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.

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.

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.

Oral administration of human serum immunoglobulin in immunodeficient patients with viral gastroenteritis. A pharmacokinetic and functional analysis.

We examined the pharmacokinetics and immunological activity of human serum immunoglobulins (HSG) possessing anti-rota-virus activity which were orally administered to three children with primary immunodeficiency syndromes and prolonged gastrointestinal excretion of rotavirus. Detailed analysis of the excretion of immunoglobulins labeled with biotin or I125 revealed that approximately 50% of the recovered radioactivity was excreted in the stools over a 3-d period. Approximately half of the excreted radioactivity recovered in the stool was in a macromolecular form with immunological activity. The remainder of the recovered radioactivity was excreted in the urine as low molecular weight fragments or free iodide. In addition, immunological and chromatographic analyses revealed that the oral administration of HSG resulted in the generation of rotavirus-specific immune complexes in the gastrointestinal tract with a subsequent decrease in the presence of uncomplexed rotavirus antigen. These studies indicate that orally administered HSG can survive passage in the gastrointestinal tract in an immunologically active form, and that the oral administration of immunoglobulins with specific reactivities has potential for the prevention or treatment of gastrointestinal infections.

Sialic acid glycoproteins inhibit in vitro and in vivo replication of rotaviruses.

We investigated the interactions of rotaviruses with glycoproteins and cells that support rotaviral replication. We found that a wide range of naturally occurring glycoproteins, including ovalbumins and ovomucoids from chicken and turkey eggs, and mucin derived from bovine submaxillary glands, inhibit the replication of rotaviruses in MA-104 cells. Our studies further indicated that the glycoproteins bind directly to rotaviruses and that virus-glycoprotein binding is dependent largely upon interactions with sialic acid oligosaccharides. We found that accessible sialic acid oligosaccharides are required for efficient rotavirus infection of MA-104 cells, thus demonstrating that sialic acid oligosaccharides play an important role in the interactions of rotaviruses with both glycoproteins and cells that support rotaviral replication. Bovine submaxillary mucin and chicken ovoinhibitor can also prevent the shedding of rotavirus antigen and the development of rotavirus gastroenteritis in a mouse model of rotavirus infection. Our findings document that a range of glycoproteins inhibit the in vivo and in vitro replication of rotaviruses and suggest that the alteration in the quantity or chemical composition of intestinal glycoproteins is a potential means for the modulation of enteric infections.

Human milk mucin inhibits rotavirus replication and prevents experimental gastroenteritis.

Acute gastrointestinal infections due to rotaviruses and other enteric pathogens are major causes of morbidity and mortality in infants and young children throughout the world. Breast-feeding can reduce the rate of serious gastroenteritis in infants; however, the degrees of protection offered against rotavirus infection vary in different populations. The mechanisms associated with milk-mediated protection against viral gastroenteritis have not been fully elucidated. We have isolated a macromolecular component of human milk that inhibits the replication of rotaviruses in tissue culture and prevents the development of gastroenteritis in an animal model system. Purification of the component indicates that the antiviral activity is associated with an acidic fraction (pI = 4.0-4.6), which is free of detectable immunoglobulins. Furthermore, high levels of antiviral activity are associated with an affinity-purified complex of human milk mucin. Deglycosylation of the mucin complex results in the loss of antiviral activity. Further purification indicated that rotavirus specifically binds to the milk mucin complex as well as to the 46-kD glycoprotein component of the complex. Binding to the 46-kD component was substantially reduced after chemical hydrolysis of sialic acid. We have documented that human milk mucin can bind to rotavirus and inhibit viral replication in vitro and in vivo. Variations in milk mucin glycoproteins may be associated with different levels of protection against infection with gastrointestinal pathogens.

Protease inhibitors suppress the in vitro and in vivo replication of rotavirus.

Rotaviruses are major causes of infectious gastroenteritis in humans and other animals. We found that a variety of protease inhibitors suppressed the replication of the SA-11 strain of rotavirus in MA-104 cell cultures. Three of these compounds, leupeptin, pentamidine, and bis (5-amidino-2-benzimidazolyl) methane (BABIM) also restricted the intestinal replication of the murine strain of rotavirus when protease inhibitor and virus were administered simultaneously to suckling mice. Repeated administration of BABIM resulted in significantly reduced levels of intestinal rotaviral antigen even if administration of the compound was begun as late as 48 h after viral inoculation. Additionally, BABIM-treated animals had significantly less intestinal replication of rotavirus than did placebo-treated controls when placed in a heavily rotavirus-contaminated environment. The use of protease inhibitors represents a novel approach to the control of this important gastrointestinal pathogen and is a potential modality for the prevention and treatment of diseases caused by other enteric viruses, for which proteolytic cleavage is necessary for efficient replication.