OC003: Can we identify perinatal brain injury in utero

Abstract Background Chorioamnionitis (CHORIO) is a principal risk factor for preterm birth and is the most common pathological abnormality found in the placentae of preterm infants. CHORIO has a multitude of effects on the maternal–placental–fetal axis including profound inflammation. Cumulatively, these changes trigger injury in the developing immune and central nervous systems, thereby increasing susceptibility to chronic sequelae later in life. Despite this and reports of neural–immune changes in children with cerebral palsy, the extent and chronicity of the peripheral immune and neuroinflammatory changes secondary to CHORIO has not been fully characterized. Methods We examined the persistence and time course of peripheral immune hyper-reactivity in an established and translational model of perinatal brain injury (PBI) secondary to CHORIO. Pregnant Sprague–Dawley rats underwent laparotomy on embryonic day 18 (E18, preterm equivalent). Uterine arteries were occluded for 60 min, followed by intra-amniotic injection of lipopolysaccharide (LPS). Serum and peripheral blood mononuclear cells (PBMCs) were collected at young adult (postnatal day P60) and middle-aged equivalents (P120). Serum and PBMCs secretome chemokines and cytokines were assayed using multiplex electrochemiluminescent immunoassay. Multiparameter flow cytometry was performed to interrogate immune cell populations. Results Serum levels of interleukin-1β (IL-1β), IL-5, IL-6, C–X–C Motif Chemokine Ligand 1 (CXCL1), tumor necrosis factor-α (TNF-α), and C–C motif chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) were significantly higher in CHORIO animals compared to sham controls at P60. Notably, CHORIO PBMCs were primed. Specifically, they were hyper-reactive and secreted more inflammatory mediators both at baseline and when stimulated in vitro. While serum levels of cytokines normalized by P120, PBMCs remained primed, and hyper-reactive with a robust pro-inflammatory secretome concomitant with a persistent change in multiple T cell populations in CHORIO animals. Conclusions The data indicate that an in utero inflammatory insult leads to neural–immune changes that persist through adulthood, thereby conferring vulnerability to brain and immune system injury throughout the lifespan. This unique molecular and cellular immune signature including sustained peripheral immune hyper-reactivity (SPIHR) and immune cell priming may be a viable biomarker of altered inflammatory responses following in utero insults and advances our understanding of the neuroinflammatory cascade that leads to perinatal brain injury and later neurodevelopmental disorders, including cerebral palsy.

Download Full-text

Outcome at Age Five Years or Older for Children with Perinatal Brain Injury Treated with Neurohabilitation or Neurodevelopmental Therapy

SSRN Electronic Journal ◽

10.2139/ssrn.3335873 ◽

2019 ◽

Author(s):

Nicolás Garófalo-Gómez ◽

Jesús Barrera-Reséndiz ◽

María Elena Juárez-Colín ◽

María del Consuelo Pedraza-Aguilar ◽

Cristina Carrillo-Prado ◽

...

Keyword(s):

Brain Injury ◽

Perinatal Brain Injury

Download Full-text

Perinatal brain injury and regulation of transcription

Current Opinion in Neurology ◽

10.1097/01.wco.0000218229.73678.a8 ◽

2006 ◽

Vol 19 (2) ◽

pp. 141-147 ◽

Cited By ~ 42

Author(s):

Ying-Chao Chang ◽

Chao-Ching Huang

Keyword(s):

Brain Injury ◽

Regulation Of Transcription ◽

Perinatal Brain Injury

Download Full-text

299 PRE-084, A Sigma-1 Receptor Ligand, Protects Against Excitotoxic Perinatal Brain Injury in Newborn Mice

Archives of Disease in Childhood ◽

10.1136/archdischild-2012-302724.0299 ◽

2012 ◽

Vol 97 (Suppl 2) ◽

pp. A87-A88

Author(s):

E. Griesmaier ◽

A. Posod ◽

M. Gross ◽

V. Neubauer ◽

K. Wegleiter ◽

...

Keyword(s):

Brain Injury ◽

Perinatal Brain Injury ◽

Receptor Ligand ◽

Newborn Mice ◽

Sigma 1 Receptor ◽

Sigma 1

Download Full-text

Abstract TP406: Ipsilesional Myelination is Impaired in Children With Perinatal Arterial Stroke

Stroke ◽

10.1161/str.48.suppl_1.tp406 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Sabrina Yu ◽

Helen Carlson ◽

Adam Kirton

Keyword(s):

Brain Injury ◽

Neurological Disorders ◽

Repeated Measures ◽

Population Based ◽

T Test ◽

Biological Processes ◽

Typically Developing ◽

Inclusion Criteria ◽

Perinatal Brain Injury ◽

Perinatal Stroke

Introduction: Stroke is a leading cause of perinatal brain injury and cerebral palsy. Current therapeutic efforts focus on optimizing developmental curves but the biological processes dictating these outcomes are poorly understood. Alterations in myelination are recognized as a major determinant of outcome in preterm brain injury but are unexplored in perinatal stroke (PS). Hypothesis: Ipsilesional delays in myelination occur in children with PS and are associated with poor developmental outcome. Methods: Participants were identified through the Alberta Perinatal Stroke Project, a population-based research cohort. Inclusion criteria were: 1) MRI-confirmed, unilateral arterial PS, 2) T1-weighted MRI >6mo, 3) absence of other neurological disorders, 4) neurological outcome (Pediatric Stroke Outcome Measure, PSOM), and 5) motor assessments (Assisting Hand Assessment, AHA; Melbourne Assessment). FreeSurfer software measured hemispheric asymmetry in myelination intensity. A second method using ImageJ validated the detection of myelination asymmetry. Overall PSOM scores were classified as poor (>1) or not. Repeated measures ANOVA compared perilesional, ipsilesional remote, and contralesional homologous regions. Myelination ratios for stroke cases were compared to typically developing controls (t-test), PSOM scores (t-test), and motor assessments (Pearson’s correlation). Results: Nineteen arterial stroke cases (mean age: 13.73±4.0yo) and 27 controls (mean age: 12.52±3.7yo) were studied. Stroke cases showed a greater degree of asymmetry with lower myelination in the lesioned hemisphere, compared to controls (p<0.001). Myelination in perilesional regions was decreased compared to ipsilesional remote (p<0.001) and contralesional homologous areas (p<0.001). Ipsilesional remote regions were decreased compared to homologous regions on the contralesional hemisphere (p=0.009). Contralesional myelination was also less than controls (p<0.001). Myelination ratios were not associated with PSOM, AHA, or Melbourne scores (p=0.144, 0.218, 0.366 respectively). Conclusion: Myelination of uninjured brain in the lesioned hemisphere is altered in children with PS. Further study is required to determine clinical significance.

Download Full-text

Glial cell responses in a murine multifactorial perinatal brain injury model

Brain Research ◽

10.1016/j.brainres.2017.12.020 ◽

2018 ◽

Vol 1681 ◽

pp. 52-63 ◽

Cited By ~ 5

Author(s):

Miriam Domowicz ◽

Natasha L. Wadlington ◽

Judith G. Henry ◽

Kasandra Diaz ◽

Miranda J. Munoz ◽

...

Keyword(s):

Brain Injury ◽

Glial Cell ◽

Perinatal Brain Injury ◽

Cell Responses ◽

Injury Model

Download Full-text

The Role of Extracellular Vesicles in the Developing Brain: Current Perspective and Promising Source of Biomarkers and Therapy for Perinatal Brain Injury

Frontiers in Neuroscience ◽

10.3389/fnins.2021.744840 ◽

2021 ◽

Vol 15 ◽

Author(s):

Teena K. J. B. Gamage ◽

Mhoyra Fraser

Keyword(s):

Stem Cell ◽

Brain Injury ◽

Extracellular Vesicles ◽

Inflammatory Responses ◽

Brain Structures ◽

Developing Brain ◽

Long Term Effects ◽

Perinatal Brain Injury ◽

Current Perspective ◽

Promising Source

This comprehensive review focuses on our current understanding of the proposed physiological and pathological functions of extracellular vesicles (EVs) in the developing brain. Furthermore, since EVs have attracted great interest as potential novel cell-free therapeutics, we discuss advances in the knowledge of stem cell- and astrocyte-derived EVs in relation to their potential for protection and repair following perinatal brain injury. This review identified 13 peer-reviewed studies evaluating the efficacy of EVs in animal models of perinatal brain injury; 12/13 utilized mesenchymal stem cell-derived EVs (MSC-EVs) and 1/13 utilized astrocyte-derived EVs. Animal model, method of EV isolation and size, route, timing, and dose administered varied between studies. Notwithstanding, EV treatment either improved and/or preserved perinatal brain structures both macroscopically and microscopically. Additionally, EV treatment modulated inflammatory responses and improved brain function. Collectively this suggests EVs can ameliorate, or repair damage associated with perinatal brain injury. These findings warrant further investigation to identify the optimal cell numbers, source, and dosage regimens of EVs, including long-term effects on functional outcomes.

Download Full-text