together, findings from the studies in this thesis highlight the importance of lifespan research. Being one of the few women-specific ageing studies, the implications of these findings for clinical practice are discussed, with a focus on modifiable midlife cardiovascular risk factors for early therapeutic intervention to maintain late life brain health and delay onset of dementia among women.