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.
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-1a 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).
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.
The aim of the study was to analyze cytokine profiles in amniotic fluid (AF) samples of children developing autism spectrum disorders (ASD) and controls, adjusting for maternal autoimmune disorders and maternal infections during pregnancy.
AF samples of 331 ASD cases and 698 controls were analyzed for inflammatory cytokines using Luminex xMAP technology utilizing a historic birth cohort. Clinical data were retrieved from nationwide registers, and case-control differences in AF cytokine levels were assessed using chi-square tests, logistic and tobit regression models.
Overall, individuals with ASD had significantly elevated AF levels of TNF-a and TNF-ß compared to controls. Analyzing individuals diagnosed only with ICD-10 codes yielded significantly elevated levels of IL-4, IL-10, TNF-a and TNF-ß in ASD patients. Restricting analysis to infantile autism cases showed significantly elevated levels of IL-4, TNF-a and TNF-ß compared to controls with no psychiatric comorbidities. Elevated levels of IL-6 and IL-5 were found in individuals with other childhood psychiatric disorders (OCPD) when compared to controls with no psychiatric comorbidities.
AF samples of individuals with ASD or OCPD showed differential cytokine profiles compared to frequency-matched controls. Further studies to examine the specificity of the reported cytokine profiles in ASD and OCPD are required.
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-ß 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.
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.
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.
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% CI 1.04 to 6.51, P = 0.04).
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.
Genes associated with cardiovascular disease may also be risk factors for congenital cerebral palsy (CP) and these associations may be modified by sex, since there is an increased risk of CP in male children. We investigated the association between CP of the child with cardiovascular disease in parents, taking sex of the child into consideration.
All parents of non-adopted singletons born in Denmark between 1973 and 2003 were included. Parents of a child with CP, confirmed by the Danish National CP registry, were considered exposed. Cox proportional hazards regressions were used to model risk of cardiovascular outcomes for exposed parents compared to all other parents beginning at the child's 10(th) birthday.
We identified 733,730 mothers and 666,652 fathers among whom 1,592 and 1,484, respectively, had a child with CP. The mean age for mothers at end of follow up was 50 ± 8 years. After adjustment for maternal age, parental education, child's sex, child's residence, child being small for gestational age and maternal hypertensive disorder during pregnancy, mothers of CP male children had an excess risk of cardiovascular disease (HR: 1.52, 95% CI: 1.16-2.00), attributable mostly to an increased incidence of hypertension and cerebrovascular disease. After additional adjustment for preterm birth, the association was markedly attenuated for cardiovascular disease (1.34, 95%CI: 1.02 - 1.76), became nonsignificant for hypertension, but remained significant for cerebrovascular disease (HR: 2.73, 95% CI: 1.45- 5.12). There was no increased risk of cardiovascular events in mothers of female CP children, or fathers of CP children of any sex.
Women that have a male child with CP are at increased risk for premature cardiovascular disease. Part of this association may be related to risk factors for preterm births.
Infections during pregnancy and after birth, and the risk of autism spectrum disorders: a register-based study utilizing a Danish historic birth cohort.
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.
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.
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).
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.
To examine the risk of schizophrenia in a Danish population after exposure to early life stress, and whether this risk is modified by DNA sequence variation, specifically two single nucleotide polymorphisms (SNPs) (rs5479 and rs56303414) from the gene HSD11B2. This gene encodes the enzyme 11-ß hydroxysteroid dehydrogenase type 2 which converts active cortisol into inactive cortisone.
A two-stage analysis involving (1) a population-based cohort study, and (2) a nested case-control study using genotype information. Stage 1 included 1,141,447 people; here, we calculated incidence rate ratios (IRR) for the risk of schizophrenia among children of mothers who experienced loss or serious illness of close relatives before, during, and after pregnancy. In stage 2, we genotyped rs5479 and rs56303414 among 1275 schizophrenia cases and 1367 controls, and investigated interactions between genotypes and early life stress on the risk of schizophrenia.
In stage 1, no increased risk of schizophrenia was found in offspring after exposure during pregnancy, but offspring exposed to early life stress at age 0-2 years had a significantly increased risk of schizophrenia (adjusted IRR 1.18, 95% confidence interval 1.07-1.31). For rs5479, the minor allele was nucleotide A, and the major allele was nucleotide C. No interaction was found between rs5479 and exposure during pregnancy. Individuals with the minor A allele of rs5479, however, had a significantly increased risk of schizophrenia after exposure to early life stress at age 3-9 years (adjusted IRR 2.06, 1.04-4.06). No interaction was found between rs56303414 and exposure in any of the time periods.
No association was found between exposure to early life stress during pregnancy and schizophrenia in the offspring investigated, whereas individuals exposed to early life stress within the first two years of life had an increased risk. No interaction was found between HSD11B2 and exposure during pregnancy, but individuals with the A allele of rs5479 had an increased risk of schizophrenia after exposure at age 3-9 years.
Maternal caffeine intake during pregnancy is associated with birth weight but not with gestational length: results from a large prospective observational cohort study.
Department of Obstetrics and Gynaecology, Sahlgrenska Academy, Sahlgrenska University Hospital/Östra, SE-416 85 Gothenburg, Sweden. verena.sengpiel@obgyn.gu.se
Pregnant women consume caffeine daily. The aim of this study was to examine the association between maternal caffeine intake from different sources and (a) gestational length, particularly the risk for spontaneous preterm delivery (PTD), and (b) birth weight (BW) and the baby being small for gestational age (SGA).
This study is based on the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health. A total of 59,123 women with uncomplicated pregnancies giving birth to a live singleton were identified. Caffeine intake from different sources was self-reported at gestational weeks 17, 22 and 30. Spontaneous PTD was defined as spontaneous onset of delivery between 22+0 and 36+6 weeks (n = 1,451). As there is no consensus, SGA was defined according to ultrasound-based (Marsal, n = 856), population-based (Skjaerven, n = 4,503) and customized (Gardosi, n = 4,733) growth curves.
The main caffeine source was coffee, but tea and chocolate were the main sources in women with low caffeine intake. Median pre-pregnancy caffeine intake was 126 mg/day (IQR 40 to 254), 44 mg/day (13 to 104) at gestational week 17 and 62 mg/day (21 to 130) at gestational week 30. Coffee caffeine, but not caffeine from other sources, was associated with prolonged gestation (8 h/100 mg/day, P
Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and age at onset of schizophrenia: no consistent evidence for an association in the Nordic population.
Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in metabolic pathways of importance for nucleotide synthesis and methylation of DNA, membranes, proteins and lipids. The MTHFR gene includes a common polymorphism (rs1801133 or C677T), which is associated with enzyme activity. The T-allele of the C677T polymorphism has been associated with earlier age at onset of schizophrenia in a Scandinavian population, although no association was found in replication attempts in other populations. Extending the study to five Nordic samples consisting of 2,198 patients with schizophrenia, including the original Scandinavian samples, there was no significant association between MTHFR C677T polymorphism and age at onset in schizophrenia. The present results do not suggest that the investigated MTHFR polymorphism has any significant influence on age at onset of schizophrenia in the Nordic population.
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-1a 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.
