Immune network dysregulation associated with child neurodevelopmental delay: modulatory role of prenatal alcohol exposure.
ABSTRACT: BACKGROUND:Evidence suggests that cytokine imbalances may be at the root of deficits that occur in numerous neurodevelopmental disorders, including schizophrenia and autism spectrum disorder. Notably, while clinical studies have demonstrated maternal cytokine imbalances with alcohol consumption during pregnancy-and data from animal models have identified immune disturbances in alcohol-exposed offspring-to date, immune alterations in alcohol-exposed children have not been explored. Thus, here we hypothesized that perturbations in the immune environment as a result of prenatal alcohol exposure will program the developing immune system, and result in immune dysfunction into childhood. Due to the important role of cytokines in brain development/function, we further hypothesized that child immune profiles might be associated with their neurodevelopmental status. METHODS:As part of a longitudinal study in Ukraine, children of mothers reporting low/no alcohol consumption or moderate-to-heavy alcohol consumption during pregnancy were enrolled in the study and received neurodevelopmental assessments. Group stratification was based on maternal alcohol consumption and child neurodevelopmental status resulting in the following groups: A/TD, alcohol-consuming mother, typically developing child; A/ND, alcohol-consuming mother, neurodevelopmental delay in the child; C/TD, control mother (low/no alcohol consumption), typically development child; and C/ND, control mother, neurodevelopmental delay in the child. Forty cytokines/chemokines were measured in plasma and data were analyzed using regression and constrained principle component analysis. RESULTS:Analyses revealed differential cytokine network activity associated with both prenatal alcohol exposure and neurodevelopmental status. Specifically, alcohol-exposed children showed activation of a cytokine network including eotaxin-3, eotaxin, and bFGF, irrespective of neurodevelopmental status. However, another cytokine network was differentially activated based on neurodevelopmental outcome: A/TD showed activation of MIP-1?, MDC, and MCP-4, and inhibition of CRP and PlGF, with opposing pattern of activation/inhibition detected in the A/ND group. By contrast, in the absence of alcohol-exposure, activation of a network including IL-2, TNF-?, IL-10, and IL-15 was associated with neurodevelopmental delay. CONCLUSIONS:Taken together, this comprehensive assessment of immune markers allowed for the identification of unique immune milieus that are associated with alcohol exposure as well as both alcohol-related and alcohol-independent neurodevelopmental delay. These findings are a critical step towards establishing unique immune biomarkers for alcohol-related and alcohol-independent neurodevelopmental delay.
Project description:Cytokines and chemokines are potent modulators of brain development and as such, dysregulation of the maternal immune system can result in deviations in the fetal cytokine balance, altering the course of typical brain development, and putting the individual on a "pathway to pathology". In the current study, we used a multi-variate approach to evaluate networks of interacting cytokines and investigated whether alterations in the maternal immune milieu could be linked to alcohol-related and alcohol-independent child neurodevelopmental delay. This was achieved through the measurement of 40 cytokines/chemokines from maternal blood samples collected during the second and third trimesters of pregnancy. Importantly, during the second trimester we identified network enrichment in levels of cytokines including IFN-?, IL-10, TNF-?, TNF-?, and CRP associated with offspring neurodevelopmental delay. However, as elevations in levels of these cytokines have previously been reported in a wide range of neurodevelopmental disorders including autism spectrum disorder and schizophrenia, we suggest that this cytokine profile is likely not disorder specific, but rather may be an indicator of neurodevelopmental delay in general. By contrast, distinct clusters of activated/inhibited cytokines were identified based on maternal alcohol consumption and child neurodevelopmental outcome. Specifically, cytokines including IL-15, IL-10, MDC, and members of the VEGF sub-family were highest in alcohol-consuming mothers of children with neurodevelopmental delay and were identified in both network analyses and examination of individual cytokines, whereas a differential and unique cytokine profile was identified in the case of alcohol-independent child neurodevelopmental delay. We propose that the current findings could provide a critical step towards the development of early biomarkers and possibly interventions for alcohol-related neurodevelopmental delay. Importantly, the current approach could be informative for understanding mechanisms linking maternal immune system dysfunction and adverse child outcomes in a range of other neurodevelopmental disorders.
Project description:<b>Objective:</b> Polyunsaturated fatty acids are vital for optimal fetal neuronal development. The relationship between maternal alcohol consumption and smoking with third trimester plasma fatty acids were examined and their association with Fetal Alcohol Spectrum Disorders (FASD).<b>Methods:</b> Moderate to heavy alcohol-using and low/unexposed comparison women were recruited during mid-pregnancy from two prenatal clinics in Ukraine. The participants' infants underwent physical and neurobehavioral exams prior to one-year of age and classified as having FASD by maternal alcohol consumption and neurobehavioral scores. A subset of mother-child pairs was selected representing three groups of cases and controls: Alcohol-Exposed with FASD (AE-FASD, n = 30), Alcohol-Exposed Normally Developing (AE-ND, n = 33), or Controls (n = 46). Third trimester maternal plasma samples were analyzed for fatty acids and levels were compared across groups.<b>Results:</b> The percent of C18:0 (p < 0.001), arachidonic acid (AA, C20:4n-6, p = 0.017) and C22:5n-6 (p = 0.001) were significantly higher in AE-FASD women than controls or AE-ND women. Alcohol-exposed women who smoked had lower C22:5n-3 (p = 0.029) and docosahexaenoic acid (DHA, C22:6n-3, p = 0.005) and higher C22:5n-6 (p = 0.013) than women consuming alcohol alone or abstainers.<b>Conclusion:</b> Alterations in fatty acid profiles were observed in moderate to heavy alcohol-consuming mothers with infants classified with FASD compared to alcohol-exposed normally developing infants or controls.
Project description:BACKGROUND:Autism spectrum disorder (ASD) is suspected to have environmental and genetic contributions. Polychlorinated biphenyls (PCBs) are environmental risk factors of interest due to their potential as neurodevelopmental toxicants and environmental persistence despite a US production ban in the 1970s. METHODS:Participants were mother-child pairs from MARBLES, a high-risk pregnancy cohort that enrolls families who have one child diagnosed with ASD and are planning to have another child. PCB concentrations were measured in maternal blood at each trimester of pregnancy using gas chromatography coupled with triple quadruple mass spectrometry. Concentrations were summed into total PCB and two categories based on function/mechanisms of action: dioxin-like (DL), and ryanodine receptor (RyR)-activating PCBs. Multinomial logistic regression assessed risk of clinical outcome classification of ASD and non-typical development (Non-TD) compared to typically developing (TD) in the children at 3 years old. RESULTS:A total of 104 mother-child pairs were included. There were no significant associations for total PCB; however, there were borderline significant associations between DL-PCBs and decreased risk for Non-TD outcome classification (adjusted OR: 0.41 (95% CI 0.15-1.14)) and between RyR-activating PCBs and increased risk for ASD outcome classification (adjusted OR: 2.63 (95% CI 0.87-7.97)). CONCLUSION:This study does not provide strong supporting evidence that PCBs are risk factors for ASD or Non-TD. However, these analyses suggest the need to explore more deeply into subsets of PCBs as risk factors based on their function and structure in larger cohort studies where non-monotonic dose-response patterns can be better evaluated.
Project description:Diagnostic criteria have recently been introduced in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), for neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE). The purpose of this study is to assess the classification of this condition using the Canadian fetal alcohol spectrum disorder (FASD) multidisciplinary diagnostic guidelines as the standard of comparison. First, classification of ND-PAE was compared with Canadian FASD diagnoses of fetal alcohol syndrome (FAS), partial FAS and alcohol-related neurodevelopmental disorder. Second, classification of ND-PAE was compared with FAS and pFAS only, a criterion for which includes facial features highly predictive of prenatal alcohol exposure and effects.Eighty-two patients underwent multidisciplinary clinical evaluations using the Canadian FASD diagnostic guidelines between 2011 and 2015. Two clinicians independently reviewed patient files for evidence of diagnostic criteria for ND-PAE when applying an impairment cut-off level of 2 or more standard deviations below the mean, or clinically significant impairment in the absence of standardized norm-referenced measures.Good interrater reliability was established between clinicians (? = 0.79). Classifications of ND-PAE and Canadian FASD diagnoses, including alcohol-related neurodevelopmental disorder, were moderately correlated (Cramer V  = 0.44, p < 0.01). However, ND-PAE possessed low sensitivity in FASD identification. Further, there was no correlation between ND-PAE and FAS/pFAS classifications (Cramer V  = 0.05, p > 0.05).Although there is considerable overlap between both sets of criteria, ND-PAE was less likely to identify patients with FASD. Although the neurobehavioral domains assessed by ND-PAE are supported in research, its diagnostic structure restricts the identification of FASD at the impairment threshold of 2 or more standard deviations. A disconnect remains with regard to impairment thresholds between FASD, which relies on neurodevelopmental data, and ND-PAE, which relies on clinical judgment.
Project description:Childhood exposure to alcohol misuse by household adults has been related to childhood developmental delay, cognitive impacts, mental illness, and problem behaviours. Most evidence comes from high income countries. This systematic review only included studies from low- and middle-income countries (LMICs). Five databases were searched from 1990-2020. Twenty-eight studies of children 0-12 years were included, with 42,599 participants from 11 LMICs. The most common outcome was behavioural problems/disorders (19 studies). Despite varying study designs, this review found that alcohol misuse by household members in LMICs is associated with adverse child neurodevelopmental outcomes, although casual inferences cannot be drawn in the absence of well conducted prospective studies. Statistically significant correlations were described between parental alcohol misuse and child emotional and behavioural difficulties, cognitive delay, and risky behaviours. In future, prospective cohort studies are recommended, with adjustment for confounders.
Project description:To examine the inter-relationships between cigarette consumption and DSM-IV nicotine dependence (ND) criteria from smoking onset in adolescence up to 7 years later, adjusting for alcohol consumption and DSM-IV alcohol dependence (AD) criteria.A cohort drawn from grades 6-10 in an urban school system was interviewed five times at 6-month intervals (waves 1-5) and 4.5 years later (wave 6). A parent was interviewed three times.Chicago, Illinois.Recent smokers (n?=?409).Structured household interviews ascertained number of cigarettes smoked, DSM-IV ND symptoms, drinks consumed, DSM-IV AD symptoms, and selected covariates. Reciprocal prospective associations between number of cigarettes smoked and ND criteria, controlling for time-varying alcohol consumption and dependence criteria, were examined with cross-lagged models.Reciprocal associations between number of cigarettes smoked and ND criteria were both significant. Cigarette consumption had stronger associations with later ND [??=?0.25, 95% confidence interval (CI)?=?0.17-0.32] than dependence had with later cigarette consumption (??=?0.09, 95% CI?=?0.01-0.16). Alcohol and cigarette consumption influenced each other; AD scores were associated with later ND scores but not the reverse. Reports of pleasant initial experiences from smoking were associated positively with cigarette consumption and ND the first year after smoking onset; later smoking onset was negatively associated with cigarette consumption the seventh year after onset; parental ND predicted cigarette consumption and ND throughout.In adolescent smokers, higher cigarette consumption predicts later severity of DSM-IV nicotine dependence more than the reverse. Smoking and drinking also influence each other mutually over time.
Project description:Disruption of neurodevelopmental trajectories can alter brain circuitry and increase the risk of psychopathology later in life. While preclinical studies have demonstrated that the immune system and cytokines influence neurodevelopment, whether immune activity and in particular which cytokines at birth are associated with psychopathology remains poorly explored in children. We used data and biological samples from 869 mother-child pairs participating in the French mother-child cohort EDEN. As proxies for immune activity at birth, we measured the levels of 27 cytokines in umbilical cord blood sera (CBS). We then explored the association between CBS cytokine levels and five psychopathological dimensions assessed in 5-year-old children using the Strengths and Difficulties Questionnaire (SDQ). Five cytokines were positively associated with psychopathology: C-X-C motif chemokine Ligand (CXCL)10, interleukin (IL)-10 and IL-12p40 with emotional symptoms, C-C motif chemokine Ligand (CCL)11 with conduct problems, and CCL11, and IL-17A with peer relationships problems. In contrast, seven cytokines were negatively associated with psychopathology: IL-7, IL-15 and Tumor Necrosis Factor (TNF)-β with emotional symptoms, CCL4 and IL-6 with conduct problems, CCL26 and IL-15 with peer relationships problems, and CCL26, IL-7, IL-15, and TNF-α with abnormal prosocial behavior. Without implying causation, these associations support the notion that cytokines influence neurodevelopment in humans and the risk of psychopathology later in life.
Project description:<h4>Background</h4>Periconceptional folate is essential for proper neurodevelopment.<h4>Objective</h4>Maternal folic acid intake was examined in relation to the risk of autism spectrum disorder (ASD) and developmental delay (DD).<h4>Design</h4>Families enrolled in the CHARGE (CHildhood Autism Risks from Genetics and Environment) Study from 2003 to 2009 were included if their child had a diagnosis of ASD (n = 429), DD (n = 130), or typical development (TD; n = 278) confirmed at the University of California Davis Medical Investigation of Neurodevelopmental Disorders Institute by using standardized clinical assessments. Average daily folic acid was quantified for each mother on the basis of dose, brands, and intake frequency of vitamins, supplements, and breakfast cereals reported through structured telephone interviews.<h4>Results</h4>Mean (±SEM) folic acid intake was significantly greater for mothers of TD children than for mothers of children with ASD in the first month of pregnancy (P1; 779.0 ± 36.1 and 655.0 ± 28.7 ?g, respectively; P < 0.01). A mean daily folic acid intake of ?600 ?g (compared with <600 ?g) during P1 was associated with reduced ASD risk (adjusted OR: 0.62; 95% CI: 0.42, 0.92; P = 0.02), and risk estimates decreased with increased folic acid (P-trend = 0.001). The association between folic acid and reduced ASD risk was strongest for mothers and children with MTHFR 677 C>T variant genotypes. A trend toward an association between lower maternal folic acid intake during the 3 mo before pregnancy and DD was observed, but not after adjustment for confounders.<h4>Conclusions</h4>Periconceptional folic acid may reduce ASD risk in those with inefficient folate metabolism. The replication of these findings and investigations of mechanisms involved are warranted.
Project description:The Video-Feedback Intervention (VFI) is a technique aimed at promoting positive parenting that has been found to be supportive of child development and parent-child interaction in different at-risk and clinical populations. The application of VFI with parents of children with neurodevelopmental disabilities (ND; e.g., cerebral palsy, sensory and/or psychomotor delay, and genetic syndromes) is growing. Nonetheless, no systematic review is currently available documenting whether this type of intervention improves children's developmental outcomes (e.g., behavioral stability and cognitive abilities), parental caregiving skills (e.g., responsive parenting), and parental emotional well-being (e.g., depressive symptomatology). In the present mini-review, 212 VFI records were retrieved from three databases (i.e., PubMed, Scopus, and Web of Science), and 10 papers were finally included. Abstracted information included age, diagnosis, methodological aspects (timing, setting, and themes), and child/parent outcomes. Significant improvements from pre- to post-VFI were observed in all studies. Specifically, the VFIs were significantly associated with better children developmental outcomes and parental caregiving skills. Inconsistent findings emerged for the VFI effects on parental emotional well-being. Overall, the current mini-review supports the potential effectiveness of parent-focused VFI interventions for parents of children with ND, despite the presence of open questions that need to be addressed in future clinical trials.
Project description:We aimed to elucidate the effect of chronic alcohol consumption on fatty liver. We assessed the consumption of alcohol in 2429 Japanese males (mean age: 54.2 ± 9 years); they were classified according to average consumption into non-drinkers (ND), light drinkers (LD), moderate drinkers (MD), and heavy drinkers (HD). The prevalence of fatty liver was the lowest in the MD and highest in the ND group (p < 0.001), while obesity was not significantly different among the groups (p = 0.133). Elevated levels of alanine aminotransferase (ALT) were the lowest in the MD group (p = 0.011) along with resistance to insulin (homeostasis model assessment-insulin resistance (HOMA-IR)), which was highest in the ND group (p = 0.001). Chronic consumption of alcohol was independently and inversely associated with fatty liver and insulin resistance after adjusting for obesity, hypertension, fasting hyperglycemia, habit of drinking sweet beverages, physical activity, and age (odds ratios are as follows: ND, 1; LD, 0.682; MD, 0.771; HD, 0.840 and ND, 1; LD, 0.724; MD, 0.701; HD, 0.800, respectively). We found that regardless of the type of alcoholic beverage, chronic consumption of alcohol is inversely associated with insulin resistance and fatty liver in Japanese males. This study had limitations, most notably the lack of investigation into diet and nutrition.