Gastrointestinal dysfunction in Parkinson’s disease: Interactions between the gut, immune markers and disease outcome

Although Parkinson’s disease (PD) is commonly characterized as a movement disorder, it is also associated with important non-motor symptoms. Gastrointestinal dysfunction in PD (GID-PD) may include weight loss, dysphagia and sialorrhoea. Constipation, the most prominent feature, is often present before the onset of motor symptoms and has a significant impact on quality of life. Accumulation of alpha-synuclein aggregates in the enteric nervous system in early stages of the disease has led to the hypothesis that, in a subset of cases, PD pathology may begin in the gut before spreading to connected areas of the nervous system. These gut changes may trigger an immune activation response which accelerates disease progression. Despite an exponential growth of research efforts on the mechanisms of the gut-brain axis’ role in the pathophysiology of PD, a comprehensive characterization of GID-PD and an understanding of its prognostic and mechanistic significance was lacking. I addressed this issue through 3 inter-related studies. I conducted a retrospective analysis of the impact of constipation severity at PD diagnosis and its relationship with long-term disease progression in a large longitudinal dataset (Chapter 2). I found a significant association between severe constipation in early PD and faster progression to dementia at an 8-year follow-up. To further explore the relationship between gut dysfunction and disease progression in PD, I developed the Gastrointestinal Dysfunction Scale – Parkinson’s Disease (GIDS-PD) and validated it against other GID assessment instruments in a large PD cohort, and proved that the GIDS-PD has good psychometric properties (Chapter 3). In Chapter 4, I used the GIDS-PD to characterize GID across PD stages. Using cross-sectional and longitudinal psychometric and objective transit time assessments, I observed that constipation is not a universal feature of PD but only affects a subtype who are likely to experience it through the disease course. I also conducted a prospective longitudinal study comparing a newly diagnosed PD cohort and household healthy controls as well as a prodromal PD cohort and collected data on gut symptoms, motor and cognitive features, and blood samples at baseline and 1 year follow-up (Chapter 5). I identified circulating peptidoglycan as a potential endotoxin of interest in the gut-brain axis and total ghrelin as potential protective agent. My project has clarified the presence of GID in the earliest stages of the disease, and investigated links with immune activation. This may pave the way for future intervention studies targeting GI function and associated immune changes in PD, with the goal of delaying disease progression.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Camacho Goncalves, Marta

Advisors dc:contributor.advisor

• Williams-Gray, Caroline
• Barker, Roger

• gastrointestinal
• gut-brain axis
• Parkinson's disease

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/71103cac-1a39-4ec1-a3bf-692b662b754d/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.108869

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/368802