Dataset Information

Untargeted metabolomics reveal dysregulations in sugar, methionine, and tyrosine pathways in the prodromal state of AD.

ABSTRACT:

Introduction

Altered metabolism may occur years before clinical manifestations of Alzheimer's disease (AD). We used untargeted metabolomics on the cerebrospinal fluid of patients with mild cognitive impairment (MCI) to uncover metabolomic derangements.

Methods

CSF from 92 normal controls and 93 MCI underwent untargeted metabolomics using high-resolution mass spectrometry with liquid chromatography. Partial least squares discriminant analysis was used followed by metabolite annotation and pathway enrichment analysis (PES). Significant features were correlated with disease phenotypes.

Results

We identified 294 features differentially expressed between the two groups and 94 were annotated. PES showed that sugar regulation (N-glycan, P = .0007; sialic acid, P = .0014; aminosugars, P = .0042; galactose, P = .0054), methionine regulation (P = .0081), and tyrosine metabolism (P = .019) pathways were differentially activated and significant features within these pathways correlated with multiple disease phenotypes.

Conclusion

There is a metabolic signature characterized by impairments in sugars, methionine, and tyrosine regulation in MCI. Targeting these pathways may offer new therapeutic approaches to AD.

SUBMITTER: Hajjar I

PROVIDER: S-EPMC7418891 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Untargeted metabolomics reveal dysregulations in sugar, methionine, and tyrosine pathways in the prodromal state of AD.

Hajjar Ihab I Liu Chang C Jones Dean P DP Uppal Karan K

Alzheimer's & dementia (Amsterdam, Netherlands) 20200811 1

<h4>Introduction</h4>Altered metabolism may occur years before clinical manifestations of Alzheimer's disease (AD). We used untargeted metabolomics on the cerebrospinal fluid of patients with mild cognitive impairment (MCI) to uncover metabolomic derangements.<h4>Methods</h4>CSF from 92 normal controls and 93 MCI underwent untargeted metabolomics using high-resolution mass spectrometry with liquid chromatography. Partial least squares discriminant analysis was used followed by metabolite annotat ...[more]

PMID: 32793799

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Project description:IntroductionHypertensive nephrosclerosis is among the leading causes of end-stage renal disease, but its pathophysiology is poorly understood. We wanted to explore early metabolic changes using gene expression and targeted metabolomics analysis.MethodsWe analyzed gene expression in kidneys biopsied from 20 patients with nephrosclerosis and 31 healthy controls with an Affymetrix array. Thirty-one amino acids were measured by liquid chromatography coupled with mass spectrometry (LC-MS) in urine samples from 62 patients with clinical hypertensive nephrosclerosis and 33 age- and sex-matched healthy controls, and major findings were confirmed in an independent cohort of 45 cases and 15 controls.ResultsAmino acid catabolism and synthesis were strongly underexpressed in hypertensive nephrosclerosis (13- and 7-fold, respectively), and these patients also showed gene expression patterns indicating decreased fatty acid oxidation (12-fold) and increased interferon gamma (10-fold) and cellular defense response (8-fold). Metabolomics analysis revealed significant distribution differences in 11 amino acids in hypertensive nephrosclerosis, among them tyrosine, phenylalanine, dopamine, homocysteine, and serine, with 30% to 70% lower urine excretion. These findings were replicated in the independent cohort. Integrated gene-metabolite pathway analysis showed perturbations of renal dopamine biosynthesis. There were also significant differences in homocysteine/methionine homeostasis and the serine pathway, which have strong influence on 1-carbon metabolism. Several of these disturbances could be interconnected through reduced regeneration of tetrahydrofolate and tetrahydrobiopterin.ConclusionEarly hypertensive nephrosclerosis showed perturbations of intrarenal biosynthesis of dopamine, which regulates natriuresis and blood pressure. There were also disturbances in serine/glycine and methionine/homocysteine metabolism, which may contribute to endothelial dysfunction, atherosclerosis, and renal fibrosis.

Project description:Purpose: To reveal molecular mechanisms of diabetic retinopathy (DR) in Asians and facilitate the identification of new therapeutic targets through untargeted metabolomics. To determine the differences in serum metabolites and metabolic pathways between different stages of diabetic retinopathy in patients with type 2 diabetic mellitus (T2DM) and proliferative DR (PDR) and non-proliferative DR (NPDR) and identify differential metabolites between T2DM and DR (NPDR and PDR) patients. Methods: This prospective observational registration study described the differential metabolites between 45 T2DM patients and 15 control cases with no significant differences in clinical characteristics. Their biospecimens and clinical information were collected and recorded in their medical reports. DR phenotypes of the subjects were verified by retina specialists. Serum metabolites were analyzed using high-resolution mass spectrometry with liquid chromatography. Untargeted metabolomics was performed on serum samples from 15 T2DM patients, 15 non-proliferative diabetic retinopathy patients, 15 proliferative diabetic retinopathy patients, and 15 diabetic controls. Discriminatory metabolic features were identified through partial least squares discriminant analysis (PLS-DA), hierarchical clustering analysis (HCA), and generalized linear regression models. Result: Through untargeted metabolomics, 931 features (523 in positive and 408 in negative modes) with 102 common metabolites highly relevant to the presence of DR were detected. In the adjusted analysis, 67 metabolic features differed significantly between T2DM and NPDR patients. Pathway analysis revealed alterations in metabolisms of amino acids and fatty acids. Glutamate, phosphatidylcholine, and 13-hydroperoxyoctadeca-9,11-dienoic acid (13-PHODE) were key contributors to these pathway differences. A total of 171 features distinguished PDR patients from T2DM patients, and pathway analysis revealed alterations in amino acid metabolism, fatty acid metabolism, nitrogen metabolism, and tricarboxylic acid cycle. Aspartate, glutamate, glutamine, ornithine, N-acetyl-l-glutamate, N-acetyl-l-aspartate, citrate, succinate, N-(L-arginino)succinate, 2-oxoglutarate, 13-hydroperoxyoctadeca-9,11-dienoic acid, methionine, lysine, threonine, phenylalanine, N(pi)-methyl-l-histidine, phosphatidylcholine, and linoleate were major contributors to the pathway differences. Between NPDR patients and PDR patients, there were 79 significant differential metabolites. Enrichment pathway analysis showed changes in amino acid metabolism, fatty acid metabolism, pantothenate, and CoA biosynthesis. Aspartate, glutamine, N-acetyl-l-glutamate, N-acetyl-l-aspartate, pantothenate, dihomo-gamma-linolenate, docosahexaenoic acid, and icosapentaenoic acid were key factors for the differences of these pathways. Conclusion: This study demonstrated that the pathways of arginine biosynthesis metabolism, linoleic acid metabolism, alanine, aspartate, and glutamate metabolism, as well as d-glutamine and d-glutamate metabolism, were dysregulated in DR patients of the Asian population. Increased levels of glutamate, aspartate, glutamine, N-acetyl-l-glutamate, and N-acetyl-l-aspartate and decreased levels of dihomo-gamma-linolenate, docosahexaenoic, and icosapentaenoic were considered as the metabolic profile that could distinguish PDR from NPDR in Asians. Phosphatidylcholine and 13-PHODE were identified as two major novel metabolite markers in advanced stages of DR in our study.

Dataset Information

Untargeted metabolomics reveal dysregulations in sugar, methionine, and tyrosine pathways in the prodromal state of AD.

Introduction

Methods

Results

Conclusion

Publications

Untargeted metabolomics reveal dysregulations in sugar, methionine, and tyrosine pathways in the prodromal state of AD.

Similar Datasets

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