Comprehensive metabolic profiling of Parkinson’s disease by liquid chromatography-mass spectrometry

Abstract

Background Parkinson’s disease (PD) is a prevalent neurological disease in the elderly with increasing morbidity and mortality. Despite enormous efforts, rapid and accurate diagnosis of PD is still compromised. Metabolomics defines the final readout of genome-environment interactions through the analysis of the entire metabolic profile in biological matrices. Recently, unbiased metabolic profiling of human sample has been initiated to identify novel PD metabolic biomarkers and dysfunctional metabolic pathways, however, it remains a challenge to define reliable biomarker(s) for clinical use. Methods We presented a comprehensive metabolic evaluation for identifying crucial metabolic disturbances in PD using liquid chromatography-high resolution mass spectrometry-based metabolomics approach. Plasma samples from 3 independent cohorts (n = 460, 223 PD, 169 healthy controls (HCs) and 68 PD-unrelated neurological disease controls) were collected for the characterization of metabolic changes resulted from PD, antiparkinsonian treatment and potential interferences of other diseases. Unbiased multivariate and univariate analyses were performed to determine the most promising metabolic signatures from all metabolomic datasets. Multiple linear regressions were applied to investigate the associations of metabolites with age, duration time and stage of PD. The combinational biomarker model established by binary logistic regression analysis was validated by 3 cohorts. Results A list of metabolites including amino acids, acylcarnitines, organic acids, steroids, amides, and lipids from human plasma of 3 cohorts were identified. Compared with HC, we observed significant reductions of fatty acids (FFAs) and caffeine metabolites, elevations of bile acids and microbiota-derived deleterious metabolites, and alterations in steroid hormones in drug-naïve PD. Additionally, we found that L-dopa treatment could affect plasma metabolome involved in phenylalanine and tyrosine metabolism and alleviate the elevations of bile acids in PD. Finally, a metabolite panel of 4 biomarker candidates, including FFA 10:0, FFA 12:0, indolelactic acid and phenylacetyl-glutamine was identified based on comprehensive discovery and validation workflow. This panel showed favorable discriminating power for PD. Conclusions This study may help improve our understanding of PD etiopathogenesis and facilitate target screening for therapeutic intervention. The metabolite panel identified in this study may provide novel approach for the clinical diagnosis of PD in the future.

In vitro genome editing rescues parkinsonism phenotypes in induced pluripotent stem cells-derived dopaminergic neurons carrying LRRK2 p.G2019S mutation

“…6 b, empty bars). These observations were in line with the clinical studies showing reduced fatty acid metabolism in plasma from patients with PD [ 40 ]. In addition, peroxisome proliferator-activated receptor (PPAR) signaling pathway, a lipid sensor [ 41 ], was consistently elevated in mutation-corrected iPSCs.…”

Multiomics implicate gut microbiota in altered lipid and energy metabolism in Parkinson’s disease

“…Both glutamate and glycine are neurotransmitters. Although that is not the case in our data, proline has been reported previously as being overrepresented in PD 24 and is known to be linked to protein metabolism and structure, cell differentiation, conceptus growth and development 39 , and gut microbiota community reequilibration in cases of dysbiosis, with L-proline dietary supplementation being known to affect gut microbial composition and gut concentrations of several bacterial metabolites 40 .…”

“…If methylation capacity is compromised due to an alteration in folate metabolism, there may be impaired phosphatidylcholine synthesis along with shunted or disrupted carnitine shuttle observed in our results. Altered carnitine metabolism, fatty acids, and steroid metabolism was also observed in a metabolomics profiling study recently reported 24 . Several studies have reported decreased levels of carnitine and acylcarnitines in plasma from PD patients 21,25,26 ; however, according to Jiménez-Jiménez et al (1997) 27 no changes were observed in acylcarnitine levels in plasma or cerebrospinal fluids of PD participants.…”

Gut-Derived Metabolite Phenylacetylglutamine and White Matter Hyperintensities in Patients With Acute Ischemic Stroke

“…Phenylacetylglutamine, another gut microbial metabolite, has been reported to correlate with chronic kidney disease, diabetes mellitus, cardiovascular disease, and Parkinson's disease (Poesen et al, 2016;Urpi-Sarda et al, 2019;Shao et al, 2021 cardiovascular disease risks in a large sample clinical study (Nemet et al, 2020). This study suggested a clinical association between elevated PAGln levels and the overall burden of WMH and P-WMH.…”