Metabolomic profiling uncovers diagnostic biomarkers and dysregulated pathways in Parkinson's disease

Abstract

Background: Parkinson's disease (PD) is the second most common neurodegenerative disorder, and it has an unclear pathogenesis and lacks validated, specific biomarker-based diagnostic approaches, particularly in PD patients with rapid eye movement (REM) sleep behavior disorder (PD-RBD).

Methods: Using untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics, serum profiles of 41 drug-naïve PD patients [including 19 PD-RBD and 22 PD without RBD (PD-nRBD) patients] and 20 healthy controls (HCs) were analyzed.

Results: Comparative analyses revealed 144 dysregulated metabolites in PD patients versus HCs, with 7 metabolites-sodium deoxycholate, S-adenosylmethionine, L-tyrosine, 3-methyl-L-tyrosine, 4,5-dihydroorotic acid, (6Z)-octadecenoic acid, and allantoin-demonstrating high classification accuracy [area under the curve (AUC) > 0.93]. Compared with PD-nPBD patients, PD-RBD patients exhibited distinct metabolic profiles, characterized by 21 differentially expressed metabolites, including suberic acid, 3-methyl-L-tyrosine, and methyl (indol-3-yl) acetate (AUC > 0.86). Notably, 3-methyl-L-tyrosine displayed dual dynamics, reflecting dopaminergic depletion in PD and compensatory metabolic adaptations in PD-RBD. Pathway enrichment analysis implicated central carbon metabolism (CCM) disruption in PD and peroxisome proliferator-activated receptor (PPAR) signaling pathway inactivation in PD-RBD.

Conclusion: These findings reveal potential serum-based biomarkers for PD and PD-RBD, highlight CCM and PPAR pathways as therapeutic targets, and underscore the role of metabolic dysregulation in PD pathophysiology.

Keywords: Parkinson’s disease; REM sleep behavior disorder; biomarkers; metabolic pathway; metabolomics.

Figure 1

Altered metabolic profiles between patients with PD and HCs. (A) OPLS-DA score plot. ESI (+): positive ion mode, R²X = 0.599, R²Y = 0.967, Q² = 0.927. (B) OPLS-DA score plot. ESI (−): negative ion mode, R²X = 0.115, R²Y = 0.972, Q² = 0.827. (C) Volcano plot of metabolites in the PD group versus the HC group. Red: upregulated metabolite; Blue: downregulated metabolite; Grey: metabolite not meeting the significance thresholds.

Figure 2

Potential metabolite biomarkers for PD diagnosis. (A-G) Box plots and ROC curves for the serum levels of (A) sodium deoxycholate, (B) S-adenosylmethionine, (C) L-tyrosine, (D) 3-methyl-L-tyrosine, (E) 4,5-dihydroorotic acid, (F) (6Z)-octadecenoic acid, and (G) allantoin for the diagnosis of PD. Data are expressed as the means ± SDs. ***p ≤ 0.001 and ****p ≤ 0.0001.

Figure 3

Altered serum metabolites of PD-RBD compared to PD-nRBD. (A) OPLS-DA score plots. ESI (+): positive ion mode, R²X = 0.564, R²Y = 0.974, Q² = 0.758. (B) OPLS-DA score plot. ESI (−): negative ion mode, R²X = 0.0938, R²Y = 0.981, Q² = 0.536. (C) Volcano plot of upregulated (red) and downregulated (blue) metabolites in the PD-RBD group versus the PD-nRBD group. (D) Heatmap of the 102 differential metabolites in the PD-RBD group versus the PD-nRBD group. Red indicates an increased level, and blue indicates a decreased level.

Figure 4

Significantly altered metabolite clusters and potential metabolite biomarkers for PD-RBD. (A) Twenty-one metabolites had VIP > 1 (also with FDR < 0.05), indicating their contribution to the classification in the OPLS-DA score plot. (B–D) Box plots and ROC curves for the serum levels of (B) suberic acid, (C) 3-methyl-L-tyrosine, and (D) methyl (indol-3-yl)acetate for the diagnosis of PD patients with RBD. Data are expressed as the means ± SD. ***p ≤ 0.001 and ****p ≤ 0.0001.

Figure 5

Scatter plot showing the KEGG pathway enrichment analysis results. (A) Pathway analysis of the significantly altered metabolites in the PD group versus the HC group. The red-to-yellow gradient signifies ascending p-values, and the dot size is scaled to show the magnitude per pathway. (B) Pathway analysis of the significantly altered metabolites in the PD-RBD group versus the PD-nRBD group.