What is normal ageing? Heterogeneity in age-related trajectories of hippocampal volume

Abstract

Age-related changes in cognition that become more salient in older age are the result of brain changes that may have started in middle age or earlier. Middle age is an important period as it may be when the seeds of the neuro-pathologies of old age are first sown, and it includes the period of reproductive ageing for women that ends with menopause. However, structural brain ageing research has primarily focused on adults over 60 years of age, with limited focus on middle age. Thus, the main objective of this thesis was to investigate age-related brain changes across the adult lifespan, with a particular focus on the periods of middle (40-60 years) and early old age (60-80 years), using hippocampal volume as a biomarker for brain ageing. The longitudinal literature on hippocampal volume change was reviewed and volumes were estimated to shrink, on average, by 0.38% per year up to age 55 years, 0.98% from 55 years, and 1.12% from 70 years onwards. Heterogeneity in hippocampal ageing was then investigated in community dwelling middle (n=431, Age=47.2 years) and older age (n=478, Age=63.0 years) adults followed for up to 12 years. In middle age, hippocampal volumes in men declined earlier and faster compared to women. However, there were no significant sex differences identified in older age. In older age, there were two distinct population groups with divergent trajectories identified. The larger group (68.5% of the population) maintained stable hippocampal volumes across the 12-year follow up, while the smaller group (31.5%) displayed significant hippocampal volume loss suggesting the latter group may be at greater risk of cognitive decline. The secondary objective of this thesis was to investigate if long term changes in behaviour may be associated with the rate of brain ageing by analysing the long-term association between changes in physical activity and hippocampal volume. Changes in physical activity were found to be positively associated with hippocampal volume, such that an extra 150 minutes of moderate physical activity per week appeared to offset 2 years of hippocampal ageing in middle and older age. Furthermore, the effects of increasing physical activity appeared to be more persistent in middle compared to older age. Finally, older carriers of the APOE-e4 genetic risk factor for Alzheimer's disease also benefited from increasing physical activity. Indeed, an extra 60 minutes of physical activity per week appeared to offset the additional volume loss experienced by the older age APOE-e4 carriers in a year. Overall, the findings of this thesis paint an optimistic picture of brain ageing in community living middle and older individuals. Given that the rates of hippocampal atrophy increase with age, and the effectiveness of changes in physical activity decrease with age, middle age or earlier may represent an optimal period for increasing physical activity. Individuals may be able to positively influence their brain ageing trajectory by adopting high levels of physical activity in young adulthood and maintaining them throughout life. Specifically, men might benefit from increasing physical activity by early middle age, whereas women might benefit by increasing physical activity before the onset of menopause. Furthermore, there is a case for Governments and Health agencies to play a more active role in health promotion by providing built environments, health programs and public education to promote greater physical activity throughout life. Moreover, employers may also play a role by providing training and resources that encourage employees to be more physically active. Finally, greater research focus on age-related brain changes in young and middle-aged individuals is needed to better understand the prodromal characteristics that lead to cognitive decline in older age. Show more