Genetic architecture of orbital telorism.

The interocular distance, or orbital telorism, is a distinctive craniofacial trait that also serves as a clinically informative measure. While its extremes, hypo- and hypertelorism, have been linked to monogenic disorders and are often syndromic, little is known about the genetic determinants of interocular distance within the general population. We derived orbital telorism measures from cranial magnetic resonance imaging by calculating the distance between the eyeballs' centre of gravity, which showed a good reproducibility with an intraclass correlation coefficient of 0.991 (95% confidence interval 0.985-0.994). Heritability estimates were 76% (standard error = 12%) with a family-based method (N = 364) and 39% (standard error = 2.4%) with a single nucleotide polymorphism-based method (N = 34 130) and were unaffected by adjustment for height (model II) and intracranial volume (model III) or head width (model IV). Genome-wide association studies in 34 130 European individuals identified 56 significantly associated genomic loci (P < 5 × 10-8) across four different models of which 46 were novel for facial morphology, and overall these findings replicated in an independent sample (N = 10 115) with telorism-related horizontal facial distance measures. Genes located nearby these 56 identified genetic loci were 4.9-fold enriched for Mendelian hypotelorism and hypertelorism genes, underlining their biological relevance. This study provides novel insights into the genetic architecture underlying interocular distance in particular, and the face in general, and explores its potential for applications in a clinical setting.

Prenatal exposure to common plasticizers: a longitudinal study on phthalates, brain volumetric measures, and IQ in youth.

Exposure to phthalates, used as plasticizers and solvents in consumer products, is ubiquitous. Despite growing concerns regarding their neurotoxicity, brain differences associated with gestational exposure to phthalates are understudied. We included 775 mother-child pairs from Generation R, a population-based pediatric neuroimaging study with prenatal recruitment, who had data on maternal gestational phthalate levels and T1-weighted magnetic resonance imaging in children at age 10 years. Maternal urinary concentrations of phthalate metabolites were measured at early, mid-, and late pregnancy. Child IQ was assessed at age 14 years. We investigated the extent to which prenatal exposure to phthalates is associated with brain volumetric measures and whether brain structural measures mediate the association of prenatal phthalate exposure with IQ. We found that higher maternal concentrations of monoethyl phthalate (mEP, averaged across pregnancy) were associated with smaller total gray matter volumes in offspring at age 10 years (ß per log10 increase in creatinine adjusted mEP = -10.7, 95%CI: -18.12, -3.28). Total gray matter volumes partially mediated the association between higher maternal mEP and lower child IQ (ß for mediated path =-0.31, 95%CI: -0.62, 0.01, p = 0.05, proportion mediated = 18%). An association of higher monoisobutyl phthalate (mIBP) and smaller cerebral white matter volumes was present only in girls, with cerebral white matter volumes mediating the association between higher maternal mIBP and lower IQ in girls. Our findings suggest the global impact of prenatal phthalate exposure on brain volumetric measures that extends into adolescence and underlies less optimal cognitive development.

Changes in Life's Essential 8 and risk of cardiovascular disease in Chinese people.

BACKGROUND: The American Heart Association recently released an updated algorithm for evaluating cardiovascular health-Life's Essential 8 (LE8). However, the associations between changes in LE8 score over time and risk of cardiovascular disease (CVD) remain unclear. METHODS: We investigated associations between 6-year changes (2006-12) in LE8 score and risk of subsequent CVD events (2012-20) among 53 363 Chinese men and women from the Kailuan Study, who were free from CVD in 2012. The LE8 score was calculated based on eight components: diet quality, physical activity, smoking status, sleep health, body mass index, blood lipids, blood glucose and blood pressure. Multivariable-adjusted Cox proportional-hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We documented 4281 incident CVD cases during a median of 7.7 years of follow-up. Compared with participants whose LE8 scores remained stable in a 6-year period, those with the large increases of LE8 score over the 6-year period had a lower risk of CVD, heart disease and stroke in the subsequent 8 years [HRs and 95% CIs: 0.67 (0.64, 0.70) for CVD, 0.65 (0.61, 0.69) for heart disease, 0.71 (0.67, 0.76) for stroke, all Ptrend < 0.001]. Conversely, those with the large decreases of LE8 score had 47%, 51% and 41% higher risk for CVD, heart disease and stroke, respectively. These associations were consistent across the subgroups stratified by risk factors. CONCLUSIONS: Improving LE8 score in a short- and moderate-term was associated with a lower CVD risk, whereas decreased LE8 score over time was associated with a higher risk.

White matter microstructure correlates of age, sex, handedness and motor ability in a population-based sample of 3031 school-age children.

Understanding the development of white matter microstructure in the general population is an imperative precursor to identifying its involvement in psychopathology. Previous studies have reported changes in white matter microstructure associated with age and different developmental patterns between boys and girls. Handedness has also been related to white matter in adults. Motor performance, tightly dependent on overall neuronal myelination, has been related to the corpus callosum. However, the association between motor performance and global white matter microstructure has not been reported in the literature. In general, these age, sex, handedness, and motor performance associations have been observed using small and poorly representative samples. We examined the relationships between age, sex, handedness, and motor performance, measured with a finger tapping task, and white matter microstructure in the forceps major and minor and in 5 tracts bilaterally (cingulum, corticospinal, inferior and superior longitudinal fasciculi, and uncinate) in a population-based sample of 3031 children between 8 and 12 years of age. Diffusion tensor imaging (DTI) data were acquired using a single, study-dedicated 3 Tesla scanner. We extracted and quantified features of white matter microstructure for each tract. We computed global DTI metrics by combining scalar values across multiple tracts into single latent factors using a confirmatory factor analysis. The adjusted linear regression models indicated that age was associated with global fractional anisotropy (FA), global mean diffusivity (MD), and almost all the tracts. Further, girls showed lower global MD than boys, while FA values differed by tract, and no age-sex interactions were found. No differences were observed in white matter microstructure between right- and left-handed children. We observed that FA in forceps major was associated with right-hand finger tapping performance. White matter FA in association tracts was only related to motor function before multiple testing correction. Our findings do not provide evidence for a relationship between finger tapping task performance and global white matter microstructure.

Genetic scores for adult subcortical volumes associate with subcortical volumes during infancy and childhood.

Individual differences in subcortical brain volumes are highly heritable. Previous studies have identified genetic variants that underlie variation in subcortical volumes in adults. We tested whether those previously identified variants also affect subcortical regions during infancy and early childhood. The study was performed within the Generation R study, a prospective birth cohort. We calculated polygenic scores based on reported GWAS for volumes of the accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen, and thalamus. Participants underwent cranial ultrasound around 7 weeks of age (range: 3-20), and we obtained metrics for the gangliothalamic ovoid, a predecessor of the basal ganglia. Furthermore, the children participated in a magnetic resonance imaging (MRI) study around the age of 10 years (range: 9-12). A total of 340 children had complete data at both examinations. Polygenic scores primarily associated with their corresponding volumes at 10 years of age. The scores also moderately related to the diameter of the gangliothalamic ovoid on cranial ultrasound. Mediation analysis showed that the genetic influence on subcortical volumes at 10 years was only mediated for 16.5-17.6% of the total effect through the gangliothalamic ovoid diameter at 7 weeks of age. Combined, these findings suggest that previously identified genetic variants in adults are relevant for subcortical volumes during early life, and that they affect both prenatal and postnatal development of the subcortical regions.

Design and overview of the Origins of Alzheimer's Disease Across the Life course (ORACLE) study.

Brain development and deterioration across the lifespan are integral to the etiology of late-life neurodegenerative disease. Factors that influence the health of the adult brain remain to be elucidated and include risk factors, protective factors, and factors related to cognitive and brain reserve. To address this knowledge gap we designed a life-course study on brain health, which received funding through the EU ERC Programme under the name Origins of Alzheimer's Disease Across the Life course (ORACLE) Study. The ORACLE Study is embedded within Generation R, a prospective population-based cohort study of children and their parents, and links this with the Rotterdam Study, a population-based study in middle-aged and elderly persons. The studies are based in Rotterdam, the Netherlands. Generation R focuses on child health from fetal life until adolescence with repeated in-person examinations, but has also included data collection on the children's parents. The ORACLE Study aims to extend the parental data collection in nearly 2000 parents with extensive measures on brain health, including neuroimaging, cognitive testing and motor testing. Additionally, questionnaires on migraine, depressive symptoms, sleep, and neurological family history were completed. These data allow for the investigation of longitudinal influences on adult brain health as well as intergenerational designs involving children and parents. As a secondary focus, the sampling is enriched by mothers (n = 356) that suffered from hypertensive disorders during pregnancy in order to study brain health in this high-risk population. This article provides an overview of the rationale and the design of the ORACLE Study.

Cortical gyrification in relation to age and cognition in older adults.

Gyrification of the cerebral cortex changes with aging and relates to development of cognitive function during early life and midlife. Little is known about how gyrification relates to age and cognitive function later in life. We investigated this in 4397 individuals (mean age: 63.5 years, range: 45.7 to 97.9) from the Rotterdam Study, a population-based cohort. Global and local gyrification were assessed from T1-weighted images. A measure for global cognition, the g-factor, was calculated from five cognitive tests. Older age was associated with lower gyrification (mean difference per year â€‹= â€‹-0.0021; 95% confidence interval â€‹= â€‹-0.0025; -0.0017). Non-linear terms did not improve the models. Age related to lower gyrification in the parietal, frontal, temporal and occipital regions, and higher gyrification in the medial prefrontal cortex. Higher levels of the g-factor were associated with higher global gyrification (mean difference per g-factor unit â€‹= â€‹0.0044; 95% confidence interval â€‹= â€‹0.0015; 0.0073). Age and the g-factor did not interact in relation to gyrification (p â€‹> â€‹0.05). The g-factor bilaterally associated with gyrification in three distinct clusters. The first cluster encompassed the superior temporal gyrus, the insular cortex and the postcentral gyrus, the second cluster the lingual gyrus and the precuneus, and the third cluster the orbitofrontal cortex. These clusters largely remained statistically significant after correction for cortical surface area. Overall, the results support the notion that gyrification varies with aging and cognition during and after midlife, and suggest that gyrification is a potential marker for age-related brain and cognitive decline beyond midlife.

Prenatal exposure to organophosphate pesticides and brain morphology and white matter microstructure in preadolescents.

BACKGROUND: Prenatal exposure to organophosphate (OP) pesticides associate with impaired neurodevelopment in humans and animal models. However, much uncertainty exists about the brain structural alterations underlying these associations. The objective of this study was to determine whether maternal OP pesticide metabolite concentrations in urine repeatedly measured during gestation are associated with brain morphology and white matter microstructure in 518 preadolescents aged 9-12 years. METHOD: Data came from 518 mother-child pairs participating in the Generation R Study, a population-based birth cohort from Rotterdam, the Netherlands. Maternal urine concentrations were determined for 6 dialkylphosphates (DAPs) including 3 dimethyl (DM) and 3 diethyl (DE) alkyl phosphate metabolites, collected at early, mid, and late pregnancy. At child's age 9-12 years, magnetic resonance imaging was performed to obtain T1-weighted images for brain volumes and surface-based cortical thickness and cortical surface area, and diffusion tensor imaging was used to measure white matter microstructure through fractional anisotropy (FA) and mean diffusivity (MD). Linear regression models were fit for the averaged prenatal exposure across pregnancy. RESULTS: DM and DE metabolite concentrations were not associated with brain volumes, cortical thickness, and cortical surface area. However, a 10-fold increase in averaged DM metabolite concentrations across pregnancy was associated with lower FA (B = -1.00, 95%CI = -1.80, -0.20) and higher MD (B = 0.13, 95%CI = 0.04, 0.21). Similar associations were observed for DE concentrations. CONCLUSIONS: This study provides the first evidence that OP pesticides may alter normal white matter microstructure in children, which could have consequences for normal neurodevelopment. No associations were observed with structural brain morphology, including brain volumes, cortical thickness, and cortical surface area.

Plant-based Diet and Adiposity Over Time in a Middle-aged and Elderly Population: The Rotterdam Study.

BACKGROUND: We aimed to explore whether adhering to a more plant-based diet, beyond strict vegan or vegetarian diets, may help prevent adiposity in a middle-aged and elderly population. METHODS: We included 9,633 participants from the Rotterdam Study, a prospective cohort in the Netherlands. Dietary data were collected using food-frequency questionnaires at baseline of three subcohorts of the Rotterdam Study (1989-1993, 2000-2001, 2006-2008). We created a plant-based diet index by giving plant-based foods positive scores and animal-based foods reverse scores. A higher score on the index reflected an overall more plant-based and less animal-based diet. Data on anthropometrics and body composition (using dual energy X-ray absorptiometry) were collected every 3-5 years from 1989 to 2016. We used multivariable linear mixed models to analyze the associations. RESULTS: In the 9,633 participants, baseline plant-based diet score ranged from 21.0 to 73.0 with a mean ± SD of 49.0 ± 7.0. In multivariable-adjusted analyses, higher adherence to a plant-based diet was associated with lower BMI, waist circumference, fat mass index, and body fat percentage across a median follow-up period of 7.1 years (per 10 points higher score, BMI: ß = -0.70 kg/m [95% CI = -0.81, -0.59]; waist circumference: -2.0 cm [-2.3, -1.7]; fat mass index: -0.66 kg/m [-0.80, -0.52]; body fat percentage: -1.1 points [-1.3, -0.84]). CONCLUSIONS: In this population-based cohort of middle-aged and elderly participants, a higher adherence to a more plant-based, less animal-based diet was associated with less adiposity over time, irrespective of general healthfulness of the specific plant- and animal-based foods.

Genetic variants for head size share genes and pathways with cancer.

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

Stage 2 Registered Report: The Bidirectional Relationship Between Brain Features and the Dysregulation Profile: A Longitudinal, Multimodal Approach.

OBJECTIVE: Youth with symptoms of emotion dysregulation are at risk for a multitude of psychiatric diagnoses later in life. However, few studies have focused on the underlying neurobiology of emotion dysregulation. This study assessed the bidirectional relationship between emotion dysregulation symptoms and brain morphology throughout childhood and adolescence. METHOD: A combined total of 8,235 children and adolescents drawn from 2 large population-based cohorts, the Generation R Study and Adolescent Brain Cognitive Development (ABCD) Study, were included. Data were acquired in 3 waves in Generation R (mean [SD] age = 7.8 [1.0] wave 1 [W1]; 10.1 [0.6] W2; 13.9 [0.5] W3) and in 2 waves in ABCD (mean [SD] age = 9.9 [0.6] W1; 11.9 [0.6] W2). Cross-lagged panel models were used to determine the bidirectional relationships between emotion dysregulation symptoms and brain morphology. The study was preregistered before performing analyses. RESULTS: In the Generation R sample, emotion dysregulation symptoms at W1 preceded lower hippocampal (ß = -.07, SE = 0.03, p = .017) and temporal pole (ß = -.19, SE = 0.07, p = .006) volumes at W2. Emotion dysregulation symptoms at W2 preceded lower fractional anisotropy in the uncinate fasciculus (ß = -.11, SE = 0.05, p = .017) and corticospinal tract (ß = -.12, SE = 0.05, p = .012). In the ABCD sample, emotion dysregulation symptoms preceded posterior cingulate (ß = .01, SE = 0.003, p = .014) and nucleus accumbens volumes (left hemisphere: ß = -.02, SE = 0.01, p = .014; right hemisphere: ß = -.02, SE = 0.01, p = .003). CONCLUSION: In population-based samples, with relatively low psychopathology symptoms in the majority of children, symptoms of emotion dysregulation can precede differential development of brain morphology. This provides the foundation for future work to assess to what extent optimal brain development can be promoted through early intervention. STUDY REGISTRATION INFORMATION: The Bidirectional Relationship Between Brain Features and the Dysregulation Profile: A Longitudinal, Multimodal Approach; https://doi.org/10.1016/j.jaac.2022.03.008. DIVERSITY & INCLUSION STATEMENT: We worked to ensure that the study questionnaires were prepared in an inclusive way. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

10-Year trajectories of depressive symptoms and subsequent brain health in middle-aged adults.

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 Bidirectional Relationship Between Brain Features and the Dysregulation Profile: A Longitudinal, Multimodal Approach.

The field of psychiatry increasingly highlights the importance of studying not only the influence of the brain on behavior, but also the long-term influences that the persistence of specific behaviors can have on the brain. A severe behavioral phenotype that puts children at risk for later psychopathology is the Child Behavior Checklist-Dysregulation Profile (CBCL-DP).1 In earlier work, Shaw et al.2 proposed a model in which the amygdala, nucleus accumbens, and orbitofrontal cortex, structures involved in the bottom-up response to emotional stimuli, are related to emotion dysregulation. Additionally, 3 key limbic white matter tracts have also been shown to be associated with CBCL-DP symptoms: the uncinate fasciculus, cingulum bundle, and forceps minor.3,4.

Attention-deficit hyperactivity disorder symptoms and brain morphology: Examining confounding bias.

Background: Associations between attention-deficit/hyperactivity disorder (ADHD) and brain morphology have been reported, although with several inconsistencies. These may partly stem from confounding bias, which could distort associations and limit generalizability. We examined how associations between brain morphology and ADHD symptoms change with adjustments for potential confounders typically overlooked in the literature (aim 1), and for the intelligence quotient (IQ) and head motion, which are generally corrected for but play ambiguous roles (aim 2). Methods: Participants were 10-year-old children from the Adolescent Brain Cognitive Development (N = 7722) and Generation R (N = 2531) Studies. Cortical area, volume, and thickness were measured with MRI and ADHD symptoms with the Child Behavior Checklist. Surface-based cross-sectional analyses were run. Results: ADHD symptoms related to widespread cortical regions when solely adjusting for demographic factors. Additional adjustments for socioeconomic and maternal behavioral confounders (aim 1) generally attenuated associations, as cluster sizes halved and effect sizes substantially reduced. Cluster sizes further changed when including IQ and head motion (aim 2), however, we argue that adjustments might have introduced bias. Conclusions: Careful confounder selection and control can help identify more robust and specific regions of associations for ADHD symptoms, across two cohorts. We provided guidance to minimizing confounding bias in psychiatric neuroimaging. Funding: Authors are supported by an NWO-VICI grant (NWO-ZonMW: 016.VICI.170.200 to HT) for HT, LDA, SL, and the Sophia Foundation S18-20, and Erasmus University and Erasmus MC Fellowship for RLM.

Sociodemographic, Lifestyle, Physical, and Psychosocial Determinants of Cognitive Reserve.

BACKGROUND: Cognitive reserve aims to explain individual differences in the susceptibility to the functional impact of dementia in the presence of equal amount of neuropathological damage. It is thought to be shaped by a combination of innate individual differences and lifetime exposures. Which determinants are associated with cognitive reserve remains unknown. OBJECTIVE: The objective of this study was to investigate the associations of sociodemographic, lifestyle, physical, and psychosocial determinants with cognitive reserve, and potential sex differences. METHODS: This cross-sectional study included 4,309 participants from the Rotterdam Study (mean age 63.9±10.7) between 2006-2016. Participants completed five cognitive tests and a brain MRI-scan. Cognitive reserve was defined as a latent variable that captures variance common across five cognitive tests, while adjusting for demographic and MRI-inferred neuropathological factors. The associations of potential determinants and cognitive reserve, adjusted for relevant confounders, were assessed with structural equation models. RESULTS: Current smoking (adjusted mean difference: -0.31, 95%confidence interval -0.42; -0.19), diabetes mellitus (-0.25, -0.40; -0.10) and depressive symptoms (-0.07/SD, -0.12; -0.03) were associated with a lower cognitive reserve whereas alcohol use (0.07/SD, 0.03; 0.12) was associated with higher cognitive reserve. Only smoking was associated with cognitive reserve in both men and women. Employment, alcohol use, diabetes, history of cancer, COPD, and depressive symptoms were only associated with cognitive reserve in women. CONCLUSION: Our study found that current smoking, diabetes mellitus, and depressive symptoms were associated with a lower cognitive reserve, whereas more alcohol use was associated with a higher cognitive reserve, but with clear differences between men and women.

QDECR: A Flexible, Extensible Vertex-Wise Analysis Framework in R.

The cerebral cortex is fundamental to the functioning of the mind and body. In vivo cortical morphology can be studied through magnetic resonance imaging in several ways, including reconstructing surface-based models of the cortex. However, existing software for surface-based statistical analyses cannot accommodate "big data" or commonly used statistical methods such as the imputation of missing data, extensive bias correction, and non-linear modeling. To address these shortcomings, we developed the QDECR package, a flexible and extensible R package for group-level statistical analysis of cortical morphology. QDECR was written with large population-based epidemiological studies in mind and was designed to fully utilize the extensive modeling options in R. QDECR currently supports vertex-wise linear regression. Design matrix generation can be done through simple, familiar R formula specification, and includes user-friendly extensions for R options such as polynomials, splines, interactions and other terms. QDECR can handle unimputed and imputed datasets with thousands of participants. QDECR has a modular design, and new statistical models can be implemented which utilize several aspects from other generic modules which comprise QDECR. In summary, QDECR provides a framework for vertex-wise surface-based analyses that enables flexible statistical modeling and features commonly used in population-based and clinical studies, which have until now been largely absent from neuroimaging research.

The interaction of cognitive and brain reserve with frailty in the association with mortality: an observational cohort study.

BACKGROUND: A higher cognitive reserve and brain reserve could decrease mortality risk, but the interaction of these factors with general age-related loss of physical fitness (eg, frailty) remains unclear with regards to mortality. We investigated the associations of cognitive and brain reserve with mortality and the interaction of cognitive and brain reserve with frailty within these associations. METHODS: Within the observational population-based cohort of the Rotterdam Study, we included participants who visited the research centre for a cognitive assessment between March 2, 2009, and March 1, 2012. Participants with an incomplete assessment of cognition, no data on education attainment, no MRI or an MRI of insufficient quality, three or more missing frailty criteria, or a dementia diagnosis were excluded. Participants were followed up until their death or May 1, 2019. Cognitive reserve was defined as a latent variable that captures variance across five cognitive tests. Brain reserve was defined as the proportion of healthy-appearing brain volume relative to total intracranial volume measured with 1·5 Tesla MRI. Frailty was defined according to Fried's frailty phenotype; participants meeting at least one of the five criteria were considered frail. Hazard ratios (HRs) for associations of cognitive reserve, brain reserve, frailty, and reserve-frailty interactions with the risk of mortality were estimated using Cox regression models. FINDINGS: 2878 individuals in the Rotterdam Study who visited the research centre for a cognitive assessment were considered eligible. 1388 individuals were excluded due to incomplete or missing data or a dementia diagnosis. 1490 participants with valid information on cognitive reserve, brain reserve, and frailty were included (mean age 74·3 years [SD 5·5]; 815 [55%] female participants). 810 (54%) participants were classified as frail. A higher cognitive reserve (HR 0·87 per SD, 95% CI 0·76-0·99, p=0·036) and a higher brain reserve (0·85 per SD, 0·72-1·00, p=0·048) were associated with a lower risk of mortality, after adjusting for sex, age, educational level, body-mass index, smoking status, and number of comorbidities. The association between cognitive reserve and mortality was more pronounced (0·77 per SD, 0·66-0·90, p=0·0012) when the cognitive reserve-frailty interaction (p=0·0078) was included, indicating that higher cognitive reserve is related to lower mortality in individuals with frailty. The brain reserve-frailty interaction was non-significant. INTERPRETATION: Higher cognitive reserve and higher brain reserve were associated with a lower mortality risk. Additionally, cognitive reserve and frailty interact in the association with mortality, such that higher cognitive reserve is particularly associated with lower mortality in frail participants. FUNDING: Netherlands Organization for Health Research and Development and EU Horizon 2020 research programme.

Multivariate Analysis and Modelling of multiple Brain endOphenotypes: Let's MAMBO!

Imaging genetic studies aim to test how genetic information influences brain structure and function by combining neuroimaging-based brain features and genetic data from the same individual. Most studies focus on individual correlation and association tests between genetic variants and a single measurement of the brain. Despite the great success of univariate approaches, given the capacity of neuroimaging methods to provide a multiplicity of cerebral phenotypes, the development and application of multivariate methods become crucial. In this article, we review novel methods and strategies focused on the analysis of multiple phenotypes and genetic data. We also discuss relevant aspects of multi-trait modelling in the context of neuroimaging data.

The association between body mass index and brain morphology in children: a population-based study.

Brain morphology is altered in both anorexia nervosa and obesity. However, it is yet unclear if the relationship between Body Mass Index-Standard Deviation Score (BMI-SDS) and brain morphology exists across the BMI-SDS spectrum, or is present only in the extremes. The study involved 3160 9-to-11 year-old children (50.3% female) who participate in Generation R, a population-based study. Structural MRI scans were obtained from all children and FreeSurfer was used to quantify both global and surface-based measures of gyrification and cortical thickness. Body length and weight were measured to calculate BMI. Dutch growth curves were used to calculate BMI-SDS. BMI-SDS was analyzed continuously and in two categories (median split). The relationship between BMI-SDS (range - 3.82 to 3.31) and gyrification showed an inverted-U shape curve in children with both lower and higher BMI-SDS values having lower gyrification in widespread areas of the brain. BMI-SDS had a positive linear association with cortical thickness in multiple brain regions. This study provides evidence for an association between BMI-SDS and brain morphology in a large sample of children from the general population and suggests that a normal BMI during childhood is important for brain development. Future studies could determine whether lifestyle modifications optimize BMI-SDS result in return to more typical patterns of brain morphology.

Resistance to developing brain pathology due to vascular risk factors: the role of educational attainment.

Brain pathology develops at different rates between individuals with similar burden of risk factors, possibly explained by brain resistance. We examined if education contributes to brain resistance by studying its influence on the association between vascular risk factors and brain pathology. In 4111 stroke-free and dementia-free community-dwelling participants (62.9 ± 10.7 years), we explored the association between vascular risk factors (hypertension and the Framingham Stroke Risk Profile [FRSP]) and imaging markers of brain pathology (markers of cerebral small vessel disease and brain volumetry), stratified by educational attainment level. Associations of hypertension and FSRP with markers of brain pathology were not significantly different between levels of educational attainment. Certain associations appeared weaker in those with higher compared to lower educational attainment, particularly for white matter hyperintensities (WMH). Supplementary residual analyses showed significant associations between higher educational attainment and stronger resistance to WMH among others. Our results suggest a role for educational attainment in resistance to vascular brain pathology. Yet, further research is needed to better characterize determinants of brain resistance.