Parkinson’s disease etiology : beyond the brain and late adulthood

Abstract: Despite much effort investigating the etiology of Parkinson’s disease (PD), the causes and the exact mechanisms underlying the disease remain elusive. Braak’s hypothesis suggests that PD pathology may start in the enteric nervous system and later spread to the brain via the vagus nerve. This hypothesis is further extended to the dual-hit hypothesis suggesting that environmental neurotropic pathogens may contribute to PD development through nasal and gut gateways that are in direct connection with each other via inhalation and ingestion. Mounting evidence also suggests the importance of neuroinflammation in the pathogenesis of PD. In this thesis, I aimed to explore the etiology of PD focusing on developmental origins related to early infection and inflammation, gastrointestinal aspects, and olfactory function using various register and population based datasets. In Study I, we conducted a cohort study to examine developmental aspects of PD regarding early life infection, parental age at birth, multiple birth. We considered birth order, sibship size, birth seasonality, and flu activity in the year of birth as surrogates for early infection and inflammation. Overall, we found that early life characteristics were not associated with future risk of PD, indicating little support for the importance of early life aspects in PD etiology. In Study II, we evaluated vagotomy and its subtypes (truncal and selective vagotomies) in relation to PD risk in a matched cohort. We found that truncal vagotomy, with the nerve trunk fully resected, appeared to be associated with a decreased risk of PD more than five years after the surgery, while selective vagotomy was not associated with the risk of PD. The results provide preliminary evidence supporting Braak’s hypothesis. In Study III, we conducted a nested case-control study in the Swedish total population and a cohort study in Swedish twins to investigate irritable bowel syndrome (IBS) diagnosis as well as IBS based on self-reported symptoms in relation to the risk of PD. The results demonstrated that IBS was linked to an elevated risk of PD. The findings add additional evidence suggesting the importance of gut-brain-axis in PD development. In Study IV, we examined whether poor olfaction is associated with long-term mortality and potential explanations for such association among older adults in a community-based cohort. We found that poor olfaction was associated with higher long-term mortality and that part of the association was explained by neurodegenerative diseases, in particular, PD and dementia, and body weight loss. In summary, by taking advantage of Swedish nationwide registers, we provide some evidence supporting Braak’s hypothesis and the importance of the gut-to-brain axis in PD development. Our data, however, do not support the importance of developmental origins of PD. Additionally, we confirmed the association between poor olfaction and mortality in healthy older adults from the Health, Aging and Body Composition study and identified PD or dementia and body weight loss as part of the potential mechanisms underlying the association.