Keuss, Sarah Elisabeth;
(2022)
The determinants and consequences of longitudinal changes in brain structure in later life: insights into preclinical Alzheimer’s disease from the 1946 British birth cohort.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Alzheimer’s disease (AD) has a long preclinical phase, beginning decades prior to the onset of dementia, during which treatments may have greater benefit. There is therefore considerable interest in understanding the changes that occur in this phase. Using data from Insight 46, a sub-study of the National Survey of Health and Development (NSHD; the 1946 British birth cohort), the primary aim of this thesis was to investigate the determinants and consequences of longitudinal changes in brain structure quantified from magnetic resonance imaging (MRI) in cognitively normal older adults. It particularly focuses on the effects of cerebral ß-amyloid (Aß) deposition, one of the pathological hallmarks of AD, and white matter hyperintensity volume (WMHV), a marker of presumed cerebrovascular disease (CVD), which commonly co-exists with AD in later life. A key finding was that being Aß positive (measured using florbetapir positron emission tomography (PET) imaging) and having greater WMHV on MRI at baseline were both associated with faster subsequent rates of global and hippocampal volume loss, and these effects were independent and not interactive. Other important results were that: having a higher WMHV at baseline was associated with greater subsequent rates of cortical thinning, including within regions known to be vulnerable in early AD (so-called AD signature regions), whereas baseline Aß deposition was not; faster progression of structural brain changes was related to faster concurrent rates of cognitive decline (or relatively less improvement) and poorer subsequent cognitive performance in Aß positive individuals; and use of global atrophy rates as an outcome provided lower sample size estimates for hypothetical preclinical AD trials than hippocampal atrophy rates. Collectively, these results emphasise the importance of early interventions and risk management targeting both Aß and CVD, and have implications for the utility of structural MRI measures as biomarkers of neurodegeneration in the preclinical phase of AD.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The determinants and consequences of longitudinal changes in brain structure in later life: insights into preclinical Alzheimer’s disease from the 1946 British birth cohort |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10154963 |
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