Download files
Abstract
Early detection of Alzheimer’s disease (AD) and other dementias is of great public health importance particularly in light of the promise of disease-modifying treatments. Functional magnetic resonance imaging (fMRI) during cognitive activity in ‘at risk’ individuals is a potential biomarker candidate that may advance this objective. Recent fMRI studies have demonstrated altered patterns of cortical activity in individuals with Mild Cognitive Impairment (MCI), a syndrome which places older adults at increased risk of dementia. The overall objective of this thesis was to investigate whether fMRI coupled with a suitably challenging cognitive task can facilitate early identification of dementia. A novel fMRI paradigm incorporating a graded visuospatial working memory task with three levels of memory load was developed for this purpose. Task difficulty was carefully controlled using an individualised calibration procedure to ensure subjects were equally challenged. Using this paradigm, task-related cortical activity was examined firstly in young healthy adults, and subsequently in individuals with MCI and cognitively normal control subjects recruited from a longitudinal population study of community-living older adults. In young adults, task performance engaged distributed brain networks including the default mode network previously shown to be dysfunctional in MCI and AD. Differences in cortical activity between MCI and cognitively normal subjects at equal task performance were dependent on memory load. Under increasing load, stronger deactivation in posteromedial cortex, a core region of the default mode network was observed in MCI subjects, particularly for more clinically severe individuals. Furthermore, in a longitudinal analysis of the MCI group, stronger posteromedial cortex deactivation to increasing memory load at baseline, predicted decline in everyday function over two years. The results of these investigations suggest that this fMRI paradigm may operate as a ‘memory stress test’ by uncovering early functional brain changes in MCI that are a harbinger of future decline. The observed functional brain alterations in individuals with MCI have implications for our understanding of the neurobiological processes occurring in the brain at the early stages of neurodegenerative disease, and may have a potential application for early diagnosis and tracking progressive longitudinal change.