Shribman, Samuel; (2022) Clinical phenotyping and biomarker discovery for neurological involvement in Wilson’s disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Wilson’s disease is an autosomal-recessive disorder of copper metabolism with neurological and hepatic presentations. Chelation therapy is used to 'de-copper' patients and monitoring is based on copper indices, such as serum non-caeruloplasmin-bound copper and 24-hour urinary copper output, which do not reflect neurological involvement. Biomarkers of end-organ damage, i.e. measures of the pathophysiological process in the brain, are needed to improve outcomes and prepare for clinical trials of novel therapies. In this thesis, I examine the pattern of movement disorders, cognitive deficits and psychiatric features in 40 prospectively-recruited patients before describing work identifying wet (fluid) and imaging biomarkers for neurological involvement using cross-sectional data from this cohort. The findings demonstrate that movement disorders are associated with cognitive deficits but not psychiatric features in chronically-treated patients and that some patients with hepatic presentations have subtle deficits in cognitive flexibility, associative learning and recognition memory for faces. I confirm previous observations that copper indices do not correlate with the severity of movement disorders and show that plasma neurofilament light is a promising monitoring biomarker. I also report preliminary data identifying serum proteins that might reflect neurological involvement using label-free proteomics. Using a combination of whole-brain, quantitative MRI analyses, I provide evidence that grey matter volumes in subcortical regions may serve as prognostic biomarkers and diffusivity in white matter tracts may serve as monitoring biomarkers. I identify neuroimaging correlates for serum non-caeruloplasmin-bound (‘free’) copper and demonstrate that increasing neurological severity is associated with widespread cortical iron deposition. I also determine the neuroanatomical bases for cognitive deficits and psychiatric features in Wilson’s disease, some of which relate to specific patterns of cortical volume loss or white matter pathology. These data support the idea that there is a spectrum of neurological involvement in Wilson’s disease, which I suggest can be modelled as a brain injury. I discuss next steps for validating these biomarkers and conclude by proposing a unifying theory for the evolution of neurological involvement in Wilson’s disease.

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