Correlation between cognitive assessment scores and circulating cerebral biomarkers in women with pre-eclampsia and eclampsia

OBJECTIVES: The cerebral injury biomarkers neurofilament light chain (NfL) and tau and the glial activation biomarker glial fibrillary acidic protein (GFAP) may reflect neurological injury in pre-eclampsia. We assessed if there was a correlation between cognitive function assessment scores and plasma concentrations of these biomarkers in pre-eclampsia. STUDY DESIGN: Women with eclampsia, pre-eclampsia and normotensive pregnancies from the South African PROVE biobank were included. Blood samples were taken at inclusion. The Montreal Cognitive Assessment was performed after delivery at the time of discharge. The correlation between cognitive assessment scores and plasma concentrations of cerebral biomarkers was analysed using Spearman correlation adjusted for time from eclamptic seizure. MAIN OUTCOME MEASURES: We included 49 women with eclampsia, 16 women with pre-eclampsia complicated by pulmonary oedema, 22 women with pre-eclampsia without pulmonary oedema, HELLP or neurological complications and 18 women with normotensive pregnancies. RESULTS: There was a correlation between impaired cognitive function and increased plasma concentrations of NfL in women with eclampsia and women with pre-eclampsia and pulmonary oedema (r = -0.37, p = 0.009 and r = -0.56, p = 0.025 respectively). No correlation between impaired cognitive function and NfL in pre-eclampsia cases without pulmonary oedema, HELLP or neurological complications or normotensive pregnancies was found. No correlation with cognitive impairment was found in any groups for tau or GFAP. CONCLUSIONS: We found a correlation between impaired cognitive function assessment and plasma NfL concentrations in women with eclampsia and pre-eclampsia complicated by pulmonary oedema. These findings suggest that acute neuroaxonal injury may cause or contribute to cognitive impairment in these women

PROVE-Pre-Eclampsia Obstetric Adverse Events:Establishment of a Biobank and Database for Pre-Eclampsia

Pre-eclampsia is a leading cause of maternal and perinatal morbidity and mortality. The burden of disease lies mainly in low-middle income countries. The aim of this project is to establish a pre-eclampsia biobank in South Africa to facilitate research in the field of pre-eclampsia with a focus on phenotyping severe disease.The approach of our biobank is to collect biological specimens, detailed clinical data, tests, and biophysical examinations, including magnetic resonance imaging (MRI) of the brain, MRI of the heart, transcranial Doppler, echocardiography, and cognitive function tests.Women diagnosed with pre-eclampsia and normotensive controls are enrolled in the biobank at admission to Tygerberg University Hospital (Cape Town, South Africa). Biological samples and clinical data are collected at inclusion/delivery and during the hospital stay. Special investigations as per above are performed in a subset of women. After two months, women are followed up by telephonic interviews. This project aims to establish a biobank and database for severe organ complications of pre-eclampsia in a low-middle income country where the incidence of pre-eclampsia with organ complications is high. The study integrates different methods to investigate pre-eclampsia, focusing on improved understanding of pathophysiology, prediction of organ complications, and potentially future drug evaluation and discovery

Cerebral biomarkers in neurological complications of preeclampsia

BACKGROUND AND OBJECTIVES: There are no tools to accurately predict who is at risk of developing neurological complications of preeclampsia and no objective methods to determine disease severity. We assessed whether plasma levels of the cerebral biomarkers neurofilament light (NfL), tau and glial fibrillary acidic protein (GFAP) could reflect disease severity in various phenotypes of preeclampsia and compared them to the angiogenic biomarkers soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng) . STUDY DESIGN: In this observational study, we included women from the South African PROVE biobank. Plasma samples taken at diagnosis (preeclampsia cases) or at admission for delivery (normotensive controls) were analyzed for concentrations of NfL, tau, GFAP, PlGF, sFlt-1 and sEng. Cerebrospinal fluid concentrations of inflammatory markers and albumin were analyzed in a subgroup of 15 women. Analyses were adjusted for gestational age, time from seizures and delivery to sampling, maternal age and parity. RESULTS: Compared to 28 normotensive pregnancies, 146 women with preeclampsia demonstrated 2.18-fold higher plasma concentrations of NfL (95% CI 1.64-2.88), 2.17-fold higher tau (1.49-3.16) and 2.77-fold higher GFAP (2.06-3.72). In total 72 women with neurological complications (eclampsia, cortical blindness and stroke) demonstrated increased plasma concentrations of tau (2.99-fold higher, 95% CI 1.92-4.65) and GFAP (3.22-fold higher, 95% CI 2.06-5.02) compared to women with preeclampsia without pulmonary edema, HELLP or neurological complications (n=31). Angiogenic markers were also higher but to a lesser extent. Women with hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome (n=20) demonstrated increased plasma concentrations of NfL (1.64-fold higher, 95% CI 1.06-2.55), tau (4.44-fold higher, 95% CI 1.85-10.66) and GFAP (1.82-fold higher, 95% CI 1.32-2.50) compared to women with preeclampsia without pulmonary edema, HELLP or neurological complications . No difference was shown in angiogenic biomarkers. There was no difference between 23 women with preeclampsia complicated by pulmonary edema and women with preeclampsia without pulmonary edema, HELLP or neurological complications for any of the biomarkers. Plasma concentrations of tau and GFAP were increased in women with several neurological complications vs eclampsia only. CONCLUSIONS: Plasma NfL, GFAP and tau are candidate biomarkers for diagnosis and possibly prediction of cerebral complications of preeclampsia

Circulating Growth Differentiation Factor 15 Is Increased Preceding Preeclampsia Diagnosis: Implications as a Disease Biomarker

Background We investigated the biomarker potential of growth differentiation factor 15 (GDF-15), a stress response protein highly expressed in placenta, to predict preeclampsia. Methods and Results In 2 prospective cohorts (cohort 1: 960 controls, 39 women who developed preeclampsia; cohort 2: 950 controls, 41 developed preeclampsia), plasma concentrations of GDF-15 at 36 weeks' gestation were significantly increased among those who developed preeclampsia (P<0.001), area under the receiver operating characteristic curves (AUC) of 0.66 and 0.71, respectively. In cohort 2 a ratio of sFlt-1/PlGF (a clinical biomarker for preeclampsia) had a sensitivity of 61.0% at 83.2% specificity to predict those who will develop preeclampsia (AUC of 0.79). A ratio of GDF-15×sFlt-1/PlGF yielded a sensitivity of 68.3% at 83.2% specificity (AUC of 0.82). GDF-15 was consistently elevated across a number of international cohorts: levels were higher in placenta and blood from women delivering <34 weeks' gestation due to preterm preeclampsia in Melbourne, Australia; and in the blood at 26 to 32 weeks' gestation among 57 women attending the Manchester Antenatal Vascular Service (MAViS, UK) who developed preeclampsia (P=0.0002), compared with 176 controls. In the Preeclampsia Obstetric adVerse Events biobank (PROVE, South Africa), plasma GDF-15 was significantly increased in women with preeclampsia with severe features (P=0.02; n=14) compared to controls (n=14). Conclusions We conclude circulating GDF-15 is elevated among women more likely to develop preeclampsia or diagnosed with the condition. It may have value as a clinical biomarker, including the potential to improve the sensitivity of sFlt-1/PlGF ratio

Genetic Variance in the Adiponutrin Gene Family and Childhood Obesity

AIM: The adiponutrin gene family consists of five genes (PNPLA1-5) coding for proteins with both lipolytic and lipogenic properties. PNPLA3 has previously been associated with adult obesity. Here we investigated the possible association between genetic variants in these genes and childhood and adolescent obesity. METHODS/RESULTS: Polymorphisms in the five genes of the adiponutrin gene family were selected and genotyped using the Sequenom platform in a childhood and adolescent obesity case-control study. Six variants in PNPLA1 showed association with obesity (rs9380559, rs12212459, rs1467912, rs4713951, rs10947600, and rs12199580, p0.05). When analyzing these SNPs in relation to phenotypes, two SNPs in the PNPLA3 gene showed association with insulin sensitivity (rs12483959: beta = -0.053, p = 0.016, and rs2072907: beta = -0.049, p = 0.024). No associations were seen for PNPLA2, PNPLA4, and PNPLA5. CONCLUSIONS: Genetic variation in the adiponutrin gene family does not seem to contribute strongly to obesity in children and adolescents. PNPLA1 exhibited a modest effect on obesity and PNPLA3 on insulin sensitivity. These data, however, require confirmation in other cohorts and ethnic groups

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Removing critical gaps in chemical test methods by developing new assays for the identification of thyroid hormone system-disrupting chemicals—the athena project

The test methods that currently exist for the identification of thyroid hormone system-disrupting chemicals are woefully inadequate. There are currently no internationally validated in vitro assays, and test methods that can capture the consequences of diminished or enhanced thyroid hormone action on the developing brain are missing entirely. These gaps put the public at risk and risk assessors in a difficult position. Decisions about the status of chemicals as thyroid hormone system disruptors currently are based on inadequate toxicity data. The ATHENA project (Assays for the identification of Thyroid Hormone axis-disrupting chemicals: Elaborating Novel Assessment strategies) has been conceived to address these gaps. The project will develop new test methods for the disruption of thyroid hormone transport across biological barriers such as the blood–brain and blood–placenta barriers. It will also devise methods for the disruption of the downstream effects on the brain. ATHENA will deliver a testing strategy based on those elements of the thyroid hormone system that, when disrupted, could have the greatest impact on diminished or enhanced thyroid hormone action and therefore should be targeted through effective testing. To further enhance the impact of the ATHENA test method developments, the project will develop concepts for better international collaboration and development in the area of thyroid hormone system disruptor identification and regulation

Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise: the TRUFFLE 2 randomised trial protocol

Introduction: Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years. Methods and analysis: Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is &lt;10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire. Ethics and dissemination: The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy. Trial registration number: Main sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical &amp; Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Supplement: "Localization and broadband follow-up of the gravitational-wave transient GW150914" (2016, ApJL, 826, L13)

This Supplement provides supporting material for Abbott et al. (2016a). We briefly summarize past electromagnetic (EM) follow-up efforts as well as the organization and policy of the current EM follow-up program. We compare the four probability sky maps produced for the gravitational-wave transient GW150914, and provide additional details of the EM follow-up observations that were performed in the different bands