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BACKGROUND: Cognitive and brain reserve refer to individual differences that allow some people to better withstand brain pathology than others. Although early life stress has been recognized as a risk factor for low reserve in late life, no research yet has studied this across midlife.OBJECTIVE: To examine the associations of life stress with brain and cognitive reserve in midlife.METHODS: We included 1,232 middle-aged women who participated in the ORACLE Study between 2002-2006). Life stress was calculated as the shared variance of four cumulative stress domains, created from items measured between pregnancy and 10 years after childbirth. Brain reserve was defined as healthy-appearing brain volume measured with MRI; cognitive reserve as better cognitive functioning than expected based on age, education, and brain MRI measures, using structural equation modelling.RESULTS: More life stress was associated with lower brain (standardized adjusted difference: -0.18 [95% CI 0.25,-0.12]) and cognitive reserve (-0.19 [-0.28,-0.10]). Although, effect sizes were typically smaller, cumulative stress domains were also associated with brain reserve (life events: -0.10 [-0.16,-0.04]; contextual stress: -0.13 [-0.19,-0.07]; parenting-related stress: -0.13[-0.19,-0.07]; interpersonal stress: -0.10 [-0.16,-0.04]) and cognitive reserve (life events: -0.18 [-0.25,-0.11]; contextual stress: -0.15 [-0.10,-0.02]; parenting-related stress: -0.10 [-0.18,-0.03]; interpersonal stress not significant).CONCLUSION: Women who experience more life stress in midlife were found to have lower reserve. Effects were primarily driven by shared variance across cumulative stress domains, suggesting that focusing on single domains may underestimate effects. The effect of life stress on lower reserve may make women with stress more prone to neurodegenerative disease later in life than women without stress.

Funder: NWO: Nederlandse organisatie voor Wetenschappelijk Onderzoek; Id: http://dx.doi.org/10.13039/501100003246, Funder: ZonMw; Id: http://dx.doi.org/10.13039/501100001826, Funder: Ministry of Youth and Families, Funder: Fulbright U.S. Student Program, Funder: Erasmus Medisch Centrum; Id: http://dx.doi.org/10.13039/501100003061, Funder: Erasmus Universiteit Rotterdam; Id: http://dx.doi.org/10.13039/501100001828, Funder: Ministerie van Volksgezondheid, Welzijn en Sport; Id: http://dx.doi.org/10.13039/501100002999, This preregistered study examined whether child temperament and executive functions moderated the longitudinal association between early life stress (ELS) and behavior problems. In a Dutch population‐based cohort (n = 2803), parents reported on multiple stressors (age 0–6 years), child temperament (age 5), and executive functions (age 4), and teachers rated child internalizing and externalizing problems (age 7). Results showed that greater ELS was related to higher levels of internalizing and externalizing problems, with betas reflecting small effects. Lower surgency buffered the positive association of ELS with externalizing problems, while better shifting capacities weakened the positive association between ELS and internalizing problems. Other child characteristics did not act as moderators. Findings underscore the importance of examining multiple protective factors simultaneously.

Depressive symptoms differ in severity and stability over time. Trajectories depicting these changes, particularly those with high late-life depressive symptoms, have been associated with poor brain health at old age. To better understand these associations across the lifespan, we examined depressive symptoms trajectories in relation to brain health in middle age. We included 1676 participants from the ORACLE Study, all were expecting a child at baseline (mean age 32.8, 66.6% women). Depressive symptoms were assessed at baseline, 3 years and 10 years after baseline. Brain health (global brain volume, subcortical structures volume, white matter lesions, cerebral microbleeds, cortical thickness, cortical surface area) was assessed 15 years after baseline. Using k-means clustering, four depressive symptoms trajectories were identified: low, low increasing, decreasing, and high increasing symptoms. The high increasing trajectory was associated with smaller brain volume compared to low symptoms, not surviving multiple testing correction. The low increasing trajectory was associated with more cortical thickness in a small region encompassing the right lateral occipital cortex compared to low symptoms. These findings show that longitudinal depressive symptoms trajectories are only minimally associated with brain health in middle age, suggesting that associations may only emerge later in life.

The link between the gut microbiome and the brain has gained increasing scientific and public interest for its potential to explain psychiatric risk. While differences in gut microbiome composition have been associated with several mental health problems, evidence to date has been largely based on animal models and human studies with modest sample sizes. In this cross-sectional study in 1,784 ten-year-old children from the multi-ethnic, population-based Generation R Study, we aimed to characterize associations of the gut microbiome with child mental health problems. Gut microbiome was assessed from stool samples using 16S rRNA sequencing. We focused on overall psychiatric symptoms as well as with specific domains of emotional and behavioral problems, assessed via the maternally rated Child Behavior Checklist. While we observed lower gut microbiome diversity in relation to higher overall and specific mental health problems, associations were not significant. Likewise, we did not identify any taxonomic feature associated with mental health problems after multiple testing correction, although suggestive findings indicated depletion of genera previously associated with psychiatric disorders, including Hungatella, Anaerotruncus and Oscillospiraceae. The identified compositional abundance differences were found to be similar across all mental health problems. Finally, we did not find significant enrichment for specific microbial functions in relation to mental health problems. In conclusion, based on the largest sample examined to date, we do not find clear evidence of associations between gut microbiome diversity, taxonomies or functions and mental health problems in the general pediatric population. In future, the use of longitudinal designs with repeated measurements of microbiome and psychiatric outcomes will be critical to identify whether and when associations between the gut microbiome and mental health emerge across development and into adulthood.

Psychopathology and cognitive development are closely related. Assessing the relationship between multiple domains of psychopathology and cognitive performance can elucidate which cognitive tasks are related to specific domains of psychopathology. This can help build theory and improve clinical decision-making in the future. In this study, we included 13,841 children and adolescents drawn from two large population-based samples (Generation R and ABCD studies). We assessed the cross-sectional relationship between three psychopathology domains (internalizing, externalizing, dysregulation profile (DP)) and four cognitive domains (vocabulary, fluid reasoning, working memory, and processing speed) and the full-scale intelligence quotient. Lastly, differential associations between symptoms of psychopathology and cognitive performance by sex were assessed. Results indicated that internalizing symptoms were related to worse performance in working memory and processing speed, but better performance in the verbal domain. Externalizing and DP symptoms were related to poorer global cognitive performance. Notably, those in the DP subgroup had a 5.0 point lower IQ than those without behavioral problems. Cognitive performance was more heavily affected in boys than in girls given comparable levels of psychopathology. Taken together, we provide evidence for globally worse cognitive performance in children and adolescents with externalizing and DP symptoms, with those in the DP subgroup being most heavily affected.

Early life stress (ELS) is associated with lower IQ and academic achievement; however, it remains unclear whether it additionally explains their discrepancy. In 2,401 children (54% girls, 30.2% migration background) from the population-based study Generation R Study, latent factors of prenatal and postnatal (age 0–10) ELS were estimated, and IQ-achievement discrepancy (age 12) was quantified as variance in academic achievement not explained by IQ. ELS was prospectively associated with larger IQ-achievement discrepancy (βprenatal = −0.24; βpostnatal = −0.28), lower IQ (βprenatal = −0.20; βpostnatal = −0.22), and lower academic achievement (βprenatal = −0.31; βpostnatal = −0.36). Associations were stronger for latent ELS than for specific ELS domains. Results point to ELS as a potential prevention target to improve academic potential.