Neonatal cytokines and chemokines and risk of Autism Spectrum Disorder: the Early Markers for Autism (EMA) study: a case-control study.

BackgroundBiologic markers of infection and inflammation have been associated with Autism Spectrum Disorders (ASD) but prior studies have largely relied on specimens taken after clinical diagnosis. Research on potential biologic markers early in neurodevelopment is required to evaluate possible causal pathways and screening profiles.ObjectiveTo investigate levels of cytokines and chemokines in newborn blood specimens as possible early biologic markers for autism.MethodsWe conducted a population-based case-control study nested within the cohort of infants born from July 2000 to September 2001 to women who participated in the prenatal screening program in Orange County, California, USA. The study population included children ascertained from the California Department of Developmental Services with Autism Spectrum Disorder (ASD, n = 84), or developmental delay but not ASD (DD, n = 49), and general population controls randomly sampled from the birth certificate files and frequency matched to ASD cases on sex, birth month and birth year (GP, n = 159). Cytokine and chemokine concentrations were measured in archived neonatal blood specimens collected for routine newborn screening.ResultsCytokines were not detected in the vast majority of newborn samples regardless of case or control status. However, the chemokine monocyte chemotactic protein-1 (MCP-1) was elevated and the chemokine Regulated upon Activation Normal T-Cell Expressed and Secreted (RANTES) was decreased in ASD cases compared to GP controls. The chemokines macrophage inflammatory protein-1alpha (MIP-1α) and RANTES were decreased in children with DD compared to GP controls.ConclusionMeasurement of immune system function in the first few days of life may aid in the early identification of abnormal neurodevelopment and shed light on the biologic mechanisms underlying normal neurodevelopment

Increased midgestational IFN-γ, IL-4 and IL-5 in women bearing a child with autism: A case-control study

<p>Abstract</p> <p>Background</p> <p>Immune anomalies have been documented in individuals with autism spectrum disorders (ASDs) and their family members. It is unknown whether the maternal immune profile during pregnancy is associated with the risk of bearing a child with ASD or other neurodevelopmental disorders.</p> <p>Methods</p> <p>Using Luminex technology, levels of 17 cytokines and chemokines were measured in banked serum collected from women at 15 to 19 weeks of gestation who gave birth to a child ultimately diagnosed with (1) ASD (<it>n </it>= 84), (2) a developmental delay (DD) but not autism (<it>n </it>= 49) or (3) no known developmental disability (general population (GP); <it>n </it>= 159). ASD and DD risk associated with maternal cytokine and chemokine levels was estimated by using multivariable logistic regression analysis.</p> <p>Results</p> <p>Elevated concentrations of IFN-γ, IL-4 and IL-5 in midgestation maternal serum were significantly associated with a 50% increased risk of ASD, regardless of ASD onset type and the presence of intellectual disability. By contrast, elevated concentrations of IL-2, IL-4 and IL-6 were significantly associated with an increased risk of DD without autism.</p> <p>Conclusion</p> <p>The profile of elevated serum IFN-γ, IL-4 and IL-5 was more common in women who gave birth to a child subsequently diagnosed with ASD. An alternative profile of increased IL-2, IL-4 and IL-6 was more common for women who gave birth to a child subsequently diagnosed with DD without autism. Further investigation is needed to characterize the relationship between these divergent maternal immunological phenotypes and to evaluate their effect on neurodevelopment.</p

Maternal infection during pregnancy and autism spectrum disorders

Abstract We conducted a nested case-control study including 407 cases and 2,075 frequency matched controls to investigate the association between maternal infections during pregnancy and risk of autism spectrum disorders (ASD). Cases, controls, and maternal infections were ascertained from Kaiser Permanente Northern California clinical databases. No overall association between diagnoses of any maternal infection during pregnancy and ASD was observed [adjusted odds ratio (OR adj ) = 1.15, 95 % confidence interval (CI) 0.92-1.43]. However, women with infections diagnosed during a hospital admission (OR adj = 1.48, 95 % CI 1.07-2.04), particularly bacterial infections (OR adj = 1.58, 95 % CI 1.06-2.37), were at increased risk of delivering a child with ASD. Multiple infections during pregnancy were associated with ASD (OR adj = 1.36, 95 % CI 1.05-1.78)

Lack of Neurotrophin-3 Results in Death of Spinal Sensory Neurons and Premature Differentiation of Their Precursors

AbstractTo understand mechanisms resulting in the absence of two-thirds of spinal sensory neurons in mice lacking NT-3, we have compared dorsal root ganglia development in normal and mutant embryos. The reduction in neurons, achieved by E13, results from several deficits: first, elevated neuronal apoptosis significantly reduces neuronal numbers; second, elevated neurogenesis between E11 and E12, without changes in rates of precursor proliferation or apoptosis, depletes the precursor pool; consequently, the reduced precursor pool prevents increases in neuronal numbers between E12 and E13, when most neurons are born in normal animals. Although deficits occur before final target innervation, we show that NT-3 is expressed at all stages in regions accessible to these neurons or their axons and is only restricted to final targets after innervation

Maternal Infection During Pregnancy and Autism Spectrum Disorders

We conducted a nested case-control study including 407 cases and 2,075 frequency matched controls to investigate the association between maternal infections during pregnancy and risk of autism spectrum disorders (ASD). Cases, controls, and maternal infections were ascertained from Kaiser Permanente Northern California clinical databases. No overall association between diagnoses of any maternal infection during pregnancy and ASD was observed [adjusted odds ratio (ORadj) = 1.15, 95 % confidence interval (CI) 0.92-1.43]. However, women with infections diagnosed during a hospital admission (ORadj = 1.48, 95 % CI 1.07-2.04), particularly bacterial infections (ORadj = 1.58, 95 % CI 1.06-2.37), were at increased risk of delivering a child with ASD. Multiple infections during pregnancy were associated with ASD (ORadj = 1.36, 95 % CI 1.05-1.78)

Prenatal and Neonatal Thyroid Stimulating Hormone Levels and Autism Spectrum Disorders

Thyroid hormones are critical for normal brain development. This study examined autism spectrum disorders (ASD) and thyroid stimulating hormone (TSH) levels measured in mid-pregnancy maternal serum and infant blood after birth. Three groups of children born in Orange County, CA in 2000-2001 were identified: ASD (n = 78), developmental delay (n = 45), and general population controls (GP) (n = 149). Samples were retrieved from prenatal and newborn screening specimen archives. Adjusted logistic regression models showed inverse associations between ASD and log transformed TSH levels in maternal serum samples (ASD vs. GP: OR [95 % CI] 0.33 [0.12-0.91], Early Onset ASD vs. GP: 0.31 [0.10-0.98]). Results for thyroid levels in newborn blood samples were similar though not significant (ASD vs. GP: 0.61 [0.18-2.04])

Maternal autoantibody profiles as biomarkers for ASD and ASD with co-occurring intellectual disability

Maternal autoantibody-related ASD (MAR ASD) is a subtype of autism in which pathogenic maternal autoantibodies (IgG) cross the placenta, access the developing brain, and cause neurodevelopmental alterations and behaviors associated with autism in the exposed offspring. We previously reported maternal IgG response to eight proteins (CRMP1, CRMP2, GDA LDHA, LDHB, NSE, STIP1, and YBOX) and that reactivity to nine specific combinations of these proteins (MAR ASD patterns) was predictive of ASD risk. The aim of the current study was to validate the previously identified MAR ASD patterns (CRMP1 + GDA, CRMP1 + CRMP2, NSE + STIP1, CRMP2 + STIP1, LDHA + YBOX, LDHB + YBOX, GDA + YBOX, STIP1 + YBOX, and CRMP1 + STIP1) and their accuracy in predicting ASD risk in a prospective cohort employing maternal samples collected prior to parturition. We used prenatal plasma from mothers of autistic children with or without co-occurring intellectual disability (ASD = 540), intellectual disability without autism (ID = 184) and general population controls (GP = 420) collected by the Early Markers for Autism (EMA) study. We found reactivity to one or more of the nine previously identified MAR ASD patterns in 10% of the ASD group compared with 4% of the ID group and 1% of the GP controls (ASD vs GP: Odds Ratio (OR) = 7.81, 95% Confidence Interval (CI) 3.32 to 22.43; ASD vs ID: OR = 2.77, 95% CI (1.19-7.47)) demonstrating that the MAR ASD patterns are strongly associated with the ASD group and could be used to assess ASD risk prior to symptom onset. The pattern most strongly associated with ASD was CRMP1 + CRMP2 and increased the odds for an ASD diagnosis 16-fold (3.32 to &gt;999.99). In addition, we found that several of these specific MAR ASD patterns were strongly associated with ASD with intellectual disability (ASD + ID) and others associated with ASD without ID (ASD-no ID). Prenatal screening for these MAR patterns may lead to earlier identification of ASD and facilitate access to the appropriate early intervention services based on each child's needs

Increased mid-gestational IFN-gamma, IL-4, and IL-5 in women giving birth to a child with autism: a case-control study

Abstract Background Immune anomalies have been documented in individuals with autism spectrum disorders (ASDs) and their family members. It is unknown whether the maternal immune profile during pregnancy is associated with the risk of bearing a child with ASD or other neurodevelopmental disorders. Methods Using Luminex technology, levels of 17 cytokines and chemokines were measured in banked serum collected from women at 15 to 19 weeks of gestation who gave birth to a child ultimately diagnosed with (1) ASD (n = 84), (2) a developmental delay (DD) but not autism (n = 49) or (3) no known developmental disability (general population (GP); n = 159). ASD and DD risk associated with maternal cytokine and chemokine levels was estimated by using multivariable logistic regression analysis. Results Elevated concentrations of IFN-γ, IL-4 and IL-5 in midgestation maternal serum were significantly associated with a 50% increased risk of ASD, regardless of ASD onset type and the presence of intellectual disability. By contrast, elevated concentrations of IL-2, IL-4 and IL-6 were significantly associated with an increased risk of DD without autism. Conclusion The profile of elevated serum IFN-γ, IL-4 and IL-5 was more common in women who gave birth to a child subsequently diagnosed with ASD. An alternative profile of increased IL-2, IL-4 and IL-6 was more common for women who gave birth to a child subsequently diagnosed with DD without autism. Further investigation is needed to characterize the relationship between these divergent maternal immunological phenotypes and to evaluate their effect on neurodevelopment