TSPO in diverse CNS pathologies and psychiatric disease: A critical review and a way forward

Abstract

The use of Translocator Protein 18 kDa (TSPO) as a clinical neuroimaging biomarker of brain injury and neuroinflammation has increased exponentially in the last decade. There has been a furious pace in the development of new radiotracers for TSPO positron emission tomography (PET) imaging and its use has now been extensively described in many neurological and mental disorders. This fast pace of research and the ever-increasing number of new laboratories entering the field often times lack an appreciation of the historical perspective of the field and introduce dogmatic, but unproven facts, related to the underlying neurobiology of the TSPO response to brain injury and neuroinflammation. Paradoxically, while in neurodegenerative disorders and in all types of CNS pathologies brain TSPO levels increase, a new observation in psychiatric disorders such as schizophrenia is decreased brain levels of TSPO measured by PET. The neurobiological bases for this new finding is currently not known, but rigorous experimental design using multiple experimental approaches and careful interpretation of results is critically important to provide the methodological and/or biological underpinnings to this new observation. This review provides a perspective of the early history of validating TSPO as a biomarker of brain injury and neuroinflammation and a critical analysis of controversial topics in the literature related to the cellular sources of the TSPO response. The latter is important in order to provide the correct interpretation of PET studies in neurodegenerative and psychiatric disorders. Furthermore, this review proposes some yet to be explored explanations to new findings in psychiatric disorders and new approaches to quantitatively assess the glial sources of the TSPO response in order to move the field forward.

Glioblastoma Exhibits Inter-Individual Heterogeneity of TSPO and LAT1 Expression in Neoplastic and Parenchymal Cells

“…In human addiction studies of methamphetamine use, an increased TSPO-PET signal was found and correlated with TSPO upregulation in reactive glial cells and activated microglia [33]. Additionally, in almost all types of CNS pathologies, TSPO levels are increased, and in some psychiatric disorders, such as schizophrenia, the TSPO signal in PET is decreased [34]. Although TSPO ligands are widely used in molecular imaging in all sorts of CNS pathologies, little is known about the role of TSPO expression and neuroinflammation in glioblastoma patients and PET imaging with TSPO radioligands is not yet standard for the imaging of brain tumor patients [18,19,[35][36][37].…”

Detecting neuroinflammation in the brain following chronic alcohol exposure in rats: A comparison between in vivo and in vitro TSPO radioligand binding

“…The differences between both studies might reflect a pathology‐specific mechanism that differentially alters TSPO levels or affinity (Notter et al., ). Specifically, while multiple studies have confirmed that increases in PK11195 binding to TSPO are due to an increase in the number of binding sites (Bmax), and not to changes in affinity (Kd), such studies have not been conducted for PBR28 (Guilarte, ). However, the fact that PBR28, but not PK11195 is influenced by TSPO genotype (polymorphism rs6971) indicates that binding of PBR28 to TSPO is sensitive to changes in affinity (Rojas, Stathis, Coughlin, Pomper, & Slusher, ).…”

Glutamate hypothesis in schizophrenia

“…Regarding the PET ligands, [ 11 C] ABP688 and [ 18 F] FPEB, which bind to an allosteric site on mGlu 5 , which co‐localizes with NMDAR functionally and has physically close interactions with NMDAR activation, have demonstrated potential as a marker for glutamatergic transmission . The translocation protein 18 kDa (TSPO) expression, which is elevated with microglial activation, is starting to be used as another target for PET studies in psychiatric disorders suspected to involve microglial activation, including schizophrenia . It is known that activated microglia induce reactive astrocytes by cytokines, which could contribute to glutamatergic dysfunction in schizophrenia via the activation of extrasynaptic NMDAR by releasing D‐serine.…”