PET studies on the immune cell marker TSPO in first episode psychosis patients

Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. In the present thesis the primary aim was to investigate immune activation in brain in early schizophrenia by examining brain TSPO availability in a cohort of first-episode psychosis (FEP) patients, never before exposed to antipsychotics.

In our first study we assessed the reproducibility of the second generation radioligand [11C]PBR28 by performing repeat measurements in 12 healthy control subjects. We found a medium test-retest reproducibility, but high reliability in [11C]PBR28 binding. A numerically lower variability was detected for subjects examined in the morning of separate days, as opposed to morning and afternoon of the same day, where higher afternoon TSPO levels were observed using secondary methods of quantification. The results suggest that diurnal variation may be a potential confounder in clinical studies.

In our second study we examined 32 healthy individuals, using [11C]PBR28, of which 26 had repeat PET measurements. We found a strong association between TSPO availability in brain and blood cells, both at baseline and when analyzing change between two PET examinations. There was also a significant correlation between change in peripheral leukocyte numbers and change in brain TSPO. The results suggest interplay between central and peripheral TSPO at physiological conditions, and that measurement of radioligand binding in blood cells may be a way to control for peripheral immune function in PET studies of TSPO in brain.

In our third study we examined 16 antipsychotic-naïve FEP patients and 16 control subjects with PET and [11C]PBR28. A significant decrease in TSPO availability in brain was detected in patients as compared to controls. The results indicate that the lack of increase in TSPO availability in earlier studies of schizophrenia was not caused by antipsychotic medication. The observed decrease suggests reduced numbers or altered function of immune cells in brain in early schizophrenia.

Finally, we examined the same cohort of FEP patients and control subjects with respect to the relationship between TSPO availability in brain and peripheral blood cells, as well as chemokine levels. The ratio between binding in brain and blood cells was significantly lower in patients as compared to control subjects. Moreover, we observed a correlation between TSPO binding in brain and levels of the chemokine YKL-40 in cerebrospinal fluid, in different directions among patients and controls respectively. These preliminary results suggest a dysregulation of brain immune cells in early schizophrenia. Future studies combining TSPO PET with pro- and anti-inflammatory immune markers are needed to clarify the role of the immune system at different stages of the disease.

List of scientific papers

I. Karin Collste, Anton Forsberg, Andrea Varrone, Nahid Amini, Shahin Aeinehband, Igor Yakushev, Christer Halldin, Lars Farde, Simon Cervenka. Test-retest reproducibility of [11C]PBR28 binding to TSPO in healthy control subjects. Eur J Nucl Med Mol Imaging. 2016, 43(1), 173–183.
https://doi.org/10.1007/s00259-015-3149-8

II. Naoki Kanegawa, Karin Collste, Anton Forsberg, Martin Schain, Ryosuke Arakawa, Aurelija Jucaite, Mats Lekander, Caroline Olgart Höglund, Eva Kosek, Jon Lampa, Christer Halldin, Lars Farde, Andrea Varrone, Simon Cervenka. In vivo evidence of a functional association between immune cells in blood and brain in healthy human subjects. Brain, Behavior and Immunity. 2016, 54; 149-157.
https://doi.org/10.1016/j.bbi.2016.01.019

III. Karin Collste, Pontus Plavén-Sigray, Helena Fatouros-Bergman, Pauliina Victorsson, Martin Schain, Anton Forsberg, Nahid Amini, Shahin Aeinehband, Sophie Erhardt, Christer Halldin, Lena Flyckt, Lars Farde, Simon Cervenka. Lower levels of the glial cell marker TSPO in drug-naive first episode psychosis patients as measured using PET and [11C]PBR28. Mol Psychiatry. Feb 14, 2017.
https://doi.org/10.1038/mp.2016.247

IV. Karin Collste, Funda Orhan, Ryosuke Arakawa, Sophie Erhardt, Lilly Schwieler, Lena Flyckt, Lars Farde, Göran Engberg, Simon Cervenka. Comparison of central and peripheral immune cell activity as measured using TSPO PET and chemokine levels in drug-naïve first-episode psychosis patients. [Manuscript]