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

Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [11C]PBR28.

Abstract 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. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [11C]PBR28. Gray matter (GM) volume of distribution (VT) derived from a two-tissue compartmental analysis with arterial input function was the main outcome measure. Statistical analyses were performed controlling for both TSPO genotype, which is known to affect [11C]PBR28 binding, and gender. There was a significant reduction of [11C]PBR28 VT in patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM VT and clinical or cognitive measures after correction for multiple comparisons. The observed decrease in TSPO binding suggests reduced numbers or altered function of immune cells in brain in early-stage schizophrenia

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

This work was supported by National Institute of Biomedical Imaging and Bioengineering Grant No. U54EB020403 (to the ENIGMA consortium)

Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 control subjects via the enhancing neuro Imaging genetics through meta analysis (ENIGMA) Consortium

BACKGROUND: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. METHODS: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. RESULTS: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. CONCLUSIONS: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia

ICT in Medicine and Health Care: Assessing Social, Ethical and Legal Issues

Abstract. Continuous developments in information and communication technologies (ICT) have resulted in an increasing use of these technologies in the practice of medicine and in the provision of medical care. This paper presents a series of perspectives from different areas of expertise on some of the ways in which ICT has changed the social picture in respect of the practice of medicine. The aim of the paper is to provide a context for further debate, in the form of a Panel Session, where the issue of Human Choice and Computing can be discussed with reference to a set of specific scenarios. The authors of this paper represent a wide variety of disciplines including law, ethics, medicine, philosophy and computer science, thus bringing a broad perspective to begin the discussions. The aim of the session is to provoke further discussion, encouraging input from other disciplines respresented by the participants, with a view to identifying the level of human choice in a social arena, which has at its heart a vulnerable community. In this environment, and in this era, the 'social' in social informatics has never been more important

Antiphospholipid antibodies in patients with myocardial infarction with and without obstructive coronary arteries

Background Recent studies demonstrate that prothrombotic antiphospholipid antibodies (aPL) are overrepresented in patients with myocardial infarction (MI) due to coronary artery disease (MICAD). However, it is not known whether aPL differ between the two subsets of MI: MICAD and MI with nonobstructive coronary arteries (MINOCA). Objectives To determine whether aPL are associated with MINOCA or MICAD, or with hypercoagulability as assessed by activated protein C–protein C inhibitor (APC–PCI) complex. Methods Well-characterized patients with MINOCA (n = 98), age- and gender-matched patients with MICAD (n = 99), and healthy controls (n = 100) were included in a cross-sectional case–control study. Autoantibodies (IgA/G/M) targeting cardiolipin and β2glycoprotein-I and specific nuclear antigens were analyzed by multiplexed bead technology. The concentration of APC–PCI was determined as a measure of hypercoagulability by an immunofluorometric sandwich assay. Results Both prevalence and titers of aPL of the IgG isotype (anti-cardiolipin and/or anti-β2glycoprotein-I) were higher in patients with MINOCA and MICAD than in controls. aPL IgG positivity was twice as frequent among patients with MICAD than MINOCA (11% vs. 6%, nonsignificant). We observed no group differences regarding aPL IgA/M or antibodies targeting specific nuclear antigens. Levels of APC–PCI were elevated in aPL IgG-positive compared to aPL IgG-negative MICAD patients. Conclusions aPL IgG, but not IgA/M, are enriched particularly in patients with MICAD but also in patients with MINOCA, as compared to controls. Interestingly, signs of hypercoagulability—measured by increased levels of the APC–PCI complex—were present in aPL IgG-positive MICAD patients, indicating an association with functional disturbances of the coagulation system

Thalamic dopamine D2-receptor availability in schizophrenia: a study on antipsychotic-naive patients with first-episode psychosis and a meta-analysis

Abstract Pharmacological and genetic evidence support a role for an involvement of the dopamine D2-receptor (D2-R) in the pathophysiology of schizophrenia. Previous molecular imaging studies have suggested lower levels of D2-R in thalamus, but results are inconclusive. The objective of the present study was to use improved methodology to compare D2-R density in whole thalamus and thalamic subregions between first-episode psychosis patients and healthy controls. Differences in thalamocortical connectivity was explored based on the D2-R results. 19 antipsychotic-naive first-episode psychosis patients and 19 age- and sex-matched healthy controls were examined using high-resolution Positron Emission Tomography (PET) and the high-affinity D2-R radioligand [ 11 C]FLB457. The main outcome was D2-R binding potential (BP ND ) in thalamus, and it was predicted that patients would have lower binding. Diffusion tensor imaging (DTI) was performed in a subgroup of 11 patients and 15 controls. D2-R binding in whole thalamus was lower in patients compared with controls (Cohen’s dz = −0.479, p  = 0.026, Bayes Factor (BF) > 4). Among subregions, lower BP ND was observed in the ROI representing thalamic connectivity to the frontal cortex (Cohen’s dz = −0.527, p  = 0.017, BF > 6). A meta-analysis, including the sample of this study, confirmed significantly lower thalamic D2-R availability in patients. Exploratory analyses suggested that patients had lower fractional anisotropy values compared with controls (Cohen’s d  = −0.692, p  = 0.036) in the inferior thalamic radiation. The findings support the hypothesis of a dysregulation of thalamic dopaminergic neurotransmission in schizophrenia, and it is hypothesized that this could underlie a disturbance of thalamocortical connectivity

Effects of age, BMI and sex on the glial cell marker TSPO : a multicentre [11C]PBR28 HRRT PET study

Purpose The purpose of this study was to investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [C-11]PBR28. Methods [C-11]PBR28 data from 140 healthy volunteers (72 males and 68 females; N = 78 with HAB and N = 62 MAB genotype; age range 19-80 years; BMI range 17.6-36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (N = 53), Turku PET centre (N = 62) and Yale University PET Center (N = 25). The total volume of distribution (V-T) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts. Results There were significant positive correlations between age and V-T in the frontal and temporal cortex. BMI showed a significant negative correlation with V-T in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher V-T. A subgroup analysis revealed a positive correlation between V-T and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects. Conclusion These findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies