Aggravation of cognitive impairments in the valproic acid-induced animal model of autism in BALB/c mice infected with Toxoplasma gondii.

PURPOSE: Toxoplasmosis is a disease caused by infection with a type of coccidial protozoan parasite called Toxoplasma gondii. The relationship between toxoplasmosis and cognitive disorders in neurodegenerative diseases has been proven. There is also evidence that children born to Toxoplasma-infected mothers are more likely to develop autism. METHODS: In the present study, Toxoplasma-infected pregnant BALB/c mice were given valproic acid to induce autism in their male offspring, and their social behaviors, learning, and memory were examined. Chronic toxoplasmosis was established in BALB/c mice by intraperitoneal injection of cyst form of T. gondii. To induce autism, 600 mg/kg of valproic acid was injected intraperitoneally into mice on the 12.5th day of pregnancy. The behavioral experiments, such as social interaction, novel object recognition, and passive avoidance tasks, were performed on male offspring at 50 days. RESULTS: Toxoplasma and valproic acid during the embryonic period caused social communication deficits and disrupted recognition memory and avoidance memory in offspring. Our findings showed that administering valproic acid to Toxoplasma-infected mothers exacerbates cognitive disorders in their offspring.

Epigenetic Manipulation of Psychiatric Behavioral Disorders Induced by Toxoplasma gondii.

Toxoplasma gondii is known to have a complex life cycle and infect almost all kinds of warm-blooded animals around the world. The brain of the host could be persistently infected by cerebral cysts, and a variety of psychiatric disorders such as schizophrenia and suicide have been reported to be related with latent toxoplasmosis. The infected animals showed fear reduction and a tendency to be preyed upon. However, the mechanism of this "parasites manipulation" effects have not been elucidated. Here, we reviewed the recent infection prevalence of toxoplasmosis and the evidence of mental and behavioral disorders induced by T. gondii and discussed the related physiological basis including dopamine dysregulation and gamma-aminobutyric acid (GABA) pathway and the controversial opinion of the necessity for cerebral cysts existence. Based on the recent advances, we speculated that the neuroendocrine programs and neurotransmitter imbalance may play a key role in this process. Simultaneously, studies in the evaluation of the expression pattern of related genes, long noncoding RNAs (lncRNAs), and mRNAs of the host provides a new point for understanding the mechanism of neurotransmitter dysfunction induced by parasite manipulation. Therefore, we summarized the animal models, T. gondii strains, and behavioral tests used in the related epigenetic studies and the responsible epigenetic processes; pinpointed opportunities and challenges in future research including the causality evidence of human psychiatric disorders, the statistical analysis for rodent-infected host to be more vulnerable preyed upon; and identified responsible genes and drug targets through epigenetics.

Dissociating direct and indirect effects: a theoretical framework of how latent toxoplasmosis affects cognitive profile across the lifespan.

About one-third of the world's population has latent toxoplasmosis, which is typically most prevalent in old age due to its lifelong persistence. Most infected people do not reveal clinically relevant symptoms, but T. gondii might trigger cognitive changes in otherwise asymptomatic individuals. As intact cognitive processes are essential for various achievements and successful aging, this review focuses on the cognitive profile associated with latent toxoplasmosis across the lifespan. It could be explained by a shift in balance between direct effects (increased dopamine synthesis) and indirect effects (neurodegeneration and chronic inflammation, which can decrease dopamine levels). Based thereon, we provide a possibly comprehensive framework of how T. gondii can differently affect cognitive performance across the lifespan (i.e., from increased catecholaminergic signaling in young age to decreased signaling in old age). We outline how future studies may inform our knowledge on the role of individual differences in response to T. gondii and how longitudinal studies can help trace the temporal dynamics in the shift of the balance between direct and indirect effects.

An investigation into the association between latent toxoplasmosis and suicide attempts among adolescents.

INTRODUCTION: There have been several studies investigating the association between Toxoplasma gondii seropositivity and psychiatric disorders although there is insufficient data on causality. Suicide, depression, and anxiety disorders have been especially investigated in this regard. In this study, we aimed to investigate whether there is any causal association between Toxoplasma gondii seropositivity and suicide attempts in adolescents. METHODOLOGY: This is a case-control study conducted between January and December 2019. A total of 27 adolescents who had attempted suicide and were aged between 12 and 18 years were included in the study. 26 age and sex ratio matched healthy volunteers were taken as the control group. A possible association between suicide attempts and Toxoplasma gondii serology (IgM and IgG) was investigated.. RESULTS: The suicide attempt group consisted of 17 females and 10 males. The mean age was 15.9 ± 1.4 (13.5-17.9) years. Toxoplasma gondii IgG seropositivity was 3.7% (1/27) in the suicide attempt group and 3.8% (1/26) in the control group. There was no significant association between the suicide attempt group and the control group in terms of the presence of Toxoplasma gondii IgG antibodies (p > 0.05). CONCLUSION: Our study is one of the few studies examining the association between Toxoplasma gondii seropositivity and suicide attempts in adolescents yet we did not find any significant association. Further evidence is needed to clarify this controversial issue.

Association of T. gondii infection with suicide: a systematic review and meta-analysis.

BACKGROUND: Findings on the association between Toxoplasma gondii (T. gondii) infection and suicide are contradictory. This paper aimed to resolve this uncertainty by conducting a meta-analysis. METHODS: We found the relevant studies using keywords include "Toxoplasmosis" and "Suicide" and the related synonyms in international databases such as ISI, Medline, and Scopus. The eligible studies were included in the meta-analysis phase. The random effect approach was applied to combine the results. RESULTS: Out Of 150 initial studies, 15 were included in the meta-analysis. Odds of suicide in people with T. gondii infection was 43% (OR: 1.43, 95%CI; 1.15 to 1.78) higher than those without this infection. The test for publication bias was not statistically significant, which indicates the absence of likely publication bias. CONCLUSION: This study confirms that T. gondii infection is a potential risk factor for suicide. To reduce cases of suicide attributable to T. gondii infection, it is recommended to implement some measures to prevent and control the transmission of the disease.

[Toxoplasmosis and behavioural changes (French translation of the article)]. / Toxoplasmose et modifications du comportement humain.

Nearly one-third of the planet's population is affected by T. gondii infection. In ophthalmology, toxoplasmosis is even considered to be the most common cause of posterior uveitis of infectious origin. Humans are only an intermediate host, and T. gondii needs to infect cats for its sexual reproduction. All the elements increasing the risk of predation by the definitive host are then favourable to the parasite. Numerous experimental animal model studies have shown that T. gondii infection is associated with predatory risk behaviours such as an attraction of infected mice to cat urine. Infection with the parasite is associated with a demethylation of the promoters of certain genes in the cerebral amygdala of the intermediate hosts, modifying dopaminergic circuits associated with fear. Similarly, T. gondii has been linked to behavioural changes in humans. Toxoplasma infection is classically associated with the frequency of schizophrenia, suicide attempts or "road rage." A more recent study shows that toxoplasma infection prevalence was a consistent, positive predictor of entrepreneurial activity. Fear of failure would be less important in infected individuals, who are more willing than others to start their own business. These elements shed interesting light on behaviours and their possible relationship with toxoplasmosis, which is generally considered benign in adults.

Interaction of Toxoplasma gondii infection and elevated blood lead levels on children's neurobehavior.

A chronic infection caused by Toxoplasma gondii was considered asymptomatic in immunologically healthy humans, but results from animal and epidemiological studies led to a reconsideration of this assumption. The objective of this study was to evaluate the seroprevalence of T. gondii infection and its possible effects on the behavior of school-aged children in Bahia, Brazil. Serum anti-body determinations were performed by Enzyme-linked Immunosorbent Assay (ELISA). Blood lead levels (BLL) were measured by graphite furnace atomic absorption spectrometry (GFAAS). The evaluation of a child's behavior was assessed using the Child Behavior Check List (CBCL). Multivariate models applying logistic regression were used to test the association of chronic T. gondii infection and BLL with behavioral outcomes in children. Seroprevalence for anti-T. gondii IgG antibody was 43.7 % (95 %-CI: 35.8-51.9). Significant associations between chronic T. gondii infection and total behavioral problems (OR = 2.50; 95 %-CI: 1.06-5.88), internalizing spectrum problems (OR = 4.35; 95 %-CI: 1.11-17.14) and rule breaking (OR = 2.61; 95 %-CI: 1.12-6.05) were observed. A possible interaction between toxoplasmosis prevalence and lead exposure was detected. Children with above the median BLL and positive for IgG anti-T. gondii showed a 5.51-fold increase (95 %-CI: 1.75-17.38) in the chance of displaying disobedient behavior. The results suggest that T. gondii infection may be contributing to the high indices of behavioral changes. Moreover, these findings are the first evidence for a possible interaction between chronic T. gondii infection and elevated blood lead levels on children's neurobehavior.

Toxoplasmosis in a Cohort of Italian Patients With Bipolar and Psychotic Disorders: How Infection May Affect Clinical Features?

This study investigated the seroprevalence of Toxoplasma gondii in a cohort of 101 Italian inpatients affected by mood or schizophrenia-spectrum disorders and compared clinical features between seronegative and seropositive subjects. Patients diagnosed according to DSM-5 criteria underwent clinical assessments and blood collection to test parasite-specific IgG/IgM serum levels. Twenty-eight patients (27.7%) had IgG anti-T. gondii, and none had IgM antibodies. We found higher prevalence rate in patients aged 40 years or older, as compared with younger. No significant association was detected between T. gondii and a specific diagnostic category; however, bipolar disorder (BD)-II showed the highest positivity rate (40.9%). The seropositive status was significantly associated with a lower presence of psychotic symptoms, higher number of total episodes of predominant excitatory polarity, longer illness duration, and lower severity of current episode, particularly anxiety, depressive, and withdrawal/retardation symptoms. These preliminary results seem to point out an association between chronic toxoplasmosis and a specific subtype of BD.

Toxoplasmosis and behavioural changes.

Nearly one-third of the planet's population is affected by Toxoplasma gondii infection. In ophthalmology, toxoplasmosis is even considered to be the most common cause of posterior uveitis of infectious origin. Humans are only an intermediate host and T. gondii needs to infect cats for its sexual reproduction. All the elements increasing the risk of predation by the definitive host are then favourable to the parasite. Numerous experimental animal model studies have shown that T. gondii infection is associated with predatory risk behaviours such as an attraction of infected mice to cat urine. Infection with the parasite is associated with a demethylation of the promoters of certain genes in the cerebral amygdala of the intermediate hosts, modifying dopaminergic circuits associated with fear. Similarly, T. gondii has been linked to behavioural changes in humans. Toxoplasma infection is classically associated with the frequency of schizophrenia, suicide attempts or "road rage". A more recent study shows that toxoplasma infection prevalence was a consistent, positive predictor of entrepreneurial activity. Fear of failure would be less important in infected individuals, who are more willing than others to start their own business. These elements shed interesting light on behaviours and their possible relationship with toxoplasmosis, which is generally considered benign in adults.

Association of Suicide Attempt With Seroprevalence of Toxoplasma gondii in Adolescents.

In this study, we aimed to explore the potential pathophysiological relationship between suicide attempts and Toxoplasma gondii infection. Fifty patients aged between 12 and 18 years who attempted suicide and 50 healthy adolescents were included in this study. All adolescents were evaluated by a child psychiatrist using a semistructured interview and Rosenberg Self-Esteem Scale (RSES), Children's Depression Inventory (CDI), and Inventory of Parent and Peer Attachment. T. gondii IgM and IgG antibodies of patients and control subjects were analyzed from blood samples by enzyme-linked immunosorbent assay. Psychiatric disorders particularly mood disorders were more common in adolescents in the patient group. Adolescents attempting suicide were found to have worse relationships with their parents; their CDI scores were higher, and their RSES scores were lower than their healthy peers. There were no significant differences between the patient and the control groups in terms of Toxoplasma IgG antibody positivity. Although the seropositivity of Toxoplasma IgG antibody was higher in the patient group than that in the control group, the difference between the two groups was not statistically significant.

Lack of circulating toxoplasma gondii DNA in seropositive patients with bipolar or schizophrenia spectrum disorders.

Toxoplasmosis has been previously associated with an increased risk of having Schizophrenia or Bipolar disorder in several epidemiological studies. The aim of this observational, cross-sectional study was to examine the seroprevalence of Toxoplasma infection in a cohort of Italian psychiatric inpatients and to verify the presence of circulating Toxoplasma gondii DNA in the seropositive subjects. Sixty-three patients affected by bipolar or schizoaffective disorders according to DSM-5 criteria were enrolled. The presence of Toxoplasma infection was firstly examined using an indirect serological method (ELFA), and three different direct PCR-based methods were performed to detect circulating DNA in the seropositive patients. The seroprevalence of infection was 28.6%, with a significant association between higher age and the infection status. PCR, nested-PCR and Real-Time PCR revealed no positive samples for Toxoplasma gondii. This result is in contrast with recent data from case-control studies that detected parasite genome in patients with different neuropsychiatric diagnosis without clinical evidence of acute toxoplasmosis. Our findings are to be interpreted with caution, because of the small sample size, the heterogeneity of enrolled patients and the observational nature of the study. Further studies are needed to better define the clinical features correlated to the seropositive status in neuropsychiatric patients.

Relationship between Toxoplasma gondii seropositivity and depression in children and adolescents.

Identification of the structural causes of depression is important for the treatment process, and toxoplasmosis may be related to psychiatric disorders. The aim of this study was to evaluate the relationship between Toxoplasma gondii (T. gondii) seropositivity and depression in children and adolescents. This case-control study included 37 children and adolescents aged 11-18 years diagnosed with depression who were followed by the Manisa Celal Bayar University Child and Adolescent Mental Health Service and 36 children and adolescents aged 11-18 years with no history of depressive episodes or psychiatric disorder treated by the Pediatric Outpatient Department. The T. gondii serology of these two groups was evaluated and compared. There were no statistically significant age or sex differences between the 37 participants with depression and the 36 healthy controls. Eight patients and two controls were seropositive for T. gondii, a statistically significant difference (p = 0.046). Seropositivity was significantly higher in patients with suicidal ideation (p = 0.005) than in those without suicidal ideation. The seropositivity of seven of the nine participants who attempted suicide was significantly higher (p < 0.001) than that of participants who did not. Thus, T. gondii infection may affect the predisposition for and severity of depression.

Impaired social behaviour and molecular mediators of associated neural circuits during chronic Toxoplasma gondii infection in female mice.

Toxoplasma gondii (T. gondii) is a neurotropic parasite that is associated with various neuropsychiatric disorders. Rodents infected with T. gondii display a plethora of behavioural alterations, and Toxoplasma infection in humans has been strongly associated with disorders such as schizophrenia, in which impaired social behaviour is an important feature. Elucidating changes at the cellular level relevant to neuropsychiatric conditions can lead to effective therapies. Here, we compare changes in behaviour during an acute and chronic T. gondii infection in female mice. Further, we notice that during chronic phase of infection, mice display impaired sociability when exposed to a novel conspecific. Also, we show that T. gondii infected mice display impaired short-term social recognition memory. However, object recognition memory remains intact. Using c-Fos as a marker of neuronal activity, we show that infection leads to an impairment in neuronal activation in the medial prefrontal cortex, hippocampus as well as the amygdala when mice are exposed to a social environment and a change in functional connectivity between these regions. We found changes in synaptic proteins that play a role in the process of neuronal activation such as synaptophysin, PSD-95 and changes in downstream substrates of cell activity such as cyclic AMP, phospho-CREB and BDNF. Our results point towards an imbalance in neuronal activity that can lead to a wider range of neuropsychiatric problems upon T. gondii infection.

Toxoplasmosis: A pathway to neuropsychiatric disorders.

Toxoplasma gondii is an obligate intracellular parasite that resides, in a latent form, in the human central nervous system. Infection with Toxoplasma drastically alters the behaviour of rodents and is associated with the incidence of specific neuropsychiatric conditions in humans. But the question remains: how does this pervasive human pathogen alter behaviour of the mammalian host? This fundamental question is receiving increasing attention as it has far reaching public health implications for a parasite that is very common in human populations. Our current understanding centres on neuronal changes that are elicited directly by this intracellular parasite versus indirect changes that occur due to activation of the immune system within the CNS, or a combination of both. In this review, we explore the interactions between Toxoplasma and its host, the proposed mechanisms and consequences on neuronal function and mental health, and discuss Toxoplasma infection as a public health issue.

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.

Toxoplasma gondii - obsessive -compulsive disorder relationship: is it different in children?

BACKGROUND AND AIM: Obsessive-compulsive disorder (OCD) is a common neuropsychiatric illness. Although the etiology of OCD is still unknown, recent investigations have associated development of OCD with infectious illness. Toxoplasma gondii (T. gondii) is a neurotropic protozoan parasite that causes infection of the central nervous system. In the last decade, a lot of researches have focused on the possible relationship between exposure to T. gondii and neuropsychiatric disorders such as schizophrenia. Therefore, in this study, it was aimed to investigate a possible association between Toxoplasma infection and OCD in children and adolescents. METHODS: We selected 55 patients with OCD (aged between 7 and 16 years) and 59 healthy children and adolescents (aged between 7 and 16 years), and investigated the seropositivity rate for anti-Toxoplasma IgG antibodies by enzyme-linked immunosorbent assay. RESULTS: The seropositivity rate for anti-T. gondii IgG antibodies among OCD patients (21.82%) was found to be higher than the rate in control group (15.25%). However, the difference between the OCD group and the control group was not statistically significant (p > .05). CONCLUSION: In contrast to studies in adult patients, the results of this study do not support the relationship between T. gondii and OCD children and adolescents.

A multicenter survey on toxoplasmosis knowledge among pregnant women in Poland (the TOWER study).

BACKGROUND: The seroprevalence of Toxoplasma gondii ranges widely in different areas of the world and different populations. Although toxoplasmosis is typically benign and asymptomatic, it induces major complications in immunocompromised individuals and during pregnancy. Prevention of maternal primary infection constitutes the major tool for avoiding congenital T. gondii infections and toxoplasmosis complications. The preventive measures depend on the women's knowledge about toxoplasmosis. The aim of the study was to assess the knowledge on toxoplasmosis among pregnant women in Poland. METHODS: The study was conducted between October 2016 and January 2017 in 3 Polish cities. During a visit in a hospital outpatient clinic, pregnant women aged > 16 years fulfilled a previously validated questionnaire. The questions concerned personal data (age, parity, educational level, place of residence), toxoplasmosis knowledge (etiology, routes of transmission, symptoms, sequelae), and sources consulted to collect information. RESULTS: Overall, 465 pregnant women participated in the survey; 439 (94.4%) were aware of toxoplasmosis. Toxoplasmosis was perceived as a zoonotic disease by 77.4%, as a parasitic disease by 41.7%, as a disease transmitted through poor hand hygiene by 8.6%, as a childhood illness by 4%, and as a congenital disease by 0.4%. Regarding the transmission route, 84.5% of women pointed at a domestic cat, 46.7% at eating raw or undercooked meat. The total of 84.3% did not know toxoplasmosis symptoms, and 12.0% stated that they did not present the symptoms. In multivariate analysis, younger age (OR, 2.74; 95% CI, 1.67-4.49; p <  0.001), city residence (OR, 13.45; 95% CI, 3.12-57.89; p <  0.003), and higher education level (OR, 6.81; 95% CI, 3.69-12.59; p <  0.001) were significantly associated with better knowledge of toxoplasmosis, and the number of children (OR, 0.32; 95% CI, 0.22-0.48; p <  0.001) - with higher knowledge of the symptoms. CONCLUSIONS: Among pregnant women in Poland, the basic knowledge on toxoplasmosis is very high (94.4%). Younger age, city residence, higher education level, and the number of children turned out significantly associated with better knowledge of T. gondii and toxoplasmosis symptoms.

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.

Moderation of the relationship between Toxoplasma gondii seropositivity and trait impulsivity in younger men by the phenylalanine-tyrosine ratio.

Previously, we reported that Toxoplasma gondii (T. gondii)-seropositivity is associated with higher impulsive sensation seeking in younger men. As dopaminergic and serotonergic signaling regulate impulsivity, and as T. gondii directly and indirectly affects dopaminergic signaling and induces activation of the kynurenine pathway leading to the diversion of tryptophan from serotonin production, we investigated if dopamine and serotonin precursors or the tryptophan metabolite kynurenine interact with the T. gondii-impulsivity association. In 950 psychiatrically healthy participants, trait impulsivity scores were related to T. gondii IgG seropositivity. Interactions were also identified between categorized levels of phenylalanine (Phe), tyrosine (Tyr), Phe:Tyr ratio, kynurenine (Kyn), tryptophan (Trp) and Kyn:Trp ratio, and age and gender. Only younger T. gondii-positive men with a high Phe:Tyr ratio, were found to have significantly higher impulsivity scores. There were no significant associations in other demographic groups, including women and older men. No significant effects or interactions were identified for Phe, Tyr, Kyn, Trp, or Kyn:Trp ratio. Phe:Tyr ratio, therefore, may play a moderating role in the association between T. gondii seropositivity and impulsivity in younger men. These results could potentially lead to individualized approaches to reduce impulsivity, based on combined demographic, biochemical and serological factors.