Decoupling of N-acetyl-aspartate and glutamate within the dorsolateral prefrontal cortex in schizophrenia

Abstract

Aberrant function of glutamatergic pathways is likely to underlie the pathology of schizophrenia. Evidence of oxidative stress in the disease pathology has also been reported. N-Acetylaspartate (NAA) is metabolically linked to both cascades and may be a key marker in exploring the interconnection of glutamatergic pathways and oxidative stress. Several studies have reported positive correlation between the levels of NAA and Glx (the sum of glutamate and glutamine) in several brain regions in healthy subjects, by using proton magnetic resonance spectroscopy ([(1)H]MRS). Interestingly, one research group recently reported decoupling of the relationship between NAA and Glx in the hippocampus of patients with schizophrenia. Here we report levels of NAA and Glx measured using [(1)H]MRS, relative to the level of creatine (Cr) as an internal control. The dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in 25 patients with schizophrenia and 17 matched healthy controls were studied. In DLPFC, NAA/Cr and Glx/Cr were significantly positively correlated in healthy controls after correction for the effect of age and smoking status and after correction for multiple comparisons (r= 0.627, P= 0.017). However, in patients with schizophrenia, the positive correlation between NAA/Cr and Glx/Cr was not observed even after correcting for these two variables (r= -0.330, P= 0.124). Positive correlation between NAA/Cr and Glx/Cr was not observed in the ACC in both groups. Decoupling of NAA and Glx in the DLPFC may reflect the interconnection of glutamatergic pathways and oxidative stress in the pathology of schizophrenia, and may possibly be a biomarker of the disease.

Figure 1. Voxel placement and sample spectra from dorsolateral prefrontal cortex (DLPFC)

A. From left to right: sagittal view, coronal view, and axial view of the voxel. B. A typical fitted spectrum (in red). Indicated are myo-inositol (mI), choline (Cho), creatine (Cr), Glx and total NAA. Above the spectrum the residual signal after fitting is displayed. The baseline is displayed below the spectrum.

Figure 2. Voxel placement and sample spectra from anterior cingulate cortex (ACC)

A. From left to right: sagittal view, coronal view, and axial view of the voxel. B. A typical fitted spectrum (in red). Indicated are myo-inositol (mI), choline (Cho), creatine (Cr), Glx and total NAA. Above the spectrum the residual signal after fitting is displayed. The baseline is displayed below the spectrum.

Figure 3. Correlation between NAA/Cr and Glx/Cr

Adjusted partial correlations between NAA/Cr and Glx/Cr of healthy controls (upper row) and patients with schizophrenia (lower row) in ACC (left column) and DLPFC (right column). Partial correlations controlling for age and smoking status in ACC (HC: r= −0.002, P= 0.996; SZ: r= −0.154, P= 0.483) and in DLPFC (HC: r= 0.627, P= 0.017 ; SZ: r= −0.330, P= 0.124).