Wren, Melissa Chloe; (2021) Radio-pathological Investigation of Tau Tracers in Neurodegenerative Diseases. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Abnormal accumulation of misfolded tau protein is a major hallmark of pathology underlying multiple neurodegenerative tauopathies, of which Alzheimer’s disease (AD) is the most common. Tau burden in AD correlates with cognitive decline and has consequently been proposed as a major biomarker of disease progression. The development of tau-specific ligands for imaging with positron emission tomography (PET) holds immense promise in accelerating clinical diagnoses of AD, and other dementias. Two distinct generations of tau PET radiotracers are at different stages of development and have been rapidly translated into clinical studies. However, the neuropathological validation of these tracers remains limited and concerns have been raised over low sensitivity and off-target binding, particularly for first-generation tau ligands. The correct interpretation of clinical PET scans requires greater understanding of tracer binding profiles at both the molecular and cellular level. Human post-mortem brain tissue provides a robust platform to validate the binding profiles of tau tracers. In this thesis, the binding profiles of structurally distinct first- (T726/Flortaucipir, THK-5117) and second-generation (PI-2620, MK-6240) tau tracers were characterised, with the ultimate aim to inform on their clinical applications. The sensitivity and specificity of tau tracers were examined using human post-mortem brain tissue from cases with AD, primary tauopathies, non-tau proteinopathies and in age-matched controls. Tracers from both generations were found to selectively depict paired-helical filament tau and therefore suited to differentiate AD from controls and non-AD dementias. Second-generation tracers had greater sensitivity to depict tau in early disease than first-generation tracers. Overall, second-generation tau radiotracers have improved upon earlier compounds, including overcoming limitations associated with off-target binding. However, for familial primary tauopathies there is currently limited clinical use for tau radiotracers. Further investigation is required to understand the clinical potential of tau PET tracers for their use to diagnose sporadic primary tauopathies.

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