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

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Abstract

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.

Highlight

► This study reports elevated levels of MCP-1 in amniotic fluid samples of individuals diagnosed later in life with autism spectrum disorders compared to matched controls.

Introduction

Since the term was first coined by the Swiss psychiatrist Eugen Bleuler a hundred years ago (Stotz-Ingenlath, 2000), autism has evolved from being an enigmatic disability to represent a challenging public health issue with substantial cost of care (Ganz, 2006). By definition, Autism Spectrum Disorders (ASD) refers to a cluster of heterogeneous neurodevelopmental disorders characterized by a triad of qualitative impairments in social interaction, communication and repetitive stereotypic behavior (Newschaffer et al., 2007). Despite the numerous research lines trying to disentangle the etiology of this group of disorders, no definitive biologic screening or diagnostic tools have been universally accepted, and the diagnostic standards are still based on behavioral criteria (American Psychiatric Association, 2000).

Prevalence of autism has been escalating over time. Most recent estimates from the US indicate that ASD prevalence could be as high as 1% (Rice, 2007). In Denmark a parallel trend has been observed with the most recent estimates being around 0.74% (Parner et al., 2008).

Chemokines represent a family of cytokines comprised of four subgroups based on their cysteine motif (C, CC, CXC, and CX3C) and have the capacity to control the attraction of leukocytes to different tissue targets (Epstein and Luster, 1998). Recently, a crucial role of chemokines in neuroinflammation has been postulated where they can function as messengers for the communication between neurons and neuroglia (Biber et al., 2008). Hence, they may actually serve as intermediate players in the well established linkage between inflammation and autism (Goines and Van de Water, 2010).

While elevated levels of chemokines have been reported in plasma and brain tissue of individuals with ASD (Ashwood et al., 2011, Vargas et al., 2005), to our knowledge, chemokine levels during pregnancy have not yet been investigated. Given the importance of the intrauterine milieu for the inception of neurodevelopmental disorders (Schlotz and Phillips, 2009), the aim of this study was to examine levels of three inducible (inflammatory) CC chemokines: Monocyte Chemotactic Protein-1 (MCP-1), Macrophage Inflammatory Protein-1α (MIP-1α) and Regulated upon Activation Normal T-Cell Expressed and Secreted (RANTES) of individuals diagnosed with ASD later in life and their controls utilizing a historic birth cohort.

Section snippets

Methods

To examine if differential levels of amniotic fluid chemokines exist in individuals diagnosed later in life with ASD compared to controls, a case-control study design was adopted. Study subjects were retrieved from a Historic Birth Cohort (HBC) kept at Statens Serum Institute (SSI) in Copenhagen, Denmark.

The HBC consists of amniotic fluid and maternal serum samples of more than 100,000 pregnant women who underwent screening or diagnostic amniocentesis and/or phlebotomy and had their biologic

Results

A flow chart of case-control selection process is presented in Fig. 1. Total of 414 ASD cases and 820 frequency-matched controls were included in the study. ASD cases comprised 94 infantile autism (IA), 126 Asperger Syndrome (AS), and 194 other ASD (O-ASD) diagnoses; average age of ASD diagnosis (defined by the first admission date registered in the DPCR) was 9.63 years. This ranged from 7.84 years for IA cases up to 11.13 years for AS. Background information for the study population is presented

Discussion

In this study, maternal amniotic fluid samples for three inducible CC chemokines (MCP-1, MIP-1α, and RANTES) were analyzed. Levels of MCP-1 were significantly elevated in ICD-10 diagnosed ASD cases compared to frequency-matched controls. No significant difference was found in the levels of MIP-1α, and RANTES. Results were comparable when excluding ASD cases with congenital malformation diagnoses or when analyzing infantile autism cases only compared to controls with no psychiatric comorbidities.

Acknowledgements

The authors thank Lasse S. Jønsson from Statens Serum Institute (SSI) and Maria Pryds for their assistance in data retrieval and Vibeke Munk from Copenhagen University for her administrative assistance. We also thank SSI Luminex Lab technical staff for their time and efforts. The Danish Historic Birth Cohort was established at Statens Serum Institute, Copenhagen with a grant from The Danish Medical Research Foundation and The Danish Ministry of the Interior and Health (Project no.

References (53)

  • P. Agergaard et al.

    Children diagnosed with congenital cardiac malformations at the national university departments of pediatric cardiology: positive predictive values of data in the Danish National Patient Registry

    Clin. Epidemiol.

    (2011)
  • American Psychiatric Association. 2000. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric...
  • T.F. Andersen et al.

    The Danish National Hospital Register. A valuable source of data for modern health sciences

    Dan. Med. Bull.

    (1999)
  • H. Ashdown et al.

    The role of cytokines in mediating effects of prenatal infection on the fetus: implications for schizophrenia

    Mol. Psychiatry

    (2006)
  • Atladottir HO, Thorsen P, Schendel D, Ostergaard L, Abdallah M, Lemcke S et al.. Maternal infection requiring...
  • A.S. Brown et al.

    Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring

    Am. J. Psychiatry

    (2004)
  • F.H. Epstein et al.

    Chemokines – chemotactic cytokines that mediate inflammation

    N. Engl. J. Med.

    (1998)
  • M.S. Esplin et al.

    Monocyte chemotactic protein-1 is increased in the amniotic fluid of women who deliver preterm in the presence or absence of intra-amniotic infection

    J. Maternal–Fetal Neonatal Med.

    (2005)
  • M. Ganz

    The Costs of Autism

  • P. Goines et al.

    The immune system’s role in the biology of autism

    Curr. Opin. Neurol.

    (2010)
  • N. Gomez-Lopez et al.

    The role of chemokines in term and premature rupture of the fetal membranes: a review

    Biol. Reprod.

    (2010)
  • J. Hesselgesser et al.

    Chemokine and chemokine receptor expression in the central nervous system

    Journal of Neurovirology

    (1999)
  • L. Heuer et al.

    The immune system in autism, Is there a connection?

  • R.-M. Holst et al.

    Expression of cytokines and chemokines in cervical and amniotic fluid: relationship to histological chorioamnionitis

    J. Matern Fetal Neonatal Med.

    (2007)
  • U.A. Kayisli et al.

    Uterine Chemokines in Reproductive Physiology and Pathology

    Am. J. Reprod. Immunol.

    (2002)
  • L. Knudsen et al.

    The Danish Medical Birth Registry

    Dan. Med. Bull.

    (1998)
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