13.4 MOLECULAR IMAGING STUDIES OF TSPO IN SCHIZOPHRENIA – RELATIONSHIP TO CENTRAL AND PERIPHERAL IMMUNE MARKERS AND NEW METHODS OF QUANTIFICATION

Abstract

Background Accumulating evidence suggests that the immune system may have a role in the disease mechanism in schizophrenia. To date, the most frequently used method for imaging of brain immune function is to use PET and radioligands for the translocator protein (TSPO), which is expressed primarily in microglia and astrocytes. This methodology has been applied in a series of studies to examine the hypothesis of glial activation in patients with schizophrenia. Results have been mixed, however medication status and disease stage differed between individual studies, and sample sizes were generally small. Moreover, a limitation of current methods of analysis of TSPO PET data is that specific binding cannot be distinguished from non-displaceable binding. Methods TSPO was investigated in a cohort of antipsychotic-naive first episode psychosis patients using the second generation radioligand [11C]PBR28. Subsequently, an individual-participant data meta-analysis of TSPO PET studies in schizophrenia was performed. In follow-up studies we first re-examined a subgroup of our cohort using PET and [11C]PBR28. We also evaluate the relationship between central TSPO binding and markers of immune activation in blood and cerebrospinal fluid (CSF) as measured by electrochemiluminescence assay, and blood cell phenotypic data obtained using the cyTOF platform. Finally, we address current shortcomings in methodology by applying a novel method to estimate specific binding to TSPO. Results Lower levels of TSPO was demonstrated in antipsychotic-naive first episode psychosis patients. This unexpected result was confirmed in the individual-participant data meta-analysis. In follow-up analyses in a subgroup of our cohort, the results indicated a normalization of TSPO. Preliminary analyses show positive correlations between chemokines in CSF and central TSPO binding, whereas in controls these variables were negatively correlated. In the cyTOF analysis, where up to 80 different phenotypic markers can be obtained from one single blood cell sample, we observed significant aberrations that were located to the monocyte population. Finally, preliminary results applying the Simultaneous Method, which utilizes time activity-curves from multiple brain regions, show that specific binding estimates were in correspondence to in vivo blocking data, and a test-retest analysis showed good reliability and precision. Conclusions The TSPO PET data together with immune marker analysis support aberrations in both central and peripheral immune cell function in schizophrenia. Methods for accurately assessing specific binding to TSPO can be of help in increasing sensitivity in clinical studies.