Abstract
Background: Glutamate may decline with age (or illness course) in schizophrenia at a greater rate than the psychiatrically healthy population as suggested by a meta-analysis. However, no studies have specifically addressed this question. Therefore, we investigated glutamate levels with magnetic resonance spectroscopy (MRS), in younger and older participants with schizophrenia in 2 separate studies with differing samples and methods. Regions strongly implicated in the pathophysiology of schizophrenia-related disorders, the anterior cingulate and the medial temporal lobe, were investigated.
Methods: MR scanning was conducted on a 3T Siemens Tim Trio equipped with a 32-channel head coil. One hundred and sixty-seven participants completed Study 1, and 86 participants completed Study 2. For Study 1, spectra were acquired from the anterior cingulate using phase rotation STEAM (PR-STEAM) (13,14): TR/TM/TE = 2000/10/6.5 ms, NEX = 128, and phases: φ1 = 135°, φ2 = 22.5°, φ13 = 112.5°, φADC = 0° and a water reference (NEX = 16). Glutamate and glutamine were quantified. For Study 2, spectra were acquired from the medial temporal lobe (i.e., hippocampus) and parietal lobe using a PRESS sequence (TR/TE = 2000, 30 ms, NEX = 256 for hippocampus and 128 for parietal and a water reference NEX = 16). Patients were evaluated for psychopathology, and all participants completed cognitive testing with a focus on attention and working memory for Study 1 and relational memory for Study 2.
Results: For Study 1, results revealed significant age (P < .001) and diagnosis (P = .001) effects for glutamate such that glutamate was lower in participants with schizophrenia compared to controls and in older versus younger participants. There was also a significant age effect (P = .007) for glutamine such that glutamine levels increased with age in both the groups. Higher anterior cingulate glutamate was related to better attention (P < .001) and working memory (P = .04). For Study 2, hippocampal glutamate was lower in older but not younger participants with schizophrenia (P = .03, Diagnosis × Age interaction). Parietal glutamate was lower in participants with schizophrenia irrespective of age (P = .013). Better relational memory performance was related to higher levels of parietal glutamate (P < .01).
Conclusion: Participants with schizophrenia were distinguished by lower anterior cingulate and parietal glutamate levels, but there was no evidence of accelerated glutamate aging in these brain regions. Lower hippocampal glutamate levels observed in older participants with schizophrenia suggests that the hippocampus may be particularly vulnerable to aging in schizophrenia. Glutamatergic interventions targeted at increasing levels in the anterior cingulate and parietal cortex and halting the decline in the hippocampus may improve cognitive function and quality of life in patients with schizophrenia.