Interaction of hippocampal volume and N-acetylaspartate concentration deficits in schizophrenia: A combined MRI and 1H-MRS study
Research highlights
► The NAA concentration in the hippocampus is significant reduced in patients with schizophrenia. ► The volume of the left and right hippocampus is significant reduced in patients with schizophrenia. ► A significant negative correlation between hippocampal NAA concentration and hippocampal volume was observed in patients with schizophrenia. ► Evidence for a coexistent structural and neurochemical dysfunction in the hippocampus of schizophrenic patients.
Introduction
Schizophrenia is characterized by a considerable phenotypic complexity, and by dint of various methodical approaches a great many cerebral abnormalities were discovered (Tandon et al., 2008, Tandon et al., 2009). Neuroimaging techniques, foremost magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H-MRS), provide evidence that schizophrenia is linked to abnormal structural and neurometabolic integrity of cortical and subcortical areas (Abbott & Bustillo, 2006, Geuze et al., 2005b, Steen et al., 2005). The best replicated findings were observed for the hippocampus (Shenton et al., 2001, Steen et al., 2005). 1H-MRS makes it possible to measure in vivo the intracranial concentration of substances presumed to be important for neuronal metabolism; hence, 1H-MRS has become of interest for identifying neurometabolic diseases. Because of its high intracranial concentration, the amino acid N-acetylaspartate (NAA) gives rise to the most prominent signal in 1H-MRS of the adult human brain; it is exclusively present in the nervous system (Birken and Oldendorf, 1989). NAA is suggested to be a marker of neuronal integrity and an indicator for the number of viable neurons (Bertolino & Weinberger, 1999, Lang et al., 2007a). However, in schizophrenia research it was less considered that NAA–the second most abundant amino acid in the human brain–is involved in the metabolism of neurotransmitters, such as N-acetyl-aspartyl-glutamate (NAAG), aspartate and glutamate (Tsai, 2005, Tyson & Sutherland, 1998). For instance, NAA is synthesized by cleavage from NAAG by N-acetylated alpha-linked L-amino dipeptidase (also termed glutamate carboxypeptidase II) with one molecule glutamate as co-product. The highest concentrations of NAA can be found in pyramidal glutamatergic neurons in rats (Moffett and Namboodiri, 1995), and NAA acts via the glutamatergic NMDA-receptor to elevate intracellular calcium (Rubin et al., 1995). This is of substantial interest because dysfunctions of glutamate and other excitatory neurotransmitters have been implicated in the psychopathology of schizophrenia (Gallinat et al., 2007, Tsai, 2005). Olney and Farber (1995) suggested a subtle excitotoxic process to potentially account for histological abnormalities without the presence of overt cell death in schizophrenia which may in part account for structural deficits observed in brain imaging studies of this disorder (Tsai et al., 1998).
In schizophrenic patients compared to controls a reduction in the levels of NAA has been observed in the anterior cingulate, prefrontal, parietal and temporal neocortex as well as in the basal ganglia, cerebellum and thalamus while, however, the most pronounced reductions were observed in the hippocampus (Fannon et al., 2003, Steen et al., 2005). It is remarkable that in patients with schizophrenia the topographic profile of NAA deficits is closely related to the profile of volumetric deficits (Honea et al., 2005, Shenton et al., 2001). Of note, these coexistent deficits have been most consistently detected in the hippocampus (Geuze et al., 2005b, Shenton et al., 2001, Wright et al., 2000). A hippocampal volume deficit in schizophrenic patients compared to controls is a robust finding which has been observed already in first episode patients (Kubicki et al., 2002), with evidence for little or no change across the course of the disease (Lieberman et al., 2001, Wood et al., 2001).
Although in schizophrenic patients NAA levels and the volume of the hippocampus are altered in the same direction it is unclear if they are related to each other. The few systematic investigations combining 1H-MRS and MRI in schizophrenia having attempted to verify this suggested connection did not find any significant correlations between the two parameters (Bertolino et al., 1996, Bertolino et al., 1998, Deicken et al., 1999, Fannon et al., 2003, Kegeles et al., 2000). This was interpreted as an argument that NAA deficits and volume reductions in schizophrenia are independent surrogate parameters of an underlying pathobiology. However, the hypothesis of a causal relationship between both parameters has only sparsely been investigated.
In the present study, we eliminated a number of possible confounds affecting previous combined MRS and MRI studies in schizophrenia: (1) We used single voxel 1H-MRS at 3 Tesla providing absolute metabolite concentrations instead of ratios. (2) Metabolite concentrations were corrected for the content of CSF and 3) we quantified NAA using a method with high test-retest reliability (Schubert et al., 2004). In addition, as a gold standard of CNS volumetry a reliable and validated delineation protocol for the hippocampus (Ballmaier et al., 2008, Narr et al., 2004) was applied to overcome problems with previously criticized volume assessment techniques (Geuze et al., 2005a, Konrad et al., 2009). The left sided hippocampus was chosen as region of interest because both NAA level reductions (Bertolino et al., 1996, Maier et al., 2000) and volume deficits (Hulshoff Pol et al., 2004, Shenton et al., 2001) have been shown highly consistent.
MRI and 1H-MRS were performed in a sample of 29 schizophrenic patients and 44 healthy controls to test the following hypotheses: In schizophrenic patients (1) a coexistent deficit of hippocampal NAA concentrations and hippocampal volume is present compared to controls, and (2) both parameters show an association indicating an interaction of neurochemistry and brain morphology in schizophrenia but not in healthy controls.
Section snippets
Subjects
All procedures of this study were approved by the ethics committee of the Charité University Medicine Berlin. After complete description of the study to the subjects informed written consent was obtained from all participants.
29 patients (19 male, 10 female) fulfilling the DSM-IV and ICD-10 criteria of schizophrenia were included. They were recruited among inpatients (n = 13) and outpatients (n = 16) of the Charité Department of Psychiatry and Psychotherapy, Campus Mitte. To confirm initial
Volumetry
Demographic and clinical characteristics are shown in Table 1. In schizophrenic patients compared to controls a hippocampal volume reduction of about 9.9% for the right and about 8.5% for the left hemisphere was detected (Table 2). For the whole sample, there was neither a significant correlation between age and the intracranial volume (r = −0.037; p = 0.759) nor between age and left (r = −0.090; p = 0.449) or right (r = 0.206; p = 0.080) hippocampal volume. The right hippocampal volume (T = 2.282; df = 71; p =
Discussion
The principal findings of this study are: (1) a significant reduction in NAA concentration in the left hippocampus and (2) a significantly reduced volume of the left and right hippocampus in schizophrenic patients compared to controls. (3) For the first time, a significant negative correlation between hippocampal NAA concentration and hippocampal volume was observed for the patients but not in controls. None of the imaging parameters were associated with psychopathology, duration of illness or
Disclosures and acknowledgments
This investigation was supported in part by a grant of the Stanley Medical Research Institute (02T-247) and NGFNplus BMBF 01GS08159. IMAGEN receives research funding from the European Community's Sixth Framework Programme (LSHM-CT-2007-037286). This paper reflects only the author's views and the Community is not liable for any use that may be made of the information contained therein.
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