Tania Da Silva, MSc; Sina Hafizi, MD; Pablo M. Rusjan, PhD; Sylvain Houle, MD, PhD; Alan A. Wilson, PhD; Ivana Prce, BSc; Napapon Sailasuta, PhD; Romina Mizrahi, MD, PhD
Background: γ-Aminobutyric acidergic (GABAergic) dysfunction and immune activation have been implicated in the pathophysiology of schizophrenia. Preclinical evidence suggests that inflammation-related abnormalities may contribute to GABAergic alterations in the brain, but this has never been investigated in vivo in humans. In this multimodal imaging study, we quantified cerebral GABA plus macromolecule (GABA+) levels in antipsychotic-naive people at clinical high risk for psychosis and in healthy volunteers. We investigated for the first time the association between GABA+ levels and expression of translocator protein 18 kDa (TSPO; a marker of microglial activation) using positron emission tomography (PET).
Methods: Thirty-five people at clinical high risk for psychosis and 18 healthy volunteers underwent 3 T proton magnetic resonance spectroscopy to obtain GABA+ levels in the medial prefrontal cortex (mPFC). A subset (29 people at clinical high risk for psychosis and 15 healthy volunteers) also underwent a high-resolution [18F]FEPPA PET scan to quantify TSPO expression. Each participant was genotyped for the TSPO rs6971 polymorphism.
Results: We found that GABA+ levels were significantly associated with TSPO expression in the mPFC (F1,40 = 10.45, p = 0.002). We found no significant differences in GABA+ levels in the mPFC (F1,51 = 0.00, p > 0.99) between people at clinical high risk for psychosis and healthy volunteers. We found no significant correlations between GABA+ levels or residuals of the association with TSPO expression and the severity of prodromal symptoms or cognition.
Limitations: Given the cross-sectional nature of this study, we could determine no cause-and-effect relationships for GABA alterations and TSPO expression.
Conclusion: Our findings suggest that TSPO expression is negatively associated with GABA+ levels in the prefrontal cortex, independent of disease status.
Submitted Oct. 11, 2017; Revised Apr. 15, 2018; Accepted May 13, 2018; Published online Sept. 26, 2018
Acknowledgements: The authors thank the excellent staff of the Research Imaging Centre at the Centre for Addiction and Mental Health — in particular Peter Truong for his Gannet GABA processing and for generating the brain region composition of the magnetic resonance spectroscopy voxel, and the Focus on Youth Psychosis Prevention clinic. The authors are grateful to Felix Raschke of National Centre for Radiation Research in Oncology, Dresden, Germany, for the voxel masking code.
Affiliations: From the Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ont., Canada (Silva, Hafizi, Rusjan, Houle, Wilson, Prce, Sailasuta, Mizrahi); the Institute of Medical Science, University of Toronto, Toronto, Ont., Canada (Silva, Rusjan, Mizrahi); the Department of Psychiatry, University of Toronto, Toronto, Ont., Canada (Rusjan, Houle, Wilson, Mizrahi); and the Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ont., Canada (Rusjan, Houle, Sailasuta, Mizrahi).
Competing interests: R. Mizrahi has received speaker fees from Otsuka Lundbeck Canada. No other competing interests declared.
Funding: This work was supported by the National Institutes of Health (NIH) R01 grant MH100043 to R. Mizrahi.
Contributors: R. Mizrahi designed the study. All authors acquired and analyzed the data. N. Sailasuta and R. Mizrahi wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.
Correspondence to: R. Mizrahi, PET Centre, Research Imaging Centre, Centre for Addiction and Mental Health, 250 College St, Toronto, Ontario, Canada, M5T 1R8; firstname.lastname@example.org