Tiemeier, H.

ADHD Symptoms and Entrepreneurial Intentions (Research Paper)

2013-03-26T00:00:00Z

The growing interest of the business world in the virtues of individ- uals with specific cognitive behavioral characteristics, such as lack of attention and hyperactivity, is not matched by scholarly work. Indi- viduals who experience the challenges associated with such character- istics are thought to thrive in work environments that embrace their talents. Given that entrepreneurship requires a distinctive mindset, we test the hypothesis that individuals who, more than others, expe- rience symptoms of attention deficit and hyperactivity (ADHD) favor entrepreneurship over wage-employment. Using data of nearly 13,000 university students, we show that symptoms of attention deficit and hyperactivity increase the likelihood of intending to startup a busi- ness directly after study. We find evidence for partial mediation of two work attributes; independence and risk tolerance. Students who experience ADHD symptoms prefer to work independently and do not shy away from working on high-risk projects, which partly explains their preference for an entrepreneurial career.

Parental psychological distress during pregnancy and early growth in preschool children: The generation R study (Article)

2013-03-01T00:00:00Z

This study separately assessed the associations of maternal and paternal psychological distress during pregnancy with early growth in preschool children. The study was based on data from a population-based cohort study involving 5,283 children and their parents (with data collected beginning in early pregnancy) in Rotterdam, the Netherlands, from 2002 to 2006. Information on parental psychological distress (symptoms of depression, anxiety, hostility, and family stress) was obtained by questionnaire in the second trimester of gestation by using the Brief Symptom Inventory and the "general functioning" subscale of the McMaster Family Assessment Device. Child height, weight, and body mass index (weight (kg)/height (m)2) were measured repeatedly from age 3 months to age 4 years. We observed no consistent associations between overall maternal psychological symptoms, depression, anxiety, or hostility and child height, weight, or body mass index after adjustment for confounders. All maternal psychological distress scores were positively associated with the risk of overweight in childhood; however, these associations attenuated toward the null and became nonsignificant after adjusting for potential confounders. We did not observe consistent associations between paternal psychological distress and growth in childhood. These results indicate that social, behavioral, or environmental factors that cluster with parental psychological distress may explain the previously suggested associations between maternal psychological distress and early childhood growth and risk of overweight. © 2013 The Author.

Genetic determinants of mortality. Can findings from genome-wide association studies explain variation in human mortality? (Article)

2013-01-28T00:00:00Z

Twin studies have estimated the heritability of longevity to be approximately 20-30 %. Genome-wide association studies (GWAS) have revealed a large number of determinants of morbidity, but so far, no new polymorphisms have been discovered to be associated with longevity per se in GWAS. We aim to determine whether the genetic architecture of mortality can be explained by single nucleotide polymorphisms (SNPs) associated with common traits and diseases related to mortality. By extensive quality control of published GWAS we created a genetic score from 707 common SNPs associated with 125 diseases or risk factors related with overall mortality. We prospectively studied the association of the genetic score with: (1) time-to-death; (2) incidence of the first of nine major diseases (coronary heart disease, stroke, heart failure, diabetes, dementia, lung, breast, colon and prostate cancers) in two population-based cohorts of Dutch and Swedish individuals (N = 15,039; age range 47-99 years). During a median follow-up of 6.3 years (max 22.2 years), we observed 4,318 deaths and 2,132 incident disease events. The genetic score was significantly associated with time-to-death [hazard ratio (HR) per added risk allele = 1.003, P value = 0.006; HR 4th vs. 1st quartile = 1.103]. The association between the genetic score and incidence of major diseases was stronger (HR per added risk allele = 1.004, P value = 0.002; HR 4th vs. 1st quartile = 1.160). Associations were stronger for individuals dying at older ages. Our findings are compatible with the view of mortality as a complex and highly polygenetic trait, not easily explainable by common genetic variants related to diseases and physiological traits.

Development of Mental Health Problems and Overweight Between Ages 4 and 11 Years: A Population-Based Longitudinal Study of Australian Children (Article)

2013-01-28T00:00:00Z

Objective: To investigate timing and strength of associations between mental health and overweight in childhood; to investigate how the cumulative burden of each of these problems affects the other. Methods: Participants were 3197 children in the population-based Longitudinal Study of Australian Children. At 4 biennial waves spanning ages 4-5 to 10-11 years, parents and teachers reported child mental health on the Strengths and Difficulties Questionnaire, and researchers measured body mass index (BMI). Outcomes were analyzed both continuously and dichotomized (clinical vs no mental health problems; overweight vs not overweight). Results: Approximately 30% of participants had overweight and/or mental health problems at some point between ages 4-5 and 10-11 years. Small positive cross-sectional mental health-BMI associations emerged at 8-9 years and strengthened by 10-11 years. In longitudinal analyses, more episodes of overweight predicted higher Total Difficulties scores by 10-11 years, mainly reflecting greater Peer Problems and, to a lesser degree, Emotional Symptoms than never-overweight children; though modest, these associations were robust to a range of sensitivity analyses. In post hoc analyses, overweight in late childhood was more strongly associated with poorer mental health at 10-11 years than early and fluctuating childhood overweight. Associations were smaller and less robust for mental health problems prospectively predicting higher BMI. Conclusions: Relationships between poorer mental health and higher BMI emerged then strengthened in middle to late childhood. In childhood, it appears that overweight precedes mental health problems, particularly peer problems and-on a lower level-emotional problems, rather than the reverse.

Pediatric population-based neuroimaging and the Generation R Study: The intersection of developmental neuroscience and epidemiology (Article)

2013-01-01T00:00:00Z

Neuroimaging studies of typically developing children and adolescents have provided valuable information on global and regional developmental trajectories of brain development. As these studies become larger and population-based, they are generating an intersection between the fields of developmental neuroscience and epidemiology. However, few of these studies have adequately probed the contribution of multiple environmental and genetic factors on brain development. Studies designed to optimally evaluate the role of multiple environmental and genetic factors on brain development require both large sample sizes and the prospective collection of multiple environmental factors. The Generation R Study is a large, prospective, prenatal-cohort study of nearly 10,000 children that began in 2002 in Rotterdam, the Netherlands. In September of 2009, 6-8 year old children from the Generation R Study were invited to participate in a magnetic resonance imaging component of the study. We provide an overview of the study design and experience for the first 801 children recruited for the neuroimaging component of the study. The protocol includes a 1-h neuropsychological assessment using the NEPSY-II, a mock scanning session, and a neuroimaging session that includes high-resolution structural, diffusion tensor, and resting-state functional MRI sequences. Image quality has been good to excellent in over 80 % of the children to date. The infusion of imaging into the Generation R Study will set the stage for evaluating the role of multiple environmental and genetic factors in both typical and atypical neurodevelopment.

The generation R study: A review of design, findings to date, and a study of the 5-HTTLPR by environmental interaction from fetal life onward (Article)

2012-11-01T00:00:00Z

Objective: First, we give an overview of child psychiatric research in the Generation R Study, a population-based cohort from fetal life forward. Second, we examine within Generation R whether the functional polymorphism (5-HTTLPR) in the promoter of the serotonin transporter gene interacts with prenatal maternal chronic difficulties, prenatal maternal anxiety or postnatal maternal anxiety to influence child emotional development. Method: A total of 2,136 northern European children were genotyped for 5-HTTLPR and rs25531. Mothers reported chronic difficulties and anxiety symptoms at 20 weeks' pregnancy and when the child was 3 years old. Child emotion recognition was observed at 3 years, and child emotional problems were assessed with the CBCL/1-5 at 5 years. Results: There were consistent main effects of maternal difficulties and anxiety on child emotional problems, but no main effect of 5-HTTLPR. Moreover, children with the s allele were at increased risk for emotional problems if their mothers reported prenatal anxiety symptoms (β = 2.02, p <.001) or postnatal anxiety symptoms (β = 1.64, p < 0.001). Also, in children of mothers with prenatal anxiety symptoms, the s allele was associated with less accurate emotion-matching (β = -0.11, p =.004). Conclusions: This population-based study shows that vulnerability due to 5-HTTLPR is not specific for certain adverse exposures or severe events, but suggests that the small effects of gene-environment interaction on emotional development become manifest early in life.

Febrile seizures and behavioural and cognitive outcomes in preschool children: The Generation R Study (Article)

2012-11-01T00:00:00Z

Aim General developmental outcome is known to be good in school-aged children who experienced febrile seizures. We examined cognitive and behavioural outcomes in preschool children with febrile seizures, including language and executive functioning outcomes. Method This work was performed in the Generation R Study, a population-based cohort study in Rotterdam from early fetal life onwards. Information about the occurrence of febrile seizures was collected by questionnaires at the ages of 1, 2, and 3years. At the age of 3years, behaviour and emotion were assessed using the Child Behavior Checklist. Information on expressive language development was obtained by the Language Development Survey at the age of 2 years 6 months. To assess executive functioning, parents completed the Behaviour Rating Inventory of Executive Function - Preschool Version when their children were 4years old. Final analyses were based on 3157 children. Results No associations were found between febrile seizures and the risk of behavioural problems or executive functioning. In contrast to single febrile seizures, recurrent febrile seizures were significantly associated with an increased risk of delayed vocabulary development (odds ratio 3.22, [95% confidence interval 1.30-7.94]). Interpretation Febrile seizures are not associated with problem behaviour or executive functioning in preschool children, but the results suggest that children with recurrent febrile seizures might be at risk for delayed language development. © The Authors. Developmental Medicine & Child Neurology

Children's eating behavior, feeding practices of parents and weight problems in early childhood: Results from the population-based Generation R Study (Article)

2012-10-30T00:00:00Z

Background: Weight problems that arise in the first years of life tend to persist. Behavioral research in this period can provide information on the modifiable etiology of unhealthy weight. The present study aimed to replicate findings from previous small-scale studies by examining whether different aspects of preschooler's eating behavior and parental feeding practices are associated with body mass index (BMI) and weight status -including underweight, overweight and obesity- in a population sample of preschool children.Methods: Cross-sectional data on the Child Eating Behaviour Questionnaire, Child Feeding Questionnaire and objectively measured BMI was available for 4987 four-year-olds participating in a population-based cohort in the Netherlands.Results: Thirteen percent of the preschoolers had underweight, 8% overweight, and 2% obesity. Higher levels of children's Food Responsiveness, Enjoyment of Food and parental Restriction were associated with a higher mean BMI independent of measured confounders. Emotional Undereating, Satiety Responsiveness and Fussiness of children as well as parents' Pressure to Eat were negatively related with children's BMI. Similar trends were found with BMI categorized into underweight, normal weight, overweight and obesity. Part of the association between children's eating behaviors and BMI was accounted for by parental feeding practices (changes in effect estimates: 20-43%), while children's eating behaviors in turn explained part of the relation between parental feeding and child BMI (changes in effect estimates: 33-47%).Conclusions: This study provides important information by showing how young children's eating behaviors and parental feeding patterns differ between children with normal weight, underweight and overweight. The high prevalence of under- and overweight among preschoolers suggest prevention interventions targeting unhealthy weights should start early in life. Although longitudinal studies are necessary to ascertain causal directions, efforts to prevent or treat unhealthy child weight might benefit from a focus on changing the behaviors of both children and their parents.

Variation in the glucocorticoid receptor gene at rs41423247 moderates the effect of prenatal maternal psychological symptoms on child cortisol reactivity and behavior (Article)

2012-10-01T00:00:00Z

Prenatal maternal psychopathology affects child development, but some children seem more vulnerable than others. Genetic variance in hypothalamic-pituitary-adrenal axis genes may influence the effect of prenatal maternal psychological symptoms on child emotional and behavioral problems. This hypothesis was tested in the Generation R Study, a population-based cohort from fetal life onward. In total, 1727 children of Northern European descent and their mothers participated in this study and were genotyped for variants in the glucocorticoid receptor (GR) gene (rs6189/rs6190, rs10052957, rs41423247, rs6195, and rs6198) and the FK506-binding protein 5 (FKBP5) gene (rs1360780). Prenatal maternal psychological symptoms were assessed at 20 weeks pregnancy and child behavior was assessed by both parents at 3 years. In a subsample of 331 children, data about cortisol reactivity were available. Based on power calculations, only those genetic variants with sufficient minor allele frequencies (rs41423247, rs10052957, and rs1360780) were included in the interaction analyses. We found that variation in GR at rs41423247 moderates the effect of prenatal maternal psychological symptoms on child emotional and behavioral problems (beta 0.41, SE 0.16, p0.009). This prenatal interaction effect was independent of mother's genotype and maternal postnatal psychopathology, and not found for prenatal psychological symptoms of the father. Moreover, the interaction between rs41423247 and prenatal psychological symptoms was also associated with decreased child cortisol reactivity (beta 2.30, p-value 0.05). These findings emphasize the potential effect of prenatal gene-environment interaction, and give insight in possible mechanisms accounting for children's individual vulnerability to develop emotional and behavioral problems.

Variation in the glucocorticoid receptor gene at rs41423247 moderates the effect of prenatal maternal psychological symptoms on child cortisol reactivity and behavior (Article)

2012-10-01T00:00:00Z

Assessing expressed emotion during pregnancy (Article)

2012-09-26T00:00:00Z

We assessed Expressed Emotion (EE) with an adapted version of the Five Minute Speech Sample in 847 pregnant women. The prevalence of high EE was 6%. High EE was significantly associated with having a first child, low income, maternal childhood trauma and lack of parental emotional warmth during childhood.

A brief observational instrument for the assessment of infant home environment: Development and psychometric testing (Article)

2012-09-01T00:00:00Z

The present paper reports on the development and the psychometric properties of a brief observational assessment of home environments for use in large-scale investigations with young infants. We generated observational items conceptually relevant for child development by two methods. First, we adapted the Infant Toddler Home Observation for Measurement of the Environment (IT-HOME) inventory for use in an exclusively observational context. Second, we added new observational items following a review of relevant literature and consulting professionals. The quality of the instrument was first evaluated in a pilot study (n = 926). In our study sample of 3406 families and their children (median age = 3.1 months, range = 1.6-6.0), exploratory factor analysis was used to identify latent constructs, Cronbach's alpha was used as a measure of internal consistency, and convergent validity was evaluated against family socio-demographic characteristics. Inter-observer agreement was investigated in a sub-sample of the respondents (n = 124). The results supported good psychometric properties of the instrument based on: (a) exploratory factor analysis yielding three meaningful latent constructs, (b) Cronbach's alphas ranging from α = 0.66 to α = 0.90, (c) inter-observer agreement ranging from r = 0.75 to r = 0.91, and (d) associations between the instrument and socio-demographic characteristics in the expected direction [e.g. Odds Ratio for low income = 15.24, 95% confidence interval (11.60, 20.01)]

Maternal thyroid autoimmunity during pregnancy and the risk of attention deficit/hyperactivity problems in children: The generation r study (Article)

2012-02-01T00:00:00Z

Background: Maternal thyroid status and autoimmunity during pregnancy have been associated with impaired development of the offspring in animal and human studies. Our objective was to examine whether elevated titers of maternal thyroid peroxidase antibodies (TPOAbs) in early pregnancy increased the risk of cognitive impairment and problem behavior in preschool children. Second, we aimed at exploring to what extent any effect on child behavior was mediated by maternal thyroid parameters during pregnancy. Methods: In the Generation R Study, a population-based cohort of 3139 children and their mothers, we measured maternal thyroid parameters (thyrotropin [TSH], free Thyroxine, and TPOAbs) at 13.5±1.8 weeks of gestation. Children's verbal and nonverbal cognitive functioning was measured at 2.5 years using the Language Development Survey and the Parent Report of Children Abilities. At 3 years, children's behavior was assessed using the Child Behavior Checklist. Results: Elevated titers of TPOAbs during pregnancy did not predict the verbal and nonverbal cognitive functioning of the children. However, elevated titers of TPOAbs in mothers were associated with externalizing problems in children (odds ratio [OR]=1.64, 95% confidence interval [CI]: 1.17-2.29, p=0.004). In particular, children of TPOAb-positive mothers were at a higher risk of attention deficit/hyperactivity problems (OR=1.77, 95% CI: 1.15-2.72, p=0.01). To explore whether the effect of maternal TPOAbs on child problem behavior was mediated by maternal thyroid parameters, we added maternal TSH to the model. After correcting for TSH, the effect of TPOAbs on externalizing problems was attenuated slightly but remained significant (OR=1.56, 95% CI: 1.14, 2.14, p=0.005). Conclusions: Our findings imply that the elevated titers of TPOAbs during pregnancy impact children's risk of problem behavior, in particular, attention deficit/hyperactivity. The observed effect is only partially explained by maternal TSH levels. These findings may point to a specific mechanism of Attention Deficit/Hyperactivity Disorder in children. Nevertheless, we can only speculate about public health implication of the study, as there is no specific treatment for TPOAb-positive pregnant women with normal thyroid function. Further investigation is needed to explore whether TPOAb-positive pregnant women and their children can benefit from close monitoring and early detection of developmental delay in populations at risk.

Recognition of scared faces and the serotonin transporter gene in young children: The Generation R Study (Article)

2011-12-01T00:00:00Z

Background: Previous research highlights the significance of a functional polymorphism located in the promoter region (5-HTTLPR) of the serotonin transporter gene in emotional behaviour. This study examined the effect of the 5-HTTLPR polymorphism on emotion processing in a large number of healthy preschoolers. Methods: The 5-HTTLPR genotype was classified in 605 children as homozygous for the short allele (SS), homozygous for the long allele (LL), or heterozygous (LS). Emotion-processing was assessed using age-appropriate computer tasks where children matched happy, sad, angry, and fearful facial expressions preceded by a shape-matching task to assess basic matching ability. Results: We found that young children could differentiate between emotion categories (F = 12.1, p <.001). The effect of 5-HTTLPR genotype depended on the emotion category presented (F = 2.3, p =.031). This effect was explained by the finding that SS children were less accurate at recognising fearful faces than LL or LS children (F = 5.3, p =.005). We did not find any significant differences as a result of 5-HTTLPR genotype for happy, sad or angry expressions (p >.05). Conclusions: Results indicate that 5-HTTLPR allele status selectively impacts the processing of fearful but not other facial expressions. This pattern is already apparent in very young typically developing children. Results may signal an early vulnerability for affective problems before disorders emerge.

Dopaminergic, serotonergic, and oxytonergic candidate genes associated with infant attachment security and disorganization? in search of main and interaction effects (Article)

2011-12-01T00:00:00Z

Background and methods: In two birth cohort studies with genetic, sensitive parenting, and attachment data of more than 1,000 infants in total, we tested main and interaction effects of candidate genes involved in the dopamine, serotonin, and oxytocin systems (DRD4, DRD2, COMT, 5-HTT, OXTR) on attachment security and disorganization. Parenting was assessed using observational rating scales for parental sensitivity (Ainsworth, Bell, & Stayton, 1974), and infant attachment was assessed with the Strange Situation Procedure. Results: We found no consistent additive genetic associations for attachment security and attachment disorganization. However, specific tests revealed evidence for a codominant risk model for COMT Val158Met, consistent across both samples. Children with the Val/Met genotype showed higher disorganization scores (combined effect size d =.22, CI =.10-.34, p <.001). Gene-by-environment interaction effects were not replicable across the two samples. Conclusions: This unexpected finding might be explained by a broader range of plasticity in heterozygotes, which may increase susceptibility to environmental influences or to dysregulation of emotional arousal. This study is unique in combining the two largest attachment cohorts with molecular genetic and observed rearing environment data to date.

The relationship between fertility and lifespan in humans (Article)

2011-12-01T00:00:00Z

Evolutionary theories of aging predict a trade-off between fertility and lifespan, where increased lifespan comes at the cost of reduced fertility. Support for this prediction has been obtained from various sources. However, which genes underlie this relationship is unknown. To assess it, we first analyzed the association of fertility with age at menarche and menopause, and with mortality in 3,575 married female participants of the Rotterdam Study. In addition, we conducted a candidate gene study where 1,664 single nucleotide polymorphisms (SNPs) in 25 candidate genes were analyzed in relation to number of children as a measure of fertility. SNPs that associated with fertility were analyzed for association with mortality. We observed no associations between fertility and age at menarche (p = 0.38) and menopause (p = 0.07). In contrast, fertility was associated with mortality. Women with two to three children had significantly lower mortality (hazard ratio (HR), 0.82; 95% confidence interval (95% CI), 0.69-0.97) compared to women with no children. No such benefit was observed for women with four or more children, who had a similar mortality risk (HR, 0.93; 95% CI, 0.76-1.13) as women with no children. The analysis of candidate genes revealed four genes that influence fertility after correction for multiple testing: CGB/LHB gene cluster (p = 0.0036), FSHR (p = 0.023), FST (p = 0.023), and INHBA (p = 0.021). However, none of the independent SNPs in these genes predicted mortality. In conclusion, women who bear two to three children live longer than those who bear none or many children, but this relationship was not mediated by the candidate genes analyzed in this study.

Assessment of maternal smoking status during pregnancy and the associations with neonatal outcomes (Article)

2011-12-01T00:00:00Z

Introduction: Single assessment of smoking during pregnancy may lead to misclassification due to underreporting or failure of smoking cessation. We examined the percentage of mothers who were misclassified in smoking status based on single assessment, as compared with repeated assessment, and whether this misclassification leads to altered effect estimates for the associations between maternal smoking and neonatal complications. Methods: This study was performed in 5,389 mothers participating in a prospective population-based cohort study in the Netherlands. Smoking status was assessed 3 times during pregnancy using questionnaires. Information on birth weight and neonatal complications was obtained from hospital records. Results: For categorizing mothers per smoking status, Cohen's Kappa coefficient was .86 (p < .001) between single and repeated assessments. Of all mothers who reported nonsmoking or first trimester-only smoking in early pregnancy, 1.7% (70 of 4,141) and 33.7% (217 of 643), respectively, were reclassified to continued smoking based on repeated assessment. Younger, shorter lower educated mothers who had non-European ethnicity experienced more stress, consumed more alcohol, and did not use folic acid supplements had higher risk of underreporting their smoking status or failure of smoking cessation. Marginal differences were found on the associations of maternal smoking with neonatal complications between single or repeated assessment. Conclusions: Our results suggest that single assessment of smoking during pregnancy leads to underestimation of the continued smoking prevalence, especially among mothers who reported quitting smoking in first trimester. However, this underestimation does not materially change the effect estimates for the associations between maternal smoking and neonatal outcomes.

A genome-wide association study of aging (Article)

2011-11-01T00:00:00Z

Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10-8). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10-5). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.

Intrauterine cannabis exposure leads to more aggressive behavior and attention problems in 18-month-old girls (Article)

2011-11-01T00:00:00Z

Background: The development of the fetal endocannabinoid receptor system may be vulnerable to maternal cannabis use during pregnancy and may produce long-term consequences in children. In this study, we aimed to determine the relationship between gestational cannabis use and childhood attention problems and aggressive behavior. Methods: Using a large general population birth cohort, we examined the associations between parental prenatal cannabis and tobacco use and childhood behavior problems at 18 months measured using the Child Behavior Checklist in N= 4077 children. Substance use was measured in early pregnancy. Results: Linear regression analyses demonstrated that gestational exposure to cannabis is associated with behavioral problems in early childhood but only in girls and only in the area of increased aggressive behavior (B= 2.02; 95% CI: 0.30-3.73; p= 0.02) and attention problems (B= 1.04; 95% CI: 0.46-1.62; p< 0.001). Furthermore, this study showed that long-term (but not short term) tobacco exposure was associated with behavioral problems in girls (B= 1.16; 95% CI: 0.20-2.12; p= 0.02). There was no association between cannabis use of the father and child behavior problems. Conclusions: Our results suggest that intrauterine exposure to cannabis is associated with an increased risk for aggressive behavior and attention problems as early as 18 months of age in girls, but not boys. Further research is needed to explore the association between prenatal cannabis exposure and child behavior at later ages. Our data support educating future mothers about the risk to their babies should they smoke cannabis during pregnancy.

Large common deletions associate with mortality at old age (Article)

2011-11-01T00:00:00Z

Copy-number variants (CNVs) are a source of genetic variation that increasingly are associated with human disease. However, the role of CNVs in human lifespan is to date unknown. To identify CNVs that influence mortality at old age, we analyzed genome-wide CNV data in 5178 participants of Rotterdam Study (RS1) and positive findings were evaluated in 1714 participants of the second cohort of the Rotterdam Study (RS2) and in 4550 participants of Framingham Heart Study (FHS). First, we assessed the total burden of rare (frequency <1%) and common (frequency >1%) CNVs for association with mortality during follow-up. These analyses were repeated by stratifying CNVs by type and size. Secondly, we assessed individual common CNV regions (CNVR) for association with mortality. We observed that the burden of common but not of rare CNVs influences mortality. A higher burden of large (≥500 kb) common deletions associated with 4% higher mortality [hazard ratio (HR) per CNV 1.04, 95% confidence interval (CI) 1.02-1.07, P 5 5.82 3 10-25] in the 11 442 participants of RS1, RS2 and FHS. In the analysis of 312 individual common CNVRs, we identified two regions (11p15.5; 14q21.3) that associated with higher mortality in these cohorts. The 11p15.5 region (combined HR 1.59, 95% CI 1.31-1.93, P 5 2.87 3 10-26) encompasses 41 genes, of which some have previously been related to longevity, whereas the 14q21.3 region (combined HR 1.57, 95% CI 1.19-2.07, P 5 1.53 3 10-23) does not encompass any genes. In conclusion, the burden of large common deletions, as well as common CNVs in 11p15.5 and 14q21.3 region, associate with higher mortality.

Spot the red herring: Breastfeeding, fruitpurée, and infant autonomic functioning-the generation R study (Article)

2011-10-01T00:00:00Z

Several studies have suggested that breastfeeding is related to infant autonomic functioning. The authors investigated whether this is a causal relation. In all, 444 mothers reported breastfeeding practices 2 mo postpartum. Infant autonomic functioning was assessed by heart rate variability at age 14 mo, after discontinuation of breastfeeding. The dose-dependent association between breastfeeding and infant autonomic functioning was tested with linear regression models adjusted for multiple confounders. The authors investigated the relation of fruitpurée consumption with infant autonomic functioning. Fruitpurée consumption has similar socioeconomic epiphenomena but is not related via the same causal mechanism to autonomic regulation as breastfeeding. Nonbreastfed infants had high sympathetic modulation [7.87 log (ms)/SD, 95% CI: 7.71-8.02], partially breastfed infants had intermediate sympathetic modulation [7.75 log (ms)/SD, 95% CI: 7.51-7.82], sympathetic modulation of exclusively breastfed infants was low [7.63 log (ms)/SD, 95% CI: 7.50-7.77]. However, this association could be explained by socioeconomic confounders. Furthermore, fruitpurée consumption was similarly associated with reduced infant sympathetic modulation. The association between breastfeeding practices and infant sympathetic modulation was accounted for by socioeconomic and environmental factors. We found a similar association between fruitpurée consumption and autonomic functioning, further suggesting that the association between breastfeeding and infant autonomic functioning is noncausal. Copyright

Postnatal parental smoking: An important risk factor for SIDS (Article)

2011-10-01T00:00:00Z

Background: Sudden infant death syndrome (SIDS) is the unexpected death of an infant that remains unexplained after a thorough investigation of the circumstances, family history, paediatric investigation and complete autopsy. In Western society, it is the leading cause of post-neonatal death below 1 year of age. In the Netherlands, the SIDS incidence is very low, which offers opportunities to assess the importance of old and new environmental risk factors. For this purpose, cases were collected through pathology departments and the working group on SIDS of the Dutch Paediatrician Foundation. A total of 142 cases were included; these occurred after the parental education on sleeping position (1987), restricted to the international age criteria and had no histological explanation. Age-matched healthy controls (N∈=∈2,841) came from a survey of the Netherlands Paediatric Surveillance Unit, completed between November 2002 and April 2003. A multivariate analysis was performed to determine the risk factors for SIDS, including sleeping position, antenatal maternal smoking, postnatal parental smoking, premature birth, gender, lack of breastfeeding and socio-economic status. Postnatal smoking was identified as an important environmental risk factor for SIDS (OR one parent∈=∈2.5 [1.2, 5.0]; both parents∈=∈5.77 [2.2, 15.5]; maternal∈=∈2.7 [1.0, 6.4]; paternal∈=∈2.4 [1.3, 4.5] ) as was prone sleeping (OR put prone to sleep∈=∈21.5 [10.6, 43.5]; turned prone during sleep∈=∈100 [46, 219]). Premature birth was also significantly associated with SIDS (OR∈=∈2.4 [1.2, 4.8]). Conclusion: Postnatal parental smoking is currently a major environmental risk factor for SIDS in the Netherlands together with the long-established risk of prone sleeping.

Associations of serum cortisol with cognitive function and dementia: The rotterdam study (Article)

2011-09-21T00:00:00Z

Higher levels of cortisol have been observed in persons with cognitive decline and dementia. It is unknown whether these higher levels are a cause or a consequence of disease. We investigated whether morning levels of serum cortisol were associated with cognitive function, cognitive decline, and the risk of dementia and Alzheimer's disease in the Rotterdam Study, a large prospective population based cohort study. Cortisol levels were assessed in fasting blood serum in 3341 participants, who were free of dementia at baseline (1997-1999). Cognitive function was assessed with a dedicated neuropsychological test battery at baseline and at follow-up examination (2002-2004). In addition, the cohort was continuously monitored for incident dementia until January 1, 2007. After a mean follow-up of 7.1 years, 243 participants had developed dementia, of whom 210 were diagnosed with Alzheimer's disease. Morning serum levels of cortisol were neither related to cognitive function at baseline, nor to annual cognitive decline. There was no relation between serum levels of cortisol and the risk of developing dementia or Alzheimer's disease. These results suggest that that morning serum cortisol is not a causal factor in the development of dementia.

The association between parenting and attachment security is moderated by a polymorphism in the mineralocorticoid receptor gene: Evidence for differential susceptibility (Article)

2011-09-01T00:00:00Z

Maternal sensitive responsiveness and extreme insensitivity only partly explain the variance in attachment security. Differences in attachment security may well be rooted in the interplay of genetic variations and environmental factors. The association between parenting (observed sensitive responsiveness and extreme insensitivity) and attachment security (assessed with the Strange Situation Procedure) was hypothesized to be moderated by genes involved in the regulation of the stress response: the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) genes. A significant G. × E interaction was found: infants carrying the minor MR allele (G) were significantly more securely attached if their mothers showed more sensitive responsiveness and significantly less securely attached if their mothers showed more extremely insensitive behaviors. These associations were not significant for carriers of the AA genotype of MR. Findings are discussed from a differential susceptibility perspective.

Epidemiological fallacies of modern psychiatric research (Article)

2011-09-01T00:00:00Z

Background: Psychiatric epidemiology is an important cornerstone of research in psychiatry and integral for the treatment and care of people suffering from psychiatric disorders. However, psychiatric epidemiology is a difficult science, which is often beset with methodological problems. Aims: In light of this, the current review sought to explore 13 of the common methodological issues in psychiatric epidemiology. Methods: Many methodological problems result from misunderstandings. As such, we sought to highlight these problems, provide evidence to counteract the myths surrounding these problems and subsequently provide recommendations to overcome these problems. To highlight and clarify these issues, examples are provided from current psychiatric literature. Results: Areas discussed in the review include problems with: taxonometry of disorders, sole reliance on self-reports, single-question diagnoses, baseline participation rates, measurement of lifetime prevalence, inconsistency of multiple informants, selection of covariates, testing of interactions, correction for multiple testing, the intermittent measurement of disorders during follow-up, evaluation of causal associations, data invalidation related to loss from follow-up and the publication of negative findings. Conclusion: Many methodological myths prevail in the area of epidemiology and this review endeavoured to elucidate and clarify these. This review was developed as a teaching tool for students, clinicians and researchers.

The Rotterdam Study: 2012 objectives and design update (Article)

2011-08-31T00:00:00Z

Abstract The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.

Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM (Article)

2011-08-30T00:00:00Z

Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N=18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values=1.6 × 10-11and 2.7 × 10-11), which were also in strong linkage disequilibrium (r2=0.7) with each other, lie in the 23-kb long commonly shared 5′ flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value=3.9 × 10-09) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value=7.1 × 10-09)-an SNP associated with blood pressure-in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value=2.2 × 10-05) and Parkinson's disease pathways (P-value=3.6 × 10-05).Molecular Psychiatry advance online publication, 30 August 2011; doi:10.1038/mp.2011.101.

Subcortical structures and the neurobiology of infant attachment disorganization: A longitudinal ultrasound imaging study (Article)

2011-08-01T00:00:00Z

Attachment disorganization in infancy is a risk factor for behavior problems and other psychopathology. Traditionally the role of parental behavior for qualitative differences in early attachment relationships has been emphasized. However, disrupted infant-parent interactions only partly explain attachment disorganization. A complementary focus on child factors such as early differences in the underlying neurobiological systems is needed. We examined whether early structural differences in the gangliothalamic ovoid, comprising the basal ganglia and the thalamus, are involved in the etiology of infant attachment disorganization. Gangliothalamic ovoid diameter was measured by ultrasound in 6-week-old participants of a prospective population-based cohort study. Attachment classification of 629 of these infants was assessed with the strange situation at 14 months of age. Neurobiological differences within the normal range were prospectively associated with attachment disorganization. Infants with a larger gangliothalamic ovoid at 6 weeks had a lower risk of attachment disorganization at 14 months (OR = 0.73 per SD increase in diameter, 95% CI 0.57-0.93, p <.05). Volume of the lateral ventricles as an index of general brain development was not associated with attachment disorganization. These findings provide new insight into the etiology of infant attachment disorganization that may in part be neurodevelopmentally determined.

Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited (Article)

2011-08-01T00:00:00Z

By studying the loci that contribute to human longevity, we aim to identify mechanisms that contribute to healthy aging. To identify such loci, we performed a genome-wide association study (GWAS) comparing 403 unrelated nonagenarians from long-living families included in the Leiden Longevity Study (LLS) and 1670 younger population controls. The strongest candidate SNPs from this GWAS have been analyzed in a meta-analysis of nonagenarian cases from the Rotterdam Study, Leiden 85-plus study, and Danish 1905 cohort. Only one of the 62 prioritized SNPs from the GWAS analysis (P<1×10-4) showed genome-wide significance with survival into old age in the meta-analysis of 4149 nonagenarian cases and 7582 younger controls [OR=0.71 (95% CI 0.65-0.77), P=3.39×10-17]. This SNP, rs2075650, is located in TOMM40 at chromosome 19q13.32 close to the apolipoprotein E (APOE) gene. Although there was only moderate linkage disequilibrium between rs2075650 and the ApoE ε4 defining SNP rs429358, we could not find an APOE-independent effect of rs2075650 on longevity, either in cross-sectional or in longitudinal analyses. As expected, rs429358 associated with metabolic phenotypes in the offspring of the nonagenarian cases from the LLS and their partners. In addition, we observed a novel association between this locus and serum levels of IGF-1 in women (P=0.005). In conclusion, the major locus determining familial longevity up to high age as detected by GWAS was marked by rs2075650, which tags the deleterious effects of the ApoE ε4 allele. No other major longevity locus was found. © 2011 The Authors. Aging Cell

Runs of homozygosity do not influence survival to old age (Article)

2011-07-29T00:00:00Z

Runs of homozygosity (ROH) are extended tracts of adjacent homozygous single nucleotide polymorphisms (SNPs) that are more common in unrelated individuals than previously thought. It has been proposed that estimating ROH on a genome-wide level, by making use of the genome-wide single nucleotide polymorphism (SNP) data, will enable to indentify recessive variants underlying complex traits. Here, we examined ROH larger than 1.5 Mb individually and in combination for association with survival in 5974 participants of the Rotterdam Study. In addition, we assessed the role of overall homozygosity, expressed as a percentage of the autosomal genome that is in ROH longer than 1.5 Mb, on survival during a mean follow-up period of 12 years. None of these measures of homozygosity was associated with survival to old age.

A study of the bidirectional association between hippocampal volume on magnetic resonance imaging and depression in the elderly (Article)

2011-07-15T00:00:00Z

Background: Hippocampal volume loss on magnetic resonance imaging (MRI) has been reported in patients with depression. It is uncertain whether a small hippocampus renders a person vulnerable to develop depression or whether it is a consequence of depression. In this study, we addressed whether smaller baseline MRI hippocampal volumes increase the risk of incident depression. We also examined whether depressive symptoms at baseline were associated with decline in hippocampal volume during follow-up. Methods: Data were obtained in a prospective population-based study over a 10-year period. A sample of 514 nondemented persons aged 60 to 90 years underwent baseline measurements in 19951996 including three-dimensional MRI scans for assessment of hippocampal volumes and depressive symptoms (measured with Center for Epidemiologic Studies Depression Scale). Follow-up MRIs were made in 19992000 and in 2006. Incident depression was identified through standardized psychiatric examinations and continuous monitoring of medical and pharmaceutical records. Results: During a mean follow-up of 6.8 years per person (range .0710.01 years), 135 of the 514 persons developed a clinically relevant episode of incident depressive symptoms. There was no association between baseline hippocampal volumes and incident depression (hazard ratio per SD decrease of average hippocampal volume .98 [.811.19], p = .84). A baseline Center for Epidemiologic Studies Depression Scale score of 16 or higher predicted a faster rate of decline in hippocampal volume. Also, incident depression was accompanied by a faster decline in left hippocampal volume. Conclusions: This study provides no evidence that a small hippocampal volume precedes the development of late-life depression. Depression, however, may lead to a faster rate of hippocampal volume decline.

The prevalence and characteristics of complicated grief in older adults (Article)

2011-07-01T00:00:00Z

Background: Complicated grief is a prolongation of the normal grieving process with distinct characteristics. It impairs mental and physical health and can potentially greatly impact the quality of life of sufferers and their families. The prevalence and characteristics of complicated grief in the general population are currently unclear. The aims of the present study were therefore to evaluate the prevalence of complicated grief in a population-based cohort, examine the overlap between anxiety and depression and identify common bereavement-related and socio-demographic characteristics. Methods: Based within the Rotterdam Study, 5741 older adults were evaluated. Complicated grief was assessed with a 17-item Inventory of Complicated Grief. Results: Prevalence within the general population was 4.8%. Current grief was reported by 1089 participants, and of these 277 (25.4%) were diagnosed with complicated grief. Inflated anxiety and depression rates were documented in people with complicated grief, but the vast majority remained free from co-morbidity. Time since bereavement and relationship to deceased, particularly when the source was a spouse or child, were predictive of complicated grief. People with complicated grief were older, had a lower level of education, and more cognitive impairment. Conclusions: The prevalence of complicated grief in older adults in the general population was noteworthy. Several factors were predictive of complicated grief and it was demonstrated as a separate condition to anxiety and depression. These findings highlight the need for prevention, diagnosis and treatment options for older adults with complicated grief and for recognition of complicated grief as a distinct diagnosis.

Prenatal and postnatal psychological symptoms of parents and family functioning: The impact on child emotional and behavioural problems (Article)

2011-07-01T00:00:00Z

Although relations of various parental psychological problems and family functioning with child development are well documented, it remains unclear whether specific prenatal or specific postnatal risk factors are independently associated with child emotional and behavioural problems, or whether observed associations can be explained by general parental psychopathology. Using a stepwise approach, we examined the effects of prenatal and postnatal parental depressive symptoms, prenatal and postnatal hostility of the parents, as well as prenatal family functioning on the risk of child emotional and behavioural problems. This study was embedded in Generation R: a population-based cohort from foetal life onwards. Mothers and fathers of 2,698 children provided information about depressive symptoms, symptoms of hostility and family functioning during pregnancy and 3 years after birth. Mother and father each reported on child behaviour when the child was 3 years old. Parental depressive symptoms increased the risk of child emotional and behavioural problems, but this increase was explained by postnatal parental hostile behaviour. Postnatal symptoms of hostility of mothers (OR = 1.34, p value <0.001) and postnatal symptoms of hostility of fathers (OR = 1.30, p value <0.001) each contributed independently to the risk of child emotional and behavioural problems. Postnatal parental hostility is associated with an increased risk of child emotional and behavioural problems, independent of parental depressive symptoms. These findings suggest that prevention and intervention strategies should focus on psychological symptoms of both mothers and fathers, in particular on hostile behaviour, in families with young children.

Transient ischemic attack and incident depression (Article)

2011-07-01T00:00:00Z

Background and Purpose- Depression after stroke is common. Like stroke, transient ischemic attack (TIA) is a manifestation of long-term atherosclerotic damage to the brain. However, the risk of depression developing after a TIA is uncertain. We studied whether TIA increases the risk of incident late-life depression. Methods- A cohort study of 5095 inhabitants of Rotterdam, the Netherlands, was performed between 1993 and 2005. Participants were aged 56 years or older and free of depression at baseline. TIA and depression were identified through regular standardized examinations and continuous monitoring of medical records. We estimated hazard ratios (HR) with time-varying Cox regression analyses, adjusting for sociodemographic and health-related factors. Results- During follow-up, 407 depressive syndromes occurred, of which 103 met criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM) for depressive disorders. TIA was significantly associated with the risk of incident depressive syndromes (HR, 1.68; 95% CI, 1.12-2.51) and DSM-defined depressive disorders (HR, 2.42; 95% CI, 1.26-4.67). The risk of depressive syndromes increased with the number of TIA a person had experienced (HR, 1.45; 95% CI, 1.17-1.81), as did the risk of depressive disorders (HR, 1.63; 95% CI, 1.18-2.24). In persons without a history of depression at baseline, we found an almost 3-fold increased risk of DSM-defined depressive disorders (HR, 2.91; 95% CI, 0.96-8.81). Conclusions- TIA was independently associated with an increased risk of incident depression. Our finding suggests that symptomatic cerebrovascular disease increases the vulnerability to late-life depression. Copyright

Is positive affect associated with survival? a population-based study of elderly persons (Article)

2011-06-06T00:00:00Z

Study results on the association of positive affect with survival are conflicting. This disagreement potentially arises from poor control for health or negative affect and for the various age groups studied. The authors examined if positive affect predicts survival; whether this association is preserved after controlling for negative affect, socioeconomic status, lifestyle, and health; and whether this association varies with age. The study is set within the population-based Rotterdam Study (1997-2007) and included 4,411 participants aged 61 years or older, followed for on average 7.19 (standard deviation = 2.20) years. Positive affect was not consistently associated with survival across all ages. A significant interaction of positive affect with age on survival (P = 0.02) was found. Subsequent age stratification revealed that positive affect independently predicted survival in elderly persons aged <80 years (per affect score, hazard ratio = 0.96, 95% confidence interval: 0.93, 0.99) but not in those aged ≥80 years in fully adjusted models (hazard ratio = 1.00, 95% confidence interval: 0.96, 1.04). In the oldest old, the association was partly explained by differences in baseline health. In conclusion, the results suggest that there may be an association of positive affect with survival in the younger and middle old but not in the oldest old in whom perception of positive affect is more likely to be determined by health.

Examining continuity of early expressive vocabulary development: The generation R study (Article)

2011-06-01T00:00:00Z

The authors investigated continuity and discontinuity of vocabulary skills in a population-based cohort in the Netherlands. Mothers of 3,759 children completed the Dutch version of the MacArthur Short Form Vocabulary Checklist (Zink & Lejaegere, 2003) at 18 months and a Dutch translation of the Language Development Survey (Rescorla, 1989) at 30 months. At both ages, expressive vocabulary delay was defined as vocabulary scores <10th age- and gender-specific percentile. Results: Of the children, 85.2% had normal vocabulary development at both ages, 6.2% were "late bloomers," 6.0% had late onset expressive vocabulary delay, and 2.6% had persistent expressive vocabulary delay. Word production and comprehension at 18 months explained 11.5% of the variance in 30-month vocabulary scores, with low birth weight, child age, gender and ethnicity, maternal age and education, and parenting stress explaining an additional 6.2%. Multinomial logistic regression was used to identify biological, demographic, and psychological factors associated with each of the vocabulary delay outcome groups relative to the typically developing group. Although multiple perinatal, demographic, and maternal psychosocial factors significantly predicted vocabulary skills at 30 months, positive predictive value and sensitivity were low. Future studies should address to what extent additional factors, such as brain maturation and genetic influences, can improve the prediction and understanding of continuity and discontinuity of language delay.

Parental family stress during pregnancy and cognitive functioning in early childhood: The Generation R Study (Article)

2011-05-09T00:00:00Z

We investigated whether parental family stress during pregnancy is associated with cognitive functioning in early childhood in a population-based cohort (n= 3139). Family stress was assessed using the Family Assessment Device at the 20th week of pregnancy and was reported by mothers and fathers. Mothers completed the MacArthur Communicative Development Inventory, measuring children's verbal cognitive functioning, when children were 18 months and they completed the Parent Report of Children's Abilities, measuring nonverbal cognitive functioning, when children were 2 years old. Maternal prenatal family stress was related to children's low word comprehension and poorer nonverbal cognitive development independent of paternal reports. In a subset of 639 children, maternal prenatal family stress was also associated with observational assessments of poor effortful control at age 37 months. Paternal prenatal family stress was only related to poorer nonverbal cognitive development, independent of the mother. When both parents had high levels of prenatal family stress, children displayed particularly poor nonverbal cognitive development. These findings emphasize the significance of parental prenatal family stress for child developmental outcomes.

Maternal thyroid function during pregnancy and behavioral problems in the offspring: The generation R study (Article)

2011-05-01T00:00:00Z

Maternal thyroid function during pregnancy is implicated in the neurodevelopment of the offspring, yet little is known about the effect of maternal thyroid parameters on the behavior of children. We investigated the association of maternal thyroid function during the first half of pregnancy with parent-reported problem behavior of the offspring up to age of 3 y. In the Generation R study, a population-based cohort of 3736 children and their mothers, data on maternal thyroid function and child's behavior were examined. The degree of internalizing and externalizing problems in the children were assessed with the Child Behavior Checklist at ages 11/2 and 3 y. Higher levels of maternal TSH during pregnancy predicted a higher externalizing scores in children at 11/2 and 3 y (B = 0.22 per SD of TSH; 95% CI: 0.04, 0.40; B = 0.10 per SD for internalizing scores; 95% CI:-0.01, 0.21). Maternal free thyroxine (T4) and total T4 were not associated with internalizing or externalizing scores of children. The linear relationship with more externalizing scores was across the range of TSH; this implies that subtle impairments of maternal thyroid function may affect the child. The results suggest that thyroid function is crucial for fetal brain development, which determines problem behavior later in life. Copyright

Short and long-term effects of smoking on cortisol in older adults (Article)

2011-05-01T00:00:00Z

We investigated concurrent as well as long-term effects of smoking on cortisol. The population consisted of 2508 elderly adults. Current smokers, as opposed to former smokers, had higher basal cortisol levels and higher morning increases of cortisol. Overall, pack-years was related to morning cortisol rise, but this was accounted for by current smokers. Time since quitting was positively associated with a greater decline in daytime cortisol indicating that the effects of smoking remit. This suggests that smoking has short-term, rather than long-term, consequences on cortisol secretion patterns.

The Neuronal Transporter Gene SLC6A15 Confers Risk to Major Depression (Article)

2011-04-28T00:00:00Z

Major depression (MD) is one of the most prevalent psychiatric disorders and a leading cause of loss in work productivity. A combination of genetic and environmental risk factors probably contributes to MD. We present data from a genome-wide association study revealing a neuron-specific neutral amino acid transporter (SLC6A15) as a susceptibility gene for MD. Risk allele carrier status in humans and chronic stress in mice were associated with a downregulation of the expression of this gene in the hippocampus, a brain region implicated in the pathophysiology of MD. The same polymorphisms also showed associations with alterations in hippocampal volume and neuronal integrity. Thus, decreased SLC6A15 expression, due to genetic or environmental factors, might alter neuronal circuits related to the susceptibility for MD. Our convergent data from human genetics, expression studies, brain imaging, and animal models suggest a pathophysiological mechanism for MD that may be accessible to drug targeting.

Cortisol diurnal rhythm and stress reactivity in constipation and abdominal pain: The generation R study (Article)

2011-04-16T00:00:00Z

OBJECTIVES: The aim of this study was to assess whether diurnal cortisol rhythm and cortisol stress reactivity were associated with functional constipation and abdominal pain in infancy. METHODS: This study was embedded in a subset of the Generation R Study, a prospective cohort study from fetal life onwards in Rotterdam, The Netherlands. Data of infants between 14 and 24 months of age (N = 483) were used. Salivary cortisol diurnal rhythm and salivary cortisol stress reactivity after a Strange Situation Procedure were assessed at the age of 14 months. Data on functional constipation was available according to the ROME II criteria and data on abdominal pain on the basis of the Abdominal Pain Index were available from questionnaire data at 24 months. RESULTS: In the second year of life, 13% of the infants had functional constipation and 17% had abdominal pain. Only 4% had symptoms of both functional constipation and abdominal pain. Diurnal cortisol rhythm did not differ significantly between children with and those without functional constipation and abdominal pain. Cortisol stress reactivity was slightly higher in infants with abdominal pain than those without it but this was not statistically significant (OR: 1.41; 95%CI: 0.46-4.31). No association was found between the cortisol stress reactivity and functional constipation. CONCLUSIONS: Our results suggest that cortisol as a marker for stress does not play a major role in functional constipation or abdominal pain in infancy.

The influence of attachment and temperament on venipuncture distress in 14-month-old infants: The Generation R Study (Article)

2011-04-01T00:00:00Z

Objective: This study examined the effects of attachment and temperament on infant distress during venipuncture. Method: The study was embedded in the Generation R Study, a prospective population-based study. Two different research procedures (i.e., blood sampling and the Ainsworth Strange Situation Procedure) yielded measures of venipuncture distress and attachment security and disorganization in 246 infants aged 14 months. Four temperament traits (distress to limitations, fear, recovery from distress, and sadness) were assessed using the maternally reported Infant Behavior Questionnaire - Revised, at the age of 6 months. Results: There were no differences between mean levels of distress during venipuncture in infants classified as having insecure attachment, but there was a trend for disorganized attachment. The temperament traits were not related to distress. However, children with a disorganized attachment and higher temperamental fear had more venipuncture distress. Conclusion: When different risk factors are present simultaneously, infant distress is heightened.

The Neuronal Transporter Gene SLC6A15 Confers Risk to Major Depression (Article)

2011-04-01T00:00:00Z

SUMMARY: Major depression (MD) is one of the most prevalent psychiatric disorders and a leading cause of loss in work productivity. A combination of genetic and environmental risk factors probably contributes to MD. We present data from a genome-wide association study revealing a neuron-specific neutral amino acid transporter (SLC6A15) as a susceptibility gene for MD. Risk allele carrier status in humans and chronic stress in mice were associated with a downregulation of the expression of this gene in the hippocampus, a brain region implicated in the pathophysiology of MD. The same polymorphisms also showed associations with alterations in hippocampal volume and neuronal integrity. Thus, decreased SLC6A15 expression, due to genetic or environmental factors, might alter neuronal circuits related to the susceptibility for MD. Our convergent data from human genetics, expression studies, brain imaging, and animal models suggest a pathophysiological mechanism for MD that may be accessible to drug targeting.

Recognition of facial expressions of emotions by 3-year-olds (Article)

2011-04-01T00:00:00Z

Very few large-scale studies have focused on emotional facial expression recognition (FER) in 3-year-olds, an age of rapid social and language development. We studied FER in 808 healthy 3-year-olds using verbal and nonverbal computerized tasks for four basic emotions (happiness, sadness, anger, and fear). Three-year-olds showed differential performance on the verbal and nonverbal FER tasks, especially with respect to fear. That is to say, fear was one of the most accurately recognized facial expressions as matched nonverbally and the least accurately recognized facial expression as labeled verbally. Sex did not influence emotion-matching nor emotion-labeling performance after adjusting for basic matching or labeling ability. Three-year-olds made systematic errors in emotion-labeling. Namely, happy expressions were often confused with fearful expressions, whereas negative expressions were often confused with other negative expressions. Together, these findings suggest that 3-year-olds' FER skills strongly depend on task specifications. Importantly, fear was the most sensitive facial expression in this regard. Finally, in line with previous studies, we found that recognized emotion categories are initially broad, including emotions of the same valence, as reflected in the nonrandom errors of 3-year-olds.

Does disturbed sleeping precede symptoms of anxiety or depression in toddlers? the Generation R study (Article)

2011-04-01T00:00:00Z

OBJECTIVE: To examine whether sleep problems in infancy and early toddlerhood precede symptoms of anxiety or depression at 3 years. METHODS: Data on specific sleep problems at 2 months and 24 months were available for 4,782 children participating in a population-based cohort in The Netherlands. The Child Behavior Checklist for toddlers containing the Anxious/Depressed syndrome scale was assessed at 36 months. We adjusted the logistic regression analyses for several confounding factors; the analyses with sleep problems at 24 months were additionally adjusted for preexisting anxiety or depressive symptoms (at 18 months). RESULTS: Dyssomnia and parental presence during sleep onset at 2 months and 24 months were associated with anxiety or depressive symptoms at 3 years (e.g., parental presence: odds ratio2 months, 1.22; 95% confidence interval, 1.04-1.44; odds ratio24months, 1.58; 95% confidence interval, 1.30-1.92). Parasomnia, short sleep duration, and absence of set bedtime at 24 months, but not at 2 months, also preceded anxiety or depressive symptoms. These significant associations were not due to children's anxiety or depressive symptoms at 18 months. Rhythmicity and co-sleeping were not associated with later anxiety or depressive symptoms. Additional analyses provided little evidence for a bidirectional association with anxiety or depressive symptoms preceding later sleep problems. CONCLUSIONS: Our findings highlight the importance of sleep problems early in life, because different sleep problems are associated with the frequency of anxiety or depressive symptoms. Therefore, healthcare practitioners must be particularly attentive to these problems in young children. Future research should address possible mechanisms underlying the association between disturbed sleeping and anxiety or depressive symptoms. Copyright

Maternal fish consumption, fetal growth and the risks of neonatal complications: The Generation R Study (Article)

2011-03-28T00:00:00Z

Maternal fish consumption during pregnancy has been suggested to affect birth outcomes. Previous studies mainly focused on birth outcomes and did not study fetal growth during pregnancy. In a prospective cohort study from early pregnancy onwards in The Netherlands, we assessed the associations of first-trimester maternal total-fish, lean-fish, fatty-fish and shellfish consumption with fetal growth characteristics in the second and third trimesters, growth characteristics at birth and the risks of neonatal complications, including pre-term birth, low birth weight and small for gestational age. In total, 3380 mothers completed a 293-item semi-quantitative FFQ to obtain information about fish consumption during the first trimester of pregnancy. Head circumference, femur length and fetal weight were estimated in the second and third trimesters by ultrasound. Information about birth anthropometrics and neonatal complications was available from hospital and midwife registries. Maternal older age, higher educational level, folic acid supplement use, alcohol use and not smoking were associated with higher fish consumption (P < 0.01). After adjustment, we observed no consistent associations of maternal total-fish consumption or specific consumption of lean fish, fatty fish or shellfish with fetal growth characteristics in the second and third trimesters and at birth. Likewise, total-fish consumption or specific consumption of any type of fish was not consistently associated with the risks of neonatal complications. These findings suggest that in a population with a relatively low fish intake, consumption of lean fish, fatty fish or shellfish in the first trimester is not associated with fetal growth or the risks of neonatal complications.

Serotonin transporter polymorphism moderates effects of prenatal maternal anxiety on infant negative emotionality (Article)

2011-03-15T00:00:00Z

Background: Consistent with the fetal programming hypothesis, effects of maternal prenatal anxiety have been found to predict various measures of infant temperament in the early postnatal period. In recent years, a polymorphism in the serotonin transporter gene (5-HTTLPR) emerged as a moderator of diverse environmental influences on different outcomes, with individuals carrying the short allele being generally more vulnerable to adversity. Methods: We tested whether the association between self-reported maternal anxiety at 20 weeks gestation (Brief Symptom Inventory) and mother-rated infant negative emotionality at 6 months after birth (Infant Behavior Questionnaire-Revised) would be moderated by the 5-HTTLPR in a large Dutch cohort sample (n = 1513). We hypothesized that infants carrying the 5-HTTLPR short allele would be more susceptible and therefore more affected by both low and high prenatal maternal anxiety vis-à-vis negative emotionality than other genotypes. Results: Findings of a significant gene X environment interaction (B = .65, p = .01) were supportive of a vulnerability model, with infants carrying the short allele being more negatively emotional when mothers reported anxiety during pregnancy, whereas there was no difference between genotypes on negative emotionality when maternal anxiety was low. Conclusions: The association between maternal anxiety during pregnancy and negative emotionality in early infancy was significant in infants carrying one or more copies of the short allele but not in those homozygous for the long allele. The 5-HTTLPR short allele might increase vulnerability to adverse environmental influences as early as the fetal period.

Genetics of cortisol secretion and depressive symptoms: A candidate gene and genome wide association approach (Article)

2011-02-14T00:00:00Z

Background: Depressive patients often have altered cortisol secretion, but few studies have investigated genetic variants in relation to both cortisol secretion and depression. To identify genes related to both these conditions, we: (1) tested the association of single nucleotide polymorphisms (SNPs) in hypothalamic-pituitary-adrenal-axis (HPA-axis) candidate genes with a summary measure of total cortisol secretion during the day (cortisolAUC), (2) performed a genome wide association study (GWAS) of cortisolAUC, and (3) tested the association of identified cortisol-related SNPs with depressive symptoms. Methods: We analyzed data on candidate SNPs for the HPA-axis, genome-wide scans, cortisol secretion (n = 1711) and depressive symptoms (the Centre for Epidemiology Studies Depression Scale, CES-D) (n = 2928) in elderly persons of the Rotterdam Study. We used data from the Whitehall II study (n = 2836) to replicate the GWAS findings. Results: Of the 1456 SNPs in 33 candidate genes, minor alleles of 4 SNPs (rs9470080, rs9394309, rs7748266 and rs1360780) in the FKBP5 gene were associated with a decreased cortisolAUC (p < 1 × 10(-4) after correction for multiple testing using permutations). These SNPs were also associated with an increased risk of depressive symptoms (rs9470080: OR 1.19 (95%CI 1.0; 1.4)). The GWAS for cortisol yielded 2 SNPs with p-values of 1 × 10(-06) (rs8062512, rs2252459), but these associations could not be replicated. Conclusions: These results suggest that variation in the FKBP5 gene is associated with both cortisolAUC and the likelihood of depressive symptoms.

Individual accumulation of heterogeneous risks explains perinatal inequalities within deprived neighbourhoods (Article)

2011-02-01T00:00:00Z

Dutch' figures on perinatal mortality and morbidity are poor compared to EU-standards. Considerable within-country differences have been reported too, with decreased perinatal health in deprived urban areas. We investigated associations between perinatal risk factors and adverse perinatal outcomes in 7,359 pregnant women participating in population-based prospective cohort study, to establish the independent role, if any, for living within a deprived urban neighbourhood. Main outcome measures included perinatal death, intrauterine growth restriction (IUGR), prematurity, congenital malformations, Apgar at 5 min < 7, and pre-eclampsia. Information regarding individual risk factors was obtained from questionnaires, physical examinations, ultrasounds, biological samples, and medical records. The dichotomous Dutch deprivation indicator was additionally used to test for unexplained deprived urban area effects. Pregnancies from a deprived neighbourhood had an increased risk for perinatal death (RR 1.8, 95% CI [1.1; 3.1]). IUGR, prematurity, Apgar at 5 min < 7, and pre-eclampsia also showed higher prevalences (P < 0.05). Residing within a deprived neighbourhood was associated with increased prevalence of all measured risk factors. Regression analysis showed that the observed neighbourhood related differences in perinatal outcomes could be attributed to the increased risk factor prevalence only, without a separated role for living within a deprived neighbourhood. Women from a deprived neighbourhood had significantly more 'possibly avoidable' risk factors. To conclude, women from a socioeconomically deprived neighbourhood are at an increased risk for adverse pregnancy outcomes. Differences regarding possibly avoidable risk factors imply that preventive strategies may prove effective.

β-Blockers and the risk of incident depression in the elderly (Article)

2011-02-01T00:00:00Z

The hypothesis that β-blockers cause depression has been both confirmed and refuted in previous studies. However, in hardly any of these studies, depression was systematically and adequately assessed. The aim of this cohort study was to examine whether β-blockers, in general, highly lipid-soluble, nonselective, or serotonergic receptor-binding β-blockers, are associated with incident depression. Between 1993 and 2005, 5104 elderly persons were followed for incident depressions. Depressions were identified by regular interview and continuous monitoring of medical records. Cases were categorized as clinically relevant depressive symptoms or as depressive syndromes, the latter including Diagnostic and Statistical Manual of Mental Disorders-IV-defined depressive disorders. Pharmacies provided information on filled β-blockers. We used Cox regression with drug use as a time-dependent variable to analyze the data, adjusted for potential demographic covariates, activity of daily living, and (contra)indications for β-blockers. We found that use of β-blockers in general did not convey an increased risk of depressive symptoms (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.37-1.59) or depressive syndromes (HR, 0.99; 95% CI, 0.53-1.84). Highly lipid-soluble β-blockers, mostly propranolol in our study, were associated with depressive symptoms during the first 3 months of use (HR, 3.31; 95% CI, 1.03-10.6), but not with depressive syndromes. Nonselective or serotonergic receptor affinity was not associated with an increased risk of depressive symptoms or syndromes independent of high lipid solubility. We conclude that β-blockers in general do not convey an increased risk of depression. Lipophilic β-blockers are associated with an increased risk of depressive symptoms. Copyright

Low autonomic arousal as vulnerability to externalising behaviour in infants with hostile mothers (Article)

2011-01-30T00:00:00Z

Maternal psychopathology and the child's autonomic nervous system functioning are risk factors for aggressive behaviour later in life. While research has shown that maternal psychopathology already affects young children, less is known about the association between autonomic functioning and aggressive behaviour in young children. In addition, maternal psychopathology and autonomic nervous system functioning may interact to determine the risk of aggressive behaviour.In a sample of 375 infants and their mothers, maternal psychiatric symptoms were assessed with the Brief Symptom Inventory and toddler aggressive behaviour with the Child Behaviour Checklist. Infant heart rate was recorded at 14. months.Maternal psychiatric problems, including hostility and depression, were associated with toddler aggressive behaviour. Maternal psychiatric problems interacted with mean heart rate (P= 0.01) and HF variability (P= 0.03) in their effect on toddler aggressive behaviour.Mothers with high psychiatric problems, in particular, high hostility, were more likely to have toddlers with high aggressive behaviour. Moreover, in the presence of maternal risk factors, low autonomic arousal renders children particularly susceptible to aggressive behaviour.

Intrauterine effects of maternal prepregnancy overweight on child cognition and behavior in 2 cohorts (Article)

2011-01-01T00:00:00Z

OBJECTIVE: Greater maternal prepregnancy adiposity has been associated with behavioral problems, such as attention-deficit/hyperactivity disorder, and lower intellectual function in offspring. However, few studies of humans have explored this, and it is unclear if intrauterine mechanisms or confounding factors drive these associations. PATIENTS AND METHODS: Parental adiposity and offspring verbal skills, nonverbal skills, and behavioral problems were assessed in the British Avon Longitudinal Study of Parents and Children (N = ∼5000) and Dutch Generation R (N = ∼2500) cohorts. We aimed to determine the plausibility of intrauterine effects by (1) adjusting for multiple confounders, (2) comparing associations between maternal and paternal overweight with offspring cognition/behaviors, and (3) searching for cross-cohort consistency. RESULTS: Maternal prepregnancy overweight was associated with reduced child verbal skills (unadjusted). However, after adjusting for confounders, this result was not consistently observed in both cohorts. Maternal overweight was also associated with child total behavior problems and externalizing problems even after adjusting for confounders. However, this was observed in Generation R only and was not replicated in the British Avon Longitudinal Study of Parents and Children. No associations of maternal overweight with child attention problems, emotional/internalizing problems, or nonverbal skills were observed in either cohort. Paternal overweight was not associated with any of the child outcomes but was also less strongly related to potential confounding factors than was maternal overweight. CONCLUSIONS: Overall, we found little consistent evidence of intrauterine effects of maternal prepregnancy overweight on child cognition and behavior. Some associations initially observed were not consistently replicated across cohorts or robust to adjustment for confounding factors and, thus, are likely to reflect confounding by socioeconomic or postnatal factors. Copyright

Childhood adversity modifies the relationship between anxiety disorders and cortisol secretion (Article)

2010-12-01T00:00:00Z

Background Internalizing psychiatric disorders and early childhood adversity have both been associated with altered basal cortisol secretion. The aim of the present study is to investigate if early childhood adversity modifies the relationship between anxiety and mood disorders and cortisol secretion. Methods A sample of 429 international adoptees was followed from childhood to adulthood. In childhood, adoptive parents provided information about abuse and neglect before adoption. As adults, adoptees completed a standardized psychiatric interview to assess internalizing disorders and collected saliva samples four times a day. Analyses of covariance were performed. Results The relationship between anxiety disorders and cortisol secretion during 1 day, as measured by the area under the curve (AUC), was dependent on the experience of severe early maltreatment (p value of interaction = .03). In adoptees with an anxiety disorder, severe maltreatment was associated with lower daily cortisol secretion compared with nonmaltreated adoptees (respective AUC means: 28.19 and 36.96; difference = -8.78; confidence interval = -14.65 to -2.90; p = .004). In adoptees without an anxiety disorder, no difference in cortisol secretion was found between persons who did or did not experience severe maltreatment early in life (respective AUC means: 34.72 and 34.20; difference = .52; confidence interval = -1.92 to 2.96; p = .67). We found no modifying effect of severe early maltreatment on the relationship between mood disorders and daily cortisol secretion. Conclusions The experience of early adversities modifies the relationship between anxiety disorders and basal cortisol seretion in adults. To understand the relationship between anxiety disorders and cortisol secretion, early maltreatment has to be taken into account.

Predicting survival and morbidity-free survival to very old age (Article)

2010-12-01T00:00:00Z

As life expectancy continually increases, it is imperative to identify determinants of survival to the extreme end of the lifespan and more importantly to identify factors that increase the chance of survival free of major morbidities. As such, the current study assessed 45 common disease factors as predictors of survival and morbidity-free survival to age 85 years. Within the Rotterdam Study, a population-based cohort, we evaluated morbidity-free participants who were able to attain age 85 within the study duration (n∈=∈2,008). Risk factors were assessed at baseline (1990-1993), and mortality and morbidities were then collected continuously until mortality or the occurrence of their 85th birthday (average time of 7.9 years). Risk factors included demographic and lifestyle variables, health and morbidity indicators and physiological makers. Major morbidities examined included dementia, cancer, cerebrovascular accident, heart failure and myocardial infarction. Logistic regression analyses demonstrated that many of the variables were independently predictive for survival and for morbidity-free ageing to 85 years. These included being female, absence of left ventricular abnormalities, stable body weight, unimpaired instrumental activities of daily living, lower C-RP levels and higher levels of femoral neck bone mineral density and albumin. Relative to non-survival, predictors were stronger for morbidity-free survival than for total survival or survival with morbidity. This suggests that lifespan and healthy survival to older age can be relatively well predicted. Understanding predictors of a long and healthy lifespan is vital for developing primary and secondary preventions to help improve the quality of life of older adults and for reducing the financial burden of the rapidly escalating ageing population.

Agreement between maternal cannabis use during pregnancy according to self-report and urinalysis in a population-based cohort: The generation R study (Article)

2010-12-01T00:00:00Z

Aim: To verify self-reported information on prenatal drug use in urine because reporting in pregnancy is sensitive to stigma and might lead to misclassification. Methods: Using semiquantitative immunochemical analysis, the presence of the urinary metabolite (11-nor-Δ9-tetrahydrocannabinol- 9-carboxylic acid) was compared to self-reported prenatal cannabis use. Sensitivity and specificity for self-report and urinalysis outcomes were calculated and Yule's Y was used as an agreement measure. Results: Urine samples were available for 3,997 pregnant women. Of these women, 92 reported having used cannabis during pregnancy (2.3%) and 71 had positive urine screens (1.8%). In total 35% of the 92 women with self-reported cannabis use also had a positive urine screen. Positive urines were relatively frequent in women reporting cannabis use before pregnancy only (7.6%) and in women with missing information (2.6%). Sensitivity and specificity of urinalysis compared to self-report were 0.46 and 0.98. Sensitivity and specificity of self-report compared to urinalysis were 0.36 and 0.99. Yule's Y amounted to 0.77, indicating substantial agreement between the measures. Conclusions: Our findings illustrate the difficulties in obtaining valid information on prenatal cannabis use. To improve the quality of cannabis use data, we suggest a 2-step approach starting with self-report. Copyright

Paroxysmal disorders in infancy and their risk factors in a population-based cohort: The Generation R Study (Article)

2010-11-01T00:00:00Z

Aim To examine the incidence of paroxysmal epileptic and non-epileptic disorders and the associated prenatal and perinatal factors that might predict them in the first year of life in a population-based cohort.Method This study was embedded in the Generation R Study, a population-based prospective cohort study from early fetal life onwards. Information about the occurrence of paroxysmal events, defined as suddenly occurring episodes with an altered consciousness, altered behaviour, involuntary movements, altered muscle tone, and/or a changed breathing pattern, was collected by questionnaires at the ages of 2, 6, and 12 months. Information on possible prenatal and perinatal determinants was obtained by measurements and questionnaires during pregnancy and after birth.Results Information about paroxysmal events in the first year of life was available in 2860 participants (1410 males, 1450 females). We found an incidence of paroxysmal disorders of 8.9% (n=255) in the first year of life. Of these participants, 17 were diagnosed with febrile seizures and two with epilepsy. Non-epileptic events included physiological events, apnoeic spells, loss of consciousness by causes other than epileptic seizures or apnoeic spells, parasomnias, and other events. Preterm birth (p<0.001) and low Apgar score at 1 minute (p<0.05) were significantly associated with paroxysmal disorders in the first year of life. Continued maternal smoking during pregnancy and preterm birth were significantly associated with febrile seizures in the first year of life (p<0.05).Interpretation Paroxysmal disorders are frequent in infancy. They are associated with preterm birth and a low Apgar score. Epileptic seizures only form a minority of the paroxysmal events in infancy. In this study, children whose mothers continued smoking during pregnancy had a higher reported incidence of febrile seizures in the first year of life. These findings may generate various hypotheses for further investigations.

National origin and behavioural problems of toddlers: The role of family risk factors and maternal immigration characteristics (Article)

2010-11-01T00:00:00Z

In many societies the prevalence of behavioural problems in school-aged children varies by national origin. We examined the association between national origin and behavioural problems in 11/2-year-old children. Data on maternal national origin and the Child Behavior Checklist for toddlers (n = 4943) from a population-based cohort in the Netherlands were used. Children from various non-Dutch backgrounds all had a significantly higher mean behavioural problem score. After adjustment for family risk factors, like family income and maternal psychopathology, the differences attenuated, but remained statistically significant. Non-Dutch mothers with immigration risk factors, such as older age at immigration or no good Dutch language skills, reported significantly more behavioural problems in their offspring. In conclusion, the present study indicated more behavioural problems in immigrant toddlers from various backgrounds. Researchers and policymakers aiming to tackle disparities in behavioural problems should take into account that risks associated with national origin are intertwined with unfavourable family and immigration characteristics.

Atherosclerosis and Incident Depression in Late Life (Article)

2010-11-01T00:00:00Z

Abstract CONTEXT: Depression is a prominent concern for older adults; therefore, it is important to identify causal mechanisms so that prevention and treatment strategies can be developed. The vascular depression hypothesis proposes that vascular factors precede the onset of depression in older adults. However, although cross-sectional associations have been established, owing to a lack of objective assessments and longitudinal data, the validity and temporal nature of this relationship is unclear. OBJECTIVE: To examine whether atherosclerosis, an asymptomatic subclinical indicator of vascular burden, increases the risk of developing depression in older adults. DESIGN: Prospective, population-based study. SETTING: Set within the Rotterdam study, participants were assessed on objective measures of generalized atherosclerosis at baseline (1997-1999) and followed up for an average of 6 years for incident depression. PARTICIPANTS: The baseline sample consisted of 3564 participants (56% female) with a mean age of 72 years who initially did not have depression or dementia. MAIN OUTCOME MEASURES: Depression was categorized into symptoms or syndromes and assessed in a multidimensional manner from physician and mental health specialist reports, pharmacy records (antidepressant usage), a clinical interview, and self-report. RESULTS: During 21 083 person-years, 429 incidents of depressive symptoms and 197 incidents of depressive syndromes occurred. Individual atherosclerotic measures and a composite measure were not predictive of incident depressive symptoms (composite measure hazard ratio, 0.93; 95% confidence interval, 0.83-1.05) or incident depressive syndromes (composite measure hazard ratio, 0.97; 95% confidence interval, 0.81-1.16). An a priori power analysis indicated a sufficient sample size (α = .05; 0.95 power). CONCLUSIONS: Atherosclerosis does not appear to increase the risk of incident depression in older adults. These findings do not support the vascular depression hypothesis and, alternatively, taking findings from prior studies into account, suggest either that depression contributes to vascular burden or that both result from an underlying biological substrate.

FKBP5 and resistant attachment predict cortisol reactivity in infants: Gene-environment interaction (Article)

2010-11-01T00:00:00Z

Quality of the parent-infant attachment relationship influences physiological stress regulation. Genetic factors also contribute to the stress regulatory HPA-axis. Quality of attachment as an index of the rearing environment (measured with the Strange Situation Procedure, SSP), and HPA-axis related SNPs (BclI, rs41423247; TthIIII, rs10052957; GR-9β, rs6198; N363S, rs6195; ER22/23EK, rs6189 and 6190; and FKBP5, rs1360780) were hypothesized to be related to cortisol reactivity in the stressful SSP. In this large population based sample, FKBP5 rs1360780, but not GR haplotype, was related to cortisol reactivity. Moreover, we found a significant interaction effect for insecure-resistant attachment and FKBP5 rs1360780, indicating a double-risk for heightened cortisol reactivity levels in infants with one or two T-alleles of the FKBP5 SNP and an insecure-resistant attachment relationship with their mother. Findings are discussed from the perspective of gene-environment interaction.

The Generation R Study: Design and cohort update 2010 (Article)

2010-11-01T00:00:00Z

The Generation R Study is a population-based prospective cohort study from fetal life until young adulthood. The study is designed to identify early environmental and genetic causes of normal and abnormal growth, development and health during fetal life, childhood and adulthood. The study focuses on four primary areas of research: (1) growth and physical development; (2) behavioural and cognitive development; (3) diseases in childhood; and (4) health and healthcare for pregnant women and children. In total, 9,778 mothers with a delivery date from April 2002 until January 2006 were enrolled in the study. General follow-up rates until the age of 4 years exceed 75%. Data collection in mothers, fathers and preschool children included questionnaires, detailed physical and ultrasound examinations, behavioural observations, and biological samples. A genome wide association screen is available in the participating children. Regular detailed hands on assessment are performed from the age of 5 years onwards. Eventually, results forthcoming from the Generation R Study have to contribute to the development of strategies for optimizing health and healthcare for pregnant women and children.

Fetal growth retardation and risk of febrile seizures (Article)

2010-10-01T00:00:00Z

OBJECTIVE: The goal was to examine the associations between fetal growth characteristics in different trimesters of pregnancy and the occurrence of febrile seizures in early childhood. METHODS: This study was embedded in a population-based, prospective, cohort study from early fetal life onward. Fetal growth characteristics (femur length, abdominal circumference, estimated fetal weight, head circumference, biparietal diameter, and transverse cerebellar diameter [TCD]) were measured with ultrasonography in the second and third trimesters of pregnancy. Information on the occurrence of febrile seizures was collected with questionnaires at the ages of 12 and 24 months. Analyses were based on data for 3372 subjects. RESULTS: In the second trimester, children in the lowest tertile of TCDs were at increased risk of developing febrile seizures, compared with children in the highest tertile (odds ratio 2.87 [95% confidence interval: 1.31-6.28]). In the third trimester, children in the lowest tertile of all general growth characteristics (femur length, abdominal circumference, and estimated fetal weight) were at increased risk of developing febrile seizures. This association was strongest for children in the lowest tertile of estimated fetal weight (odds ratio: 2.57 [95% confidence interval: 1.34-4.96]). Children in the lowest tertile of biparietal diameter in the third trimester also were at increased risk of febrile seizures. Similar but not statistically significant tendencies were observed for head circumference and TCD. CONCLUSIONS: Fetal growth retardation is associated with increased risk of febrile seizures in the first 2 years of life. Adverse environmental and genetic factors during pregnancy may be important in the development of febrile seizures.

Mother's educational level and fetal growth: The genesis of health inequalities (Article)

2010-10-01T00:00:00Z

Background: Women of low socio-economic status (SES) give birth to lighter babies. It is unknown from which moment during pregnancy socio-economic differences in fetal weight can be observed, whether low SES equally affects different fetal-growth components, or what the effect of low SES is after taking into account mediating factors. Methods: In 3545 pregnant women participating in the Generation R Study, we studied the association of maternal educational level (high, mid-high, mid-low and low) as a measure of SES with fetal weight, head circumference, abdominal circumference and femur length. We did this before and after adjusting for potential mediators, including maternal height, pre-pregnancy body mass index and smoking. Results: In fetuses of low-educated women relative to those of high-educated women, fetal growth was slower, leading to a lower fetal weight that was observable from late pregnancy onwards. In these fetuses, growth of the head [-0.16 mm/week; 95% confidence interval (CI): -0.25 to -0.07; P = 0.0004], abdomen (-0.10 mm/week; 95% CI: -0.21 to 0.01; P = 0.08) and femur (-0.03 mm/week; 95% CI: -0.05 to -0.006; P = 0.01) were all slower; from mid-pregnancy onwards, head circumference was smaller, and from late pregnancy onwards, femur length was also smaller. The negative effect of low education was greatest for head circumference (difference in standard deviation score in late pregnancy: -0.26; 95% CI: -0.36 to -0.15; P < 0.0001). This effect persevered even after adjustment for the potential mediators (adjusted difference: -0.14; 95% CI: -0.25 to -0.03; P = 0.01). Conclusions: Low maternal education is associated with a slower fetal growth and this effect appears stronger for growth of the head than for other body parts. Published by Oxford University Press on behalf of the International Epidemiological Association

Infant brain development and vulnerability to later internalizing difficulties: The generation R study (Article)

2010-10-01T00:00:00Z

Objective Although clinical studies have demonstrated smaller subcortical volumes in structures such as the amygdala, hippocampus, caudate nucleus, and thalamus in adults and adolescents with depressive disorders and anxiety, no study has assessed such structures in babies, long before the development of the disorders. This study examined whether the size of the "gangliothalamic ovoid" (encompassing the basal ganglia and thalamus) assessed during infancy is associated with increased internalizing problems in early childhood. Method Cranial ultrasounds were used to assess gangliothalamic ovoid diameter and ventricular volume at 6 weeks of postnatal age; moreover, head circumference was measured. Outcome data included ratings of internalizing and externalizing problems using the Child Behavior Checklist (reported by mothers and fathers) at 18 and/or 36 months. Analyses were based on a total of 651 children. Results Smaller gangliothalamic diameter was associated with higher Child Behavior Checklist Internalizing scores at ages 18 and 36 months. Results remained significant after correcting for head circumference and were evident for the DSM-oriented subscales of anxiety problems and affective problems. Total ventricular volume was not consistently associated with Internalizing scores. Conclusions Findings associating infant brain measurements with Child Behavior Checklist mother and father reports at two time points are consistent with previous cross-sectional reports of smaller subcortical volumes in depression. Results were not simply reflective of overall brain development, because the pattern held after adjustment for head circumference. This is the first study to point toward a biological vulnerability evident in infancy, involved in the development of internalizing problems in childhood.

Perinatal complications increase the risk of postpartum depression. The Generation R Study (Article)

2010-10-01T00:00:00Z

Objective: To examine whether specific pregnancy and delivery complications are risk factors for postpartum depression. Design: A prospective longitudinal study. Setting: Rotterdam, the Netherlands. Population A cohort of 4941 pregnant women who enrolled in the Generation R Study. Methods: Information on perinatal complications was obtained from the midwife and hospital registries or by questionnaire. Logistic regression analyses were used to calculate the risk of postpartum depression for the separate perinatal complications. Main outcome measures: Postpartum psychiatric symptoms were assessed 2 months after delivery using the Edinburgh postnatal depression scale. Results: Several perinatal complications were significantly associated with postpartum depression, namely: pre-eclampsia (adjusted OR, aOR 2.58, 95% CI 1.30-5.14), hospitalization during pregnancy (aOR 2.25, 95% CI 1.19-4.26), emergency caesarean section (aOR 1.53, 95% CI 1.02-2.31), suspicion of fetal distress (aOR 1.56, 95% CI 1.08-2.27), a medically indicated delivery provided by an obstetrician (aOR 2.43, 95% CI 1.56-3.78), and hospital admission of the baby (aOR 1.45, 95% CI 1.10-1.92). Unplanned pregnancy, thrombosis, meconium-stained amniotic fluid, and Apgar score were not associated with postpartum depression after adjustment for confounding factors, such as pre-existing psychopathological symptoms and sociodemographic characteristics. The risk of postpartum depression increased with the number of perinatal complications women experienced (P < 0.001). Conclusions: We showed that several pregnancy and delivery complications present a risk for women's mental health in the postpartum period. Obstetricians, midwives, general practitioners, and staff at baby well clinics should be aware that women who experienced perinatal complications-especially those with a number of perinatal complications-are at risk for developing postpartum depression.

Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: The generation R study (Article)

2010-09-01T00:00:00Z

Context: Thyroid hormones are essential for neurodevelopment from early pregnancy onward. Yet population-based data on the association between maternal thyroid function in early pregnancy and children's cognitive development are sparse. Objective: Our objective was to study associations of maternal hypothyroxinemia and of early pregnancy maternal TSH and free T4(FT4) levels across the entire range with cognitive functioning in early childhood. Design and Setting: We conducted a population-based cohort in The Netherlands. Participants: Participants included 3659 children and their mothers. Main Measures: In pregnant women with normal TSH levels at 13 wk gestation (SD = 1.7), mild and severe maternal hypothyroxinemia were defined as FT4concentrations below the 10th and 5th percentile, respectively. Children's expressive vocabulary at 18 months was reported by mothers using the MacArthur Communicative Development Inventory. At 30 months, mothers completed the Language Development Survey and the Parent Report of Children's Abilities measuring verbal and nonverbal cognitive functioning. Results: Maternal TSH was not related to the cognitive outcomes. An increase in maternal FT4predicted a lower risk of expressive language delay at 30 months only. However, both mild and severe maternal hypothyroxinemia was associated with a higher risk of expressive language delay across all ages [odds ratio (OR) = 1.44; 95% confidence interval (CI) = 1.09-1.91; P = 0.010 and OR = 1.80; 95% CI = 1.24-2.61; P = 0.002, respectively]. Severe maternal hypothyroxinemia also predicted a higher risk of nonverbal cognitive delay (OR = 2.03; 95% CI = 1.22-3.39; P = 0.007). Conclusions: Maternal hypothyroxinemia is a risk factor for cognitive delay in early childhood. Copyright

Heart failure and incident late-life depression (Article)

2010-08-01T00:00:00Z

Objectives: To assess whether heart failure (HF) increases the risk of developing depression and whether the use of loop diuretics in persons with HF alters this risk. Design: Population-based cohort study between 1993 and 2005. Setting: Ommoord, a district of Rotterdam, the Netherlands. Participants: Five thousand ninety-five older adults free of depression at baseline. Measurements: Detailed information on HF and depression was collected during examination rounds and through continuous monitoring of medical and pharmaceutical records. HF was defined according to the criteria of the European Society of Cardiology. Depressive episodes were categorized as clinically relevant depressive symptoms and depressive syndromes, including major depressive disorders defined according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. Hazard ratios (HRs) were calculated using multivariate Cox proportional hazard regression. Results: HF was associated with greater risk of depressive symptoms and syndromes (HR=1.41, 95% CI=1.03-1.94) and depressive syndromes only (HR=1.66, 95% CI=1.09-2.52). In participants with HF, the use of loop diuretics was associated with a lower risk of depressive symptoms and syndromes (HR=0.46, 95% CI=0.22-0.96) and depressive syndromes only (HR=0.41, 95% CI=0.16-1.00). Conclusion: HF is an independent risk factor for incident depression in elderly persons. Patient with HF require careful follow-up to monitor and prevent the onset of depression. Effective treatment of the debilitating symptoms of HF may prevent depression.

A Genome-Wide Screen for Depression in Two Independent Dutch Populations (Article)

2010-07-15T00:00:00Z

Background: Depression has a strong genetic component but candidate gene studies conducted to date have not shown consistent associations. Methods: We conducted a genome-wide parametric and nonparametric linkage analysis in a large-scale family-based study including 115 individuals with depression who were identified based on the Hospital Anxiety Depression Scale, Center for Epidemiologic Studies Depression Rating Scale, or use of antidepressive medication. Further, we investigated the most promising chromosomal regions found in the genome-wide linkage analysis with an association analysis in 734 individuals in the family-based study and 2373 individuals in the population-based study. Results: Our study demonstrated evidence for significant linkage of depression to chromosome 2p16.1-15 (logarithm of odds [LOD] = 5.13; parametric analysis) and suggestive evidence for linkage in nonparametric analysis to chromosome 5p15.33 (LOD = 2.14), 11q25 (LOD = 2.27), and 19p13.3 (LOD = 2.66). The subsequent association analysis in the family-based study showed region-wide significant association in intron 1 of the OPCML gene on chromosome 11q25 (empirical p value = .04). The association analysis in the population-based study did not show any region-wide significant association, yet showed suggestive association in intron 1 of the APLP2 gene on chromosome 11q25. Conclusions: Our linkage and association studies suggest a locus for depression on chromosomes 2p16.1-15 and 11q25. The linkage to chromosome 11q25 may be, in part, explained by the OPCML or the APLP2 gene. Further, there is evidence for a role of the GNG7 gene (chromosome 19p13.3).

Fetal growth from mid- to late pregnancy is associated with infant development: The Generation R Study (Article)

2010-07-01T00:00:00Z

Aim: The aim of this study was to investigate within a population-based cohort of 4384 infants (2182 males, 2202 females) whether fetal growth from early pregnancy onwards is related to infant development and whether this potential relationship is independent of postnatal growth. Method: Ultrasound measurements were performed in early, mid-, and late pregnancy. Estimated fetal weight was calculated using head and abdominal circumference and femur length. Infant development was measured with the Minnesota Infant Development Inventory at 12 months (SD 1.1mo, range 10-17mo). Information on postnatal head size and body weight at 7 months was obtained from medical records. Results: After adjusting for potential confounders and for postnatal growth, faster fetal weight gain from mid- to late pregnancy predicted a reduced risk of delayed social development (odds ratio [OR] 0.82; 95% confidence interval [CI] 0.71-0.95, p=0.008), self-help abilities (OR 0.84; 95% CI 0.73-0.98, p=0.023), and overall infant development (OR 0.65; 95% CI 0.49-0.87, p=0.003). Similar findings were observed for fetal head growth from mid- to late pregnancy. Interpretation: Faster fetal growth predicts a lower risk of delayed infant development independent of postnatal growth. These results suggest that reduced fetal growth between mid- and late pregnancy may determine subsequent developmental outcomes.

Attachment, depression, and cortisol: Deviant patterns in insecure-resistant and disorganized infants (Article)

2010-07-01T00:00:00Z

Both attachment insecurity and maternal depression are thought to affect infants' emotional and physiological regulation. In the current study, Strange Situation Procedure (SSP) attachment classifications, and cortisol stress reactivity and diurnal rhythm were assessed at 14 months in a prospective cohort study of 369 mother-infant dyads. Maternal lifetime depression was diagnosed prenatally using the Composite International Diagnostic Interview (CIDI). Insecure-resistant infants showed the largest increase in cortisol levels from pre-to post-SSP; the effect was even stronger when they had depressive mothers. Disorganized children showed a more flattened diurnal cortisol pattern compared to nondisorganized children. Findings are discussed from the perspective of a cumulative risk model.

Employment status and the risk of pregnancy complications: The Generation R Study (Article)

2010-06-01T00:00:00Z

Objectives: This study explored the relationships of employment status, type of unemployment and number of weekly working hours, with a wide range of pregnancy outcomes. Methods: Information on employment characteristics and pregnancy outcomes was available for 6111 pregnant women enrolled in a population-based cohort study in the Netherlands. Results: After adjustment for confounders, there were no statistically significant differences in risks of pregnancy complications between employed and unemployed women. Among unemployed women, women receiving disability benefit had an increased risk of preterm ruptured membranes (OR 3.16, 95% CI 1.49 to 6.70), elective caesarean section (OR 2.98, 95% CI 1.21 to 7.34) and preterm birth (OR 2.64, 95% CI 1.32 to 5.28) compared to housewives. Offspring of students and women receiving disability benefit had a significantly lower mean birth weight than offspring of housewives (difference: -93, 95% CI -174 to -12; and -97, 95% CI -190 to -5, respectively). In employed women, long working hours (≥40 h/week) were associated with a decrease of 45 g in offspring's mean birth weight (adjusted analysis; 95% CI -89 to -1) compared with 1-24 h/weekly working hours. Conclusions: We found no indications that paid employment during pregnancy effects the health of the mother and child. However, among unemployed and employed women, women receiving disability benefit, students and women with long working hours during pregnancy were at risk for some adverse pregnancy outcomes. More research is needed to replicate these results and explain these findings. Meanwhile, prenatal care providers should be made aware of the risks associated with specific types of unemployment and long working hours.

Genetic risk profiles for depression and anxiety in adult and elderly cohorts (Article)

2010-06-01T00:00:00Z

Abstract The first generation of genome-wide association studies (GWA studies) for psychiatric disorders has led to new insights regarding the genetic architecture of these disorders. We now start to realize that a larger number of genes, each with a small contribution, are likely to explain the heritability of psychiatric diseases. The contribution of a large number of genes to complex traits can be analyzed with genome-wide profiling. In a discovery sample, a genetic risk profile for depression was defined based on a GWA study of 1738 adult cases and 1802 controls. The genetic risk scores were tested in two population-based samples of elderly participants. The genetic risk profiles were evaluated for depression and anxiety in the Rotterdam Study cohort and the Erasmus Rucphen Family (ERF) study. The genetic risk scores were significantly associated with different measures of depression and explained up to approximately 0.7% of the variance in depression in Rotterdam Study and up to approximately 1% in ERF study. The genetic score for depression was also significantly associated with anxiety explaining up to 2.1% in Rotterdam study. These findings suggest the presence of many genetic loci of small effect that influence both depression and anxiety. Remarkably, the predictive value of these profiles was as large in the sample of elderly participants as in the middle-aged samples

A Meta-analysis of four genome-wide association studies of survival to age 90 years or older: The cohorts for heart and aging research in genomic epidemiology consortium (Article)

2010-05-01T00:00:00Z

Background.Genome-wide association studies (GWAS) may yield insights into longevity.Methods.We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort.Results.There were 273 single-nucleotide polymorphism (SNP) associations with p <. 0001, but none reached the prespecified significance level of 5 × 10-8. Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 × 10-7for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chromosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage.Conclusion.Survival studies of larger size or more extreme or specific phenotypes may support or refine these initial findings.

Retinal vascular calibers and risk of late-life depression: The rotterdam study (Article)

2010-05-01T00:00:00Z

Objectives: To test the "vascular depression" hypothesis, the authors investigated whether smaller retinal arteriolar or larger venular calibers, which are markers of cerebral microvascular disease, were associated with incident late-life depression. Methods: The authors included 3,605 participants (age ≥55 years) from the population-based Rotterdam Study with no depression at baseline (1993-1995) and fundus photographs gradable for retinal vascular caliber measurements. The authors identified persons with incident depressive symptoms and syndromes using psychiatric interviews during follow-up visits and continuous monitoring. The follow-up was complete until October 2005. Results: After a mean follow-up of 9.0 years, 555 participants developed incident depression, including 312 with depressive syndrome. Neither smaller arteriolar (age-and sex-adjusted hazard ratio: 1.01; 95% confidence interval: 0.93-1.10), nor larger venular calibers (hazard ratio: 1.02; 95% confidence interval: 0.94-1.12) were associated with incident depressive syndromes. Conclusions: Our data showed no evidence of an association between retinal vascular calibers and incident late-life depression.

Genome-wide meta-analyses identify multiple loci associated with smoking behavior (Article)

2010-05-01T00:00:00Z

Consistent but indirect evidence has implicated genetic factors in smoking behavior. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], Β = 1.03, standard error (s.e.) = 0.053, P = 2.8 × 10 73). Two 10q25 SNPs (rs1329650[G], Β = 0.367, s.e. = 0.059, P = 5.7 × 10 10; and rs1028936[A], Β = 0.446, s.e. = 0.074, P = 1.3 × 10 9) and one 9q13 SNP in EGLN2 (rs3733829[G], Β = 0.333, s.e. = 0.058, P = 1.0 × 10 8) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 × 10 8). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 × 10 8) was significantly associated with smoking cessation.

Maternal psychological distress and fetal growth trajectories: the Generation R Study (Article)

2010-04-01T00:00:00Z

Abstract BACKGROUND: Previous research suggests, though not consistently, that maternal psychological distress during pregnancy leads to adverse birth outcomes. We investigated whether maternal psychological distress affects fetal growth during the period of mid-pregnancy until birth. METHOD: Pregnant women (n=6313) reported levels of psychological distress using the Brief Symptom Inventory (anxious and depressive symptoms) and the Family Assessment Device (family stress) at 20.6 weeks pregnancy and had fetal ultrasound measurements in mid- and late pregnancy. Estimated fetal weight was calculated using head circumference, abdominal circumference and femur length. RESULTS: In mid-pregnancy, maternal distress was not linked to fetal size. In late pregnancy, however, anxious symptoms were related to fetal size after controlling for potential confounders. Anxious symptoms were also associated with a 37.73 g [95% confidence interval (CI) -69.22 to -6.25, p=0.019] lower birth weight. When we related maternal distress to fetal growth curves using multilevel models, more consistent results emerged. Maternal symptoms of anxiety or depression were associated with impaired fetal weight gain and impaired fetal head and abdominal growth. For example, depressive symptoms reduced fetal weight gain by 2.86 g (95% CI -4.48 to -1.23, p<0.001) per week. CONCLUSIONS: The study suggests that, starting in mid-pregnancy, fetal growth can be affected by different aspects of maternal distress. In particular, children of prenatally anxious mothers seem to display impaired fetal growth patterns during pregnancy. Future work should address the biological mechanisms underlying the association of maternal distress with fetal development and focus on the effects of reducing psychological distress in pregnancy.

Determinants of somatic complaints in 18-month-old children: The generation R study (Article)

2010-04-01T00:00:00Z

ObjectiveTo investigate the effect of child temperament, maternal psychologic symptoms, maternal chronic pain, and parenting stress on children's somatic complaints.MethodsThe study was embedded in the Generation R Study, a population-based cohort study. Child somatic complaints were assessed via mother-report in 5,171 children of 18 months of age. Questionnaires assessed maternal somatic symptoms, symptoms of depression, anxiety during pregnancy and 2 months after delivery, maternal chronic pain during pregnancy, parenting stress 18 months after birth, and mother-reported child temperament 6 months after birth, as the determinants.ResultsFearful temperament, temperamental falling reactivity, maternal somatic symptoms, anxiety symptoms, and parenting stress each independently and prospectively increased the likelihood of children's somatic complaints at 18 months of age.ConclusionsIn toddlers, temperament, maternal stress, and maternal somatic symptoms seem particularly important for the development of somatic complaints, but long-term research is needed to establish causality and predictive value of these factors.

A prospective study on intrauterine cannabis exposure and fetal blood flow (Article)

2010-04-01T00:00:00Z

Background: Cannabis is commonly used among pregnant women. It is unclear whether cannabis exposure causes hemodynamic modifications in the fetus, like tobacco does. Aims: This study aims to ascertain fetal blood redistribution due to intrauterine cannabis exposure. Methods: This study was embedded in the Generation R Focus Study, a population-based cohort of parents and children followed from pregnancy onwards. In late pregnancy, fetal hemodynamics was assessed with ultrasound measurements in cannabis-exposed and non-exposed fetuses. Pregnant women reported about substance use during pregnancy. A distinction was made between continued cannabis use (n=9), cannabis use only in early pregnancy (n=14), continued tobacco use (n=85), tobacco use only in early pregnancy (n=92), and no tobacco or cannabis use during pregnancy (n=85). Results: Continued cannabis use was associated with an increased pulsatility and resistance index of the uterine artery, while discontinued cannabis use was associated with a decreased pulsatility, and resistance index, as compared to controls. Additionally, continued cannabis exposure resulted in a significantly higher uterine pulsatility index and uterine resistance index compared to tobacco exposure. Continued cannabis use was found to be associated with a smaller aortic diameter, as well. No association between intrauterine cannabis exposure and the fetal cerebral vascular system was found. Conclusions: Our findings suggest that intrauterine cannabis exposure was associated with changes in hemodynamic programming of the vascular system of the fetus in late pregnancy mainly due to tobacco exposure, but intrauterine cannabis exposure did demonstrate a specific effect on the uterine blood flow.

Glucocorticoid receptor gene polymorphisms do not affect growth in fetal and early postnatal life. The Generation R Study (Article)

2010-03-03T00:00:00Z

Background: Glucocorticoids have an important role in early growth and development. Glucocorticoid receptor gene polymorphisms have been identified that contribute to the variability in glucocorticoid sensitivity. We examined whether these glucocorticoid receptor gene polymorphisms are associated with growth in fetal and early postnatal life.Methods: This study was embedded in a population-based prospective cohort study from fetal life onwards. The studied glucocorticoid receptor gene polymorphisms included BclI (rs41423247), TthIIII (rs10052957), GR-9β (rs6198), N363S (rs6195) and R23K (rs6789 and6190). Fetal growth was assessed by ultrasounds in second and third trimester of pregnancy. Anthropometric measurements in early childhood were performed at birth and at the ages of 6, 14 and 24 months postnatally. Analyses focused on weight, length and head circumference. Analyses were based on 2,414 healthy, Caucasian children.Results: Glucocorticoid receptor gene polymorphisms were not associated with fetal weight, birth weight and early postnatal weight. Also, no associations were found with length and head circumference. Neither were these polymorphisms associated with the risks of low birth weight or growth acceleration from birth to 24 months of age.Conclusions: We found in a large population-based cohort no evidence for an effect of known glucocorticoid receptor gene polymorphisms on fetal and early postnatal growth characteristics. Further systematic searches for common genetic variants by means of genome-wide association studies will enable us to obtain a more complete understanding of what genes and polymorphisms are involved in growth in fetal life and infancy.

Associations of light and moderate maternal alcohol consumption with fetal growth characteristics in different periods of pregnancy: The generation R study (Article)

2010-03-01T00:00:00Z

Background: Excessive alcohol consumption during pregnancy has adverse effects on fetal growth and development. Less consistent associations have been shown for the associations of light-to-moderate maternal alcohol consumption during pregnancy with health outcomes in the offspring. Therefore, we examined the associations of light-to-moderate maternal alcohol consumption with various fetal growth characteristics measured in different periods of pregnancy. Methods: This study was based on 7333 pregnant women participating in a population-based cohort study. Alcohol consumption habits and fetal growth were assessed in early (gestational age <17.9 weeks), mid- (gestational age 18-24.9 weeks) and late pregnancy (gestational age ≥25 weeks). We assessed the effects of different categories of alcohol consumption (no; less than one drink per week; one to three drinks per week; four to six drinks per week; one drink per day and two to three drinks per day) on repeatedly measured fetal head circumference, abdominal circumference and femur length. Results: In total, 37% of all mothers continued alcohol consumption during pregnancy, of whom the majority used less than three drinks per week. We observed no differences in growth rates of fetal head circumference, abdominal circumference or femur length between mothers with and without continued alcohol consumption during pregnancy. Compared with mothers without alcohol consumption, mothers with continued alcohol consumption during pregnancy had an increased fetal weight gain [difference 0.61 g (95% confidence interval: 0.18, 1.04) per week]. Cross-sectional analyses in mid- and late pregnancy showed no consistent associations between the number of alcoholic consumptions and fetal growth characteristics. All analyses were adjusted for potential confounders. Conclusions: Light-to-moderate maternal alcohol consumption during pregnancy does not adversely affect fetal growth characteristics. Further studies are needed to assess whether moderate alcohol consumption during pregnancy influences organ growth and function in postnatal life.

Fetal programming of infant neuromotor development: The generation R study (Article)

2010-02-01T00:00:00Z

The objective of the study was to examine whether infant neuromotor development is determined by fetal size and body symmetry in the general population. This study was embedded within the Generation R Study, a population-based cohort in Rotterdam. In 2965 fetuses, growth parameters were measured in mid-pregnancy and late pregnancy. After birth, at age 9 to 15 wks, neuromotor development was assessed with an adapted version of Touwen's Neurodevelopmental Examination. Less optimal neuromotor development was defined as a score in the highest tertile. We found that higher fetal weight was beneficial to infant neurodevelopment. A fetus with a 1-SD score higher weight in mid-pregnancy had an 11% lower risk of less optimal neuromotor development (OR: 0.89; 95% CI: 0.82-0.97). Similarly, a fetus with a 1-SD score larger abdominal-to-head circumference (AC/HC) ratio had a 13% lower risk of less optimal neuromotor development (OR: 0.87; 95% CI: 0.79-0.96). These associations were also present in late pregnancy. Our findings show that fetal size and body symmetry in pregnancy are associated with infant neuromotor development. These results suggest that differences in infant neuromotor development, a marker of behavioral and cognitive problems, are at least partly caused by processes occurring early in fetal life.

The PCLO gene and depressive disorders: replication in a population-based study (Article)

2010-02-01T00:00:00Z

Abstract: Previous genome-wide association analysis revealed a new putative candidate gene for major depression: the PCLO gene. Replication in one population-based cohort did not yield genome-wide significance and further replication efforts in clinical studies were unsuccessful. We aimed to validate the association of single-nucleotide polymorphism (SNP) rs2522833 in the PCLO gene with depression in the Rotterdam Study, a prospective population-based cohort of elderly persons. In the Rotterdam Study, we identified 579 persons with a broad depression phenotype (depressive syndromes) of whom 178 cases with DSM-defined depressive disorder. The control group consisted of 912 persons free of depression during the follow-up period and in their histories. Logistic regression analysis showed an association between rs2522833 and depressive disorders (P = 0.0025). However, no association between the broader depressive syndrome group and this SNP was observed (P = 0.20). A meta-analysis combining all studies from the original publication and our study yielded a P-value of 2.16 x 10(-3) for the association between SNP rs2522833 and depressive disorders. However, as in the previous publication, high heterogeneity between studies was observed. Thus, a meta-analysis with the findings from three population-based studies was performed. This demonstrated a genome-wide significant P-value (P = 1.93 x 10(-9)). In conclusion, this study provides additional evidence for an association between PCLO and depressive disorders in a population-based study; no association with a broader syndromal phenotype was observed.

Do social disadvantage and early family adversity affect the diurnal cortisol rhythm in infants? The Generation R Study (Article)

2010-02-01T00:00:00Z

Dysregulation of diurnal cortisol secretion patterns may explain the link between adversities early in life and later mental health problems. However, few studies have investigated the influence of social disadvantage and family adversity on the hypothalamic-pituitary-adrenal (HPA) axis early in life. In 366 infants aged 12-20 months from the Generation R Study, a population-based cohort from fetal life onwards, parents collected saliva samples from their infant at 5 moments over the course of 1 day. The area under the curve (AUC), the cortisol awakening response (CAR) and the diurnal cortisol slope were calculated as different composite measures of the diurnal cortisol rhythm. Information about social disadvantage and early adversity was collected using prenatal and postnatal questionnaires. We found that older infants showed lower AUC levels; moreover, infants with a positive CAR were significantly older. Both the AUC and the CAR were related to indicators of social disadvantage and early adversity. Infants of low income families, in comparison to high income families, showed higher AUC levels and a positive CAR. Infants of mothers who smoked during pregnancy were also significantly more likely to show a positive CAR. Furthermore, infants of mothers experiencing parenting stress showed higher AUC levels. The results of our study show that effects of social disadvantage and early adversity on the diurnal cortisol rhythm are already observable in infants. This may reflect the influence of early negative life events on early maturation of the HPA axis.

Grandparental anxiety and depression predict young children's internalizing and externalizing problems. The generation R study (Article)

2010-01-01T00:00:00Z

Background: Family history is a major risk factor for child problem behaviour, yet few studies have examined the association between grandparental psychiatric disorder and child problem behaviour. Results are inconsistent as to whether the effect of grandparental depression on child problem behaviour is independent of parental psychopathology. Methods: Mothers and their children participated in an ethnically Dutch subcohort of a population-based prospective cohort in the Netherlands. N = 816 (66%) mothers and n = 691 fathers participated in the prenatal interviews. N = 687 (84%) mothers and children and n = 565 (82%) fathers participated three years postpartum. (Grand)parental psychopathology was assessed during pregnancy of the mothers with the Family Informant Schedule and Criteria (FISC), the Composite International Diagnostic Interview (CIDI) and the Brief Symptom Inventory (BSI). Child behaviour was assessed with the Child Behavior Checklist (CBCL) by mother and father when the child was three years old. Results: Grandparental anxiety disorder predicted maternal reports of children's internalizing problems (OR = 1.98, 95% C.I. (1.20, 3.28), p-value < 0.01) and externalizing problems (OR = 1.73, 95% C.I. (1.04, 2.87), p-value = 0.03), independent of parental psychopathology. Results were similar for grandparental depression; internalizing OR = 1.75, 95% C.I (1.11, 2.75), p-value = 0.02 and externalizing OR = 1.67, 95% C.I. (1.05, 2.64) p-value = 0.03. However, grandparental psychopathology was not associated with children's problem behaviour as reported by the father. Limitations: Information on grandparental lifetime psychiatric disorder was assessed through a parental interview which may have led to an underestimation of the prevalence rates. Conclusions: These results confirm the importance of a family history including not only the parental but also the grandparental generations.

Vascular brain disease and depression in the elderly (Article)

2010-01-01T00:00:00Z

Background: Cross-sectional studies have shown an association between vascular brain disease and depression. Longitudinal data are scarce. In a population-based study we investigated this relationship both cross-sectionally and longitudinally. Methods: Brain MRIs were administered to 479 persons aged 60-90 years at baseline (1995-1996). Brain atrophy, white matter lesions and brain infarcts are all markers of vascular brain disease. At baseline and at follow-up examinations, we also identified persons with depressive symptoms and syndromes using the Center for Epidemiological Studies Depression Scale and psychiatric interviews. Medical records were continuously monitored to identify incident depression. Follow-up was complete until October 2005. Results: At baseline, 36 persons had depressive symptoms. Brain atrophy, white matter lesions, and infarcts were associated with presence of depressive symptoms. During follow-up, 92 persons developed depressive symptoms, 35 of whom were categorized as having depressive syndrome. There was no association of any MRI marker with incident depressive symptoms or syndromes. Conclusions: Markers of vascular brain disease were associated with depression cross-sectionally. However, when these markers and risk of depression were assessed longitudinally, no relationship was found.

Cerebellum development during childhood and adolescence: A longitudinal morphometric MRI study (Article)

2010-01-01T00:00:00Z

In addition to its well-established role in balance, coordination, and other motor skills, the cerebellum is increasingly recognized as a prominent contributor to a wide array of cognitive and emotional functions. Many of these capacities undergo dramatic changes during childhood and adolescence. However, accurate characterization of co-occurring anatomical changes has been hindered by lack of longitudinal data and methodologic challenges in quantifying subdivisions of the cerebellum. In this study we apply an innovative image analysis technique to quantify total cerebellar volume and 11 subdivisions (i.e. anterior, superior posterior, and inferior posterior lobes, corpus medullare, and three vermal regions) from anatomic brain MRI scans from 25 healthy females and 25 healthy males aged 5-24 years, each of whom was scanned at least three times at approximately 2-year intervals. Total cerebellum volume followed an inverted U shaped developmental trajectory peaking at age 11.8 years in females and 15.6 years in males. Cerebellar volume was 10% to 13% larger in males depending on the age of comparison and the sexual dimorphism remained significant after covarying for total brain volume. Subdivisions of the cerebellum had distinctive developmental trajectories with more phylogenetically recent regions maturing particularly late. The cerebellum's unique protracted developmental trajectories, sexual dimorphism, preferential vulnerability to environmental influences, and frequent implication in childhood onset disorders such as autism and ADHD make it a prime target for pediatric neuroimaging investigations.

Variable selection: Current practice in epidemiological studies (Article)

2009-12-01T00:00:00Z

Selection of covariates is among the most controversial and difficult tasks in epidemiologic analysis. Correct variable selection addresses the problem of confounding in etiologic research and allows unbiased estimation of probabilities in prognostic studies. The aim of this commentary is to assess how often different variable selection techniques were applied in contemporary epidemiologic analysis. It was of particular interest to see whether modern methods such as shrinkage or penalized regression were used in recent publications. Stepwise selection methods remained the predominant method for variable selection in publications in epidemiological journals in 2008. Shrinkage methods were not used in any of the reviewed articles. Editors, reviewers and authors have insufficiently promoted the new, less controversial approaches of variable selection in the biomedical literature, whereas statisticians may not have adequately addressed the method's feasibility.

Mortality and disability: The effect of overweight and obesity (Article)

2009-12-01T00:00:00Z

Context: Prevalence of obesity is increasing globally. The effect of obesity on mortality and morbidity and its implication on the future prevalence of disability in the older population has not been conclusively analyzed. Objective: To determine the influence of overweight and obesity on mortality and disability by quantifying the effect in terms of disability-free life expectancy and years lost to disability (YLD) in the older people.Design, Setting and Participants: For 5980 participants from the Rotterdam Study cohort, regression techniques were used to estimate the association of body mass index (BMI) and waist circumference (WC) separately with mortality, incident disability and recovery from disability. Disability was assessed using the Stanford Health Assessment Questionnaire Disability Index, an activity of daily living scale. Multistate life table methodology was used to calculate life expectancies. Main Outcome Measures: In total, 15-year mortality risk, 6-year disability incidence, total life expectancy, healthy life expectancy and years of disabled life expectancy. Results: We observed 2388 deaths. Our analysis revealed no association between body mass index, or WC and mortality in the healthy population. Body mass index and WC were related to disability (overweight 25 ≤BMI<30, odd ratio (OR)=1.33, 95% confidence interval (CI) (1.10; 1.61), obesity I 30≤BMI <35, OR=2.03, 95% CI (1.55; 2.65)) and negatively to recovery from disability. We observed an increase of years lost to disability with increasing weight for men (normal weight-4.69 years, 'overweight'-5.87 years and 'obesity I'-7.06 years) and for women ('normal weight'-10.95 years, 'overweight'-12.82 years, 'obesity I'-15.17 years and obesity II/III'-13.13 years).Conclusion:Results do not support the hypothesis that an increased body weight reduces total life expectancy in the older people. Although increased body weight was associated with a higher risk of becoming and remaining disabled. These results remained using WC.

Adverse Childhood Experiences and the Risk of Premature Mortality (Article)

2009-11-01T00:00:00Z

Background: Strong, graded relationships between exposure to childhood traumatic stressors and numerous negative health behaviors and outcomes, healthcare utilization, and overall health status inspired the question of whether these adverse childhood experiences (ACEs) are associated with premature death during adulthood. Purpose: This study aims to determine whether ACEs are associated with an increased risk of premature death during adulthood. Methods: Baseline survey data on health behaviors, health status, and exposure to ACEs were collected from 17,337 adults aged >18 years during 1995-1997. The ACEs included abuse (emotional, physical, sexual); witnessing domestic violence; parental separation or divorce; and growing up in a household where members were mentally ill, substance abusers, or sent to prison. The ACE score (an integer count of the eight categories of ACEs) was used as a measure of cumulative exposure to traumatic stress during childhood. Deaths were identified during follow-up assessments (between baseline appointment date and December 31, 2006) using mortality records obtained from a search of the National Death Index. Expected years of life lost (YLL) and years of potential life lost (YPLL) were computed using standard methods. The relative risk of death from all causes at age ≤65 years and at age ≤75 years was estimated across the number of categories of ACEs using multivariable-adjusted Cox proportional hazards regression. Analysis was conducted during January-February 2009. Results: Overall, 1539 people died during follow-up; the crude death rate was 91.0 per 1000; the age-adjusted rate was 54.7 per 1000. People with six or more ACEs died nearly 20 years earlier on average than those without ACEs (60.6 years, 95% CI=56.2, 65.1, vs 79.1 years, 95% CI=78.4, 79.9). Average YLL per death was nearly three times greater among people with six or more ACEs (25.2 years) than those without ACEs (9.2 years). Roughly one third (n=526) of those who died during follow-up were aged ≤75 years at the time of death, accounting for 4792 YPLL. After multivariable adjustment, adults with six or more ACEs were 1.7 (95% CI=1.06, 2.83) times more likely to die when aged ≤75 years and 2.4 (95% CI=1.30, 4.39) times more likely to die when aged ≤65 years. Conclusions: ACEs are associated with an increased risk of premature death, although a graded increase in the risk of premature death was not observed across the number of categories of ACEs. The increase in risk was only partly explained by documented ACE-related health and social problems, suggesting other possible mechanisms by which ACEs may contribute to premature death.

Levels of metabolites of organophosphate pesticides, phthalates, and bisphenol A in pooled urine specimens from pregnant women participating in the Norwegian Mother and Child Cohort Study (MoBa) (Article)

2009-09-01T00:00:00Z

Concerns about reproductive and developmental health risks of exposure to organophosphate (OP) pesticides, phthalates, and bisphenol A (BPA) among the general population are increasing. Six dialkyl phosphate (DAP) metabolites, 3,5,6-trichloro-2-pyridinol (TCPy), BPA, and fourteen phthalate metabolites were measured in 10 pooled urine samples representing 110 pregnant women who participated in the Norwegian Mother and Child Birth Cohort (MoBa) study in 2004. Daily intakes were estimated from urinary data and compared with reference doses (RfDs) and daily tolerable intakes (TDIs). The MoBa women had a higher mean BPA concentration (4.50 μg/L) than the pregnant women in the Generation R Study (Generation R) in the Netherlands and the National Health and Nutrition Examination Survey (NHANES) in the United States. The mean concentration of total DAP metabolites (24.20 μg/L) in MoBa women was higher than that in NHANES women but lower than that in Generation R women. The diethyl phthalate metabolite mono-ethyl phthalate (MEP) was the dominant phthalate metabolite in all three studies, with the mean concentrations of greater than 300 μg/L. The MoBa and Generation R women had higher mean concentrations of mono-n-butyl phthalate (MnBP) and mono-isobutyl phthalate (MiBP) than the NHANES women. The estimated average daily intakes of BPA, chlorpyrifos/chlorpyrifos-methyl and phthalates in MoBa (and the other two studies) were below the RfDs and TDIs. The higher levels of metabolites in the MoBa participants may have been from intake via pesticide residues in food (organophosphates), consumption of canned food, especially fish/seafood (BPA), and use of personal care products (selected phthalates).

The rotterdam study: 2010 objectives and design update (Article)

2009-09-01T00:00:00Z

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in close to a 1,000 research articles and reports (see www.epib.nl/ rotterdamstudy ). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.

High activity of Monoamine oxidase A is associated with externalizing behaviour in maltreated and nonmaltreated adoptees (Article)

2009-08-01T00:00:00Z

Individual differences in a functional polymorphism of the promoter of the Monoamine oxidase A (MAO-A) gene might partly explain the increased vulnerability of maltreated children for externalizing behaviour. A sample of 239 internationally adopted boys was studied. Adoptive parents provided the information about abuse and neglect before the adoption and rated externalizing behaviour of their adopted children, using the Child Behaviour Checklist. MAO-A alleles were classified in high and low activity. We found that individuals with high MAO-A activity had more externalizing behaviour than those with low MAO-A activity. No modifying effect of MAO-A on the relationship between early maltreatment on externalizing behaviour was observed. Our results suggest that in severely maltreated children, high MAO-A activity may not protect against the effects of maltreatment but may convey an increased risk for externalizing behaviour.

BclI glucocorticoid receptor polymorphism and smoking in the general population (Article)

2009-07-01T00:00:00Z

We studied the hypothesis that the BclI polymorphism of the glucocorticoid receptor gene is associated with an increased probability of being a (heavy) smoker and a decreased ability to quit smoking. The study cohort consisted of all subjects in the Rotterdam Study, a Dutch population-based cohort of people aged 55 years and older, for whom BclI genotyping and smoking status at baseline were available. In prospective analyses, the smoking status was reassessed during three additional examination rounds. Logistic regression analysis was used to study the association between BclI polymorphism and being a smoker or a heavy smoker at baseline. Furthermore, the relationship between BclI polymorphism and incident smoking cessation was tested with Cox proportional hazards analysis within those who smoked at baseline. In total, 6358 subjects were included in the study. The presence of a G-allele was not associated with current smoking at baseline [odds ratio (OR) = 0.96, 95%confidence interval (CI): 0.85-1.09] or with the incidence of smoking cessation during follow-up [hazard ratio (HR) = 0.98, 95%CI: 0.80-1.19]. Within current smokers, having a G-allele was not significantly associated with the risk of being a heavy smoker when measured by pack-years smoked (OR = 1.07, 95%CI: 0.85-1.35) or daily consumption of tobacco (OR = 1.10, 95%CI: 0.88-1.37). We were not able to replicate the earlier findings indicating that the proportion of current smokers is lower among carriers of the CC-genotype of the BclI glucocorticoid receptor. Furthermore, the BclI glucocorticoid receptor polymorphism did not predict the incidence of smoking cessation in the general elderly population.

Maternal symptoms of anxiety during pregnancy affect infant neuromotor development: The generation R study (Article)

2009-07-01T00:00:00Z

Several studies found that maternal symptoms of anxiety or depression are related to functioning and development of the offspring. Within a population-based study of 2,724 children, we investigated the effect of maternal anxiety or depression on infant neuromotor development. Symptoms of anxiety and depression were measured during pregnancy and after giving birth; infant neuromotor development was assessed by trained research nurses during a home visit at the age of 3 months. The current study showed that mothers who were anxious during pregnancy had an elevated risk of having an infant with non-optimal neuromotor development.

Paternal depressive symptoms during pregnancy are related to excessive infant crying (Article)

2009-07-01T00:00:00Z

OBJECTIVE: Excessive infant crying, or infantile colic, is a common and often stress-inducing problem for parents that can ultimately result in child abuse. From previous research it is known that maternal depression is related to excessive crying, but so far little is known about the influence of paternal depression. METHODS: In a prospective, population-based study, we obtained information on both maternal and paternal depressive symptoms at 20 weeks of pregnancy by using the Brief Symptom Inventory. Parental depressive symptoms were related to excessive crying in 4426 two-month-old infants. The definition of excessive crying was based on the widely used Wessel's criteria (ie, crying >3 hours for >3 days in the past week). RESULTS: After adjustment for depressive symptoms of the mother and relevant confounders, we found a 1.29 (95% confidence interval: 1.09-1.52) higher risk of excessive infant crying per SD of paternal depressive symptoms. CONCLUSIONS: Our findings indicate that paternal depressive symptoms during pregnancy might be a risk factor for excessive infant crying. This finding could be related to genetic transmission, interaction of a father with lasting depressive symptoms with the infant, or related indirectly through contextual stressors such as marital, familial, or economic distress. Copyright

Association between the CYP2D6*4 polymorphism and depression or anxiety in the elderly (Article)

2009-06-16T00:00:00Z

Introduction: 5-methoxytryptamine (5-MT), a precursor of serotonin, is considered to be an endogeous substrate of cytochrome P450 2D6 (CYP2D6). Homozygous carriers of the variant allele CYP2D6*4 lack CYP2D6 emzyme activity. Relative to extensive metabolizers, these poor metabolizers may have lower baseline serotonin concentrations in various brain regions, and may be more prone to depression or anxity. Aim: To test whether the CYP2D6*4/*4 genotype is associated with a predisposition to depression or anxiety disorders in the elderly. Materials & methods: We conducted a cross-sectional study within the Rotterdam Study, a population-based cohort study, among persons aged 55 years or older, who were screened for depression and anxiety disorder at two consecutive examination rounds. Logistic regression was used to analyze the association between the CYP2D6*4 polymorhism and the risk of depression or anxiety disorders. Results: The risk of major depression in CYP2D*64/*4 was not significantly different from extensive metabolizers (OR = 0.85; 95% Cl: 0.36-2.00; p = 0.72). Neither did we find an association between CYP2D6 genotype and minor depression (OR = 1.56; 95% Cl: 0.69-3.52; p = 0.28). No increased risk of anxiety disorders was found (OR = 1.19; 95% Cl: 0.68-2.09; p = 0.55). Conclusion: Variation in the CYP2D6 gene is not related to a predisposition or anxiety disorders in the elderly.

Maternal smoking during pregnancy and child behaviour problems: The generation R study (Article)

2009-06-15T00:00:00Z

Background: Several studies showed that maternal smoking in pregnancy is related to behavioural and emotional disorders in the offspring. It is unclear whether this is a causal association, or can be explained by other smoking-related vulnerability factors for child behavioural problems. Methods: Within a population-based birth cohort, both mothers and fathers reported on their smoking habits at several time-points during pregnancy. Behavioural problems were measured with the Child Behavior Checklist in 4680 children at the age of 18 months. Results: With adjustment for age and gender only, children of mothers who continued smoking during pregnancy had higher risk of Total Problems [odds ratio (OR) 1.59, 95% confidence interval (CI): 1.21-2.08] and Externalizing problems (OR 1.45, 95% CI: 1.15-1.84), compared with children of mothers who never smoked. Smoking by father when mother did not smoke, was also related to a higher risk of behavioural problems. The statistical association of parental smoking with behavioural problems was strongly confounded by parental characteristics, chiefly socioeconomic status and parental psychopathology; adjustment for these factors accounted entirely for the effect of both maternal and paternal smoking on child behavioural problems. Conclusions: Maternal smoking during pregnancy, as well as paternal smoking, occurs in the context of other factors that place the child at increased developmental risk, but may not be causally related to the child's behaviour. It is essential to include sufficient information on parental psychiatric symptoms in studies exploring the association between pre-natal cigarette smoke exposure and behavioural disorders. © Published by Oxford University Press on behalf of the International Epidemiological Association

Fetal size in mid- and late pregnancy is related to infant alertness: The generation R study (Article)

2009-06-03T00:00:00Z

The vulnerability for behavioral problems is partly shaped in fetal life. Numerous studies have related indicators of intrauterine growth, for example, birth weight and body size, to behavioral development. We investigated whether fetal size in mid- and late pregnancy is related to infant irritability and alertness. In a population-based birth cohort of 4,255 singleton full-term infants ultrasound measurements of fetal head and abdominal circumference in mid- and late pregnancy were performed. Infant irritability and alertness scores were obtained by the Mother and Baby Scales at 3 months and z-standardized. Multiple linear regression analyses revealed curvilinear associations (inverted J-shape) of measures of fetal size in both mid- and late pregnancy with infant alertness. Fetal size characteristics were not associated with infant irritability. These results suggest that alterations of intrauterine growth affecting infant alertness are already detectable from mid-pregnancy onwards.

Early neglect and abuse predict diurnal cortisol patterns in adults. A study of international adoptees (Article)

2009-06-01T00:00:00Z

Neglect and abuse early in life have been associated with increased and decreased cortisol levels, and also with an altered diurnal cortisol slope. In the present study, we investigated the long-term relationship between early maltreatment - at different levels of severity - and basal cortisol secretion in adults adopted as children. A sample of international adoptees was followed from childhood to adulthood. In childhood, adoptive parents had provided information about neglect and abuse prior to adoption. As adults, adoptees collected saliva samples four times a day. The relationship between early maltreatment and cortisol secretion was examined, primarily with multilevel analyses in 623 adoptees. Morning cortisol levels were lower in adoptees whose adoptive parents had reported severe neglect or abuse than in non-neglected or non-abused participants (respective estimates (standard errors (SEs)) and p-values: -0.33 (0.090), p = 0.0002 and -0.63 (0.20), p = 0.002). Relative to non-neglected adoptees, those who had allegedly experienced severe neglect also had a flatter diurnal slope (estimate (SE) and p-value: 0.028 (0.0088), p = 0.002). In contrast, relative to non-abused participants, adoptees whose reported abuse was moderately severe had high cortisol levels and a steeper cortisol diurnal slope (respective estimates (SEs) and p-values: 0.29 (0.13), p = 0.003 and -0.039 (0.012), p = 0.01). Thus, early neglect and abuse appear to have associations with cortisol levels and the diurnal slope, even when children are raised in another environment after their early maltreatment. Our study suggests that the severity of the early maltreatment may be related to the basal cortisol pattern.

Explaining educational inequalities in birthweight: The Generation R Study (Article)

2009-05-01T00:00:00Z

Although low socio-economic status has consistently been associated with lower birthweight, little is known about the factors whereby socio-economic disadvantage influences birthweight. We therefore examined explanatory mechanisms that may underlie the association between the educational level of pregnant women, as an indicator of socio-economic status, and birthweight. The study was embedded within a population-based cohort study in the Netherlands. Information on maternal education, offspring's birthweight and several determinants of birthweight was available for 3546 pregnant women of Dutch origin. Infants of the lowest educated women had a statistically significantly lower birthweight than infants of the highest educated women [difference adjusted for gender and gestational age: -123 g (95% CI -167, -79)]. Parity, age of the pregnant women, hypertension, parental height and parental birthweight, marital status, pregnancy planning, financial concerns, number of people in household, weight gain and smoking habits individually explained part of the differences in birthweight, while adjustment for working hours and body mass index resulted in increases in birthweight differences between the educational levels. After full adjustment, the difference in birthweight between lowest and highest education was reduced by 66%. Our study confirmed remarkable educational inequalities in birthweight, a large part of which was explained by pregnancy characteristics, anthropometrics, the psychosocial and material situation, and lifestyle-related factors. Altering smoking habits may be an option to reduce educational differences in birthweight, as many lower-educated women tend to continue smoking during pregnancy. In order to tackle inequalities in birthweight, it is important that interventions are accessible for pregnant women in lower socio-economic strata.

Maternal Psychopathology Influences Infant Heart Rate Variability: Generation R Study (Article)

2009-04-01T00:00:00Z

Abstract OBJECTIVE: To assess the determinants of heart rate (HR) and heart rate variability (HRV) in children. The autonomic nervous system as measured by HR and HRV is considered a biological marker of psychopathology in children. METHODS: We examined the relationship of maternal psychopathology with infant HR and HRV. HR was recorded at 14 months in 528 infants. The high-frequency component of HRV was used as an indicator of cardiac vagal modulation. The presence of a lifetime maternal psychiatric diagnosis was assessed with the Composite International Diagnostic Interview. Presence of maternal psychiatric symptoms during pregnancy and 2 months after birth was assessed, using the Brief Symptom Inventory. RESULTS: A maternal history of a psychiatric disorder was associated with a 0.24-standard deviation (SD) higher mean HR in the infant (beta = 0.24, 95% Confidence Interval (CI) = 0.03, 0.4, p = .025) and a 0.14-SD lower high-frequency power (beta = -0.14, 95% CI = -0.6, -0.03, p = .003). Likewise, postnatal maternal anxiety and depression symptoms were associated with infant mean HR. A 1-point increase in the mean anxiety symptom score was associated with 0.14-SD higher mean HR in the infant (beta = 0.14, 95% CI = 0.05, 0.2, p = .004), and a 1-point increase in mean depression score with a 0.11-SD increase (beta = 0.11, 95% CI = 0.01, 0.2, p = .025). No significant associations of prenatal maternal affective symptoms with infants autonomic functioning were found. CONCLUSION: Maternal lifetime psychiatric diagnosis and postnatal psychiatric symptoms are associated with infant autonomic functioning, namely, higher mean HR and lower vagal modulation.

Genome-wide Association Study of Smoking Initiation and Current Smoking (Article)

2009-03-13T00:00:00Z

For the identification of genes associated with smoking initiation and current smoking, genome-wide association analyses were carried out in 3497 subjects. Significant genes that replicated in three independent samples (n = 405, 5810, and 1648) were visualized into a biologically meaningful network showing cellular location and direct interaction of their proteins. Several interesting groups of proteins stood out, including glutamate receptors (e.g., GRIN2B, GRIN2A, GRIK2, GRM8), proteins involved in tyrosine kinase receptor signaling (e.g., NTRK2, GRB14), transporters (e.g., SLC1A2, SLC9A9) and cell-adhesion molecules (e.g., CDH23). We conclude that a network-based genome-wide association approach can identify genes influencing smoking behavior.

Impact of early childhood adversities on adult psychiatric disorders (Article)

2009-02-12T00:00:00Z

Background: This study investigated international adoptees who were taken out of their problematic environments as a consequence of their adoption to determine the effects of early adversities on adult psychiatric disorders, and to study whether these effects emerged de novo after childhood. Methods: A total of 1,364 adoptees (63.5% of the baseline sample) were followed. Parents provided information about early adversities prior to adoption, and mental health problems in childhood and adolescence. In adulthood, adoptees completed a standardized interview, generating DSM-IV diagnoses. Results: Children who experienced multiple adversities had an increased risk of having anxiety disorders (OR = 2.22; 95% CI: 1.11-4.45), mood disorders (OR = 2.20; 95% CI: 1.00-4.86) or substance abuse/dependence (OR = 3.81; 95% CI: 1.62-8.98) in adulthood. Several effects remained significant after correction for mental health problems in childhood and adolescence. Conclusions: Severe early adversities increase the risk ofadult psychopathology, even when children are taken out of their problematic environments. Results suggest that psychiatric disorders may arise de novo after childhood due to early experiences.

Early childhood adversities and trajectories of psychiatric problems in adoptees: Evidence for long lasting effects (Article)

2009-02-01T00:00:00Z

The aim of the present study is to investigate whether early childhood adversities determine the longitudinal course of psychiatric problems from childhood to adulthood; in particular if the impact of early maltreatment on psychopathology decreases as time passes. A sample of 1,984 international adoptees was followed (955 males and 1029 females; adopted at the mean age of 29 months). Parents provided information about abuse, neglect and number of placements prior to adoption at baseline and completed the Child Behavior Checklist or the Young Adult Behavior Checklist three times when their children were between 10 and 30 years of age. Multilevel analyses were performed to determine trajectories of psychiatric problems. Experience of early childhood adversity prior to adoption substantially increased the level of psychiatric problems, especially when maltreatment was severe. Moreover, the impact of early adversities on psychiatric problems remained markedly stable. This suggests that vulnerability of early-maltreated children persists even if they are taken out of their problematic environments and are raised in enriched circumstances.

Socioeconomic inequalities in infant temperament: The Generation R Study (Article)

2009-01-01T00:00:00Z

Background: A low socioeconomic status (SES) has consistently been associated with behavioural problems during childhood. The studies of SES and behaviour in infants used temperament as a behavioural measure. However, these studies in younger children yielded inconsistent findings. Furthermore, they generally did not examine explanatory mechanisms underlying the association between SES and temperament. We investigated the association between SES and temperament in infancy. Methods: The study was embedded in the Generation R study, a population-based cohort in The Netherlands. Maternal and paternal education, family income, and maternal occupational status were used as indicators of SES. At the age of 6 months, 4,055 mothers filled out six scales of the Infant Behaviour Questionnaire-Revised. Results: Lower SES was associated with more difficult infant temperament as measured by five of the six temperament dimensions (e.g. Fear: unadjusted z-score difference between lowest and highest education: 0.57 (95%CI: 0.43, 0.71)). Only the direction of the association between SES and Sadness was reversed. The effect of SES on Distress to Limitations, Recovery from Distress, and Duration of Orienting scores was largely explained by family stress and maternal psychological well-being. These covariates could not explain the higher levels of Activity and Fear nor the lower Sadness scores of infants from low SES groups. Conclusions: SES inequalities in temperament were already present in six months old infants and could partially be explained by family stress and maternal psychological well-being. The results imply that socioeconomic inequalities in mental health in adults may have their origin early in life.

Shared genetic factors in the co-occurrence of symptoms of depression and cardiovascular risk factors (Article)

2009-01-01T00:00:00Z

Background: We aim to investigate the extent to which shared genetic and shared environmental factors play a role in the co-occurrence of symptoms of depression and cardiovascular risk factors. Methods: The analyses included 2383 individuals from a genetically isolated population in the Netherlands (mean age 48.7 years (standard deviation 15.1), percentage of women 56.9%). Symptoms of depression were assessed using the Center for Epidemiology Studies Depression Scale (CES-D) and the Depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). Assessment of cardiovascular risk factors included systolic and diastolic blood pressure, plasma, glucose levels, high and low density lipoprotein (HDL, LDL) and total cholesterol levels. Results: Overall, we found that HADS-D was significantly correlated to total cholesterol levels (correlation coefficient [ρ] = 0.05), and inversely associated to HDL (ρ = - 0.06). Statistically significant genetic correlations (ρG) were found between CES-D scores and total plasma cholesterol (ρG = 0.30), LDL (ρG = 0.31) and total cholesterol/HDL ratios (ρG = 0.25). For HADS-D scores, a significant genetic correlation was found with total cholesterol/HDL ratios (ρG = 0.27). Environmental correlations (ρE) with an opposite direction were found between CES-D and both total cholesterol (ρE = - 0.16) and LDL (ρE = - 0.15). Limitation: By adjusting for sibship, we are taking into account environmental effects, however we cannot exclude dominance variance. Conclusions: Our study shows that there is evidence for shared genetic factors contributing to the co-occurrence of symptoms of depression and lipid levels. This finding suggests a joint genetic pathogenesis. Future research is encouraged to assess susceptibility genes for mood disorders to be studied for cardiovascular disorders and vice versa.

Maternal folic acid supplement use in early pregnancy and child behavioural problems: The Generation R Study (Article)

2009-01-01T00:00:00Z

Folate deficiency during embryogenesis is an established risk factor for neural tube defects in the fetus. An adequate folate nutritional status is also important for normal fetal growth and brain development. The aim of the present research was to study the association between folic acid use of the mother during pregnancy and child behavioural development. Within a population-based cohort, we prospectively assessed folic acid supplement use during the first trimester by questionnaire. Child behavioural and emotional problems were assessed with the Child Behaviour Checklist at the age of 18 months in 4214 toddlers. Results showed that children of mothers who did not use folic acid supplements in the first trimester had a higher risk of total problems (OR 1·44; 95 % CI 1·12, 1·86). Folic acid supplement use protected both from internalising (OR of no supplement use 1·65; 95 % CI 1·24, 2·19) and externalising problems (OR 1·45; 95 % CI 1·17, 1·80), even when adjusted for maternal characteristics. Birth weight and size of the fetal head did not mediate the association between folic acid use and child behaviour. In conclusion, inadequate use of folic acid supplements during early pregnancy may be associated with a higher risk of behavioural problems in the offspring. Folic acid supplementation in early pregnancy, aimed to prevent neural tube defects, may also reduce mental health problems in children.

The effect of catechol-O-methyltransferase Met/Val functional polymorphism on smoking cessation: retrospective and prospective analyses in a cohort study (Article)

2009-01-01T00:00:00Z

Objective The Met/Val functional polymorphism of the gene-encoding catechol-O-methyltransferase (COMT) is one of the most widely tested variants for association with different phenotypes of addictive behavior, but replication has been inconsistent for smoking status. We investigated the relationship of this COMT single nucleotide polymorphism with smoking cessation in elderly persons in retrospective and prospective analyses. Methods The study is embedded in the population-based Rotterdam Study cohort and included 5115 persons aged 55 years and more. In the retrospective analyses using logistic regression, current smokers who had smoked 10 or more cigarettes daily for 10 or more years were compared with former smokers. In the prospective analyses, we followed 1195 current smokers up to 12 years and used Cox proportional hazard model to detect the effect of the COMT single nucleotide polymorphism on self-reported incidence of smoking cessation. Results The Val/Val genotype of COMT had a consistent association with smoking cessation as compared with the Met/Met+Met/Val genotypes in retrospective [odds ratio=0.79, 95% confidence interval (CI): 0.66-0.96, P=0.02] and prospective analyses (hazard ratio=0.80, 95% CI: 0.63-1.01, P=0.06). In the pooled analyses of prevalent and incident cessation cases that we compared with persisting smokers, the odds ratio was 0.70 (95% CI: 0.55-0.88, P=0.003). No sex difference and no effect of the COMT polymorphism on smoking initiation were observed. Conclusion Our results suggest that COMT Met/Val polymorphism is strongly associated with smoking cessation. The Met allele is the risk allele that decreases the likelihood of smoking cessation in men and women. Pharmacogenetics and Genomics 19:45-51

Incidence and recurrence of late-life depression (Article)

2008-12-01T00:00:00Z

Context: Depression is common in old age. Nevertheless, few incidence studies have established how often depression occurs in elderly persons with and without a history of depression. Objectives: To determine the incidence and recurrence rates of depression in an elderly population. Design, Setting, and Participants: A cohort study of community-dwelling elderly persons aged 56 years or older residing in Rotterdam, the Netherlands, performed between September 1993 and October 2005 and encompassing baseline and 2 follow-up examinations as well as continuous procedures. The study population consisted of 5653 participants free of dementia. Depression was identified through standardized psychiatric examinations, monitoring of medical records, registration of antidepressant use, and self-reported histories of depression. We categorized the depression as depressive syndromes, including DSM-IV-defined major depression, or clinically relevant depressive symptoms. Main Outcome Measures: Incidence and recurrence rates for depressive syndromes as well as for depressive syndromes and symptoms combined. In addition to overall rates, sex- and age-specific rates were calculated. Results: During the follow-up period of 8 years on average, 566 depressive syndromes and 1073 episodes of clinically relevant depressive symptoms occurred. For depressive syndromes, the incidence rate was 7.0 (95% confidence interval, 6.0-8.3) per 1000 person-years and the recurrence rate was 27.5 (95% confidence interval, 23.7-32.1) per 1000 person-years. The incidence and recurrence rates more than doubled when episodes of depressive symptoms were included. The recurrence rate of depressive syndromes was equal for women and men, but all other rates were almost twice as high for women compared with men. No rates seemed to change with age. Conclusions: The incidence rate of depression in the elderly population is low except when episodes of clinically relevant depressive symptoms are accounted for. Most late-life depression occurs in persons with a history of depression. Moreover, the recurrence rate of depressive syndromes does not differ between men and women.

The generation R study: Design and cohort update until the age of 4 years (Article)

2008-12-01T00:00:00Z

The Generation R Study is a population-based prospective cohort study from fetal life until young adulthood. The study is designed to identify early environmental and genetic causes of normal and abnormal growth, development and health from fetal life until young adulthood. The study focuses on four primary areas of research: (1) growth and physical development; (2) behavioural and cognitive development; (3) diseases in childhood; and (4) health and healthcare for pregnant women and children. In total, 9,778 mothers with a delivery date from April 2002 until January 2006 were enrolled in the study. Of all eligible children at birth, 61% participate in the study. In addition, more detailed assessments are conducted in a subgroup of 1,232 pregnant women and their children. Data collection in the prenatal phase and postnatal phase until the age of 4 years includes questionnaires, detailed physical and ultrasound examinations, behavioural observations and biological samples. This paper gives an update of the study design and cohort profile until the children's age of 4 years. Eventually, results forthcoming from the Generation R Study have to contribute to the development of strategies for optimizing health and healthcare for pregnant women and children.

Demographic, emotional and social determinants of cannabis use in early pregnancy: The Generation R study (Article)

2008-12-01T00:00:00Z

Aims: To ascertain demographic, emotional and social determinants of cannabis use in early pregnancy. Design: This study was embedded in the Generation R study, a multiethnic population-based cohort of parents and their children, followed from pregnancy to childhood. Setting: Rotterdam, The Netherlands. Participants: Mothers enrolled in pregnancy who answered questions about their own and their partners substance use before and during pregnancy (n = 7610). Measurements: Using self-report questionnaires, information was collected on maternal demographics, psychopathology, delinquency, childhood trauma, social stress, family functioning, and parental alcohol, tobacco and substance use. Multinomial logistic regression analysis was used, with non-using women as reference. Findings: 246 (3.2%) women used cannabis before pregnancy and 220 (2.9%) women used cannabis both before and during pregnancy. The strongest determinant for maternal cannabis use during pregnancy was cannabis use by the biological father of the child (OR = 38.56; 95%CI = 26.14-58.88). Maternal cannabis use during pregnancy was also independently associated with being single (OR = 4.25; 95%CI = 2.33-7.75) or having a partner without being married (OR = 2.75; 95%CI = 1.56-4.85), childhood trauma (OR = 1.39; 95%CI = 1.22-1.57) and delinquency (OR = 3.37; 95%CI = 1.90-5.98), but not with maternal age, ethnicity, psychopathology, family functioning and perceived stress. Being religious was protective (Islam: OR = 0.25; 95%CI = 0.09-0.65) for maternal cannabis use during pregnancy. Additionally, lower educational level determined continued cannabis use in ever-users (OR = 3.22; 95%CI = 1.54-6.74). Conclusions: Our results showed that multiple demographic, emotional and social characteristics were associated with maternal cannabis use. These characteristics should be considered when investigating offspring exposed to cannabis in utero, as they may play an important role in mother-child interaction and child development.

What is spared by fetal brain-sparing? Fetal circulatory redistribution and behavioral problems in the general population (Article)

2008-11-01T00:00:00Z

Intrauterine growth restriction has been linked to infant behavioral problems. While typically only birth weight is examined, here the authors assessed fetal circulatory redistribution, also called the "brain-sparing effect," which is a fetal adaptive reaction to placental insufficiency. They aimed to investigate whether fetal circulatory redistribution protects against behavioral problems. Within the Generation R Study (Rotterdam, the Netherlands, 2003-2007), fetal circulation variables for the umbilical artery and the middle and anterior cerebral arteries were assessed with Doppler ultrasound in late pregnancy. Ratios between placental resistance and cerebral resistance were related to behavioral problems, as measured by the Child Behavior Checklist, in 935 toddlers aged 18 months. The umbilical/anterior cerebral ratio was associated with the Total Problems summary score from the Child Behavior Checklist (per standard-deviation increase, odds ratio = 1.2, 95% confidence interval: 1.0, 1.5). Children with higher umbilical/anterior cerebral ratios had higher risks of internalizing problems, emotional reactivity, somatic complaints, and attention problems. A high umbilical/middle cerebral ratio was related to higher scores on the Internalizing and Somatic Complaints scales. The authors conclude that infants with circulatory redistribution in gestation are more likely to have behavioral problems. This suggests that "brain-sparing" does not completely spare the brain and indicates underlying pathology with consequences for later behavior.

Long sleep duration is associated with serum cholesterol in the elderly: The rotterdam study (Article)

2008-11-01T00:00:00Z

Objective: Epidemiological studies have repeatedly found increased mortality associated with both habitual short and long sleep duration. The mechanisms behind these associations are unclear. We investigated whether objectively measured sleep duration, time in bed, and sleep fragmentation were associated with total cholesterol and high density lipoprotein (HDL) cholesterol in community-dwelling elderly. Methods: This cross-sectional study was conducted among 768 participants of the Rotterdam Study, aged 57 to 97 years. Sleep parameters were assessed with actigraphy, a validated method that infers wakefulness and sleep from arm movement. Cholesterol levels in serum were determined in fasting blood samples. All regression analyses were adjusted for age, gender, body mass index, smoking, depressive symptoms, and heart failure. Results: Sleep duration was positively associated with total cholesterol level: β = 0.11 (95% confidence interval = 0.03 0.18) mmol/l per hour of sleep. Persons who slept longer, and spent more time in bed, also had a higher total/HDL cholesterol ratio. A less fragmented sleep was also associated with higher total cholesterol. Some of these associations showed significant interactions with age. The association between time in bed and total/HDL ratio was mainly driven by persons aged < 65, whereas the relationship between sleep fragmentation and total cholesterol level was most prominent in persons aged ≥70. Conclusions: A longer sleep duration was related to higher total cholesterol level and a higher total/HDL cholesterol ratio. Two separate mechanisms, a longer time in bed and sleep fragmentation, seem to explain these associations in different age categories. Copyright

Does gestational duration within the normal range predict infant neuromotor development? (Article)

2008-10-01T00:00:00Z

Aim: To examine the extent to which infant neuromotor development is determined by gestational duration and birth weight within the normal range. Methods: The study was embedded within the Generation R Study, a population-based cohort in Rotterdam, the Netherlands. An adapted version of Touwen's Neurodevelopmental Examination was used to assess 3224 infants (1576 males and 1648 females) at corrected ages between 9 and 15 weeks. Non-optimal neuromotor development was defined as a score in the highest tertile. Results: Infant neuromotor development was significantly affected by gestational duration (odds ratio 0.8, 95% confidence interval 0.7;0.8). Adding a quadratic term of gestational duration to the model revealed a highly significant curvilinear association between gestational duration and neuromotor development; after adjusting for post-conceptional age this was still significant. Although babies with a 1 kg lower birth weight had a 30% higher risk of non-optimal neuromotor development, this association disappeared after adjustment for post-conceptional age. Conclusions: Our findings indicate that differences in infant neuromotor development can be explained even by variations in gestational duration within the normal range. If an infant is found to have minor neuromotor delays, account should be taken of this.

Salivary cortisol is related to atherosclerosis of carotid arteries (Article)

2008-10-01T00:00:00Z

Background: Dysregulation of the hypothalamic-pituitary-adrenal axis has been suggested as an independent risk factor for ischemic heart disease. The aim of our study was to evaluate whether two markers of the hypothalamic-pituitary- adrenal axis activity, the level of salivary cortisol and the diurnal salivary cortisol pattern, are associated with atherosclerosis of the carotid arteries in an elderly population. Methods and Results: A total of 1866 participants of the Rotterdam Study, a population-based cohort study in the elderly, provided four salivary cortisol samples throughout 1 d, and underwent ultrasonography to examine the presence of plaques in the common, internal, and bifurcation sites of both carotid arteries. Two summary measures of the separate cortisol values were computed: area under the curve (AUC), which is a measure of total cortisol exposure while awake; and the slope, which is a measure of diurnal cortisol decline. Results: Total cortisol exposure while awake (AUC) was associated with higher plaque scores (β = 0.08 per SD of AUC, 95% confidence interval 0.00-0.16; P = 0.04) in a fully adjusted linear regression model. Persons with an AUC in the highest tertile had a higher number of plaques of carotid arteries compared with those in the lowest tertile (3.08 vs. 2.80, 95% confidence interval of difference 0.09-0.48; P = 0.005). There was no relation between diurnal cortisol decline and plaque score. Conclusion: Our results support the hypothesis that increased total cortisol exposure is independently associated with atherosclerosis of the carotid arteries. Copyright

Urinary metabolite concentrations of organophosphorous pesticides, bisphenol A, and phthalates among pregnant women in Rotterdam, the Netherlands: The Generation R study (Article)

2008-09-05T00:00:00Z

Concern about potential health impacts of low-level exposures to organophosphorus (OP) pesticides, bisphenol A (BPA), and phthalates among the general population is increasing. We measured levels of six dialkyl phosphate (DAP) metabolites of OP pesticides, a chlorpyrifos-specific metabolite (3,5,6-trichloro-2-pyridinol, TCPy), BPA, and 14 phthalate metabolites in urine samples of 100 pregnant women from the Generation R study, the Netherlands. The unadjusted and creatinine-adjusted concentrations were reported, and compared to National Health and Nutrition Examination Survey and other studies. In general, these metabolites were detectable in the urine of the women from the Generation R study and compared with other groups, they had relatively high-level exposures to OP pesticides and several phthalates but similar exposure to BPA. The median concentrations of total dimethyl (DM) metabolites was 264.0 nmol/g creatinine (Cr) and of total DAP was 316.0 nmol/g Cr. The median concentration of mono-ethyl phthalate (MEP) was 222.0 μg/g Cr; the median concentrations of mono-isobutyl phthalate (MiBP) and mono-n-butyl phthalate (MnBP) were above 50 μg/g Cr. The median concentrations of the three secondary metabolites of di-2-ethylhexyl phthalate (DEHP) were greater than 20 μg/g Cr. The data indicate that the Generation R study population provides a wide distribution of selected environmental exposures. Reasons for the relatively high levels and possible health effects need investigation.

Depressive symptoms and risk of stroke: The Rotterdam Study (Article)

2008-09-01T00:00:00Z

Background: Previous studies that have assessed whether the presence of depressive symptoms predisposes to stroke in the general elderly population have been contradictory. Moreover, they did not distinguish between men and women and did not perform psychiatric workups in those with depressive symptoms. This study examines the association between depressive symptoms, depressive disorder and the risk of stroke in the general population. Methods: This prospective population based cohort study included 4424 participants from the third Rotterdam Study Survey (1997-1999) who, at that time, were ≥61 years of age and free from stroke. Depressive symptoms were assessed using the Centre for Epidemiological Studies Depression Scale (CESD) and considered present if the CESD score was ≥16. Participants with depressive symptoms had a diagnostic interview for depressive disorder. Follow-up was complete until 1 January 2005. Data were analysed using Cox proportional hazards models with adjustment for relevant confounders. Results: Men with depressive symptoms (n = 73) were at increased risk of stroke (adjusted hazard ratio (HR) 2.17; 95% CI 1.11 to 4.23) and ischaemic stroke (adjusted HR 3.21; 95% CI 1.62 to 6.38). These associations were at least partly attributable to men who reported depressive symptoms but who did not fulfil Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV diagnostic criteria for depressive disorder (n = 32): they had a very high risk of stroke (adjusted HR 2.70; 95% CI 1.15 to 6.33) and ischaemic stroke (adjusted HR 4.01; 95% CI 1.68 to 9.57). In women there was no association between presence of depressive symptoms and risk of stroke. Conclusions: Presence of depressive symptoms is a strong risk factor for stroke in men but not in women.

Disagreement between subjective and actigraphic measures of sleep duration in a population-based study of elderly persons (Article)

2008-09-01T00:00:00Z

Sleep duration is an important concept in epidemiological studies. It characterizes a night's sleep or a person's sleep pattern, and is associated with numerous health outcomes. In most large studies, sleep duration is assessed with questionnaires or sleep diaries. As an alternative, actigraphy may be used, as it objectively measures sleep parameters and is feasible in large studies. However, actigraphy and sleep diaries may not measure exactly the same phenomenon. Our study aims to determine disagreement between actigraphic and diary estimates of sleep duration, and to investigate possible determinants of this disagreement. This investigation was embedded in the population-based Rotterdam Study. The study population consisted of 969 community-dwelling participants aged 57-97 years. Participants wore an actigraph and kept a sleep diary for, on average, six consecutive nights. Both measures were used to determine total sleep time (TST). In 34% of the participants, the estimated TST in the sleep diaries deviated more than 1 h from actigraphically measured TST. The level of disagreement between diary and actigraphic measures decreased with subjective and actigraphic measures of sleep quality, and increased with male gender, poor cognitive function and functional disability. Actigraphically measured poor sleep was often accompanied by longer subjective estimates of TST, whereas subjectively poor sleepers tended to report shorter TST in their diaries than was measured with actigraphy. We recommend, whenever possible, to use multiple measures of sleep duration, to perform analyses with both, and to examine the consistency of the results over assessment methods.

Cerebrovascular risk factors and incident depression in community-dwelling elderly (Article)

2008-08-01T00:00:00Z

Objective: The 'vascular depression' hypothesis suggests that late-life depression results from vascular brain damage. We studied the longitudinal association between cerebrovascular risk factors and incident depression in a large population-based study. Method: Two thousand nine hundred and thirty-one persons with the age of ≥61 years were followed up. Data on a comprehensive set of cerebrovascular risk factors were collected at baseline. Participants received a psychiatric assessment 5 years later to establish DSM-IV diagnoses. Results: Only current smoking and antihypertensive drug use were independently associated with incident depressive symptoms. Diabetes mellitus and the Framingham stroke risk score were related to incident depressive disorder. No relation with depression was observed for cholesterol, diastolic and systolic blood pressure, history of cardiovascular disease, atrial fibrillation, left ventricular hypertrophy or the use of statins and anticoagulants. Conclusion: These results moderately support the 'vascular depression' hypothesis. Copyright

Actigraphic sleep duration and fragmentation are related to obesity in the elderly: The Rotterdam Study (Article)

2008-07-01T00:00:00Z

Objective: The epidemiological evidence for the association between sleep duration and obesity in the elderly is inconsistent and has not been investigated with objective measures. Furthermore, the role of sleep fragmentation in this relationship is unknown. Our aim was to investigate the association of sleep measures with body mass index (BMI) and obesity in a normal elderly population. Design: Cross-sectional study. Subjects: A total of 983 community-dwelling elderly (mean age 68.4±6.9 years, range, 57-97). Measurements: Weight and height were measured, and sleep duration and fragmentation were assessed with on average six nights of actigraphy. Results: A quadratic model adequately described the association between continuous measures of sleep duration and BMI. Actigraphic sleep duration had a significant U-shaped relationship with BMI (β of quadratic term=0.30, 95% confidence interval (CI): 0.08, 0.52). Both short sleepers (<5 h: OR, 2.76 (95% CI: 1.38, 5.49), 5 to <6 h: OR, 1.97 (95% CI: 1.26, 3.08)) and long sleepers (≥8 h: OR, 2.93 (95% CI: 1.39, 6.16)) were more likely to be obese, compared to participants who slept 7 to <8 h. BMI increased with 0.59 kg m-2per standard deviation of sleep fragmentation (95% CI: 0.34, 0.84). After adjustment for sleep fragmentation, the association between short sleep and obesity was no longer significant. Exclusion of participants with probable sleep apnea only marginally changed these associations. Self-reported habitual sleep duration was not associated with BMI or obesity. Conclusions: Sleep duration, as measured with actigraphy, had a U-shaped relationship with BMI and obesity in an elderly population. A highly fragmented sleep is associated with a higher BMI and a higher risk of obesity, and may explain why short sleep is related to obesity. To preclude bias that can be introduced by self-report measures of sleep duration, using multiple measures of sleep parameters is recommended in future research.

Explaining Educational Inequalities in Preterm Birth. The Generation R Study (Article)

2008-06-18T00:00:00Z

BACKGROUND: Although a low socioeconomic status has consistently been associated with an increased risk of preterm birth, little is known about the pathways through which socioeconomic disadvantage influences preterm birth. AIM: To examine mechanisms that might underlie the association between the educational level of pregnant women as an indicator of socioeconomic status, and preterm birth. METHODS: The study was nested in a population-based cohort study in the Netherlands. Information was available for 3830 pregnant women of Dutch origin. FINDINGS: The lowest-educated pregnant women had a statistically significant higher risk of preterm birth (odds ratio (OR) = 1.89 (95% CI 1.28 to 2.80)) than the highest educated women. This increased OR was reduced by up to 22% after separate adjustment for age, height, preeclampsia, intrauterine growth restriction, financial concerns, long-lasting difficulties, psychopathology, smoking habits, alcohol consumption, and body mass index (BMI) of the pregnant women. Joint adjustment for these variables resulted in a reduction of 89% of the increased risk of preterm birth among low-educated pregnant women (fully adjusted OR = 1.10 (95% CI 0.66 to 1.84)). CONCLUSIONS: Pregnant women with a low educational level have a nearly twofold higher risk of preterm birth than women with a high educational level. This elevated risk could largely be explained by pregnancy characteristics, indicators of psychosocial well-being, and lifestyle habits. Apparently, educational inequalities in preterm birth go together with an accumulation of multiple adverse circumstances among women with a low education. A number of explanatory mechanisms unravelled in the present study seem to be modifiable by intervention programmes.

HPA-axis activity as a predictor of future disruptive behaviors in young adolescents (Article)

2008-05-01T00:00:00Z

Low HPA-axis activity has been proposed as a risk factor for disruptive behaviors. However longitudinal data on this topic are practically lacking. In the present study we investigated if low HPA-axis activity predicted future disruptive behaviors. We included 1,399 boys and girls from the Dutch general population, initially aged 10-12 years. At the first assessment, basal cortisol levels were assessed. At the first assessment and at follow-up 2 years later disruptive behaviors were assessed with parent and self-report questionnaires. The results suggest that the association between low cortisol levels at 8.00 p.m. and future disruptive behaviors according to the parents was only present for boys. More importantly however, the results suggest that low HPA-axis activity is not a good predictor for disruptive behaviors, but could be valuable to identify those with a poor prognosis, once disruptive behaviors are present in preadolescence. Copyright

Determinants of chronic benzodiazepine use in the elderly: A longitudinal study (Article)

2008-04-01T00:00:00Z

AIMS: The risk of adverse events due to chronic benzodiazepine use is high in the elderly. Clinicians need to be able to identify those persons who are at risk of chronic benzodiazepine use, but little is known about the determinants. This study determined social and health related factors that predict new-onset chronic benzodiazepine use in community-dwelling elderly. METHODS: This study was embedded in an ongoing cohort study among 5364 persons aged ≥57 years. Drug-dispensing medication records were available for the period between 1991 and 2003. We defined chronic benzodiazepine use as use during at least 180 days in a period of 365 consecutive days. The association of various social, psychiatric and somatic variables with new-onset chronic benzodiazepine use was studied with a Cox proportional hazards analysis. RESULTS: Symptoms of depression, hypertension, pain related joint complaints and the perception of poor physical health predicted new-onset chronic use. In the subsample of participants who had filled at least one prescription in the follow-up period, of these variables only pain related joint complaints increased the risk of new-onset chronic use. Living alone protected against chronic benzodiazepine use. CONCLUSIONS: The elderly with poor mental and physical health are at an increased risk of chronic benzodiazepine use. Living alone was found to decrease the risk of chronic use, which suggests that social factors may determine drug usage patterns. Very few characteristics predicted chronic benzodiazepine use once patients had received their first prescription. For clinicians, identification of patients at high risk is therefore not straightforward.

Foetal growth determines cerebral ventricular volume in infants. The Generation R Study (Article)

2008-02-15T00:00:00Z

The cerebral ventricular system is a marker of brain development and a predictor of neurodevelopmental outcome. In premature or dysmature neonates, neuroanatomical structures including the ventricular system appear to be altered. The present study aims to provide information on the association between foetal growth and neonatal cerebral ventricular size in the normal population. Within the Generation R Study, a population-based cohort study, we used three-dimensional cranial ultrasound to determine lateral ventricular volume in 778 term infants aged 4-12 weeks. Foetal growth characteristics were repeatedly measured in early, mid- and late pregnancy and analysed in relation to ventricular volume divided by head circumference. Results revealed positive associations between foetal head circumference in late pregnancy and log-transformed ventricular volume (β = 0.077, 95% confidence interval (0.017; 0.136), equivalent to a 7.7% increase in ventricular volume per standard deviation of head circumference). Similarly, in a per week-longer gestational duration, ventricular volume in infancy was 6.0% larger. Multilevel modelling demonstrated that reduced growth of foetal head circumference and biparietal diameter during pregnancy were associated with decreased ventricular volume in infancy. In conclusion, foetal maturation is positively associated to cerebral ventricular size in term infants. Larger ventricular size in term infants needs to be distinguished from ventricular enlargement due to intraventricular haemorrhage or white matter damage in premature or dysmature infants. Moreover, the naturally occurring enlargement of ventricles during infancy should be considered in interpreting reports on increased ventricular volumes in several neuropsychiatric disorders.

Angiotensinogen M235T polymorphism and symptoms of depression in a population-based study and a family-based study. (Article)

2008-01-01T00:00:00Z

BACKGROUND: Evidence suggests that the angiotensinogen (AGT) gene is involved in depression. The aim of this paper is to examine the association between the AGT M235T polymorphism and symptoms of depression in two independent populations; a population-based study, and a family-based study. METHODS: Symptoms of depression were scored using the Centre of Epidemiological Studies Depression Scale (CES-D) and compared between the MM, MT, and TT genotype groups. The extent to which AGT M235T explains the heritability of the scores was examined using a variance components analysis. RESULTS: A significant relationship between the AGT M235T polymorphism and CES-D scores was found in men in both populations. The heritability estimate was 32%. The AGT genotype contributed to 1% of the total variance of the CES-D scores. CONCLUSION: Our findings suggest that the AGT gene is involved in the aetiology of symptoms of depression in men.

The Generation R Study Biobank: A resource for epidemiological studies in children and their parents (Article)

2007-12-01T00:00:00Z

The Generation R Study is a population-based prospective cohort study from fetal life until young adulthood. The study is designed to identify early environmental and genetic causes of normal and abnormal growth, development and health from fetal life until young adulthood. In total, 9,778 mothers were enrolled in the study. Prenatal and postnatal data collection is conducted by physical examinations, questionnaires, interviews, ultrasound examinations and biological samples. Major efforts have been conducted for collecting biological specimens including DNA, blood for phenotypes and urine samples. In this paper, the collection, processing and storage of these biological specimens are described. Together with detailed phenotype measurements, these biological specimens form a unique resource for epidemiological studies focused on environmental exposures, genetic determinants and their interactions in relation to growth, health and development from fetal life onwards.

The Rotterdam Study: Objectives and design update (Article)

2007-11-01T00:00:00Z

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in the Netherlands. The study targets cardiovascular, neurological, ophthalmological and endocrine diseases. As of 2008 about 15,000 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in some 600 research articles and reports (see http://www.epib.nl/rotterdamstudy ). This article gives the reasons for the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.

Disruptive behaviors and HPA-axis activity in young adolescent boys and girls from the general population (Article)

2007-10-01T00:00:00Z

It is important to investigate associations between biological factors and disruptive behaviors in children and adolescents. Antisocial, aggressive, and criminal behaviors in adults often begin early in life. Disruptive behaviors are often thought to be associated with low activity of the hypothalamic-pituitary-adrenal (HPA) axis. Cortisol, the end-product of this axis, can be measured to investigate HPA-axis activity. Previous studies on this topic concerned clinical or high risk samples. The aim of the present study was to investigate to which extent HPA-axis functioning plays a role in disruptive behaviors in pre-adolescents from the general population. One thousand seven hundred and sixty eight 10- to 12-year-olds from the Dutch general population were investigated. Disruptive behaviors were assessed with the Child Behavior Checklist, the Youth Self-Report, and the Antisocial Behavior Questionnaire. Baseline morning and evening salivary cortisol levels were assessed. Unexpectedly, small associations were found between disruptive behaviors, including attention problems, and higher cortisol levels. However, all effect sizes of significant effects were very small. Our study indicated that HPA-axis functioning may be more relevant in clinical or high risk samples than at the general population level. The association between HPA-axis functioning and attention problems, that has gotten less attention than that with aggressive or delinquent behaviors, requires further research. Furthermore, because effect sizes were relatively small, it can be concluded that, in pre-adolescence, the measures of baseline HPA-axis functioning that were used for the present study can not be used as biological markers for disruptive behaviors.

Sleep duration and hypertension are not associated in the elderly (Article)

2007-09-01T00:00:00Z

Several large studies have shown that both short and long average sleep durations increase the risk of hypertension in adults. We investigated whether sleep duration is also associated with hypertension in the elderly. This cross-sectional study was conducted in 5058 participants of the population-based Rotterdam Study, aged 58 to 98 years. Blood pressure was measured at the research center. Hypertension was defined as a systolic blood pressure of ≥160 mm Hg and/or a diastolic blood pressure of ≥100 mm Hg or current use of antihypertensive medication. In all of the participants, sleep duration was assessed by self-report. In a subsample of 975 subjects, it was additionally measured with actigraphy, a validated method that infers wakefulness and sleep from the presence or absence of limb movement. After adjustment for age and gender and additionally for body mass index, smoking, depressive symptoms, sleep medication use, diabetes mellitus, myocardial infarction, and stroke, none of the odds ratios (varying from 0.54; 95% CI: 0.27 to 1.08; to 1.19; 95% CI: 0.89 to 1.58) reflected a significant association between sleep duration and hypertension, whether measured by self-report or actigraphy. This study strongly suggests that sleep duration is not associated with hypertension in the elderly.

Effects of maternal smoking in pregnancy on prenatal brain development. The generation R study (Article)

2007-02-01T00:00:00Z

Nicotine, as has been shown in animal studies, is a neuroteratogen, even in concentrations that do not cause growth retardation. In humans, there is only indirect evidence for negative influences of nicotine on brain development from studies on the association between maternal smoking in pregnancy and behavioural and cognitive development in the offspring. We investigated the associations of maternal smoking in pregnancy with foetal head growth characteristics in 7042 pregnant women. This study was embedded in the Generation R Study, a population-based prospective cohort study from foetal life until adulthood. Maternal smoking was assessed by questionnaires in early, mid- and late pregnancy. Head circumference, biparietal diameter, transcerebellar diameter and atrial width of lateral ventricles were repeatedly measured by ultrasound. When mothers continued to smoke during pregnancy, foetal head circumference showed a growth reduction of 0.13 mm [95% confidence interval (CI): -0.18, -0.09] per week compared to foetuses of mothers who never smoked during pregnancy. Biparietal diameter of foetuses with smoking mothers grew 0.04 mm (95% CI: -0.05, -0.02) less per week than that of foetuses of nonsmoking mothers. Atrial width of lateral ventricle was 0.12 mm (95% CI: -0.22, -0.02) smaller and transcerebellar diameter was 0.08 mm (95% CI: -0.15, -0.00) smaller if mothers smoked, but growth per week of these characteristics was not affected by maternal smoking in pregnancy. In conclusion, continuing to smoke during pregnancy leads to reduced growth of the foetal head. Further research should focus on the causal pathway from prenatal cigarette exposure via brain development to behavioural and cognitive functions.

Relationship between atherosclerosis and late-life depression: the Rotterdam Study. (Article)

2004-04-01T00:00:00Z

CONTEXT: Depression in late life has been associated with vascular abnormalities. Several studies have demonstrated that persons with brain infarcts are more likely to have depressive disorders. Furthermore, depression is related to the subsequent development of ischemic heart disease. OBJECTIVE: To investigate the relationship between atherosclerosis at different locations and depression in the general population. DESIGN: Cross-sectional population-based study. SETTING: The Rotterdam Study, a population-based cohort study. PARTICIPANTS: In 4019 men and women 60 years and older, we assessed atherosclerosis at different locations, including common carotid intima-media thickness, plaques in the carotid arteries, the ankle-brachial blood pressure index, and aortic atherosclerosis. An overall measure of extracoronary atherosclerosis was obtained in 3747 persons by computing the principal component of these extracoronary atherosclerosis measures. In a subgroup of 1986 persons, we additionally measured coronary calcifications. MAIN OUTCOME MEASURE: All subjects were screened for depressive symptoms. Screen-positive subjects had a psychiatric interview to diagnose depressive disorder. RESULTS: More severe extracoronary atherosclerosis was associated with a higher prevalence of depressive disorders. For every 1-standard deviation increase, the prevalence increased by 30%. Furthermore, we found a strong relationship of severe coronary and aortic calcifications with depressive disorders (odds ratio, 3.89; 95% confidence interval, 1.55-9.77; and odds ratio, 2.00; 95% confidence interval, 1.02-3.96, respectively). CONCLUSIONS: Atherosclerosis and depression are associated in the elderly. This finding is compatible with the vascular depression hypothesis. However, the cross-sectional nature of the study does not allow causal inferences. In particular, earlier depressive episodes may have contributed to the development of atherosclerosis.

Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study (Article)

2002-01-01T00:00:00Z

OBJECTIVE: The associations of vitamin B(12), folate, and homocysteine with depression were examined in a population-based study. METHOD: The authors screened 3,884 elderly people for depressive symptoms. Subjects with positive screening results had psychiatric workups. Folate, vitamin B(12), and homocysteine blood levels were compared in 278 persons with depressive symptoms, including 112 with depressive disorders, and 416 randomly selected reference subjects. Adjustments were made for age, gender, cardiovascular disease, and functional disability. RESULTS: Hyperhomocysteinemia, vitamin B(12) deficiency, and to a lesser extent, folate deficiency were all related to depressive disorders. For folate deficiency and hyperhomocysteinemia, the association with depressive disorders was substantially reduced after adjustment for functional disability and cardiovascular disease, but for vitamin B(12) this appeared independent. CONCLUSIONS: The association of vitamin B(12) and folate with depressive disorders may have different underlying mechanisms. Vitamin B(12) may be causally related to depression, whereas the relation with folate is due to physical comorbidity.

Cerebral haemodynamics and depression in the elderly (Article)

2002-01-01T00:00:00Z

BACKGROUND: Evidence from epidemiological and neuroimaging studies suggests that cerebrovascular disease is associated with depressive disorders in the elderly, but the extent to which it contributes to the pathogenesis of late life depression is unclear. OBJECTIVE: To investigate the relation between cerebral haemodynamics and depression in a population based study, using transcranial Doppler ultrasonography. METHODS: Cerebral blood flow velocity and CO2 induced vasomotor reactivity in the middle cerebral artery were measured in 2093 men and women who participated in the Rotterdam study. All subjects were screened for depressive symptoms using the Center of Epidemiological Studies Depression scale, and those with a score of 16 or over had a psychiatric work up. In a semistructured interview, diagnoses of depressive disorders according to the DSM-IV and subthreshold depressive disorder were established. Analyses of covariance controlled for age, sex, stroke, cognitive score, and cardiovascular risk factors were used to compare means of haemodynamic variables. RESULTS: Subjects with depressive symptoms had reduced blood flow velocities (mean difference, -2.9 cm/s; 95% confidence interval (CI), -5.0 to -0.8; p = 0.008) and lower vasomotor reactivity (mean difference -0.5%/kPa; 95% CI, -1.0 to -0.05; p = 0.03). Blood flow velocity was reduced most in subjects suffering from a DSM-IV depressive disorder (mean difference, -4.9 cm/s; 95% CI, -8.5 to -1.4; p = 0.006). The overall reduction in vasomotor reactivity was accounted for by subjects with subthreshold depressive disorder. CONCLUSIONS: Depression in late life is associated with cerebral haemodynamic changes that can be assessed by transcranial Doppler ultrasonography. The observed reduction in cerebral blood flow velocity could be a result of reduced demand in more seriously depressed cases with a DSM-IV disorder, whereas reduced CO2 induced cerebral vasomotor reactivity is a possible causal factor for subthreshold depressive disorder.