The combined role of serotonin and interleukin-6 as biomarker for autism

doi:10.1016/j.neuroscience.2014.10.011

Neuroscience

Volume 284, 22 January 2015, Pages 290-296

https://doi.org/10.1016/j.neuroscience.2014.10.011 Get rights and content

Highlights

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Whole blood concentration of 5-HT in autism individuals was significantly elevated.
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Plasma concentration of IL-6 in autism individuals was significantly elevated.
•
Combination of 5-HT and IL-6 produced best in diagnosis of autism.
•
The present study may supply a simple clinical method for the diagnosis of autism.

Abstract

Autism is a severe neurodevelopmental disorder characterized by impairments in social interaction and repetitive behaviors. Diagnosis of autism is currently phenotype based with no reliable laboratory test available to assist clinicians. It has been shown that dysfunction of serotonin (5-HT) and interleukin-6 (IL-6) are involved in autism. The goal of this study was to evaluate the combined role of 5-HT and IL-6 as potential biomarkers for autism. The whole blood concentration of 5-HT and plasma concentration of IL-6 of individuals with autism were significantly elevated compared with the control group, and the concentration of 5-HT and IL-6 had positive correlations with the severity of autism. The results of receiver operating characteristic (ROC) analysis indicated that the combination of 5-HT and IL-6 produced the best sensitivity and specificity for diagnosis of autism. Therefore, the present study has revealed a simple clinical method with great potential for assisting the diagnosis of autism.

Introduction

Autism is a severe neurodevelopmental disorder of childhood typically characterized by substantial impairments in social skills and communications, restricted interests, and repetitive behaviors, whose symptoms manifest in the early developmental period (Association, 2013). A recent systematic review of literature suggested a median Autism Spectrum Disorder (ASD) prevalence of 62/10,000 globally and 65.5/10,000 in the US and Canada (Elsabbagh et al., 2012). The Centers for Disease Control (CDC) reported an estimate of 1 in 88 children identified as having ASD in the United States (Baio, 2012). However, it has been noted that the incidence showed a significant increase in recent years (Hertz-Picciotto and Delwiche, 2009).

There are diagnostic criteria listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Statistical Classification of Diseases and Related Health Problems (ICD-10). Assessment tools such as the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADI-R) are widely used. However, the disorder is currently diagnosed solely using core behavioral criteria selected to define autism, and there is presently no trusted laboratory test available to aid clinicians. In addition, individuals with autism vary enormously in clinical presentation, severity, developmental trajectory, and treatment response. This complexity is spurring an intensive search to identify biological markers that are able to aid clinicians in achieving earlier diagnoses and in predicting clinical prognosis as well as treatment response.

Several lines of evidences suggested that alterations in serotonergic neurotransmitter system might represent one of the biological substrates of the disorder. Serotonin (5-hydroxytryptamine; 5-HT) has specific functions in the central nervous system (CNS) and periphery where it regulates many physiological activities. In human studies, 5-HT has been demonstrated to be important for prenatal and postnatal brain development by regulating both, serotonergic outgrowth and maturation of target regions (Whitaker-Azmitia, 2001). Problems in serotonergic signaling in some of these systems have been implicated as comorbidities that occur with autism (Meyer, 2013). Hyperserotonemia, or elevated blood 5-HT levels are occurred in 25–35% of individuals with ASD (Hanley et al., 1977, Cook et al., 1993, Hranilovic et al., 2007). Some data suggested an association of hyperserotonemia with stereotyped or self-injurious behavior, although results have been inconsistent (Kolevzon et al., 2010, Sacco et al., 2010, Veenstra-VanderWeele et al., 2012). Abnormalities in the brain serotonin system are also reported in ASD, including evidence of altered serotonin synthesis and receptor binding, as well as dystrophic serotonergic axons (Chugani et al., 1997, Makkonen et al., 2008, Nakamura et al., 2010, Azmitia et al., 2011). Thus, the overall evidence implicates the dysfunction of 5-HT system in autism.

Growing bodies of evidences implicate immunological disturbances in autism and a lot of studies have reported cytokine abnormalities in the peripheral blood of autistic patients (Ashwood et al., 2011; Goines and Ashwood, 2013, Ricci et al., 2013). Observations indicated significant increases in the plasma level of interleukin-6 (IL-6) in autism compared with typically developing controls (Emanuele et al., 2010; Ashwood et al., 2011; Malik et al., 2011). Further, increased IL-6 is found in postmortem brain specimens from autism subjects (Li et al., 2009, Wei et al., 2011). What is more, Vargas et al. have demonstrated that IL-6 was increased in the anterior cingulated gyrus of autistic brains and also in the cerebrospinal fluid of autistic children (Vargas et al., 2005). IL-6 levels are associated with core deficits of autism or impairments in associated behaviors and/or onset patterns of autism (Okada et al., 2007; Ashwood et al., 2008).

It has been demonstrated that IL-6 is an important target of 5-HT in vivo (Miyata et al., 2001, Tian et al., 2011, Li et al., 2013). Evidence suggested that 5-HT₇ receptor stimulation in human microglial cells is linked to induction of IL-6 gene expression (Mahe et al., 2005). The 5-HT receptor antagonist rescues IL-6-induced pulmonary hypertension (Miyata et al., 2001). The separate role of blood 5-HT and IL-6 in autism, coupled with the evidence for interaction between them led us to examine the role of peripheral 5-HT and IL-6 as biomarkers in autism.

Therefore, the present study aimed to evaluate the alterations of 5-HT and IL-6 levels in autism and their roles as potential biomarkers for autism. Importantly, the present study sought to examine the combined effects of 5-HT and IL-6 as biomarker in autism, which may supply a more useful and reliable method assisting the diagnosis of autism.

Section snippets

Subjects

Thirty-five individuals with autism and thirty-one health control individuals were selected after clinical evaluations. Participants were placed in one of two groups: (1) diagnosed with autism or (2) confirmed as typically developing controls. Autism diagnosis was performed using gold-standard assessments based on Diagnostic and Statistical Manual of Mental Disorders (4th edition) (DSM-IV) criteria by qualified trained clinicians. Participants were excluded from the study if they had a

Demographic features

Demographic features between two groups were similar. There were no statistically significant differences between the groups with respect to the differentiations of age, sex, body mass index (BMI) (Table 1).

The production of WB 5-HT and plasma IL-6

There was a significant difference noted in median whole blood concentration of 5-HT and plasma concentration of IL-6 between the autism and control individuals. The individuals with autism showed an elevated median 5-HT concentration of 158.96 ng/mL (range, 67.44–336.27 ng/mL), whereas the

Discussion

The results of this study demonstrated that as compared to the healthy controls, the individuals with autism showed a higher level of 5-HT and IL-6. And ROC analysis indicated the 5-HT and IL-6 were the potential biomarkers in diagnosis of autism. The combination of two factors gave the best sensitivity and specificity in diagnosis of autism. The WB 5-HT and plasma IL-6 are associated with the severity level of autism measured by the CARS scores.

In the present research, individuals with autism

Conclusions

The present study showed that, as compared to healthy individuals, individuals with autism showed an elevated level of 5-HT and IL-6. 5-HT and IL-6 showed a significant positive correlation with the severity of autism. The combination of 5-HT and IL-6 performed the best as a biomarker in the diagnosis of autism.

Conflict of interest

No potential conflict of interests relevant to this article was reported.

Acknowledgments

This research was supported by National Natural Science Foundation of China (Nos. 81401130, 31371043) and grants from the East China Normal University (No. 7119297K).

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View full text

The combined role of serotonin and interleukin-6 as biomarker for autism

Highlights

Abstract

Introduction

Section snippets

Subjects

Demographic features

The production of WB 5-HT and plasma IL-6

Discussion

Conclusions

Conflict of interest

Acknowledgments

J Neuroimmunol

Brain Behav Immun

Neuropharmacology

Life Sci

Neurosci Lett

Eur Neuropsychopharmacol

Neurotoxicol Teratol

Psychiatry Res

Biol Psychiatry

J Neuroimmunol

Biochem Biophys Res Commun

Neuropharmacology

Immunobiology

Brain Res

Chest

J Am Acad Child Adolesc Psychiatry

Prog Neuro-Psychopharmacol Biol Psychiatry

J Neuroimmunol

Brain Res Bull

Amniotic fluid inflammatory cytokines: potential markers of immunologic dysfunction in autism spectrum disorders

World J Biol Psychiatry

Liquid-chromatographic determination of serotonin and tryptophan in whole blood and plasma

Clin Chem

Brief report: platelet-poor plasma serotonin in autism

J Autism Dev Disord

Diagnostic and statistical manual of mental disorders

Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder

Mol Psychiatry

Altered serotonin synthesis in the dentatothalamocortical pathway in autistic boys

Ann Neurol

Autism and developmental abnormalities in children with perinatal cocaine exposure

J Natl Med Assoc