IL-33 receptor ST2 regulates the cognitive impairments associated with experimental cerebral malaria.

Cerebral malaria (CM) is associated with a high mortality rate and long-term neurocognitive impairment in survivors. The murine model of experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA (PbA)-infection reproduces several of these features. We reported recently increased levels of IL-33 protein in brain undergoing ECM and the involvement of IL-33/ST2 pathway in ECM development. Here we show that PbA-infection induced early short term and spatial memory defects, prior to blood brain barrier (BBB) disruption, in wild-type mice, while ST2-deficient mice did not develop cognitive defects. PbA-induced neuroinflammation was reduced in ST2-deficient mice with low Ifng, Tnfa, Il1b, Il6, CXCL9, CXCL10 and Cd8a expression, associated with an absence of neurogenesis defects in hippocampus. PbA-infection triggered a dramatic increase of IL-33 expression by oligodendrocytes, through ST2 pathway. In vitro, IL-33/ST2 pathway induced microglia expression of IL-1ß which in turn stimulated IL-33 expression by oligodendrocytes. These results highlight the IL-33/ST2 pathway ability to orchestrate microglia and oligodendrocytes responses at an early stage of PbA-infection, with an amplification loop between IL-1ß and IL-33, responsible for an exacerbated neuroinflammation context and associated neurological and cognitive defects.

Gut microbiota disturbance during helminth infection: can it affect cognition and behaviour of children?

BACKGROUND: Bidirectional signalling between the brain and the gastrointestinal tract is regulated at neural, hormonal, and immunological levels. Recent studies have shown that helminth infections can alter the normal gut microbiota. Studies have also shown that the gut microbiota is instrumental in the normal development, maturation and function of the brain. The pathophysiological pathways by which helminth infections contribute to altered cognitive function remain poorly understood. DISCUSSION: We put forward the hypothesis that gastrointestinal infections with parasitic worms, such as helminths, induce an imbalance of the gut-brain axis, which, in turn, can detrimentally manifest in brain development. Factors supporting this hypothesis are: 1) research focusing on intelligence and school performance in school-aged children has shown helminth infections to be associated with cognitive impairment, 2) disturbances in gut microbiota have been shown to be associated with important cognitive developmental effects, and 3) helminth infections have been shown to alter the gut microbiota structure. Evidence on the complex interactions between extrinsic (parasite) and intrinsic (host-derived) factors has been synthesised and discussed. While evidence in favour of the helminth-gut microbiota-central nervous system hypothesis is circumstantial, it would be unwise to rule it out as a possible mechanism by which gastrointestinal helminth infections induce childhood cognitive morbidity. Further empirical studies are necessary to test an indirect effect of helminth infections on the modulation of mood and behaviour through its effects on the gut microbiota.

Subclinical Inflammation in Asymptomatic Schoolchildren With Plasmodium falciparum Parasitemia Correlates With Impaired Cognition.

BACKGROUND: Subclinical inflammation and cognitive deficits have been separately associated with asymptomatic Plasmodium falciparum infections in schoolchildren. However, whether parasite-induced inflammation is associated with worse cognition has not been addressed. We conducted a cross-sectional pilot study to better assess the effect of asymptomatic P. falciparum parasitemia and inflammation on cognition in Kenyan schoolchildren. METHODS: We enrolled 240 children aged 7-14 years residing in high malaria transmission in Western Kenya. Children performed five fluid cognition tests from a culturally adapted NIH toolbox and provided blood samples for blood smears and laboratory testing. Parasite densities and plasma concentrations of 14 cytokines were determined by quantitative PCR and multiplex immunoassay, respectively. Linear regression models were used to determine the effects of parasitemia and plasma cytokine concentrations on each of the cognitive scores as well as a composite cognitive score while controlling for age, gender, maternal education, and an interaction between age and P. falciparum infection status. RESULTS: Plasma concentrations of TNF, IL-6, IL-8, and IL-10 negatively correlated with the composite score and at least one of the individual cognitive tests. Parasite density in parasitemic children negatively correlated with the composite score and measures of cognitive flexibility and attention. In the adjusted model, parasite density and TNF, but not P. falciparum infection status, independently predicted lower cognitive composite scores. By mediation analysis, TNF significantly mediated ~29% of the negative effect of parasitemia on cognition. CONCLUSIONS: Among schoolchildren with PCR-confirmed asymptomatic P. falciparum infections, the negative effect of parasitemia on cognition could be mediated, in part, by subclinical inflammation. Additional studies are needed to validate our findings in settings of lower malaria transmission and address potential confounders that could affect both inflammation and cognitive performance.

MicroRNA-146a switches microglial phenotypes to resist the pathological processes and cognitive degradation of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and currently has no effective treatment. Mainstream research on the mechanisms and therapeutic targets of AD is focused on the two most important hallmarks, Aß and Tau, but the results from clinical studies are not encouraging. Abnormal microglial polarization is a clear typical pathological feature in the progression of AD. Microglia can be neuroprotective by degrading and removing Aß and Tau. However, under AD conditions, microglia transform into a pro-inflammatory phenotype that decreases the phagocytic activity of microglia, damages neurons and promotes the pathology of AD. We previously reported that a miR-146a polymorphism is associated with sporadic AD risk, and the nasal administration of miR-146a mimics reduced cognitive impairment and the main pathological features of AD. However, it is not clear by what mechanism miR-146a resists the pathological process of AD. In this study, we discovered that microglia-specific miR-146a overexpression reduced cognitive deficits in learning and memory, attenuated neuroinflammation, reduced Aß levels, ameliorated plaque-associated neuritic pathology, and prevented neuronal loss in APP/PS1 transgenic mice. In addition, we found that miR-146a switched the microglial phenotype, reduced pro-inflammatory cytokines and enhanced phagocytic function to protect neurons in vitro and in vivo. Moreover, transcriptional analysis confirmed that miR-146a opposed the pathological process of AD mainly through neuroinflammation-related pathways. In summary, our results provide sufficient evidence for the mechanism by which miR-146a opposes AD and strengthen the conclusion that miR-146a is a promising target for AD and other microglia-related diseases.

Angiostrongylus cantonensis causes cognitive impairments in heavily infected BALB/c and C57BL/6 mice.

BACKGROUND: Parasitic infections may cause significant effects on behavior, learning, and memory of the host. In the brain of mice heavily infected with Angiostrongylus cantonensis, severe damage has been observed in the hippocampus. This component has been considered to have associations with spatial learning and memory in humans and vertebrates. This study was designed to determine the impairments in behavior, learning, and memory in BALB/c and C57BL/6 mice heavily infected with the parasite. METHODS: Each mouse was inoculated with 50 third-stage larvae of A. cantonensis. After infection, daily changes in weight and dietary consumption, worm recoveries and survival rates were determined. The forced swimming test, open field test, and Morris water maze test were employed to evaluate depression- and anxiety-like behavior as well as impairments in spatial learning and memory, respectively. RESULTS: The worm recovery rate in the BALB/c mice was significantly lower than that of C57BL/6 mice from day 14 post-infection. The survival rate in infected BALB/c mice decreased to 0% by day 25 whereas those with swim-training survived three more days. On day 42, the C57BL/6 mice had a survival rate of 85.7% in the swimming group and 70% in the non-swimming group. Significant differences were found in weight between infected and non-infected BALB/c and C57BL/6 mice from day 13 and day 12, respectively with corresponding changes in their dietary consumption. Depression-like behavior was found in the infected BALB/c mice but not in C57BL/6 mice. However, anxiety-like behavior was found to occur only in C57BL/6 mice. Impaired spatial learning and memory were also found in the two strains of mice which occurred from day 14 post-infection. CONCLUSIONS: Results of this study indicate that A. cantonensis causes depression, anxiety, and impairments in spatial learning and memory in heavily infected mice. Moreover, significantly higher severity was observed in the Th-2 dominant BALB/c mice.

The association of Toxoplasma gondii IgG and cognitive function scores: NHANES 2013-2014.

Toxoplasma gondii (T. gondii) causes chronic, latent infections of global concern. Its subclinical influence on behavior and cognition are poorly understood. The objective of this research is to determine the relationship of T. gondii IgG with cognition using National Health and Nutrition Examination Survey data, 2013-2014 in older adults ≥60 years. A composite cognitive function score was created by adding the scores of the memory test, language/verbal fluency, and working memory test. T. gondii IgG was dichotomized at <33 IU/mL (negative) and ≥33 IU/mL (positive). There were 19.2% of the participants who were T. gondii IgG+. The memory function and language/verbal fluency subtests failed to reach significance; however, the difference in the working memory test was significant. In the multivariable ordinal logistic regression analysis, controlling for potential confounders, the odds of cognitive function scores decreasing in quartiles among people with positive vs. negative T. gondii IgG are 1.55 (95% CI: 1.08, 2.21; p = .0170). Establishing an evidence base for the association of T. gondii IgG and cognition is complex, but essential.

Detection of Taenia solium DNA in the Urine of Neurocysticercosis Patients.

Neurocysticercosis (NCC), caused by Taenia solium larvae that reside in the central nervous system, results in serious public health and medical issues in many regions of the world. Current diagnosis of NCC is complex requiring both serology and costly neuroimaging of parasitic cysts in the brain. This diagnostic pipeline can be problematic in resource-constrained settings. There is an unmet need for a highly sensitive and clinically informative diagnostic test to complement the present diagnostic approaches. Here, we report that T. solium-derived cell-free DNA is readily detectable in the urine of patients with the subarachnoid and parenchymal forms of NCC, and discuss the potential utility of this approach in enhancing and refining T. solium diagnostics.

Soil-transmitted helminth infection, loss of education and cognitive impairment in school-aged children: A systematic review and meta-analysis.

BACKGROUND: Evidence of an adverse influence of soil transmitted helminth (STH) infections on cognitive function and educational loss is equivocal. Prior meta-analyses have focused on randomized controlled trials only and have not sufficiently explored the potential for disparate influence of STH infection by cognitive domain. We re-examine the hypothesis that STH infection is associated with cognitive deficit and educational loss using data from all primary epidemiologic studies published between 1992 and 2016. METHODS: Medline, Biosis and Web of Science were searched for original studies published in the English language. Cognitive function was defined in four domains (learning, memory, reaction time and innate intelligence) and educational loss in two domains (attendance and scholastic achievement). Pooled effect across studies were calculated as standardized mean differences (SMD) to compare cognitive and educational measures for STH infected/non-dewormed children versus STH uninfected /dewormed children using Review Manager 5.3. Sub-group analyses were implemented by study design, risk of bias (ROB) and co-prevalence of Schistosoma species infection. Influential studies were excluded in sensitivity analysis to examine stability of pooled estimates. FINDINGS: We included 36 studies of 12,920 children. STH infected/non-dewormed children had small to moderate deficits in three domains-learning, memory and intelligence (SMD: -0.44 to -0.27, P<0.01-0.03) compared to STH-uninfected/dewormed children. There were no differences by infection/treatment status for reaction time, school attendance and scholastic achievement (SMD: -0.26 to -0.16, P = 0.06-0.19). Heterogeneity of the pooled effects in all six domains was high (P<0.01; I2 = 66-99%). Application of outlier treatment reduced heterogeneity in learning domain (P = 0.12; I2 = 33%) and strengthened STH-related associations in all domains but intelligence (SMD: -0.20, P = 0.09). Results varied by study design and ROB. Among experimental intervention studies, there was no association between STH treatment and educational loss/performance in tests of memory, reaction time and innate intelligence (SMD: -0.27 to 0.17, P = 0.18-0.69). Infection-related deficits in learning persisted within design/ROB levels (SMD: -0.37 to -52, P<0.01) except for pre-vs post intervention design (n = 3 studies, SMD = -0.43, P = 0.47). Deficits in memory, reaction time and innate intelligence persisted within observational studies (SMD: -0.23 to -0.38, all P<0.01) and high ROB strata (SMD:-0.37 to -0.83, P = 0.07 to <0.01). Further, in Schistosoma infection co-prevalent settings, associations were generally stronger and statistically robust for STH-related deficits in learning, memory and reaction time tests(SMD:-0.36 to -0.55, P = 0.003-0.02). STH-related deficits in school attendance and scholastic achievement was noted in low (SMD:-0.57, P = 0.05) and high ROB strata respectively. INTERPRETATION: We provide evidence of superior performance in five of six educational and cognitive domains assessed for STH uninfected/dewormed versus STH infected/not-dewormed school-aged children from helminth endemic regions. Cautious interpretation is warranted due to high ROB in some of the primary literature and high between study variability in most domains. Notwithstanding, this synthesis provides empirical support for a cognitive and educational benefit of deworming. The benefit of deworming will be enhanced by strategically employing, integrated interventions. Thus, multi-pronged inter-sectoral strategies that holistically address the environmental and structural roots of child cognitive impairment and educational loss in the developing world may be needed to fully realize the benefit of mass deworming programs.

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.

Latent toxoplasma infection in real-world schizophrenia: Results from the national FACE-SZ cohort.

OBJECTIVE: Latent Toxoplasma infection has been associated with widespread brain immune activation, increased blood brain barrier permeability, neural disruption, increased dopamine release in dopaminergic neurons, with NMDA activation and with schizophrenia (SZ) onset risk. Toxoplasma has been suggested to be a source of chronic low-grade inflammation and this inflammation has been associated with cognitive impairment in SZ. The objective of the present study were (i) to determine if latent Toxoplasma infection was associated with specific clinical features in stabilized SZ subjects, with cognitive impairment and with increased low-grade peripheral inflammation and (ii) to determine if Treatments with Anti-Toxoplasmic Activity (TATA) were associated with improved outcomes in subjects with latent Toxoplasma infection. METHODS: A comprehensive 2 daylong clinical and neuropsychological battery was administered in 250 SZ subjects included between 2015 and 2017 in the national FondaMental Expert Center (FACE-SZ) Cohort. Solid phase-enzyme microplate immunoassay methods were used to measure IgG class of antibodies to T. gondii in blood sample. Latent Toxoplasma infection was defined by T. gondii IgG ratio ≥0.8, equivalent to ≥10 international units. Chronic peripheral inflammation was defined by highly sensitive C reactive protein blood level ≥ 3 mg/L. RESULTS: Latent Toxoplasma infection has been found in 184 (73.6%) of this national multicentric sample. In the multivariate analyses, latent Toxoplasma infection has been significantly associated with higher PANSS negative (aOR = 1.1 [1.1-1.1], p = 0.04) and excitement subscores (aOR = 1.3 [1.1-1.6], p = 0.01), with two specific symptoms (i.e., reference delusion (aOR = 3.6 [1.2-10.6] p = 0.01) and alogia (aOR = 16.7 [2.0-134.7], p = 0.008)) and with chronic low-grade peripheral inflammation (27.2% vs. 7.6%, aOR = 3.8 [1.4-10.3], p = 0.004). Extrapyramidal symptoms remained significantly associated with latent Toxoplasma infection. On the opposite, no significant association of latent Toxoplasma infection with age, gender, age at SZ onset, suicide behavior or cognitive deficits has been found in these models (all p > 0.05). TATA were associated with lower depressive symptoms (aOR = 0.8[0.7-0.9], p = 0.01), and with lower rates of chronic peripheral inflammation (20.9% vs. 48.6%, aOR = 3.5 [1.5-7.9], p = 0.003) but not with higher cognitive scores (p > 0.05). CONCLUSION: The present findings suggest that Toxoplasma is almost 3 times more frequent in SZ population compared to general population in France. The potential cerebral underpinnings of the association of latent Toxoplasma infection and the above-mentioned outcomes have been discussed. Future studies should confirm that TATA may be effective to reduce Toxoplasma-associated depressive symptoms and low-grade peripheral inflammation.

Effects of perinatal diet and prenatal stress on the behavioural profile of aged male and female rats.

The present work studies whether chronic prenatal stress (PS) influences the long-term sex-dependent neuropsychological status of offspring and the effects of an early dietary intervention in the dam. In addition, dams were fed with either a high-fat sugar diet (HFSD) or methyl donor supplemented diet (MDSD). PS procedure did not affect body weight of the offspring. MDSD induced decreases in body weight both in male and female offspring (1 month) that were still present in aged rats. HFSD induced an increase in body weight both in male and female offspring that did not persist in aged rats. In the Porsolt forced swimming test, only young males showed increases in immobility time that were reversed by MDSD. In old female rats (20 months), PS-induced cognitive impairment in both the novel object recognition test (NORT) and in the Morris water maze that was reversed by MDSD, whereas in old males, cognitive impairments and reversion by MDSD was evident only in the Morris water maze. HFSD induced cognitive impairment in both control and PS old rats, but there was no additive effect of PS and HFSD. It is proposed here that the diversity of symptoms following PS could arise from programming effects in early brain development and that these effects could be modified by dietary intake of the dam.

Toxoplasma Gondii Moderates the Association between Multiple Folate-Cycle Factors and Cognitive Function in U.S. Adults.

Toxoplasma gondii (T. gondii) is a microscopic, apicomplexan parasite that can infect muscle or neural tissue, including the brain, in humans. While T. gondii infection has been associated with changes in mood, behavior, and cognition, the mechanism remains unclear. Recent evidence suggests that T. gondii may harvest folate from host neural cells. Reduced folate availability is associated with an increased risk of neurodevelopmental disorders, neurodegenerative diseases, and cognitive decline. We hypothesized that impairment in cognitive functioning in subjects seropositive for T. gondii might be associated with a reduction of folate availability in neural cells. We analyzed data from the third National Health and Nutrition Examination Survey to determine the associations between T. gondii infection, multiple folate-cycle factors, and three tests of cognitive functioning in U.S. adults aged 20 to 59 years. In these analyses, T. gondii moderated the associations of folate, vitamin B-12, and homocysteine with performance on the Serial Digit Learning task, a measure of learning and memory, as well as the association of folate with reaction time. The results of this study suggest that T. gondii might affect brain levels of folate and/or vitamin B-12 enough to affect cognitive functioning.

Anemia and growth retardation associated with Schistosoma haematobium infection in Mali: a possible subtle impact of a neglected tropical disease.

Background: The aim of this cross-sectional study was to investigate a possible association of Schistosoma haematobium with child growth development and describe a plausible schistosomiasis-related anemia in children and adults in a highly schistosomiasis endemic area of Mali. Methods: Urine, feces and blood samples from 399 participants of both sexes (2-40 years of age) were analyzed and supplemented by anthropometric measurements. Results: S. haematobium prevalence was 79.8%, S. mansoni 13.2% and Plasmodium falciparum 80.2%. S. haematobium infection intensity as five categories was significantly associated with anemia; i.e., odds of having anemia in the highest and the next highest category was 3.25 (95% CL 1.61-6.55; p<0.01) and 2.45 (95% CL 1.28-4.70; p<0.01), respectively, of that in the three lower categories combined after adjusting for age group and gender and the interaction between the two factors. Anemia was most pronounced in the 2-5 year olds males (55.5%, n=98). P. falciparum infection was not significantly associated with anemia. Stunting (body mass index [BMI] for age z-score<-2.00) was observed in 2.6% (2/78) of the 2-5 years olds and in 7.7% (14/182) in the 6-19 years age group. Lower BMI-z-scores (as continuous variable) were associated with anemia (p<0.05) while high intensity of S. haematobium infection was not significant when adjusting for age group and anemia. Participants with malaria infection had lower z-scores (as continuous variables) of weight and height for age. Lower height for age z-scores were also associated with anemia. Conclusions: S. haematobium infection is likely to impact on child growth and possibly also anemia in all age groups and advocates for inclusion of whole populations into future control programes.