Searching for prognostic biomarkers of Parkinson's Disease development in the Spanish EPIC cohort through a multiplatform metabolomics approach

Objective: The lack of knowledge about the onset and progression of Parkinson's disease (PD) hampers its early diagnosis and treatment. Our aim was to determine the biochemical remodeling induced by PD in a really early and pre-symptomatic stage and unveiling early potential diagnostic biomarkers adopting a multiplatform (LC-MS, GC-MS, CE-MS) untargeted metabolomics approach. Methods: 41,437 healthy volunteers from the European Prospective Study on Nutrition and Cancer (EPIC)-Spain cohort were followed for around 15 years to ascertain incident PD. For this study, baseline pre-clinical plasma samples of 39 randomly selected individuals (46% females, 41-69 years old) that developed PD (Pre-PD group) and the corresponding control group (n=39, 46% females, 41-69 years old) were analyzed. The metabolic differences were investigated by univariate and multivariate data analyses, followed by pathway-based metabolite analyses to obtain possible clues on biological functions. Results: Our results exposed significantly lower levels of seven free fatty acids in the pre-PD subjects, together with alterations in other metabolite classes. Our finding revealed alterations in fatty acids metabolism, mitochondrial dysfunction, oxidative stress, and gut-brain axis dysregulation. Conclusions: Although the biological purpose of these events is still unknown, the mechanisms involved in the remodeling of the suggested metabolic pathways seem to appear long before the development of PD hallmarks. These findings might be considered as worthy potential markers whose alteration might lead to the development of PD hallmarks in the future. Consequently, this study is of inestimable value since this is the first study conducted with samples collected many years before the disease development.