Objective: We attempted to identify a metabolomic signature distinctive of Parkinson’s disease (PD) through an untargeted metabolomics approach.

Background: Using an high-performance liquid chromatography targeted approach, we recently showed increased cerebrospinal fluid and serum serine enantiomers levels as putative biochemical signature of PD [1,2]. Recent serum metabolomics evidence showed a dysregulation of multiple amino acids pathways in PD patients compared to healthy controls (HC) [3].

Method: Sixty-nine idiopathic PD patients (mean age: 72 years; mean disease duration: 6.0 years) and thirty-two age-matched HC were enrolled. Untargeted metabolomics was carried out using Nuclear Magnetic Resonance (¹H-NMR) on serum samples. Partial least-squares discriminant analysis (PLS-DA) and Pathway enrichment analysis were used to identify metabolites and biochemical pathways discriminating the two groups.

Results: Serum metabolomics identified two distinct clusters for PD patients and HC (0.88 and 0.97 accuracy for PC1 and PC2, respectively, with positive 0.52 and 0.63 Q2 indices) [Figure1]. Multivariate analyses revealed 11 metabolites independently associated with PD (i.e. with variable importance in projection (VIP) score > 1), including L-glutamate, L-proline, pyruvate and L-serine [Figure2]. Univariate analyses showed (i) increased L-glutamate and (ii) reduced L-Proline and 2-oxoglutarate levels in PD compared to HC, all showing an high predictive power for PD (area under the curve: 0.99, 0.89 and 0.94, respectively) [Figure3]. Finally, pathway analysis identified 21 pathways overrepresented in PD at FDR < 0.05, almost all involved in amino acid or energy metabolism. Among these, glycine-serine pathway showed the best discriminating value (p = 3.10^-16) [Figure4].

Conclusion: We identified glycine-serine pathway dysregulation as a distinctive signature of PD. Our results support the hypothesis that dysregulated amino acids and energy metabolism plays a key role in PD physiopathology and pave the way for future studies evaluating its diagnostic and prognostic value.

PLS-DA score scatter plots for PD and HC

ROC curves for PD prediction

Enrichment pathways analysis.

References: [1] A. Di Maio, T. Nuzzo, L. Gilio, M. Serra, F. Buttari, F. Errico, A. De Rosa, M.S. Bassi, M. Morelli, J. Sasabe, D. Sulzer, M. Carta, D. Centonze, A. Usiello, Homeostasis of serine enantiomers is disrupted in the post-mortem caudate putamen and cerebrospinal fluid of living Parkinson’s disease patients, Neurobiol. Dis. 184 (2023) 106203. https://doi.org/10.1016/j.nbd.2023.106203.

[2] A. Imarisio, I. Yahyavi, M. Avenali, A. Di Maio, G. Buongarzone, C. Galandra, M. Picascia, A. Filosa, C. Gasparri, M.C. Monti, M. Rondanelli, C. Pacchetti, F. Errico, E.M. Valente, A. Usiello, Blood D-serine levels correlate with aging and dopaminergic treatment in Parkinson’s disease, Neurobiol. Dis. 192 (2024) 106413. https://doi.org/10.1016/j.nbd.2024.106413.

[3] K.C. Paul, K. Zhang, D.I. Walker, J. Sinsheimer, Y. Yu, C. Kusters, I. Del Rosario, A.D. Folle, A.M. Keener, J. Bronstein, D.P. Jones, B. Ritz, Untargeted serum metabolomics reveals novel metabolite associations and disruptions in amino acid and lipid metabolism in Parkinson’s disease, Mol. Neurodegener. 18 (2023) 1–16. https://doi.org/10.1186/s13024-023-00694-5.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/untargeted-serum-metabolomics-identifies-glycine-serine-metabolism-disruption-as-biochemical-bignature-in-parkinsons-disease/