Antony Ambler

Persistent cannabis users show neuropsychological decline from childhood to midlife

Recent reports show that fewer adolescents believe that regular cannabis use is harmful to health. Concomitantly, adolescents are initiating cannabis use at younger ages, and more adolescents are using cannabis on a daily basis. The purpose of the present study was to test the association between persistent cannabis use and neuropsychological decline and determine whether decline is concentrated among adolescent-onset cannabis users. Participants were members of the Dunedin Study, a prospective study of a birth cohort of 1,037 individuals followed from birth (1972/1973) to age 38 y. Cannabis use was ascertained in interviews at ages 18, 21, 26, 32, and 38 y. Neuropsychological testing was conducted at age 13 y, before initiation of cannabis use, and again at age 38 y, after a pattern of persistent cannabis use had developed. Persistent cannabis use was associated with neuropsychological decline broadly across domains of functioning, even after controlling for years of education. Informants also reported noticing more cognitive problems for persistent cannabis users. Impairment was concentrated among adolescent-onset cannabis users, with more persistent use associated with greater decline. Further, cessation of cannabis use did not fully restore neuropsychological functioning among adolescent-onset cannabis users. Findings are suggestive of a neurotoxic effect of cannabis on the adolescent brain and highlight the importance of prevention and policy efforts targeting adolescents.

ELEVATED INFLAMMATION LEVELS IN DEPRESSED ADULTS WITH A HISTORY OF CHILDHOOD MALTREATMENT

CONTEXT The association between depression and inflammation is inconsistent across research samples. OBJECTIVE To test whether a history of childhood maltreatment could identify a subgroup of depressed individuals with elevated inflammation levels, thus helping to explain previous inconsistencies. DESIGN Prospective longitudinal cohort study. SETTING New Zealand. PARTICIPANTS A representative birth cohort of 1000 individuals was followed up to age 32 years as part of the Dunedin Multidisciplinary Health and Development Study. Study members were assessed for history of childhood maltreatment and current depression. MAIN OUTCOME MEASURES Inflammation was assessed using a clinically relevant categorical measure of high-sensitivity C-reactive protein (>3 mg/L) and a dimensional inflammation factor indexing the shared variance of continuous measures of high-sensitivity C-reactive protein, fibrinogen, and white blood cells. RESULTS Although depression was associated with high levels of high-sensitivity C-reactive protein (relative risk,1.45; 95% confidence interval,1.06-1.99), this association was significantly attenuated and no longer significant when the effect of childhood maltreatment was taken into account. Individuals with current depression and a history of childhood maltreatment were more likely to have high levels of high-sensitivity C-reactive protein compared with control subjects (n = 27; relative risk, 2.07; 95% confidence interval, 1.23-3.47). In contrast, individuals with current depression only had a nonsignificant elevation in risk (n = 109; relative risk, 1.40; 95% confidence interval, 0.97-2.01). Results were generalizable to the inflammation factor. The elevated inflammation levels in individuals who were both depressed and maltreated were not explained by correlated risk factors such as depression recurrence, low socioeconomic status in childhood or adulthood, poor health, or smoking. CONCLUSIONS A history of childhood maltreatment contributes to the co-occurrence of depression and inflammation. Information about experiences of childhood maltreatment may help to identify depressed individuals with elevated inflammation levels and, thus, at greater risk of cardiovascular disease.

A longitudinal study of epigenetic variation in twins.

DNA methylation is a key epigenetic mechanism involved in the developmental regulation of gene expression. Alterations in DNA methylation are established contributors to inter-individual phenotypic variation and have been associated with disease susceptibility. The degree to which changes in loci-specific DNA methylation are under the influence of heritable and environmental factors is largely unknown. In this study, we quantitatively measured DNA methylation across the promoter regions of the dopamine receptor 4 gene (DRD4), the serotonin transporter gene (SLC6A4/SERT) and the X-linked monoamine oxidase A gene (MAOA) using DNA sampled at both ages 5 and 10 years in 46 MZ twin-pairs and 45 DZ twin-pairs (total n=182). Our data suggest that DNA methylation differences are apparent already in early childhood, even between genetically identical individuals, and that individual differences in methylation are not stable over time. Our longitudinal-developmental study suggests that environmental influences are important factors accounting for interindividual DNA methylation differences, and that these influences differ across the genome. The observation of dynamic changes in DNA methylation over time highlights the importance of longitudinal research designs for epigenetic research.

Etiological and clinical features of childhood psychotic symptoms: results from a birth cohort

CONTEXT It has been reported that childhood psychotic symptoms are common in the general population and may signal neurodevelopmental processes that lead to schizophrenia. However, it is not clear whether these symptoms are associated with the same extensive risk factors established for adult schizophrenia. OBJECTIVE To examine the construct validity of childrens self-reported psychotic symptoms by testing whether these symptoms share the risk factors and clinical features of adult schizophrenia. DESIGN Prospective, longitudinal cohort study of a nationally representative birth cohort in Great Britain. PARTICIPANTS A total of 2232 twelve-year-old children followed up since age 5 years (retention, 96%). Main Outcome Measure Childrens self-reported hallucinations and delusions. RESULTS Childrens psychotic symptoms are familial and heritable and are associated with social risk factors (eg, urbanicity); cognitive impairments at age 5; home-rearing risk factors (eg, maternal expressed emotion); behavioral, emotional, and educational problems at age 5; and comorbid conditions, including self-harm. CONCLUSIONS The results provide a comprehensive picture of the construct validity of childrens self-reported psychotic symptoms. For researchers, the findings indicate that children who have psychotic symptoms can be recruited for neuroscience research to determine the pathogenesis of schizophrenia. For clinicians, the findings indicate that psychotic symptoms in childhood are often a marker of an impaired developmental process and should be actively assessed.

A Discordant Monozygotic Twin Design Shows Blunted Cortisol Reactivity Among Bullied Children

OBJECTIVE Childhood adverse experiences are known to engender persistent changes in stress-related systems and brain structures involved in mood, cognition, and behavior in animal models. Uncertainty remains about the causal effect of early stressful experiences on physiological response to stress in human beings, as the impact of these experiences has rarely been investigated while controlling for both genetic and shared environmental influences. METHOD We tested whether bullying victimization, a repeated adverse experience in childhood, influences cortisol responses to a psychosocial stress test (PST) using a discordant monozygotic (MZ) twin design. Thirty pairs (43.3% males) of 12-year-old MZ twins discordant for bullying victimization were identified in the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative 1994-1995 cohort of families with twins. RESULTS Bullied and nonbullied MZ twins showed distinct patterns of cortisol secretion after the PST. Specifically, bullied twins exhibited a blunted cortisol response compared with their nonbullied MZ co-twins, who showed the expected increase. This difference in cortisol response to stress could not be attributed to childrens genetic makeup, their familial environments, pre-existing and concomitant individual factors, or the perception of stress and emotional response to the PST. CONCLUSION Results from this natural experiment provide support for a causal effect of adverse childhood experiences on the neuroendocrine response to stress.

Mothers and Children as Informants of Bullying Victimization: Results from an Epidemiological Cohort of Children

Stressful events early in life can affect children’s mental health problems. Collecting valid and reliable information about children’s bad experiences is important for research and clinical purposes. This study aimed to (1) investigate whether mothers and children provide valid reports of bullying victimization, (2) examine the inter-rater reliability between the two informants, (3) test the predictive validity of their reports with children’s emotional and behavioral problems and (4) compare the genetic and environmental etiology of bullying victimization as reported by mothers and children. We assessed bullying victimization in the Environmental-Risk (E-Risk) Longitudinal Twin Study, a nationally-representative sample of 1,116 families with twins. We collected reports from mothers and children during private interviews, including detailed narratives. Findings showed that we can rely on mothers and children as informants of bullying victimization: both informants provided information which adhered to the definition of bullying as involving repeated hurtful actions between peers in the presence of a power imbalance. Although mothers and children modestly agreed with each other about who was bullied during primary and secondary school, reports of bullying victimization from both informants were similarly associated with children’s emotional and behavioral problems and provided similar estimates of genetic and environmental influences. Findings from this study suggest that collecting information from multiple informants is ideal to capture all instances of bullying victimization. However, in the absence of child self-reports, mothers can be considered as a viable alternative, and vice versa.

Childhood to Early-Midlife Systolic Blood Pressure Trajectories Early-Life Predictors, Effect Modifiers, and Adult Cardiovascular Outcomes

Previous studies examining blood pressure change over time have modeled an average population trajectory. Recent research among older adults suggests there may be subgroups with different blood pressure trajectories. Identifying subgroups at risk of developing adult hypertension early in life can inform effective risk reduction efforts. We sought to identify different systolic blood pressure trajectories from childhood, their correlated risk factors, and early-midlife cardiovascular outcomes. Blood pressure data at ages 7, 11, 18, 26, 32, and 38 years from a longitudinal, representative birth cohort study (n=975) were used to identify 4 distinct trajectory groups via group-based trajectory modeling: normal (21.8%), high-normal (43.3%), prehypertensive (31.6%), and hypertensive (4.2%). The categories refer to blood pressure beginning at the age of 7 years and most recently measured at the age of 38 years. Family history of high blood pressure (odds ratio [OR], 43.23; 95% confidence interval [CI], 5.27–354.65), male sex (OR, 109.48; 95% CI, 26.82–446.96), being first born (OR, 2.5; 95% CI, 1.00–8.69) and low birth weight (OR, 2.79; 95% CI, 2.49–3.09) were associated with hypertensive group membership (compared with the normal group). Higher body mass index and cigarette smoking resulted in increasing blood pressure across trajectories, particularly for the higher blood pressure groups. Prehypertensive and hypertensive trajectory groups had worse cardiovascular outcomes by early midlife. Harmful blood pressure trajectories are identifiable in childhood, associated with both antecedent and modifiable risk factors over time, and predict adult cardiovascular disease risk. Early detection and subsequent targeted prevention and intervention may reduce the lifecourse burden associated with higher blood pressure. # Novelty and Significance {#article-title-34}Previous studies examining blood pressure change over time have modeled an average population trajectory. Recent research among older adults suggests there may be subgroups with different blood pressure trajectories. Identifying subgroups at risk of developing adult hypertension early in life can inform effective risk reduction efforts. We sought to identify different systolic blood pressure trajectories from childhood, their correlated risk factors, and early-midlife cardiovascular outcomes. Blood pressure data at ages 7, 11, 18, 26, 32, and 38 years from a longitudinal, representative birth cohort study (n=975) were used to identify 4 distinct trajectory groups via group-based trajectory modeling: normal (21.8%), high-normal (43.3%), prehypertensive (31.6%), and hypertensive (4.2%). The categories refer to blood pressure beginning at the age of 7 years and most recently measured at the age of 38 years. Family history of high blood pressure (odds ratio [OR], 43.23; 95% confidence interval [CI], 5.27–354.65), male sex (OR, 109.48; 95% CI, 26.82–446.96), being first born (OR, 2.5; 95% CI, 1.00–8.69) and low birth weight (OR, 2.79; 95% CI, 2.49–3.09) were associated with hypertensive group membership (compared with the normal group). Higher body mass index and cigarette smoking resulted in increasing blood pressure across trajectories, particularly for the higher blood pressure groups. Prehypertensive and hypertensive trajectory groups had worse cardiovascular outcomes by early midlife. Harmful blood pressure trajectories are identifiable in childhood, associated with both antecedent and modifiable risk factors over time, and predict adult cardiovascular disease risk. Early detection and subsequent targeted prevention and intervention may reduce the lifecourse burden associated with higher blood pressure.

Perinatal Complications and Aging Indicators by Midlife

BACKGROUND: Perinatal complications predict increased risk for morbidity and early mortality. Evidence of perinatal programming of adult mortality raises the question of what mechanisms embed this long-term effect. We tested a hypothesis related to the theory of developmental origins of health and disease: that perinatal complications assessed at birth predict indicators of accelerated aging by midlife. METHODS: Perinatal complications, including both maternal and neonatal complications, were assessed in the Dunedin Multidisciplinary Health and Development Study cohort (N = 1037), a 38-year, prospective longitudinal study of a representative birth cohort. Two aging indicators were assessed at age 38 years, objectively by leukocyte telomere length (TL) and subjectively by perceived facial age. RESULTS: Perinatal complications predicted both leukocyte TL (β = −0.101; 95% confidence interval, −0.169 to −0.033; P = .004) and perceived age (β = 0.097; 95% confidence interval, 0.029 to 0.165; P = .005) by midlife. We repeated analyses with controls for measures of family history and social risk that could predispose to perinatal complications and accelerated aging, and for measures of poor health taken in between birth and the age-38 follow-up. These covariates attenuated, but did not fully explain the associations observed between perinatal complications and aging indicators. CONCLUSIONS: Our findings provide support for early-life developmental programming by linking newborns’ perinatal complications to accelerated aging at midlife. We observed indications of accelerated aging “inside,” as measured by leukocyte TL, an indicator of cellular aging, and “outside,” as measured by perceived age, an indicator of declining tissue integrity. A better understanding of mechanisms underlying perinatal programming of adult aging is needed.

The Origins of Cognitive Deficits in Victimized Children: Implications for Neuroscientists and Clinicians

OBJECTIVE Individuals reporting a history of childhood violence victimization have impaired brain function. However, the clinical significance, reproducibility, and causality of these findings are disputed. The authors used data from two large cohort studies to address these research questions directly. METHOD The authors tested the association between prospectively collected measures of childhood violence victimization and cognitive functions in childhood, adolescence, and adulthood among 2,232 members of the U.K. E-Risk Study and 1,037 members of the New Zealand Dunedin Study who were followed up from birth until ages 18 and 38 years, respectively. Multiple measures of victimization and cognition were used, and comparisons were made of cognitive scores for twins discordant for victimization. RESULTS Individuals exposed to childhood victimization had pervasive impairments in clinically relevant cognitive functions, including general intelligence, executive function, processing speed, memory, perceptual reasoning, and verbal comprehension in adolescence and adulthood. However, the observed cognitive deficits in victimized individuals were largely explained by cognitive deficits that predated childhood victimization and by confounding genetic and environmental risks. CONCLUSIONS Findings from two population-representative birth cohorts totaling more than 3,000 individuals and born 20 years and 20,000 km apart suggest that the association between childhood violence victimization and later cognition is largely noncausal, in contrast to conventional interpretations. These findings support the adoption of a more circumspect approach to causal inference in the neuroscience of stress. Clinically, cognitive deficits should be conceptualized as individual risk factors for victimization as well as potential complicating features during treatment.

Social Isolation and Mental Health at Primary and Secondary School Entry: A Longitudinal Cohort Study

Objective We tested whether children who are socially isolated early in their schooling develop mental health problems in early adolescence, taking into account their mental health and family risk at school entry. Method We used data from the Environmental Risk (E-Risk) Longitudinal Twin Study, a birth cohort of 2,232 children born in England and Wales in 1994 and 1995. We measured social isolation using mothers’ and teachers’ reports at ages 5 and 12 years. We assessed mental health symptoms via mothers’ and teachers’ ratings at age 5 and self-report measures at age 12. We collected mother-reported information about the family environment when children were 5 years old. We conducted regression analyses to test concurrent and longitudinal associations between early family factors, social isolation, and mental health difficulties. Results At both primary and secondary school, children who were socially isolated experienced greater mental health difficulties. Children with behavioral problems or attention-deficit/hyperactivity disorder (ADHD) symptoms at age 5 years had an elevated risk of becoming more socially isolated at age 12. However, children who were isolated at age 5 did not have greater mental health symptoms at age 12, over and above pre-existing difficulties. Conclusion Although social isolation and mental health problems co-occur in childhood, early isolation does not predict worse mental health problems later on. However, children who exhibit problematic behaviors may struggle to cope with the social challenges that accompany their progression through the early school years.