Mahoney, CJ; (2015) Structural network degeneration in the frontotemporal lobar degenerations. Doctoral thesis , UCL (University College London).

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Abstract

Frontotemporal lobar degenerations (FTLD) represent a group of neurodegenerative conditions characterised by their often overlapping but yet diverse clinical, radiological and pathological features. Clinically they may manifest as either a behavioural syndrome, termed behavioural variant frontotemporal dementia (bvFTD) or as a language led dementia, termed primary progressive aphasia (PPA). The same protein can cause multiple disease phenotypes, whilst the same clinical phenotype may result from any of several different proteinopathies. Our understanding of this apparent divergence (or indeed convergence) remains poor. The concept of network-led neurodegeneration may offer an explanation. This suggests that specific brain networks are vulnerable to certain proteins and an attack on certain brain networks may result in a certain disease phenotype, and may also facilitate disease propagation, through network connections. The advent of diffusion tensor imaging (DTI) now allows us to explore the microstructure of white matter and as it is white matter that binds functional networks together, understanding the changes in white matter across the spectrum of FTLD may provide insights into its disease biology. Specifically DTI may allow us to establish the profiles of structural network degeneration in FTLD and enable us to relate these changes to known functional networks, which govern key aspects of cognition affected in FTLD. This thesis will investigate white matter microstructural changes across the spectrum of FTLD and will examine both cross-sectional and longitudinal white matter changes. The initial chapters will set out to establish these changes in both clinically and molecularly defined individuals affected with bvFTD and the subsequent chapters will study those with PPA. The primary aim of this thesis is to establish the profiles of white matter pathology across the spectrum of FTLD using advanced imaging methods. Secondary aims include establishing the role of DTI as a potential imaging biomarker for future clinical trials in FTLD, and exploring differences in sensitivity and specificity of each DTI metric, establishing optimal metrics for studying white matter tract pathology in FTLD.

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