MICROGLIAL ACTIVATION IN MEDICATED PATIENTS WITH FIRST-EPISODE PSYCHOSIS: PRELIMINARY RESULTS FROM A [18F]DPA-714 PET IMAGING STUDY

Abstract Background Dysfunction of brain-resident microglia is hypothesised to play a key role in the development of mental disorders including schizophrenia (1). The 18-kDa translocator protein (TSPO) is known to be a sensitive and robust biomarker of microglial activation in the brain (2). Using PET imaging, previous studies, including from our group (3), have shown increased expression of TSPO in the brains of patients with schizophrenia relative to controls (4). However, findings across studies have been inconsistent, with others indicating no change or decreased TSPO expression in patients (5). Thus, it remains unclear if microglial activation plays a primary role in the illness. Aims & Objectives To test the relevance of microglial activation in schizophrenia, we carried out a randomised, placebo-controlled study involving 3-month intervention with natalizumab in patients with first-episode psychosis, combined with longitudinal assessments of central/peripheral immune markers (ClinicalTrials.gov NCT03093064). Here, we present findings from the baseline case-control comparison of the study. Methods Case-control comparison of patients with first-episode psychosis and matched healthy controls. Patients were recruited from community Early Intervention services across London. Healthy controls, with no history of psychosis and matched for age, sex, and TSPO genotype, were recruited from the same geographical area. As a marker of microglial activation, we used [18F]DPA-714 PET imaging and quantified TSPO binding using the supervised clustering algorithm (6). Total, temporal, and frontal gray matter (GM) were defined as a priori regions of interest (ROI). Serum and cerebrospinal fluid (CSF) samples were collected for cytokine analysis. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), and Calgary Depression Scale for Schizophenia (CDSS). Results 62 patients with DSM-5 psychotic disorders (mean age 27.5, 42 male, median duration of illness 22 months) and 41 healthy controls (mean age 29.2, 23 male) completed baseline assessments. Groups did not differ significantly in demographic variables including age, sex, ethnicity, and BMI. All patients were on antipsychotic treatment with a median chlorpromazine equivalent dose (7) of 287mg/day. ANCOVA with age and TSPO genotype included as covariates showed that TSPO binding was elevated in patients compared to controls in the total GM (mean± SE 1.098±0.002 vs. 1.091±0.003, p=0.038, partial eta squared 0.043) and temporal GM (mean± SE 1.095±0.003 vs. 1.084±0.004, p=0.016, partial eta squared 0.057). There was no significant difference in TSPO binding in the frontal lobe GM. Serum and CSF cytokine analyses are ongoing. There was no significant correlation between PANSS total or subscale scores, SANS negative symptom scores, or CDSS depressive symptom scores and TSPO binding in the a priori ROIs. Discussion & Conclusions Baseline case-control comparison from this study indicates that microglial activation is increased in the total and temporal lobe GM of patients with first-episode psychosis relative to controls. This is the largest investigation to date quantifying microglia activation in patients with psychotic disorders. Implications of the PET findings will be discussed in the context of ongoing investigations of serum/CSF cytokines. References 1.Calcia et al., Psychopharmacology (Berl), 2016 2.Turkheimer et al., Biochem Soc Trans, 2015 3.Bloomfield et al., Am J Psychiatry, 2016 4.Reis Marques et al., Psychol Med, 2019 5.Plavé n-Sigray et al., Biol Psychiatry, 2018 6.Schubert et al., Eur J Nucl Med Mol Imaging, 2021 7.Leucht et al., Schizophr Bull 2016

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