Age-related changes in anterior cingulate cortex glutamate in schizophrenia: A ¹H MRS Study at 7 Tesla

Abstract

The extent of age-related changes in glutamate and other neurometabolites in the anterior cingulate cortex (ACC) in individuals with schizophrenia remain unclear. Magnetic resonance spectroscopy (MRS) at 7 T, which yields precise measurements of various metabolites and can distinguish glutamate from glutamine, was used to determine levels of ACC glutamate and other metabolites in 24 individuals with schizophrenia and 24 matched controls. Multiple regression analysis revealed that ACC glutamate decreased with age in patients but not controls. No changes were detected in levels of glutamine, N-acetylaspartate, N-acetylaspartylglutamic acid, myo-inositol, GABA, glutathione, total creatine, and total choline. These results suggest that age may be an important modifier of ACC glutamate in schizophrenia.

Introduction

Imaging, post-mortem pathology, and genetic studies of schizophrenia have shown disruption of the glutamatergic system, yet the specifics remain unclear (Coyle, 2006, Wijtenburg et al., 2015). The components of the glutamate system have considerable potential as biomarkers of disease progression, though much is unknown, including the brain regions where measurement may yield the most useful information. The anterior cingulate cortex (ACC) is a region of particular interest in schizophrenia because of its involvement in emotion, attention, and cognition (Benes, 2009, Reid et al., 2010) and anatomic evidence for its disruption in the disease (Roberts et al., 2015, Fornito et al., 2009). Glutamatergic dysfunction may be modulated by hypofunction of the N-methyl-D-aspartate receptor (NMDAR), leading to increased glutamate release in the ACC, neurodegeneration, and subsequent decreased ACC glutamate levels (Plitman et al., 2014). In humans, NMDAR antagonists lead to increased glutamate release and psychotic symptoms (Stone et al., 2012, Moghaddam and Javitt, 2012). Chronic NMDAR antagonist administered to rats leads to patterns of neurodegeneration similar to those found in schizophrenia, including in the ACC (Olney and Farber, 1995).

Severity of symptoms in schizophrenia often decreases with advancing age, and the role of the glutamatergic system in these changes is not understood (Jeste et al., 2011). Investigations of glutamate changes using magnetic resonance spectroscopy (MRS), which non-invasively quantifies steady-state concentrations of metabolites in specific brain regions, have reached inconsistent findings. This inconsistency is likely due to a combination of variation in voxel location, different methods of data acquisition and analysis (Wijtenburg et al., 2015, Rowland et al., 2013, Chang et al., 2007), and differences in patient populations, including age, disease duration, medication use, and included/excluded co-morbidities. A meta-analysis of studies using MRS at field strengths of 1.5 to 4 T revealed lower levels of glutamate in the medial prefrontal region in older patients (Marsman et al., 2013). Separating glutamate and glutamine at lower field strengths has proved challenging, despite promising new approaches (Zhang and Shen, 2015, Ramadan et al., 2013). Studies have shown improved precision of glutamate measurement, distinguishing it from glutamine, at 7 T compared to lower field strengths (Mekle et al., 2009, Pradhan et al., 2015, Tkáč et al., 2009). In the current study, therefore, the enhanced spectral sensitivity and resolution of 7 T MRS was used to explore differences in ACC glutamate with age in patients with schizophrenia and healthy control subjects.