Objective: We sought to identify a signature distinctive of Parkinson’s disease (PD) through two independent metabolomics approaches.

Background: A recent meta-analysis showed a considerable inconsistency among the findings obtained by 74 original PD-focused metabolomics studies, highlighting the need for high-quality studies validated through multiple assays [1].

Method: We enrolled 88 sporadic PD patients and 34 age-matched HC [Table 1]. Untargeted metabolomics was carried out using untargeted Nuclear Magnetic Resonance (¹H-NMR) and targeted (n = 44 metabolites) ultraperformance liquid chromatography/mass spectrometry (UPLC/MS) on serum samples. Partial least-squares discriminant analysis (PLS-DA) and Pathway enrichment analyses were used to uncover metabolites and biochemical pathways discriminating the two groups.

Results: ¹H-NMR univariate analyses showed higher concentrations of serine, creatinine, and pyruvic acid and lower levels of 2-oxoglutarate and proline in the blood of PD patients compared to HC [Figure 1a]. PLS-DA identified two distinct clusters for PD patients and HC [Figure 1b]. Multivariate analyses revealed 13 metabolites associated with PD (i.e. with variable importance in projection (VIP) score>1), including 2-oxoglutarate and several molecules related to amino acids and energy metabolism [Figure 1c]. ¹H-NMR pathway analysis identified 20 pathways overrepresented in PD at FDR < 0.05. Among these, glycine-serine pathway showed the best discriminating value (p = 3.10^-16) [Figure 1d].

Univariate UPLC/MS analysis highlighted 7 aminoacids as statistically relevant, including threonine, glycine, and cystathionine (higher in PD than HC), and kynurenine, glutamic acid, allo-isoleucine, and alanine (reduced in PD) [Figure 2a]. Multivariate VIP score UPLC/MS analysis identified kynurenine, threonine, glycine, and glutamic acid as major contributors in the groups discrimination [Figure 2b-c]. Enrichment analysis revealed a dysregulation of 6 pathways in PD [Figure 2d]. In line with our previous HPLC study on PD patients’ serum [2], we found a positive correlation between glycine levels and MDS-UPDRS-III score[Figure 3].

Conclusion: We identified disrupted homeostasis of molecules related to energy metabolism, NMDA receptor-modulating amino acids,  dopamine biosynthesis, and glutathione as distinct serum signatures in PD patients.

Figure 1. 1H-NMR metabolomics results.

Figure 2. UPLC/MS analysis results.

Figure 3. Clinical-biochemical correlation matrix

Table 1. Clinical-demographics features

References: 1 Luo, X., Liu, Y., Balck, A., Klein, C., & Fleming, R. M. T. (2024). Identification of metabolites reproducibly associated with Parkinson’s Disease via meta-analysis and computational modelling. Npj Parkinson’s Disease, 10(1), 126. https://doi.org/10.1038/s41531-024-00732-z

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

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MDS Abstracts - https://www.mdsabstracts.org/abstract/1h-nmr-and-uplc-ms-metabolomics-identify-disrupted-homeostasis-of-energy-amino-acids-and-glutathione-metabolism-as-serum-signatures-in-parkinsons-disease-patients/