White Matter Injury Of Prematurity Research Articles

All but Small: miRNAs from Wharton's Jelly-Mesenchymal Stromal Cell Small Extracellular Vesicles Rescue Premature White Matter Injury after Intranasal Administration.

White matter injury (WMI) is a common neurological issue in premature-born neonates, often causing long-term disabilities. We recently demonstrated a key beneficial role of Wharton's jelly mesenchymal stromal cell-derived small extracellular vesicles (WJ-MSC-sEVs) microRNAs (miRNAs) in WMI-related processes in vitro. Here, we studied the functions of WJ-MSC-sEV miRNAs in vivo using a preclinical rat model of premature WMI. Premature WMI was induced in rat pups through inflammation and hypoxia-ischemia. Small EVs were purified from the culture supernatant of human WJ-MSCs. The capacity of WJ-MSC-sEV-derived miRNAs to decrease microglia activation and promote oligodendrocyte maturation was evaluated by knocking down (k.d) DROSHA in WJ-MSCs, releasing sEVs containing significantly less mature miRNAs. Wharton's jelly MSC-sEVs intranasally administrated 24 h upon injury reached the brain within 1 h, remained detectable for at least 24 h, significantly reduced microglial activation, and promoted oligodendrocyte maturation. The DROSHA k.d in WJ-MSCs lowered the therapeutic capabilities of sEVs in experimental premature WMI. Our results strongly indicate the relevance of miRNAs in the therapeutic abilities of WJ-MSC-sEVs in premature WMI in vivo, opening the path to clinical application.

MicroRNA Cargo in Wharton’s Jelly MSC Small Extracellular Vesicles: Key Functionality to In Vitro Prevention and Treatment of Premature White Matter Injury

SummaryPreterm birth is the leading cause of childhood morbidity and mortality and can result in white matter injury (WMI), leading to long-term neurological disabilities with global health burden. Mesenchymal stromal cell-derived small extracellular vesicles (MSC-sEV) are a promising therapeutic agent for treating perinatal neurological injury. They carry microRNAs (miRNAs) predicted to be involved in the onset of premature WMI. We hypothesize that miRNAs have a key function in the beneficial effects of MSC-sEV. We isolated MSC from umbilical cord tissue, the Wharton’s jelly (WJ), and purified small extracellular vesicles (sEV) from WJ-MSC culture supernatant by ultracentrifugation and size exclusion chromatography. The miRNA content was quantified by real-time polymerase chain reaction. A luciferase gene assay validated silencing of TP53 and TAOK1, which we previously identified as predicted target genes of MSC-sEV miRNAs by Next Generation Sequencing and pathway enrichment analysis. The impact of sEV miRNAs on oligodendroglial maturation and neuronal apoptosis was evaluated using an in vitro oxygen-glucose deprivation model (OGD/R) by knocking-down DROSHA in WJ-MSC, which initiates miRNA processing. WJ-MSC-sEV contained miRNAs involved in WMI, namely hsa-miR-22-3p, hsa-miR-21-5p, hsa-miR-27b-3p, and the hsa-let-7 family. The luciferase assay strongly indicated an inhibitory effect of sEV miRNAs on the gene expression of TP53 and TAOK1. Small EV initiated oligodendrocyte maturation and reduced OGD/R-mediated neuronal apoptosis. Knocking-down DROSHA in WJ-MSC reduced the expression of sEV miRNAs and led to the loss of their beneficial effects. Our in vitro study strongly indicates the key function of miRNAs in the therapeutic potential of WJ-MSC-sEV in premature WMI.

Neuroradiological Mimics of Periventricular Leukomalacia

Periventricular leukomalacia (PVL) is a term reserved to describe white matter injury in the premature brain. In this review article, the authors highlight the common and rare pathologies mimicking the chronic stage of PVL and propose practical clinico-radiological criteria that would aid in diagnosis and management. The authors first describe the typical brain MRI (magnetic resonance imaging) features of PVL. Based on their clinical presentation, pathologic entities and their neuroimaging findings were clustered into distinct categories. Three clinical subgroups were identified: healthy children, children with stable/nonprogressive neurological disorder, and those with progressive neurological disorder. The neuroradiological discriminators are described in each subgroup with relevant differential diagnoses. The mimics were broadly classified into normal variants, acquired, and inherited disorders. The term "PVL" should be used appropriately as it reflects its pathomechanism. The phrase "white matter injury of prematurity" or "brain injury of prematurity" is more specific. Discrepancies in imaging and clinical presentation must be tread with caution and warrant further investigations to exclude other possibilities.

HIFα Regulates Developmental Myelination Independent of Autocrine Wnt Signaling.

The developing CNS is exposed to physiological hypoxia, under which hypoxia-inducible factor α (HIFα) is stabilized and plays a crucial role in regulating neural development. The cellular and molecular mechanisms of HIFα in developmental myelination remain incompletely understood. A previous concept proposes that HIFα regulates CNS developmental myelination by activating the autocrine Wnt/β-catenin signaling in oligodendrocyte progenitor cells (OPCs). Here, by analyzing a battery of genetic mice of both sexes, we presented in vivo evidence supporting an alternative understanding of oligodendroglial HIFα-regulated developmental myelination. At the cellular level, we found that HIFα was required for developmental myelination by transiently controlling upstream OPC differentiation but not downstream oligodendrocyte maturation and that HIFα dysregulation in OPCs but not oligodendrocytes disturbed normal developmental myelination. We demonstrated that HIFα played a minor, if any, role in regulating canonical Wnt signaling in the oligodendroglial lineage or in the CNS. At the molecular level, blocking autocrine Wnt signaling did not affect HIFα-regulated OPC differentiation and myelination. We further identified HIFα-Sox9 regulatory axis as an underlying molecular mechanism in HIFα-regulated OPC differentiation. Our findings support a concept shift in our mechanistic understanding of HIFα-regulated CNS myelination from the previous Wnt-dependent view to a Wnt-independent one and unveil a previously unappreciated HIFα-Sox9 pathway in regulating OPC differentiation.SIGNIFICANCE STATEMENT Promoting disturbed developmental myelination is a promising option in treating diffuse white matter injury, previously called periventricular leukomalacia, a major form of brain injury affecting premature infants. In the developing CNS, hypoxia-inducible factor α (HIFα) is a key regulator that adapts neural cells to physiological and pathologic hypoxic cues. The role and mechanism of HIFα in oligodendroglial myelination, which is severely disturbed in preterm infants affected with diffuse white matter injury, is incompletely understood. Our findings presented here represent a concept shift in our mechanistic understanding of HIFα-regulated developmental myelination and suggest the potential of intervening with an oligodendroglial HIFα-mediated signaling pathway to mitigate disturbed myelination in premature white matter injury.

Advance in MRI assessment of white matter injury and brain development in premature infants

Premature white matter injury(WMI) is the immature white matter injury caused by ischemia, hypoxia and inflammation, which will affect normal neurodevelopment process and cause poor neurological outcomes.MRI has been widely used in early diagnosis of WMI because it can reflect the anatomical and pathological changes of WMI in premature infants.Functional MRI, such as diffusion-tensor imaging and magnetic resonance spectroscopy, can help quantitative assessment of the severity of WMI and neurodevelopment process so as to predict its neurodevelopment prognosis.This review summarizes the progresses in the application of MRI in the quantitative assessment of WMI and brain development in preture infants and its neurological outcomes. Key words: White matter injury; Brain development; Premature infant

Early periventricular leukomalacia in preterm neonates

Background: Preterm neonates are at increased risk for brain injury. More than 10% will sustain neurological injuries leading to significant learning disabilities, motor developmental delay, cerebral palsy, seizures and mental retardation. Periventricular leukomalacia (PVL) is the most common form of white matter injury of prematurity. The objective of the present study was to identify the incidence of early periventricular leukomalacia (PVL) and its associated risk factors in the study group.Methods: All preterm neonates with either Gestational age <32weeks and/or Birth weight <1500 grams who were admitted to Neonatal Intensive Care Unit within the period of 1st November 2013 to 30th April 2015 were taken for study. A total of 112 babies met the inclusion criteria but 104 were finally taken into the study. Screening of intraventricular haemorrhage and early PVL changes in VLBW babies was done by neurosonogram on day 3 and day 14 of life by a single well qualified radiologist. Follow up cranial ultrasound was done weekly for the babies who were diagnosed to have IVH and/or PVL by day 14 of life.Results: The incidence of early periventricular leukomalacia in very low birth weight babies in present study was 7.7%. It was seen that 87.5% babies had periventricular flares and 12.5% babies had cystic changes. It was seen that birth weight<1000grams (OR 0.006; CI:0.00-0.50; p value 0.023) and neonatal sepsis (OR 80.9; CI:1.65-3947.6;p value 0.027) significantly increased the risk of developing PVL in VLBW babies. The duration of hospital stay was found to be significantly increased in babies having PVL.Conclusions: The incidence of early periventricular leukomalacia in babies born <32weeks gestation and/or birth weight<1500grams is 7.7%. Birth weight <1000 grams and neonatal sepsis were found to increase the risk of periventricular leukomalacia in these babies.

White Matter Injury of Prematurity: Its Mechanisms and Clinical Features.

A developing central nervous system is vulnerable to various insults such as infection and ischemia. While increased understanding of the dynamic nature of brain development allows a deeper insight into the pathophysiology of perinatal brain injury, the precise nature of specific fetal and neonatal brain injuries and their short- and long-term clinical consequences need special attention and further elucidation. The current review will describe the pathophysiological aspects and clinical significance of white matter injury of prematurity, a main form of perinatal brain injury in premature newborns, with a particular emphasis on its potential antenatal components.

Application of diffusion tensor imaging in the neonatal brain development and injury

Diffusion tensor imaging (DTI) can reflect the brain structure and development more quantitatively and intuitively than conventional magnetic resonance sequence by obtaining the diffusion properties of water molecules.In neonatal brain developmental research, DTI could be used to study the developmental regularities of white matter tracts and cerebral structure deformity.It can also help to explore the relationship between white matter microstructure and neurodevelopmental outcome.In the study of brain injury, including premature white matter injury, hypoxic ischemic encephalopathy, neonatal stroke, and so on, DTI can diagnose the brain microstructure injury precisely, evaluate the effectiveness of interventions and predict the long-term neurodevelopmental outcome.DTI may have good prospect in research and clinical application on neonatal brain development and injury. Key words: Diffusion tensor imaging; Infant, newborn; Brain development; Brain injury

Monitoring of newborns at high risk for brain injury.

Due to the increasing number of surviving preterm newborns and to the recognition of therapeutic hypothermia as the current gold standard in newborns with hypoxic-ischaemic encephalopathy, there has been a growing interest in the implementation of brain monitoring tools in newborns at high risk for neurological disorders.Among the most frequent neurological conditions and presentations in the neonatal period, neonatal seizures and neonatal status epilepticus, paroxysmal non-epileptic motor phenomena, hypoxic-ischaemic encephalopathy, white matter injury of prematurity and stroke require specific approaches to diagnosis. In this review we will describe the characteristics, aims, indications and limitations of routinely available diagnostic techniques such as conventional and amplitude-integrated EEG, evoked potentials, cranial ultrasound and brain MRI. We will conclude by briefly outlining potential future perspectives from research studies.

Edge density imaging: Mapping the anatomic embedding of the structural connectome within the white matter of the human brain

The structural connectome has emerged as a powerful tool to characterize the network architecture of the human brain and shows great potential for generating important new biomarkers for neurologic and psychiatric disorders. The edges of the cerebral graph traverse white matter to interconnect cortical and subcortical nodes, although the anatomic embedding of these edges is generally overlooked in the literature. Mapping the paths of the connectome edges could elucidate the relative importance of individual white matter tracts to the overall network topology of the brain and also lead to a better understanding of the effect of regionally-specific white matter pathology on cognition and behavior. In this work, we introduce edge density imaging (EDI), which maps the number of network edges that pass through every white matter voxel. Test–retest analysis shows good to excellent reliability for edge density (ED) measurements, with consistent results using different cortical and subcortical parcellation schemes and different diffusion MR imaging acquisition parameters. We also demonstrate that ED yields complementary information to both traditional and emerging voxel-wise metrics of white matter microstructure and connectivity, including fractional anisotropy, track density, fiber orientation dispersion and neurite density. Our results demonstrate spatially ordered variations of ED throughout the white matter, notably including greater ED in posterior than anterior cerebral white matter. The EDI framework is employed to map the white matter regions that are enriched with pathways connecting rich club nodes and also those with high densities of intra-modular and inter-modular edges. We show that periventricular white matter has particularly high ED and high densities of rich club edges, which is significant for diseases in which these areas are selectively affected, ranging from white matter injury of prematurity in infants to leukoaraiosis in the elderly. Using edge betweenness centrality, we identify specific white matter regions involved in a large number of shortest paths, some containing highly connected rich club edges while others are relatively isolated within individual modules. Overall, these findings reveal an intricate relationship between white matter anatomy and the structural connectome, motivating further exploration of EDI for biomarkers of cognition and behavior.

Corpus callosum thickness in children: an MR pattern-recognition approach on the midsagittal image.

Thickening of the corpus callosum is an important feature of development, whereas thinning of the corpus callosum can be the result of a number of diseases that affect development or cause destruction of the corpus callosum. Corpus callosum thickness reflects the volume of the hemispheres and responds to changes through direct effects or through Wallerian degeneration. It is therefore not only important to evaluate the morphology of the corpus callosum for congenital anomalies but also to evaluate the thickness of specific components or the whole corpus callosum in association with other findings. The goal of this pictorial review is raise awareness that the thickness of the corpus callosum can be a useful feature of pathology in pediatric central nervous system disease and must be considered in the context of the stage of development of a child. Thinning of the corpus callosum can be primary or secondary, and generalized or focal. Primary thinning is caused by abnormal or failed myelination related to the hypomyelinating leukoencephalopathies, metabolic disorders affecting white matter, and microcephaly. Secondary thinning of the corpus callosum can be caused by diffuse injury such as hypoxic-ischemic encephalopathy, human immunodeficiency virus (HIV) encephalopathy, hydrocephalus, dysmyelinating conditions and demyelinating conditions. Focal disturbance of formation or focal injury also causes localized thinning, e.g., callosal dysgenesis, metabolic disorders with localized effects, hypoglycemia, white matter injury of prematurity, HIV-related atrophy, infarction and vasculitis, trauma and toxins. The corpus callosum might be too thick because of a primary disorder in which the corpus callosum finding is essential to diagnosis; abnormal thickening can also be secondary to inflammation, infection and trauma.

White Matter NAA/Cho and Cho/Cr Ratios at MR Spectroscopy Are Predictive of Motor Outcome in Preterm Infants

To determine (a) whether diffuse white matter injury of prematurity is associated with an increased choline (Cho)-to-creatine (Cr) ratio and a reduced N-acetylaspartate (NAA)-to-Cho ratio and whether these measures can be used as biomarkers of outcome and (b) if changes in peak area metabolite ratios at magnetic resonance (MR) spectroscopy are associated with changes in T2 and fractional anisotropy (FA) at MR imaging. The local ethics committee approved this study, and informed parental consent was obtained for each infant. At term-equivalent age, 43 infants born at less than 32 weeks gestation underwent conventional and quantitative diffusion-tensor and T2-weighted MR imaging. Single-voxel point-resolved proton (hydrogen 1) MR spectroscopy was performed from a 2-cm(3) voxel centered in the posterior periventricular white matter. Outcome was evaluated by using Bayley scales at a corrected age of 1 year. Associations were investigated with Pearson product moment or Spearman rank order correlation. Differences in ratios in infants with and infants without impairment were tested by using t tests. NAA/Cho and Cho/Cr ratios correlated with the scaled gross motor score and the composite motor score, independent of gestational age (P < .05). FA at diffusion-tensor MR imaging and T2 at MR imaging correlated with the NAA/Cho ratio (P < .05 for both) but not with the Cho/Cr ratio. Infants with motor scores of less than 85 (impaired) had an increased Cho/Cr ratio (P < .03) and a reduced NAA/Cho ratio (P < .01) compared to those without impairment. A combination of increased Cho/Cr ratio and decreased NAA/Cho ratio predicted impaired motor outcome at a corrected age of 1 year with a sensitivity of 0.80 (95% confidence interval [CI]: 0.57, 0.94) and a specificity of 0.80 (95% CI: 0.66, 0.88). The combination of Cho/Cr and NAA/Cho ratios measured in the posterior periventricular white matter at term-equivalent age is predictive of motor outcome at 1 year in infants born at less than 32 weeks gestation.

Pathogenesis of cerebral white matter injury of prematurity

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...

Diffusion tensor imaging: serial quantitation of white matter tract maturity in premature newborns

Magnetic resonance diffusion tensor imaging (DTI) enables the discrimination of white matter pathways before myelination is evident histologically or on conventional MRI. In this investigation, 14 premature neonates with no evidence of white matter abnormalities by conventional MRI were studied with DTI. A custom MR-compatible incubator with a novel high sensitivity neonatal head coil and improved acquisition and processing techniques were employed to increase image quality and spatial resolution. The technical improvements enabled tract-specific quantitative characterization of maturing white matter, including several association tracts and subcortical projection tracts not previously investigated in neonates by MR. Significant differences were identified between white matter pathways, with earlier maturing commissural tracts of the corpus callosum, and deep projection tracts of the cerebral peduncle and internal capsule exhibiting lower mean diffusivity ( D av) and higher fractional anisotropy (FA) than later maturing subcortical projection and association pathways. Maturational changes in white matter tracts included reductions in D av and increases in FA with age due primarily to decreases in the two minor diffusion eigenvalues ( λ 2 and λ 3). This work contributes to the understanding of normal white matter development in the preterm neonatal brain, an important step toward the use of DTI for the improved evaluation and treatment of white matter injury of prematurity.