Cytomegalovirus antibodies are associated with mood disorders, suicide, markers of neuroinflammation, and microglia activation in postmortem brain samples.

Cytomegalovirus (CMV) is a common, neurotrophic herpesvirus that can be reactivated by inflammation and cause central nervous system disease. We hypothesize that CMV may contribute to the neuroinflammation that underlies some psychiatric disorders by (1) exacerbating inflammation through the induction of anti-viral immune responses, and (2) translating peripheral inflammation into neuroinflammation. We investigated whether the presence of anti-CMV antibodies in blood were associated with mental illness, suicide, neuroinflammation, and microglial density in the dorsolateral prefrontal cortex (DLPFC) in postmortem samples. Data (n = 114 with schizophrenia; n = 78 with bipolar disorder; n = 87 with depression; n = 85 controls) were obtained from the Stanley Medical Research Institute. DLPFC gene expression data from a subset of 82 samples were categorized into "high" (n = 30), and "low" (n = 52) inflammation groups based on a recursive two-step cluster analysis using expression data for four inflammation-related genes. Measurements of the ratio of non-ramified to ramified microglia, a proxy of microglial activation, were available for a subset of 49 samples. All analyses controlled for age, sex, and ethnicity, as well as postmortem interval, and pH for gene expression and microglial outcomes. CMV seropositivity significantly increased the odds of a mood disorder diagnosis (bipolar disorder: OR = 2.45; major depression: OR = 3.70) and among the psychiatric samples, of suicide (OR = 2.09). Samples in the upper tercile of anti-CMV antibody titers were more likely to be members of the "high" inflammation group (OR = 4.41, an effect driven by schizophrenia and bipolar disorder samples). CMV positive samples also showed an increased ratio of non-ramified to ramified microglia in layer I of the DLPFC (Cohen's d = 0.81) as well as a non-significant increase in this ratio for the DLPFC as a whole (d = 0.56). The results raise the possibility that the reactivation of CMV contributes to the neuroinflammation that underlies some cases of psychiatric disorders.

Prospects and Pitfalls of Plasma Complement C4 in Schizophrenia: Building a Better Biomarker.

Complex brain disorders like schizophrenia may have multifactorial origins related to mis-timed heritable and environmental factors interacting during neurodevelopment. Infections, inflammation, and autoimmune diseases are over-represented in schizophrenia leading to immune system-centered hypotheses. Complement component C4 is genetically and neurobiologically associated with schizophrenia, and its dual activity peripherally and in the brain makes it an exceptional target for biomarker development. Studies to evaluate the biomarker potential of plasma or serum C4 in schizophrenia do so to understand how peripheral C4 might reflect central nervous system-derived neuroinflammation, synapse pruning, and other mechanisms. This effort, however, has produced mostly conflicting results, with peripheral C4 sometimes elevated, reduced, or unchanged between comparison groups. We undertook a pilot biomarker development study to systematically identify sociodemographic, genetic, and immune-related variables (autoimmune, infection-related, gastrointestinal, inflammatory), which may be associated with plasma C4 levels in schizophrenia (SCH; n = 335) and/or in nonpsychiatric comparison subjects (NCs; n = 233). As with previously inconclusive studies, we detected no differences in plasma C4 levels between SCH and NCs. In contrast, levels of general inflammation, C-reactive protein (CRP), were significantly elevated in SCH compared to NCs (ANOVA, F = 20.74, p < 0.0001), suggestive that plasma C4 and CRP may reflect different sources or causes of inflammation. In multivariate regressions of C4 gene copy number variants, plasma C4 levels were correlated only for C4A (not C4B, C4L, C4S) and only in NCs (R Coeff = 0.39, CI = 0.01-0.77, R2 = 0.18, p < 0.01; not SCH). Other variables associated with plasma C4 levels only in NCs included sex, double-stranded DNA IgG, tissue-transglutaminase (TTG) IgG, and cytomegalovirus IgG. Toxoplasma gondii IgG was the only variable significantly correlated with plasma C4 in SCH but not in NCs. Many variables were associated with plasma C4 in both groups (body mass index, race, CRP, N-methyl-D-aspartate receptor (NMDAR) NR2 subunit IgG, TTG IgA, lipopolysaccharide-binding protein (LBP), and soluble CD14 (sCD14). While the direction of most C4 associations was positive, autoimmune markers tended to be inverse, and associated with reduced plasma C4 levels. When NMDAR-NR2 autoantibody-positive individuals were removed, plasma C4 was elevated in SCH versus NCs (ANOVA, F = 5.16, p < 0.02). Our study was exploratory and confirmation of the many variables associated with peripheral C4 requires replication. Our preliminary results point toward autoimmune factors and exposure to the pathogen, T. gondii, as possibly significant contributors to variability of total C4 protein levels in plasma of individuals with schizophrenia.

Maternal autoantibody profiles as biomarkers for ASD and ASD with co-occurring intellectual disability.

Maternal autoantibody-related ASD (MAR ASD) is a subtype of autism in which pathogenic maternal autoantibodies (IgG) cross the placenta, access the developing brain, and cause neurodevelopmental alterations and behaviors associated with autism in the exposed offspring. We previously reported maternal IgG response to eight proteins (CRMP1, CRMP2, GDA LDHA, LDHB, NSE, STIP1, and YBOX) and that reactivity to nine specific combinations of these proteins (MAR ASD patterns) was predictive of ASD risk. The aim of the current study was to validate the previously identified MAR ASD patterns (CRMP1 + GDA, CRMP1 + CRMP2, NSE + STIP1, CRMP2 + STIP1, LDHA + YBOX, LDHB + YBOX, GDA + YBOX, STIP1 + YBOX, and CRMP1 + STIP1) and their accuracy in predicting ASD risk in a prospective cohort employing maternal samples collected prior to parturition. We used prenatal plasma from mothers of autistic children with or without co-occurring intellectual disability (ASD = 540), intellectual disability without autism (ID = 184) and general population controls (GP = 420) collected by the Early Markers for Autism (EMA) study. We found reactivity to one or more of the nine previously identified MAR ASD patterns in 10% of the ASD group compared with 4% of the ID group and 1% of the GP controls (ASD vs GP: Odds Ratio (OR) = 7.81, 95% Confidence Interval (CI) 3.32 to 22.43; ASD vs ID: OR = 2.77, 95% CI (1.19-7.47)) demonstrating that the MAR ASD patterns are strongly associated with the ASD group and could be used to assess ASD risk prior to symptom onset. The pattern most strongly associated with ASD was CRMP1 + CRMP2 and increased the odds for an ASD diagnosis 16-fold (3.32 to >999.99). In addition, we found that several of these specific MAR ASD patterns were strongly associated with ASD with intellectual disability (ASD + ID) and others associated with ASD without ID (ASD-no ID). Prenatal screening for these MAR patterns may lead to earlier identification of ASD and facilitate access to the appropriate early intervention services based on each child's needs.

Homeostatic regulation of neuronal excitability by probiotics in male germ-free mice.

Emerging evidence indicates that probiotics can influence the gut-brain axis to ameliorate somatic and behavioral symptoms associated with brain disorders. However, whether probiotics have effects on the electrophysiological activities of individual neurons in the brain has not been evaluated at a single-neuron resolution, and whether the neuronal effects of probiotics depend on the gut microbiome status have yet to be tested. Thus, we conducted whole-cell patch-clamp recording-assisted electrophysiological characterizations of the neuronal effects of probiotics in male germ-free (GF) mice with and without gut microbiome colonization. Two weeks of treatment with probiotics (Lactobacillus rhamnosus and Bifidobacterium animalis) significantly and selectively increased the intrinsic excitability of hippocampal CA1 pyramidal neurons, whereas reconstituting gut microbiota in GF mice reversed the effects of the probiotics leading to a decreased intrinsic excitability in hippocampal neurons. This bidirectional modulation of neuronal excitability by probiotics was observed in hippocampal neurons with corresponding basal membrane property and action potential waveform changes. However, unlike the hippocampus, the amygdala excitatory neurons did not show any electrophysiological changes to the probiotic treatment in either GF or conventionalized GF mice. Our findings demonstrate for the first time how probiotic treatment can have a significant influence on the electrophysiological properties of neurons, bidirectionally modulating their intrinsic excitability in a gut microbiota and brain area-specific manner.

A hidden menace? Cytomegalovirus infection is associated with reduced cortical gray matter volume in major depressive disorder.

Human cytomegalovirus (HCMV) infection is associated with neuropathology in patients with impaired immunity and/or inflammatory diseases. However, the association between gray matter volume (GMV) and HCMV has never been examined in major depressive disorder (MDD) despite the presence of inflammation and impaired viral immunity in a subset of patients. We tested this relationship in two independent samples consisting of 179 individuals with MDD and 41 healthy controls (HC) (sample 1) and 124 MDD participants and 148 HCs (sample 2). HCMV positive (HCMV+) and HCMV negative (HCMV-) groups within each sample were balanced on up to 11 different clinical/demographic variables using inverse probability of treatment weighting. GMV of 87 regions was measured with FreeSurfer. There was a main effect of HCMV serostatus but not diagnosis that replicated across samples. Relative to HCMV- subjects, HCMV+ subjects in sample 1 showed a significant reduction of volume in six regions (puncorrected < 0.05). The reductions in GMV of the right supramarginal gyrus (standardized beta coefficient (SBC) = -0.26) and left fusiform gyrus (SBC = -0.25) in sample 1 were replicated in sample 2: right supramarginal gyrus (puncorrected < 0.05, SBC = -0.32), left fusiform gyrus (PFDR < 0.01, SBC = -0.51). Posthoc tests revealed that the effect of HCMV was driven by differences between the HCMV+ and HCMV- MDD subgroups. HCMV IgG level, a surrogate marker of viral activity, was correlated with GMV in the left fusiform gyrus (r = -0.19, Puncorrected = 0.049) and right supramarginal gyrus (r = -0.19, puncorrected = 0.043) in the HCMV+ group of sample 1. Conceivably, HCMV infection may be a treatable source of neuropathology in vulnerable MDD patients.

Expression of HLA and Autoimmune Pathway Genes in Liver Biopsies of Young Subjects With Autoimmune Hepatitis Type 1.

OBJECTIVES: To test the hypothesis that autoimmune hepatitis (AIH type I) in young subjects is due to genetic differences in proinflammatory genes responding to viral triggers in patients and controls. METHODS: Intrahepatic gene expression was compared between AIH type I (n = 24, age 9-30 years) patients (hereafter referred to as the AIH group) and controls (n = 21, age 4-25 years). RNA sequencing was performed on complementary DNA (cDNA) libraries made from total RNA extracted from formalin-fixed paraffin-embedded (FFPE) liver biopsy samples. Gene expression levels were quantified, and differentially expressed genes were functionally analyzed. Pathway analysis was performed using the databases Kyoto Encyclopedia of Genes and Genomes (KEGG) and PANTHER. The remaining sequences were mapped to the RefSeq complete set of viral genomes. RESULTS: Differential gene analysis identified 181 genes that were significantly differentially expressed (136 upregulated in the AIH group). Autoimmune pathway genes such as CD19 and CD20 which are important in B cell regulation and maturation as well as, CD8 and LY9 , which are T-cell related, were upregulated in our AIH group. Genes implicated in AIH pathogenesis including CXCL10 , which is thought to be associated with AIH severity and progression, complement genes ( C1QA, C1QB , and C1QC ), and human leucocyte antigen ( HLA ) genes ( HLA-DRB1, HLA-DRA, HLA-B , and HLA-C ) were upregulated in samples from the AIH group. Specific viral etiologies were not found. CONCLUSIONS: Unbiased next-generation sequencing and differential gene expression analysis of the AIH group has not only added support for the role of B cells in the pathogenesis and treatment of AIH but also has introduced potential new therapeutic targets: CXCL10 (anti- CXCL10 ) and several complement system-related genes.

Robust kernel association testing (RobKAT).

Testing the association between single-nucleotide polymorphism (SNP) effects and a response is often carried out through kernel machine methods based on least squares, such as the sequence kernel association test (SKAT). However, these least-squares procedures are designed for a normally distributed conditional response, which may not apply. Other robust procedures such as the quantile regression kernel machine (QRKM) restrict the choice of the loss function and only allow inference on conditional quantiles. We propose a general and robust kernel association test with a flexible choice of the loss function, no distributional assumptions, and has SKAT and QRKM as special cases. We evaluate our proposed robust association test (RobKAT) across various data distributions through a simulation study. When errors are normally distributed, RobKAT controls type I error and shows comparable power with SKAT. In all other distributional settings investigated, our robust test has similar or greater power than SKAT. Finally, we apply our robust testing method to data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) clinical trial to detect associations between selected genes including the major histocompatibility complex (MHC) region on chromosome six and neurotropic herpesvirus antibody levels in schizophrenia patients. RobKAT detected significant association with four SNP sets (HST1H2BJ, MHC, POM12L2, and SLC17A1), three of which were undetected by SKAT.

Serological Responses to Toxoplasma gondii and Matrix Antigen 1 Predict the Risk of Subsequent Toxoplasmic Encephalitis in People Living With Human Immunodeficiency Virus (HIV).

BACKGROUND: Clinically useful predictors for fatal toxoplasmosis are lacking. We investigated the value of serological assays for antibodies to whole Toxoplasma antigens and to peptide antigens of the Toxoplasma cyst matrix antigen 1 (MAG1), for predicting incident toxoplasmic encephalitis (TE) in people living with human immunodeficiency virus (HIV; PLWH). METHODS: We performed a nested case control study, conducted within the Multicenter AIDS Cohort Study (MACS), using serum samples obtained 2 years prior to diagnosis of TE from 28 cases, and 37 HIV disease-matched Toxoplasma seropositive controls at matched time-points. Sera were tested for Toxoplasma antibodies using a commercial assay and for antibodies to MAG1_4.2 and MAG1_5.2 peptides in enzyme-linked immunosorbent assay (ELISA). RESULTS: Two years prior to clinical diagnosis, 68% of TE cases were MAG1_4.2 seropositive compared with 16% of controls (odds ratio [OR] 25.0, 95% confidence interval [CI] 3.14-199.18). Corresponding results for MAG1_5.2 seropositivity were 36% and 14% (OR 3.6, 95% CI .95-13.42). Higher levels of antibody to MAG1_4.2 (OR 18.5 per doubling of the optical density [OD] value, 95% CI 1.41-242) and to Toxoplasma (OR 2.91 for each OD unit increase, 95% CI 1.48-5.72) were also associated with the risk of TE. When seropositivity was defined as the presence of MAG1 antibody or relatively high levels of Toxoplasma antibody, the sensitivity was 89% and specificity was 68% for subsequent TE. CONCLUSIONS: Antibodies to MAG1 showed predictive value on the occurrence of TE in PLWH, and the predictive performance was further improved by adding the levels of Toxoplasma antibody. These measures could be clinically useful for predicting subsequent diseases in multiple at-risk populations.

Cytomegalovirus infection associated with smaller dentate gyrus in men with severe mental illness.

Cytomegalovirus (CMV) infection is usually inapparent in healthy adults but persists for life. Neural progenitor/stem cells are main CMV targets, and dentate gyrus (DG) a major neurogenic niche. Smaller DG volume has been repeatedly reported in severe mental illness (SMI). Considering the suggested immune system, blood-brain barrier and DG disturbances in SMI, we hypothesized that CMV exposure is associated with smaller DG volume in patients, but not healthy controls (HC). Due to the differential male and female immune response to CMV, we hypothesized sex-dependent associations. 381 adult patients with SMI (schizophrenia spectrum or bipolar spectrum disorders) and 396 HC were included. MRI scans were obtained with 1.5T Siemens MAGNETOM Sonata scanner or 3T General Electric Signa HDxt scanner, and processed with FreeSurfer v6.0. CMV immunoglobulin G antibody concentrations were measured by solid phase immunoassay. We investigated main and interaction effects of CMV status (antibody positivity/CMV + vs. negativity/CMV-) and sex on DG in patients and HC. Among patients, there was a significant CMV-by-sex interaction on DG (p = 0.009); CMV + male patients had significantly smaller DG volume than CMV- male patients (p = 0.001, 39 mm3 volume difference) whereas no CMV-DG association was found in female patients. Post-hoc analysis among male patients showed that the CMV-DG association was present in both hemispheres and in both patients with schizophrenia spectrum and bipolar spectrum disorders, and further, that higher CMV antibody titers were associated with smaller DG. No CMV-DG association was found in HC. The results indicate a DG vulnerability to CMV infection in men with SMI.

Nitrated meat products are associated with mania in humans and altered behavior and brain gene expression in rats.

Mania is a serious neuropsychiatric condition associated with significant morbidity and mortality. Previous studies have suggested that environmental exposures can contribute to mania pathogenesis. We measured dietary exposures in a cohort of individuals with mania and other psychiatric disorders as well as in control individuals without a psychiatric disorder. We found that a history of eating nitrated dry cured meat but not other meat or fish products was strongly and independently associated with current mania (adjusted odds ratio 3.49, 95% confidence interval (CI) 2.24-5.45, p < 8.97 × 10-8). Lower odds of association were found between eating nitrated dry cured meat and other psychiatric disorders. We further found that the feeding of meat preparations with added nitrate to rats resulted in hyperactivity reminiscent of human mania, alterations in brain pathways that have been implicated in human bipolar disorder, and changes in intestinal microbiota. These findings may lead to new methods for preventing mania and for developing novel therapeutic interventions.

Host-parasite interaction associated with major mental illness.

Clinical studies frequently report that patients with major mental illness such as schizophrenia and bipolar disorder have co-morbid physical conditions, suggesting that systemic alterations affecting both brain and peripheral tissues might underlie the disorders. Numerous studies have reported elevated levels of anti-Toxoplasma gondii (T. gondii) antibodies in patients with major mental illnesses, but the underlying mechanism was unclear. Using multidisciplinary epidemiological, cell biological, and gene expression profiling approaches, we report here multiple lines of evidence suggesting that a major mental illness-related susceptibility factor, Disrupted in schizophrenia (DISC1), is involved in host immune responses against T. gondii infection. Specifically, our cell biology and gene expression studies have revealed that DISC1 Leu607Phe variation, which changes DISC1 interaction with activating transcription factor 4 (ATF4), modifies gene expression patterns upon T. gondii infection. Our epidemiological data have also shown that DISC1 607 Phe/Phe genotype was associated with higher T. gondii antibody levels in sera. Although further studies are required, our study provides mechanistic insight into one of the few well-replicated serological observations in major mental illness.

Development of Methods to Extract RNA From Archived Pediatric Needle Liver Biopsies to Produce Sequencing Data.

ABSTRACT: Genetic susceptibility has been proposed as etiopathogenic in several pediatric liver diseases including autoimmune hepatitis (AIH). High throughput sequencing (HTPS) has been applied to archived needle liver biopsies obtained from adults but rarely to pediatric biopsies. For conclusive diagnosis of AIH, most subjects have an initial formalin-fixed paraffin embedded (FFPE) needle liver biopsy that is eventually archived and may be stored for decades. OBJECTIVE: Our goal was to develop methods to utilize tissue from archived needle liver biopsies for extraction of RNA sufficient to produce HTPS data. METHODS: We extracted total RNA from 45 FFPE needle liver biopsy samples (24 AIH type 1 patients and 21 controls [ages 15_11 and 19_10]; biopsy storage time 0.5-20 years) and constructed cDNA libraries that were then sequenced on an Illumina HiSeq2000 platform. RESULTS: Forty (89%) of the libraries produced high-quality sequences for further analyses. The average number of sequences obtained per library from HTPS was 55,136,519 (range 14,914,291-184,027,499). There was a significant inverse relationship between the number of human reads obtained and the age of the specimen (P < 2_10_7). It was possible to classify more than 90% of the reads as known genes in samples that had been stored for less than 10 years. CONCLUSIONS: Archived needle liver biopsies can be used for sequence based interrogation of the etiologic origins of complex liver diseases of young subjects, such as AIH.

Deciphering microbiome and neuroactive immune gene interactions in schizophrenia.

The body's microbiome represents an actively regulated network of novel mechanisms that potentially underlie the etiology and pathophysiology of a wide range of diseases. For complex brain disorders such as schizophrenia, understanding the cellular and molecular pathways that intersect the bidirectional gut-brain axis is anticipated to lead to new methods of treatment. The means by which the microbiome might differ across neuropsychiatric and neurological disorders are not known. Brain disorders as diverse as schizophrenia, major depression, Parkinson's disease and multiple sclerosis appear to share a common pathology of an imbalanced community of commensal microbiota, often measured in terms of a leaky gut phenotype accompanied by low level systemic inflammation. While environmental factors associated with these disease states might contribute to intestinal pathologies, products from a perturbed microbiome may also directly promote specific signs, symptoms and etiologies of individual disorders. We hypothesize that in schizophrenia, it is the putatively unique susceptibility related to genes that modulate the immune system and the gut-brain pleiotropy of these genes which leads to a particularly neuropathological response when challenged by a microbiome in dysbiosis. Consequences from exposure to this dysbiosis may occur during pre- or post-natal time periods and thus may interfere with normal neurodevelopment in those who are genetically predisposed. Here, we review the evidence from the literature which supports the idea that the intersection of the microbiome and immune gene susceptibility in schizophrenia is relevant etiologically and for disease progression. Figuring prominently at both ends of the gut-brain axis and at points in between are proteins encoded by genes found in the major histocompatibility complex (MHC), including select MHC as well as non-MHC complement pathway genes.

Association of exposure to Toxoplasma gondii, Epstein-Barr Virus, Herpes Simplex virus Type 1 and Cytomegalovirus with new-onset depressive and anxiety disorders: An 11-year follow-up study.

BACKGROUND: Some prevalent infections have been associated with common mental disorders, but there are few longitudinal studies, and results are inconsistent. We aimed to assess whether serological evidence of exposure to Toxoplasma gondii (T. gondii), Epstein-Barr Virus (EBV), Herpes Simplex virus Type 1 (HSV-1) and Cytomegalovirus (CMV) predict development of new-onset depressive and anxiety disorders. METHODS: In a nationally representative sample of the Finnish adult population aged 30 and over (BRIF8901, n = 8028), IgG antibodies for T. gondii, EBV, HSV-1 and CMV were measured in plasma samples. The population was followed up for 11 years and new-onset depressive and anxiety disorders were diagnosed with the Composite International Diagnostic Interview. Associations were analysed controlling for sex, age, educational level, region of residence and marital status, and in separate analyses also for C-reactive protein level. RESULTS: Seropositivity and serointensity of the four infectious agents were not associated with an increased risk of new-onset depressive or anxiety disorders. Seropositivity for CMV at baseline was associated with a lower risk of new-onset generalized anxiety disorder (adjusted OR 0.43, 95% CI 0.22-0.86 for CMV positive persons). CONCLUSION: The results of this large, nationally representative longitudinal study suggest that common viral infections are not significant risk factors for common mental disorders. The association of CMV with a lower risk of generalized anxiety disorder warrants further investigation.

Diagnosis-independent loss of T-cell costimulatory molecules in individuals with cytomegalovirus infection.

Major depressive disorder (MDD) is associated with physiological changes commonly observed with increasing age, such as inflammation and impaired immune function. Age-related impaired adaptive immunity is characterized by the loss of naive T-cells and the reciprocal accumulation of memory T-cells together with the loss of T-cell co-stimulatory molecules. Additionally, the presence and activity of cytomegalovirus (CMV) alters the architecture of the T-cell compartment in a manner consistent with premature aging. Because CMV is also thought to reactivate with psychological stress, this study tested whether MDD influences age-related phenotypes of T-cell populations in the context of CMV infection in young and middle-aged adults. Morning blood samples from volunteers with a DSM-IV diagnosis of MDD (n = 98, mean age(SD) = 36(10) years, 74.5% female, 57.1% CMV+) and comparison controls (n = 98, mean age(SD) = 34(10) years, 68.4% female, 51.0% CMV+) were evaluated for CMV IgG antibody status and the distribution of late differentiated (CD27-CD28-) cells within CD4+ and CD8+ T-cell subsets, i.e. naive (CCR7+CD45RA+), effector memory (EM, CCR7-CD45RA-), central memory (CM, CCR7+CD45RA-) and effector memory cells re-expressing CD45RA (EMRA, CCR7-CD45RA+). Mixed linear regression models controlling for age, sex, ethnicity and flow cytometry batch showed that CMV seropositivity was associated with a reduction in naive T-cells, expansion of EMRA T-cells, and a greater percent distribution of CD27-CD28- cells within CD4+ and CD8+ memory T-cell subsets (p's < 0.004), but there was no significant effect of MDD, nor any significant interaction between CMV and diagnosis. Unexpectedly, depressed men were less likely to be CMV+ and depressed women were more likely to be CMV+ than sex-matched controls suggesting a possible interaction between sex and MDD on CMV susceptibility, but this three-way interaction did not significantly affect the T-cell subtypes. Our findings suggest that depression in young and middle-aged adults does not prematurely advance aging of the T-cell compartment independently of CMV, but there may be significant sex-specific effects on adaptive immunity that warrant further investigation.

Exposure to common infections and risk of suicide and self-harm: a longitudinal general population study.

Common infectious agents, such as Toxoplasma gondii (T. gondii) and several human herpes viruses, have been linked to increased risk of self-harm. The aim of this study was to investigate the associations between self-harm and seropositivity to T. gondii, Epstein-Barr virus (EBV), Herpes Simplex virus Type 1 (HSV-1), and Cytomegalovirus (CMV). IgM and IgG antibodies to these infections were measured in the Health 2000 project nationally representative of the whole Finnish adult population, and 6250 participants, age 30 and over, were followed for 15 years via registers. In addition, lifetime suicidal ideation and suicide attempts based on medical records and interview were assessed within a subsample of 694 participants screened to a substudy for possible psychotic symptoms or as controls. Among the 6250 participants, 14 individuals died of suicide and an additional 4 individuals had a diagnosis of intentional self-harm during follow-up. Serological evidence of lifetime or acute infections was not found to be associated with these suicidal outcomes. However, in the subsample, those seropositive for CMV had fewer suicide attempts compared to those seronegative, adjusting for gender, age, educational level, childhood family size, regional residence, CRP, and screen status (OR for multiple attempts = 0.40, 95% confidence interval 0.20‒0.83, p = 0.014). To conclude, common infections were not associated with risk of death by suicide or with self-harm diagnoses at a 15-year follow-up in the general population sample. Our finding of an increased number of suicide attempts among persons seronegative for CMV calls for further research.

Persistent Toxoplasma Infection of the Brain Induced Neurodegeneration Associated with Activation of Complement and Microglia.

Toxoplasma gondii, a common neurotropic parasite, is increasingly being linked to neuropsychiatric disorders, including schizophrenia, Alzheimer's disease, and Parkinson's disease. However, the pathogenic mechanisms underlying these associations are not clear. Toxoplasma can reside in the brain for extensive periods in the form of tissue cysts, and this process requires a continuous immune response to prevent the parasite's reactivation. Because neuroinflammation may promote the onset and progression of neurodegenerative diseases, we investigated neurodegeneration-associated pathological changes in a mouse model of chronic Toxoplasma infection. Under conditions of high-grade chronic infection, we documented the presence of neurodegeneration in specific regions of the prefrontal cortex, namely, the anterior cingulate cortex (ACC) and somatomotor cortex (SC). Neurodegeneration occurred in both glutamatergic and GABAergic neurons. Neurons that showed signs of degeneration expressed high levels of CX3CL1, were marked by profoundly upregulated complement proteins (e.g., C1q and C3), and were surrounded by activated microglia. Our findings suggest that chronic Toxoplasma infection leads to cortical neurodegeneration and results in CX3CL1, complement, and microglial interactions, which are known to mediate the phagocytic clearance of degenerating neurons. Our study provides a mechanistic explanation for the link between Toxoplasma infection and psychiatric disorders.

Reduced immunity to measles in adults with major depressive disorder.

BACKGROUND: Depression can impair the immunogenicity of vaccine administration in adults. Whereas many vaccinations are administered in childhood, it is not known whether adolescent or adult onset depression is associated with impairments in the maintenance of protection of childhood vaccines. This study tested the hypothesis that individuals with adolescent or adult onset mood disorders would display compromised immunity to measles, a target of childhood vaccination. METHODS: IgG antibodies to measles were quantified using a solid phase immunoassay in volunteers with bipolar disorder (BD, n = 64, mean age of onset = 16.6 ± 5.6), currently depressed individuals with major depressive disorder (cMDD, n = 85, mean age of onset = 17.9 ± 7.0), remitted individuals with a history of MDD (rMDD, n = 82, mean age of onset = 19.2 ± 8.6), and non-depressed comparison controls (HC, n = 202), all born after the introduction of the measles vaccine in the USA in 1963. RESULTS: Relative to HC, both the cMDD group (p = 0.021, adjusted odds ratios (OR) = 0.47, confidence interval (CI) = 0.24-0.90), and the rMDD group (p = 0.038, adjusted OR = 0.50, CI = 0.26-0.97) were less likely to test seropositive for measles. Compared with unmedicated MDD participants, currently medicated MDD participants had a longer lifetime duration of illness and were less likely to test seropositive for measles. CONCLUSIONS: Individuals with adolescent or adult onset MDD are less likely to test seropositive for measles. Because lower IgG titers are associated with increased risk of measles infection, MDD may increase the risk and severity of infection possibly because of impaired maintenance of vaccine-related protection from measles.

Large-scale study of Toxoplasma and Cytomegalovirus shows an association between infection and serious psychiatric disorders.

BACKGROUND: Common infectious pathogens have been associated with psychiatric disorders, self-violence and risk-taking behavior. METHODS: This case-control study reviews register data on 81,912 individuals from the Danish Blood Donor Study to identify individuals who have a psychiatric diagnosis (N = 2591), have attempted or committed suicide (N = 655), or have had traffic accidents (N = 2724). For all cases, controls were frequency matched by age and sex, resulting in 11,546 participants. Plasma samples were analyzed for immunoglobulin G (IgG) antibodies against Toxoplasma gondii and cytomegalovirus (CMV). RESULTS: T. gondii was detected in 25·9% of the population and was associated with schizophrenia (odds ratio [OR], 1·47; 95% confidence interval [CI], 1·03-2·09). Accounting for temporality, with pathogen exposure preceding outcome, the association was even stronger (IRR, 2·78; 95% CI, 1·27-6·09). A very weak association between traffic accident and toxoplasmosis (OR, 1·11; 95% CI, 1·00-1·23, p = 0.054) was found. CMV was detected in 60·8% of the studied population and was associated with any psychiatric disorder (OR, 1·17; 95% CI, 1·06-1·29), but also with a smaller group of neurotic, stress-related, and somatoform disorders (OR, 1·27; 95% CI, 1·12-1·44), and with attempting or committing suicide (OR, 1·31; 95% CI, 1·10-1·56). Accounting for temporality, any psychiatric disorder (IRR, 1·37; 95% CI, 1·08-1·74) and mood disorders (IRR, 1·43; 95% CI, 1·01-2·04) were associated with exposure to CMV. No association between traffic accident and CMV (OR, 1·06; 95% CI, 0·97-1·17) was found. CONCLUSIONS: This large-scale serological study is the first study to examine temporality of pathogen exposure and to provide evidence of a causal relationship between T. gondii and schizophrenia, and between CMV and any psychiatric disorder.

Chronic Toxoplasma gondii Infection Induces Anti-N-Methyl-d-Aspartate Receptor Autoantibodies and Associated Behavioral Changes and Neuropathology.

Anti-NMDA receptor (NMDAR) autoantibodies have been postulated to play a role in the pathogenesis of NMDAR hypofunction, which contributes to the etiology of psychotic symptoms. Toxoplasma gondii is a pathogen implicated in psychiatric disorders and associated with elevation of NMDAR autoantibodies. However, it remains unclear whether parasite infection is the cause of NMDAR autoantibodies. By using mouse models, we found that NMDAR autoantibody generation had a strong temporal association with tissue cyst formation, as determined by MAG1 antibody seroreactivity (r = 0.96; P < 0.0001), which is a serologic marker for the cyst burden. The presence of MAG1 antibody response, but not T. gondii IgG response, was required for NMDAR autoantibody production. The pathogenic relevance of NMDAR autoantibodies to behavioral abnormalities (blunted response to amphetamine-triggered activity and decreased locomotor activity and exploration) and reduced expression of synaptic proteins (the GLUN2B subtype of NMDAR and PSD-95) has been demonstrated in infected mice. Our study suggests that NMDAR autoantibodies are specifically induced by persistent T. gondii infection and are most likely triggered by tissue cysts. NMDAR autoantibody seroreactivity may be a novel pathological hallmark of chronic toxoplasmosis, which raises questions about NMDAR hypofunction and neurodegeneration in the infected brain.