Metabolomics approach revealed robust changes in amino acid and biogenic amine signatures in patients with schizophrenia in the early course of the disease

Parksepp, Madis; Leppik, Liisa; Koch, Kadri; Uppin, Kärt; Kangro, Raul; Haring, Liina; Vasar, Eero; Zilmer, Mihkel

doi:10.1038/s41598-020-71014-w

Cited by 43 publications

(41 citation statements)

References 58 publications

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“…We further performed a gene enrichment analysis using 227 DEGs compiled from microarray studies. Enrichment of arginine, proline metabolism pathway in our analysis is in agreement with the findings of the recent metabolomics study which reported changes in amino acid signatures in SCZ affected individuals (He et al, 2012 ; Parksepp et al, 2020 ). In addition to this a study by Chen et al reported arginine and proline metabolism as one of the differential metabolic pathways in violent schizophrenia affected participants (Chen et al, 2020 ).…”

Section: Discussionsupporting

confidence: 92%

Peripheral Blood-Based Gene Expression Studies in Schizophrenia: A Systematic Review

Wagh

Vyas

Agrawal³

et al. 2021

Front. Genet.

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Schizophrenia is a disorder that is characterized by delusions, hallucinations, disorganized speech or behavior, and socio-occupational impairment. The duration of observation and variability in symptoms can make the accurate diagnosis difficult. Identification of biomarkers for schizophrenia (SCZ) can help in early diagnosis, ascertaining the diagnosis, and development of effective treatment strategies. Here we review peripheral blood-based gene expression studies for identification of gene expression biomarkers for SCZ. A literature search was carried out in PubMed and Web of Science databases for blood-based gene expression studies in SCZ. A list of differentially expressed genes (DEGs) was compiled and analyzed for overlap with genetic markers, differences based on drug status of the participants, functional enrichment, and for effect of antipsychotics. This literature survey identified 61 gene expression studies. Seventeen out of these studies were based on expression microarrays. A comparative analysis of the DEGs (n = 227) from microarray studies revealed differences between drug-naive and drug-treated SCZ participants. We found that of the 227 DEGs, 11 genes (ACOT7, AGO2, DISC1, LDB1, RUNX3, SIGIRR, SLC18A1, NRG1, CHRNB2, PRKAB2, and ZNF74) also showed genetic and epigenetic changes associated with SCZ. Functional enrichment analysis of the DEGs revealed dysregulation of proline and 4-hydroxyproline metabolism. Also, arginine and proline metabolism was the most functionally enriched pathway for SCZ in our analysis. Follow-up studies identified effect of antipsychotic treatment on peripheral blood gene expression. Of the 27 genes compiled from the follow-up studies AKT1, DISC1, HP, and EIF2D had no effect on their expression status as a result of antipsychotic treatment. Despite the differences in the nature of the study, ethnicity of the population, and the gene expression analysis method used, we identified several coherent observations. An overlap, though limited, of genetic, epigenetic and gene expression changes supports interplay of genetic and environmental factors in SCZ. The studies validate the use of blood as a surrogate tissue for biomarker analysis. We conclude that well-designed cohort studies across diverse populations, use of high-throughput sequencing technology, and use of artificial intelligence (AI) based computational analysis will significantly improve our understanding and diagnostic capabilities for this complex disorder.

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Section: Discussionsupporting

confidence: 92%

Peripheral Blood-Based Gene Expression Studies in Schizophrenia: A Systematic Review

Wagh

Vyas

Agrawal³

et al. 2021

Front. Genet.

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“…Several studies have been performed to identify metabolites changes and biomarkers in schizophrenia (6,7). Abnormal biological levels have been reported in patients with schizophrenia for several metabolites, including N-acetyl aspartate, lactic acid, tryptophan, glutamic acid, phospholipids, kynurenine, and creatine (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

A Metabolomics Study of Serum in Hospitalized Patients With Chronic Schizophrenia

et al. 2021

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Purpose: Metabolomics has attracted attention as a new method for understanding the molecular mechanisms of psychiatric disorders. Current metabolomics technology allows us to measure over hundreds of metabolites at a time and is a useful indicator of the consequences of complex and continuous changes in metabolic profiles due to the execution of genomic information and external factors of biological activity. Therefore, metabolomics is imperative to the discovery of biomarkers and mechanisms associated with pathophysiological processes. In this study, we investigated metabolites changes in hospitalized patients with chronic schizophrenia compared to that in healthy controls, and examined the correlations between the metabolites and psychiatric symptoms.Patients and Methods: Thirty patients with schizophrenia and ten healthy controls participated in this study between September 2019 and June 2020. The mean duration of disease in patients with schizophrenia was 26 years. Clinical and neuropsychiatric symptoms of patients with schizophrenia were assessed using the Positive and Negative Syndrome Scale (PANSS). Metabolomics was conducted using Capillary Electrophoresis Fourier Transform Mass Spectrometry (CE-FTMS), using serum samples from patients with schizophrenia and healthy controls. Metabolomics assigned a candidate compound to the 446 (cation 279, anion 167) peaks. Hierarchical cluster analysis (HCA), principal component analysis (PCA), logistic regression analysis, receiver operating characteristic (ROC) analysis, and linear regression analysis were used to analyze the metabolites changes, identifying the disease and the relationship between metabolites and psychiatric symptoms.Results: HCA showed that approximately 60% of metabolites had lower peak values in patients with schizophrenia than in healthy controls. Glutamate metabolism and the urea cycle had the highest proportions in the metabolic pathway, which decreased in patients with schizophrenia. PCA showed a clear separation between patients with schizophrenia and healthy controls in the first principal component (the contribution ratio of the first principal component was 15.9%). Logistic regression analysis suggested that the first principal component was a predictor of disease (odds = 1.36, 95%CI = 1.11–1.67, p = 0.0032). ROC analysis showed a sensitivity of 93% and a specificity of 100% for the diagnosis of schizophrenia with a cut-off value of the first principal component; −3.33 (AUC = 0.95). We extracted the high factor loading for the first principal component. Gamma-glutamyl-valine (γ-Glu-Val) was significantly negatively correlated with PANSS total scores (r = −0.45, p = 0.012) and PANSS general scores (r = −0.49, p = 0.0055). Gamma-glutamyl-phenylalanine (γ-Glu-Phe) was significantly negatively correlated with PANSS total score (r = −0.40, p = 0.031) and PANSS general score (r = −0.41, p = 0.025). Tetrahydrouridine was significantly positively correlated with PANSS negative scores (r = 0.53, p = 0.0061).Conclusion: Metabolites changes in hospitalized patients with chronic schizophrenia showed extensive and generalized declines. Glutamate metabolism and the urea cycle had the highest proportions in the metabolic pathway, which decreased in the schizophrenia group. Metabolomic analysis was useful to identify chronic schizophrenia. Some glutamate compound metabolites had a relationship with psychiatric symptoms.

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“…Specifically, the differential expression of creatinine reflected the perturbations of normal energy metabolism levels in schizophrenia patients, possibly leading to psychiatric symptoms [33] . Ornithine has been reported as a biomarker for SZs in serum or plasma [34] . The abnormal expression of ornithine in schizophrenia fits with decreased urea metabolism [35] .…”

Section: Resultsmentioning

confidence: 99%

Design of Multi‐Shelled Hollow Cr₂O₃Spheres for Metabolic Fingerprinting

Zhou

Liu

et al. 2021

Angewandte Chemie

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Schizophrenia (SZ) detection enables effective treatment to improve the clinical outcome, but objective and reliable SZ diagnostics are still limited. An ideal diagnosis of SZ suited for robust clinical screening must address detection throughput, low invasiveness, and diagnosis accuracy. Herein, we built a multi‐shelled hollow Cr2O3 spheres (MHCSs) assisted laser desorption/ionization mass spectrometry (LDI MS) platform for the direct metabolic profiling of biofluids towards SZ diagnostics. The MHCSs displayed strong light absorption for enhanced ionization and microscale surface roughness with stability for the effective LDI of metabolites. We profiled urine and serum metabolites (≈1 μL) with the enhanced LDI efficacy in seconds. We discriminated SZ patients (SZs) from healthy controls (HCs) with the highest area under the curve (AUC) value of 1.000 for the blind test. We identified four compounds with optimal diagnostic power as a simplified metabolite panel for SZ and demonstrated the metabolite quantification for clinic use. Our approach accelerates the growth of new platforms toward a precision diagnosis in the near future.

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Metabolomics approach revealed robust changes in amino acid and biogenic amine signatures in patients with schizophrenia in the early course of the disease

Abstract: p = 4e−04) at baseline than CSs (full details of the data generation and fitting procedures are given in Supplementary material Tables S4-S6).

Cited by 43 publications

References 58 publications

Peripheral Blood-Based Gene Expression Studies in Schizophrenia: A Systematic Review

Peripheral Blood-Based Gene Expression Studies in Schizophrenia: A Systematic Review

A Metabolomics Study of Serum in Hospitalized Patients With Chronic Schizophrenia

Design of Multi‐Shelled Hollow Cr₂O₃Spheres for Metabolic Fingerprinting

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Metabolomics approach revealed robust changes in amino acid and biogenic amine signatures in patients with schizophrenia in the early course of the disease

Abstract: p = 4e−04) at baseline than CSs (full details of the data generation and fitting procedures are given in Supplementary material Tables S4-S6).

Cited by 43 publications

References 58 publications

Peripheral Blood-Based Gene Expression Studies in Schizophrenia: A Systematic Review

Peripheral Blood-Based Gene Expression Studies in Schizophrenia: A Systematic Review

A Metabolomics Study of Serum in Hospitalized Patients With Chronic Schizophrenia

Design of Multi‐Shelled Hollow Cr2O3Spheres for Metabolic Fingerprinting

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Product

Resources

About

Design of Multi‐Shelled Hollow Cr₂O₃Spheres for Metabolic Fingerprinting