Imaging Neuroinflammation in Gray and White Matter in Schizophrenia: An In-Vivo PET Study With [18F]-FEPPA

Abstract

Neuroinflammation and abnormal immune responses have been implicated in schizophrenia (SCZ). Past studies using positron emission tomography (PET) that examined neuroinflammation in patients with SCZ in vivo using the translocator protein 18kDa (TSPO) target were limited by the insensitivity of the first-generation imaging agent [(11)C]-PK11195, scanners used, and the small sample sizes studied. Present study uses a novel second-generation TSPO PET radioligand N-acetyl-N-(2-[(18)F]fluoroethoxybenzyl)-2-phenoxy-5-pyridinamine ([(18)F]-FEPPA) to evaluate whether there is increased neuroinflammation in patients with SCZ. A cross-sectional study was performed using [(18)F]-FEPPA and a high-resolution research tomograph (HRRT). Eighteen patients with SCZ with ongoing psychotic symptoms and 27 healthy volunteers (HV) were recruited from a tertiary psychiatric clinical setting and the community, respectively. All participants underwent [(18)F]-FEPPA PET and magnetic resonance imaging, and PET data were analyzed to obtain [(18)F]-FEPPA total volume of distribution (VT) using a 2-tissue compartment model with an arterial plasma input function, as previously validated. All subjects were classified as high-, medium- or low-affinity [(18)F]-FEPPA binders on the basis of rs6971 polymorphism, and genotype information was incorporated into the analyses of imaging outcomes. No significant differences in neuroinflammation indexed as [(18)F]-FEPPA VT were observed between groups in either gray (F(1,39) = 0.179, P = .674) or white matter regions (F(1,38) = 0.597, P = .445). The lack of significant difference in neuroinflammation in treated patients with SCZ in the midst of a psychotic episode and HV suggests that neuroinflammatory processes may take place early in disease progression or are affected by antipsychotic treatment.

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.…”

“…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).…”

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

“…Even though the underlying mechanisms and functional role of increased hippocampal IL--1β expression remains to be examined in our model, our data clearly demonstrate that abnormal pro--inflammatory cytokine expression in the brain can occur without concomitant microglia abnormalities. These findings may also have important implications for the current attempts to define "neuroinflammation" in neurodevelopmental disorders such as schizophrenia and autism, especially for those that rely on the examination of microglia only (Doorduin et al, 2009;Kenk et al, 2015;Morgan et al, 2010;Pasternak et al, 2015;Tetreault et al, 2012;van Berckel et al, 2008).…”