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Positron emission tomography in vivo characterisation of the pathology of frontotemporal dementia


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Authors

Bevan-Jones, William Richard 

Abstract

Frontotemporal dementia (FTD) is clinically and pathologically diverse, encompassing the behavioural variant FTD; non-fluent variant primary progressive aphasia; and semantic variant primary progressive aphasia. These are usually associated with either tau or TDP-43 pathology, with highly variable clinicopathological correlations. Neuroinflammation also contributes to the pathogenesis of FTD, but its relevance to the disease spectrum is incompletely understood. There is a critical need for better understanding of how drivers of pathophysiology, such as neuroinflammation and protein aggregation, relate to the heterogeneity of clinical disease in vivo. This knowledge gap currently forms a significant barrier to the development of effective treatments in FTD.
I review the clinical, pathological and genetic features of FTD and the role of PET for measuring in vivo components of pathophysiology in this setting. I then describe a series of case studies and group analysis of FTD syndromes, using positron emission tomography (PET) radioligands to visualise and quantify different aspects of pathophysiology in vivo.
[18F]AV-1451tau was introduced primarily to study tau pathology in Alzheimer’s disease using, which differs from FTD tauopathy in several respects. I examined the sensitivity and specificity of [18F]AV-1451 in FTD, in vivo, through (i) [18F]AV-1451 imaging of the FTLD-tau pathology in a case of FTD due to a MAPT 10+16 mutation in the microtubule associated protein tau, and a second pre-symptomatic case with the same mutation; (ii) [18F]AV-1451 imaging of a cohort of seven cases with Semantic Dementia and one case of FTD from a C9orf72 expansion, both strongly associated with TDP-43 pathology without tau; and (iii) the increase in [18F]AV-1451 binding, and changes in the distribution of binding, in thirty one patients spanning the three major FTD syndromes in comparison to matched controls. The literature on the role of neuroinflammation in FTD is more limited. I used the PET ligand [11C]PK-11195, as an established marker of activated microglia. I report the elevation in [11C]PK-11195 binding, and the change in its distribution, in a case of a pre-symptomatic MAPT 10+16 mutation carrier; and in twenty nine patients spanning the three major FTD syndromes in comparison to matched controls. In addition to reporting the correlations between PET ligand binding and disease severity, I describe the relationship across regions and across syndromes between [18F]AV-1451 and [11C]PK-11195 binding. In view of the marked variations in affinity of [18F]AV-1451 for different tau isoforms and TDP43-pathology, my analyses focus on multivariate distributions rather than absolute binding potential. The results show high correlations between [18F]AV-1451 and [11C]PK-11195 binding in each FTD syndrome. However, in the healthy MAPT 10+16 carrier, the distribution of elevated [11C]PK-11195 binding is much more extensive that the elevation of [18F]AV-1451, suggesting that inflammation might precede the aggregation of tau.
I discuss the limitations of the PET ligands, and summarise the insights into FTD pathogenesis arising from my series of observational studies. The role of new PET ligands, and the integration of PET in future clinical trials are discussed.

Description

Date

2019-04-09

Advisors

Rowe, James Benedict
O'Brien, John

Keywords

Frontotemporal dementia, Positron emission tomography, Tau, Neuroinflammation, AV1451, PK11195, Behavoural variant frontotemporal dementia, Semantic dementia, Progressive non-fluent aphasia, Microglia, TDP-43, Genetic FTD

Qualification

Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge