Porter, Marie-Claire Anne; (2020) The development of imaging biomarkers for the diagnosis of human prion disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Future therapeutic trials in human prion disease will require the use of biomarkers of disease activity such as MRI in order to assess efficacy of treatment. Whilst the development of biomarkers is of importance it is also necessary to be able to understand and interpret what imaging findings characterise at post-mortem and furthermore how they correlate with clinical symptoms. In this thesis I investigate whether both conventional and quantitative imaging parameters can act as biomarkers to predict disease progression in symptomatic patients. I also assess what conventional MRI findings represent on a microstructural level and how imaging findings correlate with clinical symptoms of prion disease such as sleep disturbance. This work is detailed in four projects, the first of which I investigate if abnormalities found on conventional MRI brain scans, PRNP genotype and prion strain can act as predictors of disease progression in patients with the sporadic form of prion disease. I was unable to show that conventional MR brain imaging helps to predict disease progression in this patient group, but I was able to show that codon 129 remains the main predictor of disease progression and strain subtype has an additional effect. In the second project I test the hypothesis that MTR, a quantitative imaging parameter can predict disease progression in symptomatic patients. I found that both on cross-sectional and longitudinal analysis there were significant differences in symptomatic patients and that there was a strong correlation with the MRC Scale score, clinical outcome measure, and MTR value in patients with symptomatic disease which could be used as a clinical biomarker in combination to predict response to therapeutics in future clinical trials. In the third project I focus on investigating the prevalence of sleep disturbance and its association with other features of disease and imaging findings. I found that sleep disturbance was highly prevalent in all forms of prion disease. I also found that there was a significant association found between thalamic signal change seen on MRI scan and sleep symptomatology. In order to capture more data on the diversity of sleep symptoms in this population I constructed the Prion Disease Sleep Questionnaire a bedside screening tool that can be used to both record and monitor the incidence and severity of sleep disturbance. In the final project I assess if specific histopathological findings on post-mortem correlate with cortical imaging abnormalities seen on DWI in patients diagnosed with sporadic CJD. I found that there were significant difference between patients with and without cortical ribboning present on their MRI brain scans those with DWI signal change had more frontal cortex spongiosis than those that didn’t. There was also a modest correlation identified between the 3 histopathological parameters: PrPSc, deposition, gliosis and spongiosis.

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