Cognitive symptoms in Primary Biliary Cholangitis (PBC)

Abstract

Patients with primary biliary cholangitis (PBC) may suffer from cognitive symptoms in addition to the primary disease burden. These symptoms impact on quality of life but, to date, we have no pharmacological therapies demonstrated to improve these symptoms. It is crucial to understand the nature of cognitive symptoms and underlying neuropathological processes in PBC for the development of effective future clinical trials. In this thesis, neuropsychometric assessments and magnetic resonance Diffusion Tensor Imaging (DTI) measurements were used to determine the nature of cognitive symptoms in PBC, and to explore white matter pathology, as a potential explanation, respectively. In this thesis, cognitive deficits in PBC were found in multiple domains with pronounced impairments in memory, attention, and emotional cognition. Neuropsychometric testing demonstrated cognitive deficits in both patients reporting significant cognitive difficulties and asymptomatic patients, compared to a normative population. Therefore, cognitive symptoms in PBC may be influenced by behavioural variation. Nevertheless, those reporting cognitive symptoms are typically the group with the highest unmet clinical need, and likely to be prioritized for interventional studies. We found that PBC-40 cognitive scores were not closely associated with fractional anisotropy (FA) values from deep white matter tracts, contrary to what we had hypothesised. This suggests that cognitive symptoms do not arise from white matter tract dysfunction, although we acknowledge that we only studied a small number of a priori regions. Only patients with cholestasis demonstrated significant cognitive deficits. Based on these findings, we propose that cognitive symptoms may only become apparent when cholestasis is established, and therefore aggressive treatment for cholestasis at an early stage may be needed. Overall, the characterisation of cognitive symptoms in PBC, together with exploratory brain imaging, are important steps for informing the design of future PBC therapeutic trials by establishing reference endpoints for future studies.