Imaging Microglial Activation in Untreated First-Episode Psychosis: A PET Study With [¹⁸F]FEPPA

Abstract

Objective Neuroinflammation and abnormal immune responses are increasingly implicated in the pathophysiology of schizophrenia. Previous positron emission tomography (PET) studies targeting the translocator protein 18 kDa (TSPO) have been limited by high nonspecific binding of the first-generation radioligand, low-resolution scanners, small sample sizes, and psychotic patients being on antipsychotics or not being in the first episode of their illness. The present study uses the novel second-generation TSPO PET radioligand [18F]FEPPA to evaluate whether microglial activation is elevated in the dorsolateral prefrontal cortex and hippocampus of untreated patients with first-episode psychosis. Method Nineteen untreated patients with first-episode psychosis (14 of them antipsychotic naive) and 20 healthy volunteers underwent a high-resolution [18F]FEPPA PET scan and MRI. Dynamic PET data were analyzed using the validated two-tissue compartment model with arterial plasma input function with total volume of distribution (VT) as outcome measure. All analyses were corrected for TSPO rs6971 polymorphism (which is implicated in differential binding affinity). Results No significant differences were observed between patients and healthy volunteers in microglial activation, as indexed by [18F]FEPPA VT, in either the dorsolateral prefrontal cortex or the hippocampus. There were no significant correlations between [18F]FEPPA VT and duration of illness, clinical presentation, or neuropsychological measures after adjusting for multiple testing. Conclusions The lack of significant differences in [18F]FEPPA VT between groups suggests that microglial activation is not present in first-episode psychosis.

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.…”