Adriana Anton

We investigated the longstanding idea that the onset of psychotic symptoms in schizophrenia arises from an early phase of glutamate neurotoxicity, possibly related to loss of GABA restraint, oxidative stress or inflammation, that cumulatively results in a later phase of synaptic loss in keeping with magnetic resonance spectroscopy (MRS) evidence of reduced glutamate in schizophrenia, especially in older patients. We evaluated this hypothesis in a 3-centre MRS study to determine whether abnormalities in glutamate in dorsal anterior cingulate cortex (dACC) differed between people with minimally treated ‘Recent’ onset schizophrenia and an ‘Established’ group with > 10 years of illness. We tested the hypothesised mechanisms of reduced GABA in either or both dACC and occipital cortex, and depletion of dACC glutathione, a measure of central inflammation. We explored predicted associations between MRS variables, circulating cytokines and clinical symptoms. The Established group showed significantly greater dACC glutamate deficit than the Recent group which was not accounted for by lifetime exposure to antipsychotic drugs or by their greater CRP or IL-6 levels nor was the deficit associated with glutathione depletion. The greater dACC glutamate deficit in established illness is compatible with loss of synapses occurring after onset of symptoms but there was little to suggest underpinning excitotoxicity, inflammation, or oxidative stress. GABA was reduced in patients versus controls across dACC and occipital voxels. Only dACC GABA content correlated significantly with symptoms, lower content with greater positive and negative symptoms across both groups and this is supportive of a pathophysiological role of GABA in psychosis.

It is widely thought that the onset of psychotic symptoms in schizophrenia may arise from an early neurotoxic phase, possibly related to oxidative stress or inflammation, and a late residual damage phase associated with persistent negative symptoms. We tested this hypothesis in a 3-centre study using magnetic resonance spectroscopy (MRS) to determine whether abnormalities in glutamate, glutamine and GABA content in anterior cingulate cortex (ACC) differed between people with minimally treated ‘Recent’ onset schizophrenia and an ‘Established’ group with > 10 years of treatment. We tested whether neurochemical abnormalities were i) mediated by raised circulating inflammatory cytokine concentrations, c-reactive protein (CRP) and interleukin-6 (IL-6), or depletion of glutathione and ii) associated with ratings of positive and negative symptoms. Relative to age-matched controls, the Established group showed significantly greater reduction in ACC glutamate than the Recent group, which did not differ from controls. This effect was not attributable to antipsychotic drug exposure. Patient ACC glutathione was negatively correlated with age. IL-6 was increased in both clinical groups, while increases in CRP were greater in the Established than Recent group. Elevated CRP was entirely accounted for by greater antipsychotic drug exposure and BMI, while residual elevation in IL-6 in the Established group did not account for their lower ACC glutamate. GABA was reduced relative to controls across ACC and occipital voxels. This reduction was not associated with drug treatment, BMI or cytokine levels. Only ACC GABA content correlated significantly with symptoms, lower content with greater positive and negative symptoms across both groups.

Impaired cognition is associated with lower quality of life and poor outcomes in schizophrenia. Brain glutamate may contribute to both clinical outcomes and cognition, but these relationships are not well-understood. We studied a multicentre cohort of 85 participants with non-affective psychosis using proton magnetic resonance spectroscopy. Glutamate neurometabolites were measured in the anterior cingulate cortex (ACC). Cognition was assessed using the Brief Assessment for Cognition in Schizophrenia (BACS). Patients were categorised as antipsychotic responders or non-responders based on treatment history and current symptom severity. Inverted U-shaped associations between glutamate or Glx (glutamate + glutamine) with BACS subscale and total scores were examined with regression analyses. We then tested for an interaction effect of the antipsychotic response group on the relationship between glutamate and cognition. ACC glutamate and Glx had a positive linear association with verbal memory after adjusting for age, sex and chlorpromazine equivalent dose (glutamate, β = 3.73, 95% CI = 1.26–6.20, P = 0.004; Glx, β = 3.38, 95% CI = 0.84–5.91, P = 0.01). This association did not differ between good and poor antipsychotic response groups. ACC glutamate was also positively associated with total BACS score (β = 3.12, 95% CI = 0.01–6.23, P = 0.046), but this was not significant after controlling for antipsychotic dose. Lower glutamatergic metabolites in the ACC were associated with worse verbal memory, and this relationship was independent of antipsychotic response. Further research on relationships between glutamate and cognition in antipsychotic responsive and non-responsive illness could aid the stratification of patient groups for targeted treatment interventions.

Dissolution dynamic nuclear polarisation (dDNP) of ¹³C‐labelled pyruvate in magnetic resonance spectroscopy/imaging (MRS/MRSI) has the potential for monitoring tumour progression and treatment response. Pyruvate delivery, its metabolism to lactate and efflux were investigated in rat P22 sarcomas following simultaneous intravenous administration of hyperpolarised ¹³C‐labelled pyruvate (¹³C₁‐pyruvate) and urea (¹³C‐urea), a nonmetabolised marker. A general mathematical model of pyruvate‐lactate exchange, incorporating an arterial input function (AIF), enabled the losses of pyruvate and lactate from tumour to be estimated, in addition to the clearance rate of pyruvate signal from blood into tumour, K_ip, and the forward and reverse fractional rate constants for pyruvate‐lactate signal exchange, k_pl and k_lp. An analogous model was developed for urea, enabling estimation of urea tumour losses and the blood clearance parameter, K_iu. A spectral fitting procedure to blood time‐course data proved superior to assuming a gamma‐variate form for the AIFs. Mean arterial blood pressure marginally correlated with clearance rates. K_iu equalled K_ip, indicating equivalent permeability of the tumour vasculature to urea and pyruvate. Fractional loss rate constants due to effluxes of pyruvate, lactate and urea from tumour tissue into blood (k_po, k_lo and k_uo, respectively) indicated that T₁s and the average flip angle, θ, obtained from arterial blood were poor surrogates for these parameters in tumour tissue. A precursor‐product model, using the tumour pyruvate signal time‐course as the input for the corresponding lactate signal time‐course, was modified to account for the observed delay between them. The corresponding fractional rate constant, k_avail, most likely reflected heterogeneous tumour microcirculation. Loss parameters, estimated from this model with different TRs, provided a lower limit on the estimates of tumour T₁ for lactate and urea. The results do not support use of hyperpolarised urea for providing information on the tumour microcirculation over and above what can be obtained from pyruvate alone. The results also highlight the need for rigorous processes controlling signal quantitation, if absolute estimations of biological parameters are required.

Background Glutathione (GSH) is an important brain antioxidant and a number of studies have reported its measurement by edited and nonedited localized ¹H spectroscopy techniques within a range of applications in healthy volunteers and disease states. Good test–retest reproducibility is key when assessing the efficacy of treatments aimed at modulating GSH levels within the central nervous system or when noninvasively assessing changes in GSH content over time. Purpose To evaluate the intraday (in vitro and in vivo) and 1-month apart (in vivo) test–retest reproducibility of GSH measurements from GSH-edited MEGA-PRESS acquisitions at 3 T in a phantom and in the brain of a cohort of middle-aged and older healthy volunteers. Study Type Prospective. Subjects/Phantoms A phantom containing physiological concentrations of GSH and metabolites with overlapping spectral signatures and 10 healthy volunteers (4 F, 6 M, 55 ± 14 years old). Field strength/Sequence GSH-edited spectra were acquired at 3 T using the MEGA-PRESS sequence. Assessment The phantom was scanned twice and the healthy subjects were scanned three times (on two separate days, 1 month apart). GSH was quantified from each acquisition, with the in vivo voxels placed at the primary motor cortex (PMC) and the occipital cortex (OCC). Statistical Tests Mean coefficients of variation (CV) were used to assess short-term (in vitro and in vivo) and longer-term (in vivo) test–retest reproducibility. Results In vitro, the CV was 2.3%. In vivo, the mean intraday CV was 3.3% in the PMC and 2.4% in the OCC, while the CVs at 1 month apart were 4.6% in the PMC and 7.8% in the OCC. Data Conclusion GSH-edited MEGA-PRESS spectroscopy allows measurement of GSH with excellent precision. Evidence Level 1 Technical Efficacy Stage 2

Magnetic resonance spectroscopy (MRS) is a research tool for measuring the concentration of metabolites such as γ‐aminobutyric acid (GABA) and glutamate in the brain. MEGA‐PRESS has been the preferred pulse sequence for GABA measurements due to low physiological GABA concentrations, hence low signal. To compensate, researchers incorporate long acquisition durations (7–10 min) making functional measurements of this metabolite challenging. Here, the acquisition duration and sample sizes required to detect specific concentration changes in GABA using MEGA‐PRESS at 3 T are presented for both between‐groups and within‐session study designs. 75 spectra were acquired during rest using MEGA‐PRESS from 41 healthy volunteers in 6 different brain regions at 3 T with voxel sizes between 13 and 22 cm³. Between‐group and within‐session variance was calculated for different acquisition durations and power calculations were performed to determine the number of subjects required to detect a given percentage change in GABA/NAA signal ratio. Within‐subject variability was assessed by sampling different segments of a single acquisition. Power calculations suggest that detecting a 15% change in GABA using a 2 min acquisition and a 27 cm³ voxel size, depending on the region, requires between 8 and 93 subjects using a within‐session design. A between‐group design typically requires more participants to detect the same difference. In brain regions with suboptimal shimming, the subject numbers can be up to 4‐fold more. Collecting data for longer than 4 min in brain regions examined in this study is deemed unnecessary, as variance in the signal did not reduce further for longer durations.