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Several lines of evidence implicate microglial activation and abnormal immune response in the etiology of psychosis. Previous positron emission tomography (PET) neuroimaging studies of the translocator protein 18 kDa, TSPO, were limited by low affinity of the first-generation radioligand, low-resolution scanners, and small sample sizes. Moreover, there is a dearth of literature on microglial activation in individuals at clinical high risk (CHR) for psychosis. We used a novel second-generation TSPO radioligand, [F]FEPPA, to examine whether microglial activation is elevated in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of antipsychotic-naive CHR. Twenty-four CHR (antipsychotic-naive n=22) and 23 healthy volunteers (HV) completed a high resolution [F]FEPPA PET scan and MRI. The PET data were analyzed using the validated two-tissue compartment model with arterial plasma input function with total volume of distribution (V) as outcome measure. All analyses were controlled for the TSPO rs6971 polymorphism. We did not observe any significant differences in microglial activation, as indexed by [F]FEPPA V, between CHR and HV in either the DLPFC (F=0.41, p=0.52) or the hippocampus (F=2.78, p=0.10). Exploratory associations show that in CHR, [F]FEPPA V was positively correlated with apathy (DLPFC: r=0.55, p=0.008; hippocampus: r=0.52, p=0.013) and state anxiety (DLPFC: r=0.60, p=0.003; hippocampus: r=0.48, p=0.024). The lack of significant group differences in [F]FEPPA V suggests that microglial activation is not significantly elevated in the clinical high risk state that precedes psychosis.

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