PET studies of the glial cell marker TSPO in psychosis patients - a meta-analysis using individual participant data

Abstract

Background: Accumulating evidence suggests that the immune system may be an important target for new treatment approaches in schizophrenia. Positron emission tomography (PET) and radioligands binding to the translocator protein (TSPO), which is expressed in glial cells in brain including immune cells, represents a potential method for patient stratification and treatment monitoring. This study examined if patients with first episode psychosis and schizophrenia had altered TSPO levels as compared to healthy control subjects. Methods: PubMed was searched for studies comparing patients with psychosis to healthy controls using second-generation TSPO radioligands. The outcome measure was distribution volume (V T ), an index of TSPO levels, in frontal cortex (FC), temporal cortex (TC) and hippocampus (HIP). Bayes factors (BF) were applied to examine the relative support for higher, lower or no-change of TSPO levels in patients as compared to healthy controls. Results: Five studies, with 75 patients with first-episode psychosis or schizophrenia and 77 healthy control subjects were included. BF showed strong support for lower patient V T relative to no-change (all BF>32) or relative to an increase (all BF>422) in all brain regions. From the posterior distributions, mean patient-control differences in standardized V T values were -0.48 for FC (95% credible interval (CredInt)=-0.88 to -0.09), -0.47 for TC (CredInt=-0.87 to -0.07) and -0.63 for HIP (CredInt=-1.00 to -0.25). Discussion: The observed reduction of TPSO in patients may correspond to altered function or lower density of brain immune cells. Future studies should focus on investigating the underlying biological mechanisms and their relevance for treatment.Keywords: positron emission tomography, psychosis, schizophrenia, translocator protein, microglia, immuneactivation, meta-analysis *Corresponding author: pontus.plaven-sigray@ki.se. 1. CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/228742 doi: bioRxiv preprint first posted online Dec. 5, 2017; IntroductionGenetic, epidemiological and biomolecular data suggest that the immune system is involved in the pathophysiology of schizophrenia (1-3). When translating these findings into clinical trials, initial studies have shown positive effect of medication targeting the immune system when used as addon treatment to antipsychotics (4-6). To aid further development of this therapeutic approach, tools for directly assessing the status of the brain immune system are needed to allow for patient stratification and monitoring of treatment effects.Using Positron Emission Tomography (PET), the localization and activation state of central nervous system (CNS) immune response modulators can be assessed with radioligands targeting the glial cell marker 18 kDa translocator protein (TSPO) (7-9). During the last decade, a handful of TSPO PET studies have been performed in patients with early-sta...

Increased levels of midbrain immune-related transcripts in schizophrenia and in murine offspring after maternal immune activation

“…Increasing evidence suggests that the immune system is involved in the pathogenesis and pathophysiology of schizophrenia. Support for this notion includes epidemiological findings of increased risk of schizophrenia following earlylife exposure to infectious pathogens or inflammatory stimuli [1][2][3], along with postmortem and imaging studies demonstrating glial anomalies [4][5][6][7][8][9][10][11][12][13][14][15] and increased expression of cytokines and other mediators of inflammation in the brain and periphery in people with schizophrenia [4][5][6][7][16][17][18][19][20][21]. Noticeable inflammatory abnormalities, however, are evident only in a subgroup of schizophrenia cases [4][5][6]17] and may predict poorer clinical outcomes and treatment responses [18,20].…”

Prednisolone versus placebo addition in the treatment of patients with recent-onset psychotic disorder: A trial design

“…The activation of microglia cells provides a possible route by which an inflammatory state in the brain could cause increased grey matter (GM) loss and consequently contribute to more severe negative and cognitive symptoms. However, another meta-analysis found lower levels of glial cell markers in first episode psychosis and schizophrenia patients in comparison with healthy controls, suggesting a lower density of immune cells and glial cells (17).…”

“…First, a significant association with the major histocompatibility complex (MHC) region, best known for its role in immunity, on chromosome 6p21. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22].1 was observed in a large genome wide association study (GWAS), including over 30,000 patients with schizophrenia (9). An association between MHC and psychosis was also described by Saito and colleagues (10).…”