The lack of association between herpes simplex virus 1 or Toxoplasma gondii infection and cognitive decline in the general population: An 11-year follow-up study.

BACKGROUND: Inflammation has been suggested to be one, possibly treatable, cause of cognitive decline and dementia. The purpose of the present article was to investigate whether the herpes simplex virus 1 (HSV-1) or Toxoplasma gondii (T. gondii) infections are related to cognitive decline or dementia. METHOD: The Health 2000 survey, conducted 2000-2001, is a population-representative sample of people over 30 years old that involved 7112 participants. The sample was followed up in the year 2011, in the Health 2011 study. At both time points, cognitive performance was assessed with two tests from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) assessing verbal fluency and verbal learning. In addition, the abbreviated Mini-Mental State Examination was administered to people aged over 55. In addition, tests assessing reaction and movement time were performed at baseline. Dementia diagnoses from nationwide health care registers were followed up until the end of year 2013. The presence of HSV-1 and T. gondii immunoglobulin G (IgG) was determined by solid-phase immunoassay at baseline. RESULTS: HSV-1 or T. gondii seropositivity, or IgG antibody levels, were not associated with cognitive decline when investigated as infection × time interactions. In addition, the infections were not associated with the risk of dementia. CONCLUSIONS: In a large sample of participants that is representative of the whole country and with a long follow-up, the results suggest that latent HSV-1 or T. gondii infections are not related to either decline in cognitive performance or dementia risk.

The complement system: a gateway to gene-environment interactions in schizophrenia pathogenesis.

The pathogenesis of schizophrenia is considered to be multi-factorial, with likely gene-environment interactions (GEI). Genetic and environmental risk factors are being identified with increasing frequency, yet their very number vastly increases the scope of possible GEI, making it difficult to identify them with certainty. Accumulating evidence suggests a dysregulated complement pathway among the pathogenic processes of schizophrenia. The complement pathway mediates innate and acquired immunity, and its activation drives the removal of damaged cells, autoantigens and environmentally derived antigens. Abnormalities in complement functions occur in many infectious and autoimmune disorders that have been linked to schizophrenia. Many older reports indicate altered serum complement activity in schizophrenia, though the data are inconclusive. Compellingly, recent genome-wide association studies suggest repeat polymorphisms incorporating the complement 4A (C4A) and 4B (C4B) genes as risk factors for schizophrenia. The C4A/C4B genetic associations have re-ignited interest not only in inflammation-related models for schizophrenia pathogenesis, but also in neurodevelopmental theories, because rodent models indicate a role for complement proteins in synaptic pruning and neurodevelopment. Thus, the complement system could be used as one of the 'staging posts' for a variety of focused studies of schizophrenia pathogenesis. They include GEI studies of the C4A/C4B repeat polymorphisms in relation to inflammation-related or infectious processes, animal model studies and tests of hypotheses linked to autoimmune diseases that can co-segregate with schizophrenia. If they can be replicated, such studies would vastly improve our understanding of pathogenic processes in schizophrenia through GEI analyses and open new avenues for therapy.

Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation.

Immune abnormalities have been described in some individuals with autism spectrum disorders (ASDs) as well as their family members. However, few studies have directly investigated the role of prenatal cytokine and chemokine profiles on neurodevelopmental outcomes in humans. In the current study, we characterized mid-gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD (N=415), developmental delay (DD) without ASD (N=188), and general population (GP) controls (N=428) using a bead-based multiplex technology. The ASD group was further divided into those with intellectual disabilities (developmental/cognitive and adaptive composite score<70) (ASD+ID, N=184) and those without (composite score⩾70) (ASD-noID, N=201). Levels of cytokines and chemokines were compared between groups using multivariate logistic regression analyses, adjusting for maternal age, ethnicity, birth country and weight, as well as infant gender, birth year and birth month. Mothers of children with ASD+ID had significantly elevated mid-gestational levels of numerous cytokines and chemokines, such as granulocyte macrophage colony-stimulating factor, interferon-γ, interleukin-1α (IL-1α) and IL-6, compared with mothers of children with either ASD-noID, those with DD, or GP controls. Conversely, mothers of children with either ASD-noID or with DD had significantly lower levels of the chemokines IL-8 and monocyte chemotactic protein-1 compared with mothers of GP controls. This observed immunologic distinction between mothers of children with ASD+ID from mothers of children with ASD-noID or DD suggests that the intellectual disability associated with ASD might be etiologically distinct from DD without ASD. These findings contribute to the ongoing efforts toward identification of early biological markers specific to subphenotypes of ASD.

Natural cause mortality in persons with serious mental illness.

OBJECTIVE: To identify the determinants of natural cause mortality in a cohort of individuals with serious mental illness assessed prospectively. METHOD: Persons with schizophrenia (n = 789) and bipolar disorder (n = 498), mean age of 38 (s.d. 12.6) years, underwent an in-person clinical assessment. They also had a blood sample drawn from which infectious disease markers were measured. Mortality was subsequently determined utilizing data from the National Death Index following a period of up to 16.9 years. RESULTS: A total of 6.8% (87 of 1287) of persons died of natural causes. Mortality was predicted in a multivariate model by baseline cigarette smoking (RR = 6.29, 95% CI 1.41, 3.72, P = 0.00076); divorced or widowed status (RR = 1.90, CI 1.21, 2.99); reduced cognitive score (RR = 0.73, CI 0.61, 0.87); receipt of antidepressant medication (RR = 1.74, CI 1.12, 2.71); elevated levels of antibodies to Epstein-Barr virus (EBV) (RR = 1.29, CI 1.01, 1.66); and a genitourinary (RR = 1.82, CI 1.16, 2.86), respiratory (RR = 1.82, CI 1.16, 2.86), or cardiac (RR = 2.09, CI 1.33, 3.29) condition. There was an additive effect of smoking and both a cardiac and a respiratory condition but not elevated EBV antibody levels. CONCLUSION: Smoking is a modifiable behaviour which is associated with mortality in this population.

Infections and exposure to anti-infective agents and the risk of severe mental disorders: a nationwide study.

OBJECTIVE: Severe infections are associated with increased risks of mental disorders; however, this is the first large-scale study investigating whether infections treated with anti-infective agents in the primary care setting increase the risks of schizophrenia and affective disorders. METHOD: We identified all individuals born in Denmark 1985-2002 (N = 1 015 447) and studied the association between infections treated with anti-infective agents and the subsequent risk of schizophrenia and affective disorders during 1995-2013. Cox regression analyses were adjusted for important confounders. RESULTS: Infections treated with anti-infective agents were associated with increased risks of schizophrenia by a hazard rate ratio (HRR) of 1.37 (95%-CI = 1.20-1.57) and affective disorders by a HRR of 1.64 (95%-CI = 1.48-1.82), fitting a dose-response and temporal relationship (P < 0.001). The excess risk was primarily driven by infections treated with antibiotics, whereas infections treated with antivirals, antimycotics, and antiparasitic agents were not significant after mutual adjustment. Individuals with infections requiring hospitalization had the highest risks for schizophrenia (HRR = 2.05; 95%-CI = 1.77-2.38) and affective disorders (HRR = 2.59; 95%-CI = 2.31-2.89). CONCLUSION: Infections treated with anti-infective agents and particularly infections requiring hospitalizations were associated with increased risks of schizophrenia and affective disorders, which may be mediated by effects of infections/inflammation on the brain, alterations of the microbiome, genetics, or other environmental factors.

Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci.

Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10(-6)) and rs8057927 in CDH13 (P=1.39 × 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10(-7)). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 × 10(-2)). Significant interaction with maternal CMV infection was found for rs7902091 (P(SNP × CMV)=7.3 × 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies.

Beyond the association. Toxoplasma gondii in schizophrenia, bipolar disorder, and addiction: systematic review and meta-analysis.

OBJECTIVE: To perform a meta-analysis on studies reporting prevalence of Toxoplasma gondii (T. gondii) infection in any psychiatric disorder compared with healthy controls. Our secondary objective was to analyze factors possibly moderating heterogeneity. METHOD: A systematic search was performed to identify studies into T. gondii infection for all major psychiatric disorders versus healthy controls. Methodological quality, publication bias, and possible moderators were assessed. RESULTS: A total of 2866 citations were retrieved and 50 studies finally included. Significant odds ratios (ORs) with IgG antibodies were found in schizophrenia (OR 1.81, P < 0.00001), bipolar disorder (OR 1.52, P = 0.02), obsessive-compulsive disorder (OR 3.4, P < 0.001), and addiction (OR 1.91, P < 0.00001), but not for major depression (OR 1.21, P = 0.28). Exploration of the association between T. gondii and schizophrenia yielded a significant effect of seropositivity before onset and serointensity, but not IgM antibodies or gender. The amplitude of the OR was influenced by region and general seroprevalence. Moderators together accounted for 56% of the observed variance in study effects. After controlling for publication bias, the adjusted OR (1.43) in schizophrenia remained significant. CONCLUSION: These findings suggest that T. gondii infection is associated with several psychiatric disorders and that in schizophrenia reactivation of latent T. gondii infection may occur.

Immune alterations in acute bipolar depression.

OBJECTIVE: Immunologic abnormalities have been found in bipolar disorder and acute mania. However, there have been fewer studies of patients with acute bipolar depression. METHOD: Blood samples were obtained from individuals with acute bipolar depression, acute mania, and controls. These samples were evaluated for antibodies to human herpesviruses, gliadin, Toxoplasma gondii, and endogenous retroviruses as well as for C-reactive protein (CRP) and pentraxin-3 using immunoassay methods. Linear regression models were used to compare the levels of the markers controlling for demographic and clinical variables. A subset of the bipolar depressed group was evaluated at a 6-month follow-up. RESULTS: The sample consisted of 82 individuals with acute bipolar depression, 147 with acute mania, and 280 controls. The levels of CRP and IgG antibodies to an endogenous retrovirus, Mason-Pfizer monkey virus (MPMV), were significantly elevated in the bipolar depressed group. Levels of pentraxin-3 were reduced in both psychiatric groups. An evaluation of 32 individuals 6 months after hospitalization for bipolar depression showed a significant decrease in the levels of MPMV antibodies, but not a change in the other markers. CONCLUSION: Individuals with acute bipolar depression show immune alterations. Some of the alterations are similar to those found in acute mania.

Cytomegalovirus Antibody Elevation in Bipolar Disorder: Relation to Elevated Mood States.

The neurobiology of mood states is complicated by exposure to everyday stressors (e.g., psychosocial, ubiquitous environmental infections like CMV), each fluctuating between latency and reactivation. CMV reactivation induces proinflammatory cytokines (e.g., TNF-α) associated with induction of neurotoxic metabolites and the presence of mood states in bipolar disorder (BD). Whether CMV reactivation is associated with bipolar diagnoses (trait) or specific mood states is unclear. We investigated 139 BD type I and 99 healthy controls to determine if concentrations of IgG antibodies to Herpesviridae (e.g., CMV, HSV-1, and HSV-2) were associated with BD-I diagnosis and specific mood states. We found higher CMV antibody concentration in BD-I than in healthy controls (T234 = 3.1, P uncorr = 0.002; P corr = 0.006) but no difference in HSV-1 (P > 0.10) or HSV-2 (P > 0.10). Compared to euthymic BD-I volunteers, CMV IgG was higher in BD-I volunteers with elevated moods (P < 0.03) but not different in depressed moods (P > 0.10). While relationships presented between BD-I diagnosis, mood states, and CMV antibodies are encouraging, they are limited by the study's cross sectional nature. Nevertheless, further testing is warranted to replicate findings and determine whether reactivation of CMV infection exacerbates elevated mood states in BD-I.

Persistent infection with neurotropic herpes viruses and cognitive impairment.

BACKGROUND: Herpes virus infections can cause cognitive impairment during and after acute encephalitis. Although chronic, latent/persistent infection is considered to be relatively benign, some studies have documented cognitive impairment in exposed persons that is untraceable to encephalitis. These studies were conducted among schizophrenia (SZ) patients or older community dwellers, among whom it is difficult to control for the effects of co-morbid illness and medications. To determine whether the associations can be generalized to other groups, we examined a large sample of younger control individuals, SZ patients and their non-psychotic relatives (n=1852). Method Using multivariate models, cognitive performance was evaluated in relation to exposures to herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and cytomegalovirus (CMV), controlling for familial and diagnostic status and sociodemographic variables, including occupation and educational status. Composite cognitive measures were derived from nine cognitive domains using principal components of heritability (PCH). Exposure was indexed by antibodies to viral antigens. RESULTS: PCH1, the most heritable component of cognitive performance, declines with exposure to CMV or HSV-1 regardless of case/relative/control group status (p = 1.09 × 10-5 and 0.01 respectively), with stronger association with exposure to multiple herpes viruses (ß = -0.25, p = 7.28 × 10-10). There were no significant interactions between exposure and group status. CONCLUSIONS: Latent/persistent herpes virus infections can be associated with cognitive impairments regardless of other health status.

Identification of a biological signature for schizophrenia in serum.

Biomarkers are now used in many areas of medicine but are still lacking for psychiatric conditions such as schizophrenia (SCZ). We have used a multiplex molecular profiling approach to measure serum concentrations of 181 proteins and small molecules in 250 first and recent onset SCZ, 35 major depressive disorder (MDD), 32 euthymic bipolar disorder (BPD), 45 Asperger syndrome and 280 control subjects. Preliminary analysis resulted in identification of a signature comprised of 34 analytes in a cohort of closely matched SCZ (n=71) and control (n=59) subjects. Partial least squares discriminant analysis using this signature gave a separation of 60-75% of SCZ subjects from controls across five independent cohorts. The same analysis also gave a separation of ~50% of MDD patients and 10-20% of BPD and Asperger syndrome subjects from controls. These results demonstrate for the first time that a biological signature for SCZ can be identified in blood serum. This study lays the groundwork for development of a diagnostic test that can be used as an aid for distinguishing SCZ subjects from healthy controls and from those affected by related psychiatric illnesses with overlapping symptoms.

Toxoplasma gondii, Herpesviridae and long-term risk of transition to first-episode psychosis in an ultra high-risk sample.

BACKGROUND: Ultra high-risk (UHR) criteria were introduced to identify people at imminent risk of developing psychosis. To improve prognostic accuracy, additional clinical and biological risk factors have been researched. Associations between psychotic disorders and infections with Toxoplasma gondii and Herpesviridae have been found. It is unknown if exposure to those pathogens increases the risk of transition to psychosis in UHR cohorts. METHODS: We conducted a long-term follow-up of 96 people meeting UHR criteria, previously seen at the Personal Assessment and Crisis Evaluation (PACE) clinic, a specialized service in Melbourne, Australia. Transition to psychosis was assessed using the Comprehensive Assessment of the At-Risk Mental State (CAARMS) and state public mental health records. The relationship between IgG antibodies to Herpesviridae (HSV-1, HSV-2, CMV, EBV, VZV) and Toxoplasma gondii and risk for transition was examined with Cox regression models. RESULTS: Mean follow-up duration was 6.46 (±3.65) years. Participants who transitioned to psychosis (n = 14) had significantly higher antibody titers for Toxoplasma gondii compared to those who did not develop psychosis (p = 0.03). After adjusting for age, gender and year of baseline assessment, seropositivity for Toxoplasma gondii was associated with a 3.6-fold increase in transition hazard in multivariate Cox regression models (HR = 3.6; p = 0.036). No significant association was found between serostatus for Herpesviridae and risk of transition. CONCLUSIONS: Exposure to Toxoplasma gondii may contribute to the manifestation of positive psychotic symptoms and increase the risk of transitioning to psychosis in UHR individuals.

Are some cases of psychosis caused by microbial agents? A review of the evidence.

The infectious theory of psychosis, prominent early in the twentieth century, has recently received renewed scientific support. Evidence has accumulated that schizophrenia and bipolar disorder are complex diseases in which many predisposing genes interact with one or more environmental agents to cause symptoms. The protozoan Toxoplasma gondii and cytomegalovirus are discussed as examples of infectious agents that have been linked to schizophrenia and in which genes and infectious agents interact. Such infections may occur early in life and are thus consistent with neurodevelopmental as well as genetic theories of psychosis. The outstanding questions regarding infectious theories concern timing and causality. Attempts are underway to address the former by examining sera of individuals prior to the onset of illness and to address the latter by using antiinfective medications to treat individuals with psychosis. The identification of infectious agents associated with the etiopathogenesis of schizophrenia might lead to new methods for the diagnosis, treatment and prevention of this disorder.

Cytomegalovirus antibody in cerebrospinal fluid of schizophrenic patients detected by enzyme immunoassay.

By means of enzyme immunoassay techniques to detect the presence of antibody to cytomegalovirus, the cerebrospinal fluid of 178 patients with schizophrenia, 17 patients with bipolar disorders, and 11 other psychiatric patients was compared with that of 79 neurological patients and 41 normal control subjects. The cerebrospinal fluid of 20 of the schizophrenic patients and 3 of the patients with bipolar disorders showed significant increases in immunoglobulin M antibody to cytomegalovirus; no difference was found in patients on or off psychotropic medications.

Enzyme-linked immunosorbent assay for identification of rotaviruses from different animal species.

Rotaviruses cause gastroenteritis in man and a wide variety of animal species. They cross-react in many immunologic tests and have a similar appearance by electron microscopy, making differentiation among them difficult. Rotaviruses derived from different host species were distinguished by postinfection serum blocking virus activity in an enzyme-linked immunosorbent assay (ELISA). Thirty-three rotavirus isolates from children living in three different parts of the world could not be differentiated by this technique, but they were distinct from four strains recovered from calves, and a series of strains isolated from piglets, foals, monkeys, and infant mice. The four bovine strains were similar, but they could be differentiated from the other animal strains, each of which exhibited a distinct pattern when tested by the ELISA blocking technique.

Rotaviral immunity in gnotobiotic calves: heterologous resistance to human virus induced by bovine virus.

The possibility of immunizing human infants against rotaviruses, which cause severe dehydrating diarrheal disease, may depend on the use of a related rotavirus, derived from another animal species, as a source of antigen. To test the feasibility of this approach, calves were infected in utero with a bovine rotavirus and challenged with bovine or human type 2 rotavirus shortly after birth. Infection in utero with bovine rotavirus induced resistance to diarrheal disease caused by the human virus as well as the homologous bovine virus. These data suggest that the bovine virus is sufficiently related antigenically to the human type 2 virus to warrant further evaluation of the former as a source of vaccine.

Toxoplasma and schizophrenia.

Research on infectious agents as a possible cause of schizophrenia has become prominent in the past decade. Toxoplasma gondii has emerged as a prime candidate for a variety of reasons; (i) many studies have reported that individuals with schizophrenia, compared to controls, have a higher prevalence of antibodies to T. gondii, (ii) some individuals with adult toxoplasmosis develop psychotic symptoms similar to those of schizophrenia, (iii) epidemiologically, there are many similarities between toxoplasmosis and schizophrenia, (iv) antipsychotic drugs known to be effective in schizophrenia also inhibit some parasites, including T. gondii, (v) Toxoplasma has been shown to induce elevated levels of dopamine in experimentally infected animals (elevated dopamine is commonly seen in individuals with schizophrenia) and (vi) studies have shown that individuals with schizophrenia, compared to controls, have had greater exposure to cats in childhood. A number of questions remain concerning a role for Toxoplasma in the aetiology of schizophrenia, including the roles of strain variation, the timing and source of infection, and the role of host genes in determining disease susceptibility. The establishment of a firm association between Toxoplasma and the aetiology of schizophrenia and related disorders would represent a major breakthrough in the understanding of these disorders and would lead to novel methods for their treatment and prevention.