Parker, Thomas David; (2019) Investigating the relationship between β-amyloid and grey matter macrostructure and microstructure in ageing and dementia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Decades occur between the emergence of aspects of Alzheimer’s disease pathology and the onset of its clinical symptoms. β-amyloid deposition and grey matter damage are both key events within the Alzheimer’s disease pathophysiological continuum, yet the precise nature of the relationships between the two during this pre-symptomatic period is unclear. This thesis explores these relationships using β-amyloid positron emission tomography and multi-modal magnetic resonance imaging data from Insight 46 – a cohort of approximately 400 cognitively normal adults born in Britain during the same week of March 1946. Using automated estimates of subcortical grey matter volumes, there was evidence of β-amyloid-associated volume loss in the hippocampus, certain hippocampal subfields, amygdala and thalamus in cognitively normal older adults. To investigate cortical grey matter changes a surface-based approach was used to estimate cortical thickness from structural magnetic resonance imaging. Neurite orientation dispersion and density imaging was used to estimate cortical neurite density and orientation dispersion indices. Proof of concept analyses in a cohort of patients with established Alzheimer’s disease revealed that even accounting for cortical atrophy, microstructural properties were decreased in established disease. In Insight 46, increasing β-amyloid deposition was associated with decreased neurite density index in several cortical regions, whilst cortical orientation dispersion index demonstrated non-linear associations. These relationships were independent of cortical thickness highlighting the capacity of cortical microstructural metrics to provide information above and beyond that derived from macrostructural techniques alone. There was also evidence in Insight 46 that even over a two-year scanning period increasing age at scanning was associated with lower hippocampal (including individual subfields) and amygdala volumes, as well as decreased cortical thickness and neurite orientation dispersion and density imaging metrics. This thesis presents evidence that β-amyloid deposition and ageing both significantly influence grey matter structure in older adulthood, even in the absence of cognitive impairment.

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