Mok, Tze How; (2023) Defining the onset of prion infection and neurodegeneration in healthy individuals at risk of prion disease. Doctoral thesis (M.D(Res)), UCL (University College London).

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Abstract

Healthy individuals at risk of prion disease are expected to exhibit subclinical prion replication followed by emergence of toxicity, heralding proximity to clinical onset, based on mouse inoculation studies. This silent incubation period, if recapitulated in humans, will be amenable to fluid biomarker discovery which may inform study designs for preventative strategies. The central output of this thesis revolves around testing a longitudinal biofluid archive assembled from individuals with high lifetime risk of prion disease, including 16 whom subsequently developed inherited prion disease (IPD), using real-time quaking-induced conversion (RT-QuIC) assay and single molecule array platforms. Two distinct biomarker trajectories, depending on speed of clinical evolution, were discerned. CSF RT-QuIC seeding activity was detectable with over three years’ follow-up in asymptomatic E200K (fast IPD) mutation carriers, but with no definable presymptomatic neurodegenerative phase in one converter. In contrast, P102L (slow IPD) mutation carriers showed sequential rises in plasma glial fibrillary acidic protein followed by neurofilament light up to four years pre-conversion; a bespoke P102L RT-QuIC assay was only partially sensitive. Consequently, we propose a new preclinical staging system featuring clinical, seeding and neurodegeneration components, for validation with larger prion at-risk cohorts, and with potential application to other neurodegenerative proteopathies. Additionally, we tackled uncertainties that exist over disease penetrance for specific at-risk populations, with implications on epidemiological case definition, and study/trial enrolment eligibility. Firstly, we highlighted the clinical resemblance to sporadic CJD, and necessity of autopsy confirmation, in the first definite case of variant CJD in an individual heterozygous at PRNP codon 129, raising concerns over disease surveillance accuracy and ascertainment of population risk. Secondly, we interrogated multiple lines of evidence to resolve ambiguities over the penetrance of rare PRNP variants – T201S and 2-OPRI, resulting in their reclassification as either benign or low-risk variants, thus avoiding erroneous inclusion into primary prevention studies/trials.

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