Neuroinflammation as measured by positron emission tomography in patients with recent onset and established schizophrenia: implications for immune pathogenesis

From Springer Nature via Jisc Publications RouterHistory: received 2020-01-06, rev-recd 2020-06-09, accepted 2020-06-18, registration 2020-06-19, pub-electronic 2020-06-30, online 2020-06-30, pub-print 2021-09Publication status: PublishedFunder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265; Grant(s): MR/K020803/1, MR/K020803/1, MR/K020803/1, MR/K020803/1, MR/K020803/1Abstract: Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO), which is upregulated in activated microglia, is a method for investigating whether immune activation is evident in the brain of adults with schizophrenia. This study aimed to measure TSPO availability in the largest patient group to date, and to compare it between patients with recent onset (ROS) and established (ES) schizophrenia. In total, 20 ROS patients (14 male), 21 ES (13 male), and 21 healthy controls completed the study. Patients were predominantly antipsychotic-medicated. Participants underwent a PET scan using the TSPO-specific radioligand [11C](R)-PK11195. The primary outcome was binding potential (BPND) in the anterior cingulate cortex (ACC). Secondary outcomes were BPND in six other regions. Correlations were investigated between TSPO availability and symptom severity. Data showed that mean BPND was higher in older (ES and controls) compared with younger (ROS and controls) individuals, but did not significantly differ between ROS or ES and their respective age-matched controls (ACC; ANOVA main effect of diagnosis: F1,58 = 0.407, p = 0.526). Compared with controls, BPND was lower in antipsychotic-free (n = 6), but not in medicated, ROS patients. BPND in the ES group was negatively correlated with positive symptoms, and positively correlated with negative symptom score. Our data suggest ageing is associated with higher TSPO but a diagnosis of schizophrenia is not. Rather, subnormal TSPO levels in drug-free recent-onset patients may imply impaired microglial development and/or function, which is counteracted by antipsychotic treatment. The development of novel radioligands for specific immune-mechanisms is needed for further clarification

Validation of the Portuguese version of the Community Assessment of Psychic Experiences and characterization of psychotic experiences in a Brazilian sample

Objective: We investigated: i) the reliability and validity of a Brazilian version of the Community Assessment of Psychic Experiences (CAPE), developed to detect and characterize psychotic experiences in the general population; and ii) the association between psychotic experiences, childhood adversity, and cannabis use in a population-based sample. Methods: We performed factorial analyses and generalized linear models with CAPE scores as the dependent variable in a sample composed of 217 first-episode psychosis patients, 104 unaffected biological siblings, and 319 non-psychotic population-based participants. Results: After removing seven items from its positive dimension and two items from its negative dimension, a 33-item Brazilian version of the CAPE showed acceptable adjustment indices (confirmatory fit index = 0.895; goodness of fit index = 0.822; parsimony goodness of fit index = 0.761; root mean square error of approximation [RMSEA] = 0.055, p [RMSEA p 0.05] = 0.04) and internal consistency in all its dimensions (4 0.70). Childhood adversity was associated with higher scores in all three dimensions, as well as with total score. Lifetime cannabis use was associated with higher scores only in the positive dimension. Conclusion: The proposed Brazilian version of the CAPE corroborates the tridimensional approach for assessing psychosis-proneness, and the frequency and severity of psychotic manifestations are distributed as a spectrum in the general population.FAPESP; CNPq; FC-Z; DLR; Fundação para a Ciência e a Tecnologia-FCT; FEDERinfo:eu-repo/semantics/publishedVersio

Plasma prevalence of anti-N-methyl-d-aspartate receptor IgG antibodies in early stages of psychosis.

We investigated the feasibility of including plasma anti-NMDAR antibody screening in the assessment of first-episode psychosis patients in an early intervention programme in the Southern hemisphere. Anti-NMDAR IgG antibodies were assessed by ELISA in 166 patients (64.0% men), 166 matched population-based controls and 76 patients' siblings (30.3% men). Fisher's exact test and ANOVA were performed. Positive anti-NMDAR antibody patients were more often observed in bipolar disorder (10.0%) than schizophrenia (2.4%) or psychotic depression (3.1%), although no significant differences were observed. Our results are not conclusive regarding the inclusion of plasma anti-NMDAR IgG antibodies in differential diagnostic protocols for psychosis

Epigenetic-mediated N -methyl-D-aspartate receptor changes in the brain of isolated reared rats

Aim: We investigated: Grin1, Grin2a, Grin2b DNA methylation; NR1 and NR2 mRNA/protein in the prefrontal cortex (PFC); and hippocampus of male Wistar rats exposed to isolation rearing. Materials & methods: Animals were kept isolated or grouped (n = 10/group) from weaning for 10 weeks. Tissues were dissected for RNA/DNA extraction and N-methyl-D-aspartate receptor subunits were analyzed using quantitative reverse transcription (RT)-PCR, ELISA and pyrosequencing. Results: Isolated-reared animals had: decreased mRNA in PFC for all markers, increased NR1 protein in hippocampus and hypermethylation of Grin1 in PFC and Grin2b in hippocampus, compared with grouped rats. Associations between mRNA/protein and DNA methylation were found for both brain areas. Conclusion: This study indicates that epigenetic DNA methylation may underlie N-methyl-D-aspartate receptor mRNA/protein expression alterations caused by isolation rearing

Prolonged Periods of Social Isolation From Weaning Reduce the Anti-inflammatory Cytokine IL-10 in Blood and Brain

Life stressors during critical periods are reported to trigger an immune dysfunction characterised by abnormal production of inflammatory cytokines. Despite the relationship between early stressors and schizophrenia is described, the evidence on inflammatory biomarkers remains limited. We aimed to investigate whether an imbalance between pro- and anti-inflammatory cytokines in the brain is reflected in the peripheral blood of rats submitted to post-weaning social isolation (pwSI), a model with validity to study schizophrenia. We evaluated pro- and anti-inflammatory cytokines (IL-6, TNF-α, and IL-10) simultaneously at blood, prefrontal cortex and hippocampal tissues (Milliplex MAP), including the respective cytokines gene expression (mRNA) (qRT-PCR TaqMan mastermix). We also performed a correlation matrix to explore significant correlations among cytokines (protein and mRNA) in blood and brain, as well as cytokines and total number of square crossings in the open field for isolated-reared animals. Male Wistar rats (n = 10/group) were kept isolated (n = 1/cage) or grouped (n = 3–4/cage) since weaning for 10 weeks. After this period, rats were assessed for locomotion and sacrificed for blood and brain cytokines measurements. Prolonged pwSI decreased IL-10 protein and mRNA in the blood, and IL-10 protein in the hippocampus, along with decreased IL-6 and its mRNA expression in the prefrontal cortex. Our results also showed that cytokines tend to correlate to one-another among the compartments investigated, although blood and brain correlations are far from perfect. IL-10 hippocampal levels were negatively correlated with hyperlocomotion in the open field. Despite the unexpected decrease in IL-6 and unchanged TNF-α levels contrast to the expected pro-inflammatory phenotype, this may suggest that reduced anti-inflammatory signalling may be critical for eliciting abnormal behaviour in adulthood. Altogether, these results suggest that prolonged early-life adverse events reduce the ability to build proper anti-inflammatory cytokine that is translated from blood-to-brain

Lifetime cannabis use and childhood trauma associated with CNR1 genetic variants increase the risk of psychosis: findings from the STREAM study

Objectives: Gene-environment interactions increase the risk of psychosis. The objective of this study was to investigate gene-gene and gene-environment interactions in psychosis, including single nucleotide variants (SNVs) of dopamine-2 receptor (D2R), N-methyl-d-aspartate receptor (NMDAR), and cannabinoid receptor type 1 (CB1R), lifetime cannabis use, and childhood trauma. Methods: Twenty-three SNVs of genes encoding D2R (DRD2: rs1799978, rs7131056, rs6275), NMDAR (GRIN1: rs4880213, rs11146020; GRIN2A: rs1420040, rs11866328; GRIN2B: rs890, rs2098469, rs7298664), and CB1R (CNR1: rs806380, rs806379, rs1049353, rs6454674, rs1535255, rs2023239, rs12720071, rs6928499, rs806374, rs7766029, rs806378, rs10485170, rs9450898) were genotyped in 143 first-episode psychosis patients (FEPp) and 286 communitybased controls by Illumina HumanCoreExome-24 BeadChip. Gene-gene and gene-environment associations were assessed using nonparametric Multifactor Dimensionality Reduction software. Results: Single-locus analyses among the 23 SNVs for psychosis and gene-gene interactions were not significant (p 4 0.05 for all comparisons); however, both environmental risk factors showed an association with psychosis (p o 0.001). Moreover, gene-environment interactions were significant for an SNV in CNR1 and cannabis use. The best-performing model was the combination of CNR1 rs12720071 and lifetime cannabis use (p o 0.001), suggesting an increased risk of psychosis. Conclusion: Our study supports the hypothesis of gene-environment interactions for psychosis involving T-allele carriers of CNR1 SNVs, childhood trauma, and cannabis use

Estresse precoce e inflamação nas psicoses: da bancada à pesquisa de base populacional

Epidemiological studies suggest an interaction between biological and environmental factors in the development of psychoses and early-life stress constitutes an important risk factor. Recently, significant attention has been given to the inflammatory hypothesis of psychoses; yet, investigations on the relationship between early-life stress, inflammation and psychoses are scarce. We aimed to investigate associations between early-life stress and inflammatory cytokines in a preclinical model of schizophrenia (post-weaning social isolation), as well as in a clinical study of first-episode psychosis (FEP) patients, unaffected siblings and communitybased controls. i) Preclinical study: male Wistar rats (n=20) were submitted to post-weaning social isolation for 10 weeks. After that, rats were assessed for locomotion in the open field (20 minutes) and euthanised for cytokines measurement. Cytokines protein and gene expression (IL-6, TNF-?, IL-10) were measured in the peripheral blood as well as in the prefrontal cortex and hippocampus. Social isolated rats had decreased IL-10 protein and gene expression in the blood and decreased IL-10 protein in the hippocampus. We also observed reduced IL-6 protein and gene expression in the prefrontal cortex. IL-10 hippocampal levels were negatively correlated with hyperlocomotion in the open field. Although the unexpected decrease in IL-6 and unchanged TNF-? levels contrast to the expected pro-inflammatory phenotype, this may suggest that reduced anti-inflammatory signalling may be critical for eliciting abnormal behaviour in adulthood. Altogether, these results suggest that prolonged early-life adverse events reduce the anti-inflammatory cytokine IL-10 and this is translated from blood-to-brain. ii) Clinical study: we recruited 114 first-episode psychosis (FEP) patients, 57 unaffected siblings of FEP patients, and 251 community-based controls. Cytokines plasma levels (IL-1?, TNF-?, IFN-?, IL-6, IL-4, IL-10 and TGF-?) were measured and differences across the three groups analysed after controlling for age, gender, body mass index and tobacco smoking. Childhood maltreatment was measured by the Childhood Trauma Questionnaire and plasma cytokines by multiplex. FEP had significantly higher levels of IL-6, TNF-?, IL-10 and TGF-? when compared with controls, and also higher levels of IL-1?, IL-6, TNF-?, and IL-10 whencompared with their siblings. Siblings presented decreased IL-1? when compared with controls. Physical childhood abuse was associated with increased levels of TGF-? in FEP. Experience of childhood maltreatment, specifically physical abuse, may contribute as a long-term immune priming for the TGF-? pathway in both patients and community-based controls. Normal or reduced levels of cytokines in siblings represent possibly a protective factor. In conclusion, the results from our preclinical and clinical study do not support associations between enhanced pro-inflammatory cytokines and early-life stress in psychoses. The blunted inflammatory profile found in chronic pwSI may represent stress-exposure during the latter stages of the disorder, contrasting the high inflammatory profile during earlier stages. The type and duration of adverse experiences may impact differently on the levels of inflammatory markers across different populations. Moreover, it is highly possible that the inflammatory profile reported in our clinical population arise from cumulative risk factors that will need to be explored in future investigations.Estudos epidemiológicos sugerem interações entre fatores biológicos e ambientais no desenvolvimento dos transtornos psicóticos, e o estresse precoce constitui-se um fator de risco importante. Atualmente tem-se dado grande atenção à hipótese inflamatória nas psicoses. Há uma escassez, todavia, de investigações que se concentrem na relação da tríade: estresse precoce, perfil inflamatório e psicoses. O objetivo do nosso estudo foi avaliar associações entre estresse precoce e citocinas inflamatórias em um estudo pré-clínico de esquizofrenia e em um estudo clínico envolvendo pacientes em primeiro episódio psicótico (PEP), seus irmãos e controles de base populacional. i) Estudo pré-clínico: Ratos Wistar machos (n=20) foram submetidos ao isolamento social a partir do desmame por 10 semanas. Após, os animais foram testados no campo aberto para avaliação da atividade locomotora (20 minutos) e eutanasiados para a mensuração das citocinas. A expressão proteica e gênica das citocinas (IL-6, TNF-?, IL- 10) foi mensurada no sangue periférico, no córtex pré-frontal e hipocampo. Ratos isolados apresentaram redução da expressão proteica e gênica de IL-10 no sangue, bem como redução proteica desta citocina no hipocampo. No córtex pré-frontal, houve redução da expressão proteica e gênica de IL-6. Correlação negativa foi observada entre os níveis de IL-10 no hipocampo com a atividade locomotora dos animais isolados. Embora reduções de IL-6 e ausência de alterações de TNF-? contrastem o perfil pró-inflamatório esperado, nossos resultados sugerem que a redução de IL-10 pode ser um fator crítico para a ocorrência de alterações comportamentais na vida adulta. ii) Estudo clínico: Foram recrutados 114 pacientes, 57 irmãos e 251 controles de base populacional residentes na região de Ribeirão Preto. As citcocinas (IL-1?, TNF-?, IFN-?, IL-6, IL-4, IL-10 and TGF-?) foram mensuradas no plasma e todos os participantes responderam ao Childhood Trauma Questionnaire para investigar a ocorrência de traumas na infância. Todas as análises foram controladas para variáveis de confusão (idade, sexo, índice de massa corpórea e uso de tabaco). Pacientes apresentaram elevados níveis de IL-6, TNF-?, IL-10 e TGF-? quando comparados aos controles, e altos níveis de IL-1?, IL-6, TNF-?, e IL-10 quando comparados com seus irmãos. Os irmãos apresentaramníveis reduzidos de IL-1? quando comparados com os controles. O abuso físico foi associado com altos níveis de TGF-? nos pacientes. Experiências traumáticas na infância, em especial o abuso físico, parece modular os níveis de TGF-? entre os diferentes diagnósticos. A ausência de alterações ou redução de citocinas nos irmãos sugere um efeito protetor. Em conclusão, os resultados dos nossos estudos pré-clínico e clínico não suportam associações entre citocinas pró-inflamatórias e estresse precoce no contexto das psicoses. O perfil inflamatório observado no modelo pré-clínico parece representar fases tardias da psicose, em contraste ao perfil inflamatório observado durante os estágios iniciais do transtorno. O tipo e a duração da exposição aos eventos adversos parecem modular de maneira distinta as concentrações de citocinas entre as diferentes populações estudadas. No entanto, é provável que o perfil inflamatório observado em nossa população clínica advenha de fatores de risco cumulativos que precisam ser explorados em futuras investigações