DNA methylation in relation to gestational age and brain dysmaturation in preterm infants.

Preterm birth is associated with dysconnectivity of structural brain networks and is a leading cause of neurocognitive impairment in childhood. Variation in DNA methylation 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 the 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 or regions. We tested the hypothesis that variation in DNA methylation could underpin the association between low gestational age at birth and atypical brain development by linking differentially methylated probes with measures of white matter connectivity derived from diffusion MRI metrics: peak width skeletonized mean diffusivity, peak width skeletonized fractional anisotropy and peak width skeletonized neurite density index. Gestational age at birth was associated with widespread differential methylation at term equivalent age, with genome-wide significant associations observed for 8870 CpG probes (P < 3.6 × 10-8) and 1767 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 that explained 23.5% of the variance in DNA methylation, and this was negatively associated with gestational age at birth. The first principal component was associated with peak width of skeletonized mean diffusivity (ß = 0.349, P = 8.37 × 10-10) and peak width skeletonized neurite density index (ß = 0.364, P = 4.15 × 10-5), but not with peak width skeletonized fraction anisotropy (ß = -0.035, P = 0.510); these relationships mirrored the imaging metrics' associations with gestational age at birth. Low gestational age at birth has a profound and widely distributed effect on the neonatal saliva methylome that is apparent at term equivalent age. 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 DNA methylation and image markers of white matter tract microstructure suggest that variation in DNA methylation may provide a link between preterm birth and the dysconnectivity of developing brain networks that characterizes atypical brain development in preterm infants.

Translational neuroscience: the state of the nation (a PhD student perspective).

Many brain disorders are currently untreatable. It has been suggested that taking a 'translational' approach to neuroscientific research might change this. We discuss what 'translational neuroscience' is and argue for the need to expand the traditional translational model if we are to make further advances in treating brain disorders.

Peak Width of Skeletonized Water Diffusion MRI in the Neonatal Brain.

Preterm birth is closely associated with cognitive impairment and generalized dysconnectivity of neural networks inferred from water diffusion MRI (dMRI) metrics. Peak width of skeletonized mean diffusivity (PSMD) is a metric derived from histogram analysis of mean diffusivity across the white matter skeleton, and it is a useful biomarker of generalized dysconnectivity and cognition in adulthood. We calculated PSMD and five other histogram based metrics derived from diffusion tensor imaging (DTI) and neurite orientation and dispersion imaging (NODDI) in the newborn, and evaluated their accuracy as biomarkers of microstructural brain white matter alterations associated with preterm birth. One hundred and thirty five neonates (76 preterm, 59 term) underwent 3T MRI at term equivalent age. There were group differences in peak width of skeletonized mean, axial, and radial diffusivities (PSMD, PSAD, PSRD), orientation dispersion index (PSODI) and neurite dispersion index (PSNDI), all p < 10-4. PSFA did not differ between groups. PSNDI was the best classifier of gestational age at birth with an accuracy of 81±10%, followed by PSMD, which had 77±9% accuracy. Models built on both NODDI metrics, and on all dMRI metrics combined, did not outperform the model based on PSNDI alone. We conclude that histogram based analyses of DTI and NODDI parameters are promising new image markers for investigating diffuse changes in brain connectivity in early life.

DNA methylation and brain structure and function across the life course: A systematic review.

MRI has enhanced our capacity to understand variations in brain structure and function conferred by the genome. We identified 60 studies that report associations between DNA methylation (DNAm) and human brain structure/function. Forty-three studies measured candidate loci DNAm; seventeen measured epigenome-wide DNAm. MRI features included region-of-interest and whole-brain structural, diffusion and functional imaging features. The studies report DNAm-MRI associations for: neurodevelopment and neurodevelopmental disorders; major depression and suicidality; alcohol use disorder; schizophrenia and psychosis; ageing, stroke, ataxia and neurodegeneration; post-traumatic stress disorder; and socio-emotional processing. Consistency between MRI features and differential DNAm is modest. Sources of bias: variable inclusion of comparator groups; different surrogate tissues used; variation in DNAm measurement methods; lack of control for genotype and cell-type composition; and variations in image processing. Knowledge of MRI features associated with differential DNAm may improve understanding of the role of DNAm in brain health and disease, but caution is required because conventions for linking DNAm and MRI data are not established, and clinical and methodological heterogeneity in existing literature is substantial.