While the role of dopamine in positive symptoms of schizophrenia (SCZ) is well established, it is increasingly recognized that dopamine may only be a final common pathway of different etiological factors. Several lines of evidence point towards a role for neuroinflammation in the pathogenesis of SCZ. Neuroinflammation is also possibly related to brain atrophy, which is a consistent finding in SCZ. Positron emission tomography (PET) of translocator protein 18Kd (TSPO), a microglial mitochondrial protein provides an opportunity to study microglia activity, a marker of neuroinflammation, in-vivo. Previous studies used [11C]-PK1195, a radiotracer with many deficiencies as a PET radiotracer, and only in treated patients with SCZ. However, the role of microglia activation/neuroinflammation in antipsychotic naive SCZ, its relation to brain atrophy and clinical symptoms has not been examined using PET. Importantly, examination of neuroinflammation in Clinical high risk (CHR) subjects, which provides an opportunity for early intervention and possibly better outcome, has never been undertaken. Thus, the proposed study aims to obtain first in-vivo imaging data using a high-resolution (HRRT) scanner to investigate whether SCZ related disorders are associated with increased neuroinflammation by measuring [18F]-FEPPA binding in three groups of individuals (36 in each): antipsychotic naive SCZ patients, CHR and matched healthy volunteers (HV). [18F]-FEPPA is a novel radiotracer with desirable properties developed at Centre for addiction and mental health (CAMH), Toronto. Subjects will be scheduled for one PET scan and MRI scan each. The main objective is to test whether there is a significant effect of group (SCZ, CHR and HV) on [18F]-FEPPA binding in hippocampus and dorsolateral prefrontal cortex (DLPFC), while controlling for genotype. On Post-hoc analysis, we hypothesize that both antipsychotic naive SCZ and CHR will have higher [18F]-FEPPA binding in hippocampus and DLPFC, as compared to HV. This study addresses a relevant question in schizophrenia research; the role of neuroinflammation in the pathophysiology of SCZ, without the confound of antipsychotic medications, using state of the art imaging technology and second generation TSPO radioligands while controlling for genotype. Understanding the neurobiological changes associated with microglia activation has the potential to identify novel treatment targets (i.e. decrease neuroinflammation) in SCZ and in those at clinical high risk for the disease. There is increasing recognition that early identification and intervention is critical for better outcome in SCZ. By examining CHR and antipsychotic naive SCZ, potential early treatments can be conceived that could have significant impact on final outcome of SCZ, and even delay or abort its occurrence.
Worldwide schizophrenia ranks eighth among ten leading causes of years lived with disability and is associated with a significant economic and social burden on families who care for patients with schizophrenia. Using Positron emission tomography scans, this project will examine the role of brain inflammation in the early stages of schizophrenia and in those at risk of developing schizophrenia, in comparison with healthy individuals. The study findings have potential to identify those at risk early in the disease, and provide novel treatment targets in schizophrenia, and possibly even delay or abort transition to schizophrenia in those at risk.
|Mizrahi, Romina (2016) Social Stress and Psychosis Risk: Common Neurochemical Substrates? Neuropsychopharmacology 41:666-74|
|Kenk, Miran; Selvanathan, Thiviya; Rao, Naren et al. (2015) Imaging neuroinflammation in gray and white matter in schizophrenia: an in-vivo PET study with [18F]-FEPPA. Schizophr Bull 41:85-93|