Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [11C]PBR28

Abstract

Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [C]PBR28. Gray matter (GM) volume of distribution (V) derived from a two-tissue compartmental analysis with arterial input function was the main outcome measure. Statistical analyses were performed controlling for both TSPO genotype, which is known to affect [C]PBR28 binding, and gender. There was a significant reduction of [C]PBR28 V in patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM V and clinical or cognitive measures after correction for multiple comparisons. The observed decrease in TSPO binding suggests reduced numbers or altered function of immune cells in brain in early-stage schizophrenia.

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.…”

“…To overcome variability that may be associated with the arterial measurements (27,67), relative measures of binding, such as distribution volume ratios (DVRs), have been proposed (22). Of the studies included in this meta-analysis, one study reported a significantly higher DVR in patients with schizophrenia and people at clinical risk for psychosis (22), whereas three studies showed no difference in schizophrenia (23)(24)(25). More recently, one study found no evidence of higher DVR in high-risk individuals compared with HCs (68).…”

“…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.…”