BACKGROUND: Accumulating evidence suggests that the immune system may be an important target for new treatment approaches in schizophrenia. Positron emission tomography and radioligands binding to the translocator protein (TSPO), which is expressed in glial cells in the brain including immune cells, represents a potential method for patient stratification and treatment monitoring. This study examined whether patients with first-episode psychosis and schizophrenia had altered TSPO levels compared with healthy control subjects. METHODS: PubMed was searched for studies comparing patients with psychosis with healthy control subjects using second-generation TSPO radioligands. The outcome measure was total distribution volume (V T ), an index of TSPO levels, in frontal cortex, temporal cortex, and hippocampus. Bayes factors (BFs) were applied to examine the relative support for higher, lower, or no difference in patients' TSPO levels compared with healthy control subjects. RESULTS: Five studies, with 75 participants with first-episode psychosis or schizophrenia and 77 healthy control subjects, were included. BFs showed strong support for lower V T in patients relative to no difference (all BFs .

Here, we examined reproducibility of [ 11 C]PBR28 binding in healthy subjects as quantified on a regional and voxel-by-voxel basis. In addition, a preliminary analysis of diurnal changes in TSPO availability was performed. MethodsTwelve subjects were examined with HRRT PET and [ 11 C]PBR28, six in the morning and afternoon on the same day, and six in the morning of two separate days. Regional Volume of distribution (V T ) values were derived using a region-of-interest based two-tissue compartmental analysis (2TCM), as well as a parametric approach. Metabolite-corrected arterial plasma was used as input function. ResultsFor the whole sample, the mean absolute variability of V T in gray matter (GM) was 18.3 ± 12.7 %. Intraclass Correlation Coefficient values in GM regions ranged from 0.90 to 0.94. Reducing the time of analysis from 91 to 63 minutes yielded a variability of 16.9 ± 14.9%. There was a strong correlation between the parametric and 2TCM-derived GM values (r=0.99). A significant increase in GM V T was observed between morning and afternoon examinations when using secondary methods of quantification (p=0.028). For the subjects examined at the same time of the day, the absolute variability was 15.9 ± 12.2 % for the 91 minute 2TCM data. [15,16], the study was designed so that six subjects were examined in the morning and afternoon on the same day, and six subjects at the same time point on two different days. Conclusions Methods SubjectsThe study was conducted at the Karolinska University Hospital, Solna, Sweden and was approved by the regional Ethics Committee in Stockholm and the Radiation Safety Committee at the Karolinska University Hospital, Stockholm.Subjects were recruited by advertisement and provided written informed consent. They were healthy according to medical history, clinical examination and routine laboratory tests in blood and urine. All subjects were assessed by a senior psychiatrist (K.C.), using the Mini International Neuropsychiatric Interview (MINI) for psychiatric diagnoses. None of the subjects had previously been exposed to psychopharmacological medication. Furthermore, a negative illegal drug screening test was ascertained in all subjects, prior to PET examination. None of the subjects were on any medication at the time of the study. No brain abnormality was detected on magnetic resonance imaging (MRI), as evaluated by a neuroradiologist at the MR-centre, Karolinska University Hospital, Solna.As demonstrated both in vitro and in vivo, [ 11 C]PBR28 binding is influenced by an identified single point mutation in the TSPO gene [8,17]. At screening, a blood sample was collected and genotyping was performed according to the description below. In total, 15 subjects were recruited. Of these, one was a low affinity binder (LAB) and was therefore excluded from the analysis. Two additional subjects were excluded due to technical issues with the PET measurements. The remaining twelve subjects were six men and six women, with a mean age of 23.9 SD ± 3.1 years. Six were high affinity binders ...

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 [C]PBR28. Gray matter (GM) volume of distribution (V) 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 [C]PBR28 binding, and gender. There was a significant reduction of [C]PBR28 V in patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM V 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.

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 [ 11 C]PBR28. Methods [ 11 C]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. Electronic supplementary material The online version of this article (10.1007/s00259-019-04403-7) contains supplementary material, which is available to authorized users.

Microglia, the resident macrophages in the central nervous system, are thought to be maintained by a local self-renewal mechanism. Although preclinical and in vitro studies have suggested that the brain may contain immune cells also from peripheral origin, the functional association between immune cells in the periphery and brain at physiological conditions is poorly understood. We examined 32 healthy individuals using positron emission tomography (PET) and [(11)C]PBR28, a radioligand for the 18-kDa translocator protein (TSPO) which is expressed both in brain microglia and blood immune cells. In 26 individuals, two measurements were performed with varying time intervals. In a subgroup of 19 individuals, of which 12 had repeat examinations, leukocyte numbers in blood was measured on each day of PET measurements. All individuals were genotyped for TSPO polymorphism and categorized as high, mixed, and low affinity binders. We assessed TSPO binding expressed as total distribution volume of [(11)C]PBR28 in brain and in blood cells. TSPO binding in brain was strongly and positively correlated to binding in blood cells both at baseline and when analyzing change between two PET examinations. Furthermore, there was a significant correlation between change of leukocyte numbers and change in TSPO binding in brain, and a trend-level correlation to change in TSPO binding in blood cells. These in vivo findings indicate an association between immunological cells in blood and brain via intact BBB, suggesting a functional interaction between these two compartments, such as interchange of peripherally derived cells or a common regulatory mechanism. Measurement of radioligand binding in blood cells may be a way to control for peripheral immune function in PET studies using TSPO as a marker of brain immune activation.

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.

Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson's disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.

These data demonstrate activation of monocytes in FEP and strengthens the idea of an immune dysfunction of psychotic disorders. Further studies are required to perceive a role of YKL-40 and MCP-1 in the initiation and progression of schizophrenia.