K. Collste

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

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.

In vivo evidence of a functional association between immune cells in blood and brain in healthy human subjects.

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.

CSF GABA is reduced in first-episode psychosis and associates to symptom severity

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.

Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium

Based on the role of the superior temporal gyrus (STG) in auditory processing, language comprehension and self‐monitoring, this study aimed to investigate the relationship between STG cortical thickness and positive symptom severity in schizophrenia.

Cerebrospinal fluid levels of sphingolipids associate with disease severity in first episode psychosis patients

Alterations in brain lipid composition have been described in schizophrenia (Hamazaki et al., 2015; Schmitt et al., 2004; Amminger et al., 2012), a disease characterized by positive and negative symptoms as well as with deficits in cognitive function (Fatouros-Bergman et al., 2014). Specifically, decreased levels of sphingomyelins and hexosylceramides in thalamus (Schmitt et al., 2004) and reduced gene expression of the sphingolipid pathway in prefrontal cortical samples (Narayan et al., 2009) have been described, as well as an association between sphingomyelin levels in red blood cell (RBC) membranes and symptom severity (Tessier et al., 2016). Sphingomyelins and hexosylceramides (Supplemental Material) are sphingolipids that possess structural as well as signaling functions in the brain. In a previous study (Checa et al., 2015), we found increased levels of HexCer24:1 in the cerebrospinalfluid (CSF) of patientswith schizophrenia,who served as part of the disease control group. This led us to hypothesize that the observed alterations may form part of pathophysiological mechanisms of the disease. Using liquid chromatography tandemmass spectrometry (Supplementary Material) we measured CSF levels of HexCer24:1 in cohortswith first episode psychosis (FEP) patients, chronic schizophrenia, or schizoaffective disorder. Levels of other hexosylceramides and sphingomyelins were measured as an exploratory aim. FEP patients (n = 44) were recruited within the Karolinska Schizophrenia Project (Orhan et al., 2017), whereas chronic patients (n = 23) were included from Linköping (Skogh et al., 2011). Twenty-five of 44 FEP patientswere drug naïve to antipsychoticmedication. Psychotic symptoms and global functioningwere assessed andmeasuredwith Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF) and Clinical Global Impression (CGI). In the FEP cohort, patients on antipsychotic medication presented lower GAF symptoms scores relative to drug-naïve patients (p= 0.026) and higher CGI scores (p = 0.077), indicating a more severe stage of the disease (Supplementary Material). All chronic patients were on treatment with oral olanzapine. Sphingolipids from two control groups of healthy volunteers, age-matched with FEP patients and patients with chronic schizophrenia were analyzed (n= 20 and n= 10, respectively). CSF levels of sphingolipids did not differ between FEP patients and healthy controls or between chronic patients and healthy controls (Table 1). Amongst FEP patients, the levels of HexCer24:1 (p = 0.011) were higher in patients that had received antipsychotic treatment

Increased number of monocytes and plasma levels of MCP-1 and YKL-40 in first-episode psychosis

Accumulating evidence implicates immune activation in the development of schizophrenia. Here, monocyte numbers, monocyte chemoattractant protein‐1 (MCP‐1) and chitinase‐3‐like protein 1 (YKL‐40) were investigated in plasma and cerebrospinal fluid (CSF) in first‐episode psychosis (FEP) patients.

Cognitive Performance in Drug-naÏve First Episode Schizophrenia (FES) Patients

Introduction A majority of the studies on cognition in schizophrenia have been conducted in drug-treated patients. In healthy subjects, administration of antipsychotic medication has been found to have a negative impact on cognitive performance in domains such as speed of processing and attention. Antipsychotic drugs occupy the D2-dopamine receptor, a receptor subtype that has been related to cognitive function. Studies employing Positron Emission Tomography have shown that poor performance in several cognitive domains is associated to low D2-receptor binding. It is therefore crucial to examine cognition in drug-naive patients with schizophrenia. Objectives In FES patients: To examine the profile of cognitive impairments in the absence of antipsychotic medication and compare with the cognitive profile of patients who are on antipsychotic medication. Aims To study cognition in FES. Methods The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery was administered to 60 patients with early schizophrenia and 30 healthy controls, 50% of the patients were drug-naive. This research is ongoing and a part of the Karolinska Schizophrenia Project (KaSP), a multidisciplinary research consortium that examines the pathophysiology of schizophrenia. Results Preliminary findings show that patients perform worse than healthy controls in all cognitive domains, with no significant differences between drug-naive and medicated patients. Attention and Visual memory were the domains with the greatest impairments. The results are compared with our previous meta-analytic findings in drug-naive patients. Conclusion These preliminary findings confirm the existence of cognitive impairments at the early stage of schizophrenia in the absence of antipsychotic medication.