Redox Dysregulation in Schizophrenia Revealed by in vivo NAD+/NADH Measurement

Abstract

Balance between the redox pair of nicotinamide adenine dinucleotides (oxidized NAD+ and reduced NADH), reflects the oxidative state of cells and the ability of biological systems to carry out energy production. A growing body of evidence suggests that an "immuno-oxidative" pathway including oxidative stress, mitochondrial dysfunction, neuroinflammation, and cell-mediated immune response may contribute to disruptions in brain activity in schizophrenia (SZ). The aim of this study is to assess possible redox imbalance in SZ patients by using a novel in vivo 31 P MRS technique. The participants included 40 healthy controls, 21 chronic SZ, 13 first-episode (FE) SZ, and 18 FE bipolar disorder (BD) patients (as a psychiatric control group). All participants initially underwent structural imaging at a 3 Tesla (3 T) and 31 P MRS measurements were performed on a 4 T MR scanner. NAD+ and NADH components were determined by nonlinear least-square fitting of the model simulated spectra; these incorporated prior chemical shift and coupling constant information to in vivo resonances obtained from 31 P MRS experiments. We found a significant reduction in the NAD+/NADH ratio in chronically ill SZ patients compared to a matched healthy control group, and in FE SZ patients compared to both a matched FE BD patient group and a matched healthy control group. These findings provide evidence for redox imbalance in the brain in all phases of SZ, potentially reflecting oxidative stress.

Brain bioenergetics and redox state measured by 31 P magnetic resonance spectroscopy in unaffected siblings of patients with psychotic disorders

“…A converging body of evidence has suggested a role for oxidative stress and altered antioxidant defenses in psychotic disorders (Yao and Keshavan, 2011). In a recent study, we found evidence of a significant reduction in NAD+/NADH measured by 31 P MRS, reflecting redox imbalance, in the brain of patients with first episode and chronic schizophrenia (Kim et al, 2017), compared to healthy controls. To our knowledge, no studies have previously measured NAD metabolites using 31 P MRS in unaffected relatives of patients with psychotic disorders.…”

“…Patients, siblings and controls were excluded if they had a history of significant medical or neurologic illness, history of significant head trauma, contraindication to MR scan (including claustrophobia) or pregnancy. Of note, the unaffected sibling data we present here is entirely new, but 28 patients and 11 controls in this analysis overlap with the study population in our recent study (Kim et al, 2017), and we include them for comparison purposes. The study was approved by the McLean Hospital Institutional Review Board, and participants provided written informed consent.…”

“…Brain anatomic imaging and 31 P MRS were acquired from the frontal lobe of the brain by a specially designed half helmet dual-tuned surface coil placed on the forehead (supplementary Figure S1). 31 P MRS measures, HEP and phospholipid metabolites, and NAD analyses were extracted from a 31 P MRS study using a magnetization transfer approach ( 31 P-MT-MRS) to quantify creatine kinase and ATP synthetase reaction rates (Du et al, 2014; Kim et al, 2017). Details of the 31 P MRS techniques have been described previously (Du et al, 2014; Kim et al, 2017), and more information is provided in the supplementary material.…”

“…A recent advance in the 31 P MRS literature is the ability to quantify nicotinamide adenine dinucleotide (NAD+) and its reduced form NADH (Kim et al, 2017; Lu et al, 2016), which play crucial roles in redox reactions related to energy metabolism and antioxidant activity. We recently demonstrated the feasibility of a novel 31 P MRS approach to quantify phosphorus NAD metabolite resonance signals in the brain (Kim et al, 2017).…”

“…We recently demonstrated the feasibility of a novel 31 P MRS approach to quantify phosphorus NAD metabolite resonance signals in the brain (Kim et al, 2017). The balance between the redox pair of NAD+ and NADH concentrations reflects the oxidative state of cells, and the NAD+/NADH ratio may be used as a measure of oxidative stress (Blacker et al, 2014).…”