Differences in mid-gestational and early postnatal neonatal cytokines and chemokines are associated with patterns of maternal autoantibodies in the context of autism.

Associations between maternal immune dysregulation (including autoimmunity and skewed cytokine/chemokine profiles) and offspring neurodevelopmental disorders such as autism have been reported. In maternal autoantibody-related autism, specific maternally derived autoantibodies can access the fetal compartment to target eight proteins critical for neurodevelopment. We examined the relationship between maternal autoantibodies to the eight maternal autoantibody-related autism proteins and cytokine/chemokine profiles in the second trimester of pregnancy in mothers of children later diagnosed with autism and their neonates' cytokine/chemokine profiles. Using banked maternal serum samples from 15 to 19 weeks of gestation from the Early Markers for Autism Study and corresponding banked newborn bloodspots, we identified three maternal/offspring groups based on maternal autoantibody status: (1) mothers with autoantibodies to one or more of the eight maternal autoantibody-related autismassociated proteins but not a maternal autoantibody-related autism-specific pattern, (2) mothers with a known maternal autoantibody-related autism pattern, and (3) mothers without autoantibodies to any of the eight maternal autoantibody-related autism proteins. Using a multiplex platform, we measured maternal second trimester and neonatal cytokine/chemokine levels. This combined analysis aimed to determine potential associations between maternal autoantibodies and the maternal and neonatal cytokine/chemokine profiles, each of which has been shown to have implications on offspring neurodevelopment independently.

Serum interleukin-17 A and homocysteine levels in children with autism.

BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that typically emerges early in childhood. This study aimed to explore the potential link between serum levels of vitamin B12 and homocysteine (Hcy) and the severity of ASD symptoms in children. METHODS: In this study, 50 children diagnosed with ASD comprised the observation group, while 50 healthy children constituted the control group. Serum levels of IL-17 A, Hcy, folate, and vitamin B12 were compared between the study group and control group, as well as among children with different degrees of ASD severity. The correlation between the Childhood Autism Rating Scale (CARS) score and serum levels of IL-17 A, Hcy, folate, and vitamin B12 was examined. Additionally, the relationship between serum IL-17 A and Hcy levels and their association with the severity ASD were explored. RESULTS: Compared to the control group, the observation group demonstrated elevated serum Hcy and IL-17 A levels alongside decreased folate and vitamin B12 levels. Individuals with severe ASD exhibited higher Hcy and IL-17 A levels but lower folate and vitamin B12 levels compared to those with mild to moderate ASD. The CARS score showed negative correlations with serum folate and vitamin B12 levels and positive correlations with serum IL-17 A and Hcy levels in ASD patients. Additionally, serum Hcy and IL-17 A levels were correlated with ASD severity. CONCLUSION: Children diagnosed with ASD presented with reduced serum vitamin B12 levels and increased levels of Hcy, potentially contributing to the onset and severity of ASD.

Up-regulated serum levels of TAM receptor tyrosine kinases in a group of Egyptian autistic children.

TAM receptor family belongs to receptor tyrosine kinases (TAMRTKs). It includes three receptors; Tyro-3, Axl and Mer. TAMRTKs has a great role in resolution of inflammation due to their role in clearance of apoptotic cells by macrophages. Dysregulated TAM signaling pathways are associated with many autoimmune diseases and chronic inflammatory disorders. Autism may be an autoimmune disease in some patients. This work was the first study that investigated serum levels of the soluble ectodomain shed TAMRTKs in a group of autistic children. Serum levels of TAMRTKs were measured by ELISA in 30 autistic children aged between 3.5 and 11 years and 30 age and sex-matched healthy control children. Serum levels of TAMRTKs were significantly higher in autistic children than healthy control children (P < 0.001). Patients with severe autism had significantly higher serum levels of TAMRTKs than patients with mild to moderate autism (P < 0.01). In addition, there were significant positive correlations between scores of the Childhood Autism Rating Scale (CARS) and serum levels of TAMRTKs in autistic patients, (P < 0.01). In conclusions, serum levels of TAMRTKs were up-regulated in autistic children with significant positive correlations with the degree of the disease severity. This initial report requires further studies to investigate the relationship between TAMRTKs and autism.

Hyperandrogenism? Increased 17, 20-Lyase Activity? A Metanalysis and Systematic Review of Altered Androgens in Boys and Girls with Autism.

Introduction: There is increasing evidence that steroid hormone levels and, especially, androgen levels are elevated in autism. An overactivity of 17, 20-lyase with a higher production of the testosterone precursors dehydroepiandrosterone (DHEA) and androstenedione/androstenediol seems especially present in autism. Methods: An encompassing literature analysis was performed, searching for altered androgens in children with autism and using preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. Included were all studies published before 31 March 2021 found using the following electronic databases: PubMed, Google Scholar, Cochrane Library, Scopus, and TRIP. Eight studies with boys and three studies with girls where steroid hormone measurements were performed from either plasma, urine, or saliva were found and analyzed. Analyses were performed for DHEA(-S/-C), androstenedione/androstenediol, and testosterone. Effect sizes were calculated for each parameter between mean concentrations for children with autism versus healthy controls. Results: Higher levels of androgens in autism were detected, with the majority of calculated effect sizes being larger than one. Conclusions: We found higher levels of the main testosterone precursors DHEA, androstenedione, and androstenediol, likely causing an additionally higher level of testosterone, and an increased 17, 20-lyase activity is therefore implied. Medications already used in PCOS such as metformin might be considered to treat hyperandrogenism in autism following further research.

A potential role for the adrenal gland in autism.

Androgens have been implicated in autism pathophysiology as recently, prenatal exposure to elevated androgens has been proposed as risk factor. However, published data on postnatal sex hormone levels in autistic children are controversial and the source of prenatal androgen exposure in autism remains unknown. Therefore, this study investigated postnatal sex hormone levels and dehydroepiandrosterone (DHEA) to shed light on a potential role for the adrenal gland in autism pathophysiology. A case-control study investigating estradiol (E2), DHEA, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels was conducted with 31 Saudi males with autism and 28 healthy, age-matched boys plasma. Moreover, correlation analysis with measured hormones and previously measured total testosterone (TT) and free testosterone (FT) in the same group of autism was conducted. DHEA was significantly higher (p < 0.05) in the autism group compared to controls. DHEA positively correlated with previously measured TT (r = + 0.79, p < 0.001) and FT (r = + 0.72, p < 0.001) levels in the same autism group. FSH levels were also significantly higher in the autism group than in the control group (p < 0.01). To the best of our knowledge, this is the first study to report a strong positive correlation between TT, FT and DHEA, suggesting an adrenal source for elevated androgen levels.

Plasma levels of nerve growth factor in Egyptian autistic children: Relation to hyperserotonemia and autoimmunity.

Hyperserotonemia and brain-specific autoantibodies are detected in some autistic children. Nerve growth factor (NGF) stimulates the proliferation of B lymphocytes with production of antibodies and also increases mast cell serotonin release. This work was the first to investigate the relationship between plasma NGF and both hyperserotonemia and the frequency of serum anti-myelin basic protein (anti-MBP) auto-antibodies in 22 autistic children aged between 4 and 12 years and 22 healthy-matched controls. Levels of NGF, serotonin and anti-MBP were significantly higher in autistic children than healthy control children (P < 0.001). There was a significant positive correlation between NGF and serotonin levels in autistic patients (P < 0.01). In contrast, there was a non-significant correlation between NGF and anti-MBP levels (P > 0.05). In conclusions, serum NGF levels were elevated and significantly correlated to hyperserotonemia found in many autistic children.

Cerebrospinal fluid and serum protein markers in autism: A co-twin study.

No robust biomarkers have yet been identified for autism spectrum disorder (ASD) or autistic traits. Familial factors likely influence biomarkers such as protein concentrations. Comparing twins with ASD or high autistic traits to the less affected co-twin allows estimating the impact of familial confounding. We measured 203 proteins in cerebrospinal fluid (n = 86) and serum (n = 127) in twins (mean age 14.2 years, 44.9% females) enriched for ASD and other neurodevelopmental conditions. Autistic traits were assessed by using the parent-report version of the Social Responsiveness Scale-2. In cerebrospinal fluid, autistic traits correlated negatively with three proteins and positively with one. In serum, autistic traits correlated positively with 15 and negatively with one. Also in serum, six were positively-and one negatively-associated with ASD. A pathway analysis of these proteins revealed immune system enrichment. In within twin pair analyses, autistic traits were associated with serum B-cell activating factor (BAFF) only, whereas Cystatin B (CSTB) remained significantly associated with ASD. These associations did not remain significant when only considering monozygotic twins. For the remainder, the within-pair analysis indicated familial confounding, including shared environment and genes, influencing both autism and protein levels. Our findings indicate proteins involved in immunity as putative biomarkers of autistic traits and ASD with partial genetic confounding. Although some results are in line with previous studies in general, further studies are needed for replication.

A profile and review of findings from the Early Markers for Autism study: unique contributions from a population-based case-control study in California.

BACKGROUND: The Early Markers for Autism (EMA) study is a population-based case-control study designed to learn more about early biologic processes involved in ASD. METHODS: Participants were drawn from Southern California births from 2000 to 2003 with archived prenatal and neonatal screening specimens. Across two phases, children with ASD (n = 629) and intellectual disability without ASD (ID, n = 230) were ascertained from the California Department of Developmental Services (DDS), with diagnoses confirmed according to DSM-IV-TR criteria based on expert clinical review of abstracted records. General population controls (GP, n = 599) were randomly sampled from birth certificate files and matched to ASD cases by sex, birth month and year after excluding individuals with DDS records. EMA has published over 20 papers examining immune markers, endogenous hormones, environmental chemicals, and genetic factors in association with ASD and ID. This review summarizes the results across these studies, as well as the EMA study design and future directions. RESULTS: EMA enabled several key contributions to the literature, including the examination of biomarker levels in biospecimens prospectively collected during critical windows of neurodevelopment. Key findings from EMA include demonstration of elevated cytokine and chemokine levels in maternal mid-pregnancy serum samples in association with ASD, as well as aberrations in other immune marker levels; suggestions of increased odds of ASD with prenatal exposure to certain endocrine disrupting chemicals, though not in mixture analyses; and demonstration of maternal and fetal genetic influence on prenatal chemical, and maternal and neonatal immune marker and vitamin D levels. We also observed an overall lack of association with ASD and measured maternal and neonatal vitamin D, mercury, and brain-derived neurotrophic factor (BDNF) levels. LIMITATIONS: Covariate and outcome data were limited to information in Vital Statistics and DDS records. As a study based in Southern California, generalizability for certain environmental exposures may be reduced. CONCLUSIONS: Results across EMA studies support the importance of the prenatal and neonatal periods in ASD etiology, and provide evidence for the role of the maternal immune response during pregnancy. Future directions for EMA, and the field of ASD in general, include interrogation of mechanistic pathways and examination of combined effects of exposures.

Effect of non-invasive brain stimulation on behavior and serum brain-derived neurotrophic factor and insulin-like growth factor-1 levels in autistic patients.

Aberrant neural connectivity and intra-cortical inhibitory dysfunction are key features of autism. Non-invasive brain stimulation (NIBS) protocols have been proposed that modulate this aberrant plasticity. However, additional investigations are needed to evaluate the impact of this intervention on biological biomarkers of the disease. We recently demonstrated alterations in serum insulin-like growth factor-1 (IGF-1) and brain-derived neurotrophic factor (BDNF) immunoreactivity in subjects with autism compared to controls. The aim of this pilot study was to explore the change in serum levels of the neurotrophic factors BDNF and IGF-1 in patients undergoing NIBS therapy. Sixteen subjects with autism spectrum disorder (ASD) were tested 1 week before and 1 week after NIBS to determine the short-term outcome on behavior using the total score on the autism behavior checklist, autism treatment evaluation checklist, clinical global impression severity and the autism diagnostic interview. ASD subjects younger than 11 years old (n = 11) were treated with transcranial direct current stimulation (tDCS), and those 11 years and older (n = 5) were treated with repetitive transcranial magnetic stimulation (rTMS). Serum levels of BDNF and IGF-1 were evaluated by Enzyme-Linked Immuno-Sorbent Assay before and after the intervention with NIBS. A significant reduction in scores on the clinical behavioral scales was observed in patients treated with NIBS (ABC-T p = .002, CGI-S p = .008, ADI-T and ATEC-T p < .0001). There was a trend towards reduced serum BDNF levels after NIBS (p = .061), while there was no change in IGF-1 levels. These data support further studies on the potential of BDNF as a biomarker to measure the effectiveness of NIBS in autism.

Oxytocin-induced increase in N,N-dimethylglycine and time course of changes in oxytocin efficacy for autism social core symptoms.

BACKGROUND: Oxytocin is expected as a novel therapeutic agent for autism spectrum disorder (ASD) core symptoms. However, previous results on the efficacy of repeated administrations of oxytocin are controversial. Recently, we reported time-course changes in the efficacy of the neuropeptide underlying the controversial effects of repeated administration; however, the underlying mechanisms remained unknown. METHODS: The current study explored metabolites representing the molecular mechanisms of oxytocin's efficacy using high-throughput metabolomics analysis on plasma collected before and after 6-week repeated intranasal administration of oxytocin (48 IU/day) or placebo in adult males with ASD (N = 106) who participated in a multi-center, parallel-group, double-blind, placebo-controlled, randomized controlled trial. RESULTS: Among the 35 metabolites measured, a significant increase in N,N-dimethylglycine was detected in the subjects administered oxytocin compared with those given placebo at a medium effect size (false discovery rate (FDR) corrected P = 0.043, d = 0.74, N = 83). Furthermore, subgroup analyses of the participants displaying a prominent time-course change in oxytocin efficacy revealed a significant effect of oxytocin on N,N-dimethylglycine levels with a large effect size (PFDR = 0.004, d = 1.13, N = 60). The increase in N,N-dimethylglycine was significantly correlated with oxytocin-induced clinical changes, assessed as changes in quantifiable characteristics of autistic facial expression, including both of improvements between baseline and 2 weeks (PFDR = 0.006, r = - 0.485, N = 43) and deteriorations between 2 and 4 weeks (PFDR = 0.032, r = 0.415, N = 37). LIMITATIONS: The metabolites changes caused by oxytocin administration were quantified using peripheral blood and therefore may not directly reflect central nervous system changes. CONCLUSION: Our findings demonstrate an association of N,N-dimethylglycine upregulation with the time-course change in the efficacy of oxytocin on autistic social deficits. Furthermore, the current findings support the involvement of the N-methyl-D-aspartate receptor and neural plasticity to the time-course change in oxytocin's efficacy. TRIAL REGISTRATION: A multi-center, parallel-group, placebo-controlled, double-blind, confirmatory trial of intranasal oxytocin in participants with autism spectrum disorders (the date registered: 30 October 2014; UMIN Clinical Trials Registry: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017703 ) (UMIN000015264).

Proinflammatory mediators and their associations with medication and comorbid traits in children and adults with ADHD.

Peripheral immune activation can influence neurodevelopment and is increased in autism, but is less explored in attention deficit hyperactivity disorder (ADHD). Patients with ADHD often display comorbid autism traits and gastrointestinal (GI) symptoms. Plasma protein levels of two acute phase reactants, C-reactive protein (CRP) and serum amyloid A (SAA), and two endothelial adhesion molecules, soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1), which share important roles in inflammation, were analyzed in 154 patients with ADHD and 61 healthy controls. Their associations with ADHD diagnosis, severity, medication and comorbid autistic symptoms, emotion dysregulation and GI symptoms were explored. The ADHD patients had increased levels of sICAM-1 and sVCAM-1 compared to healthy controls (p = 8.6e-05, p = 6.9e-07, respectively). In children with ADHD, the sICAM-1 and sVCAM-1 levels were higher among those with ADHD medication than among children (p = 0.0037, p = 0.0053, respectively) and adults (p = 3.5e-09, p = 1.9e-09, respectively) without ADHD medication. Among the adult ADHD patients, higher sICAM-1 levels were associated with increased comorbid autistic symptoms in the domains attention to detail and imagination (p = 0.0081, p = 0.00028, respectively), and higher CRP levels were associated with more GI symptoms (p = 0.014). sICAM-1 and sVCAM-1 levels were highly correlated with each other, and so were CRP and SAA levels. To conclude, vascular inflammatory activity may be overrepresented in ADHD, with elevated sICAM-1 and sVCAM-1 levels and this may in children be a consequence of current ADHD medication, and in adults relate to increased comorbid autistic symptoms. Replication is warranted.

Polyunsaturated Fatty Acids in Newborn Bloodspots: Associations With Autism Spectrum Disorder and Correlation With Maternal Serum Levels.

We conducted a population-based case-control study to examine newborn polyunsaturated fatty acid (PUFA) levels in association with autism spectrum disorder (ASD) and assess PUFA correlation across two time points. ASD cases (n = 200) were identified through the Department of Developmental Services and matched to live-birth population controls (n = 200) on birth month, year (2010-2011), and sex. Nonesterified PUFAs were measured by isotope dilution liquid chromatography-high resolution mass spectrometry from archived newborn dried blood spots and maternal mid-pregnancy serum samples. Crude and adjusted conditional logistic regression models were used to examine the association between neonatal PUFA levels, categorized in quartiles and according to distributional extremes, and ASD. Cubic splines were utilized to examine nonlinear relationships between continuous neonatal PUFAs and ASD. The correlation between neonatal and maternal levels was examined using Pearson correlation coefficients. In adjusted analyses of neonatal PUFA levels, no clear trends emerged, though there was an elevated odds ratio of ASD for the third quartile of linoleic acid, relative to the first (adjusted odds ratio = 2.49, 95% confidence interval: 1.31, 4.70). Cubic spline analysis suggested a nonlinear association between linoleic acid and ASD, though this was not robust to sensitivity analyses. While individual PUFAs were significantly correlated with one another within a given time point, aside from docohexaseanoic acid, PUFAs were not correlated across maternal and neonatal samples. Overall, our findings do not support an association between neonatal PUFA levels and ASD. Future work should confirm and expand these findings by examining associations with phenotypic subgroups and considering PUFAs in other time points. LAY SUMMARY: In this study, we examined whether levels of fats known as polyunsaturated fatty acids, measured in newborns, were related to later child diagnosis of autism spectrum disorder (ASD). Overall, we did not find strong evidence for hypothesized reduction in risk of ASD based on newborn levels of these fats. Future studies in larger samples and considering other time points may be useful to explain whether these fats are important in brain development related to ASD. Autism Res 2020, 13: 1601-1613. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

Risperidone accelerates bone loss in rats with autistic-like deficits induced by maternal lipopolysaccharides exposure.

AIMS: Patients with neurodevelopmental disorders, usually suffer from bone diseases. Many studies have revealed a higher risk of fracture after atypical antipsychotic drug Risperidone (RIS) treatment, which is usually used to treat such disorders. It remains debatable whether neurodevelopmental disorders by itself are the cause of bone diseases or pharmacotherapy may be the reason. MATERIALS AND METHODS: This study attempts to evaluate the biomechanical, histological, stereological, and molecular properties of bones in the offspring of Lipopolysaccharide (LPS) and saline-treated mothers that received saline, drug vehicle or the atypical antipsychotic drug risperidone (RIS) at different days of postnatal development. After postnatal drug treatment, animals were assessed for autistic-like behaviors. Then their bones were taken for evaluations. RESULTS: Maternal LPS exposure resulted in deficits in all behavioral tests and RIS ameliorated these behaviors (p < 0.01& p < 0.05). The administration of LPS and RIS individually led to a significant decrease in the biomechanical parameters such as bone stiffness, strength and the energy used to fracture of bone. The numerical density of osteocalcin-positive cells were significantly decreased in these groups. These rats also had decreased RUNX2 and osteocalcin gene expression. When LPS rats were treated with RIS, these conditions were accelerated (p < 0.001). DISCUSSIONS: The results of our preclinical study, consistent with previous studies in animals, explore that autistic-like deficits induced by prenatal exposure to LPS, can reduce bone stability and bone mass similar to those observed in neurodevelopmental disorders, and, for the first time, reveal that this condition worsened when these animals were treated with RIS.

Biomarker study of the biological parameter and neurotransmitter levels in autistics.

Autism is a prevalent developmental disorder that combines repetitive behaviours, social deficits and language abnormalities. The present study aims to assess the autistic subjects using DSM IV-TR criteria followed with the analysis of neurotransmitters, biochemical parameters, oxidative stress and its ions in two groups of autistic subjects (group I < 12 years; group II ≥ 12 years). Antioxidants show a variation of 10% increase in controls compared to autistic age < 12 years. The concentration of pyruvate kinase and hexokinase is elevated in controls approximately 60% and 45%, respectively, with the significance of 95 and 99%. Autistic subjects showed marked variation in levels of neurotransmitters, oxidative stress and its related ions. Cumulative assessment of parameters related to biochemical markers and neurotransmitters paves the way for autism-based research, although these observations draw interest in an integrated approach for autism.

The association between newborn screening analytes as measured on a second screen and childhood autism in a Texas Medicaid population.

Autism (or autism spectrum disorder [ASD]) is an often disabling childhood neurologic condition of mostly unknown cause. We previously explored whether there was an association of ASD with any analyte measured in the first newborn screening blood test. Here we explore the second screen. Our matched case-control study examined data on 3-5 year-old patients with any ASD diagnosis in the Texas Medicaid system in 2010-2012. Subjects were linked to their 2007-2009 newborn screening blood test data, which included values for 36 analytes or analyte ratios. Data were available for 3,005 cases and 6,212 controls. The most compelling associations were evident for fatty acid oxidation analytes octanoylcarnitine (C8) and octanoylcarnitine/acetylcarnitine (C8/C2). Their adjusted odds ratios comparing 10th versus first analyte deciles were between 1.42 and 1.54 in total births, term births, and males. C8 was consistent with first screen results. Adipylcarnitine (C6DC), an organic acid analyte, showed opposite results in the two screens. Several other analytes exhibiting significant associations in the first screen did not in the second. Our results provide evidence that abnormal newborn blood levels of some carnitines may be associated with risk of later ASD, possibly related to their involvement with mitochondrial function in the developing brain.

The putative etiology and prevention of autism.

Since the initial psychological report by Leo Kanner in 1943, relatively little formal biochemical/neurological research on the cause of autism, other than peripheral searches for genomic mutations, had been carried until the end of the 20th century. As a result of studies on twin sets and the conclusion that autism was largely a hereditary defect, numerous investigations have sought various genetic faults in particular. However, such studies were able to reveal a plausible etiology for this malady in only a small percentage of instances. Key bio-molecular characteristics of this syndrome have been uncovered when the potential roles of the glia were studied in depth. Findings related to biochemical deficiencies appearing early in the newborn, such as depressed IGF-1 (insulin-like growth factor #1) in neurogenesis/myelination, are becoming emphasized in many laboratories. Progress leading to timely diagnoses and subsequent prevention of central nervous system dysconnectivity now seems plausible. The tendency for an infant to develop autism may currently be determinable and preventable before irreversible psychosocial disturbances become established. These discussions about glial function will be inter-spersed with comments about their apparent relevance to autism. The concluding portion of this presentation will be a detailed review and summation of this diagnosis and prevention proposition.

A heritable profile of six miRNAs in autistic patients and mouse models.

Autism spectrum disorder (ASD) is a group of developmental pathologies that impair social communication and cause repetitive behaviors. The suggested roles of noncoding RNAs in pathology led us to perform a comparative analysis of the microRNAs expressed in the serum of human ASD patients. The analysis of a cohort of 45 children with ASD revealed that six microRNAs (miR-19a-3p, miR-361-5p, miR-3613-3p, miR-150-5p, miR-126-3p, and miR-499a-5p) were expressed at low to very low levels compared to those in healthy controls. A similar but less pronounced decrease was registered in the clinically unaffected parents of the sick children and in their siblings but never in any genetically unrelated control. Results consistent with these observations were obtained in the blood, hypothalamus and sperm of two of the established mouse models of ASD: valproic acid-treated animals and Cc2d1a+/- heterozygotes. In both instances, the same characteristic miRNA profile was evidenced in the affected individuals and inherited together with disease symptoms in the progeny of crosses with healthy animals. The consistent association of these genetic regulatory changes with the disease provides a starting point for evaluating the changes in the activity of the target genes and, thus, the underlying mechanism(s). From the applied societal and medical perspectives, once properly confirmed in large cohorts, these observations provide tools for the very early identification of affected children and progenitors.

Mercury as a hapten: A review of the role of toxicant-induced brain autoantibodies in autism and possible treatment considerations.

BACKGROUND: Mercury has many direct and well-recognized neurotoxic effects. However, its immune effects causing secondary neurotoxicity are less well-recognized. Mercury exposure can induce immunologic changes in the brain indicative of autoimmune dysfunction, including the production of highly specific brain autoantibodies. Mercury, and in particular, Thimerosal, can combine with a larger carrier, such as an endogenous protein, thereby acting as a hapten, and this new molecule can then elicit the production of antibodies. METHODS: A comprehensive search using PubMed and Google Scholar for original studies and reviews related to autism, mercury, autoantibodies, autoimmune dysfunction, and haptens was undertaken. All articles providing relevant information from 1985 to date were examined. Twenty-three studies were identified showing autoantibodies in the brains of individuals diagnosed with autism and all were included and discussed in this review. RESULTS: Research shows mercury exposure can result in an autoimmune reaction that may be causal or contributory to autism, especially in children with a family history of autoimmunity. The autoimmune pathogenesis in autism is demonstrated by the presence of brain autoantibodies (neuroantibodies), which include autoantibodies to: (1) human neuronal progenitor cells; (2) myelin basic protein (MBP); (3) neuron-axon filament protein (NAFP); (4) brain endothelial cells; (5) serotonin receptors; (6) glial fibrillary acidic protein (GFAP); (7) brain derived neurotrophic factor (BDNF); (8) myelin associated glycoprotein (MAG); and (9) various brain proteins in the cerebellum, hypothalamus, prefrontal cortex, cingulate gyrus, caudate putamen, cerebral cortex and caudate nucleus. CONCLUSION: Recent evidence suggests a relationship between mercury exposure and brain autoantibodies in individuals diagnosed with autism. Moreover, brain autoantibody levels in autism are found to correlate with both autism severity and blood mercury levels. Treatments to reduce mercury levels and/or brain autoantibody formation should be considered in autism.

Autistic-like behaviours and associated brain structural plasticity are modulated by oxytocin in maternally separated rats.

BACKGROUND: Early psycho-social experiences influence the developing brain and possible onset of various neurodevelopmental disorders, such as Autism Spectrum Disorder (ASD). ASD is characterized by a variety of brain abnormalities, including alteration of oxytocin receptors in the brain. Recently, early life adverse experiences, such as maternal separation (MS), have been shown to constitute risk factors for ASD in preclinical studies. Therefore, the main aims of the current study were to i) explore the association between onset of autistic-like behaviours and molecular/structural changes in the brain following MS, and ii) evaluate the possible beneficial effects of oxytocin treatment on the same parameters. METHOD AND MATERIAL: Male rats were exposed to the maternal separation from post-natal day (PND) 1 to PND14. After weaning, daily injections of oxytocin (1 mg/kg, ip) were administered (PND 22-30), followed by examination of autism-related behaviours at adolescence (PND 42-50). Brain structural plasticity was examined using stereological methods, and the plasma level of brain derived neurotrophic factor (BDNF) was analysed using ELISA. RESULTS: We found that maternal separation induced autistic-like behaviours, which was associated with increase in the hippocampal CA1 stratum radiatum (CA1.SR) volume. In addition, we observed increase in the infralimbic brain region volume and in the number of the pyramidal neurons in the same brain region. Maternal separation significantly increased the plasma BDNF levels. Treatment with oxytocin improved autistic like behaviours, normalized the number of neurons and the volume of the infralimbic region as well as the plasma BDNF level (p < 0.05). CONCLUSION: Maternal separation induced autistic-like behaviours, brain structural impairment together with plasma BDNF level abnormality, which could be improved by oxytocin treatment.

Neurodevelopmental effects of prenatal vitamin D in humans: systematic review and meta-analysis.

Diverse studies have investigated the impact of prenatal exposure to vitamin D levels on brain development; however, evidence in humans has never been systematically reviewed. This article summarized evidence of the association between 25-hydroxyvitamin D [25(OH)D] levels in maternal blood in pregnancy or newborn blood at birth and neurodevelopmental outcomes, including cognition, psychomotor performance, language development, behavioral difficulties, attention deficit and hyperactivity disorder (ADHD), and autistic traits. PubMed, Web of Science and SCOPUS databases were systematically searched for epidemiologic studies published through May 2018 using keywords. Random-effects meta-analyses were conducted. Of 260 identified articles, 25 were included in the present review. Comparing the highest vs. the lowest category of prenatal 25(OH)D levels, the pooled beta coefficients were 0.95 (95% CI -0.03, 1.93; p = 0.05) for cognition, and 0.88 (95% CI -0.18, 1.93; p = 0.10) for psychomotor development. The pooled relative risk for ADHD was 0.72 (95% CI, 0.59, 0.89; p = 0.002), and the pooled odds ratio for autism-related traits was 0.42 (95% CI, 0.25, 0.71; p = 0.001). There was little evidence for protective effects of high prenatal 25(OH)D for language development and behavior difficulties. This meta-analysis provides supporting evidence that increased prenatal exposure to 25(OH)D levels is associated with improved cognitive development and reduced risk of ADHD and autism-related traits later in life. Associations represent a potentially high public health burden given the current prevalence of vitamin D deficiency and insufficiency among childbearing aging and pregnant women.