From inflammatory reactions to neurotransmitter changes: Implications for understanding the neurobehavioral changes in mice chronically infected with Toxoplasma gondii.

Toxoplasma gondii is a protozoan parasite that can cause a latent infection in the central nervous system, leading to neurobehavioral abnormalities in the host. However, the mechanism underlying these changes remains relatively unexplored. In this study, we detected behavioral changes, pathological injury, secretion of neurotransmitters and related signal pathway in mice infected by T. gondii using behavioral test, histopathology, immunofluorescence staining, western blotting, HPLC and real time PCR. Mice showed neurobehavioral disturbances two months after infection with T. gondii. Histopathology revealed the activation of astrocytes and microglia, apoptosis of neurons and decreases in synapses in the brain of infected mice. Excessive secretion of cytokines and chemokines was detected in the brains of mice infected by T. gondii compared to uninfected mice. Furthermore, T. gondii infection led to abnormalities in neurotransmitters and the activation of NF-κB and dopamine (DA) signaling pathways in the infected mice. In conclusion, excessive activation of the inflammation in the brain could induce neuronal apoptosis in mice chronically infected with T. gondii. Dysregulation of the dopaminergic neurotransmitter could provide an explanation of neurobehavioral disorders in infected hosts.

Relationship Between Toxoplasma gondii and Mood Disturbance in Women Veterans.

BACKGROUND: Toxoplasma gondii is an intracellular protozoan parasite with zoonotic potential that causes acute and chronic diseases, which has been associated with schizophrenia, depression, bipolar disorder, and suicidal behavior. Military personnel may be at increased risk for exposure to the parasite when deployed to countries with high prevalence rates. METHODS: Women Veterans were recruited to participate in the study at an event to recognize women Veterans and later through e-mails. Blood samples were collected from 70 women Veterans (mean age: 47 years) and analyzed for T. gondii IgG titer. Participants completed a demographic instrument, Center for Epidemiologic Studies Depression scale, Profile of Mood States (POMS), and Post-Traumatic Stress Disorder Checklist-Military. RESULTS: The infectivity rate was lower than the rate in the United States (11.4% [8 out of 70 were seropositive], but 6 of the 8 [75%] had been deployed outside the United States. Pearson correlations and t tests showed significant relationships between T. gondii seropositivity and Center for Epidemiologic Studies Depression score), POMS-depression, POMS-confusion, and POMS-anger subscale scores, and total mood disturbance score. CONCLUSIONS: This study is the first to describe biobehavioral relationships between chronic T. gondii infection, depression, and dysphoric moods in a military veteran population.

Cognitive and affective predictors of rehabilitation participation after stroke.

OBJECTIVE: To examine associations between cognitive and affective impairments and rehabilitation participation during stroke rehabilitation. DESIGN: Secondary analyses of stroke patients who received acetylcholinesterase inhibitors during inpatient rehabilitation. SETTING: University-affiliated inpatient rehabilitation facilities. PARTICIPANTS: Patients (N=44) admitted to inpatient stroke rehabilitation with impairment in attention, memory, or executive functions. INTERVENTIONS: Secondary analysis of patients receiving inpatient stroke rehabilitation care plus random assignment to one of two acetylcholinesterase inhibitors or no drug at rehabilitation admission. MAIN OUTCOME MEASURES: Correlations between measures of cognitive (Digit Span, Hopkins Verbal Learning Test, Executive Interview) and affective impairments (Hamilton Rating Scale for Depression, Apathy Evaluation Scale) and participation (Pittsburgh Rehabilitation and Participation Scale) were examined. Significant correlates of participation were examined in a linear multiple regression model. RESULTS: Executive functions and depressive symptoms were significant correlates of participation. After controlling for baseline disability, executive functions predicted participation, but depressive symptoms did not (F(4,32)=9.35; R(2)=.54, P<.001). CONCLUSIONS: These findings are an important first step toward understanding potentially modifiable clinical factors that contribute to rehabilitation participation and overall functional status after rehabilitation. A better understanding of cognitive impairment and rehabilitation participation may be used to develop strategies for improving functional outcomes after stroke.

Toxoplasma gondii antibody titers and history of suicide attempts in patients with recurrent mood disorders.

Toxoplasma gondii (T.gondii) is an obligate intracellular protozoan parasite infecting one-third of the world population, residing relatively silently in the brain of the immunocompetent host. We hypothesized that T.gondii seropositivity and serointensity are associated with having a history of attempting suicide and, in those attempting suicide, a greater number of attempts. T.gondii seropositivity and antibody titers were compared between (a) patients with recurrent mood disorders with history of suicide attempt (99 individuals) versus (b) patients with recurrent mood disorders without history of suicide attempt (119 individuals), and (c) healthy controls (39 individuals). Diagnosis was made using the Structured Clinical Interview for DSM-IV. Statistical methods included chi square, analysis of variance, and linear and logistic regression analyses. Suicide attempters had higher T.gondii antibody titers than nonsuicide attempters (p = 0.004). The logistic regression analysis revealed a predictive association between titers of anti- T.gondii antibodies and history of suicide attempt with OR = 1.55 (1.14-2.12), p = 0.006. No significant relationship was found between T.gondii seropositivity and suicide attempt status, number of prior suicide attempts, and recurrent mood disorder diagnosis. Although preliminary and bearing replication, this is the first report, to our knowledge, of an association between attempting suicide and T. gondii.

Interventions for acute mood episodes in patients with bipolar disorder.

For patients with bipolar disorder who present in an acute mood episode, quick intervention is needed to minimize hospitalization and prevent catastrophic consequences. Clinicians should consider patients' treatment history, cycling patterns, and the current stage in the disease course before selecting a treatment and should choose agents with a rapid and robust onset of action when initiating pharmacotherapy. Overall treatment of acute episodes should be designed for a smooth transition into maintenance therapy, the success of which is the long-term treatment goal.

Parasites as causative agents of human affective disorders? The impact of anti-psychotic, mood-stabilizer and anti-parasite medication on Toxoplasma gondii's ability to alter host behaviour.

With increasing pressure to understand transmissible agents, renewed recognition of infectious causation of both acute and chronic diseases is occurring. Epidemiological and neuropathological studies indicate that some cases of schizophrenia may be associated with environmental factors, such as exposure to the ubiquitous protozoan Toxoplasma gondii. Reasons for this include T. gondii's ability to establish persistent infection within the central nervous system, its ability to manipulate intermediate host behaviour, the occurrence of neurological and psychiatric symptoms in some infected individuals, and an association between infection with increased incidence of schizophrenia. Moreover, several of the medications used to treat schizophrenia and other psychiatric disease have recently been demonstrated in vitro to possess anti-parasitic, and in particular anti-T. gondii, properties. Our aim here was thus to test the hypothesis that the anti-psychotic and mood stabilizing activity of some medications may be achieved, or at least augmented, through their in vivo inhibition of T. gondii replication and invasion in infected individuals. In particular we predicted, using the epidemiologically and clinically applicable rat-T. gondii model system, and following a previously described and neurologically characterized 'feline attraction' protocol that haloperidol (an anti-psychotic used in the treatment of mental illnesses including schizophrenia) and/or valproic acid (a mood stabilizer used in the treatment of mental illnesses including schizophrenia), would be, at least, as effective in preventing the development of T. gondii-associated behavioural and cognitive alterations as the standard anti-T. gondii chemotherapeutics pyrimethamine with Dapsone. We demonstrate that, while T. gondii appears to alter the rats' perception of predation risk turning their innate aversion into a 'suicidal' feline attraction, anti-psychotic drugs prove as efficient as anti-T. gondii drugs in preventing such behavioural alterations. Our results have important implications regarding the aetiology and treatment of such disorders.

Herpesviruses and Toxoplasma gondii in orbital frontal cortex of psychiatric patients.

Herpes simplex virus (HSV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus-6 (HHV-6) are viruses capable of establishing latency. All of these infect the CNS and have been detected in human postmortem brains. Toxoplasma gondii is a protozoan organism which can reactivate in the brains of previously infected immunocompromised individuals. To screen for the presence of herpesviruses and T. gondii in postmortem orbital frontal brain samples from patients with schizophrenia, affective disorders, and controls, we used nested-polymerase chain reaction (n-PCR)/sequencing. We identified HHV-6B sequences in 2/51 postmortem brain samples but no sequences from other herpesviruses. We did not detect sequences of T. gondii in the postmortem brains. Additional studies including ones directed at the sensitive detection of viral nucleic acids in multiple brain regions should be directed at confirming or excluding a role for viruses and protozoa in the etiology of these disorders.