Walsh, Ella Phoebe; (2021) White matter hyperintensities in sporadic and familial Alzheimer's disease: investigations into their pathological basis and biomarker potential. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis is a detailed investigation into white matter hyperintensities (WMHs) in Alzheimer’s disease (AD). WMHs, of presumed vascular origin, are increasingly recognised in the aetiology of AD. However their underlying pathology may be variable and their relationship to the hallmark pathological features of AD is not yet fully understood. Associations of WMHs with CSF amyloid beta (Aβ ) and tau at baseline were explored in a cohort from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). A further study in ADNI was carried out exploring associations between plasma neurofilament light (NFL) and WMHs. WMH accrual across the disease course was modelled using longitudinal data from the Dominantly Inherited Alzheimer Network (DIAN) cohort. Finally, to enable exploration of the pathological basis of WMHs, an ex vivo MRI pipeline with subsequent pathological investigations was developed and carried out. Firstly, a higher WMH burden was found to associate with lower CSF Aβ across diagnostic groups, but no significant associations were found with CSF tau biomarkers. Plasma NFL was found to associate with WMHs, in an age depen- dent, but vascular-risk independent manner. Secondly, WMH accrual was found to increase throughout the disease course as demonstrated by associations with esti- mated years to onset (EYO) in the DIAN cohort. The highest rate of accrual was seen in the APP mutation group. Additionally, WMHs and brain atrophy changes were shown to track together across the disease course. Lastly, the ex vivo-histology pipeline was shown to be effective, enabling the registration of multiple modalities and revealing varying degrees of myelin loss. Abstract 4 In summary, this work extends existing knowledge about how WMHs associate with classical AD markers such as Aβ, tau and brain atrophy. Furthermore this work suggests that, instead of just reflecting vascular comorbidity, WMHs are a core feature of AD. Impact Statement Alzheimer’s disease (AD) is a neurodegenerative disease with no effective treatment or cure. Not only does AD have debilitating consequences for patients and carers, it places a huge socio-economic burden on society as a whole. Evidence suggests that AD is a multifactorial disease for which early intervention is necessary for effective treatment. It is therefore imperative that biomarkers identifying early-stage disease, as well as capturing the full spectrum of pathological changes, are identified and characterised. This thesis investigates white matter hyperintensities (WMHs) as a potential biomarker of AD. A key finding in this PhD is that WMHs associate with amyloid beta (Aβ) across the full disease course. This result aids understanding of how WMHs interact with other AD biomarkers and creates opportunities for further research into the mechanism underlying this finding. The fact that my paper on this work has been cited five times since its publication last year in 2020, shows that there is is active demand for this research. In Chapter 5 I provided evidence that WMHs are an important marker of dis- ease progression in a cohort of autosomal dominant inherited AD (ADAD) patients and their relatives. As well as being an important finding in terms of the use of WMHs as a biomarker, very little research into WMHs in ADAD has been carried out previously, meaning that this work will be important to the AD field. I also found differences in WMH accrual between mutation groups, which has important implications for future treatments in ADAD as it highlights the heterogeneous na- ture of the disease. In Chapter 6 I developed a novel MRI-histology pipeline in order to answer key Impact Statement 6 and under-researched questions about the underlying pathology of an MRI signal. The impact of the development of this methodology could be substantial, providing the starting point for a tool that could predict the underlying pathology of WMHs based on appearance and location, for eventual use in a clinical setting. WMHs have long been considered a marker of SVD, however I have shown how WMH are increased in AD and associated with key AD biomarkers, both in a cohort of low vascular risk (ADNI) and in a young ADAD cohort (DIAN). This thesis provides important evidence that WMH on their own should not automatically be taken as evidence of a vascular contribution.

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