ORCID Profile
0000-0003-3904-8960
Current Organisation
The University of Edinburgh
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Publisher: Cold Spring Harbor Laboratory
Date: 20-10-2022
DOI: 10.1101/2022.10.18.22281194
Abstract: Preterm birth is closely associated with a phenotype that includes brain dysmaturation and neurocognitive impairment, commonly termed Encephalopathy of Prematurity (EoP), of which systemic inflammation is considered a key driver. DNA methylation (DNAm) signatures of inflammation from peripheral blood associate with poor brain imaging outcomes in adult cohorts. However, the robustness of DNAm inflammatory scores in infancy, their relation to comorbidities of preterm birth characterised by inflammation, neonatal neuroimaging metrics of EoP, and saliva cross-tissue applicability are unknown. Using salivary DNAm from 258 neonates (n = 155 preterm, gestational age at birth 23.28 – 34.84 weeks, n = 103 term, gestational age at birth 37.00 – 42.14 weeks), we investigated the impact of a DNAm surrogate for C-reactive protein (DNAm CRP) on brain structure and other clinically defined inflammatory exposures. We assessed i) if DNAm CRP estimates varied between preterm infants at term equivalent age and term infants, ii) how DNAm CRP related to different types of inflammatory exposure (maternal, fetal and postnatal) and iii) whether elevated DNAm CRP associated with poorer measures of neonatal brain volume and white matter connectivity. Higher DNAm CRP was linked to preterm status (−0.0107 ± 0.0008, compared with - 0.0118 ± 0.0006 among term infants p 0.001), as well as perinatal inflammatory diseases, including histologic chorioamnionitis, sepsis, bronchopulmonary dysplasia, and necrotising enterocolitis (OR range |2.00 | to |4.71|, p 0.01). Preterm infants with higher DNAm CRP scores had lower brain volume in deep grey matter, white matter, and hippoc i and amygdalae (β range |0.185| to |0.218|). No such associations were observed for term infants. Association magnitudes were largest for measures of white matter microstructure among preterms, where elevated epigenetic inflammation associated with poorer global measures of white matter integrity (β range |0.206| to |0.371|), independent of other confounding exposures. Epigenetic biomarkers of inflammation provide an index of innate immunity in relation to neonatal health. Such DNAm measures complement biological and clinical metrics when investigating the determinants of neurodevelopmental differences.
Publisher: BMJ
Date: 14-03-2022
DOI: 10.1136/ARCHDISCHILD-2021-323296
Abstract: Hypothalamic-pituitary-adrenal (HPA) axis adaptation is a potential mechanism linking early life exposures with later adverse health. This study tested the hypothesis that preterm birth is associated with adaptation of diurnal cortisol regulation across infancy. A secondary analysis was conducted of saliva cortisol measured morning, midday and evening, monthly, across infancy, as part of a birth cohort conducted in Linköping, Sweden. Diurnal cortisol regulation of infants born extremely preterm (n=24), very preterm (n=27) and at term (n=130) were compared across infancy through random coefficients regression models. Compared with infants born at term, infants born extremely preterm (−17.2%, 95% CI: −30.7 to −1.2), but not very preterm (1.7%, 95% CI: −14.1 to 20.4), had a flattened diurnal slope across infancy. Extremely preterm birth is associated with a flattened diurnal slope in infancy. This pattern of cortisol regulation could contribute to adverse metabolic and neurodevelopmental phenotypes observed in this population.
Publisher: Frontiers Media SA
Date: 12-09-2018
Publisher: Springer Science and Business Media LLC
Date: 06-04-2022
DOI: 10.1038/S41586-022-04554-Y
Abstract: Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify in idual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight 1 . Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future s le of MRI data ( www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the ersity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories 2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones 3 , showed high stability of in iduals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of in idual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.
Publisher: Springer Science and Business Media LLC
Date: 05-09-2017
DOI: 10.1038/S41467-017-00422-W
Abstract: Preterm birth places infants in an adverse environment that leads to abnormal brain development and cerebral injury through a poorly understood mechanism known to involve neuroinflammation. In this study, we integrate human and mouse molecular and neuroimaging data to investigate the role of microglia in preterm white matter damage. Using a mouse model where encephalopathy of prematurity is induced by systemic interleukin-1β administration, we undertake gene network analysis of the microglial transcriptomic response to injury, extend this by analysis of protein-protein interactions, transcription factors and human brain gene expression, and translate findings to living infants using imaging genomics. We show that DLG4 (PSD95) protein is synthesised by microglia in immature mouse and human, developmentally regulated, and modulated by inflammation DLG4 is a hub protein in the microglial inflammatory response and genetic variation in DLG4 is associated with structural differences in the preterm infant brain. DLG4 is thus apparently involved in brain development and impacts inter-in idual susceptibility to injury after preterm birth.
Publisher: BMJ
Date: 07-03-2022
DOI: 10.1136/ARCHDISCHILD-2021-321593
Abstract: To determine if preterm birth is associated with adaptation of the hypothalamic–pituitary–adrenal (HPA) axis and whether HPA axis programming relates to the degree of prematurity (defined as extremely preterm birth at weeks or very preterm birth at 28–32 weeks gestation). This study reports findings from a prospective birth cohort. Saliva cortisol concentrations were measured prevaccination and postvaccination, and in the morning and evening, at 4 months chronological age. Infants born at a single Scottish hospital. 45 term-born, 42 very preterm and 16 extremely preterm infants. Cortisol stress response to vaccination (postvaccination minus prevaccination cortisol concentrations), diurnal slope (log-transformed morning minus log-transformed evening cortisol values) and mean log-transformed daily cortisol. Compared with infants born at term, infants born extremely preterm had a blunted cortisol response to vaccination (5.8 nmol/L vs 13.1 nmol/L, difference in means: −7.3 nmol/L, 95% CI −14.0 to −0.6) and a flattened diurnal slope (difference in geometric means: −72.9%, 95% CI −87.1 to −42.8). In contrast, the cortisol response to vaccination (difference in means −2.7 nmol/L, 95% CI −7.4 to 2.0) and diurnal slope at 4 months (difference in geometric means: −33.6%, 95% CI −62.0 to 16.0) did not differ significantly in infants born very preterm compared with infants born at term. Infants born extremely preterm have blunted cortisol reactivity and a flattened diurnal slope. These patterns of HPA axis regulation are commonly seen after childhood adversity and could contribute to later metabolic and neurodevelopmental phenotypes observed in this population.
Publisher: Cold Spring Harbor Laboratory
Date: 02-02-2017
DOI: 10.1101/105288
Abstract: 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-in idual susceptibility to injury. Preterm 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 . The 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 . Microglia 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-1β (IL1B) and tumour necrosis factor α (TNF-α) 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 inflammation 25, 26 A 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. In 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-in idual 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 . In 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.
Publisher: Cold Spring Harbor Laboratory
Date: 10-06-2021
DOI: 10.1101/2021.06.08.447489
Abstract: Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify in idual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight 1 . Here, we built an interactive resource to benchmark brain morphology, www.brainchart.io , derived from any current or future s le of magnetic resonance imaging (MRI) data. With the goal of basing these reference charts on the largest and most inclusive dataset available, we aggregated 123,984 MRI scans from 101,457 participants aged from 115 days post-conception through 100 postnatal years, across more than 100 primary research studies. Cerebrum tissue volumes and other global or regional MRI metrics were quantified by centile scores, relative to non-linear trajectories 2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones 3 showed high stability of in idual centile scores over longitudinal assessments and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared to non-centiled MRI phenotypes, and provided a standardised measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In sum, brain charts are an essential first step towards robust quantification of in idual deviations from normative trajectories in multiple, commonly-used neuroimaging phenotypes. Our collaborative study proves the principle that brain charts are achievable on a global scale over the entire lifespan, and applicable to analysis of erse developmental and clinical effects on human brain structure. Furthermore, we provide open resources to support future advances towards adoption of brain charts as standards for quantitative benchmarking of typical or atypical brain MRI scans.
Publisher: Springer Science and Business Media LLC
Date: 23-09-2022
Publisher: Cold Spring Harbor Laboratory
Date: 10-04-2021
DOI: 10.1101/2021.04.08.21255064
Abstract: Preterm birth is associated with dysconnectivity of structural brain networks and is a leading cause of neurocognitive impairment in childhood. Variation in DNA methylation (DNAm) is associated with early exposure to extrauterine life but there has been little research exploring its relationship with brain development. Using genome-wide DNA methylation data from saliva of 258 neonates, we investigated the impact of gestational age on the methylome and performed functional analysis to identify enriched gene sets from probes that contributed to differentially methylated probes (DMPs) or regions (DMRs). We tested the hypothesis that variation in DNAm could underpin the association between preterm birth and atypical brain development by linking DMPs with measures of white matter connectivity derived from diffusion MRI metrics: peak width of skeletonised mean diffusivity (PSMD), fractional anisotropy (PSFA) and neurite density index (PSNDI). Gestational age at birth was associated with widespread differential methylation, with genome-wide significant associations observed for 8,870 CpG probes ( p .6×10 −8 ) and 1,767 differentially methylated regions. Functional analysis identified 14 enriched gene ontology terms pertaining to cell-cell contacts and cell-extracellular matrix contacts. Principal component analysis of probes with genome-wide significance revealed a first principal component (PC1) that explained 23.5% of variance in DNAm, and this was negatively associated with gestational age at birth. PC1 was associated with PSMD (β=0.349, p =8.37×10 −10 ) and PSNDI (β=0.364, p =4.15×10 −5 ), but not with PSFA (β=−0.035, p =0.510) these relationships mirrored the imaging metrics’ associations with gestational age at birth. Gestational age at birth has a profound and widely distributed effect on the neonatal saliva methylome. Enriched gene ontology terms related to cell-cell contacts reveal pathways that could mediate the effect of early life environmental exposures on development. Finally, associations between differential DNAm and image markers of white matter tract microstructure suggest that variation in DNAm may provide a link between preterm birth and the dysconnectivity of developing brain networks that characterises atypical brain development in preterm infants.
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2015
End Date: 2019
Funder: Wellcome Trust
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