Perspective: Solving the Heterogeneity Conundrum of TSPO PET Imaging in Psychosis

Livia De Picker,Manuel Morrens

doi:10.3389/fpsyt.2020.00362

Abstract

Positron emission tomography using ligands targeting translocator protein 18 kDa (TSPO PET) is an innovative method to visualize and quantify glial inflammatory responses in the central nervous system in vivo. Compared to some other neuropsychiatric disorders, findings of TSPO PET in schizophrenia and related psychotic disorders have been considerably more heterogeneous. Two conflicting meta-analyses have been published on the topic within the last year: one asserting evidence for decreased TSPO uptake, while the other observed increased TSPO uptake in a selection of studies. In this paper, we review and discuss five hypotheses which may explain the observed variability of TSPO PET findings in psychotic illness, namely that (1) an inflammatory phenotype is only present in a subgroup of psychosis patients; (2) heterogeneity is caused by interference of antipsychotic medication; (3) interference of other clinical confounders in the study populations (such as age, sex, BMI, smoking, and substance use); or (4) methodological variability between studies (such as choice of tracer and kinetic model, genotyping, study power, and diurnal effects); and (5) the glial responses underlying changes in TSPO expression are themselves heterogeneous and dynamic. Finally, we propose four key recommendations for future research proposals to mitigate these different causes of heterogeneity.

Highlights

Heterogeneity seems to come with the territory of psychiatry, and the study of positron emission tomography (PET) imaging of immune alterations in the central nervous system using nuclear ligands targeting translocator protein 18 kDA (TSPO) in psychotic disorders is no different
Both microglia and astrocytes have been implicated in post-mortem research of schizophrenia patients
Even at the level of simple nosology, clinicians and researchers in psychotic disorders understand that diagnostic categories do not represent valid underlying constructs and are more likely to encompass a wider range of disease entities or subgroups, emerging as a similar clinical syndrome

Summary

INTRODUCTION

Heterogeneity seems to come with the territory of psychiatry, and the study of positron emission tomography (PET) imaging of immune alterations in the central nervous system using nuclear ligands targeting translocator protein 18 kDA (TSPO) in psychotic disorders is no different. TSPO levels in psychotic illness could be differentially altered in specific symptomatic states (i.e., acute psychotic syndrome, negative symptoms) or stages throughout the illness course (i.e., prodromal, relapsing-remitting, chronic, and treatment-resistant), depending on the differential recruitment from different cellular sources Both microglia and astrocytes have been implicated in post-mortem research of schizophrenia patients. In these same subjects, plasma KA levels mimicked this effect (cfr Figure 1; unpublished data) Even if these findings only concern a relatively small sample size of n = 10 patients, they corroborate the interesting question whether dynamic TSPO changes could be related to a differential recruitment of microglial and astrocytic populations in an agedependent or illness-specific pattern. Both minocycline and COX-2 inhibitor celecoxib have been shown to be clinically beneficial when used as add-on treatment to antipsychotics in psychotic patients, even though the TSPO PET results in psychotic patients have been ambivalent [1]

DISCUSSION AND RECOMMENDATIONS

Findings

DATA AVAILABILITY STATEMENT