King's College London

Research portal

Long-Term Neuropathological Changes Associated with Cerebral Palsy in a Nonhuman Primate Model of Hypoxic-Ischemic Encephalopathy

Research output: Contribution to journalArticle

Standard

Long-Term Neuropathological Changes Associated with Cerebral Palsy in a Nonhuman Primate Model of Hypoxic-Ischemic Encephalopathy. / McAdams, Ryan M; Fleiss, Bobbi; Traudt, Christopher; Schwendimann, Leslie; Snyder, Jessica M; Haynes, Robin L; Natarajan, Niranjana; Gressens, Pierre; Juul, Sandra E.

In: Developmental Neuroscience, Vol. 39, No. 1-4, 10.05.2017, p. 124-140.

Research output: Contribution to journalArticle

Harvard

McAdams, RM, Fleiss, B, Traudt, C, Schwendimann, L, Snyder, JM, Haynes, RL, Natarajan, N, Gressens, P & Juul, SE 2017, 'Long-Term Neuropathological Changes Associated with Cerebral Palsy in a Nonhuman Primate Model of Hypoxic-Ischemic Encephalopathy', Developmental Neuroscience, vol. 39, no. 1-4, pp. 124-140. https://doi.org/10.1159/000470903

APA

McAdams, R. M., Fleiss, B., Traudt, C., Schwendimann, L., Snyder, J. M., Haynes, R. L., ... Juul, S. E. (2017). Long-Term Neuropathological Changes Associated with Cerebral Palsy in a Nonhuman Primate Model of Hypoxic-Ischemic Encephalopathy. Developmental Neuroscience, 39(1-4), 124-140. https://doi.org/10.1159/000470903

Vancouver

McAdams RM, Fleiss B, Traudt C, Schwendimann L, Snyder JM, Haynes RL et al. Long-Term Neuropathological Changes Associated with Cerebral Palsy in a Nonhuman Primate Model of Hypoxic-Ischemic Encephalopathy. Developmental Neuroscience. 2017 May 10;39(1-4):124-140. https://doi.org/10.1159/000470903

Author

McAdams, Ryan M ; Fleiss, Bobbi ; Traudt, Christopher ; Schwendimann, Leslie ; Snyder, Jessica M ; Haynes, Robin L ; Natarajan, Niranjana ; Gressens, Pierre ; Juul, Sandra E. / Long-Term Neuropathological Changes Associated with Cerebral Palsy in a Nonhuman Primate Model of Hypoxic-Ischemic Encephalopathy. In: Developmental Neuroscience. 2017 ; Vol. 39, No. 1-4. pp. 124-140.

Bibtex Download

@article{ae727f2bbb8b4de58dad4b862881856f,
title = "Long-Term Neuropathological Changes Associated with Cerebral Palsy in a Nonhuman Primate Model of Hypoxic-Ischemic Encephalopathy",
abstract = "BACKGROUND: Cerebral palsy (CP) is the most common motor disability in childhood, with a worldwide prevalence of 1.5-4/1,000 live births. Hypoxic-ischemic encephalopathy (HIE) contributes to the burden of CP, but the long-term neuropathological findings of this association remain limited.METHODOLOGY: Thirty-four term Macaca nemestrina macaques were included in this long-term neuropathological study: 9 control animals delivered by cesarean section and 25 animals with perinatal asphyxia delivered by cesarean section after 15-18 min of umbilical cord occlusion (UCO). UCO animals were randomized to saline (n = 11), therapeutic hypothermia (TH; n = 6), or TH + erythropoietin (Epo; n = 8). Epo was given on days 1, 2, 3, and 7. Animals had serial developmental assessments and underwent magnetic resonance imaging with diffusion tensor imaging at 9 months of age followed by necropsy. Histology and immunohistochemical (IHC) staining of brain and brainstem sections were performed.RESULTS: All UCO animals demonstrated and met the standard diagnostic criteria for human neonates with moderate-to-severe HIE. Four animals developed moderate-to-severe CP (3 UCO and 1 UCO + TH), 9 had mild CP (2 UCO, 3 UCO + TH, 3 UCO + TH + Epo, and 1 control), and 2 UCO animals died. None of the animals treated with TH + Epo died, had moderate-to-severe CP, or demonstrated signs of long-term neuropathological toxicity. Compared to animals grouped together as having no CP (no-CP; controls and mild CP only), animals with CP (moderate and severe) demonstrated decreased fractional anisotropy of multiple white-matter tracts including the corpus callosum and internal capsule, when using Tract-Based Spatial Statistics (TBSS). Animals with CP had decreased staining for cortical neurons and increased brainstem glial scarring compared to animals without CP. The cerebellar cell density of the internal granular layer and white matter was decreased in CP animals compared to that in control animals without CP.CONCLUSIONS/SIGNIFICANCE: In this nonhuman primate HIE model, animals treated with TH + Epo had less brain pathology noted on TBSS and IHC staining, which supports the long-term safety of TH + Epo in the setting of HIE. Animals that developed CP showed white-matter changes noted on TBSS, subtle histopathological changes in both the white and gray matter, and brainstem injury that correlated with CP severity. This HIE model may lend itself to further study of the relationship between brainstem injury and CP.",
keywords = "Journal Article",
author = "McAdams, {Ryan M} and Bobbi Fleiss and Christopher Traudt and Leslie Schwendimann and Snyder, {Jessica M} and Haynes, {Robin L} and Niranjana Natarajan and Pierre Gressens and Juul, {Sandra E}",
note = "{\circledC} 2017 S. Karger AG, Basel.",
year = "2017",
month = "5",
day = "10",
doi = "10.1159/000470903",
language = "English",
volume = "39",
pages = "124--140",
journal = "Developmental Neuroscience",
issn = "0378-5866",
publisher = "S. Karger AG",
number = "1-4",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Long-Term Neuropathological Changes Associated with Cerebral Palsy in a Nonhuman Primate Model of Hypoxic-Ischemic Encephalopathy

AU - McAdams, Ryan M

AU - Fleiss, Bobbi

AU - Traudt, Christopher

AU - Schwendimann, Leslie

AU - Snyder, Jessica M

AU - Haynes, Robin L

AU - Natarajan, Niranjana

AU - Gressens, Pierre

AU - Juul, Sandra E

N1 - © 2017 S. Karger AG, Basel.

PY - 2017/5/10

Y1 - 2017/5/10

N2 - BACKGROUND: Cerebral palsy (CP) is the most common motor disability in childhood, with a worldwide prevalence of 1.5-4/1,000 live births. Hypoxic-ischemic encephalopathy (HIE) contributes to the burden of CP, but the long-term neuropathological findings of this association remain limited.METHODOLOGY: Thirty-four term Macaca nemestrina macaques were included in this long-term neuropathological study: 9 control animals delivered by cesarean section and 25 animals with perinatal asphyxia delivered by cesarean section after 15-18 min of umbilical cord occlusion (UCO). UCO animals were randomized to saline (n = 11), therapeutic hypothermia (TH; n = 6), or TH + erythropoietin (Epo; n = 8). Epo was given on days 1, 2, 3, and 7. Animals had serial developmental assessments and underwent magnetic resonance imaging with diffusion tensor imaging at 9 months of age followed by necropsy. Histology and immunohistochemical (IHC) staining of brain and brainstem sections were performed.RESULTS: All UCO animals demonstrated and met the standard diagnostic criteria for human neonates with moderate-to-severe HIE. Four animals developed moderate-to-severe CP (3 UCO and 1 UCO + TH), 9 had mild CP (2 UCO, 3 UCO + TH, 3 UCO + TH + Epo, and 1 control), and 2 UCO animals died. None of the animals treated with TH + Epo died, had moderate-to-severe CP, or demonstrated signs of long-term neuropathological toxicity. Compared to animals grouped together as having no CP (no-CP; controls and mild CP only), animals with CP (moderate and severe) demonstrated decreased fractional anisotropy of multiple white-matter tracts including the corpus callosum and internal capsule, when using Tract-Based Spatial Statistics (TBSS). Animals with CP had decreased staining for cortical neurons and increased brainstem glial scarring compared to animals without CP. The cerebellar cell density of the internal granular layer and white matter was decreased in CP animals compared to that in control animals without CP.CONCLUSIONS/SIGNIFICANCE: In this nonhuman primate HIE model, animals treated with TH + Epo had less brain pathology noted on TBSS and IHC staining, which supports the long-term safety of TH + Epo in the setting of HIE. Animals that developed CP showed white-matter changes noted on TBSS, subtle histopathological changes in both the white and gray matter, and brainstem injury that correlated with CP severity. This HIE model may lend itself to further study of the relationship between brainstem injury and CP.

AB - BACKGROUND: Cerebral palsy (CP) is the most common motor disability in childhood, with a worldwide prevalence of 1.5-4/1,000 live births. Hypoxic-ischemic encephalopathy (HIE) contributes to the burden of CP, but the long-term neuropathological findings of this association remain limited.METHODOLOGY: Thirty-four term Macaca nemestrina macaques were included in this long-term neuropathological study: 9 control animals delivered by cesarean section and 25 animals with perinatal asphyxia delivered by cesarean section after 15-18 min of umbilical cord occlusion (UCO). UCO animals were randomized to saline (n = 11), therapeutic hypothermia (TH; n = 6), or TH + erythropoietin (Epo; n = 8). Epo was given on days 1, 2, 3, and 7. Animals had serial developmental assessments and underwent magnetic resonance imaging with diffusion tensor imaging at 9 months of age followed by necropsy. Histology and immunohistochemical (IHC) staining of brain and brainstem sections were performed.RESULTS: All UCO animals demonstrated and met the standard diagnostic criteria for human neonates with moderate-to-severe HIE. Four animals developed moderate-to-severe CP (3 UCO and 1 UCO + TH), 9 had mild CP (2 UCO, 3 UCO + TH, 3 UCO + TH + Epo, and 1 control), and 2 UCO animals died. None of the animals treated with TH + Epo died, had moderate-to-severe CP, or demonstrated signs of long-term neuropathological toxicity. Compared to animals grouped together as having no CP (no-CP; controls and mild CP only), animals with CP (moderate and severe) demonstrated decreased fractional anisotropy of multiple white-matter tracts including the corpus callosum and internal capsule, when using Tract-Based Spatial Statistics (TBSS). Animals with CP had decreased staining for cortical neurons and increased brainstem glial scarring compared to animals without CP. The cerebellar cell density of the internal granular layer and white matter was decreased in CP animals compared to that in control animals without CP.CONCLUSIONS/SIGNIFICANCE: In this nonhuman primate HIE model, animals treated with TH + Epo had less brain pathology noted on TBSS and IHC staining, which supports the long-term safety of TH + Epo in the setting of HIE. Animals that developed CP showed white-matter changes noted on TBSS, subtle histopathological changes in both the white and gray matter, and brainstem injury that correlated with CP severity. This HIE model may lend itself to further study of the relationship between brainstem injury and CP.

KW - Journal Article

U2 - 10.1159/000470903

DO - 10.1159/000470903

M3 - Article

C2 - 28486224

VL - 39

SP - 124

EP - 140

JO - Developmental Neuroscience

JF - Developmental Neuroscience

SN - 0378-5866

IS - 1-4

ER -

View graph of relations

© 2018 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454