GABA levels and TSPO expression in people at clinical high risk for psychosis and healthy volunteers: a PET-MRS study

Abstract

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 (F_1,40 = 10.45, p = 0.002). We found no significant differences in GABA+ levels in the mPFC (F_1,51 = 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.

Fig. 1

(A) Axial, sagittal and coronal views of the voxel placement in the medial prefrontal cortex. (B) Typical fitting results from a patient: magnetic resonance spectroscopy acquired for the “off” and “on” conditions (see text). (C) Difference between the “on” and “off” spectra before (pre) and after (post) signal alignment using Gannet software. (D) Gaussian lineshape fitting of edited GABA resonance showing GABA resonance at 3.0 ppm, fitted signal and residual. Cho = choline; Cr = creatine; fit = model of best fit; GABA = γ-aminobutyric acid; NAA = N-acetylaspartate; ppm = parts per million; pre = before spectral alignment; post = after spectral alignment; spec = GABA-edited spectrum.

Fig. 2

GABA+/H₂O levels in the medial prefrontal cortex (mPFC) of healthy volunteers (HV; n = 18) and people at clinical high risk (CHR) for psychosis (n = 35). GABA+ = γ-aminobutyric acid plus macromolecule.

Fig. 3

Associations between residuals of regressing [¹⁸F]FEPPA V_T on TSPO genotype and residuals of regressing GABA+/H₂O levels in medial prefrontal cortex (mPFC) on TSPO genotype in people at clinical high risk (CHR) for psychosis (r = −0.49, p = 0.008) and healthy volunteers (HV; r = −0.53, p = 0.053). GABA+ = γ-aminobutyric acid plus macromolecule; TSPO = translocator protein 18 kDa; V_T = total distribution volume.