Metabolic Maturation of White Matter Is Altered in Preterm Infants

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Abstract

Significant physiological switches occur at birth such as the transition from fetal parallel blood flow to a two-circuit serial system with increased arterial oxygenation of blood delivered to all organs including the brain. In addition, the extra-uterine environment exposes premature infants to a host of stimuli. These events could conceivably alter the trajectory of brain development in premature infants. We used in vivo magnetic resonance spectroscopy to measure absolute brain metabolite concentrations in term and premature-born infants without evidence of brain injury at equivalent post-conceptional age. Prematurity altered the developmental time courses of N-acetyl-aspartate, a marker for axonal and neuronal development, creatine, an energy metabolite, and choline, a membrane metabolite, in parietal white matter. Specifically, at term-equivalency, metabolic maturation in preterm infants preceded development in term infants, but then progressed at a slower pace and trajectories merged at ≈340–370 post-conceptional days. In parieto/occipital grey matter similar trends were noticed but statistical significance was not reached. The timing of white matter development and synchronization of white matter and grey matter maturation in premature-born infants is disturbed. This may contribute to the greater risk of long-term neurological problems of premature infants and to their higher risk for white matter injury.

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Most cited references 26

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Neonatal MRI to predict neurodevelopmental outcomes in preterm infants.

Lianne J Woodward, Peter Anderson, Nicola Austin … (2006)

Very preterm infants are at high risk for adverse neurodevelopmental outcomes. Magnetic resonance imaging (MRI) has been proposed as a means of predicting neurodevelopmental outcomes in this population. We studied 167 very preterm infants (gestational age at birth, 30 weeks or less) to assess the associations between qualitatively defined white-matter and gray-matter abnormalities on MRI at term equivalent (gestational age of 40 weeks) and the risks of severe cognitive delay, severe psychomotor delay, cerebral palsy, and neurosensory (hearing or visual) impairment at 2 years of age (corrected for prematurity). At two years of age, 17 percent of infants had severe cognitive delay, 10 percent had severe psychomotor delay, 10 percent had cerebral palsy, and 11 percent had neurosensory impairment. Moderate-to-severe cerebral white-matter abnormalities present in 21 percent of infants at term equivalent were predictive of the following adverse outcomes at two years of age: cognitive delay (odds ratio, 3.6; 95 percent confidence interval, 1.5 to 8.7), motor delay (odds ratio, 10.3; 95 percent confidence interval, 3.5 to 30.8), cerebral palsy (odds ratio, 9.6; 95 percent confidence interval, 3.2 to 28.3), and neurosensory impairment (odds ratio, 4.2; 95 percent confidence interval, 1.6 to 11.3). Gray-matter abnormalities (present in 49 percent of infants) were also associated, but less strongly, with cognitive delay, motor delay, and cerebral palsy. Moderate-to-severe white-matter abnormalities on MRI were significant predictors of severe motor delay and cerebral palsy after adjustment for other measures during the neonatal period, including findings on cranial ultrasonography. Abnormal findings on MRI at term equivalent in very preterm infants strongly predict adverse neurodevelopmental outcomes at two years of age. These findings suggest a role for MRI at term equivalent in risk stratification for these infants. Copyright 2006 Massachusetts Medical Society.

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Pathogenesis of cerebral white matter injury of prematurity.

O Khwaja, J J Volpe (2008)

Cerebral white matter injury, characterised by loss of premyelinating oligodendrocytes (pre-OLs), is the most common form of injury to the preterm brain and is associated with a high risk of neurodevelopmental impairment. The unique cerebrovascular anatomy and physiology of the premature baby underlies the exquisite sensitivity of white matter to the abnormal milieu of preterm extrauterine life, in particular ischaemia and inflammation. These two upstream mechanisms can coexist and amplify their effects, leading to activation of two principal downstream mechanisms: excitotoxicity and free radical attack. Upstream mechanisms trigger generation of reactive oxygen and nitrogen species. The pre-OL is intrinsically vulnerable to free radical attack due to immaturity of antioxidant enzyme systems and iron accumulation. Ischaemia and inflammation trigger glutamate receptor-mediated injury leading to maturation-dependent cell death and loss of cellular processes. This review looks at recent evidence for pathogenetic mechanisms in white matter injury with emphasis on targets for prevention and treatment of injury.

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Abnormal cerebral structure is present at term in premature infants.

Simon Warfield, T Inder, Petra Hüppi … (2005)

Long-term studies of the outcome of very prematurely born infants have clearly documented that the majority of such infants have significant motor, cognitive, and behavioral deficits. However, there is a limited understanding of the nature of the cerebral abnormality underlying these adverse neurologic outcomes. The overall aim of this study was to define quantitatively the alterations in cerebral tissue volumes at term equivalent in a large longitudinal cohort study of very low birth weight premature infants in comparison to term-born infants by using advanced volumetric 3-dimensional magnetic resonance imaging (MRI) techniques. We also aimed to define any relationship of such perinatal lesions as white matter (WM) injury or other potentially adverse factors to the quantitative structural alterations. Additionally, we wished to identify the relationship of the structural alterations to short-term neurodevelopmental outcome. From November 1998 to December 2000, 119 consecutive premature infants admitted to the neonatal intensive care units at Christchurch Women's Hospital (Christchurch, New Zealand) and the Royal Women's Hospital (Melbourne, Australia) were recruited (88% of eligible) after informed parental consent to undergo an MRI scan at term equivalent. Twenty-one term-born infants across both sites were recruited also. Postacquisition advanced 3-dimensional tissue segmentation with 3-dimensional reconstruction was undertaken to estimate volumes of cerebral tissues: gray matter (GM; cortical and deep nuclear structures), WM (myelinated and unmyelinated), and cerebrospinal fluid (CSF). In comparison to the term-born infants, the premature infants at term demonstrated prominent reductions in cerebral cortical GM volume (premature infants [mean +/- SD]: 178 +/- 41 mL; term infants: 227 +/- 26 mL) and in deep nuclear GM volume (premature infants: 10.8 +/- 4.1 mL; term infants: 13.8 +/- 5.2 mL) and an increase in CSF volume (premature infants: 45.6 +/- 22.1 mL; term infants: 28.9 +/- 16 mL). The major predictors of altered cerebral volumes were gestational age at birth and the presence of cerebral WM injury. Infants with significantly reduced cortical GM and deep nuclear GM volumes and increased CSF volume volumes exhibited moderate to severe neurodevelopmental disability at 1 year of age. This MRI study of prematurely born infants further defines the nature of quantitative cerebral structural abnormalities present as early as term equivalent. The abnormalities particularly involve cerebral neuronal regions including both cortex and deep nuclear structures. The pattern of cerebral alterations is related most significantly to the degree of immaturity at birth and to concomitant WM injury. The alterations are followed by abnormal short-term neurodevelopmental outcome.

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Author and article information

Contributors

Pierre Gressens: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 22 January 2014

Volume: 9

Issue: 1

Electronic Location Identifier: e85829

Affiliations

[1 ]Department of Radiology, Children’s Hospital Los Angeles, Los Angeles, California, United States of America

[2 ]Division of Neonatology, Children’s Hospital Los Angeles, Los Angeles, California, United States of America

[3 ]Dornsife Cognitive Neuroscience Imaging Center, USC, Los Angeles, California, United States of America

[4 ]Rudi Schulte Research Institute, Santa Barbara, California, United States of America

Robert Debre Hospital, France

Author notes

* E-mail: sbluml@ 123456chla.usc.edu

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: SB JLW LP MDN AP. Analyzed the data: SB JLW LP MDN AP. Wrote the paper: SB JLW LP MDN AP.

[¤]

Current address: Department of Pediatric Radiology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States of America

Article

Publisher ID: PONE-D-13-36799

DOI: 10.1371/journal.pone.0085829

PMC ID: 3899075

PubMed ID: 24465731

SO-VID: c108b694-011e-439e-bbad-78e932982048

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 6 September 2013

Date accepted : 2 December 2013

Page count

Pages: 9

Funding

This work was supported by Rudi Schulte Research Institute (SB), National Institutes of Health (K23NS063371 to AP, 1UL1RR031986 to AP, JLW, LP, and P50NS019632 to JLW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Metabolic Maturation of White Matter Is Altered in Preterm Infants

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Abstract

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Most cited references 26

Neonatal MRI to predict neurodevelopmental outcomes in preterm infants.

Pathogenesis of cerebral white matter injury of prematurity.

Abnormal cerebral structure is present at term in premature infants.

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