Desana Kocevska

Incidental Findings on Brain Imaging in the General Pediatric Population

Brain MRI in 3966 children from the population-based Generation R Study (mean age, 10.1 years) revealed incidental findings in 25.6%. Most findings did not require neurosurgical intervention, but 7 children (0.18%) had suspected primary brain tumors.

Sedentary time assessed by actigraphy and mortality: The Rotterdam Study.

Research suggests that sedentary behavior is a risk factor for mortality. However, most studies rely on questionnaires, which are prone to reporting error. We examined the association between sedentary time assessed by actigraphy and mortality among 1839 participants, aged 45-98years, from the prospective population-based Rotterdam Study, enrolled between 2004 and 2007. Participants wore an actigraph around the wrist for seven days. Sedentary time was evaluated continuously, per 1h/day increase, and categorically in three groups (<8, 8-11, ≥11h/day). The lowest category was used as reference. Mortality risks were examined using Cox proportional hazard models, adjusted for confounders and biological risk factors. We examined the association between sedentary behavior and mortality over and beyond other activity measures (including physical activity (PA) and activities of daily living (ADL)) in a final model. During 11years of follow-up (median: 7.5years, interquartile range: 6.6-8.3years), 212 participants (11.5%) died. In the multivariable model, the hazard ratio (HR) and 95% confidence interval (95% CI) per 1 more hour/day sedentary time was 1.09 (1.00, 1.18). The HR (95% CI) after adjustment for PA and ADL was 1.04 (0.96, 1.13). Participants sedentary for ≥11h/day had a higher mortality risk (HR: 1.80, 95% CI: 1.14, 2.84) than those sedentary <8h/day, in the multivariable model. After adjusting for PA and ADL, this association was clearly attenuated (HR: 1.50, 95% CI: 0.93, 2.41). In conclusion, our study suggests that sedentary behavior is a risk factor for mortality. Further investigation is needed to examine whether this association is distinct from the effect of other measures of activity.

The developmental course of sleep disturbances across childhood relates to brain morphology at age seven. The Generation R Study.

Objectives Little is known about the impact of sleep disturbances on the structural properties of the developing brain. This study explored associations between childhood sleep disturbances and brain morphology at 7 years. Methods Mothers from the Generation R cohort reported sleep disturbances in 720 children at ages 2 months, 1.5, 2, 3, and 6 years. T1-weighted Magnetic Resonance Imaging (MRI) images were used to assess brain structure at 7 years. Associations of sleep disturbances at each age and of sleep disturbance trajectories with brain volumes (total brain volume, cortical and subcortical grey matter, white matter) were tested with linear regressions. To assess regional differences, sleep disturbance trajectories were tested as determinants for cortical thickness in whole-brain analyses. Results Sleep disturbances followed a declining trend from toddlerhood onwards. Infant sleep was not associated with brain morphology at age 7. Per SD sleep disturbances (one frequent symptom or two less frequent symptoms) at 2 and 3 years of age, children had -6.3 (-11.7 to -0.8) cm3 and -6.4 (-11.7 to -1.7) cm3 smaller grey matter volumes, respectively. Sleep disturbances at age 6 years were associated with global brain morphology (grey matter: -7.3 (-12.1 to -2.6), p value = .01). Consistently, trajectory analyses showed that more adverse developmental course of childhood sleep disturbances are associated with smaller grey matter volumes and thinner dorsolateral prefrontal cortex. Conclusion Sleep disturbances from age 2 years onwards are associated with smaller grey matter volumes. Thinner prefrontal cortex in children with adverse sleep disturbance trajectories may reflect effects of sleep disturbances on brain maturation.

Early Childhood Sleep Patterns and Cognitive Development at Age 6 Years: The Generation R Study

Objective To explore the association of sleep duration and awakening frequency with cognitive outcomes in young children. Methods Mothers of 2,800 children from the Generation R cohort reported sleep duration and awakenings at childrens age 24 months. At age 6 years, validated Dutch measures were used to assess childrens nonverbal intelligence and language comprehension. Results We found a nonlinear association of total sleep time at 24 months with nonverbal intelligence ( p  = 0.03) and language comprehension ( p  = 0.04) at 6 years. Toddlers sleeping within the recommended 11-14 hr had more favorable cognitive development compared with both extremes. Frequent awakenings were negatively associated with nonverbal intelligence, but not with verbal comprehension. Conclusion Sleep duration in toddlerhood has an inverted-U-shaped relation with childhood cognitive measures. Frequent awakenings are associated with lower nonverbal intelligence. Given the marked decline in sleep duration and awakenings in toddlerhood, developmental changes of sleep patterns might be important for cognitive development.

Macronutrient Intakes in Infancy Are Associated with Sleep Duration in Toddlerhood

BACKGROUND Dietary composition has been associated with sleep indexes. However, most of the evidence is based on cross-sectional data, and studies in young children are lacking. OBJECTIVE The aim of this study was to explore the longitudinal associations of macronutrient composition of the diet with sleep duration and consolidation (number of awakenings) in infancy and early childhood. METHODS The study was performed in 3465 children from the Generation R Study, a population-based cohort study in the Netherlands. Mothers reported their childs food intake at 13 mo of age by using a validated food-frequency questionnaire and their childs sleep patterns at 2 and 3 y of age. We used nutrient substitution models to assess the associations of relative macronutrient intakes with sleep indexes and adjusted the models for sociodemographic and lifestyle factors. RESULTS Isocaloric substitution of fat intake by protein or carbohydrate in infancy was associated with longer total sleep duration at 2 but not 3 y of age. For each 5% increase in energy intake of either protein or carbohydrate at the expense of fat, sleep duration at 2 y of age was longer by 6 min (95% CI: 0.4, 12 min) and 4 min (95% CI: 2, 6 min), respectively. Further exploration of macronutrient subtypes indicated no consistent differences between saturated or unsaturated fat and that intake of plant compared with animal protein or Trp did not explain the association of higher total protein intake with longer sleep duration at 2 y of age. Replacing unsaturated with saturated fat was associated with 7 min (95% CI: -13, -1 min) shorter total sleep duration at 3 y of age. Macronutrient intakes were not associated with sleep consolidation. CONCLUSIONS Our results suggest that the macronutrient composition of the diet is associated with sleep duration in young children. Future research should further study the causality of this association and explore the underlying mechanisms.

Genetic studies of accelerometer-based sleep measures in 85,670 individuals yield new insights into human sleep behaviour

Sleep is an essential human function but its regulation is poorly understood. Identifying genetic variants associated with quality, quantity and timing of sleep will provide biological insights into the regulation of sleep and potential links with disease. Using accelerometer data from 85,670 individuals in the UK Biobank, we performed a genome-wide association study of 8 accelerometer-derived sleep traits. We identified 47 genetic associations across the sleep traits (P<5×10−8) and replicated our findings in 5,819 individuals from 3 independent studies. These included 10 novel associations for sleep duration and 26 for sleep quality. Most newly identified variants were associated with a single sleep trait, but variants previously associated with restless legs syndrome were observed to be associated with multiple sleep traits. As a group, sleep quality loci were enriched for serotonin processing genes and all sleep traits were enriched for cerebellar-expressed genes. These findings provide new biological insights into sleep characteristics.

The Prospective Association of the Diurnal Cortisol Rhythm With Sleep Duration and Perceived Sleeping Problems in Pre-schoolers: The Generation R Study.

Objective Cortisol, the end product of the hypothalamic-pituitary-adrenal axis, plays an important role in modulating sleep. Yet, studies investigating the association between diurnal cortisol rhythm and sleep patterns in young children are scarce. We tested the hypothesis that the diurnal cortisol rhythm is associated with shorter sleep duration and more sleep problems across early childhood. Methods This study was embedded in Generation R, a population-based cohort from fetal life onward. Parents collected saliva samples from their infant at five moments during day 1. In 322 infants aged 12 to 20 months, we determined the diurnal cortisol rhythm by calculating the area under the curve (AUC), the cortisol awakening response (CAR), and the diurnal slope. Sleep duration and sleep behavior were repeatedly assessed across ages of 14 months to 5 years. Generalized estimating equation models were used to assess related cortisol measures to sleep duration and sleep behavior. Results The diurnal cortisol slope and the CAR, but not the AUC, were associated with sleep duration across childhood. Children with flatter slopes and children with a more positive CAR were more likely to have shorter nighttime sleep duration (&bgr; per nmol/L/h slope = −0.12, 95% confidence interval = −0.19 to −0.05, p = .001; &bgr; per nmol/L CAR = −0.01, 95% confidence interval = −0.02 to 0.00, p = .04). Cortisol measures did not predict sleep problems. Conclusions The present study suggests that a flatter diurnal cortisol slope and a more marked morning rise, which can indicate stress (or hypothalamic-pituitary-adrenal dysregulation), have a long-term association with sleep regulation.

Apnea-hypopnea index, nocturnal arousals, oxygen desaturation and structural brain changes: A population-based study

Sleep apnea has been related to brain changes such as atrophy. However, which component of sleep apnea, the apnea-hypopnea index (AHI), nocturnal oxygen desaturation or arousals, can explain this association is unclear. In this large population-based study (n=681, mean age 62.1 years), we investigated the associations of AHI, nocturnal oxygen desaturation and arousals with global and regional gray matter and white matter volumes and with white matter lesion volumes. All participants underwent one night of polysomnography and MRI scanning of their brain. Gray matter, white matter and white matter lesion volumes adjusted for intracranial volume were studied as markers of brain atrophy. Nocturnal oxygen desaturation was related to whole brain white matter atrophy independent of covariates (multivariable adjusted B=−8.3, 95% CI=−16.7; −0.02). This association was most prominently reflected in the association between more oxygen desaturation and a smaller white matter parietal volume (B=−3.95 ml, 95% CI=−6.02; −1.88). Furthermore, oxygen desaturation was related to a smaller hippocampus (B=−0.22 ml, 95% CI=−0.42; −0.01). Although a higher AHI was related to smaller parietal gray (B=−0.05, 95% CI=−0.09; −0.004) and white matter (B=−0.06, 95% CI=−0.12; −0.10) volumes, these associations disappeared when adding oxygen desaturation to the model. We did not find a relation between arousals and gray and white matter brain atrophy and white matter lesion volumes. This suggests that oxygen desaturation mainly explains the association between sleep apnea and brain damage.

Prenatal and early postnatal measures of brain development and childhood sleep patterns

BackgroundBrain development underlies maturation of sleep patterns throughout childhood. Intrauterine head growth—marker of early neurodevelopment—has not been associated with childhood sleep characteristics. We explored associations between ultrasonographic measures of prenatal and early postnatal neurodevelopment and childhood sleep.MethodsA total of 6,808 children from a population-based birth cohort (Generation R) were included. Head circumference (HC) and lateral ventricles size were assessed with mid- and late-pregnancy fetal ultrasounds, and with cranial ultrasound 3–20 weeks postnatally. Mothers reported children’s sleep duration at 2 and 3 years, and sleep problems at 1.5, 3, and 6 years.ResultsLarger ventricular size, but not HC, was related to longer sleep duration at 3 years (β=0.06 h, 95% confidence interval (CI): 0.02; 0.10 in late-pregnancy and β=0.11 h, 95% CI: 0.02; 0.20 in early infancy, mid-pregnancy parameters were unrelated to sleep duration). Larger HC in mid-pregnancy was associated with a reduced risk for being a “problematic sleeper” up to the age of 6 years (odds ratio (OR): 0.94, 95% CI: 0.89; 0.99). Consistently, children with larger HC in early infancy were less likely to be “problematic sleepers” at 3 and 6 years.ConclusionsThis study shows that variations in fetal and neonatal brain size may underlie behavioral expression of sleep in childhood. Albeit small effect estimates, these associations provide evidence for neurodevelopmental origins of sleep.

Exome-wide meta-analysis identifies rare 3'-UTR variant in ERCC1/CD3EAP associated with symptoms of sleep apnea

Obstructive sleep apnea (OSA) is a common sleep breathing disorder associated with an increased risk of cardiovascular and cerebrovascular diseases and mortality. Although OSA is fairly heritable (~40%), there have been only few studies looking into the genetics of OSA. In the present study, we aimed to identify genetic variants associated with symptoms of sleep apnea by performing a whole-exome sequence meta-analysis of symptoms of sleep apnea in 1,475 individuals of European descent. We identified 17 rare genetic variants with at least suggestive evidence of significance. Replication in an independent dataset confirmed the association of a rare genetic variant (rs2229918; minor allele frequency = 0.3%) with symptoms of sleep apnea (p-valuemeta = 6.98 × 10−9, βmeta = 0.99). Rs2229918 overlaps with the 3′ untranslated regions of ERCC1 and CD3EAP genes on chromosome 19q13. Both genes are expressed in tissues in the neck area, such as the tongue, muscles, cartilage and the trachea. Further, CD3EAP is localized in the nucleus and mitochondria and involved in the tumor necrosis factor-alpha/nuclear factor kappa B signaling pathway. Our results and biological functions of CD3EAP/ERCC1 genes suggest that the 19q13 locus is interesting for further OSA research.