Regional Decoupling of N-acetyl-aspartate and Glutamate in Schizophrenia

Nina V Kraguljac,Meredith A Reid,David M White,Adrienne C Lahti,Jan Den Hollander

doi:10.1038/npp.2012.126

Nina V Kraguljac, Meredith A Reid + Show 3 more

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Journal: Neuropsychopharmacology	Publication Date: Jul 18, 2012
Citations: 81	License type: cc-by

Affiliation: University of Alabama at Birmingham

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Proton magnetic resonance spectroscopy (¹H-MRS) allows the non-invasive measurement of several metabolites, including N-acetyl-aspartate (NAA), an amino acid exclusively synthesized in the mitochondria of neurons, and glutamate, an amino acid involved in excitatory neurotransmission and metabolism. In view of recent postmortem studies in schizophrenia (SZ) revealing mitochondrial abnormalities as well as perturbed expression of the enzymes regulating the glutamate-glutamine cycle, we hypothesized that a disruption in the homeostasis of NAA and glutamate in SZ is present. Fifty subjects with SZ and 48 matched healthy controls (HC) were enrolled in this ¹H-MRS study. Voxels were placed in the anterior cingulate cortex (ACC) and hippocampus; NAA/Cr and glutamate + glutamine (Glx)/Cr ratios were obtained. We did not find any significant differences between the groups in metabolite levels in both the ACC and hippocampus. In the hippocampus we found that NAA/Cr and Glx/Cr ratios were significantly correlated in HC (r=0.40, p<0.01 (corrected p=0.048)) but not in SZ (r=-0.06; p=0.71), a difference that was statistically significant (z=2.22, p=0.02). Although no differences in neurometabolites between SZ and HC were apparent, correlations between NAA/Cr and Glx/Cr in healthy subjects in the hippocampus were found, and this correlation was lost in subjects with SZ. To our knowledge, this is the first study to suggest decoupling of these metabolites, a pathophysiological change that may be unique to SZ. However, these results warrant replication and further exploration before definite conclusions can be drawn.

Highlights

Proton magnetic resonance spectroscopy (1H-MRS) allows the non-invasive measurement of several metabolites that have critical roles in cellular functions
There were no significant differences in gray or white matter content of voxel as well as NAA/Cr and glutamate and glutamine (Glx)/Cr measurements between SZ and healthy controls (HC) subjects in either the anterior cingulate cortex (ACC) or the hippocampus (Tables 2 and 3)
In the ACC, NAA/Cr and Glx/Cr ratios were trend-level positively correlated in both subjects with SZ and healthy controls

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Proton magnetic resonance spectroscopy (1H-MRS) allows the non-invasive measurement of several metabolites that have critical roles in cellular functions. N-acetyl-aspartate (NAA) is an amino acid thought to be primarily synthesized in the mitochondria of neurons that can be measured relatively with MRS (Bates et al, 1996). Clark et al (2006) hypothesize NAA to be a reservoir for protecting the concentration of glutamate, maintaining low levels of glutamate and having the ability to rapidly produce it. They further speculate that NAA can be converted to glutamate, but glutamate can be converted back into NAA, via a multi step, multi cell and multi compartment cycle (Clark et al, 2006). In MRS studies conducted in healthy subjects, positive correlations between NAA and Glx have been identified in the dorsal ACC, cerebellum (Waddell et al, 2011), and pregenual ACC (Walter et al, 2009)

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