Decoupling of N-acetyl-aspartate and glutamate within the dorsolateral prefrontal cortex in schizophrenia.
ABSTRACT: Aberrant function of glutamatergic pathways is likely to underlie the pathology of schizophrenia. Evidence of oxidative stress in the disease pathology has also been reported. N-Acetylaspartate (NAA) is metabolically linked to both cascades and may be a key marker in exploring the interconnection of glutamatergic pathways and oxidative stress. Several studies have reported positive correlation between the levels of NAA and Glx (the sum of glutamate and glutamine) in several brain regions in healthy subjects, by using proton magnetic resonance spectroscopy ([(1)H]MRS). Interestingly, one research group recently reported decoupling of the relationship between NAA and Glx in the hippocampus of patients with schizophrenia. Here we report levels of NAA and Glx measured using [(1)H]MRS, relative to the level of creatine (Cr) as an internal control. The dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in 25 patients with schizophrenia and 17 matched healthy controls were studied. In DLPFC, NAA/Cr and Glx/Cr were significantly positively correlated in healthy controls after correction for the effect of age and smoking status and after correction for multiple comparisons (r= 0.627, P= 0.017). However, in patients with schizophrenia, the positive correlation between NAA/Cr and Glx/Cr was not observed even after correcting for these two variables (r= -0.330, P= 0.124). Positive correlation between NAA/Cr and Glx/Cr was not observed in the ACC in both groups. Decoupling of NAA and Glx in the DLPFC may reflect the interconnection of glutamatergic pathways and oxidative stress in the pathology of schizophrenia, and may possibly be a biomarker of the disease.
Project description:The glutamatergic system is a key point in pathogenesis of schizophrenia. Sarcosine (N-methylglycine) is an exogenous amino acid that acts as a glycine transporter inhibitor. It modulates glutamatergic transmission by increasing glycine concentration around NMDA (N-methyl-d-aspartate) receptors. In patients with schizophrenia, the function of the glutamatergic system in the prefrontal cortex is impaired, which may promote negative and cognitive symptoms. Proton nuclear magnetic resonance (¹H-NMR) spectroscopy is a non-invasive imaging method enabling the evaluation of brain metabolite concentration, which can be applied to assess pharmacologically induced changes. The aim of the study was to evaluate the influence of a six-month course of sarcosine therapy on the concentration of metabolites (NAA, N-acetylaspartate; Glx, complex of glutamate, glutamine and ?-aminobutyric acid (GABA); mI, myo-inositol; Cr, creatine; Cho, choline) in the left dorso-lateral prefrontal cortex (DLPFC) in patients with stable schizophrenia. Fifty patients with schizophrenia, treated with constant antipsychotics doses, in stable clinical condition were randomly assigned to administration of sarcosine (25 patients) or placebo (25 patients) for six months. Metabolite concentrations in DLPFC were assessed with 1.5 Tesla ¹H-NMR spectroscopy. Clinical symptoms were evaluated with the Positive and Negative Syndrome Scale (PANSS). The first spectroscopy revealed no differences in metabolite concentrations between groups. After six months, NAA/Cho, mI/Cr and mI/Cho ratios in the left DLPFC were significantly higher in the sarcosine than the placebo group. In the sarcosine group, NAA/Cr, NAA/Cho, mI/Cr, mI/Cho ratios also significantly increased compared to baseline values. In the placebo group, only the NAA/Cr ratio increased. The addition of sarcosine to antipsychotic therapy for six months increased markers of neurons viability (NAA) and neurogilal activity (mI) with simultaneous improvement of clinical symptoms. Sarcosine, two grams administered daily, seems to be an effective adjuvant in the pharmacotherapy of schizophrenia.
Project description:Changes in brain pathology as schizophrenia progresses have been repeatedly suggested by previous studies. Meta-analyses of previous proton magnetic resonance spectroscopy ((1)H MRS) studies at each clinical stage of schizophrenia indicate that the abnormalities of N-acetylaspartate (NAA) and glutamatergic metabolites change progressively. However, to our knowledge, no single study has addressed the possible differences in (1)H MRS abnormalities in subjects at 3 different stages of disease, including those at ultrahigh risk for psychosis (UHR), with first-episode schizophrenia (FES), and with chronic schizophrenia (ChSz). In the current study, 24 patients with UHR, 19 FES, 25 ChSz, and their demographically matched 3 independent control groups (n = 26/19/28 for the UHR, FES, and ChSz control groups, respectively) underwent (1)H MRS in a 3-Tesla scanner to examine metabolites in medial prefrontal cortex. The analysis revealed significant decreases in the medial prefrontal NAA and glutamate + glutamine (Glx) levels, specifically in the ChSz group as indexed by a significant interaction between stage (UHR/FES/ChSz) and clinical status (patients/controls) (P = .008). Furthermore, the specificity of NAA and Glx reductions compared with the other metabolites in the patients with ChSz was also supported by a significant interaction between the clinical status and types of metabolites that only occurred at the ChSz stage (P = .001 for NAA, P = .004 for Glx). The present study demonstrates significant differences in (1)H MRS abnormalities at different stages of schizophrenia, which potentially correspond to changes in glutamatergic neurotransmission, plasticity, and/or excitotoxicity and regional neuronal integrity with relevance for the progression of schizophrenia.
Project description:Dysfunction of the glutamatergic system, the main stimulating system in the brain, has a major role in pathogenesis of schizophrenia. The frontal white matter (WM) is partially composed of axons from glutamatergic pyramidal neurons and glia with glutamatergic receptors. The natural amino acid sarcosine, a component of a normal diet, inhibits the glycine type 1 transporter, increasing the glycine level. Thus, it modulates glutamatergic transmission through the glutamatergic ionotropic NMDA (N-methyl-d-aspartate) receptor, which requires glycine as a co-agonist. To evaluate the concentrations of brain metabolites (NAA, N-acetylaspartate; Glx, complex of glutamate, glutamine, and ?-aminobutyric acid (GABA); mI, myo-inositol; Cr, creatine; Cho, choline) in the left frontal WM, Proton Nuclear Magnetic Resonance (¹H-NMR) spectroscopy was used. Twenty-five patients randomly chosen from a group of fifty with stable schizophrenia (DSM-IV-TR) and dominant negative symptoms, who were receiving antipsychotic therapy, were administered 2 g of sarcosine daily for six months. The remaining 25 patients received placebo. Assignment was double blinded. ¹H-NMR spectroscopy (1.5 T) was performed twice: before and after the intervention. NAA, Glx and mI were evaluated as Cr and Cho ratios. All patients were also assessed twice with the Positive and Negative Syndrome Scale (PANSS). Results were compared between groups and in two time points in each group. The sarcosine group demonstrated a significant decrease in WM Glx/Cr and Glx/Cho ratios compared to controls after six months of therapy. In the experimental group, the final NAA/Cr ratio significantly increased and Glx/Cr ratio significantly decreased compared to baseline values. Improvement in the PANSS scores was significant only in the sarcosine group. In patients with schizophrenia, sarcosine augmentation can reverse the negative effect of glutamatergic system overstimulation, with a simultaneous beneficial increase of NAA/Cr ratio in the WM of the left frontal lobe. Our results further support the glutamatergic hypothesis of schizophrenia.
Project description:Studies have shown that individuals with schizophrenia suffer from memory impairments. In this study, we combined proton magnetic resonance spectroscopy (¹H-MRS) and functional magnetic resonance imaging (fMRI) to clarify the neurobiology of memory deficits in schizophrenia.We used single-voxel MRS acquired in the left hippocampus and fMRI during performance of a memory task to obtain measures of neurochemistry and functional response in 28 stable, medicated participants with schizophrenia (SZ) and 28 matched healthy controls (HC).The SZ group had significantly decreased blood oxygen level-dependent (BOLD) signal in left inferior frontal gyrus (IFG) during encoding and in the anterior cingulate cortex (ACC) and superior temporal gyrus (STG) during retrieval. We did not find significant differences in N-acetylaspartate/creatine (NAA/Cr) or glutamate+glutamine (Glx/Cr) levels between the groups, but did find a significant positive correlation between NAA/Cr and Glx/Cr in the HC group that was absent in the SZ group. There were no significant correlations between BOLD and MRS measured in the hippocampus. Further analyses revealed a negative correlation between left IFG BOLD and task performance in the SZ group. Finally, in the HC group, the left IFG BOLD was positively correlated with Glx/Cr.We replicated findings of reduced BOLD signal in left IFG and of an altered relationship between IFG BOLD response and task performance in the SZ. The absence of correlation between NAA/Cr and Glx/Cr levels in patients might suggest underlying pathologies of the glutamate-glutamine cycle and/or mitochondria.
Project description:Neuroimaging and electrophysiologic studies have consistently provided evidence of impairment in anterior cingulate cortex/medial frontal cortex function in people with schizophrenia. In this study, we sought to clarify the nature of this abnormality by combining proton magnetic resonance spectroscopy (1H-MRS) with functional magnetic resonance imaging (fMRI) at 3T.We used single-voxel MRS acquired in the dorsal anterior cingulate cortex and fMRI during performance of a Stroop color-naming task to investigate the neurochemistry and functional response of the anterior cingulate cortex/medial frontal cortex in 26 stable, medicated subjects with schizophrenia and 23 matched healthy control subjects.In schizophrenia subjects, we found decreased blood oxygen level-dependent signal in the medial frontal wall, with significant clusters restricted to more dorsal regions compared with healthy subjects. In addition, we observed a trend-level decrease in N-acetylaspartate/creatine (NAA/Cr) levels and a significant positive correlation between NAA/Cr level and the blood oxygen level-dependent signal in schizophrenia subjects that did not exist in healthy subjects. Furthermore, in this group of medicated subjects, we did not find evidence of decreased glutamate + glutamine(Glx)/Cr levels, but there was a significant negative correlation between Glx/Cr levels and negative symptoms.Our results suggest that abnormal NAA levels, which may reflect a neuronal dysfunction related to schizophrenia, affect neuronal physiology, as evidenced by reduced blood oxygen level-dependent response.
Project description:Schizophrenia is associated with extensive neurocognitive and behavioral impairments. Studies indicate that N-acetylaspartate (NAA), a marker of neuronal integrity, and choline, a marker of cell membrane turnover and white matter integrity, may be altered in schizophrenia. Davunetide is a neurotrophic peptide that can enhance cognitive function in animal models of neurodegeneration. Davunetide has recently demonstrated modest functional improvement in a study of people with schizophrenia. In a subset of these subjects, proton magnetic resonance spectroscopy ((1)H-MRS) was conducted to explore the effects of davunetide on change in NAA/creatine (NAA/Cr) and choline/creatine (choline/Cr) over 12 weeks of treatment. Of 63 outpatients with schizophrenia who received randomized davunetide (5 and 30 mg/day) or placebo in the parent clinical trial, 18 successfully completed (1)H-MRS in dorsolateral prefrontal cortex (DLPFC) at baseline and at 12 weeks. Cognition was assessed using the MATRICS Consensus Cognitive Battery (MCCB). NAA/Cr was unchanged for combined high- and low-dose davunetide groups (N=11). NAA/Cr in the high-dose davunetide group (N=8) suggested a trend increase of 8.0% (P=0.072) over placebo (N=7). Choline/Cr for combined high- and low-dose davunetide groups suggested a 6.4% increase (P=0.069), while the high-dose group showed a 7.9% increase (P=0.040) over placebo. Baseline NAA/Cr correlated with the composite MCCB score (R=0.52, P=0.033), as did individual cognitive domains of attention/vigilance, verbal learning, and social cognition; however, neither metabolite correlated with functional capacity. In this exploratory study, 12 weeks of adjunctive davunetide appeared to produce modest increases in NAA/Cr and choline/Cr in DLPFC in people with schizophrenia. This is consistent with a potential neuroprotective mechanism for davunetide. The data also support use of MRS as a useful biomarker of baseline cognitive function in schizophrenia. Future clinical and preclinical studies are needed to fully define the mechanism of action and cognitive effects of davunetide in schizophrenia.
Project description:There is increasing evidence that abnormalities in glutamate signalling may contribute to the pathophysiology of attention-deficit hyperactivity disorder (ADHD). Proton magnetic resonance spectroscopy ([1H]MRS) can be used to measure glutamate, and also its metabolite glutamine, in vivo. However, few studies have investigated glutamate in the brain of adults with ADHD naive to stimulant medication. Therefore, we used [1H]MRS to measure the combined signal of glutamate and glutamine (Glu+Gln; abbreviated as Glx) along with other neurometabolites such as creatine (Cr), N-acetylaspartate (NAA) and choline. Data were acquired from three brain regions, including two implicated in ADHD-the basal ganglia (caudate/striatum) and the dorsolateral prefrontal cortex (DLPFC)-and one 'control' region-the medial parietal cortex. We compared 40 adults with ADHD, of whom 24 were naive for ADHD medication, whereas 16 were currently on stimulants, against 20 age, sex and IQ-matched healthy controls. We found that compared with controls, adult ADHD participants had a significantly lower concentration of Glx, Cr and NAA in the basal ganglia and Cr in the DLPFC, after correction for multiple comparisons. There were no differences between stimulant-treated and treatment-naive ADHD participants. In people with untreated ADHD, lower basal ganglia Glx was significantly associated with more severe symptoms of inattention. There were no significant differences in the parietal 'control' region. We suggest that subcortical glutamate and glutamine have a modulatory role in ADHD adults; and that differences in glutamate-glutamine levels are not explained by use of stimulant medication.
Project description:Background: Brain functional dysconnectivity, as well as altered network organization, have been demonstrated to occur in schizophrenia. Brain networks are increasingly understood to exhibit modular community structures, which provides advantages in robustness and functional adaptivity. The frontoparietal network (FPN) serves as an important functional module, and metabolic and functional alterations in the FPN are associated with the pathophysiology of schizophrenia. However, how intra-modular biochemical disruptions lead to inter-modular dysfunction of the FPN, remains unclear. In this study, we aim to investigate alterations in the modular functional-metabolic coupling of the FPN, in patients with schizophrenia. Methods: We combined resting-state functional magnetic resonance imaging (rs-fMRI) and magnetic resonance spectroscopy (MRS) technology and acquired multimodal neuroimaging data in 20 patients with schizophrenia and 26 healthy controls. For the MRS, the dorsolateral prefrontal cortex (DLPFC) region within the FPN was explored. Metabolites including gamma aminobutyric acid (GABA), N-aspart-acetyl (NAA) and glutamate + glutamine (Glx) were quantified, using LCModel software. A graph theoretical approach was applied for functional modular parcellation. The relationship between inter/intra-modular connectivity and metabolic concentration was examined using the Pearson correlation analysis. Moreover, correlations with schizophrenia symptomatology were investigated by the Spearman correlation analysis. Results: The functional topological network consisted of six modules in both subject groups, namely, the default mode, frontoparietal, central, hippocampus, occipital, and subcortical modules. Inter-modular connectivity between the frontoparietal and central modules, and the frontoparietal and the hippocampus modules was decreased in the patient group compared to the healthy controls, while the connectivity within the frontoparietal modular increased in the patient group. Moreover, a positive correlation between the frontoparietal and central module functional connectivity and the NAA in the DLPFC was found in the healthy control group (r = 0.614, p = 0.001), but not in the patient group. Significant functional dysconnectivity between the frontoparietal and limbic modules was correlated with the clinical symptoms of patients. Conclusions: This study examined the links between functional connectivity and the neuronal metabolic level in the DLPFC of SCZ. Impaired functional connectivity of the frontoparietal areas in SCZ, may be partially explained by a neurochemical-functional connectivity decoupling effect. This disconnection pattern can further provide useful insights in the cognitive and perceptual impairments of schizophrenia in future studies.
Project description:Glial disturbances are highly implicated in the pathophysiology of schizophrenia and may be linked with glutamatergic dysregulation. Myo-inositol (mI), a putative marker of glial cells, and choline (Cho), representative of membrane turnover, are both present in larger concentrations within glial cells than in neurons, and their elevation is often interpreted to reflect glial activation. Proton magnetic resonance spectroscopy ((1)H-MRS) allows for the evaluation of mI, Cho, glutamate, glutamate + glutamine (Glx), and N-acetylaspartate (NAA). A collective investigation of these measures in antipsychotic-naive patients experiencing their first nonaffective episode of psychosis (FEP) can improve the understanding of glial dysfunction and its implications in the early stages of schizophrenia. 3-Tesla (1)H-MRS (echo time = 35 ms) was performed in 60 antipsychotic-naive patients with FEP and 60 age- and sex-matched healthy controls. mI, Cho, glutamate, Glx, and NAA were estimated using LCModel and corrected for cerebrospinal fluid composition within the voxel. mI, Cho, and glutamate were elevated in the FEP group. After correction for multiple comparisons, mI positively correlated with grandiosity. The relationships between mI and glutamate, and Cho and glutamate, were more positive in the FEP group. These findings are suggestive of glial activation in the absence of neuronal loss and may thereby provide support for the presence of a neuroinflammatory process within the early stages of schizophrenia. Dysregulation of glial function might result in the disruption of glutamatergic neurotransmission, which may influence positive symptomatology in patients with FEP.
Project description:The anterior cingulate cortex (ACC) is involved in emotion regulation and salience processing. Prior research has implicated ACC dysfunction in suicidal ideation (SI) and suicidal behavior. This study aimed to quantify ACC glutamatergic concentrations and to examine relationships with SI in a sample of healthy and depressed adolescents. Forty adolescents underwent clinical evaluation and proton magnetic resonance spectroscopy (1H-MRS) at 3?T, utilizing a 2-dimensional J-averaged PRESS sequence sampling a medial pregenual ACC voxel. Cerebrospinal fluid-corrected ACC metabolite concentrations were compared between healthy control (HC, n?=?16), depressed without SI (Dep/SI-, n?=?13), and depressed with SI (Dep/SI+, n?=?11) youth using general linear models covarying for age, sex, and psychotropic medication use. Relationships between ACC metabolites and continuous measures of SI were examined using multiple linear regressions. ROC analysis was used to determine the ability of glutamate+glutamine (Glx) and the N-acetylaspartate (NAA)/Glx ratio to discriminate Dep/SI-?and Dep/SI+?adolescents. Dep/SI+?adolescents had higher Glx than Dep/SI-?participants (padj?=?0.012) and had lower NAA/Glx than both Dep/SI-?(padj?=?0.002) and HC adolescents (padj?=?0.039). There were significant relationships between SI intensity and Glx (pFDR?=?0.026), SI severity and NAA/Glx (pFDR?=?0.012), and SI intensity and NAA/Glx (pFDR?=?0.004). ACC Glx and NAA/Glx discriminated Dep/SI-?from Dep/SI+?participants. Uncoupled NAA-glutamatergic metabolism in the ACC may play a role in suicidal ideation and behavior. Longitudinal studies are needed to establish whether aberrant glutamatergic metabolism corresponds to acute or chronic suicide risk. Glutamatergic biomarkers may be promising targets for novel risk assessment and interventional strategies for suicidal ideation and behavior.