Biology subjects

Edwards, A. D.

Publications and source records attributed to Edwards, A. D..

8 recordsLinked to original sources

bioRxiv2018

Genes associated with neuropsychiatric disease increase vulnerability to abnormal deep grey matter development

1.BackgroundNeuropsychiatric disease has polygenic determinants but is often precipitated by environmental pressures, including adverse perinatal events. However, the way in which genetic vulnerability and early-life adversity interact remains obscure. Preterm birth is associated with abnormal brain development and psychiatric disease. We hypothesised that the extreme environmental stress of premature extra-uterine life could contribute to neuroanatomic abnormality in genetically vulnerable individuals.\n\nMethodsWe combined Magnetic Resonance Imaging (MRI) and genome-wide single nucleotide polymorphism (SNP) data from 194 infants, born before 33 weeks of gestation, to test the prediction that: the characteristic deep grey matter abnormalities seen in preterm infants are associated with polygenic risk for psychiatric illness. Summary statistics from a meta-analysis of SNP data for five psychiatric disorders were used to compute individual polygenic risk scores (PRS). The variance explained by the PRS in the relative volumes of four deep grey matter structures (caudate nucleus, thalamus, subthalamic nucleus and lentiform nucleus) was estimated using linear regression both for the full, mixed-ancestral, cohort and a subsample of European infants.\n\nResultsThe PRS was negatively associated with: lentiform volume in the full cohort ({beta}=-0.24, p=8x10-4) and the European subsample ({beta}=-0.24, p=8x10-3); and with subthalamic nuclear volume in the full cohort ({beta}=-0.18, p=0.01) and the European subsample ({beta}=-0.26, p=3x10-3).\n\nConclusionsGenetic variants associated with neuropsychiatric disease increase vulnerability to abnormal deep grey matter development and are associated with neuroanatomic changes in the perinatal period. This suggests a mechanism by which perinatal adversity leads to later neuropsychiatric disease in genetically predisposed individuals.

neuroscience↗

bioRxiv2018

Loss of the Wnt/β-catenin pathway in microglia of the developing brain drives pro-inflammatory activation leading to white matter injury

Microglia of the developing brain have unique functional properties but how their activation states is regulated is poorly understood. Inflammatory activation of microglia in the still-developing brain of preterm born infants is associated with permanent neurological sequelae in 9 million infants every year. Investigating the regulators of microglial activation in the developing brain with multiple models of neuroinflammation-mediated injury and primary human microglia we found that a reduction in Wnt/{beta}-catenin signalling is necessary and sufficient to drive an oligodendrocyte-injurious microglial phenotype. We validated in a cohort of preterm born infants that genomic variation in the WNT pathway is associated with the levels of connectivity found in their brains. Using a Wnt agonist delivered by a BBB penetrant microglia-specific targeting nanocarrier we prevented in our animal model the pro-inflammatory microglial activation, white matter injury and behavioural deficits. Collectively, these data validate that the Wnt pathway regulates microglial activation, is critical in the evolution of an important form of human brain injury and is a viable therapeutic target.

immunology↗

bioRxiv2018

Abnormal microstructural development of the cerebral cortex in neonates with congenital heart disease is associated with impaired cerebral oxygen delivery

BackgroundAbnormal macrostructural development of the cerebral cortex has been associated with hypoxia in infants with congenital heart disease (CHD). Animal studies have suggested that hypoxia results in cortical dysmaturation at the cellular level. New magnetic resonance imaging (MRI) techniques offer the potential to investigate the relationship between cerebral oxygen delivery and microstructural development of the cortex in newborn infants with CHD.\n\nMethodsWe measured macrostructural and microstructural properties of the cortex in 48 newborn infants with complex CHD and 48 age-matched healthy controls. Cortical volume and gyrification index were calculated from high resolution structural MRI. Neurite density and orientation dispersion indices were modelled using high angular resolution diffusion MRI. Cerebral oxygen delivery was estimated in infants with CHD using phase contrast MRI and pre-ductal pulse oximetry. We used tract-based spatial statistics to examine voxel-wise group differences in cortical microstructure.\n\nResultsMicrostructural development of the cortex was abnormal in 48 infants with CHD, with regions of increased fractional anisotropy (FA) and reduced orientation dispersion index (ODI) compared to 48 healthy controls, correcting for gestational age at birth and scan (FWE-corrected for multiple comparisons at P<0.05). Regions of reduced cortical ODI in infants with CHD were related to impaired cerebral oxygen delivery (R2=0.637, n=39). Cortical ODI was associated with gyrification index (R2=0.589, P<0.0001, n=48).\n\nConclusionsThis study suggests that the primary component of cerebral cortex dysmaturation in CHD is impaired dendritic arborisation, which may underlie abnormal macrostructural findings reported in this population. The degree of impairment was related to cerebral oxygen delivery, supporting the hypothesis that maternal oxygen therapy may be beneficial in this population.

neuroscience↗

bioRxiv2018

The network properties of the brain at the time of normal birth support the acquisition of language processing

Language acquisition appears to rely at least in part on recruiting pre-existing brain structures. We hypothesized that the neural substrate for language can be characterized by distinct, non-trivial network properties of the brain, that modulate language acquisition early in development. We tested whether these brain network properties present at the normal age of birth predicted later language abilities, and whether these were robust against perturbation by studying infants exposed to the extreme environmental stress of preterm birth.\n\nWe found that brain network controllability and integration predicted respectively phonological, bottom-up and syntactical, top-down language skills at 20 months, and that syntactical but not phonological functions were modulated by premature extrauterine life. These data show that the neural substrate for language acquisition is a network property present at term corrected age. These distinct developmental trajectories may be relevant to the emergence of social interaction after birth.

neuroscience↗

bioRxiv2017

High Dynamic Range Bacterial Cell Detection in a Novel "Lab-In-A-Comb" for High-Throughput Antibiotic Susceptibility Testing of Clinical Urine Samples

Antibiotic resistance in urinary tract infection is a major global challenge, and improved cost-effective and rapid antibiotic susceptibility tests (AST) are urgently needed to inform correct antibiotic selection. Although microfluidic technology can miniaturise AST, the high dynamic range of pathogen density found in clinical urine samples makes direct testing of clinical samples - rather than testing colonies from overnight agar plates - extremely challenging. We evaluated for the first time how pathogen concentration in urine affects microfluidic AST using a novel microplate-compatible high-throughput microfluidic AST system termed \"Lab-on-a-Comb\". When tested with clinical E. coli isolates at standardised density, these devices gave identical antibiotic susceptibility profiles to standard disc diffusion and microtitre plate tests. Bacterial detection directly in synthetic urine spiked with clinical E. coli UTI isolates was possible over a very large dynamic range of starting cell densities, from 103 - 108 CFU/mL which covers the range of pathogen cell densities found in patient urine. The lowest cell density where cell growth was reproducibly detected optically was 9.6x102 CFU/mL, corresponding to one single CFU detected in a 1 L microcapillary-an unprecedented level of sensitivity. Cell growth kinetics followed a simple Monod model with fast growth limited by the substrate availability and an estimated doubling time of 24.5 min, indicating optimal E. coli growth conditions within these microfluidic devices. There was a trade-off between sensitivity and speed of detection, with 105 CFU/mL detection possible within 2h, but 6h incubation required at 103 CFU/mL.

microbiology↗

bioRxiv2017

Multimodal Surface Matching with Higher-Order Smoothness Constraints

The accurate alignment of brains is fundamental to the statistical sensitivity and spatial localisation of group studies in brain imaging, and cortical surface-based alignment is generally accepted to be superior to volume-based approaches at aligning cortical areas. However, human subjects have considerable variation in cortical folding, and in the location of cortical areas relative to these folds, which makes aligning cortical areas based on folding alone a challenging problem. The Multimodal Surface Matching (MSM) tool is a flexible spherical registration approach that enables accurate registration of surfaces based on a variety of different features. Using MSM, we have previously shown that using areal features such as resting state-networks and myelin maps to drive cross-subject surface alignment improves group task fMRI statistics and map sharpness. However, the initial implementation of MSMs regularisation function did not penalize all forms of surface distortion evenly. In some cases, this allowed peak distortions to exceed neurobiologically plausible limits unless the regularisation strength was increased, in which case this prevented the algorithm from fully maximizing surface alignment. Here, we propose a new regularisation penalty, derived from physically relevant equations of strain (deformation) energy, and demonstrate that its use leads to improved and more robust alignment of multi-modal imaging data. In addition, since spherical warps incorporate projection distortions that are unavoidable when mapping from a convoluted cortical surface to the sphere, we also propose constraints to enforce smooth deformation of cortical anatomies. We test the impact of this approach for longitudinal modeling of cortical development for neonates (born between 32 and 45 weeks) and demonstrate that the proposed method increases the biological interpretability of the distortion fields and improves the statistical significance of population-based analysis relative to other spherical methods.

neuroscience↗

bioRxiv2017

The Developing Human Connectome Project: a Minimal Processing Pipeline for Neonatal Cortical Surface Reconstruction

The Developing Human Connectome Project (dHCP) seeks to create the first 4-dimensional connectome of early life. Understanding this connectome in detail may provide insights into normal as well as abnormal patterns of brain development. Following established best practices adopted by the WU-MINN Human Connectome Project (HCP), and pioneered by FreeSurfer, the project utilises cortical surface-based processing pipelines. In this paper, we propose a fully automated processing pipeline for the structural Magnetic Resonance Imaging (MRI) of the developing neonatal brain. This proposed pipeline consists of a refined framework for cortical and sub-cortical volume segmentation, cortical surface extraction, and cortical surface inflation, which has been specifically designed to address considerable differences between adult and neonatal brains, as imaged using MRI. Using the proposed pipeline our results demonstrate that images collected from 465 subjects ranging from 28 to 45 weeks post-menstrual age (PMA) can be processed fully automatically; generating cortical surface models that are topologically correct, and correspond well with manual evaluations of tissue boundaries in 85% of cases. Results improve on state-of-the-art neonatal tissue segmentation models and significant errors were found in only 2% of cases, where these corresponded to subjects with high motion. Downstream, these surfaces will enhance comparisons of functional and diffusion MRI datasets, supporting the modelling of emerging patterns of brain connectivity.

neuroscience↗

bioRxiv2017

Integrative genomics study of microglial transcriptome reveals effect of DLG4 (PSD95) on white matter in preterm infants.

Preterm birth places newborn infants in an adverse environment that leads to brain injury linked to neuroinflammation. To characterise this pathology, we present a translational bioinformatics investigation, with integration of human and mouse molecular and neuroimaging datasets to provide a deeper understanding of the role of microglia in preterm white matter damage. We examined preterm neuroinflammation in a mouse model of encephalopathy of prematurity induced by IL1B exposure, carrying out a gene network analysis of the cell-specific transcriptomic response to injury, which we extended to analysis of protein-protein interactions, transcription factors, and human brain gene expression, including translation to preterm infants by means of imaging-genetics approaches in the brain. We identified the endogenous synthesis of DLG4 (PSD95) protein by microglia in mouse and human, modulated by inflammation and development. Systemic genetic variation in DLG4 was associated with structural features in the preterm infant brain, suggesting that genetic variation in DLG4 may also impact white matter development and inter-individual susceptibility to injury.\n\nPreterm birth accounts for 11% of all births 1, and is the leading global cause of deaths under 5 years of age 2. Over 30% of survivors experience motor and/or cognitive problems from birth 3, 4, which last into adulthood 5. These problems include a 3-8 fold increased risk of symptoms and disorders associated with anxiety, inattention and social and communication problems compared to term-born infants 6. Prematurity is associated with a 4-12 fold increase in the prevalence of Autism Spectrum Disorders (ASD) compared to the general population 7, as well as a risk ratio of 7.4 for bipolar affective disorder among infants born below 32 weeks of gestation 8.\n\nThe characteristic brain injury observed in contemporary cohorts of preterm born infants includes changes to the grey and white matter tissues, that specifically include oligodendrocyte maturation arrest, hypomyelination and cortical changes visualised as decreases in fractional anisotropy 9-13. Exposure of the fetus and postnatal infant to systemic inflammation is an important contributing factor to brain injury in preterm born infants 12, 14, 15, and the persistence of inflammation is associated with poorer neurological outcome 16. Sources of systemic inflammation include maternal/fetal infections such as chorioamnionitis (which it is estimated affects a large number of women at a sub-clinical level), with the effect of systemic inflammation in the brain being mediated predominantly by the microglial response 17.\n\nMicroglia are unique yolk-sac derived resident phagocytes of the brain 18, 19, found preferentially within the developing white matter as a matter of normal developmental migration 12. Microglial products associated with white matter injury include pro-inflammatory cytokines, such as interleukin-1{beta} (IL1B) and tumour necrosis factor (TNF-)20, which can lead to a sub-clinical inflammatory situation associated with unfavourable outcomes 21. In addition to being key effector cells in brain inflammation, they are critical for normal brain development in processes such as axonal growth and synapse formation 22, 23. The role of microglia in neuroinflammation is dynamic and complex, reflected in their mutable phenotypes including both pro-inflammatory and restorative functions 24. Despite their important neurobiological role, the time course and nature of the microglial responses in preterm birth are currently largely unknown, and the interplay of inflammatory and developmental processes is also unclear. We, and others, believe that a better understanding of the molecular mechanisms underlying microglial function could harness their beneficial effects and mitigate the brain injury of prematurity and other states of brain inflammation25, 26\n\nA clinically relevant experimental mouse model of IL1B-induced systemic inflammation has been developed to study the changes occurring in the preterm human brain 27, 28. This model recapitulates the hallmarks of encephalopathy of prematurity including oligodendrocyte maturation delay with consequent dysmyelination, associated magnetic resonance imaging (MRI) phenotypes and behavioural deficits. Here, we take advantage of this model system to characterise the molecular underpinnings of the microglial response to IL1B-driven systemic inflammation and investigate its role in concurrent development.\n\nIn preterm infants MRI is used extensively to provide in-vivo correlates of white and grey matter pathology, allowing clinical assessment and prognostication. Diffusion MRI (d-MRI) measures the displacement of water molecules in the brain, and provides insight into the underlying tissue structure. Various d-MRI measures of white matter have been associated with developmental outcome in children born preterm 29-32, with up to 60% of inter-individual variability in structural and functional features attributable to genetic factors 33, 34. White matter abnormalities are linked to associated grey matter changes at both the imaging and cellular level 10, 35, 36, with functional and structural consequences lasting into adulthood 37, 38. Tract Based Statistics (TBSS) allows quantitative whole-brain white matter analysis of d-MRI data at the voxel level while avoiding problems due to contamination by signals arising from grey matter 39. This permits voxel-wise statistical testing and inferences to be made about group differences or associations with greater statistical power. TBSS has been shown to be an effective tool for studying white matter development and injury in the preterm brain 40, providing a macroscopic in vivo quantitative measure of white matter integrity that is associated with cognitive, fine motor, and gross motor outcome 11, 41, 42.\n\nIn this work we take a translational systems biology approach to investigate the role of microglia in preterm neuroinflammation and brain injury. We integrate microglial cell-type specific data from a mouse model of perinatal neuroinflammatory brain injury with experimental ex vivo and in vitro validation, translation to the human brain across the lifespan including analysis of human microglia, and assessment of the impact of genetic variation on structure of the preterm brain. We add to the understanding of the neurobiology of prematurity by: a) revealing the endogenous expression of DLG4 (PSD95) by microglia in early development, which is modulated by developmental stage and inflammation; and b) finding an association between systemic genetic variability in DLG4 and white matter structure in the preterm neonatal brain.

genomics↗