White matter injury but not germinal matrix hemorrhage induces elevated osteopontin expression in human preterm brains

AbstractOsteopontin (OPN) is a matricellular protein that mediates various physiological functions and is implicated in neuroinflammation, myelination, and perinatal brain injury. However, its expression in association with brain injury in preterm infants is unexplored. Here we examined the expression of OPN in postmortem brains of preterm infants and explored how this expression is affected in brain injury. We analyzed brain sections from cases with white matter injury (WMI) and cases with germinal matrix hemorrhage (GMH) and compared them to control cases having no brain injury. WMI cases displayed moderate to severe tissue injury in the periventricular and deep white matter that was accompanied by an increase of microglia with amoeboid morphology. Apart from visible hemorrhage in the germinal matrix, GMH cases displayed diffuse white matter injury in the periventricular and deep white matter. In non-injured preterm brains, OPN was expressed at low levels in microglia, astrocytes, and oligodendrocytes. OPN expression was significantly increased in regions with white matter injury in both WMI cases and GMH cases. The main cellular source of OPN in white matter injury areas was amoeboid microglia, although a significant increase was also observed in astrocytes in WMI cases. OPN was not expressed in the germinal matrix of any case, regardless of whether there was hemorrhage. In conclusion, preterm brain injury induces elevated OPN expression in microglia and astrocytes, and this increase is found in sites closely related to injury in the white matter regions but not with the hemorrhage site in the germinal matrix. Thus, it appears that OPN takes part in the inflammatory process in white matter injury in preterm infants, and these findings facilitate our understanding of OPN’s role under both physiological and pathological conditions in the human brain that may lead to greater elucidation of disease mechanisms and potentially better treatment strategies.

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Consensus Approach for Standardizing the Screening and Classification of Preterm Brain Injury Diagnosed With Cranial Ultrasound: A Canadian Perspective

Frontiers in Pediatrics ◽

10.3389/fped.2021.618236 ◽

2021 ◽

Vol 9 ◽

Author(s):

Khorshid Mohammad ◽

James N. Scott ◽

Lara M. Leijser ◽

Hussein Zein ◽

Jehier Afifi ◽

...

Keyword(s):

Brain Injury ◽

White Matter ◽

Preterm Infants ◽

Intraventricular Hemorrhage ◽

White Matter Injury ◽

Cranial Ultrasound ◽

Consensus Approach ◽

Germinal Matrix ◽

Very Preterm Infants ◽

Very Preterm

Acquired brain injury remains common in very preterm infants and is associated with significant risks for short- and long-term morbidities. Cranial ultrasound has been widely adopted as the first-line neuroimaging modality to study the neonatal brain. It can reliably detect clinically significant abnormalities that include germinal matrix and intraventricular hemorrhage, periventricular hemorrhagic infarction, post-hemorrhagic ventricular dilatation, cerebellar hemorrhage, and white matter injury. The purpose of this article is to provide a consensus approach for detecting and classifying preterm brain injury to reduce variability in diagnosis and classification between neonatologists and radiologists. Our overarching goal with this work was to achieve homogeneity between different neonatal intensive care units across a large country (Canada) with regards to classification, timing of brain injury screening and frequency of follow up imaging. We propose an algorithmic approach that can help stratify different grades of germinal matrix-intraventricular hemorrhage, white matter injury, and ventricular dilatation in very preterm infants.

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A Model of Germinal Matrix Hemorrhage in Preterm Rat Pups

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2020.535320 ◽

2020 ◽

Vol 14 ◽

Author(s):

Masako Jinnai ◽

Gabriella Koning ◽

Gagandeep Singh-Mallah ◽

Andrea Jonsdotter ◽

Anna-Lena Leverin ◽

...

Keyword(s):

Brain Injury ◽

White Matter ◽

Subcortical White Matter ◽

Brain Maturation ◽

Germinal Matrix ◽

Motor Functions ◽

Germinal Matrix Hemorrhage ◽

Rat Pups ◽

Extremely Preterm ◽

Extremely Preterm Infants

Germinal matrix hemorrhage (GMH) is a serious complication in extremely preterm infants associated with neurological deficits and mortality. The purpose of the present study was to develop and characterize a grade III and IV GMH model in postnatal day 5 (P5) rats, the equivalent of preterm human brain maturation. P5 Wistar rats were exposed to unilateral GMH through intracranial injection into the striatum close to the germinal matrix with 0.1, 0.2, or 0.3 U of collagenase VII. During 10 days following GMH induction, motor functions and body weight were assessed and brain tissue collected at P16. Animals were tested for anxiety, motor coordination and motor asymmetry on P22–26 and P36–40. Using immunohistochemical staining and neuropathological scoring we found that a collagenase dose of 0.3 U induced GMH. Neuropathological assessment revealed that the brain injury in the collagenase group was characterized by dilation of the ipsilateral ventricle combined with mild to severe cellular necrosis as well as mild to moderate atrophy at the levels of striatum and subcortical white matter, and to a lesser extent, hippocampus and cortex. Within 0.5 h post-collagenase injection there was clear bleeding at the site of injury, with progressive increase in iron and infiltration of neutrophils in the first 24 h, together with focal microglia activation. By P16, blood was no longer observed, although significant gray and white matter brain infarction persisted. Astrogliosis was also detected at this time-point. Animals exposed to GMH performed worse than controls in the negative geotaxis test and also opened their eyes with latency compared to control animals. At P40, GMH rats spent more time in the center of open field box and moved at higher speed compared to the controls, and continued to show ipsilateral injury in striatum and subcortical white matter. We have established a P5 rat model of collagenase-induced GMH for the study of preterm brain injury. Our results show that P5 rat pups exposed to GMH develop moderate brain injury affecting both gray and white matter associated with delayed eye opening and abnormal motor functions. These animals develop hyperactivity and show reduced anxiety in the juvenile stage.

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Technical Nuances in Neuroendoscopic Lavage for Germinal Matrix Hemorrhage in Preterm Infants: Twenty Tips and Pearls after More than One Hundred Procedures

Pediatric Neurosurgery ◽

10.1159/000516183 ◽

2021 ◽

pp. 1-9

Author(s):

Jorge Tirado-Caballero ◽

Jorge Herreria-Franco ◽

Mónica Rivero-Garvía ◽

Gloria Moreno-Madueño ◽

Maria Jose Mayorga-Buiza ◽

...

Keyword(s):

Preterm Infants ◽

Cerebrospinal Fluid Leak ◽

Tips And Tricks ◽

Germinal Matrix ◽

Suitable Alternative ◽

Posthemorrhagic Hydrocephalus ◽

Mortality And Morbidity ◽

Germinal Matrix Hemorrhage ◽

Preoperative Stage ◽

Fluid Leak

Introduction: Posthemorrhagic hydrocephalus in preterm infants is a serious entity related to high mortality and morbidity. Neuroendoscopic lavage (NEL) is a suitable alternative for the management of this pathology. However, as with every endoscopic technique, it requires some experience and several cases to master. Methods: We present a descriptive study of some technical nuances, tips, and tricks that have been learned in the last 8 years with over a hundred NELs performed in preterm infants. These variations are classified into 3 categories according to their temporal relationship with the surgical procedure: preoperative stage, intraoperative stage, and postoperative stage. We include a brief description of each one and the reasons why they are included in our current clinical practice. Results: Twenty tips and pearls were described in detail and are reported here. Preoperative, intraoperative, and postoperative variations were exposed and related to the most frequent complications of this procedure: infection, cerebrospinal fluid leak, and rebleeding. Conclusions: NEL is a useful technique for the management of germinal matrix hemorrhage in preterm infants. These technical nuances have improved the results of our technique and helped us to prevent complications related to the procedure.

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Factors associated with neurodevelopment in preterm infants with systematic inflammation

BMC Pediatrics ◽

10.1186/s12887-021-02583-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Eun Sun Lee ◽

Ee-Kyung Kim ◽

Seung han Shin ◽

Young-Hun Choi ◽

Young Hwa Jung ◽

...

Keyword(s):

White Matter ◽

Preterm Infants ◽

Systemic Inflammation ◽

Head Circumference ◽

Brain Mri ◽

White Matter Injury ◽

Social Emotional ◽

Postmenstrual Age ◽

Neurodevelopmental Impairment ◽

Near Term

Abstract Background Several studies have suggested that adverse neurodevelopment could be induced by systemic inflammation in preterm infants. We aimed to investigate whether preterm infants with systemic inflammation would have impaired neurodevelopment and which biomarkers and neurophysiologic studies during inflammation are associated with poor neurodevelopment. Methods This prospective cohort study enrolled infants born before 30 weeks of gestation or with birth weight < 1250 g. Infants were grouped according to the presence of systemic inflammation: Control (no inflammation, n = 49), I (systemic inflammation, n = 45). Blood and cerebrospinal fluid samples for markers of brain injury and inflammation were collected and amplitude-integrated electroencephalography (aEEG) was performed within 4 h of septic workup. We evaluated aEEG at 35 weeks postmenstrual age (PMA), head circumference at 36 weeks PMA, and brain MRI at discharge. The Bayley Scales of Infant and Toddler Development III (Bayley-III) was performed at a corrected age (CA) of 18 months. Results The I group had more white matter injuries (2 vs. 26.7%, Control vs. I, respectively) at the time of discharge, lower brain functional maturation (9.5 vs. 8), and smaller head size (z-score − 1.45 vs. -2.12) at near-term age and poorer neurodevelopment at a CA of 18 months than the control (p < 0.05). Among the I group, the proportion of immature neutrophils (I/T ratios) and IL-1 beta levels in the CSF were associated with aEEG measures at the day of symptom onset (D0). Seizure spike on aEEG at D0 was significantly correlated with motor and social-emotional domains of Bayley-III (p < 0.05). The I/T ratio and CRP and TNF-α levels of blood at D0, white matter injury on MRI at discharge, head circumference and seizure spikes on aEEG at near-term age were associated with Bayley-III scores at a CA of 18 months. Conclusions Systemic inflammation induced by clinical infection and NEC are associated with neurodevelopmental impairment in preterm infants. The seizure spike on aEEG, elevated I/T ratio, CRP, and plasma TNF-alpha during inflammatory episodes are associated with poor neurodevelopment.

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White Matter Injury in Early Brain Injury after Subarachnoid Hemorrhage

Cell Transplantation ◽

10.1177/0963689718812054 ◽

2018 ◽

Vol 28 (1) ◽

pp. 26-35 ◽

Cited By ~ 5

Author(s):

Jinwei Pang ◽

Jianhua Peng ◽

Ping Yang ◽

Li Kuai ◽

Ligang Chen ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

White Matter ◽

Early Brain Injury ◽

Therapeutic Strategies ◽

White Matter Injury ◽

High Morbidity ◽

Normal Brain ◽

Neurological Outcomes ◽

Multiple Substrates

Subarachnoid hemorrhage (SAH) is a major cause of high morbidity, disability, and mortality in the field of neurovascular disease. Most previous SAH studies have focused on improving cerebral blood flow, reducing cerebral vasospasm, reducing neuronal calcium overload, and other treatments. While these studies showed exciting findings in basic science, therapeutic strategies based on the findings have not significantly improved neurological outcomes in patients with SAH. Currently, the only drug proven to effectively reduce the neurological defects of SAH patients is nimodipine. Current advances in imaging technologies in the field of stroke have confirmed that white matter injury (WMI) plays an important role in the prognosis of types of stroke, and suggests that WMI protection is essential for functional recovery and poststroke rehabilitation. However, WMI injury in relation to SAH has remained obscure until recently. An increasing number of studies suggest that the current limitations for SAH treatment are probably linked to overlooked WMI in previous studies that focused only on neurons and gray matter. In this review, we discuss the biology and functions of white matter in the normal brain, and discuss the potential pathophysiology and mechanisms of early brain injury after SAH. Our review demonstrates that WMI encompasses multiple substrates, and, therefore, more than one pharmacological approach is necessary to preserve WMI and prevent neurobehavioral impairment after SAH. Strategies targeting both neuronal injury and WMI may potentially provide a novel future for SAH knowledge and treatment.

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