Differential regional N-acetylaspartate deficits in postmortem brain in schizophrenia, bipolar disorder and major depressive disorder

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Abstract

There is substantial evidence for the involvement of the hippocampus and subcortical regions in the neuropathology of schizophrenia. Deficits of N-acetylaspartate (NAA) have been found in schizophrenia and bipolar disorder which may reflect neuronal loss and/or dysfunction. N-acetylaspartylglutamate (NAAG) is the most abundant peptide transmitter in the mammalian nervous system. It is an agonist at presynaptic metabotropic glutamate receptors mGluR3, inhibiting glutamate release. NAA and NAAG and were measured in hippocampal, striatal, amygdala and cingulate gyrus regions of human postmortem tissue from controls and subjects with schizophrenia, bipolar disorder and major depressive disorder. There are significant deficits in hippocampal NAA concentrations in all patient groups. In the amygdala there are significant NAA deficits in schizophrenia and depression and significant deficits of NAAG in the amygdala in the depression group. The deficits in NAA reported in this study confirm the importance of hippocampal and other subcortical structures in the neuropathology of the major psychiatric disorders.

Introduction

There is substantial evidence for the involvement of the hippocampus and subcortical regions in the neuropathology of schizophrenia. There are volumetric reductions in these regions and both neurones and glia are affected (Harrison, 2008).

As it is a non-invasive neurochemical technique, magnetic resonance spectroscopy (MRS) has become an important tool in monitoring disease progression and in therapy evaluation in patients with neurodegenerative and psychiatric disorders. A major signal using this technique is from NAA. NAA, an amino acid present in high concentrations in the CNS, is synthesised in neuronal mitochondria from acetyl-coenzyme A and aspartate by the enzyme NAA transferase. It is considered a neuron-specific metabolite (Moffett et al., 1991) and its reduction a marker of neuronal loss. In addition, a study demonstrating the reversibility of NAA deficits following acute brain injury indicates that NAA may be a marker of both neuronal integrity and function (De Stefano et al., 1995). Although the biological function of NAA is not fully understood it has been shown to reflect glutamate concentrations and thus may provide a marker of glutamatergic neuronal function (Petroff et al., 2002).

In schizophrenia, frontal lobe NAA deficits have been shown to correlate with psychopathology and it may therefore be useful as an indicator of disease severity (Sigmundsson et al., 2003). Of particular interest are the numerous MRS studies that measure brain NAA in discrete brain regions in psychiatric patients. These have provided many reports of changes of NAA concentrations in schizophrenia, some in bipolar disorder and a few in depressions.

Although earlier work proved quite varied, probably due to the wide range of sampling techniques used and the variability in voxel size, recent findings have been more consistent. A meta-analysis of MRS studies on schizophrenia has reported there is a consensus that NAA is reduced by 5% in the hippocampus and in the frontal lobe noting however that most work is inadequately powered to detect deficits of 10% (Steen et al., 2005). A study of the precision and variability of MRS measurements of NAA in the cingulate gyrus and hippocampus using schizophrenic and control subjects, suggests that more than 200 subjects would be needed to detect a 5% difference between patients and controls (Venkatraman et al., 2006). A systematic review of NAA estimated by MRS in bipolar disorder shows reductions in the prefrontal and cingulate cortex, hippocampus and basal ganglia (Yildiz-Yesiloglu and Ankerst, 2006). A relationship between NAA in the dorsolateral prefrontal cortex and depression has been reported (Grachev et al., 2003).

N-acetylaspartylglutamate (NAAG) is the most abundant peptide transmitter in the mammalian nervous system. It is an agonist at presynaptic metabotropic glutamate receptors mGluR3 thus inhibiting glutamate release and may therefore be important in the regulation of NMDA receptors (Moghaddam and Adams, 1998). Inhibition of NAAG degrading enzymes are associated with a reduction of schizophrenia-like symptoms in animal models (Olszewski et al., 2008). Despite the potential relevance of this peptide it is not known whether NAAG concentrations in the brains of psychiatric patients are altered; MRS rarely differentiates NAA from NAAG. This postmortem study measuring the two compounds separately allows us to determine whether NAAG changes are apparent in psychiatric illness.

Three postmortem studies of brain tissue have estimated NAA and NAAG. Omori et al. (1997) examined thalamus from schizophrenic subjects by in vitro MRS and found NAA deficits, relative to creatine, although they were not statistically significant; Tsai et al. (1995) determined NAA and NAAG in postmortem tissue from schizophrenic subjects. They reported increased NAAG concentrations and both decreased activity of the enzyme cleaving NAAG, N-acetyl-alpha-linked acidic dipeptidase (NAALADase) and decreased glutamate concentrations in the hippocampus. Lastly, previous postmortem work from this laboratory examining frontal and temporal cortex tissue found losses of NAA in temporal cortex from schizophrenic and bipolar subjects and of NAAG in temporal cortex from schizophrenic subjects (Nudmamud et al., 2003). The present study extends this work by looking at hippocampal and subcortical structures employing an improved technique of taking tissue from frozen sections. This enables us to use small quantities of tissue and provides precise dissections.

Section snippets

Methods

Brain tissue, as frozen sections, from patients with schizophrenia, bipolar disorder and depression and from controls were provided by the Stanley Foundation Neuropathology Consortium and stored at −70 °C. Demographic details are provided in Table 1. This series of 60 matched and well-characterised subjects (15 per group) has been fully described by Torrey et al. (2000). There were no significant differences between groups with regard to age, sex, postmortem delay, brain pH, brain weight or

Results

For NAA there was a significant overall difference between the diagnosis groups (F (3, 56) = 3.138, P = 0.032), and there was a significant difference between the brain regions (F (6, 336) = 30.492, P < 0.001). For NAAG there was no overall difference between the diagnosis groups (F (3, 56) = 1.658, P = 0.186), but a significant difference between the brain regions (F (6, 336) = 24.612, P < 0.001).

The means and SEM together with the significant results generated by the pairwise comparisons are

Discussion

Reductions of NAA in psychiatric illness have largely been demonstrated using MRS and, although the sampling size in MRS has improved considerably over the years, it is still large compared to the sampling size for postmortem work. The voxel size, even in recent MRS studies, is likely to be several cubic centimetres (Ohrmann et al., 2008). These larger sampling sizes in MRS studies mean that there are inevitably contributions from both white and grey matter, and potentially also from CSF,

Role of funding source

This research was supported by a research grant from the Theodore and Vada Stanley Foundation to GPR. Postmortem brain specimens were donated by the Stanley Foundation Brain Bank and Neuropathology Consortium courtesy of Drs. Llewellyn B. Bigelow, Juraj Cervenak, Mary M. Herman, Thomas M. Hyde, Joel E. Kleinman, Michael B. Knable, José D. Paltań, Robert M. Post, E. Fuller Torrey, Maree J. Webster and Robert H. Yolken.

The Stanley Foundation had no further role in the analysis and interpretation

Contributors

The work for the paper was done under the supervision of Gavin Reynolds. Lindsay Reynolds performed the analysis of the postmortem samples, analysed the results, did the literature searches and wrote the first draft. Both authors have contributed to and approved the final manuscript.

Conflict of interest

None declared.

Acknowledgements

Statistical advice was provided by Simon T. Bate.

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