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Brain Metabolism in Schizophrenia and First-Degree Relatives: a 7T MRS study
Anna Min Wang1,2, Subechhya Pradhan1,2, Stephanie Korenic3, S. Andrea Wijtenburg3, Laura M. Rowland3, and Peter B. Barker1,2

1Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States, 2Kennedy Krieger Institute, Baltimore, MD, United States, 3Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, United States

Synopsis

Brain metabolism was investigated in 38 patients with schizophrenia (SZ), 38 healthy control (HC) subjects, and 11 first degree relatives of SZ patients using 7T MRS in 5 brain regions. Multiple metabolic abnormalities were found in SZ patients, including increases in the ratio of glutamine to glutamate, increased levels of brain lactate, and decreased levels of γ-aminobuytric acid (GABA) and N-acetylaspartate-glutamate (NAAG). Many of these changes also correlated with measures of cognitive performance and negative symptom severity. 7T MRS is an excellent tool for the non-invasive investigation of brain pathophysiology in SZ.

Purpose

Schizophrenia (SZ) is a severe psychiatric disorder characterized by positive, negative, and cognitive symptoms. The glutamatergic and GABAergic neurotransmitter systems may play important roles in the pathophysiology of schizophrenia (1), and thus are potential targets for the novel interventions. Previous MRS studies reported glutamate (Glu) and glutamine (Gln) changes in SZ patients with variable results (2). Effective separation and quantification of Glu and Gln under high field strength (7T) benefits the study of the glutamatergic system in SZ, and other important molecules such as lactate. Brain lactate concentration is used as the biomarker for mitochondrial dysfunction and may be altered in SZ (3). This study utilized 7T MRS to investigate these neurochemical differences between SZ and healthy subjects.

Methods

Subjects: 38 SZ patients (SZ, 21 males, 33.9±12.6 y.o.), 38 healthy controls (HC, 19 males, 30.5±10.4 y.o.) and 11 first-degree relatives of SZ patients (FDR, 2 males, 35.9±12.0 y.o.) were recruited. General cognitive function was assessed in all subjects with the MATRICS Consensus Cognitive Battery (MCCB). Psychiatric symptom severity in patients was assessed with the Scale for the Assessment of Negative Symptoms (SANS). MR protocols: All participants were scanned using a 7T scanner (Philips ‘Achieva’, Netherlands) with a 32-channel head coil. T1W images were acquired using an MPRAGE sequence (0.8 mm isotropic resolution). Spectra were recorded from anterior cingulate cortex (ACC; 30×20×20 mm3), left centrum semiovale (CSO; 40×20×15 mm3), left dorsolateral prefrontal cortex (DLPFC; 25×20×20 mm3), left hippocampus (Hippo; 20×20×20 mm3), and bilateral thalamus (Thal, 20×30×15 mm3) using a STEAM sequence (TE/TM/TR = 14/33/3000 ms). VAPOR water suppression was used, and a water-unsuppressed reference was acquired from each voxel. Data Analysis: Spectra were analyzed using the LCModel software and a basis set simulated using the ‘VESPA’ package. Metabolite concentrations were normalized using the unsuppressed water reference. Metabolite concentrations were only included in statistical analyses when the corresponding Cramér-Rao low bound was below 20% except for Lactate (Lac) and N-acetylaspartate-glutamate (NAAG) (<30%) (4). MPRAGE images was segmented using ‘SPM8’ and gray matter, white matter and cerebrospinal fluid (CSF) fractions were calculated for each MRS voxel. Metabolite concentrations were CSF corrected except for Lac. Between group differences for γ-aminobuytric acid (GABA), Lac, N-acetylaspartate (NAA), NAAG and the ratio of Gln/Glu between SZ, HC and FDR groups were assessed using one-way ANOVAs. Metabolite concentrations (and ratio) were also compared between SZ and HC groups only using two-tailed t-tests. The relationships between the metabolite concentrations (or ratio) and the MCCB or SANS scores were analyzed with Pearson's correlations.

Results

Figure 1 presents the T1W images from a HC subject with the voxel localization in five brain regions and a representative spectrum from the CSO with LCModel fit. Significant inter-group differences were found for the concentrations of GABA in Hippo (p=0.032), Lac in Thal (p=0.019) and the Gln/Glu ratio in CSO (p=0.021). Comparing the SZ to HC group, the Gln/Glu ratio was significantly increased in ACC, CSO and Thal, and Lac concentration was increased in ACC and Thal (Figure 2). The concentrations of NAAG in CSO (p=0.038) and GABA in Hippo (p=0.009) were significantly decreased.

In all subjects, the Gln/Glu ratio was significantly negatively correlated with MCCB scores in the CSO and DLPFC. Lac concentrations were significantly negatively correlated with MCCB scores in ACC, CSO and Thal (Figure 3). The concentrations of NAA in ACC, DLPFC and Thal, and GABA in Hippo, were all significantly positively correlated with MCCB scores. In SZ patients, GABA and NAA concentrations in ACC were significantly negatively correlated with SANS scores.

Discussion

The widespread increase in the Gln/Glu ratio in SZ suggests increased Gln synthesis in patients with SZ, but could also reflect abnormal Gln/Glu cycling. Moreover, the negative correlation between Gln/Glu ratios and MCCB scores suggests that Gln/Glu cycling is linked with the cognitive function. Along with the finding of GABA and NAAG concentration decrease in SZ, the study echoes the previous theories of SZ, which predicts the dysfunction of both glutamatergic and GABAergic systems (5, 6). Lactate levels were also increased in two of five of the brain regions studied, and correlated negatively with MCCB scores, suggesting that anaerobic glycolysis (perhaps secondary to mitochondrial dysfunction (7)) is associated with SZ and related to cognitive performance.

Conclusion

This study revealed multiple metabolic alterations in SZ patients, most notably increased Gln/Glu ratios and increased levels of lactate. The underlying mechanisms for these changes remain to be determined. Nevertheless, 7T MRS is a valuable tool for the non-invasive investigation of brain metabolism and pathophysiology in patients with SZ.

Acknowledgements

The authors acknowledge the funding support from NIH grant: R01 MH096263.

References

1. Lisman JE, Coyle JT, Green RW, Javitt DC, Benes FM, Heckers S, et al. Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci. 2008;31(5):234-42.

2. Merritt K, Egerton A, Kempton MJ, Taylor MJ, McGuire PK. Nature of Glutamate Alterations in Schizophrenia: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies. JAMA Psychiatry. 2016;73(7):665-74.

3. Schmiedel J, Jackson S, Schafer J, Reichmann H. Mitochondrial cytopathies. J Neurol. 2003;250(3):267-77.

4. Rowland LM, Pradhan S, Korenic S, Wijtenburg SA, Hong LE, Edden RA, et al. Elevated brain lactate in schizophrenia: a 7T magnetic resonance spectroscopy study. Translational Psychiatry. 2016;6(11): e967

5. Carlsson A, Waters N, Holm-Waters S, Tedroff J, Nilsson M, Carlsson ML. Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu Rev Pharmacol Toxicol. 2001;41(1):237-60.

6. Kantrowitz JT, Javitt DC. N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia? Brain Res Bull. 2010;83(3-4):108-21.

Figures

Figure 1. (a) T1W images from a healthy subject. Red boxes represent the MRS localization for the five brain regions. (b) Typical spectrum acquired from the CSO voxel from a HC subject.

Figure 2. The Gln/Glu ratio (a) and lactate concentration (b) in all brain regions. The p-values of the t-comparison between SZ and HC groups are provided above the bars. The significant p-values are highlighted red. The blue asteroids above the bars stand for significant inter-group differences in one-way ANOVAs (*: p<0.05).

Figure 3. (a) Correlations between the Gln/Glu ratios and MCCB scores in 5 brain regions. (b) Correlations between the lactate concentrations and MCCB scores in 5 brain regions. The significant correlations are marked with asteroids (*: p<0.05; **: p<0.01).

Proc. Intl. Soc. Mag. Reson. Med. 26 (2018)
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