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

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.