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A DTI-based tractography study of effects on brain structure associated with prenatal alcohol exposure in newborns.

ABSTRACT: Prenatal alcohol exposure (PAE) is known to have severe, long-term consequences for brain and behavioral development already detectable in infancy and childhood. Resulting features of fetal alcohol spectrum disorders include cognitive and behavioral effects, as well as facial anomalies and growth deficits. Diffusion tensor imaging (DTI) and tractography were used to analyze white matter (WM) development in 11 newborns (age since conception <45 weeks) whose mothers were recruited during pregnancy. Comparisons were made with nine age-matched controls born to abstainers or light drinkers from the same Cape Coloured (mixed ancestry) community near Cape Town, South Africa. DTI parameters, T1 relaxation time, proton density and volumes were used to quantify and investigate group differences in WM in the newborn brains. Probabilistic tractography was used to estimate and to delineate similar tract locations among the subjects for transcallosal pathways, cortico-spinal projection fibers, and cortico-cortical association fibers. In each of these WM networks, the axial diffusivity was the parameter that showed the strongest association with maternal drinking. The strongest relations were observed in medial and inferior WM, regions in which the myelination process typically begins. In contrast to studies of older individuals with PAE, fractional anisotropy did not exhibit a consistent and significant relation with alcohol exposure. To our knowledge, this is the first DTI-tractography study of prenatally alcohol exposed newborns.

SUBMITTER: Taylor PA

PROVIDER: S-EPMC4311768 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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A DTI-based tractography study of effects on brain structure associated with prenatal alcohol exposure in newborns.

Taylor Paul A PA Jacobson Sandra W SW van der Kouwe André A Molteno Christopher D CD Chen Gang G Wintermark Pia P Alhamud Alkathafi A Jacobson Joseph L JL Meintjes Ernesta M EM

Human brain mapping 20140903 1

Prenatal alcohol exposure (PAE) is known to have severe, long-term consequences for brain and behavioral development already detectable in infancy and childhood. Resulting features of fetal alcohol spectrum disorders include cognitive and behavioral effects, as well as facial anomalies and growth deficits. Diffusion tensor imaging (DTI) and tractography were used to analyze white matter (WM) development in 11 newborns (age since conception <45 weeks) whose mothers were recruited during pregnancy ...[more]

PMID: 25182535

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Project description:Brain developmental lesions are a devastating consequence of prenatal alcohol exposure (PAE). We recently showed that PAE affects cortical vascular development with major effects on angiogenesis and endothelial cell survival. The underlying molecular mechanisms of these effects remain poorly understood. This study aimed at characterizing the ethanol exposure impact on the autophagic process in brain microvessels in human fetuses with fetal alcohol syndrome (FAS) and in a PAE mouse model. Our results indicate that PAE induces an increase of autophagic vacuole number in human fetal and neonatal mouse brain cortical microvessels. Subsequently, ex vivo studies using green fluorescent protein (GFP)-LC3 mouse microvessel preparations revealed that ethanol treatment alters autophagy in endothelial cells. Primary cultures of mouse brain microvascular endothelial cells were used to characterize the underlying molecular mechanisms. LC3 and p62 protein levels were significantly increased in endothelial cells treated with 50?mM ethanol. The increase of autophagic vacuole number may be due to excessive autophagosome formation associated with the partial inhibition of the mammalian target of rapamycin pathway upon ethanol exposure. In addition, the progression from autophagosomes to autolysosomes, which was monitored using autophagic flux inhibitors and mRFP-EGFP vector, showed a decrease in the autolysosome number. Besides, a decrease in the Rab7 protein level was observed that may underlie the impairment of autophagosome-lysosome fusion. In addition, our results showed that ethanol-induced cell death is likely to be mediated by decreased mitochondrial integrity and release of apoptosis-inducing factor. Interestingly, incubation of cultured cells with rapamycin prevented ethanol effects on autophagic flux, ethanol-induced cell death and vascular plasticity. Taken together, these results are consistent with autophagy dysregulation in cortical microvessels upon ethanol exposure, which could contribute to the defects in angiogenesis observed in patients with FAS. Moreover, our results suggest that rapamycin represents a potential therapeutic strategy to reduce PAE-related brain developmental disorders.

Project description:Prenatal cocaine exposure has been associated with numerous behavioral phenotypes in clinical populations, including impulsivity, reduced attention, alterations in social behaviors, and delayed language and sensory-motor development. Detecting associated changes in brain structure in these populations has proven difficult, and results have been inconclusive and inconsistent. Due to their more controlled designs, animal models may shed light on the neuroanatomical changes caused by prenatal cocaine; however, to maximize clinical relevance, data must be carefully collected using translational methods. The goal of this study was two-fold: (1) to determine if prenatal cocaine alters developmental neuroanatomy using methods that are available to human researchers, specifically structural MRI and diffusion tensor imaging, and (2) to determine the feasibility of rodent in vivo neuroimaging for usage in longitudinal studies of developmental disorders. Cocaine-exposed (prenatal days 1-20, 30mg/kg/day) rat pups were sedated and imaged live using diffusion tensor imaging and postmortem (fixed) using magnetic resonance histology on postnatal day 14. Volume and diffusion properties in whole brain as well as specific regions of interest were then assessed from the resulting images. Whole brain analyses revealed that cocaine-exposed animals showed no change in whole brain volume. Additionally, we found alterations in fractional anisotropy across regions associated with reward processing and emotional regulation, especially in the thalamus and globus pallidus, as well as sex-dependent effects of cocaine in the right cortex. Reductions in fractional anisotropy were paired with reductions only in axial diffusivity, which preliminarily suggests that the changes observed here may be due to axonal damage, as opposed to reductions in myelination of the affected regions/pathways. Our data indicate that prenatal cocaine may target a number of developing brain structures but does not result in overt changes to brain volumes. These results highlight not only the brain alterations that result from prenatal cocaine but also the advancements in live imaging that allow longitudinal study designs in other models.

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A DTI-based tractography study of effects on brain structure associated with prenatal alcohol exposure in newborns.

Publications

A DTI-based tractography study of effects on brain structure associated with prenatal alcohol exposure in newborns.

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