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 ³¹P 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 ³¹P 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 ³¹P 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.

Keywords: 31P MRS; NAD+ and NADH; oxidative stress; redox state; schizophrenia.

Fig. 1.

(a) In vivo summed ³¹P spectra from 7 series of spectra with/without magnetization transfer obtained from a representative healthy participant (top) and a chronic schizophrenia (SZ) patient (bottom). γ-ATP resonance is smaller compared with the other 2 ATP resonances due to the direct RF saturation effect as part of the ³¹P-MT-MRS experiment. (b) Fitting results from the healthy (left) and SZ participant (right).

Fig. 2.

Box and whisker plot showing NAD+ (a and d), NADH (b and e), and RR (c and f) in the control and chronic schizophrenia (SZ) groups as well as in FE SZ, FE BD patients, and their age-matched control group. Individual data are also shown to the right of box plots. Bottom and top boundaries of each box indicate 25th and 75th percentiles, lower and upper whiskers indicate first and 99th percentiles. A horizontal line and filled square inside each box indicate median and mean values, respectively.

Fig. 3.

The summed spectra for healthy control and chronic schizophrenia (SZ) groups and the difference between them (a) as well as the fit results (b and c). The difference spectra and fitted Uridine diphosphate glucose (UDPG) signal are scaled by factor of 2.

Fig. 4.

Age dependence of intracellular NADH level (a) and RR (b) in chronic schizophrenia (SZ) (red filled circles) and matched controls (black filled circles). R-values = Pearson correlation coefficients. In order to visualize the whole trend of redox state age-dependence, data from FE SZ (red open circles) and matched controls (black open circles) are presented. The older healthy group was recruited age/sex-matched for the chronic SZ group, and the younger healthy group matched for the FE SZ group. Some of the chronic SZ patients are relatively young, close in age to some FE SZ patients, and likewise for older and younger healthy participants. In fact, a correlation with age that includes all healthy participants together (since they are all comparable) is nonsignificant (R = 0.268, P = .095 for NADH and R = 9.297, P = .062 for Redox Ratio [RR]). This finding requires further investigation in children and adolescents.

Fig. 5.

Diagram of metabolic pathways involving NAD+ and NADH redox reactions. Oxidative stress can induce redox imbalance in either cytosolic and/or mitochondria compartment, leading to mitochondrial dysfunction. The elevated NADH levels in patients with schizophrenia (SZ) can arise from either abnormal elevation in glycolysis in the cytosol, or disruption/inefficiency in the electron transport chain (ETC) of mitochondria, or both.