Metabolomic Profiling of Post-Mortem Brain Reveals Changes in Amino Acid and Glucose Metabolism in Mental Illness Compared with Controls

Rong Zhang,Tong Zhang,Ali Muhsen Ali,Mohammed Al Washih,Benjamin Pickard,David G Watson

doi:10.1016/j.csbj.2016.02.003

Abstract

Metabolomic profiling was carried out on 53 post-mortem brain samples from subjects diagnosed with schizophrenia, depression, bipolar disorder (SDB), diabetes, and controls. Chromatography on a ZICpHILIC column was used with detection by Orbitrap mass spectrometry. Data extraction was carried out with m/z Mine 2.14 with metabolite searching against an in-house database. There was no clear discrimination between the controls and the SDB samples on the basis of a principal components analysis (PCA) model of 755 identified or putatively identified metabolites. Orthogonal partial least square discriminant analysis (OPLSDA) produced clear separation between 17 of the controls and 19 of the SDB samples (R2CUM 0.976, Q2 0.671, p-value of the cross-validated ANOVA score 0.0024). The most important metabolites producing discrimination were the lipophilic amino acids leucine/isoleucine, proline, methionine, phenylalanine, and tyrosine; the neurotransmitters GABA and NAAG and sugar metabolites sorbitol, gluconic acid, xylitol, ribitol, arabinotol, and erythritol. Eight samples from diabetic brains were analysed, six of which grouped with the SDB samples without compromising the model (R2 CUM 0.850, Q2 CUM 0.534, p-value for cross-validated ANOVA score 0.00087). There appears on the basis of this small sample set to be some commonality between metabolic perturbations resulting from diabetes and from SDB.

Highlights

Mental illness, most commonly schizophrenia, depression, and bipolar disorder (‘SDB’) is common: schizophrenia has a European prevalence of 0.2–2.6%, depression 3.1–10.1%, and bipolar disorder 0.2–1.1% [1]
The highest Variable importance in the projection (VIP) in the Orthogonal projections to latent structures (OPLS)-DA model (Fig. 2) of the SDB samples against the controls are the branched chain amino acids leucine/isoleucine and valine (BCAs) which are elevated above the levels found in the controls
There have been a number of recent metabolomics studies of obesity and insulin resistance and it has been observed that there is a distinct metabolic signature linked to metabolic syndrome where the plasma levels of branched chain amino acids (BCAs) leucine, isoleucine, and valine were elevated together with methionine, glutamine, phenylalanine, tyrosine, asparagine, and arginine [41,42]

Summary

Introduction

Most commonly schizophrenia, depression, and bipolar disorder (‘SDB’) is common: schizophrenia has a European prevalence of 0.2–2.6%, depression 3.1–10.1%, and bipolar disorder 0.2–1.1% [1]. These conditions are a major burden on the health-care systems and on the relatives of affected people. Such illnesses are heterogeneous and present with psychosis or mood state features that vary over time and across individuals. In the past 10 years, mass spectrometry-based metabolomics has evolved as a method for profiling a wide range of low-molecular-weight metabolites [6,7]. There have been several studies which have carried out metabolomic profiling in mental illness [10,11,12,13,14,15,16,17], but these have not been as extensive as those into other diseases such as cancer

Methods

Results

Discussion

Conclusion