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BackgroundIn psychotic and mood disorders, immune alterations are hypothesized to underlie cognitive symptoms, as they have been associated with elevated blood levels of inflammatory cytokines, kynurenine metabolites, and markers of microglial activation. The current meta-analysis synthesizes all available clinical evidence on the associations between immunomarkers (IMs) and cognition in these psychiatric illnesses.MethodsPubmed, Web of Science, and Psycinfo were searched for peer-reviewed studies on schizophrenia spectrum disorder (SZ), bipolar disorder (BD), or major depressive disorder (MDD) including an association analysis between at least one baseline neuropsychological outcome measure (NP) and one IM (PROSPERO ID:CRD42021278371). Quality assessment was performed using BIOCROSS. Correlation meta-analyses, and random effect models, were conducted in Comprehensive Meta-Analysis version 3 investigating the association between eight cognitive domains and pro-inflammatory and anti-inflammatory indices (PII and AII) as well as individual IM.ResultsSeventy-five studies (n = 29,104) revealed global cognitive performance (GCP) to be very weakly associated to PII (r = −0.076; p = 0.003; I2 = 77.4) or AII (r = 0.067; p = 0.334; I2 = 38.0) in the combined patient sample. Very weak associations between blood–based immune markers and global or domain-specific GCP were found, either combined or stratified by diagnostic subgroup (GCP x PII: SZ: r = −0.036, p = 0.370, I2 = 70.4; BD: r = −0.095, p = 0.013, I2 = 44.0; MDD: r = −0.133, p = 0.040, I2 = 83.5). We found evidence of publication bias.DiscussionThere is evidence of only a weak association between blood-based immune markers and cognition in mood and psychotic disorders. Significant publication and reporting biases were observed and most likely underlie the inflation of such associations in individual studies.

IntroductionIn schizophrenia, abnormal synaptic pruning during adolescence may be due to an altered Complement system activity. While this hypothesis is supported by C4 overexpression in various brain regions of individuals with schizophrenia, such alterations should be replicated and extended to other brain regions relevant to schizophrenia. Moreover, transcriptional studies of genes coding for proteins regulating the Complement system activity are lacking. Furthermore, it remains unknown whether cerebral and peripheral expression of C4 and Complement control proteins (CCP) are related.ObjectivesTo identify altered expression of C4 and CCP (CSMD1, CSMD2, CD46) coding genes at the cerebral and peripheral levels in schizophrenic individuals.MethodsWe explored C4 and CCP coding genes expression at the cerebral and peripheral levels. Using shinyGEO application we analyzed gene expression from eight Gene Expression Omnibus datasets obtained from 196 schizophrenic individuals and 182 control subjects. First, we compared gene expression between schizophrenic patients and controls in postmortem cerebral samples from 7 different brain regions. Then, we compared gene expression between schizophrenic patients and controls in 4 peripheral tissues.ResultsWe observed C4 overexpression in the DLPFC, parietal, temporal cortex and associative striatum of schizophrenic individuals. We report altered transcriptional patterns of CCP genes in the DLPFC, hippocampus and cerebellum of schizophrenic individuals. CD46 expression was altered in opposite directions between brain and blood of schizophrenic individuals. No significant alteration of C4 expression was observed in peripheral tissues.ConclusionsOur results support the hypothesis of an altered Complement system activity in various brain regions of schizophrenic individuals which may disrupt the synaptic pruning process during adolescence.DisclosureNo significant relationships.

This paper presents a method for automatic segmentation of white matter fiber bundles from massive dMRI tractography datasets. The method is based on a multi-subject bundle atlas derived from a two-level intra-subject and inter-subject clustering strategy. This atlas is a model of the brain white matter organization, computed for a group of subjects, made up of a set of generic fiber bundles that can be detected in most of the population. Each atlas bundle corresponds to several inter-subject clusters manually labeled to account for subdivisions of the underlying pathways often presenting large variability across subjects. An atlas bundle is represented by the multi-subject list of the centroids of all intra-subject clusters in order to get a good sampling of the shape and localization variability. The atlas, composed of 36 known deep white matter bundles and 47 superficial white matter bundles in each hemisphere, was inferred from a first database of 12 brains. It was successfully used to segment the deep white matter bundles in a second database of 20 brains and most of the superficial white matter bundles in 10 subjects of the same database. [Display omitted] ► We propose an automatic and robust method for fiber bundle segmentation in massive tractography datasets. ► The method is based on a novel HARDI multi-subject human brain fiber bundle atlas, composed of 36 known deep white matter bundles. ► The atlas also contains 47 superficial white matter bundles in each hemisphere, included in a multisubject bundle atlas for the first time. ► The method considers the fiber shape, position and length information in the segmentation, leading to better results than ROI-based approaches. ► Results can be used for population studies where each generic bundle is analyzed separately.

IntroductionSchizophrenia and bipolar disorder are severe mental illnesses that are known to have a considerable overlap in underlying pathophysiological mechanisms. More specifically, disturbances in the kynurenine pathway have been hypothesized as processes bridging altered immune responses and clinical manifestations of these illnesses.ObjectivesThe aim of this study was to investigate the abnormalities in serum kynurenine metabolites in schizophrenic and bipolar patients and the impact of clinical factors.MethodsFour patient groups were included in the current study: 1) Acute bipolar inpatients (n=205); 2) stable bipolar outpatients (n=116); 3) acute schizophrenia inpatients (n=111) and 4) stable schizophrenia outpatients (n=75); and one healthy control group (n=185). Clinical symptoms were established using symptom severity scales. The quantitative determination of serum kynurenine metabolites was performed using LC-MS/MS. General linear model and multivariate linear regression analyses were used to perform the statistical analysis with JMP Pro 15.ResultsIn line with previous research, the results indicate that serum kynurenine metabolites are disturbed in schizophrenic and bipolar patients compared to healthy controls. Whereas no differences were observed between schizophrenia and bipolar disorder, illness state and duration of illness clearly impacted kynurenine metabolite levels. Acutely ill patients had significantly lower levels compared to stable patients, which seemed to be driven by psychotic symptoms.ConclusionsTo conclude, the results confirm the involvement of the kynurenine pathway in the pathophysiology of schizophrenia and bipolar disorder by lowered peripheral kynurenine metabolite level. In addition, an important role of acute psychotic symptoms and longer illness duration on these metabolite aberrances is demonstrated.DisclosureNo significant relationships.

IntroductionThe synaptic pruning process is based on the joint action of the complement system and microglia. In schizophrenia, accumulating evidence support that abnormal synaptic pruning during adolescence may be due to an altered Complement system activity. While this hypothesis is supported by C4 overexpression in various brain regions of individuals with schizophrenia, such alterations should be replicated and extended to other brain regions. Moreover, transcriptional studies of genes encoding regulators of the complement system activity (complement control proteins, CCP) and microglia-specific genes are lacking. Furthermore, it remains unknown whether brain and peripheral expression of such genes are related.ObjectivesTo explore expression of C4 as well as 4 CCP encoding genes and 10 microglia-specific genes at the brain and peripheral levels in individuals with schizophrenia as compared to healthy controls.MethodsWe analyzed candidate gene expression from 9 Gene Expression Omnibus datasets obtained from 333 individuals with schizophrenia and 306 healthy controls (HC). We first compared expression of the candidate genes between individuals with schizophrenia and HC in postmortem brain samples from 7 different brain regions. Then, the same comparison was made in 4 different peripheral tissues.ResultsRegarding the complement system, we observed C4 overexpression in the DLPFC, parietal, temporal cortex and associative striatum of individuals with schizophrenia. We report distinct altered expression patterns of CCP genes in the DLPFC, hippocampus and cerebellum of individuals with schizophrenia. Only CD46 expression was altered in the blood of individuals with schizophrenia. Regarding microglia, we report an underexpression of several microglia-specific genes in the cerebellum, associative striatum, hippocampus and parietal cortex of individuals with schizophrenia vs. HC. At the peripheral level, we observed a mixed altered expression pattern in the whole blood of individuals with schizophrenia.ConclusionsFirstly, our results suggest that the CCP-mediated regulatory mechanisms of the Complement system are impaired in the brain of individuals with schizophrenia, potentially contributing to an excessive Complement system activity (CSA). Secondly, our results support the hypothesis of a widespread underexpression of microglia-specific genes in brain tissues of individuals with schizophrenia. Functionally, the observed transcriptional alterations may be related to the synaptic pruning impairment. Alternatively, they may translate a compensatory mechanism for neuroinflammation. In the whole blood, the altered transcriptional pattern may represent a potential peripheral signature of SZ.Disclosure of InterestNone Declared

Elevated whole-blood serotonin and decreased plasma melatonin (a circadian synchronizer hormone that derives from serotonin) have been reported independently in patients with autism spectrum disorders (ASDs). Here, we explored, in parallel, serotonin, melatonin and the intermediate N -acetylserotonin (NAS) in a large cohort of patients with ASD and their relatives. We then investigated the clinical correlates of these biochemical parameters. Whole-blood serotonin, platelet NAS and plasma melatonin were assessed in 278 patients with ASD, their 506 first-degree relatives (129 unaffected siblings, 199 mothers and 178 fathers) and 416 sex- and age-matched controls. We confirmed the previously reported hyperserotonemia in ASD (40% (35–46%) of patients), as well as the deficit in melatonin (51% (45–57%)), taking as a threshold the 95th or 5th percentile of the control group, respectively. In addition, this study reveals an increase of NAS (47% (41–54%) of patients) in platelets, pointing to a disruption of the serotonin-NAS–melatonin pathway in ASD. Biochemical impairments were also observed in the first-degree relatives of patients. A score combining impairments of serotonin, NAS and melatonin distinguished between patients and controls with a sensitivity of 80% and a specificity of 85%. In patients the melatonin deficit was only significantly associated with insomnia. Impairments of melatonin synthesis in ASD may be linked with decreased 14-3-3 proteins. Although ASDs are highly heterogeneous, disruption of the serotonin-NAS–melatonin pathway is a very frequent trait in patients and may represent a useful biomarker for a large subgroup of individuals with ASD.

IntroductionA 10-15 years decrease in life expectancy has been observed in individuals with bipolar disorder (BD) and has been associated with premature cellular aging, but mechanisms involved remain unclear. Our team recently identified a subgroup of young individuals with prematurely shortened telomere length (TL).ObjectivesThe aims of the present study were to replicate this observation in a larger sample and to analyze the expression levels of genes associated with age or TL in a subsample of these individuals.MethodsTL was measured by qPCR using peripheral blood DNA from 542 individuals with BD. Clustering analyzes were performed with age and TL as classification variables to identify similar groups.Gene expression of 29 genes, including 20 associated with age and 9 with TL, was analyzed by RT-qPCR using peripheral blood RNA in a subgroup of 129 individuals. Gene expressions were compared between groups obtained from the previous clustering analyzes by Kruskal-Wallis and Mann-Whitney tests.ResultsClustering analyzes identified 3 subgroups and replicated the clustering previously described: a subgroup of aged individuals with a low TL (mean age : 51.73 years ; mean TL : 2), a subgroup of young individuals with a high TL (mean age : 29.02 years ; mean TL : 4.36) and a subgroup of young individuals but with a low TL (mean age : 29.64 years ; mean TL : 1.96). None of the tested clinical variables were significantly associated with this subgroup.Furthermore, gene expression level analyzes showed that only POT1 expression was different between the two subgroups of young individuals, with a downregulation of POT1 expression in the subgroup with a lower TL level. POT1 is a protein involved in the maintenance of TL. POT1 binds to another protein TPP1 allowing the recruitment of telomerase, the enzyme which extends TL. Our hypothesis is that in the subgroup presenting a lower POT1 expression, the POT1-TPP1 complex cannot form and thus prevents telomerase recruitment and TL elongation.ConclusionsThis study confirms, on a larger sample, the existence of a subgroup of young individuals with BD presenting accelerated cellular aging. The observed decrease of POT1 expression level suggests a newly described cellular mechanism in individuals with BD, that may contribute to telomere shortening.Disclosure of InterestNone Declared

Many studies have shown associations between a history of childhood trauma and more severe or complex clinical features of bipolar disorders (BD), including suicide attempts and earlier illness onset. However, the psychopathological mechanisms underlying these associations are still unknown. Here, we investigated whether affective lability mediates the relationship between childhood trauma and the severe clinical features of BD. A total of 342 participants with BD were recruited from France and Norway. Diagnosis and clinical characteristics were assessed using the Diagnostic Interview for Genetic Studies (DIGS) or the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I). Affective lability was measured using the short form of the Affective Lability Scale (ALS-SF). A history of childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Mediation analyses were performed using the SPSS process macro. Using the mediation model and covariation for the lifetime number of major mood episodes, affective lability was found to statistically mediate the relationship between childhood trauma experiences and several clinical variables, including suicide attempts, mixed episodes and anxiety disorders. No significant mediation effects were found for rapid cycling or age at onset. Our data suggest that affective lability may represent a psychological dimension that mediates the association between childhood traumatic experiences and the risk of a more severe or complex clinical expression of BD.

Purpose of Review A global study of multimorbidity in schizophrenia, especially of the association with physical conditions, might offer much needed etiological insights. Recent Findings Our review suggests that life-style factors and medication related to schizophrenia are only part of the explanation of the increase in risk for cardiovascular, metabolic, pulmonary disorders, and some cancers. Positive associations with autoimmune disorders (with the exception of rheumatoid arthritis) and epilepsy are promising avenues of research but to date have not been fully exploited. The same holds for the negative comorbidity seen for rheumatoid arthritis and some cancers (e.g., prostate). Summary As a whole, our review suggests that most of the explored conditions have a different prevalence in schizophrenia than in the general population. Several hypotheses emerged from this review such as the role of immune and genetic factors, of sex hormones, and of more general variability factors.

Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity. Recent studies of rare structural and sequence variants have identified hundreds of loci involved in ASD, but our knowledge of the overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory action in immature neurons. GlyRs containing the α2 subunit are highly expressed in the embryonic brain, where they promote cortical interneuron migration and the generation of excitatory projection neurons. We previously identified a rare microdeletion of the X-linked gene GLRA2, encoding the GlyR α2 subunit, in a boy with autism. The microdeletion removes the terminal exons of the gene ( GLRA2 Δex8–9 ). Here, we sequenced 400 males with ASD and identified one de novo missense mutation, p.R153Q, absent from controls. In vitro functional analysis demonstrated that the GLRA2 Δex8 – 9 protein failed to localize to the cell membrane, while the R153Q mutation impaired surface expression and markedly reduced sensitivity to glycine. Very recently, an additional de novo missense mutation (p.N136S) was reported in a boy with ASD, and we show that this mutation also reduced cell-surface expression and glycine sensitivity. Targeted glra2 knockdown in zebrafish induced severe axon-branching defects, rescued by injection of wild type but not GLRA2 Δex8–9 or R153Q transcripts, providing further evidence for their loss-of-function effect. Glra2 knockout mice exhibited deficits in object recognition memory and impaired long-term potentiation in the prefrontal cortex. Taken together, these results implicate GLRA2 in non-syndromic ASD, unveil a novel role for GLRA2 in synaptic plasticity and learning and memory, and link altered glycinergic signaling to social and cognitive impairments.