Interaction between TSPO-a neuroimmune marker-and redox status in clinical high risk for psychosis: a PET-MRS study

Abstract

Altered neuroimmune response and oxidative stress have both been implicated in the pathophysiology of schizophrenia. While preclinical studies have proposed several pathways regarding potential interactions between oxidative stress and neuroimmune imbalance in the development of psychosis, the molecular mechanisms underlying this interaction are not yet understood. To date, no study has investigated this link in vivo in the human brain. We conducted the first in vivo study linking translocator protein 18 kDa (TSPO) expression and glutathione (a major brain antioxidant and a marker for redox status) in the medial prefrontal cortex (mPFC) of a relatively large sample of participants (N = 48) including 27 antipsychotic-naïve individuals at clinical high risk for psychosis and 21 matched healthy volunteers using high-resolution PET with TSPO radioligand, [¹⁸F]FEPPA, and 3T proton magnetic resonance spectroscopy (¹H MRS). The omnibus model (including TSPO genotype as covariate) was significant (F_{(4, 43)} = 10.01, p < 0.001), with a significant group interaction (t = -2.10, p = 0.04), suggesting a different relation between [¹⁸F]FEPPA V_T and glutathione in each clinical group. In healthy volunteers, but not in individuals at clinical high risk for psychosis, we found a significant negative association between glutathione levels and [¹⁸F]FEPPA V_T (r = -0.60, p = 0.006). We observed no significant group differences with respect to [¹⁸F]FEPPA V_T or glutathione levels. These findings suggest an abnormal interaction between TSPO expression and redox status in the clinical high risk states for psychosis.

Fig. 1

Volume of interest (20 × 40 × 30 mm³) location used in ¹H MRS scan of the medial prefrontal cortex for quantification of glutathione

Fig. 2

(A): Typical fitting results from a patient, a MRS sub-spectra acquired for the “on” condition (see text), b “off” condition, c subtracted to obtain clean GSH resonance at 2.9 p.p.m., d frequency domain model-fitting of edited GSH resonance only, and e residual of the difference between c and d. (B): A representative single-subject-GSH-edited spectrum clearly showing the 2.95 p.p.m. GSH resonance

Fig. 3

Association between [¹⁸F]FEPPA V_T and glutathione levels in mPFC (controlling for TSPO genotype). The graph presents the significant interaction between group × glutathione levels on [¹⁸F]FEPPA V_T (F_{(4, 43)} = 10.01, p < 0.001; t = −2.10, p = 0.04). The significant correlation in healthy volunteers remains after excluding healthy volunteer with the highest glutathione value (r = −0.51, p = 0.025)