Pace of Aging in older adults matters for healthspan and lifespan.

As societies age, policy makers need tools to understand how demographic aging will affect population health and to develop programs to increase healthspan. The current metrics used for policy analysis do not distinguish differences caused by early-life factors, such as prenatal care and nutrition, from those caused by ongoing changes in people's bodies due to aging. Here we introduce an adapted Pace of Aging method designed to quantify differences between individuals and populations in the speed of aging-related health declines. The adapted Pace of Aging method, implemented in data from N=13,626 older adults in the US Health and Retirement Study, integrates longitudinal data on blood biomarkers, physical measurements, and functional tests. It reveals stark differences in rates of aging between population subgroups and demonstrates strong and consistent prospective associations with incident morbidity, disability, and mortality. Pace of Aging can advance the population science of healthy longevity.

Association between genetic and socioenvironmental risk for schizophrenia during upbringing in a UK longitudinal cohort.

BACKGROUND: Associations of socioenvironmental features like urbanicity and neighborhood deprivation with psychosis are well-established. An enduring question, however, is whether these associations are causal. Genetic confounding could occur due to downward mobility of individuals at high genetic risk for psychiatric problems into disadvantaged environments. METHODS: We examined correlations of five indices of genetic risk [polygenic risk scores (PRS) for schizophrenia and depression, maternal psychotic symptoms, family psychiatric history, and zygosity-based latent genetic risk] with multiple area-, neighborhood-, and family-level risks during upbringing. Data were from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally-representative cohort of 2232 British twins born in 1994-1995 and followed to age 18 (93% retention). Socioenvironmental risks included urbanicity, air pollution, neighborhood deprivation, neighborhood crime, neighborhood disorder, social cohesion, residential mobility, family poverty, and a cumulative environmental risk scale. At age 18, participants were privately interviewed about psychotic experiences. RESULTS: Higher genetic risk on all indices was associated with riskier environments during upbringing. For example, participants with higher schizophrenia PRS (OR = 1.19, 95% CI = 1.06-1.33), depression PRS (OR = 1.20, 95% CI = 1.08-1.34), family history (OR = 1.25, 95% CI = 1.11-1.40), and latent genetic risk (OR = 1.21, 95% CI = 1.07-1.38) had accumulated more socioenvironmental risks for schizophrenia by age 18. However, associations between socioenvironmental risks and psychotic experiences mostly remained significant after covariate adjustment for genetic risk. CONCLUSION: Genetic risk is correlated with socioenvironmental risk for schizophrenia during upbringing, but the associations between socioenvironmental risk and adolescent psychotic experiences appear, at present, to exist above and beyond this gene-environment correlation.

A risk calculator to predict adult attention-deficit/hyperactivity disorder: generation and external validation in three birth cohorts and one clinical sample.

AIM: Few personalised medicine investigations have been conducted for mental health. We aimed to generate and validate a risk tool that predicts adult attention-deficit/hyperactivity disorder (ADHD). METHODS: Using logistic regression models, we generated a risk tool in a representative population cohort (ALSPAC - UK, 5113 participants, followed from birth to age 17) using childhood clinical and sociodemographic data with internal validation. Predictors included sex, socioeconomic status, single-parent family, ADHD symptoms, comorbid disruptive disorders, childhood maltreatment, ADHD symptoms, depressive symptoms, mother's depression and intelligence quotient. The outcome was defined as a categorical diagnosis of ADHD in young adulthood without requiring age at onset criteria. We also tested Machine Learning approaches for developing the risk models: Random Forest, Stochastic Gradient Boosting and Artificial Neural Network. The risk tool was externally validated in the E-Risk cohort (UK, 2040 participants, birth to age 18), the 1993 Pelotas Birth Cohort (Brazil, 3911 participants, birth to age 18) and the MTA clinical sample (USA, 476 children with ADHD and 241 controls followed for 16 years from a minimum of 8 and a maximum of 26 years old). RESULTS: The overall prevalence of adult ADHD ranged from 8.1 to 12% in the population-based samples, and was 28.6% in the clinical sample. The internal performance of the model in the generating sample was good, with an area under the curve (AUC) for predicting adult ADHD of 0.82 (95% confidence interval (CI) 0.79-0.83). Calibration plots showed good agreement between predicted and observed event frequencies from 0 to 60% probability. In the UK birth cohort test sample, the AUC was 0.75 (95% CI 0.71-0.78). In the Brazilian birth cohort test sample, the AUC was significantly lower -0.57 (95% CI 0.54-0.60). In the clinical trial test sample, the AUC was 0.76 (95% CI 0.73-0.80). The risk model did not predict adult anxiety or major depressive disorder. Machine Learning approaches did not outperform logistic regression models. An open-source and free risk calculator was generated for clinical use and is available online at https://ufrgs.br/prodah/adhd-calculator/. CONCLUSIONS: The risk tool based on childhood characteristics specifically predicts adult ADHD in European and North-American population-based and clinical samples with comparable discrimination to commonly used clinical tools in internal medicine and higher than most previous attempts for mental and neurological disorders. However, its use in middle-income settings requires caution.

Genetics and Crime: Integrating New Genomic Discoveries Into Psychological Research About Antisocial Behavior.

Drawing on psychological and sociological theories of crime causation, we tested the hypothesis that genetic risk for low educational attainment (assessed via a genome-wide polygenic score) is associated with criminal offending. We further tested hypotheses of how polygenic risk relates to the development of antisocial behavior from childhood through adulthood. Across the Dunedin and Environmental Risk (E-Risk) birth cohorts of individuals growing up 20 years and 20,000 kilometers apart, education polygenic scores predicted risk of a criminal record with modest effects. Polygenic risk manifested during primary schooling in lower cognitive abilities, lower self-control, academic difficulties, and truancy, and it was associated with a life-course-persistent pattern of antisocial behavior that onsets in childhood and persists into adulthood. Crime is central in the nature-nurture debate, and findings reported here demonstrate how molecular-genetic discoveries can be incorporated into established theories of antisocial behavior. They also suggest that improving school experiences might prevent genetic influences on crime from unfolding.

Structural alterations within cerebellar circuitry are associated with general liability for common mental disorders.

Accumulating mental-health research encourages a shift in focus toward transdiagnostic dimensional features that are shared across categorical disorders. In support of this shift, recent studies have identified a general liability factor for psychopathology-sometimes called the 'p factor'- that underlies shared risk for a wide range of mental disorders. Identifying neural correlates of this general liability would substantiate its importance in characterizing the shared origins of mental disorders and help us begin to understand the mechanisms through which the 'p factor' contributes to risk. Here we believe we first replicate the 'p factor' using cross-sectional data from a volunteer sample of 1246 university students, and then using high-resolution multimodal structural neuroimaging, we demonstrate that individuals with higher 'p factor' scores show reduced structural integrity of white matter pathways, as indexed by lower fractional anisotropy values, uniquely within the pons. Whole-brain analyses further revealed that higher 'p factor' scores are associated with reduced gray matter volume in the occipital lobe and left cerebellar lobule VIIb, which is functionally connected with prefrontal regions supporting cognitive control. Consistent with the preponderance of cerebellar afferents within the pons, we observed a significant positive correlation between the white matter integrity of the pons and cerebellar gray matter volume associated with higher 'p factor' scores. The results of our analyses provide initial evidence that structural alterations in corticocerebellar circuitry supporting core functions related to the basic integration, coordination and monitoring of information may contribute to a general liability for common mental disorders.

Childhood body mass index and endothelial dysfunction evaluated by peripheral arterial tonometry in early midlife.

BACKGROUND/OBJECTIVES: Endothelial dysfunction predicts mortality but it is unknown whether childhood obesity predicts adult endothelial dysfunction. The aim of this study was to determine whether anthropometric indices of body fat in childhood, adolescence and early midlife are associated with endothelial dysfunction in early midlife. SUBJECTS/METHODS: Participants belonged to a representative birth cohort of 1037 individuals born in Dunedin, New Zealand in 1972 and 1973 and followed to age 38 years, with 95% retention (the Dunedin Multidisciplinary Health and Development Study). We assessed anthropometric indices of obesity at ages 3, 5, 7, 9, 11, 13, 15, 18, 21, 26, 32 and 38 years. We tested associations between endothelial function assessed by peripheral arterial tonometry (PAT) at age 38 and; age 38 cardiovascular risk factors; age 3 body mass index (BMI); and four BMI trajectory groups from childhood to early midlife. RESULTS: Early midlife endothelial dysfunction was associated with BMI, large waist circumference, low high-density lipoprotein cholesterol, low cardiorespiratory fitness and increased high-sensitivity C-reactive protein. After adjustment for sex and childhood socioeconomic status, 3-year-olds with BMI 1 s.d. above the mean had Framingham-reactive hyperemia index (F-RHI) ratios that were 0.10 below those with normal BMI (ß=-0.10, 95% confidence interval (CI) -0.17 to -0.03, P=0.007) at age 38. Cohort members in the 'overweight', 'obese' and 'morbidly obese' trajectories had F-RHI ratios that were 0.08 (ß=-0.08, 95% CI -0.14 to -0.03, P=0.003), 0.13 (ß=-0.13, 95% CI -0.21 to -0.06, P<0.001) and 0.17 (ß=-0.17, 95% CI -0.33 to -0.01, P=0.033), respectively, below age-peers in the 'normal' trajectory. CONCLUSIONS: Childhood BMI and the trajectories of BMI from childhood to early midlife predict endothelial dysfunction evaluated by PAT in early midlife.

Sleeping with one eye open: loneliness and sleep quality in young adults.

BACKGROUND: Feelings of loneliness are common among young adults, and are hypothesized to impair the quality of sleep. In the present study, we tested associations between loneliness and sleep quality in a nationally representative sample of young adults. Further, based on the hypothesis that sleep problems in lonely individuals are driven by increased vigilance for threat, we tested whether past exposure to violence exacerbated this association. METHOD: Data were drawn from the Environmental Risk (E-Risk) Longitudinal Twin Study, a birth cohort of 2232 twins born in England and Wales in 1994 and 1995. We measured loneliness using items from the UCLA Loneliness Scale, and sleep quality using the Pittsburgh Sleep Quality Index. We controlled for covariates including social isolation, psychopathology, employment status and being a parent of an infant. We examined twin differences to control for unmeasured genetic and family environment factors. RESULTS: Feelings of loneliness were associated with worse overall sleep quality. Loneliness was associated specifically with subjective sleep quality and daytime dysfunction. These associations were robust to controls for covariates. Among monozygotic twins, within-twin pair differences in loneliness were significantly associated with within-pair differences in sleep quality, indicating an association independent of unmeasured familial influences. The association between loneliness and sleep quality was exacerbated among individuals exposed to violence victimization in adolescence or maltreatment in childhood. CONCLUSIONS: Loneliness is robustly associated with poorer sleep quality in young people, underscoring the importance of early interventions to mitigate the long-term outcomes of loneliness. Special care should be directed towards individuals who have experienced victimization.

The global coverage of prevalence data for mental disorders in children and adolescents.

AIMS: Children and adolescents make up almost a quarter of the world's population with 85% living in low- and middle-income countries (LMICs). Globally, mental (and substance use) disorders are the leading cause of disability in young people; however, the representativeness or 'coverage' of the prevalence data is unknown. Coverage refers to the proportion of the target population (ages 5-17 years) represented by the available data. METHODS: Prevalence data for conduct disorder (CD), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), eating disorders (EDs), depression, and anxiety disorders were sourced from systematic reviews conducted for the Global Burden of Disease Study 2010 (GBD 2010) and 2013 (GBD 2013). For each study, the location proportion was multiplied by the age proportion to give study coverage. Location proportion was calculated by dividing the total study location population by the total study location population. Age proportion was calculated by dividing the population of the country aged within the age range of the study sample by the population of the country aged within the age range of the study sample. If a study only sampled one sex, study coverage was halved. Coverage across studies was then summed for each country to give coverage by country. This method was repeated at the region and global level, and separately for GBD 2013 and GBD 2010. RESULTS: Mean global coverage of prevalence data for mental disorders in ages 5-17 years was 6.7% (CD: 5.0%, ADHD: 5.5%, ASDs: 16.1%, EDs: 4.4%, depression: 6.2%, anxiety: 3.2%). Of 187 countries, 124 had no data for any disorder. Many LMICs were poorly represented in the available prevalence data, for example, no region in sub-Saharan Africa had more than 2% coverage for any disorder. While coverage increased between GBD 2010 and GBD 2013, this differed greatly between disorders and few new countries provided data. CONCLUSIONS: The global coverage of prevalence data for mental disorders in children and adolescents is limited. Practical methodology must be developed and epidemiological surveys funded to provide representative prevalence estimates so as to inform appropriate resource allocation and support policies that address mental health needs of children and adolescents.

The association between cognitive function and subsequent depression: a systematic review and meta-analysis.

Despite a growing interest in understanding the cognitive deficits associated with major depressive disorder (MDD), it is largely unknown whether such deficits exist before disorder onset or how they might influence the severity of subsequent illness. The purpose of the present study was to conduct a systematic review and meta-analysis of longitudinal datasets to determine whether cognitive function acts as a predictor of later MDD diagnosis or change in depression symptoms. Eligible studies included longitudinal designs with baseline measures of cognitive functioning, and later unipolar MDD diagnosis or symptom assessment. The systematic review identified 29 publications, representing 34 unique samples, and 121 749 participants, that met the inclusion/exclusion criteria. Quantitative meta-analysis demonstrated that higher cognitive function was associated with decreased levels of subsequent depression (r = -0.088, 95% confidence interval. -0.121 to -0.054, p < 0.001). However, sensitivity analyses revealed that this association is likely driven by concurrent depression symptoms at the time of cognitive assessment. Our review and meta-analysis indicate that the association between lower cognitive function and later depression is confounded by the presence of contemporaneous depression symptoms at the time of cognitive assessment. Thus, cognitive deficits predicting MDD likely represent deleterious effects of subclinical depression symptoms on performance rather than premorbid risk factors for disorder.

Which adolescents develop persistent substance dependence in adulthood? Using population-representative longitudinal data to inform universal risk assessment.

BACKGROUND: To our knowledge, there are no universal screening tools for substance dependence that (1) were developed using a population-based sample, (2) estimate total risk briefly and inexpensively by incorporating a relatively small number of well-established risk factors, and (3) aggregate risk factors using a simple algorithm. We created a universal screening tool that incorporates these features to identify adolescents at risk for persistent substance dependence in adulthood. METHOD: Participants were members of a representative cohort of 1037 individuals born in Dunedin, New Zealand in 1972-1973 and followed prospectively to age 38 years, with 95% retention. We assessed a small set of childhood and adolescent risk factors: family history of substance dependence, childhood psychopathology (conduct disorder, depression), early exposure to substances, frequent substance use in adolescence, sex, and childhood socioeconomic status. We defined the outcome (persistent substance dependence in adulthood) as dependence on one or more of alcohol, tobacco, cannabis, or hard drugs at ⩾3 assessment ages: 21, 26, 32, and 38 years. RESULTS: A cumulative risk index, a simple sum of nine childhood and adolescent risk factors, predicted persistent substance dependence in adulthood with considerable accuracy (AUC = 0.80). CONCLUSIONS: A cumulative risk score can accurately predict which adolescents in the general population will develop persistent substance dependence in adulthood.

5-HTTLPR and use of antidepressants after colorectal cancer including a meta-analysis of 5-HTTLPR and depression after cancer.

The serotonin-transporter-linked polymorphic region (5-HTTLPR) is one of the most extensively investigated candidates to be involved in gene-environment interaction associated with depression. Nevertheless, the interaction remains controversial. In an original study, we tested the hypothesis that risk for use of antidepressants following a diagnosis of colorectal cancer is associated with bi- and triallelic genotypes of 5-HTTLPR. In addition, in an inclusive meta-analysis, we tested the hypothesis that depression following a diagnosis of cancer is associated with biallelic 5-HTTLPR genotype. We created an exposed-only cohort of 849 colorectal cancer patients from the Danish Diet, Cancer and Health cohort study. The hypothesized association was investigated with Cox regression models and competing risk analyses. Five studies comprising a total of 1484 cancer patients were included in the meta-analysis. Nationwide registries provided information on dates of diagnosis of colorectal cancer and use of antidepressants. Unadjusted odds ratios of depression according to the biallelic 5-HTTLPR genotype were included in the meta-analysis. 5-HTTLPR genotypes were not associated with use of antidepressants after colorectal cancer. Estimated hazard ratios ranged 0.92-1.08, and we observed no statistically significant associations across biallelic and triallelic genotypes in crude as well as adjusted models. The meta-analysis showed no statistically significant associations of 5-HTTLPR biallelic genotype with depression after cancer. Our findings in an original study and a meta-analysis do not support the hypothesis of an association between the 5-HTTLPR genotype and depression after cancer.

Social jetlag, obesity and metabolic disorder: investigation in a cohort study.

BACKGROUND: Obesity is one of the leading causes of preventable death worldwide. Circadian rhythms are known to control both sleep timing and energy homeostasis, and disruptions in circadian rhythms have been linked with metabolic dysfunction and obesity-associated disease. In previous research, social jetlag, a measure of chronic circadian disruption caused by the discrepancy between our internal versus social clocks, was associated with elevated self-reported body mass index, possibly indicative of a more generalized association with obesity and metabolic dysfunction. METHODS: We studied participants from the population-representative Dunedin Longitudinal Study (N=1037) to determine whether social jetlag was associated with clinically assessed measurements of metabolic phenotypes and disease indicators for obesity-related disease, specifically, indicators of inflammation and diabetes. RESULTS: Our analysis was restricted to N=815 non-shift workers in our cohort. Among these participants, we found that social jetlag was associated with numerous clinically assessed measures of metabolic dysfunction and obesity. We distinguished between obese individuals who were metabolically healthy versus unhealthy, and found higher social jetlag levels in metabolically unhealthy obese individuals. Among metabolically unhealthy obese individuals, social jetlag was additionally associated with elevated glycated hemoglobin and an indicator of inflammation. CONCLUSIONS: The findings are consistent with the possibility that 'living against our internal clock' may contribute to metabolic dysfunction and its consequences. Further research aimed at understanding that the physiology and social features of social jetlag may inform obesity prevention and have ramifications for policies and practices that contribute to increased social jetlag, such as work schedules and daylight savings time.

A heavy burden on young minds: the global burden of mental and substance use disorders in children and youth.

BACKGROUND: Mental and substance use disorders are common and often persistent, with many emerging in early life. Compared to adult mental and substance use disorders, the global burden attributable to these disorders in children and youth has received relatively little attention. METHOD: Data from the Global Burden of Disease Study 2010 was used to investigate the burden of mental and substance disorders in children and youth aged 0-24 years. Burden was estimated in terms of disability-adjusted life years (DALYs), derived from the sum of years lived with disability (YLDs) and years of life lost (YLLs). RESULTS: Globally, mental and substance use disorders are the leading cause of disability in children and youth, accounting for a quarter of all YLDs (54.2 million). In terms of DALYs, they ranked 6th with 55.5 million DALYs (5.7%) and rose to 5th when mortality burden of suicide was reattributed. While mental and substance use disorders were the leading cause of DALYs in high-income countries (HICs), they ranked 7th in low- and middle-income countries (LMICs) due to mortality attributable to infectious diseases. CONCLUSIONS: Mental and substance use disorders are significant contributors to disease burden in children and youth across the globe. As reproductive health and the management of infectious diseases improves in LMICs, the proportion of disease burden in children and youth attributable to mental and substance use disorders will increase, necessitating a realignment of health services in these countries.

Internalizing disorders and leukocyte telomere erosion: a prospective study of depression, generalized anxiety disorder and post-traumatic stress disorder.

There is evidence that persistent psychiatric disorders lead to age-related disease and premature mortality. Telomere length has emerged as a promising biomarker in studies that test the hypothesis that internalizing psychiatric disorders are associated with accumulating cellular damage. We tested the association between the persistence of internalizing disorders (depression, generalized anxiety disorder and post-traumatic stress disorder) and leukocyte telomere length (LTL) in the prospective longitudinal Dunedin Study (n=1037). Analyses showed that the persistence of internalizing disorders across repeated assessments from ages 11 to 38 years predicted shorter LTL at age 38 years in a dose-response manner, specifically in men (ß=-0.137, 95% confidence interval (CI): -0.232, -0.042, P=0.005). This association was not accounted for by alternative explanatory factors, including childhood maltreatment, tobacco smoking, substance dependence, psychiatric medication use, poor physical health or low socioeconomic status. Additional analyses using DNA from blood collected at two time points (ages 26 and 38 years) showed that LTL erosion was accelerated among men who were diagnosed with internalizing disorder in the interim (ß=-0.111, 95% CI: -0.184, -0.037, P=0.003). No significant associations were found among women in any analysis, highlighting potential sex differences in internalizing-related telomere biology. These findings point to a potential mechanism linking internalizing disorders to accelerated biological aging in the first half of the life course, particularly in men. Because internalizing disorders are treatable, the findings suggest the hypothesis that treating psychiatric disorders in the first half of the life course may reduce the population burden of age-related disease and extend health expectancy.

Childhood maltreatment, juvenile disorders and adult post-traumatic stress disorder: a prospective investigation.

BACKGROUND: We examine prospectively the influence of two separate but potentially inter-related factors in the etiology of post-traumatic stress disorder (PTSD): childhood maltreatment as conferring a susceptibility to the PTSD response to adult trauma and juvenile disorders as precursors of adult PTSD. METHOD: The Dunedin Multidisciplinary Health and Development Study (DMHDS) is a birth cohort (n = 1037) from the general population of New Zealand's South Island, with multiple assessments up to age 38 years. DSM-IV PTSD was assessed among participants exposed to trauma at ages 26-38. Complete data were available on 928 participants. RESULTS: Severe maltreatment in the first decade of life, experienced by 8.5% of the sample, was associated significantly with the risk of PTSD among those exposed to adult trauma [odds ratio (OR) 2.64, 95% confidence interval (CI) 1.16-6.01], compared to no maltreatment. Moderate maltreatment, experienced by 27.2%, was not associated significantly with that risk (OR 1.55, 95% CI 0.85-2.85). However, the two estimates did not differ significantly from one another. Juvenile disorders (ages 11-15), experienced by 35% of the sample, independent of childhood maltreatment, were associated significantly with the risk of PTSD response to adult trauma (OR 2.35, 95% CI 1.32-4.18). CONCLUSIONS: Severe maltreatment is associated with risk of PTSD response to adult trauma, compared to no maltreatment, and juvenile disorders, independent of earlier maltreatment, are associated with that risk. The role of moderate maltreatment remains unresolved. Larger longitudinal studies are needed to assess the impact of moderate maltreatment, experienced by the majority of adult trauma victims with a history of maltreatment.

Specificity of childhood psychotic symptoms for predicting schizophrenia by 38 years of age: a birth cohort study.

BACKGROUND: Childhood psychotic symptoms have been used as a subclinical phenotype of schizophrenia in etiological research and as a target for preventative interventions. However, recent studies have cast doubt on the specificity of these symptoms for schizophrenia, suggesting alternative outcomes such as anxiety and depression. Using a prospective longitudinal birth cohort we investigated whether childhood psychotic symptoms predicted a diagnosis of schizophrenia or other psychiatric disorders by 38 years of age. METHOD: Participants were drawn from a birth cohort of 1037 children from Dunedin, New Zealand, who were followed prospectively to 38 years of age (96% retention rate). Structured clinical interviews were administered at age 11 to assess psychotic symptoms and study members underwent psychiatric assessments at ages 18, 21, 26, 32 and 38 to obtain past-year DSM-III-R/IV diagnoses and self-reports of attempted suicides since adolescence. RESULTS: Psychotic symptoms at age 11 predicted elevated rates of research diagnoses of schizophrenia and posttraumatic stress disorder (PTSD) and also suicide attempts by age 38, even when controlling for gender, social class and childhood psychopathology. No significant associations were found for persistent anxiety, persistent depression, mania or persistent substance dependence. Very few of the children presenting with age-11 psychotic symptoms were free from disorder by age 38. CONCLUSIONS: Childhood psychotic symptoms were not specific to a diagnosis of schizophrenia in adulthood and thus future studies of early symptoms should be cautious in extrapolating findings only to this clinical disorder. However, these symptoms may be useful as a marker of adult mental health problems more broadly.

Exposure to violence during childhood is associated with telomere erosion from 5 to 10 years of age: a longitudinal study.

There is increasing interest in discovering mechanisms that mediate the effects of childhood stress on late-life disease morbidity and mortality. Previous studies have suggested one potential mechanism linking stress to cellular aging, disease and mortality in humans: telomere erosion. We examined telomere erosion in relation to children's exposure to violence, a salient early-life stressor, which has known long-term consequences for well-being and is a major public-health and social-welfare problem. In the first prospective-longitudinal study with repeated telomere measurements in children while they experienced stress, we tested the hypothesis that childhood violence exposure would accelerate telomere erosion from age 5 to age 10 years. Violence was assessed as exposure to maternal domestic violence, frequent bullying victimization and physical maltreatment by an adult. Participants were 236 children (49% females; 42% with one or more violence exposures) recruited from the Environmental-Risk Longitudinal Twin Study, a nationally representative 1994-1995 birth cohort. Each child's mean relative telomere length was measured simultaneously in baseline and follow-up DNA samples, using the quantitative PCR method for T/S ratio (the ratio of telomere repeat copy numbers to single-copy gene numbers). Compared with their counterparts, the children who experienced two or more kinds of violence exposure showed significantly more telomere erosion between age-5 baseline and age-10 follow-up measurements, even after adjusting for sex, socioeconomic status and body mass index (B=-0.052, s.e.=0.021, P=0.015). This finding provides support for a mechanism linking cumulative childhood stress to telomere maintenance, observed already at a young age, with potential impact for life-long health.

Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity.

Endocannabinoids are released 'on-demand' on the basis of physiological need, and can be pharmacologically augmented by inhibiting their catabolic degradation. The endocannabinoid anandamide is degraded by the catabolic enzyme fatty acid amide hydrolase (FAAH). Anandamide is implicated in the mediation of fear behaviors, including fear extinction, suggesting that selectively elevating brain anandamide could modulate plastic changes in fear. Here we first tested this hypothesis with preclinical experiments employing a novel, potent and selective FAAH inhibitor, AM3506 (5-(4-hydroxyphenyl)pentanesulfonyl fluoride). Systemic AM3506 administration before extinction decreased fear during a retrieval test in a mouse model of impaired extinction. AM3506 had no effects on fear in the absence of extinction training, or on various non-fear-related measures. Anandamide levels in the basolateral amygdala were increased by extinction training and augmented by systemic AM3506, whereas application of AM3506 to amygdala slices promoted long-term depression of inhibitory transmission, a form of synaptic plasticity linked to extinction. Further supporting the amygdala as effect-locus, the fear-reducing effects of systemic AM3506 were blocked by intra-amygdala infusion of a CB1 receptor antagonist and were fully recapitulated by intra-amygdala infusion of AM3506. On the basis of these preclinical findings, we hypothesized that variation in the human FAAH gene would predict individual differences in amygdala threat-processing and stress-coping traits. Consistent with this, carriers of a low-expressing FAAH variant (385A allele; rs324420) exhibited quicker habituation of amygdala reactivity to threat, and had lower scores on the personality trait of stress-reactivity. Our findings show that augmenting amygdala anandamide enables extinction-driven reductions in fear in mouse and may promote stress-coping in humans.

Risk factors prospectively associated with adult obsessive-compulsive symptom dimensions and obsessive-compulsive disorder.

BACKGROUND: Very few longitudinal studies have evaluated prospective neurodevelopmental and psychosocial risk factors for obsessive-compulsive disorder (OCD). Furthermore, despite the heterogeneous nature of OCD, no research has examined risk factors for its primary symptom dimensions, such as contamination/washing. METHOD: Potential risk factors for symptoms or diagnosis of OCD in adulthood and for specific adult obsessive-compulsive (OC) symptom dimensions were examined in the Dunedin Study birth cohort. The presence of obsessions and compulsions and psychological disorders was assessed using the Diagnostic Interview Schedule (DIS) at ages 26 and 32 years. Individuals with a diagnosis of OCD at either age (n=36) were compared to both a healthy control group (n=613) and an anxious control group (n=310) to determine whether associations between a risk factor and an OCD diagnosis were specific. RESULTS: Childhood neurodevelopmental, behavioral, personality and environmental risk factors were associated with a diagnosis of OCD and with OC symptoms at ages 26 and 32. Social isolation, retrospectively reported physical abuse and negative emotionality were specific predictors of an adult OCD diagnosis. Of note, most risk factors were associated with OC symptoms in adulthood and several risk factors predicted specific OCD dimensions. Perinatal insults were linked to increased risk for symmetry/ordering and shameful thoughts dimensions, whereas poor childhood motor skills predicted the harm/checking dimension. Difficult temperament, internalizing symptoms and conduct problems in childhood also predicted specific symptom dimensions and lower IQ non-specifically predicted increased risk for most dimensions. CONCLUSIONS: The current findings underscore the need for a dimensional approach in evaluating childhood risk factors for obsessions and compulsions.