The role of dopaminergic medication, lipid, and endocannabinoid pathway alterations in idiopathic and PRKN/PINK1-mediated Parkinson’s disease – a large-scale targeted metabolomics study

Alterations in many metabolites and biochemical pathways have been described in Parkinson’s Disease (PD). However, only a small fraction of these have been replicated in independent studies. As almost every PD patient is treated with dopaminergic medication, it is challenging to discriminate between disease- and drug-related effects, especially in relation to dopamine metabolism. We conducted a large-scale metabolomic study in plasma from 140 idiopathic (IPD), 19 PRKN/PINK1 -linked PD patients, and 64 healthy controls to disentangle disease-related metabolite alterations from drug-related effects. We distinguished between L-Dopa and non-L-Dopa treated PD patients to uncover nuanced metabolic changes associated with different therapies. We demonstrate that L-Dopa treatment uniquely influences the metabolome, with methyldopa and methoxytyramine, both L-Dopa breakdown products, elevated in L-Dopa-treated IPD and PRKN/PINK -linked PD patients. These alterations were not seen in untreated IPD patients and those on agonist treatment only. Polyamine metabolism alterations, notably elevation of putrescine and ornithine, were partly caused by L-Dopa treatment but also found in non-L-Dopa treated PD patients. In non-L-Dopa-treated patients, endocannabinoid metabolites were lowered and associated with disease duration. We observed lipid metabolism alterations, highlighting potential crosslinks with alpha-synuclein and providing insights into pathophysiological mechanisms. All PRKN/PINK1- linked PD patients received L-Dopa treatment. However, our data potentially support the well-established role of oxidative damage in these subtypes of PD. In conclusion, our study emphasizes the significant impact of L-Dopa treatment on the metabolome, which might be of relevance not only for metabolomics studies but also for PD biomarker research in general. Finally, our study highlights potential biomarkers and pathways crucial for the understanding disease mechanisms of PD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This project has received funding under the EU Horizon 2020 programme, grant agreement 668738. Alexander Balck was funded by the German Research Foundation (DFG) for a research stay in Leiden, the Netherlands. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the ethics committees at the University of Luebeck, Luebeck, Germany and University College London, London, United Kingdom. All participants gave written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All results after statistical analyses are available within the article and its supplementary material. The raw data that support the findings of this study are available from the corresponding author, upon reasonable request.