Perturbational Profiling of Metabolites in Patient Fibroblasts Implicates α-Aminoadipate as a Potential Biomarker for Bipolar Disorder

Abstract

Many studies suggest the presence of aberrations in cellular metabolism in bipolar disorder. We studied the metabolome in bipolar disorder to gain insight into cellular pathways that may be dysregulated in bipolar disorder and to discover evidence of novel biomarkers. We measured polar and nonpolar metabolites in fibroblasts from subjects with bipolar I disorder and matched healthy control subjects, under normal conditions and with two physiologic perturbations: low-glucose media and exposure to the stress-mediating hormone dexamethasone. Metabolites that were significantly different between bipolar and control subjects showed distinct separation by principal components analysis methods. The most statistically significant findings were observed in the perturbation experiments. The metabolite with the lowest p value in both the low-glucose and dexamethasone experiments was α-aminoadipate, whose intracellular level was consistently lower in bipolar subjects. Our study implicates α-aminoadipate as a possible biomarker in bipolar disorder that manifests under cellular stress. This is an intriguing finding given the known role of α-aminoadipate in the modulation of kynurenic acid in the brain, especially as abnormal kynurenic acid levels have been implicated in bipolar disorder.

Keywords: 2-Aminoadipate; 2-Aminoadipic acid; Bipolar disorder; Kynurenic acid; Metabolic profiling; α-Aminoadipate.

Fig. 1

Separation of bipolar disorder patients and controls in a PLS-DA model with a panel of metabolites that were significantly different between the two groups. PLS-DA plots are shown for metabolite profiles with different VIP thresholds. O refers to bipolar subjects and X to healthy control subjects.

Fig. 2

Distribution of normalized metabolite levels in bipolar disorder patients (BDP) and control subjects for the metabolites that were significantly different between the two groups when grown under normal conditions. * Denotes significance at p < 0.05 (unpaired t test).

Fig. 3

Separation of bipolar disorder patients and controls with perturbational profiling. Separation of bipolar disorder patients and control subjects in a PLS-DA model is shown for metabolites using different VIP thresholds for the low-glucose experiment (a) and the dexamethasone experiment (b). O refers to bipolar subjects and X to healthy control subjects.

Fig. 4

Metabolite patterns under low-glucose conditions. Differences in metabolite levels between bipolar disorder patients (BPD) and healthy controls subjects for metabolites significantly different between the two groups. * Denotes significance at p < 0.05 (unpaired t test).

Fig. 5

Metabolite patterns with exposure to dexamethasone. Differences in metabolite levels between bipolar disorder patients (BDP) and control subjects for metabolites significantly different between the two groups. * Denotes significance at p < 0.05 (unpaired t test).