Paula Krakowiak

Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome

Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. A potential role for immune dysfunction has been suggested in ASD. To test this hypothesis, we investigated evidence of differential cytokine release in plasma samples obtained from 2 to 5 year-old children with ASD compared with age-matched typically developing (TD) children and children with developmental disabilities other than autism (DD). Participants were recruited as part of the population based case-control CHARGE (Childhood Autism Risks from Genetics and Environment) study and included: 97 participants with a confirmed diagnosis of ASD using standard assessments (DSM IV criteria and ADOS, ADI-R), 87 confirmed TD controls, and 39 confirmed DD controls. Plasma was isolated and cytokine production was assessed by multiplex Luminex™ analysis. Observations indicate significant increases in plasma levels of a number of cytokines, including IL-1β, IL-6, IL-8 and IL-12p40 in the ASD group compared with TD controls (p<0.04). Moreover, when the ASD group was separated based on the onset of symptoms, it was noted that the increased cytokine levels were predominantly in children who had a regressive form of ASD. In addition, increasing cytokine levels were associated with more impaired communication and aberrant behaviors. In conclusion, using larger number of participants than previous studies, we report significantly shifted cytokine profiles in ASD. These findings suggest that ongoing inflammatory responses may be linked to disturbances in behavior and require confirmation in larger replication studies. The characterization of immunological parameters in ASD has important implications for diagnosis, and should be considered when designing therapeutic strategies to treat core symptoms and behavioral impairments of ASD.

Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders.

OBJECTIVE: We examined whether metabolic conditions (MCs) during pregnancy (diabetes, hypertension, and obesity) are associated with autism spectrum disorder (ASD), developmental delays (DD), or impairments in specific domains of development in the offspring. METHODS: Children aged 2 to 5 years (517 ASD, 172 DD, and 315 controls) were enrolled in the CHARGE (Childhood Autism Risks from Genetics and the Environment) study, a population-based, case-control investigation between January 2003 and June 2010. Eligible children were born in California, had parents who spoke English or Spanish, and were living with a biological parent in selected regions of California. Children’s diagnoses were confirmed by using standardized assessments. Information regarding maternal conditions was ascertained from medical records or structured interview with the mother. RESULTS: All MCs were more prevalent among case mothers compared with controls. Collectively, these conditions were associated with a higher likelihood of ASD and DD relative to controls (odds ratio: 1.61 [95% confidence interval: 1.10–2.37; odds ratio: 2.35 [95% confidence interval: 1.43–3.88], respectively). Among ASD cases, children of women with diabetes had Mullen Scales of Early Learning (MSEL) expressive language scores 0.4 SD lower than children of mothers without MCs (P < .01). Among children without ASD, those exposed to any MC scored lower on all MSEL and Vineland Adaptive Behavior Scales (VABS) subscales and composites by at least 0.4 SD (P < .01 for each subscale/composite). CONCLUSIONS: Maternal MCs may be broadly associated with neurodevelopmental problems in children. With obesity rising steadily, these results appear to raise serious public health concerns.

Sleep problems in children with autism spectrum disorders, developmental delays, and typical development: a population-based study

This study compared parent‐reported sleep characteristics in 2‐ to 5‐year‐old children with autism spectrum disorders (ASD) to children with other developmental delays (DD) and typical development (TD). We included 529 children (303 ASD [167 males], 63 DD [46 males], and 163 TD [134 males]) enrolled in the CHARGE study, an ongoing population‐based case–control study. The mean age of participants was 3.6 years (standard deviation, 0.8 years). ASD diagnosis was confirmed with Autism Diagnostic Interview‐Revised (ADI‐R) and Autism Diagnostic Observation Schedules (ADOS). Cognitive and adaptive functioning was assessed using Mullen Scales of Early Learning (MSEL) and Vineland Adaptive Behavior Scales (VABS), respectively. Demographic, medical and sleep history information were ascertained from California birth records, telephone interview, medical assessments at clinic visit, and parent‐administered questionnaires. Fifty‐three percent of children with ASD had at least one frequent sleep problem, followed by 46% of children with DD, and 32% of the TD group (P < 0.0001). Exploratory factor analyses of sleep history data yielded two factors: sleep onset problems and night waking. Children with ASD had marginally higher sleep onset factor scores and significantly higher night waking factor scores compared with the TD group. Factor scores for children with DD were intermediate between the ASD and TD groups. Cognitive or adaptive development did not predict severity of sleep problems in the ASD group.

Decreased transforming growth factor beta1 in autism: A potential link between immune dysregulation and impairment in clinical behavioral outcomes

Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. There is evidence of both immune dysregulation and autoimmune phenomena in autism. We examined the regulatory cytokine transforming growth factor beta-1 (TGF beta 1) because of its role in controlling immune responses. Plasma levels of active TGF beta 1 were evaluated in 75 children with ASD compared with 68 controls. Children with ASD had significantly lower plasma TGF beta 1 levels compared with typically developing controls (p=0.0017) and compared with children with developmental disabilities other than ASD (p=0.0037), after adjusting for age and gender. In addition, there were significant correlations between psychological measures and TGF beta 1 levels, such that lower TGF beta 1 levels were associated with lower adaptive behaviors and worse behavioral symptoms. The data suggest that immune responses in autism may be inappropriately regulated due to reductions in TGF beta 1. Such immune dysregulation may predispose to the development of possible autoimmune responses and/or adverse neuroimmune interactions during critical windows in development.

Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders

A role for immune dysfunction has been suggested in autism spectrum disorders (ASD). Elevated levels of chemokines have been detected in the brain and CSF of individuals with ASD but, to date, no study has examined chemokine levels in the plasma of children with this disorder. In the current study, we determined whether there were differential profiles of chemokines in the plasma of children with ASD compared to age-matched typically developing controls and children with developmental disabilities other than ASD. Increased MCP-1, RANTES and eotaxin levels were observed in ASD children compared with both control groups (p<0.03), and increased chemokine production was associated with higher aberrant behavior scores and more impaired developmental and adaptive function.. Elevated MCP-1, RANTES and eotaxin in some ASD children and their association with more impaired behaviors may have etiological significance. Chemokines and their receptors might provide unique targets for future therapies in ASD.

Altered T cell responses in children with autism

Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. A potential etiologic role for immune dysfunction in ASD has been suggested. Dynamic adaptive cellular immune function was investigated in 66 children with a confirmed diagnosis of ASD and 73 confirmed typically developing (TD) controls 2-5 years-of-age. In vitro stimulation of peripheral blood mononuclear cells with PHA and tetanus was used to compare group-associated cellular responses. The production of GM-CSF, TNFα, and IL-13 were significantly increased whereas IL-12p40 was decreased following PHA stimulation in ASD relative to TD controls. Induced cytokine production was associated with altered behaviors in ASD children such that increased pro-inflammatory or T(H)1 cytokines were associated with greater impairments in core features of ASD as well as aberrant behaviors. In contrast, production of GM-CSF and T(H)2 cytokines were associated with better cognitive and adaptive function. Following stimulation, the frequency of CD3(+), CD4(+) and CD8(+) T cells expressing activation markers CD134 and CD25 but not CD69, HLA-DR or CD137 were significantly reduced in ASD, and suggests an altered activation profile for T cells in ASD. Overall these data indicate significantly altered adaptive cellular immune function in children with ASD that may reflect dysfunctional immune activation, along with evidence that these perturbations may be linked to disturbances in behavior and developmental functioning. Further longitudinal analyzes of cellular immunity profiles would delineate the relationship between immune dysfunction and the progression of behavioral and developmental changes throughout the course of this disorder.

Reduced Levels of Immunoglobulin in Children With Autism Correlates With Behavioral Symptoms

Objectives: To assay if plasma antibody levels in children with autism or developmental delays (DD) differ from those with typical development as an indicator of immune function and to correlate antibody levels with severity of behavioral symptoms.

Regression in Autism: Prevalence and Associated Factors in the CHARGE Study

OBJECTIVE The aim of this study was to examine the prevalence of regressive autism and associated demographic, medical, and developmental factors by using 2 different definitions of regression based on the Autism Diagnostic Interview, Revised. METHODS Subjects were aged 2 to 5 years, with autism (AU) or autism spectrum disorder (ASD) confirmed by standardized measures. Children with regression, defined as a) loss of both language and social skills or b) loss of either language or social skills, were compared with each other and to children with AU or ASD with no reported loss of skills on developmental and adaptive functioning. Parents reported on seizure, gastrointestinal, and sleep concerns. RESULTS Fifteen percent (50/333) of the combined AU-ASD group lost both language and social skills; 41% (138/333) lost either language or social skills. No differences were found between the 2 samples of children with regression. Few developmental, demographic, or medical differences were found between the combined regression group and children without loss of skills, in both the larger AU-ASD sample and the more homogeneous AU-only sample. Children with regression had significantly lower communication scores than children without regression. CONCLUSIONS The prevalence of regression in a large sample of young children with AU and ASD varies depending on the definition used; requiring loss of language significantly underestimates the frequency of developmental regression. Children with regression performed significantly less well than those without regression on 2 measures of communication, but the clinical meaningfulness of these differences is uncertain because of the small effect sizes.

Autism-specific maternal autoantibodies recognize critical proteins in developing brain

Autism spectrum disorders (ASDs) are neurodevelopmental in origin, affecting an estimated 1 in 88 children in the United States. We previously described ASD-specific maternal autoantibodies that recognize fetal brain antigens. Herein, we demonstrate that lactate dehydrogenase A and B (LDH), cypin, stress-induced phosphoprotein 1 (STIP1), collapsin response mediator proteins 1 and 2 (CRMP1, CRMP2) and Y-box-binding protein to comprise the seven primary antigens of maternal autoantibody-related (MAR) autism. Exclusive reactivity to specific antigen combinations was noted in 23% of mothers of ASD children and only 1% of controls. ASD children from mothers with specific reactivity to LDH, STIP1 and CRMP1 and/or cypin (7% vs 0% in controls; P<0.0002; odds ratios of 24.2 (95% confidence interval: 1.45–405)) had elevated stereotypical behaviors compared with ASD children from mothers lacking these antibodies. We describe the first panel of clinically significant biomarkers with over 99% specificity for autism risk thereby advancing our understanding of the etiologic mechanisms and therapeutic possibilities for MAR autism.

Polybrominated diphenyl ethers in relation to autism and developmental delay: A case-control study

BackgroundPolybrominated diphenyl ethers (PBDEs) are flame retardants used widely and in increasing amounts in the U.S. over the last few decades. PBDEs and their metabolites cross the placenta and studies in rodents demonstrate neurodevelopmental toxicity from prenatal exposures. PBDE exposures occur both via breastfeeding and hand-to-mouth activities in small children.MethodsParticipants were 100 children from the CHARGE (CH ildhood A utism R isk from G enetics and the E nvironment) Study, a case-control epidemiologic investigation of children with autism/autism spectrum disorder, with developmental delay and from the general population. Diagnoses of autism were confirmed by the Autism Diagnostic Observation Schedule and Autism Diagnostic Inventory-Revised, and of developmental delay using the Mullens Scales of Early Learning and the Vineland Adaptive Behavior Scales. Typically developing controls were those with no evidence of delay, autism, or autism spectrum disorder. Eleven PBDE congeners were measured by gas chromatography/mass spectrometry from serum specimens collected after children were assessed. Logistic regression was used to evaluate the association between plasma PBDEs and autism.ResultsChildren with autism/autism spectrum disorder and developmental delay were similar to typically developing controls for all PBDE congeners, but levels were high for all three groups.ConclusionsPlasma samples collected post-diagnosis in this study may not represent early life exposures due to changes in diet and introduction of new household products containing PBDEs. Studies with direct measurements of prenatal or infant exposures are needed to assess the possible causal role for these compounds in autism spectrum disorders.