What life course theoretical models best explain the relationship between exposure to childhood adversity and psychopathology symptoms: recency, accumulation, or sensitive periods?

BACKGROUND: Although childhood adversity is a potent determinant of psychopathology, relatively little is known about how the characteristics of adversity exposure, including its developmental timing or duration, influence subsequent mental health outcomes. This study compared three models from life course theory (recency, accumulation, sensitive period) to determine which one(s) best explained this relationship. METHODS: Prospective data came from the Avon Longitudinal Study of Parents and Children (n = 7476). Four adversities commonly linked to psychopathology (caregiver physical/emotional abuse; sexual/physical abuse; financial stress; parent legal problems) were measured repeatedly from birth to age 8. Using a statistical modeling approach grounded in least angle regression, we determined the theoretical model(s) explaining the most variability (r2) in psychopathology symptoms measured at age 8 using the Strengths and Difficulties Questionnaire and evaluated the magnitude of each association. RESULTS: Recency was the best fitting theoretical model for the effect of physical/sexual abuse (girls r2 = 2.35%; boys r2 = 1.68%). Both recency (girls r2 = 1.55%) and accumulation (boys r2 = 1.71%) were the best fitting models for caregiver physical/emotional abuse. Sensitive period models were chosen alone (parent legal problems in boys r2 = 0.29%) and with accumulation (financial stress in girls r2 = 3.08%) more rarely. Substantial effect sizes were observed (standardized mean differences = 0.22-1.18). CONCLUSIONS: Child psychopathology symptoms are primarily explained by recency and accumulation models. Evidence for sensitive periods did not emerge strongly in these data. These findings underscore the need to measure the characteristics of adversity, which can aid in understanding disease mechanisms and determining how best to reduce the consequences of exposure to adversity.

Exposure to childhood adversity and deficits in emotion recognition: results from a large, population-based sample.

BACKGROUND: Emotion recognition skills are essential for social communication. Deficits in these skills have been implicated in mental disorders. Prior studies of clinical and high-risk samples have consistently shown that children exposed to adversity are more likely than their unexposed peers to have emotion recognition skills deficits. However, only one population-based study has examined this association. METHODS: We analyzed data from children participating in the Avon Longitudinal Study of Parents and Children, a prospective birth cohort (n = 6,506). We examined the association between eight adversities, assessed repeatedly from birth to age 8 (caregiver physical or emotional abuse; sexual or physical abuse; maternal psychopathology; one adult in the household; family instability; financial stress; parent legal problems; neighborhood disadvantage) and the ability to recognize facial displays of emotion measured using the faces subtest of the Diagnostic Assessment of Non-Verbal Accuracy (DANVA) at age 8.5 years. In addition to examining the role of exposure (vs. nonexposure) to each type of adversity, we also evaluated the role of the timing, duration, and recency of each adversity using a Least Angle Regression variable selection procedure. RESULTS: Over three-quarters of the sample experienced at least one adversity. We found no evidence to support an association between emotion recognition deficits and previous exposure to adversity, either in terms of total lifetime exposure, timing, duration, or recency, or when stratifying by sex. CONCLUSIONS: Results from the largest population-based sample suggest that even extreme forms of adversity are unrelated to emotion recognition deficits as measured by the DANVA, suggesting the possible immutability of emotion recognition in the general population. These findings emphasize the importance of population-based studies to generate generalizable results.

Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke.

Primary intracerebral haemorrhage and lacunar ischaemic stroke are acute manifestations of progressive cerebral microvascular disease. Current paradigms suggest atherosclerosis is a chronic, dynamic, inflammatory condition precipitated in response to endothelial injury from various environmental challenges. Myeloperoxidase plays a central role in initiation and progression of vascular inflammation, but prior studies linking myeloperoxidase with stroke risk have been inconclusive. We hypothesized that genetic determinants of myeloperoxidase levels influence the development of vascular instability, leading to increased primary intracerebral haemorrhage and lacunar stroke risk. We used a discovery cohort of 1409 primary intracerebral haemorrhage cases and 1624 controls from three studies, an extension cohort of 12 577 ischaemic stroke cases and 25 643 controls from NINDS-SiGN, and a validation cohort of 10 307 ischaemic stroke cases and 29 326 controls from METASTROKE Consortium with genome-wide genotyping to test this hypothesis. A genetic risk score reflecting elevated myeloperoxidase levels was constructed from 15 common single nucleotide polymorphisms identified from prior genome-wide studies of circulating myeloperoxidase levels (P < 5 × 10-6). This genetic risk score was used as the independent variable in multivariable regression models for association with primary intracerebral haemorrhage and ischaemic stroke subtypes. We used fixed effects meta-analyses to pool estimates across studies. We also used Cox regression models in a prospective cohort of 174 primary intracerebral haemorrhage survivors for association with intracerebral haemorrhage recurrence. We present effects of myeloperoxidase elevating single nucleotide polymorphisms on stroke risk per risk allele, corresponding to a one allele increase in the myeloperoxidase increasing genetic risk score. Genetic determinants of elevated circulating myeloperoxidase levels were associated with both primary intracerebral haemorrhage risk (odds ratio, 1.07, P = 0.04) and recurrent intracerebral haemorrhage risk (hazards ratio, 1.45, P = 0.006). In analysis of ischaemic stroke subtypes, the myeloperoxidase increasing genetic risk score was strongly associated with lacunar subtype only (odds ratio, 1.05, P = 0.0012). These results, demonstrating that common genetic variants that increase myeloperoxidase levels increase risk of primary intracerebral haemorrhage and lacunar stroke, directly implicate the myeloperoxidase pathway in the pathogenesis of cerebral small vessel disease. Because genetic variants are not influenced by environmental exposures, these results provide new support for a causal rather than bystander role for myeloperoxidase in the progression of cerebrovascular disease. Furthermore, these results support a rationale for chronic inflammation as a potential modifiable stroke risk mechanism, and suggest that immune-targeted therapies could be useful for treatment and prevention of cerebrovascular disease.

Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.

Rare Coding Variation and Risk of Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage has a substantial genetic component. We performed a preliminary search for rare coding variants associated with intracerebral hemorrhage. METHODS: A total of 757 cases and 795 controls were genotyped using the Illumina HumanExome Beadchip (Illumina, Inc, San Diego, CA). Meta-analyses of single-variant and gene-based association were computed. RESULTS: No rare coding variants were associated with intracerebral hemorrhage. Three common variants on chromosome 19q13 at an established susceptibility locus, encompassing TOMM40, APOE, and APOC1, met genome-wide significance (P<5e-08). After adjusting for the APOE epsilon alleles, this locus was no longer convincingly associated with intracerebral hemorrhage. No gene reached genome-wide significance level in gene-based association testing. CONCLUSIONS: Although no coding variants of large effect were detected, this study further underscores a major challenge for the study of genetic susceptibility loci; large sample sizes are required for sufficient power except for loci with large effects.

Childhood adversity and insomnia in adolescence.

OBJECTIVE: The study aims to evaluate the association between exposure to childhood adversity and insomnia, with an emphasis on the role of adversity type, timing, and accumulation (i.e., the number of specific types of adversities the child reported being exposed to). METHODS: Our analytic sample comprised 9582 adolescents from the National Comorbidity Survey Replication Adolescent Supplement (NCS-A), a nationally representative population-based sample. We examined the association between 18 different types of retrospectively reported adversities (capturing interpersonal violence, accidents and injuries, social network or witnessing events, and other adverse events) and risk of self-reported past-year insomnia. We also examined whether the age at first exposure to adversity was associated with the risk of insomnia, and whether exposure to a greater number of different types of adversities (ie, accumulation) conferred an elevated risk of insomnia. In addition, we performed a sensitivity analysis excluding adolescents with a past-year diagnosis of major depression, dysthymia, post-traumatic stress disorder (PTSD), or generalized anxiety disorder. RESULTS: Almost one-third of adolescents reported insomnia, with a higher prevalence among girls and those from racial/ethnic minority groups. Adolescents exposed to at least one childhood adversity of any type (59.41%) were more likely than their nonexposed peers to experience insomnia (across adversities, prevalence ratios (PRs) ranged from 1.31 to 1.89). Risk of insomnia differed based on the age at first exposure to adversity as well as the type of adversity. Adolescents exposed to a greater number of different types of adversities had a higher risk of insomnia compared to those experiencing fewer adversities. These results were similar, by and large, to those obtained after excluding adolescents with at least one of the four past-year psychiatric disorders. CONCLUSIONS: Exposure to adversity confers an elevated risk of insomnia. This association varied by type, timing, and accumulation of exposure and did not appear to be driven by psychiatric disorders. Given the well-documented physical and mental health consequences of insomnia, such findings further support the need for practitioners to screen children for exposure to childhood adversity and insomnia symptoms.

APOE polymorphisms influence longitudinal lipid trends preceding intracerebral hemorrhage.

OBJECTIVE: We sought to determine whether APOE genotype influences a previously observed decline in serum total cholesterol (TC) and low-density lipoprotein (LDL) levels preceding primary intracerebral hemorrhage (ICH), as a potential demonstration of nonamyloid mechanisms of APOE in ICH risk. METHODS: We performed a single-center retrospective longitudinal analysis using patients with known APOE genotype drawn from an ongoing cohort study of ICH. Serum lipid measurements for TC, triglycerides (TGs), LDL, and high-density lipoprotein (HDL) collected within 2 years before and after index ICH were extracted from electronic medical records. Piecewise linear mixed-effects models were used to compare APOE allele-specific effects on temporal serum lipid trends in ICH. Demographics, medical history, medications, and health maintenance data were included as fixed effects. Inter- and intraindividual variations in lipid levels were modeled as random effects. RESULTS: A total of 124 ICH cases were analyzed. APOE ε4 carriers had greater rates of decline in serum TC and LDL within 6 months preceding ICH (TC: -7.30 mg/dL/mo, p = 0.0035; LDL: -8.44 mg/dL/mo, p = 0.0001). Conversely, serum TC and LDL levels in APOE ε2 carriers were unchanged within the same time period. APOE genotype had no associations with serum HDL or TG trends. CONCLUSIONS: APOE allele status predicts serum TC and LDL changes preceding acute ICH. Our results have implications for ongoing efforts in dissecting the role of dyslipidemia in cerebrovascular disease risk. APOE genotype-specific influence on lipid trends provides a clue for one mechanism by which APOE may influence risk of ICH. Further characterization of the metabolic roles of APOE is needed to improve the understanding of APOE biology in cerebrovascular disease risk.

Does developmental timing of exposure to child maltreatment predict memory performance in adulthood? Results from a large, population-based sample.

Although maltreatment is a known risk factor for multiple adverse outcomes across the lifespan, its effects on cognitive development, especially memory, are poorly understood. Using data from a large, nationally representative sample of young adults (Add Health), we examined the effects of physical and sexual abuse on working and short-term memory in adulthood. We examined the association between exposure to maltreatment as well as its timing of first onset after adjusting for covariates. Of our sample, 16.50% of respondents were exposed to physical abuse and 4.36% to sexual abuse by age 17. An analysis comparing unexposed respondents to those exposed to physical or sexual abuse did not yield any significant differences in adult memory performance. However, two developmental time periods emerged as important for shaping memory following exposure to sexual abuse, but in opposite ways. Relative to non-exposed respondents, those exposed to sexual abuse during early childhood (ages 3-5), had better number recall and those first exposed during adolescence (ages 14-17) had worse number recall. However, other variables, including socioeconomic status, played a larger role (than maltreatment) on working and short-term memory. We conclude that a simple examination of "exposed" versus "unexposed" respondents may obscure potentially important within-group differences that are revealed by examining the effects of age at onset to maltreatment.

Subacute decline in serum lipids precedes the occurrence of primary intracerebral hemorrhage.

OBJECTIVE: We aimed to describe the temporal variation in circulating lipid levels among patients with intracerebral hemorrhage (ICH) and investigate their association with ICH risk. METHODS: This was a single-center, retrospective, longitudinal, case-control analysis using cases drawn from an ongoing cohort study of primary ICH and controls drawn from a hospital-based clinical data registry. Piecewise linear mixed-effect random coefficient models were used to determine the significance of changes in serum lipid trends on ICH risk. RESULTS: Two hundred twelve ICH cases and 301 control individuals were analyzed. Overall trends in serum total cholesterol (TC) and low-density lipoprotein (LDL) levels differed between ICH cases and non-ICH controls (p = 0.00001 and p = 0.0092, respectively). Patients with ICH experience accelerated decline in serum TC and LDL levels during 6 months immediately preceding ICH, compared with levels between 6 and 24 months pre-ICH (TC: -29.25 mg/dL, p = 0.001; LDL: -21.48 mg/dL, p = 0.0038), which was not observed in non-ICH controls. Subgroup analysis confirmed that this phenomenon cannot be attributed to statin or alcohol exposure. Serum triglycerides and high-density lipoprotein trends did not differ between groups. CONCLUSIONS: Longitudinal lipid levels differ between ICH cases and non-ICH controls, most notably for a decline in serum TC and LDL levels within 6 months preceding primary ICH, independent of statin or alcohol use. These changes in serum TC and LDL trends suggest a biological pathway that precipitates ICH occurrence. Further studies are needed to replicate these results and characterize rate of change in serum lipids as a potential biomarker of impending acute cerebral injury.

APOE ε4 and lipid levels affect risk of recurrent nonlobar intracerebral hemorrhage.

OBJECTIVE: Genetic variants ε2/ε4 within the APOE gene are established risk factors for lobar intracerebral hemorrhage (ICH). Published preliminary data suggest a potential role for APOE ε4 in risk of nonlobar ICH. We therefore investigated the role of APOE in recurrent nonlobar ICH, and sought to clarify whether effects of APOE on circulating lipids mediate this association. METHODS: Three hundred sixty-three survivors of nonlobar ICH were followed prospectively for ICH recurrence, with APOE genotype determined at enrollment. All participants had clinical, demographic, and laboratory data captured at time of index ICH and during follow-up. Using a multivariate model, we performed association and interaction analyses of the relationships among APOE genotype, lipid levels, and recurrent nonlobar ICH. RESULTS: We observed 29 nonlobar ICH recurrences among 363 survivors. APOE ε4 was associated with recurrent nonlobar ICH (hazard ratio = 1.31; 95% confidence interval = 1.02-2.69; p = 0.038) after adjustment for age/sex/ethnicity and cardiovascular risk factors. Increasing low-density lipoprotein (LDL) levels were associated with decreased risk of recurrent nonlobar ICH (p = 0.027), as were decreasing HDL levels (p = 0.046). LDL levels modified the association of APOE ε4 with recurrent nonlobar ICH (mediation p < 0.05). No associations were identified between APOE ε2 and recurrent nonlobar ICH. CONCLUSION: APOE ε4 is associated with recurrent ICH in nonlobar brain regions, providing further evidence for its causal role in ICH unrelated to cerebral amyloid angiopathy. LDL levels modulated this effect, suggesting that circulating lipid levels may mediate a portion of the role of APOE ε4 in nonlobar ICH.

CT angiography spot sign in intracerebral hemorrhage predicts active bleeding during surgery.

OBJECTIVE: To determine whether the CT angiography (CTA) spot sign marks bleeding complications during and after surgery for spontaneous intracerebral hemorrhage (ICH). METHODS: In a 2-center study of consecutive spontaneous ICH patients who underwent CTA followed by surgical hematoma evacuation, 2 experienced readers (blinded to clinical and surgical data) reviewed CTAs for spot sign presence. Blinded raters assessed active intraoperative and postoperative bleeding. The association between spot sign and active intraoperative bleeding, postoperative rebleeding, and residual ICH volumes was evaluated using univariable and multivariable logistic regression. RESULTS: A total of 95 patients met inclusion criteria: 44 lobar, 17 deep, 33 cerebellar, and 1 brainstem ICH; ≥1 spot sign was identified in 32 patients (34%). The spot sign was the only independent marker of active bleeding during surgery (odds ratio [OR] 3.4; 95% confidence interval [CI] 1.3-9.0). Spot sign (OR 4.1; 95% CI 1.1-17), female sex (OR 6.9; 95% CI 1.7-37), and antiplatelet use (OR 4.6; 95% CI 1.2-21) were predictive of postoperative rebleeding. Larger residual hematomas and postoperative rebleeding were associated with higher discharge case fatality (OR 3.4; 95% CI 1.1-11) and a trend toward increased case fatality at 3 months (OR 2.9; 95% CI 0.9-8.8). CONCLUSIONS: The CTA spot sign is associated with more intraoperative bleeding, more postoperative rebleeding, and larger residual ICH volumes in patients undergoing hematoma evacuation for spontaneous ICH. The spot sign may therefore be useful to select patients for future surgical trials.

APOE ε variants increase risk of warfarin-related intracerebral hemorrhage.

OBJECTIVE: We aimed to assess the effect of APOE ε variants on warfarin-related intracerebral hemorrhage (wICH), evaluated their predictive power, and tested for interaction with warfarin in causing wICH. METHODS: This was a prospective, 2-stage (discovery and replication), case-control study. wICH was classified as lobar or nonlobar based on the location of the hematoma. Controls were sampled from ambulatory clinics (discovery) and random digit dialing (replication). APOE ε variants were directly genotyped. A case-control design and logistic regression analysis were utilized to test for association between APOE ε and wICH. A case-only design and logistic regression analysis were utilized to test for interaction between APOE ε and warfarin. Receiver operating characteristic curves were implemented to evaluate predictive power. RESULTS: The discovery stage included 319 wICHs (44% lobar) and 355 controls. APOE ε2 was associated with lobar (odds ratio [OR] 2.46; p < 0.001) and nonlobar wICH (OR 1.67; p = 0.04), whereas ε4 was associated with lobar (OR 2.09; p < 0.001) but not nonlobar wICH (p = 0.35). The replication stage (63 wICHs and 1,030 controls) confirmed the association with ε2 (p = 0.03) and ε4 (p = 0.003) for lobar but not for nonlobar wICH (p > 0.20). Genotyping information on APOE ε variants significantly improved case/control discrimination of lobar wICH (C statistic 0.80). No statistical interaction between warfarin and APOE was found (p > 0.20). CONCLUSIONS: APOE ε variants constitute strong risk factors for lobar wICH. APOE exerts its effect independently of warfarin, although power limitations render this absence of interaction preliminary. Evaluation of the predictive ability of APOE in cohort studies is warranted.