Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [¹¹C]PBR28 PET Brain Imaging Study

Abstract

Objective-To determine whether microglial activity, measured using translocator-protein positron emission tomographic imaging (PET), is increased in unmedicated subjects presenting with sub-clinical symptoms indicating they are at ultra high risk of psychosis, and to determine if it is elevated in schizophrenia after controlling for a translocator specific genetic polymorphism.Method-Here we use the second generation radioligand [ 11 C]PBR28 and PET to image microglial activity in the brains of subjects at ultra high risk for psychosis. Subjects were recruited from early intervention centres. We also imaged a cohort of patients with schizophrenia and healthy controls for comparison, in total 56 subjects completed the study. At screening, subjects were genotyped to account for the rs6971 polymorphism in the gene encoding the 18Kd Translocator Protein. The main outcome measure was total grey matter [ 11 C]PBR28 binding ratio, representing microglial activity. Conclusion-Microglial activity is elevated in schizophrenia and in subjects with sub-clinical symptoms who are at ultra high risk of psychosis, and is related to at risk symptom severity. This indicates that neuroinflammation is linked to the risk of psychosis and related disorders, and the expression of sub-clinical symptoms. Follow up of ultra high risk subjects will determine whether this is specific to the later development of schizophrenia or risk factors in general. Results-[

Positron Emission Tomography Studies of the Glial Cell Marker Translocator Protein in Patients With Psychosis: A Meta-analysis Using Individual Participant Data

“…This has important implications for sensitivity and the power to detect differences between patients with psychosis and control subjects. Indeed, the power to detect an expected significant medium-sized difference between diagnostic groups (at alpha = .05) has ranged from 23% to 34% in previous designs (22)(23)(24)(25)(26). Medication status has also differed both between and within these studies.…”

“…To our knowledge, there are currently five published studies reporting such data, using the radioligands [ 11 C]PBR28, [ 18 F]FEPPA, and [ 11 C]DPA713 (22)(23)(24)(25)(26). To ascertain that no relevant studies were omitted from this meta-analysis, we performed a systematic literature search on PubMed.…”

“…Both authors concluded independently that five studies (22)(23)(24)(25)(26) fulfilled the inclusion criteria for this meta-analysis (see PRISMA flowchart in Supplemental Figure S3). Each corresponding author provided anonymized individual participant V T values from FC [three studies (22)(23)(24)], dorsolateral prefrontal cortex [two studies (25,26)], TC (all studies), and HIP (all studies). For all subsequent analyses in this study, the V T values from FC and dorsolateral prefrontal cortex were considered to represent the same ROI.…”

“…Concerns regarding the low signal-to-noise ratio of (R)-[ 11 C]PK11195 sparked the development of a series of second-generation TSPO radioligands, showing much greater specific binding (18)(19)(20)(21). These tools have subsequently been used to revisit the question of higher levels of TSPO in psychosis (22)(23)(24)(25)(26). When employing gold standard outcome measures of binding in the absence of a reference region (total distribution volume [V T ] obtained using kinetic modeling with metabolite-corrected arterial plasma as input function), higher TSPO expression has so far not been found in patients.…”

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

“…Interestingly, no correlations between increased peripheral blood cytokine concentrations or increased symptoms of depression and increased TSPO binding in the brain were found after endotoxin in humans, although marked increases in TSPO binding were observed (Sandiego et al, 2015). In terms of studies in patient populations, mixed results have been found regarding TSPO binding in depression and schizophrenia with both positive and negative results (Hannestad et al, 2013;Kenk et al, 2015;Bloomfield et al, 2016;Coughlin et al, 2016). Nevertheless, at least one study in patients with depression has provided promising evidence of increased TSPO binding in the prefrontal cortex, insula, and anterior cingulate cortex that correlated with depression symptom severity (Setiawan et al, 2015).…”