Sulfadiazine Plus Pyrimethamine Therapy Reversed Multiple Behavioral and Neurocognitive Changes in Long-Term Chronic Toxoplasmosis by Reducing Brain Cyst Load and Inflammation-Related Alterations.

Toxoplasma gondii infects one-third of the world population. For decades, it has been considered a silent lifelong infection. However, chronically T. gondii-infected persons may present psychiatric and neurocognitive changes as anxiety, depression, and memory loss. In a model of long-term chronic infection, behavioral alterations parallel neuroinflammation and systemic high cytokine levels, and may reflect brain cyst load. Recent findings support that in chronic infection an active parasite-host interplay involves an immune-mediated control of tissue cysts. Here, we tested the idea that etiological treatment in chronic phase may add advantage to intrinsic immune-mediated cyst control and impact behavioral changes. Thus, we combined sulfadiazine-plus-pyrimethamine (S+P), the first-choice therapy for toxoplasmosis, to study the association of brain cyst load and biological processes related to the immune response (neuroinflammation, blood-brain barrier -BBB- disruption and serum cytokine levels), with behavioral and neurocognitive changes of long-term chronic infection. Female C57BL/6 mice (H-2b) were infected (5 cysts, ME-49 strain) and treated with S+P from 30 to 60 days postinfection (dpi), compared with vehicle (Veh)-treated and noninfected controls. At endpoints (pre-therapy, 30 dpi; S+P therapy, 60 dpi; after ceased therapy, 90 dpi), independent groups were subjected to behavioral tests, and brain tissues and sera were collected. Multiple behavioral and neurocognitive changes were detected in the early (30 dpi) and long-term (60 and 90 dpi) chronic infection. S+P therapy resolved locomotor alterations, anxiety, and depressive-like behavior, partially or transiently ameliorated hyperactivity and habituation memory loss. Analysis after therapy cessation showed that S+P therapy reduced the number of stimuli required for aversive memory consolidation. S+P therapy resulted in reduced brain cyst load, neuroinflammation and BBB disruption, and lowered systemic Th1-cytokine levels. Correlation analysis revealed association between IFNγ, TNF and MCP-1/CCL2 serum levels, brain cyst load and behavioral and neurocognitive alterations. Moreover, principal-component analysis (PCA-2D and 3D projections) highlighted distinction between clusters (noninfected; Veh-treated and S+P-treated infected). Thus, our data suggest that S+P therapy added gain to intrinsic brain cyst control and, direct or indirectly, ameliorated inflammation-related alterations, traits associated with behavioral and neurocognitive alterations.

Selective forgetting of self-threatening statements: Mnemic neglect for dementia information in people with mild dementia.

OBJECTIVE: We tested whether people with dementia manifest selective forgetting for self-threatening information, the mnemic neglect effect (MNE). This selective forgetting is observed among healthy adults in the recall, but not the recognition, of self-threatening feedback. METHODS: Sixty-four statements about dementia were rated for their level of negativity by 280 staff and students at University of the West of England. The 12 statements rated as most negative and the 12 statements rated as least negative were then read to 62 people with dementia. Participants were randomized to 1 of 2 conditions with the statements referring either to self or to another person. High-negativity and self-referent statements had strong threat potential. Participants recalled the statements and then completed a recognition task, which consisted of the 24 previously read statements and 24 new statements. RESULTS: Participants manifested the MNE: They recalled fewer high-negativity (compared with low-negativity) statements, but only when these referred to the self rather than another person. This pattern occurred independently of levels of depression or anxiety. Participants also made more self-protective intrusion errors when the statements referred to the self than another person. Participants did not differ in their recognition of statements. CONCLUSION: The MNE occurs among people with dementia. The selective forgetting of highly negative, self-referent statements serves to protect the self against the threat that dementia represents. Given the similarities between the MNE and the clinical phenomenon of repression, the findings may mark psychological processes that are implicated in the acceptance (or lack thereof) of a dementia diagnosis.

Chronic Helminth Infection Perturbs the Gut-Brain Axis, Promotes Neuropathology, and Alters Behavior.

Helminth infections in children are associated with impaired cognitive development; however, the biological mechanisms for this remain unclear. Using a murine model of gastrointestinal helminth infection, we demonstrate that early-life exposure to helminths promotes local and systemic inflammatory responses and transient changes in the gastrointestinal microbiome. Behavioral and cognitive analyses performed 9-months postinfection revealed deficits in spatial recognition memory and an anxiety-like behavioral phenotype in worm-infected mice, which was associated with neuropathology and increased microglial activation within the brain. This study demonstrates a previously unrecognized mechanism through which helminth infections may influence cognitive function, via perturbations in the gut-immune-brain axis.

Cognitive deficits and educational loss in children with schistosome infection-A systematic review and meta-analysis.

BACKGROUND: By means of meta-analysis of information from all relevant epidemiologic studies, we examined the hypothesis that Schistosoma infection in school-aged children (SAC) is associated with educational loss and cognitive deficits. METHODOLOGY/PRINCIPAL FINDINGS: This review was prospectively registered in the PROSPERO database (CRD42016040052). Medline, Biosis, and Web of Science were searched for studies published before August 2016 that evaluated associations between Schistosoma infection and cognitive or educational outcomes. Cognitive function was defined in four domains-learning, memory, reaction time, and innate intelligence. Educational outcome measures were defined as attendance and scholastic achievement. Risk of bias (ROB) was evaluated using the Newcastle-Ottawa quality assessment scale. Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated to compare cognitive and educational measures for Schistosoma infected /not dewormed vs. uninfected/dewormed children. Sensitivity analyses by study design, ROB, and sequential exclusion of individual studies were implemented. Thirty studies from 14 countries, including 38,992 SAC between 5-19 years old, were identified. Compared to uninfected children and children dewormed with praziquantel, the presence of Schistosoma infection and/or non-dewormed status was associated with deficits in school attendance (SMD = -0.36, 95%CI: -0.60, -0.12), scholastic achievement (SMD = -0.58, 95%CI: -0.96, -0.20), learning (SMD = -0.39, 95%CI: -0.70, -0.09) and memory (SMD = -0.28, 95%CI: -0.52, -0.04) tests. By contrast, Schistosoma-infected/non-dewormed and uninfected/dewormed children were similar with respect to performance in tests of reaction time (SMD = -0.06, 95%CI: -0.42, 0.30) and intelligence (SMD = -0.25, 95%CI: -0.57, 0.06). Schistosoma infection-associated deficits in educational measures were robust among observational studies, but not among interventional studies. The significance of infection-associated deficits in scholastic achievement was sensitive to ROB. Schistosoma infection-related deficits in learning and memory tests were invariant by ROB and study design. CONCLUSION/SIGNIFICANCE: Schistosoma infection/non-treatment was significantly associated with educational, learning, and memory deficits in SAC. Early treatment of children in Schistosoma-endemic regions could potentially mitigate these deficits. TRIAL REGISTRATION: ClinicalTrials.gov CRD42016040052.

Relation between acetylcholinesterase and Na+, K+-ATPase activities with impaired memory of mice experimentally infected by Trypanosoma cruzi.

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and causes severe cardiac and brain damage, leading to behavioral alterations in humans and animals. However, the mechanisms involved in memory impairment during T. cruzi infection remain unknown. It has long been recognized that the enzymatic activities of acetylcholinesterase (AChE) and Na+, K+-ATPase are linked with memory dysfunction during other trypanosomiasis. Thus, the aim of this study was to evaluate the involvement of cerebral AChE and Na+, K+-ATPase activities in the memory impairment during T. cruzi (Colombian strain) infection. A significant decrease on latency time during the inhibitory avoidance task was observed in animals infected by T. cruzi compared to uninfected animals, findings compatible to memory dysfunction. Moreover, the cerebral AChE activity increased, while the Na+, K+-ATPase decreased in T. cruzi infected compared to uninfected animals. Histopathology revealed mild to moderate multifocal gliosis in the cerebral cortex and light focal meningeal lymphoplasmacytic infiltrate, which may have contributed to memory loss. Based on these evidences, we can conclude that T. cruzi (Colombian strain) causes memory impairment in mice experimentally infected. Moreover, the changes in AChE and Na+, K+-ATPase activities may be considered a mechanism involved in disease pathogenesis.

Nerolidol-loaded nanospheres prevent behavioral impairment via ameliorating Na+, K+-ATPase and AChE activities as well as reducing oxidative stress in the brain of Trypanosoma evansi-infected mice.

The aim of this study was to investigate the effect of nerolidol-loaded nanospheres (N-NS) on the treatment of memory impairment caused by Trypanosoma evansi in mice, as well as oxidative stress, and Na+, K+-ATPase and acetylcholinesterase (AChE) activities in brain tissue. Animals were submitted to behavioral tasks (inhibitory avoidance task and open-field test) 4 days postinfection (PI). Reactive oxygen species (ROS) and thiobarbituric acid-reactive substance (TBARS) levels and catalase (CAT), superoxide dismutase (SOD), Na+, K+-ATPase and AChE activities were measured on the fifth-day PI. T. evansi-infected mice showed memory deficit, increased ROS and TBARS levels and SOD and AChE activities, and decreased CAT and Na+, K+-ATPase activities compared to uninfected mice. N-NS prevented memory impairment and oxidative stress parameters (except SOD activity), while free nerolidol (N-F) restored only CAT activity. Also, N-NS treatment was able to prevent alterations in Na+, K+-ATPase and AChE activities caused by T. evansi infection. A significantly negative correlation was observed between memory and ROS production (p < 0.001; r = -0.941), as well as between memory and AChE activity (p < 0.05; r = -0.774). On the contrary, a significantly positive correlation between memory and Na+, K+-ATPase activity was observed (p < 0.01; r = 0.844). In conclusion, N-NS was able to reverse memory impairment and to prevent increased ROS and TBARS levels due to amelioration of Na+, K+-ATPase and AChE activities and to activation of the antioxidant enzymes, respectively. These results suggest that N-NS treatment may be a useful strategy to treat memory dysfunction and oxidative stress caused by T. evansi infection.

Selenium attenuates apoptosis, inflammation and oxidative stress in the blood and brain of aged rats with scopolamine-induced dementia.

A potent antioxidant, selenium might modulate dementia-induced progression of brain and blood oxidative and apoptotic injuries. The present study explores whether selenium protects against experimental dementia (scopolamine, SCOP)-induced brain, and blood oxidative stress, apoptosis levels, and cytokine production in rats. Thirty-two rats were equally divided into four groups. The first group was used as an untreated control. The second group was treated with SCOP to induce dementia. The third and fourth groups received 1.5 mg/kg selenium (sodium selenite) and SCOP + selenium, respectively. Dementia was induced in the second and forth groups by intraperitoneal SCOP (1 mg/kg) administration. Brain, plasma, and erythrocyte lipid peroxidation levels as well as plasma TNF-α, interleukin (IL)-1ß, and IL-4 levels were high in the SCOP group though they were low in selenium treatments. Selenium and selenium + SCOP treatments increased the lowered glutathione peroxidase activity, reduced glutathione, vitamins A and E concentrations in the brain, erythrocytes and plasma of the SCOP group. Apoptotic value expressions as active caspase-3, procaspase-9, and PARP were also increased by SCOP, while they were decreased by selenium and selenium + SCOP treatments. In conclusion, selenium induced protective effects against experimental dementia-induced brain, and blood oxidative injuries and apoptosis through regulation of cytokine production, vitamin E, glutathione concentrations, and glutathione peroxidase activity.

Reduced ERPs and theta oscillations underlie working memory deficits in Toxoplasma gondii infected seniors.

Toxoplasma gondii is one of the most widespread infections in humans. Recent studies give evidence for memory deficits in infected older adults. To investigate working memory dysfunction in infected elderly, a double-blinded electrophysiological study was conducted. 84 persons derived from a sample of 131 healthy participants with the mean age of 70 years were assigned to two groups of 42 non-infected and 42 infected individuals. The outcome measures were behavioral performance, target and response-related ERPs, and time-frequency wavelets during performance in a n-back working-memory task. The infected individuals showed a reduced rate of detected targets and diminished P3b amplitude both in target-locked as well as response-locked data compared to the non-infected group. Time-frequency decomposition of the EEG-signals revealed lower evoked power in the theta frequency range in the target-locked as well as in the response-locked data in infected individuals. The reported effects were comparable with differences between healthy young and old adults described previously. Taking together, the reduced working-memory performance accompanied by an attenuated P3b and frontal theta activity may suggest neurotransmitter imbalance like dopamine and norepinephrine in T. gondii infected individuals. In face of a high prevalence of T. gondii infection and the increasing ratio of older population their accelerated memory decline may have substantial socioeconomic consequences.

Toxoplasma gondii impairs memory in infected seniors.

Almost 30% of humans present a Toxoplasma gondii positive antibody status and its prevalence increases with age. The central nervous system is the main target. However, little is known about the influence of asymptomatic i.e. latent Toxoplasmosis on cognitive functions in humans. To investigate neurocognitive dysfunctions in asymptomatic older adults with T. gondii positive antibody status a double-blinded neuropsychological study was conducted. The participants were classified from a population-based sample (N=131) of healthy participants with an age of 65 years and older into two groups with 42 individuals each: Toxoplasmosis positive (T-pos; IgG>50 IU/ml) and Toxoplasmosis negative (T-neg; IgG=0 IU/ml). The outcome measures were a computer-based working-memory test (2-back) and several standardized psychometric tests of memory and executive cognitive functions. T-pos seniors showed an impairment of different aspects of memory. The rate of correctly detected target symbols in a 2-back task was decreased by nearly 9% (P=0.020), corresponding to a performance reduction of about 35% in working memory relative to the T-neg group. Moreover, T-pos seniors had a lower performance in a verbal memory test, both regarding immediate recall (10% reduction; P=0.022), delayed recognition (6%; P=0.037) and recall from long-term memory assessed by the word fluency tests (12%; P=0.029). In contrast, executive functions were not affected. The effects remained mostly unchanged after controlling for medication. The impairment of memory functions in T-pos seniors was accompanied by a decreased self-reported quality of life. Because of the high prevalence of asymptomatic Toxoplasmosis and an increasing population of older adults this finding is of high relevance for public health.

Neurological sequelae in survivors of cerebral malaria.

INTRODUCTION: Cerebral malaria is a common cause of neurological sequelae and death in childhood. Information on persistent neurological sequelae post hospital discharge and their predisposing factors are scarce. METHODS: This is a prospective study describing persisting neurological impairments post discharge among children treated for cerebral malaria. In addition the study was designed to investigate the frequency of persistent neurologic deficits and the risk factors for their persistence in these patients. The case records of 160 patients treated for CM at the Paediatrics Department of University College Hospital, Ibadan from January 2004 to November 2006 were reviewed to recruit cases. Recruited survivors were then followed up for information concerning the presence and persistence of neurological sequelae. RESULTS: A total of 160 children aged 9 months to 134 months were admitted and treated for CM during the study period. One hundred and thirty one (81.9%) survived while 29 (18.1%) died. The 131 survivors of cerebral malaria consisted of 64 boys and 67 girls. Neurological sequelae occurred in 13.7% of survivors of cerebral malaria at discharge and 4.6% at follow up. Six children with neurological deficits at discharge had persistence of deficits 6 months post-hospital discharge and one at 24 months. No associations were found between hypoglycemia, anemia, age, sex and multiplicity of convulsions, and persistence of neurologic sequelae. The persisting neurologic deficits among survivors at follow up were: memory impairment (1.5%), seizure disorders (0.8%), visual impairment (0.8%), speech impairment (0.8%), monoparesis (0.8%) and hyperactivity (0.8%) at follow up. The longest persisting sequelae lasted for at least 24 months. CONCLUSION: Neurologic deficits are not uncommon complications of CM. Neurologic sequelae may persist for as long as 24 months or more in survivors of childhood CM. There is no association between the risk factors for neurologic deficits and persistent neurologic sequelae.

Minocycline improves functional outcomes, memory deficits, and histopathology after endovascular perforation-induced subarachnoid hemorrhage in rats.

Subarachnoid hemorrhage (SAH) results in significant long-lasting cognitive dysfunction. Therefore, evaluating acute and long-term outcomes after therapeutic intervention is important for clinical translation. The aim of this study was to use minocycline, a known neuroprotectant agent, to evaluate the long-term benefits in terms of neurobehavior and neuropathology after experimental SAH in rats, and to determine which neurobehavioral test would be effective for long-term evaluation. SAH was induced by endovascular perforation in adult male Sprague-Dawley rats (n=118). The animals were treated with intraperitoneal injection of minocycline (45 mg/kg or 135 mg/kg) or vehicle 1 h after SAH induction. In the short-term, animals were euthanized at 24 and 72 h for evaluation of neurobehavior, brain water content, and matrix metalloproteinase (MMP) activity. In the long-term, neurobehavior was evaluated at days 21-28 post-SAH, and histopathological analysis was done at day 28. High-dose but not low-dose minocycline reduced brain water content at 24 h, and therefore only the high-dose regimen was used for further evaluation, which reduced MMP-9 activity at 24 h. Further, high-dose minocycline improved spatial memory and attenuated neuronal loss in the hippocampus and cortex. The rotarod, T-maze, and water maze tests, but not the inclined plane test, detected neurobehavioral deficits in SAH rats at days 21-28. This study demonstrates that minocycline attenuates long-term functional and morphological outcomes after endovascular perforation-induced SAH. Long-term neurobehavioral assessments using the rotarod, T-maze, and water maze tests could be useful to evaluate the efficacy of therapeutic intervention after experimental SAH.

Influence of intracerebral administration of NO agents in dorsal hippocampus (CA1) on cannabinoid state-dependent memory in the step-down passive avoidance test.

In the present study, the effects of nitric oxide agents on WIN55, 212-2 induced state-dependent memory of passive avoidance task were examined in mice. One-trial step-down paradigm was used for the assessment of memory retention in adult male NMRI mice. Post-training intra-CA1 administration of CB1 and CB2 receptor agonists, WIN55, 212-2 (0.25, 0.5 and 1 microg/mouse), dose-dependently decreased memory retrieval. The memory impairment induced by post-training administration of WIN55, 212-2 (1 microg/mouse) was restored by pre-test administration of the same dose of the drug (1 microg/mouse, intra-CA1), showing the WIN55, 212-2 state-dependent memory. Single intra-CA1 administration of L-arginine (0.3, 1 and 3 microg/mouse) or L-NAME (0.3, 1 and 3 microg/mouse), 5 min pre-test could not alter memory retrieval. On the other hand, in the animals in which retrieval was impaired due to post-training administration of WIN55, 212-2 (1 microg/mouse), pre-test intra-CA1 administration of l-arginine (1 and 3 microg/mouse), but not L-NAME (0.3, 1 and 3 microg/mouse) 24h after training restored memory retrieval. Also, in the animals which received both post-training (1 microg/mouse) and pre-test injections of WIN55, 212-2 (1 microg/mouse), the injection of L-NAME (3 microg/mouse, intra-CA1), 2 min before pre-test administration decreased retrieval. Furthermore, in the animals under the influence of post-training administration of WIN55, 212-2 (1 microg/mouse), pre-test co-administration of non-effective doses of WIN55, 212-2 (0.25 microg/mouse) and L-arginine (0.3 and 1 microg/mouse), increased the restoration of memory by pre-test WIN55, 212-2. These findings may demonstrate the involvement of NO in state-dependent memory induced by intra-CA1 administration of WIN55, 212-2.

Helminth infection and cognitive impairment among Filipino children.

The objective of this study was to examine the independent effect of infection with each of four helminths (Ascaris lumbricoides, Schistosoma japonicum, Necator americanus, and Trichuris trichiura) on cognitive function after adjusting for the potential confounders nutritional status, socioeconomic status (SES), hemoglobin, sex, and the presence of other helminthes. This cross-sectional study was carried out in a rural village in Leyte, The Philippines in 319 children 7-18 years old. Three stools were collected and read in duplicate by the Kato Katz method. Infection intensity was defined by World Health Organization criteria. Cognitive tests were culturally adapted and translated. Learning and memory cognitive domains were each defined by three subscales of the Wide Range Assessment of Memory and Learning, which had an inter-rater reliability >/= 0.92 and test-retest reliabilities ranging from 0.61 to 0.89. A household SES questionnaire was administered. A logistic regression model was used to quantify the association between performance in different cognitive domains (learning, memory, verbal fluency, and the Philippine Non-Verbal Intelligence Test) and helminth infections. After adjusting for age, sex, nutritional status, hemoglobin, and SES, S. japonicum infection was associated with poor performance on tests of learning (odds ratio [OR] = 3.04, 95% confidence interval [CI] = 1.1-6.9), A. lumbricoides infection was associated with poor performance on tests of memory (OR = 2.2, 95% CI = 1.04-4.7), and T. trichiura infection was associated with poor performance on tests of verbal fluency (OR = 4.5, 95% CI = 1.04-30). Helminth infection was associated with lower performance in three of the four cognitive domains examined in this study. These relationships remained after rigorous control for other helminths and important confounding covariates.

Sleep and memory deficits in the rat produced by experimental infection with Trypanosoma cruzi.

We investigated whether the infection with Trypanosoma cruzi in rats could produce functional alterations of the central nervous system. The experimental group received an injection of 150,000 trypomastigotes / rat, whereas the control group received a saline injection. Spontaneous alternation behavior (SAB) tests and sleep-wake cycle recordings were obtained at the end of the parasitaemia. Results showed that the infected animals had significant sleep impairments, as denoted by an increase in the number of wake periods and a reduction of rapid eye movement sleep amount. SAB performance was also found to be impaired in these animals, as compared to the control group. Our results suggest that the rat is a suitable model for brain dysfunction studies in Chagas' disease.

[Diagnosis of neurocysticercosis: a case report]. / Diagnostic de la neurocysticercose: à propos d'un cas.

Neurocysticercosis is the most frequent parasitosis of central nervous system in the world. Neurological manifestations are in relation with locations number and topography, inflammatory reactions level and state of development of the parasite. Epilepsy is the main revealing symptom. Among other neurological manifestations, chronic headache, focal neurological signs, ataxia, language and behaviour disorder are the most anecdotal. The authors report a case of neurocysticercosis in a 71-year-old man with dysarthria and memory problems. Suspected by computed tomography, diagnosis was confirmed by immunoserologic assays such as enzyme-linked immunosorbent assay (ELISA) or enzyme-linked immunoelectrotransfer blot assay (EITB). This later emphasized on active form of the cyst. Specific treatment used albendazole as antihelminthic drug. Clinical evolution was good: neuroimaging and immunoserology results were normal respectively 2 and 6 months after the drug therapy.

Treatment of persistent Pfiesteria-human illness syndrome.

Patients with exposure to Pfiesteria toxin have developed an illness, Pfiesteria-human illness syndrome, characterized by skin lesions, headache, myalgias, conjunctival irritation, bronchospasm, abdominal pain, secretory diarrhea, recent memory loss, and difficulties with number sequencing. Not all patients demonstrated all features of the syndrome. The natural history of Pfiesteria-human illness syndrome shows that most patients' symptoms improve without treatment. This article reports the improvement of symptoms that had persisted for over one month in five patients, which the author attributes to treatment with cholestyramine. These patients were self-referred to the Pocomoke River Rash and Associated Illness Center, a clinic that opened on August 6, 1997, in response to the need for a central facility for diagnosis of human illness acquired from Pfiesteria. Until the Pfiesteria toxin(s) is isolated and characterized, and laboratory diagnostic tests are available, physicians must be able to recognize Pfiesteria-human illness syndrome and intervene when symptoms, particularly memory loss and diarrhea, cause significant impairment in daily activities. There are no precedents for the treatment of Pfiesteria or any dinoflagellate toxin-related human illness reported in the literature. The successful use of cholestyramine reported here may provide a model for understanding dinoflagellate toxin physiology in the human body. This paper reports an uncontrolled observational study. When identification of the toxin is completed, a basis for properly controlled studies will be available.