Assessment of Expression of lncRNAs in Autistic Patients.

Autism is a severe neurodevelopmental condition with unknown pathobiology. Nevertheless, multiple pieces of evidence suggest long non-coding RNA (lncRNA) dysregulation may be a contributing factor to this disorder. We investigated the association between the expression of five specific lncRNAs and autism. Peripheral blood was collected from 30 children with autism and 41 healthy children. The expression levels of PCAT-29, lincRNA-ROR, LINC-PINT, lincRNA-p21, and PCAT-1 were calculated. Then, their significance as biomarkers was also evaluated. The expression of LincRNA-ROR (27 times), LINC-PINT (5.26 times), LincRNA-p21 (4.54 times), PCAT-29 (16.66 times), and PCAT-1 (25 times) genes was significantly decreased in patients compared to the control group (p values < 0.05). According to the ROC curve analysis for each lncRNA, LincRNA-ROR, LINC-PINT, LincRNA-p21, PCAT-29, and PCAT-1 lncRNAs with diagnostic power of 0.85, 0.67, 0.64, 0.74, and 0.84, respectively, could be used as diagnostic biomarkers for autism. Additionally, significant positive correlations were reported between expression levels of PCAT-1 and PCAT-29 genes. Moreover, a positive correlation was detected between expression levels of lincRNA-ROR and patients' age. The current study shows further pieces of evidence for deregulation of lncRNAs in autistic patients that show these lncRNAs may play an important part in the pathogenesis of ASD. However, the role of lncRNA in the neurobiology of autism needs to be investigated further.

Unraveling the metabolomic architecture of autism in a large Danish population-based cohort.

BACKGROUND: The prevalence of autism in Denmark has been increasing, reaching 1.65% among 10-year-old children, and similar trends are seen elsewhere. Although there are several factors associated with autism, including genetic, environmental, and prenatal factors, the molecular etiology of autism is largely unknown. Here, we use untargeted metabolomics to characterize the neonatal metabolome from dried blood spots collected shortly after birth. METHODS: We analyze the metabolomic profiles of a subset of a large Danish population-based cohort (iPSYCH2015) consisting of over 1400 newborns, who later are diagnosed with autism and matching controls and in two Swedish population-based cohorts comprising over 7000 adult participants. Mass spectrometry analysis was performed by a timsTOF Pro operated in QTOF mode, using data-dependent acquisition. By applying an untargeted metabolomics approach, we could reproducibly measure over 800 metabolite features. RESULTS: We detected underlying molecular perturbations across several metabolite classes that precede autism. In particular, the cyclic dipeptide cyclo-leucine-proline (FDR-adjusted p = 0.003) and the carnitine-related 5-aminovaleric acid betaine (5-AVAB) (FDR-adjusted p = 0.03), were associated with an increased probability for autism, independently of known prenatal and genetic risk factors. Analysis of genetic and dietary data in adults revealed that 5-AVAB was associated with increased habitual dietary intake of dairy (FDR-adjusted p < 0.05) and with variants near SLC22A4 and SLC22A5 (p < 5.0e - 8), coding for a transmembrane carnitine transporter protein involved in controlling intracellular carnitine levels. CONCLUSIONS: Cyclo-leucine-proline and 5-AVAB are associated with future diagnosis of autism in Danish neonates, both representing novel early biomarkers for autism. 5-AVAB is potentially modifiable and may influence carnitine homeostasis.

Maternal Steroid Hormone Levels in Early Pregnancy and Autism in the Offspring: A Population-Based, Nested Case-Control Study.

BACKGROUND: A role for prenatal steroid hormones in the etiology of autism has been proposed, but evidence is conflicting. METHODS: Here, we examined serum levels of maternal estradiol, testosterone, 17-hydroxyprogesterone (OHP), and cortisol from the first trimester of gestation (mean = 10.1 weeks) in relation to the odds of diagnosed autism with and without co-occurring intellectual disability (ID) in the offspring (n = 118 autism with ID, n = 249 autism without ID, n = 477 control). Levels of maternal hormones were measured using highly sensitive liquid chromatography tandem mass spectrometry, standardized according to gestational timing of sample collection, and analyzed with restricted cubic spline logistic regression models adjusting for child's sex and maternal health, demographic, and socioeconomic factors. RESULTS: We observed significant nonlinear associations between maternal estradiol, 17-OHP, and cortisol with autism, which varied with the presence of co-occurring ID. Compared to mean levels, lower levels of estradiol were associated with higher odds of autism with ID (odds ratio for concentrations 1 SD below the mean = 1.66; 95% CI, 1.24-2.11), while higher cortisol levels were associated with lower odds (odds ratio for 1 SD above the mean = 0.55; 95% CI, 0.36-0.88). In contrast, higher 17-OHP was associated with increased odds of autism without ID (odds ratio for 1 SD above the mean = 1.49; 95% CI, 1.11-1.99). We observed no evidence for interaction with sex of the child. CONCLUSIONS: These findings support the notion that the maternal steroid hormonal environment in early pregnancy may contribute to autism, but also emphasize the complex relationship between early-life steroid exposure and autism.

Maternal selenium deficiency during pregnancy in association with autism and ADHD traits in children: The Odense Child Cohort.

BACKGROUND: Selenoproteins regulate pathways controlling neurodevelopment, e.g., redox signaling and thyroid hormone metabolism. However, studies investigating maternal selenium in relation to child neurodevelopmental disorders are scarce. METHODS: 719 mother-child pairs from the prospective population-based Odense Child Cohort study in Denmark were included. Three selenium biomarkers, i.e. concentrations of serum selenium, selenoprotein P (SELENOP), and activity of glutathione peroxidase 3 (GPX3), along with serum copper, zinc and iron were measured in early third trimester (at 28.9+/-0.8 weeks of pregnancy). ADHD and ASD traits in children were assessed systematically using the established Child Behaviour Checklist at 5 years of age, based on a Danish reference cohort with cut-off at 90th percentile. Multivariable regression models adjusted for biologically relevant confounders were applied. RESULTS: 155 of 719 (21.6 %) children had ASD traits and 59 of 719 (8.2 %) children had traits of ADHD at 5 years of age. In crude and adjusted models, all three selenium biomarkers associated inversely with ADHD traits. For ADHD, fully adjusted OR for 10 µg/L increment in selenium was 0.76 (95 % CI 0.60, 0.94), for one mg/L increment in SELENOP was 0.73 (0.56, 0.95), and for 10 U/L increment in GPx3 was 0.93 (0.87,1.00). Maternal total selenium was inversely associated with child ASD traits, OR per 10 µg/L increment was 0.85 (0.74, 0,98). SELENOP and GPx3 were not associated with ASD traits. The associations were specific to selenium, as other trace elements such as copper, zinc, or iron were not associated with the outcomes. CONCLUSIONS: The results provide coherent evidence for selenium deficiency as a risk factor for ADHD and ASD traits in an environment with borderline supply, the causality of which should be elucidated in a randomized controlled trial.

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.

Validation of plasma protein glycation and oxidation biomarkers for the diagnosis of autism.

Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder in children. It is currently diagnosed by behaviour-based assessments made by observation and interview. In 2018 we reported a discovery study of a blood biomarker diagnostic test for ASD based on a combination of four plasma protein glycation and oxidation adducts. The test had 88% accuracy in children 5-12 years old. Herein, we present an international multicenter clinical validation study (N = 478) with application of similar biomarkers to a wider age range of 1.5-12 years old children. Three hundred and eleven children with ASD (247 male, 64 female; age 5.2 ± 3.0 years) and 167 children with typical development (94 male, 73 female; 4.9 ± 2.4 years) were recruited for this study at Sidra Medicine and Hamad Medical Corporation hospitals, Qatar, and Hospital Regional Universitario de Málaga, Spain. For subjects 5-12 years old, the diagnostic algorithm with features, advanced glycation endproducts (AGEs)-Nε-carboxymethyl-lysine (CML), Nω-carboxymethylarginine (CMA) and 3-deoxyglucosone-derived hydroimidazolone (3DG-H), and oxidative damage marker, o,o'-dityrosine (DT), age and gender had accuracy 83% (CI 79 - 89%), sensitivity 94% (CI 90-98%), specificity 67% (CI 57-76%) and area-under-the-curve of receiver operating characteristic plot (AUROC) 0.87 (CI 0.84-0.90). Inclusion of additional plasma protein glycation and oxidation adducts increased the specificity to 74%. An algorithm with 12 plasma protein glycation and oxidation adduct features was optimum for children of 1.5-12 years old: accuracy 74% (CI 70-79%), sensitivity 75% (CI 63-87%), specificity 74% (CI 58-90%) and AUROC 0.79 (CI 0.74-0.84). We conclude that ASD diagnosis may be supported using an algorithm with features of plasma protein CML, CMA, 3DG-H and DT in 5-12 years-old children, and an algorithm with additional features applicable for ASD screening in younger children. ASD severity, as assessed by ADOS-2 score, correlated positively with plasma protein glycation adducts derived from methylglyoxal, hydroimidazolone MG-H1 and Nε(1-carboxyethyl)lysine (CEL). The successful validation herein may indicate that the algorithm modifiable features are mechanistic risk markers linking ASD to increased lipid peroxidation, neuronal plasticity and proteotoxic stress.

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.

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.

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.

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.

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.

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.

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.

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.