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      Neonatal White Matter Abnormalities an Important Predictor of Neurocognitive Outcome for Very Preterm Children

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          Abstract

          Background

          Cerebral white matter abnormalities on term MRI are a strong predictor of motor disability in children born very preterm. However, their contribution to cognitive impairment is less certain.

          Objective

          Examine relationships between the presence and severity of cerebral white matter abnormalities on neonatal MRI and a range of neurocognitive outcomes assessed at ages 4 and 6 years.

          Design/Methods

          The study sample consisted of a regionally representative cohort of 104 very preterm (≤32 weeks gestation) infants born from 1998–2000 and a comparison group of 107 full-term infants. At term equivalent, all preterm infants underwent a structural MRI scan that was analyzed qualitatively for the presence and severity of cerebral white matter abnormalities, including cysts, signal abnormalities, loss of white matter volume, ventriculomegaly, and corpus callosal thinning/myelination. At corrected ages 4 and 6 years, all children underwent a comprehensive neurodevelopmental assessment that included measures of general intellectual ability, language development, and executive functioning.

          Results

          At 4 and 6 years, very preterm children without cerebral white matter abnormalities showed no apparent neurocognitive impairments relative to their full-term peers on any of the domain specific measures of intelligence, language, and executive functioning. In contrast, children born very preterm with mild and moderate-to-severe white matter abnormalities were characterized by performance impairments across all measures and time points, with more severe cerebral abnormalities being associated with increased risks of cognitive impairment. These associations persisted after adjustment for gender, neonatal medical risk factors, and family social risk.

          Conclusions

          Findings highlight the importance of cerebral white matter connectivity for later intact cognitive functioning amongst children born very preterm. Preterm born children without cerebral white matter abnormalities on their term MRI appear to be spared many of the cognitive impairments commonly associated with preterm birth. Further follow-up will be important to assess whether this finding persists into the school years.

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          Most cited references32

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          Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis.

          The cognitive and behavioral outcomes of school-aged children who were born preterm have been reported extensively. Many of these studies have methodological flaws that preclude an accurate estimate of the long-term outcomes of prematurity. To estimate the effect of preterm birth on cognition and behavior in school-aged children. MEDLINE search (1980 to November 2001) for English-language articles, supplemented by a manual search of personal files maintained by 2 of the authors. We included case-control studies reporting cognitive and/or behavioral data of children who were born preterm and who were evaluated after their fifth birthday if the attrition rate was less than 30%. From the 227 reviewed studies, cognitive data from 15 studies and behavioral data from 16 studies were selected. Data on population demographics, study characteristics, and cognitive and behavioral outcomes were extracted from each study, entered in a customized database, and reviewed twice to minimize error. Differences between the mean cognitive scores of cases and controls were pooled. Homogeneity across studies was formally tested using a general variance-based method and graphically using Galbraith plots. Linear meta-analysis regression models were fitted to explore the impact of birth weight and gestational age on cognitive outcomes. Study-specific relative risks (RRs) were calculated for the incidence of attention-deficit/hyperactivity disorder (ADHD) and pooled. Quality assessment of the studies was performed based on a 10-point scale. Publication bias was examined using Begg modified funnel plots and formally tested using the Egger weighted-linear regression method. Among 1556 cases and 1720 controls, controls had significantly higher cognitive scores compared with children who were born preterm (weighted mean difference, 10.9; 95% confidence interval [CI], 9.2-12.5). The mean cognitive scores of preterm-born cases and term-born controls were directly proportional to their birth weight (R(2) = 0.51; P<.001) and gestational age (R(2) = 0.49; P<.001). Age at evaluation had no significant correlation with mean difference in cognitive scores (R(2) = 0.12; P =.20). Preterm-born children showed increases in externalizing and internalizing behaviors in 81% of studies and had more than twice the RR for developing ADHD (pooled RR, 2.64; 95% CI, 1.85-3.78). No differences were noted in cognition and behaviors based on the quality of the study. Children who were born preterm are at risk for reduced cognitive test scores and their immaturity at birth is directly proportional to the mean cognitive scores at school age. Preterm-born children also show an increased incidence of ADHD and other behaviors.
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            Neonatal MRI to predict neurodevelopmental outcomes in preterm infants.

            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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              Grey and white matter distribution in very preterm adolescents mediates neurodevelopmental outcome.

              Very preterm (VPT) birth is associated with altered cortical development and long-term neurodevelopmental sequelae. We used voxel-based morphometry to investigate white (WM) and grey matter (GM) distribution in VPT adolescents and controls, and the association with gestational age and neonatal ultrasound findings in the VPT individuals. GM and WM volumes were additionally investigated in relation to adolescent neurodevelopmental outcome. Structural MRI data were acquired with a 1.5 Tesla machine in 218 VPT adolescents (<33 weeks, gestation) and 128 controls aged 14-15 years, and analysed using SPM2 software. VPT individuals compared to controls showed reduced GM in temporal, frontal, occipital cortices and cerebellum, including putamen, insula, cuneus, fusiform gyrus, thalamus and caudate nucleus, and increased GM predominantly in temporal and frontal lobes, including cingulate and fusiform gyri and cerebellum. WM loss was concentrated in the brainstem, internal capsule, temporal and frontal regions and the major fasciculi. WM excesses were observed in temporal, parietal and frontal regions. Investigation of the inter-relationships between brain regions and changes revealed that all selected areas where between-group increased and decreased WM and GM volumes differences were observed, were structurally associated, highlighting the influence that abnormalities in one brain area may exert over others. VPT individuals with evidence of periventricular haemorrhage and ventricular dilatation on neonatal ultrasound exhibited the greatest WM and GM alterations. VPT adolescents obtained lower scores than controls on measures of language and executive function and were more likely to show cognitive impairment compared to controls (27% versus 14%, respectively). Several areas where VPT individuals demonstrated decreased GM and WM volume were linearly associated with gestational age and mediated cognitive impairment. To summarize, our data demonstrates that VPT birth is associated with altered brain structure in adolescence. GM and WM alterations are associated with length of gestation and mediate adolescent neurodevelopmental impairment. Thus, anatomical brain changes may contribute to specific cognitive deficits associated with VPT birth and could be used in the identification of those individuals who may be at increased risk for cognitive impairment.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                28 December 2012
                : 7
                : 12
                : e51879
                Affiliations
                [1 ]Canterbury Child Development Research Group, Department of Psychology, University of Canterbury, Christchurch, New Zealand
                [2 ]New Zealand Brain Research Institute, Christchurch, New Zealand
                [3 ]Department of Psychology, University of Oregon, Eugene, Oregon, United States of America
                [4 ]Departments of Pediatrics, Neurology and Radiology, Washington University School of Medicine, St Louis, Missouri, United States of America
                Hôpital Robert Debré, France
                Author notes

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

                Conceived and designed the experiments: LW TI CC. Performed the experiments: CC LW. Analyzed the data: LW SB CC. Wrote the paper: LW. Assisted with editing the manuscript: CC SB TI.

                Article
                PONE-D-12-28689
                10.1371/journal.pone.0051879
                3532310
                23284800
                59e817b8-f1fe-4d25-9262-6f26176dd22b
                Copyright @ 2012

                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
                : 18 September 2012
                : 7 November 2012
                Page count
                Pages: 9
                Funding
                Funding for this study was provided by the following funding organizations: the New Zealand Health Research Council of New Zealand (ref no: 03/196) (URL: http://www.hrc.govt.nz/); the Neurological Foundation of New Zealand (ref no. 0227PG) (URL: http://www.neurological.org.nz/) and Canterbury Medical Research Foundation (ref. no. 05/01) (URL: http://www.cmrf.org.nz/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Neuroscience
                Developmental Neuroscience
                Medicine
                Clinical Research Design
                Cohort Studies
                Neurology
                Developmental and Pediatric Neurology
                Pediatrics
                Child Development
                Developmental and Pediatric Neurology
                Neonatology
                Radiology
                Diagnostic Radiology
                Magnetic Resonance Imaging

                Uncategorized
                Uncategorized

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