Levodopa and dopamine dynamics in Parkinson’s disease metabolomics

Branco, R. C.; Ellsworth, W.; Niezwiecki, M. M.; Butkovich, L. M.; Walker, D. I.; Huddleston, D. E.; Jones, D. P.; Miller, G. W.

doi:10.1101/306266

bioRxiv · 10.1101/306266

Levodopa and dopamine dynamics in Parkinson’s disease metabolomics

Branco, R. C.·Ellsworth, W.·Niezwiecki, M. M.·Butkovich, L. M.·Walker, D. I.·Huddleston, D. E.·Jones, D. P.·Miller, G. W.

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Abstract

Parkinsons disease (PD) is a progressive neurological disorder caused by a combination of genetic and environmental factors. Metabolomics is a powerful tool that can be used to screen for potential biomarkers, exogenous toxicants, and metabolic network changes associated with disease states. Here, we used high-resolution metabolomics to compare over 10,000 plasma metabolic features from older adults with and without PD in an untargeted approach. We performed a network analysis that demonstrates that the presence of the PD drug levodopa influences variation observed between PD and control patients. Metabolome wide association studies and discrimination analysis identified significant differentiation in the metabolomics profile of older adults with and without PD. Notably, 15 metabolic features (ten of which we putatively identified) differed between PD and control adults with p < 0.05 and a corrected false discovery rate less than 20%. Furthermore, 13 metabolic networks were identified to be functionally different between PD and non-PD patients. Lastly, the dopaminergic toxic intermediate DOPAL differed between PD and non-PD populations, which supports the dopaminergic sequestration model of PD. These individual metabolites and metabolic networks have been implicated in past PD pathogenesis models, including the beta-carboline harmalol and the glycosphingolipid metabolism pathway including the ganglioside GM2. We recommend that future studies take into account the confounding effects of levodopa in metabolomic analyses of disease versus control patients, and encourage validation of several promising metabolic markers of PD.

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Branco, R. C., Ellsworth, W., Niezwiecki, M. M., Butkovich, L. M., Walker, D. I., Huddleston, D. E., Jones, D. P., Miller, G. W.. 2018-04-23. Levodopa and dopamine dynamics in Parkinson’s disease metabolomics. https://doi.org/10.1101/306266

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