Genetic Burden for Late-Life Neurodegenerative Disease and Its Association With Early-Life Lipids, Brain, Behavior, and Cognition

Background: Genetics play a significant role in the etiology of late-life neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia. Part of the individual differences in risk for these diseases can be traced back decades before the onset of disease symptoms. Previous studies have shown evidence for plausible links of apolipoprotein E (APOE), the most important genetic marker for Alzheimer’s disease, with early-life cognition and neuroimaging markers. We aimed to assess whether genome-wide genetic burden for the aforementioned neurodegenerative diseases plays a role in early-life processes. Methods: We studied children from the Generation R Study, a prospective birth cohort. APOE genotypes and polygenic genetic burdens for Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia were obtained through genome-wide genotyping. Non-verbal intelligence was assessed through cognitive tests at the research center around the age of 6 years, and educational attainment through a national school performance test around the age of 11 years. The Child Behavior Checklist was administered around the age of 10 years, and data from the anxious/depressed, withdrawn/depressed, and the internalizing behavior problems scales were used. Children participated in a neuroimaging study when they were 10 years old, in which structural brain metrics were obtained. Lipid serum profiles, which may be influenced by APOE genotype, were assessed from venal blood obtained around the age of 6 years. The sample size per analysis varied between 1,641 and 3,650 children due to completeness of data. Results: We did not find evidence that APOE genotype or the polygenic scores impact on childhood nonverbal intelligence, educational attainment, internalizing behavior, and global brain structural measures including total brain volume and whole brain fractional anisotropy (all p > 0.05). Carriership of the APOE ε2 allele was associated with lower and APOE ε4 with higher low-density lipoprotein cholesterol concentrations when compared to APOE ε3/ε3 carriers. Conclusion: We found no evidence that genetic burden for late-life neurodegenerative diseases associates with early-life cognition, internalizing behavior, or global brain structure

Memory deficits following neonatal critical illness: A common neurodevelopmental pathway

Summary Over the last decade, knowledge has emerged that children growing up after neonatal critical illness, irrespective of underlying diagnosis, are at risk of memory impairment and school problems. Strikingly, these problems are manifest even when intelligence is normal. In this review, we propose a common neurodevelopmental pathway following neonatal critical illness by demonstrating that the survivors of preterm birth, congenital heart disease, and severe respiratory failure, share an increased risk of long-term memory deficits and associated hippocampal alterations. Rather than being a consequence of underlying diagnosis, we suggest that this shared vulnerability is most likely related to common conditions associated with neonatal critical illness. These include hypoxia, neuroinflammation, stress, exposure to anaesthetics, or a complex interplay of these factors at different postconceptional ages. Future work should be aimed at improving early identification of patients at risk and evaluating intervention modalities, such as cognitive or exercise training

A prospective population-based study of gestational vitamin D status and brain morphology in preadolescents

Low vitamin D level during pregnancy has been associated with adverse neurodevelopmental outcomes such as autism spectrum disorders (ASD) in children. However, the underlying neurobiological mechanism remains largely unknown. This study investigated the association between gestational 25-hydroxyvitamin D [25(OH)D] concentration and brain morphology in 2597 children at the age of 10 years in the population-based Generation R Study. We studied both 25(OH)D in maternal venous blood in mid-gestation and in umbilical cord blood at delivery, in relation to brain volumetric measures and surface-based cortical metrics including cortical thickness, surface area, and gyrification using linear regression. We found exposure to higher maternal 25(OH)D concentrations in mid-gestation was associated with a larger cerebellar volume in children (b ​= ​0.02, 95%CI 0.001 to 0.04), however this association did not remain after co

Neonatal critical illness and development: white matter and hippocampus alterations in school-age neonatal ECMO survivors

Aim: Examine the neurobiology of long-term neuropsychological deficits following neonatal extracorporeal membrane oxygenation (ECMO). Method: This cross-sectional study assessed white matter integrity and hippocampal volume of ECMO survivors (8-15yrs) and healthy controls (8-17yrs) using Diffusion Tensor Imaging and structural MRI, respectively. Neuropsychological outcome was evaluated in patients. Included clinical predictors of white matter integrity: age start ECMO, ECMO duration, highest oxygenation index before ECMO, highest mean airway pressure and mechanical ventilation duration. Results: Patients (n=23) had lower global fractional anisotropy than controls (n=54)(patients=.368; controls=.381; p=.02), but similar global mean diffusivity (p=.41). Patients had lower fractional anisotropy in the left cingulum bundle (patients=.345; controls=.399; p<.001) and higher mean diffusivity in a region of the left parahippocampal cingulum (patients=.916; controls=.871; p<.001). Higher global mean diffusivity predicted worse verbal memory in patients (n=17)(β=-.74, p=.01). Patients (n=23) had smaller bilateral hippocampal volume than controls (n=43)(left: p< .001; right: p< .001). In patients, this was related to worse verbal memory (left: β=.65, p=.02; right: β=.71, p=.01). Interpretation: Neonatal ECMO survivors are at risk for long-term brain alterations, which may partly explain long-term neuropsychological impairments. Neuroimaging may contribute to better risk stratification of long-term impairments

White Matter Microstructure and the General Psychopathology Factor in Children

Objective: Co-occurrence of behavioral and emotional problems in childhood is widespread, and previous studies have suggested that this reflects vulnerability to experience a range of psychiatric problems, often termed a general psychopathology factor. However, the neurobiological substrate of this general factor is not well understood. We tested the hypothesis that lower overall white matter microstructure is associated with higher levels of the general psychopathology factor in children and less with specific factors. Method: Global white matter microstructure at age 10 years was related to general and specific psychopathology factors. These factors were estimated using a latent bifactor model with multiple informants and instruments between ages 6 and 10 years in 3,030 children from the population-based birth cohort Generation R. The association of global white matter microstructure and the psychopathology factors was examined with a structural equation model adjusted for sex, age at scan, age at psychopathology assessment, parental education/income, and genetic ancestry. Results: A 1-SD increase of the global white matter factor was associated with a β = −0.07SD (standard error [SE] = 0.02, p < .01) decrease in general psychopathology. In contrast, a 1-SD increase of white matter microstructure predicted an increase of β = +0.07 SD (SE = 0.03, p < .01) specific externalizing factor levels. No association was found with the specific internalizing and specific attention factor. Conclusion: The results suggest that general psychopathology in childhood is related to white matter structure across the brain and not only to specific tracts. Taking into account general psychopathology may also help reveal neurobiological mechanisms behind specific symptoms that are otherwise obscured by comorbidity

Prenatal Maternal Stress and Child IQ

The evidence for negative influences of maternal stress during pregnancy on child cognition remains inconclusive. This study tested the association between maternal prenatal stress and child intelligence in 4,251 mother–child dyads from a multiethnic population-based cohort in the Netherlands. A latent factor of prenatal stress was constructed, and child IQ was tested at age 6 years. In Dutch and Caribbean participants, prenatal stress was not associated with child IQ after adjustment for maternal IQ and socioeconomic status. In other ethnicities no association was found; only in the Moroccan/Turkish group a small negative association between prenatal stress and child IQ was observed. These results suggest that prenatal stress does not predict child IQ, except in children from less acculturated minority groups

Prematurity, Opioid Exposure and Neonatal Pain: Do They Affect the Developing Brain?

Background: Traditionally, 10 years ago, children born preterm often routinely received morphine, especially during mechanical ventilation. Studies in neonatal rats, whose stage of brain development roughly corresponds to that of children born preterm, found negative long-term effects after pain and opioid exposure. Objectives: We studied possible effects of prematurity, procedural pain and opioids in humans 10 years later. We hypothesized that these factors would negatively influence neurobiological, neuropsychological and sensory development later in life. Methods: We included 19 children born preterm who as neonates participated in an RCT on the short-term effects of morphine administration and who previously participated in our follow-up studies at ages 5 and 8/9 years. We assessed associations between brain morphology (n = 11), neuropsychological functioning (n = 19) and thermal sensitivity (n = 17) and prematurity, opioid exposure and neonatal pain. Results: Significant correlations (coefficients 0.60-0.85) of gestational age, number of painful procedures and morphine exposure with brain volumes were observed. Significant correlations between these factors and thermal sensitivity were not established. Neuropsychological outcome was significantly moderately correlated with morphine exposure in only two subtests, and children performed in general 'average' by Dutch norms. Conclusions: Although prematurity, opioid exposure and neonatal pain were significantly associated with brain volume, no major associations with neuropsychological functioning or thermal sensitivity were detected. Our findings suggest that morphine administration during neonatal life does not affect neurocognitive performance or thermal sensitivity during childhood in children born preterm without brain damage during early life. Future studies with larger sample sizes are needed to confirm these findings