The role of dopaminergic medication and specific pathway alterations in idiopathic and PRKN/PINK1-mediated Parkinson's disease

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease, with a rapidly increasing prevalence worldwide. Biomarkers monitoring state and progression are urgently needed, and metabolomics from easily accessible biofluids holds the potential to elucidate pathophysiological underpinnings in PD. Several studies suggested metabolomic differences between patients and controls, but findings are controversial, and independent replication is scarce. We thus applied state-of-the-art, large-scale metabolomics in patients with idiopathic and monogenic PD and controls from two independent samples, analyzed by a strict meta-analysis approach. Thereby, we (i) debunked that l-Dopa medication and not disease status causes the most substantial metabolomic differences and (ii) identified polyamine metabolism alterations, partly, but not entirely associated with l-Dopa treatment. Furthermore, we found explorative but robust evidence for alterations in endocannabinoid metabolites; detected lipid metabolism alterations, highlighting potential crosslinks with alpha-synuclein pathology; and provided evidence for a metabolomic signature for the role of oxidative damage in patients with PRKN- and PINK1-linked PD.

Fig. 1.. Levels of 3-methoxytyramine and methyldopa are increased in patients with IPD treated with l-Dopa (l-Dopa^positive) but not elevated in untreated patients and patients with agonist treatment only (l-Dopa^negative).

(A and B) HC, healthy controls; UL, University of Lübeck; UCL, University College London. Data were analyzed as described in the statistics section. No significance levels are depicted in the figure, as data uncorrected for site effects are shown, while statistical calculations were performed by meta-analysis as described in the methods part.

Fig. 2.. (+/−)-16-HDoHE, ornithine, and putrescine are increased in patients with IPD treated with l-Dopa (l-Dopa^positive) but not elevated in untreated patients and patients with agonist treatment only (l-Dopa^negative).

(A to C) Data were analyzed as described in the “Statistics” section. No significance levels are depicted in the figure, as data uncorrected for site effects are shown, while statistical calculations were performed by meta-analysis as described in Materials and Methods.

Fig. 3.. Exploratory associations of metabolite levels with disease duration and disease severity, measured by H/Y staging, in patients with IPD not treated with l-Dopa (l-Dopa^negative).

Three metabolite levels were exploratively associated with disease duration (A to C) and two with H/Y staging (D and E) as indicated by a nominal P < 0.05. Note that the regression line is descriptive and does not correspond to the regression coefficients based on the meta-analysis. The figures reflect the data and the calculations depicted in tables S7 and S8.

Fig. 4.. Flowchart of the exclusion and inclusion process.

UCL, University College London; UL, University of Lübeck. Excluded due to clinical reasons: Patients who do not fulfill the diagnostic criteria of PD as described in the methods section. Excluded due to genetic reasons: UL: Patients were excluded due to pathogenic variants/risk variants in GBA1 (n = 10), LRRK2 (n = 2), SNCA (n = 1), heterozygous variants in PRKN or PINK1 (n = 4), and nonconclusive genetic results (n = 2). UCL: Patients were excluded due to pathogenic variants/risk variants in GBA1 (n = 12), LRRK2 (n = 7), heterozygous variants in PRKN or PINK1 (n = 6), and nonconclusive genetic results (n = 2). Patients were not suitable for metabolomic analyses if biomaterials to perform the analyses were not available.