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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 [11C]FLB457. The main outcome was D2-R binding potential (BPND) 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 BPND 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.

PurposeThe 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 [11C]PBR28.Methods[11C]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 (VT) 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.ResultsThere were significant positive correlations between age and VT in the frontal and temporal cortex. BMI showed a significant negative correlation with VT in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher VT. A subgroup analysis revealed a positive correlation between VT and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects.ConclusionThese 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.

[11C]PBR28 is a positron emission tomography radioligand used to examine the expression of the 18 kDa translocator protein (TSPO). TSPO is located in glial cells and can function as a marker for immune activation. Since TSPO is expressed throughout the brain, no true reference region exists. For this reason, an arterial input function is required for accurate quantification of [11C]PBR28 binding and the most common outcome measure is the total distribution volume (VT). Notably, VT reflects both specific binding and non-displaceable binding. Therefore, estimates of specific binding, such as binding potential (e.g. BPND) and specific distribution volume (VS) should theoretically be more sensitive to underlying differences in TSPO expression. It is unknown, however, if unbiased and accurate estimates of these outcome measures are obtainable for [11C]PBR28. The Simultaneous Estimation (SIME) method uses time-activity-curves from multiple brain regions with the aim to obtain a brain-wide estimate of the non-displaceable distribution volume (VND), which can subsequently be used to improve the estimation of BPND and VS. In this study we evaluated the accuracy of SIME-derived VND, and the reliability of resulting estimates of specific binding for [11C]PBR28, using a combination of simulation experiments and in vivo studies in healthy humans. The simulation experiments, based on data from 54 unique [11C]PBR28 examinations, showed that VND values estimated using SIME were both precise and accurate. Data from a pharmacological competition challenge (n = 5) showed that SIME provided VND values that were on average 19% lower than those obtained using the Lassen plot, but similar to values obtained using the Likelihood-Estimation of Occupancy technique. Test-retest data (n = 11) showed that SIME-derived VS values exhibited good reliability and precision, while larger variability was observed in SIME-derived BPND values. The results support the use of SIME for quantifying specific binding of [11C]PBR28, and suggest that VS can be used in complement to the conventional outcome measure VT. Additional studies in patient cohorts are warranted. •[11C]PBR28 is a radioligand for measuring TSPO, a marker for glial cell activation.•The outcome measure VT contains both specific (VS) and non-specific binding (VND).•The SIME method, that accounts for VND, was evaluated for [11C]PBR28 data.•Simulations and blocking data show that SIME accurately estimates VND.•SIME derived VS was reliable and precise, and can be used for higher sensitivity.

Schizophrenia is characterized by a multiplicity of symptoms arising from almost all domains of mental function. γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain and is increasingly recognized to have a significant role in the pathophysiology of the disorder. In the present study, cerebrospinal fluid (CSF) concentrations of GABA were analyzed in 41 first-episode psychosis (FEP) patients and 21 age- and sex-matched healthy volunteers by high-performance liquid chromatography. We found lower CSF GABA concentration in FEP patients compared with that in the healthy volunteers, a condition that was unrelated to antipsychotic and/or anxiolytic medication. Moreover, lower CSF GABA levels were associated with total and general score of Positive and Negative Syndrome Scale, illness severity and probably with a poor performance in a test of attention. This study offers clinical in vivo evidence for a potential role of GABA in early-stage schizophrenia.

BackgroundThe dopamine system is a central focus of research on the pathophysiology and treatment of schizophrenia. With regard to the dopamine D2-receptor (D2-R), Positron Emission Tomography (PET) studies have shown a small increase in striatal receptor availability. In contrast, a more recent line of research has demonstrated lower levels of D2-R (Cohen’s D = -0.32) in the thalamus, a region of key interest for the pathophysiology of schizophrenia. However, some studies included patients previously on antipsychotic medication, or were performed using radioligands with suboptimal affinity for the much lower D2-R density in thalamus compared to striatum. In addition, the resolution of previous PET systems has not allowed for a more detailed analysis of functional thalamic subregions. Here we examined a fully antipsychotic-naïve sample of first-episode psychosis patients using the high-affinity D2-R radioligand [11C]FLB457 and high-resolution PET. The aim was to a) replicate previous findings of lower D2-R in thalamus in patients and b) specifically examine patient-control differences in thalamic subregions based on their cortical connectivity.MethodsNineteen antipsychotic-naïve first episode psychosis patients (mean age = 29.3; sd = 6.3, 11 males) and 19 age- and sex matched healthy comparison subjects were included in the analysis. PET measurements were obtained using a High Resolution Research Tomograph (HRRT). A ROI for whole thalamus was defined using the FSL Harvard Oxford Subcortical Atlas, whereas ROIs for thalamic subregions were based on the Oxford Thalamic Connectivity Atlas. Binding potential (BPND) was calculated using the Logan graphical analysis with cerebellum as reference region. The statistical analyses, which were all pre-registered, were performed using frequentist and Bayesian paired-samples t-tests.ResultsThe frequentist paired t-test showed that patients had significantly lower binding than control subjects in whole thalamus (Cohen’s D = -0.479, p = 0.026). Bayes factor from the Bayesian paired t-test indicated that there was approximately 5 times more support for the hypothesis of lower BPND in patients, compared to the null hypothesis of no difference. Among subregions, the ROI corresponding to prefrontal thalamic connectivity showed the largest effect (Cohen’s D = -0.527, p = 0.017), and Bayes factor indicated that there was 6 times more support for lower BPND in patients compared to no difference.DiscussionUsing high resolution PET and a high affinity D2-R radioligand in antipsychotic-naïve first-episode psychosis patients, this study replicates the previously reported meta-analytical effect size of lower thalamic receptor availability in patients. The strongest effect was observed in the subregion dominated by connections to prefrontal cortex. The findings may reflect a dysregulation of the thalamic dopamine system in schizophrenia, which in turn could underlie aberrant functional connectivity in key fronto-thalamic circuits.

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, indifferent 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.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background: Accumulating evidence suggests that the immune system may be an important target for new treatment approaches in schizophrenia. Positron emission tomography (PET) and radioligands binding to the translocator protein (TSPO), which is expressed in glial cells in brain including immune cells, represents a potential method for patient stratification and treatment monitoring. This study examined if patients with first episode psychosis and schizophrenia had altered TSPO levels as compared to healthy control subjects. Methods: PubMed was searched for studies comparing patients with psychosis to healthy controls using second-generation TSPO radioligands. The outcome measure was distribution volume (VT), an index of TSPO levels, in frontal cortex (FC), temporal cortex (TC) and hippocampus (HIP). Bayes factors (BF) were applied to examine the relative support for higher, lower or no-change of TSPO levels in patients as compared to healthy controls.Results: Five studies, with 75 patients with first-episode psychosis or schizophrenia and 77 healthy control subjects were included. BF showed strong support for lower patient VT relative to no-change (all BF>32) or relative to an increase (all BF>422) in all brain regions. From the posterior distributions, mean patient-control differences in standardized VT values were -0.48 for FC (95% credible interval (CredInt)=-0.88 to -0.09), -0.47 for TC (CredInt=-0.87 to -0.07) and -0.63 for HIP (CredInt=-1.00 to -0.25). Discussion: The observed reduction of TPSO compared to control subjects in patients may correspond to altered function or lower density of brain immune cells. Future studies should focus on investigating the underlying biological mechanisms and their relevance for treatment.

Patients with myocardial infarction with nonobstructive coronary arteries (MINOCA), including Takotsubo syndrome (TS), are considered to have a better survival compared with those with coronary heart disease (CHD). Studies of patients with MINOCA measuring physical and mental function including matched control groups are lacking. The aim of this study was to determine the physical capacity and quality of life in patients with MINOCA. One-hundred patients with MINOCA along with TS (25%) were investigated from 2007 to 2011. A bicycle exercise stress test was performed 6 weeks after hospitalization and QoL was investigated by the Short Form Survey 36 at 3 months' follow-up. Both a healthy and a CHD group that were age and gender matched were used as controls. The MINOCA group had a lower physical capacity (139 ± 42 W) compared with the healthy control group (167 ± 53 W, p <0.001) but better than the CHD control group (124 ± 39 W, p = 0.023). Patients with MINOCA had lower physical and mental component summary scores compared with the healthy controls (p <0.001) and lower mental component summary (p = 0.012), mental health (p = 0.016), and vitality (p = 0.008) scores compared with the CHD controls. In conclusion, the findings of this first study on exercise capacity and QoL in patients with MINOCA showed both physical and mental distress from 6 weeks to 3 months after the acute event similar to CHD controls and in some perspectives even lower scores especially in the mental component of QoL.