White Matter Injury In Preterm Infants Research Articles

Dysmaturation of sleep state and electroencephalographic activity after hypoxia-ischaemia in preterm fetal sheep.

Antenatal hypoxia-ischaemia (HI) in preterm fetal sheep can trigger delayed evolution of severe, cystic white matter injury (WMI), in a similar timecourse to WMI in preterm infants. We therefore examined how severe hypoxia-ischaemia affects recovery of electroencephalographic (EEG) activity. Chronically instrumented preterm fetal sheep (0.7 gestation) received 25 min of complete umbilical cord occlusion (UCO, n = 9) or sham occlusion (controls, n = 9), and recovered for 21 days. HI was associated with a shift to lower frequency EEG activity for the first 5 days with persisting loss of EEG power in the delta and theta bands, and initial loss of power in the alpha and beta bands in the first 14 days of recovery. In the final 3 days of recovery, there was a marked rhythmic shift towards higher frequency EEG activity after UCO. The UCO group spent less time in high-voltage sleep, and in the early evening (7:02 pm ± 47 min) abruptly stopped cycling between sleep states, with a shift to a high frequency state for 2 h 48 min ± 40 min, with tonic electromyographic activity. These findings demonstrate persisting EEG and sleep state dysmaturation after severe hypoxia-ischaemia. Loss of fetal or neonatal sleep state cycling in the early evening may be a useful biomarker for evolving cystic WMI.

Effect of Hypoxia-Ischemia on the Expression of Iron-Related Proteins in Neonatal Rat Brains.

Hypoxic-ischemic white matter injury (WMI) pathogenesis in preterm infants is not well established, and iron-related proteins in the brain may play an important role in imbalanced iron metabolism. We aimed to investigate the iron-related protein changes in neonatal rats after hypoxia-ischemia (HI), clarify the role of iron-related proteins in hypoxic-ischemic WMI, and potentially provide a new target for the clinical treatment of hypoxic-ischemic WMI in preterm infants. We adopted a WMI animal model of bilateral common carotid artery electrocoagulation combined with hypoxia in neonatal 3-day-old Sprague-Dawley rats. We observed basic myelin protein (MBP) and iron-related protein expression in the brain (ferritin, transferrin receptor [TfR], and membrane iron transporter 1 [FPN1]) via Western blot and double immunofluorescence staining. The expression of MBP in the WMI group was significantly downregulated on postoperative days (PODs) 14, 28, and 56. Ferritin levels were significantly increased on PODs 3, 7, 14, and 28 and were most significant on POD 28, returning to the sham group level on POD 56. FPN1 levels were significantly increased on PODs 7, 28, and 56 and were still higher than those in the sham group on POD 56. TfR expression was significantly upregulated on PODs 1, 7, and 28 and returned to the sham group level on POD 56. Immunofluorescence staining showed that ferritin, TfR, and FPN1 were expressed in neurons, blood vessels, and oligodendrocytes in the cortex and corpus callosum on POD 28. Compared with the sham group, the immune-positive markers of three proteins in the WMI group were significantly increased. The expression of iron-related proteins in the brain (ferritin, FPN1, and TfR) showed spatiotemporal dynamic changes and may play an important role in hypoxic-ischemic WMI.

Pathogenesis from the microbial-gut-brain axis in white matter injury in preterm infants: A review.

White matter injury (WMI) in premature infants is a unique form of brain injury and a common cause of chronic nervous system conditions such as cerebral palsy and neurobehavioral disorders. Very preterm infants who survive are at high risk of WMI. With developing research regarding the pathogenesis of premature WMI, the role of gut microbiota has attracted increasing attention in this field. As premature infants are a special group, early microbial colonization of the microbiome can affect brain development, and microbiome optimization can improve outcomes regarding nervous system development. As an important communication medium between the gut and the nervous system, intestinal microbes form a microbial-gut-brain axis. This axis affects the occurrence of WMI in premature infants via the metabolites produced by intestinal microorganisms, while also regulating cytokines and mediating oxidative stress. At the same time, deficiencies in the microbiota and their metabolites may exacerbate WMI in premature infants. This confers promise for probiotics and prebiotics as treatments for improving neurodevelopmental outcomes. Therefore, this review attempted to elucidate the potential mechanisms behind the communication of gut bacteria and the immature brain through the gut-brain axis, so as to provide a reference for further prevention and treatment of premature WMI.

Association Between Assisted Reproductive Technology and White Matter Injury in Premature Infants: A Case-Control Study.

Objectives: Whether there is a link between assisted reproductive technology (ART) and brain damage in premature infants remains unclear. The aim of this study was to determine whether premature infants conceived by ART are at a greater risk of developing white matter injury (WMI), as detected by magnetic resonance imaging (MRI) or diffusion-weighted imaging (DWI) within 14 days, than those naturally conceived (NC).Methods: A retrospective case-control study was conducted on singleton premature infants with a gestational age of ≥28 weeks and <34 weeks delivered between 2017 and 2019 at Shengjing Hospital, China Medical University. This study included 638 live births that were stratified into case group (n = 218) and control group (n = 420), depending on the presence or absence of WMI. The exposure proportion of ART was compared between the case and control groups, and a logistic regression model was used to identify whether ART was an independent risk factor for WMI.Results: In the univariate analysis, the exposure proportion of ART conception was higher in cases than in controls (12.84 vs. 7.38%, p = 0.024). According to the multivariable analysis, after adjustment for other variables, the association between ART and WMI remained significant (1.82; 95% confidence interval, 1.04–3.21; P = 0.038).Conclusions: Singleton premature infants conceived by ART have a higher risk of WMI than NC infants. Given that ART is an independent risk factor for WMI in premature infants, more attention should be paid to neurodevelopmental outcomes in this group.

Cyclophilin D-dependent oligodendrocyte mitochondrial ion leak contributes to neonatal white matter injury.

Postnatal failure of oligodendrocyte maturation has been proposed as a cellular mechanism of diffuse white matter injury (WMI) in premature infants. However, the molecular mechanisms for oligodendrocyte maturational failure remain unclear. In neonatal mice and cultured differentiating oligodendrocytes, sublethal intermittent hypoxic (IH) stress activated cyclophilin D-dependent mitochondrial proton leak and uncoupled mitochondrial respiration, leading to transient bioenergetic stress. This was associated with development of diffuse WMI: poor oligodendrocyte maturation, diffuse axonal hypomyelination, and permanent sensorimotor deficit. In normoxic mice and oligodendrocytes, exposure to a mitochondrial uncoupler recapitulated the phenotype of WMI, supporting the detrimental role of mitochondrial uncoupling in the pathogenesis of WMI. Compared with WT mice, cyclophilin D-knockout littermates did not develop bioenergetic stress in response to IH challenge and fully preserved oligodendrocyte maturation, axonal myelination, and neurofunction. Our study identified the cyclophilin D-dependent mitochondrial proton leak and uncoupling as a potentially novel subcellular mechanism for the maturational failure of oligodendrocytes and offers a potential therapeutic target for prevention of diffuse WMI in premature infants experiencing chronic IH stress.

Chondroitin sulfate proteoglycans inhibit the migration and differentiation of oligodendrocyte precursor cells and its counteractive interaction with laminin.

Cerebral white matter injury (WMI) is a recognized problem in premature infants, particularly in those with very low birth weights. Although the survival rate of premature infants has notably increased due to the advancement of modern medical treatments, their likelihood of developmental disability is higher than infants with an average birth weight. It has been previously reported that oligodendrocyte precursor cells (OPCs) are selectively vulnerable to WMI in premature infants. Following brain injury, glial scars may develop within the white matter. Their main constituent is chondroitin sulphate proteoglycans (CSPGs), revealing a potential association between CSPGs and OPCs. In the present study rat OPCs were cultured in vitro, and the effect of CSPGs on the proliferation, migration and differentiation of OPCs was determined. It was revealed that CSPGs did not affect proliferation, but they did inhibit the migration and differentiation of OPCs. It was also identified that the inhibitory effect of CSPGs was counteracted by laminin. Factor analysis revealed that CSPGs and laminin served interactive roles in OPC differentiation. The effect of CSPGs on OPCs was associated with the downregulation of β1-integrin, indicating that CSPGs potentially competitively inhibit the β1-integrin signaling pathway. Collectively, these results suggest that CSPGs serve a role as inhibitors of OPC differentiation and migration, as well as indicating an interaction between CSPGs and laminin. The present study has revealed a potential novel therapeutic target for WMI in premature infants, and identified β1-integrin signaling as a pathological mechanism for dysfunctional myelination in white matter.

Combined fetal inflammation and postnatal hypoxia causes myelin deficits and autism-like behavior in a rat model of diffuse white matter injury.

Diffuse white matter injury (WMI) is a serious problem in extremely preterm infants, and is associated with adverse neurodevelopmental outcome, including cognitive impairments and an increased risk of autism‐spectrum disorders. Important risk factors include fetal or perinatal inflammatory insults and fluctuating cerebral oxygenation. However, the exact mechanisms underlying diffuse WMI are not fully understood and no treatment options are currently available. The use of clinically relevant animal models is crucial to advance knowledge on the pathophysiology of diffuse WMI, allowing the definition of novel therapeutic targets. In the present study, we developed a multiple‐hit animal model of diffuse WMI by combining fetal inflammation and postnatal hypoxia in rats. We characterized the effects on white matter development and functional outcome by immunohistochemistry, MRI and behavioral paradigms. Combined fetal inflammation and postnatal hypoxia resulted in delayed cortical myelination, microglia activation and astrogliosis at P18, together with long‐term changes in oligodendrocyte maturation as observed in 10 week old animals. Furthermore, rats with WMI showed impaired motor performance, increased anxiety and signs of autism‐like behavior, i.e. reduced social play behavior and increased repetitive grooming. In conclusion, the combination of fetal inflammation and postnatal hypoxia in rats induces a pattern of brain injury and functional impairments that closely resembles the clinical situation of diffuse WMI. This animal model provides the opportunity to elucidate pathophysiological mechanisms underlying WMI, and can be used to develop novel treatment options for diffuse WMI in preterm infants.

Region specific oligodendrocyte transcription factor expression in a model of neonatal hypoxic injury

White matter injury (WMI) of prematurity is associated with a spectrum of neurological disorders ranging from mild cognitive and behavioral deficits to cerebral palsy. Translational studies have implicated impaired oligodendrocyte development after hypoxia as the primary cause of WMI, but the underlying mechanisms remain poorly understood. The goal of this study was to identify alterations in the expression of oligodendrocyte precursor cell transcription factors in a mouse model of transient mild global hypoxia.Postnatal day (P) 7 mouse pups were exposed to hypoxia (7.5% O2) for 60minutes. We compared oligodendrocyte differentiation and subsequent myelin formation between hypoxia and sham animals at P9, P14 and P28 by examining the expression of key transcription factor regulators of oligodendrocyte differentiation (Ascl1, Olig1, Olig2, and Nkx2.2), as well as APC, a mature oligodendrocyte marker, in the major white matter regions including the corpus callosum, external capsule and anterior commissure. We also examined the effect on myelin formation by examining two myelin specific protein constituents, myelin associated glycoprotein (MAG) and myelin basic protein (MBP), in white matter tracts and whole brain lysate respectively.We found that transient hypoxia at P7 altered the expression of Ascl1, Olig1 and Nkx2.2, resulting in delayed myelination in the external capsule. In addition, our study showed that oligodendrocyte progenitor cells specified several days prior to a hypoxic event are more susceptible to maturation arrest than those specified shortly prior to hypoxia. Our results suggest that alterations of Ascl1, Olig1 and Nkx2.2 underlie impaired oligodendrocyte differentiation and deficient myelination in WMI. These transcription factors are potential therapeutic targets for the treatment of WMI in preterm infants.

Patterns of increases in interleukin-6 and C-reactive protein as predictors for white matter injury in preterm infants.

The aim of this study was to determine whether patterns of increases in serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels at birth were associated with the development of white matter injury (WMI) in preterm infants with a fetal inflammatory response (FIR). One hundred infants who were born at <32 weeks gestation and had funisitis, as determined by histological evidence of FIR, were studied. Infants were divided into four groups according to IL-6 and CRP levels at birth, with cut-off values of 200 pg/mL and 0.4 mg/dL, respectively. We compared the incidence of WMI, determined by MRI at term-equivalent age, among these groups. The number of infants in each group was 12, 43, 0, and 45 in the high IL-6 and high CRP (HH) group, high IL-6 and low CRP (HL) group, low IL-6 and high CRP (LH) group, and low IL-6 and low CRP (LL) group, respectively. The incidence of WMI was significantly higher in the HH group than in the HL group and LL group (83%, 40%, and 34%, respectively). Multiple logistic regression analysis revealed that a combined elevation in IL-6 and CRP levels was an independent predictor for the development of WMI (odds ratio, 8.3). A combined elevation in serum IL-6 and CRP levels at birth was associated with the development of WMI in preterm infants with FIR.

Pathophysiology of glia in perinatal white matter injury

Injury to the preterm brain has a particular predilection for cerebral white matter. White matter injury (WMI) is the most common cause of brain injury in preterm infants and a major cause of chronic neurological morbidity including cerebral palsy. Factors that predispose to WMI include cerebral oxygenation disturbances and maternal-fetal infection. During the acute phase of WMI, pronounced oxidative damage occurs that targets late oligodendrocyte progenitors (pre-OLs). The developmental predilection for WMI to occur during prematurity appears to be related to both the timing of appearance and regional distribution of susceptible pre-OLs that are vulnerable to a variety of chemical mediators including reactive oxygen species, glutamate, cytokines, and adenosine. During the chronic phase of WMI, the white matter displays abberant regeneration and repair responses. Early OL progenitors respond to WMI with a rapid robust proliferative response that results in a several fold regeneration of pre-OLs that fail to terminally differentiate along their normal developmental time course. Pre-OL maturation arrest appears to be related in part to inhibitory factors that derive from reactive astrocytes in chronic lesions. Recent high field magnetic resonance imaging (MRI) data support that three distinct forms of chronic WMI exist, each of which displays unique MRI and histopathological features. These findings suggest the possibility that therapies directed at myelin regeneration and repair could be initiated early after WMI and monitored over time. These new mechanisms of acute and chronic WMI provide access to a variety of new strategies to prevent or promote repair of WMI in premature infants.

Proinflammatory Cytokine-Receptor Interaction Model Improves the Predictability of Cerebral White Matter Injury in Preterm Infants

Proinflammatory cytokines have been variably linked to development of cerebral white matter injury (WMI) in preterm infants. Because soluble receptors tightly control cytokine bioactivity, we modeled cytokine-receptor interaction as a predictor of WMI. Plasma from 100 preterm infants was assayed for cytokines (tumor necrosis factor alpha, interleukin (IL-1beta, IL-6) and their soluble receptors (sTNF-RI), sTNF-RII, sIL-1RA, and sIL-6R). Cranial ultrasound (US) results were correlated with cytokine and receptor concentrations individually and with cytokine-receptor interaction models (PROC LOGISTIC; SAS Software). Receiver operating characteristic curves were constructed to determine the predictability of WMI. Fifty-two infants with normal US exams were compared with 21 infants with evidence of WMI. There was no association between individual cytokine or receptor concentrations and the development of WMI. However, modeling cytokines with their soluble receptors significantly improved the predictability of WMI. We concluded that consideration of cytokine-receptor interaction may be more important than individual cytokine concentrations alone in determining the role of inflammation in the pathogenesis of WMI in preterm infants.

Understanding intraventricular hemorrhage and white-matter injury in premature infants

Understanding intraventricular hemorrhage and white-matter injury in premature infants