Morsi W. Abdallah

Amniotic fluid chemokines and autism spectrum disorders: An exploratory study utilizing a Danish Historic Birth Cohort

INTRODUCTION Elevated levels of chemokines have been reported in plasma and brain tissue of individuals with Autism Spectrum Disorders (ASD). The aim of this study was to examine chemokine levels in amniotic fluid (AF) samples of individuals diagnosed with ASD and their controls. MATERIAL AND METHODS A Danish Historic Birth Cohort (HBC) kept at Statens Serum Institute, Copenhagen was utilized. Using data from Danish nation-wide health registers, a case-control study design of 414 cases and 820 controls was adopted. Levels of MCP-1, MIP-1α and RANTES were analyzed using Luminex xMAP technology. Case-control differences were assessed as dichotomized at below the 10th percentile or above the 90th percentile cut-off points derived from the control biomarker distributions (logistic regression) or continuous measures (tobit regression). RESULTS AND CONCLUSION AF volume for 331 cases and 698 controls was sufficient for Luminex analysis. Including all individuals in the cohort yielded no significant differences in chemokine levels in cases versus controls. Logistic regression analyses, performed on individuals diagnosed using ICD-10 only, showed increased risk for ASD with elevated MCP-1 (elevated 90th percentile adjusted OR: 2.32 [95% CI: 1.17-4.61]) compared to controls. An increased risk for infantile autism with elevated MCP-1 was also found (adjusted OR: 2.28 [95% CI: 1.16-4.48]). Elevated levels of MCP-1 may decipher an etiologic immunologic dysfunction or play rather an indirect role in the pathophysiology of ASD. Further studies to confirm its role and to identify the potential pathways through which MCP-1 may contribute to the development of ASD are necessary.

Neonatal levels of neurotrophic factors and risk of autism spectrum disorders

To examine levels of 3 neurotrophic factors (NTFs): Brain derived neurotrophic factor (BDNF), Neurotrophin‐4 (NT‐4), and transforming growth factor‐β (TGF‐β) in dried blood spot samples of neonates diagnosed with autism spectrum disorders (ASD) later in life and frequency‐matched controls.

Neonatal levels of cytokines and risk of autism spectrum disorders: An exploratory register-based historic birth cohort study utilizing the Danish Newborn Screening Biobank

The aim of the study was to analyze cytokine profiles in neonatal dried blood samples (n-DBSS) retrieved from The Danish Newborn Screening Biobank of children developing Autism Spectrum Disorders (ASD) later in life and controls. Samples of 359 ASD cases and 741 controls were analyzed using Luminex xMAP technology and clinical data were retrieved from nationwide registers. Findings showed that children developing ASD were more likely to have decreased levels of both T helper-1(Th-1)-like cytokines (i.e. IFN-γ) and Th-2like cytokines (i.e. IL-4, IL-10) which may suggest a depressed or hypoactive immune cell activity during neonatal period in ASD.

Amniotic fluid MMP-9 and neurotrophins in autism spectrum disorders: an exploratory study.

Evidence suggests that some developmental disorders, such as autism spectrum disorders (ASDs), are caused by errors in brain plasticity. Given the important role of matrix metalloproteinases (MMPs) and neurotrophins (NTs) in neuroplasticity, amniotic fluid samples for 331 ASD cases and 698 frequency‐matched controls were analyzed for levels of MMP‐9, brain‐derived neurotrophic factor, NT‐4 and transforming growth factor‐β utilizing a Danish historic birth cohort and Danish nationwide health registers. Laboratory measurements were performed using an in‐house multiplex sandwich immunoassay Luminex xMAP method, and measurements were analyzed using tobit and logistic regression. Results showed elevated levels of MMP‐9 in ASD cases compared with controls (crude and adjusted tobit regression P‐values: 0.01 and 0.06). Our results highlight the importance of exploring the biologic impact of MMP‐9 and potential therapeutic roles of its inhibitors in ASD and may indicate that neuroplastic impairments in ASD may present during pregnancy. Autism Res 2012, 5: 428–433.

Neonatal chemokine levels and risk of autism spectrum disorders: Findings from a Danish historic birth cohort follow-up study

A potential role of chemokines in the pathophysiology of Autism Spectrum Disorders (ASDs) has been previously suggested. In a recent study we examined levels of three inflammatory chemokines (MCP-1, MIP-1α and RANTES) in samples of amniotic fluid of children diagnosed later in life with ASD and controls frequency-matched to cases on gender and year of birth. In this follow-up study, levels of the same chemokines were analyzed postnatally in dried blood spot samples from the same subjects utilizing the Danish Newborn Screening Biobank. Crude estimates showed decreased levels of RANTES. In the adjusted estimates, no differences were found in levels of the three examined chemokines in ASD cases compared to controls. Our findings may cautiously suggest an altered cell-mediated immunity during the early neonatal period in ASD. Further research is needed to examine the relationship between maternal/fetal and neonatal chemokine levels and their role in ASD.

Autism spectrum disorders and maternal serum α-fetoprotein levels during pregnancy.

Objective: Numerous studies have been trying to disentangle the complex pathophysiology of autism spectrum disorders (ASD). In our study, we explored the potential role of maternal serum (MS) alpha-fetoprotein (AFP) in the prediction and the pathophysiology of ASD. Methods: A total of 112 patients with ASD and 243 control subjects were included in a case–control study, using a historic birth cohort maintained at Statens Serum Institute. Measurements of MS-AFP were obtained from a multicentre screening program, whereas clinical data were obtained from nationwide registers. Association between MS-AFP and ASD status was analyzed using logistic regression models and nonparametric tests. Results: Crude, but not adjusted, estimates showed that MS-AFP levels were slightly, but significantly, higher in mothers of children with ASD, compared with their control subject counterparts. People with ASD had an odds ratio of 2.33, with 95% confidence intervals of 1.00 to 5.39, to have MS-AFP above 2.5 multiple of median. Excluding subjects with congenital malformation comorbidities did not alter the direction of our estimates (OR 2.60; 95% Cl 1.04 to 6.51, P = 0.04). Conclusion: Biologic plausibility of its role in the pathophysiology of ASD makes AFP a good candidate for further larger-scale studies to confirm such an association and to determine whether this pattern is unique to ASD or related to other psychiatric disorders as well.

869 – Infections during pregnancy and after birth, and the risk of autism spectrum disorders: a register-based study utilizing a danish historic birth cohort

OBJECTIVE Mounting evidence suggests that immune dysfunction may play a crucial role in the pathophysiology of autism spectrum disorders (ASD). In addition, several studies have reported that congenital and postnatal infections may contribute to the neurobiological basis of ASD. This study aimed to investigate the relationship between infections during pregnancy and after birth, and ASD. METHODS A case-control study design was adopted. Both cases and controls were retrieved from a historic birth cohort (HBC) maintained at Statens Serum Institute in Copenhagen/Denmark and were followed up retrospectively during pregnancy and after birth over four pre-defined periods. Study subjects were followed-up utilizing Danish nation-wide health registers for outpatient and hospital admissions due to infections. Associations between infections and ASD were analyzed using Mantel-Haenszel estimate of the odds ratio (OR) and logistic regression models. RESULTS In total, 414 ASD cases and 820 controls were followed-up during pregnancy and a mean 16.3 years after birth. Crude, but not adjusted estimates showed that ASD cases had an increased risk of hospital admission due to infection at the end of the first year of life (OR = 1.48 [range: 1.07-2.05], P = 0.02) and at the end of the follow-up period (OR = 1.30 [range: 1.02-1.64], P = 0.03). CONCLUSION The present findings indicate that infections have a potential role in the pathophysiology of ASD; however, further studies are necessary to determine if infections etiologically contribute to ASD or if they act as an epiphenomenon due to distorted immunity in children with ASD.

O-01 - The role of immune dysfunction in the pathophysiology of autism spectrum disorders: findings from a danish historic birth cohort

Introduction Mounting evidence has suggested a pivotal role of immune dysfunction in the pathophysiology of autism spectrum disorders (ASD). In this study, levels of inflammatory cytokines were measured intrauterinely in amniotic fluid (AF) samples and postnatally in dried blood spots samples (DBSS) of children diagnosed later in life with ASD and their controls. Materials and methods Study population was retrieved from a historic birth cohort (HBC) kept at Statens Serum Institute (SSI) in Copenhagen, Denmark. The HBC comprises AF and maternal serum samples collected during antenatal screening/diagnostic tests since 1980. All singleton ASD cases who had a corresponding AF sample in the HBC and born 1982–2000 were identified utilizing Danish nation-wide health registers. Controls were selected from the HBC and frequency-matched to cases on gender and year of birth. Corresponding DBSS were indentified in the Danish Newborn Screening Biobank. Levels of selected inflammatory cytokines in AF samples and DBSS were analyzed at SSI using Luminex xMAP technology. Case-control differences were assessed as categories (logistic regression) or continuous measures (tobit regression). Results and conclusions Total of 414 cases and 820 controls were included in the study. Measurements performed on AF showed elevated levels of TNF, IL-4, and IL-10 in ASD. Discrepant pattern was seen in DBSS with elevated levels of IL-8 and sIL-6rα. While findings in this study show that immune dysfunction in ASD starts intrauterinly, the discrepant intrauterine/neonatal patterns are of a special interest. Finally, further studies to examine the specificity of these findings to ASD are necessary.