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The influence of ApoE4 on the clinical outcomes and pathophysiology of degenerative cervical myelopathy
Degenerative cervical myelopathy (DCM) is the most common cause of nontraumatic spinal cord injury in adults worldwide. Surgical decompression is generally effective in improving neurological outcomes and halting progression of myelopathic deterioration. However, a subset of patients experience subo...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Society for Clinical Investigation
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410082/ https://www.ncbi.nlm.nih.gov/pubmed/34369386 http://dx.doi.org/10.1172/jci.insight.149227 |
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author | Desimone, Alexa Hong, James Brockie, Sydney T. Yu, Wenru Laliberte, Alex M. Fehlings, Michael G. |
author_facet | Desimone, Alexa Hong, James Brockie, Sydney T. Yu, Wenru Laliberte, Alex M. Fehlings, Michael G. |
author_sort | Desimone, Alexa |
collection | PubMed |
description | Degenerative cervical myelopathy (DCM) is the most common cause of nontraumatic spinal cord injury in adults worldwide. Surgical decompression is generally effective in improving neurological outcomes and halting progression of myelopathic deterioration. However, a subset of patients experience suboptimal neurological outcomes. Given the emerging evidence that apolipoprotein E4 (ApoE4) allelic status influences neurodegenerative conditions, we examined whether the presence of the ApoE4 allele may account for the clinical heterogeneity of treatment outcomes in patients with DCM. Our results demonstrate that human ApoE4(+) DCM patients have a significantly lower extent of improvement after decompression surgery. Functional analysis of our DCM mouse model in targeted-replacement mice expressing human ApoE4 revealed delayed gait recovery, forelimb grip strength, and hind limb mechanical sensitivity after decompression surgery, compared with their ApoE3 counterparts. This was accompanied by an exacerbated proinflammatory response resulting in higher concentrations of TNF-α, IL-6, CCL3, and CXCL9. At the site of injury, there was a significant decrease in gray matter area, an increase in the activation of microglia/macrophages, and increased astrogliosis after decompression surgery in the ApoE4 mice. Our study is the first to our knowledge to investigate the pathophysiological underpinnings of ApoE4 in DCM, which suggests a possible personalized medicine approach for the treatment of DCM in ApoE4 carriers. |
format | Online Article Text |
id | pubmed-8410082 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-84100822021-09-07 The influence of ApoE4 on the clinical outcomes and pathophysiology of degenerative cervical myelopathy Desimone, Alexa Hong, James Brockie, Sydney T. Yu, Wenru Laliberte, Alex M. Fehlings, Michael G. JCI Insight Research Article Degenerative cervical myelopathy (DCM) is the most common cause of nontraumatic spinal cord injury in adults worldwide. Surgical decompression is generally effective in improving neurological outcomes and halting progression of myelopathic deterioration. However, a subset of patients experience suboptimal neurological outcomes. Given the emerging evidence that apolipoprotein E4 (ApoE4) allelic status influences neurodegenerative conditions, we examined whether the presence of the ApoE4 allele may account for the clinical heterogeneity of treatment outcomes in patients with DCM. Our results demonstrate that human ApoE4(+) DCM patients have a significantly lower extent of improvement after decompression surgery. Functional analysis of our DCM mouse model in targeted-replacement mice expressing human ApoE4 revealed delayed gait recovery, forelimb grip strength, and hind limb mechanical sensitivity after decompression surgery, compared with their ApoE3 counterparts. This was accompanied by an exacerbated proinflammatory response resulting in higher concentrations of TNF-α, IL-6, CCL3, and CXCL9. At the site of injury, there was a significant decrease in gray matter area, an increase in the activation of microglia/macrophages, and increased astrogliosis after decompression surgery in the ApoE4 mice. Our study is the first to our knowledge to investigate the pathophysiological underpinnings of ApoE4 in DCM, which suggests a possible personalized medicine approach for the treatment of DCM in ApoE4 carriers. American Society for Clinical Investigation 2021-08-09 /pmc/articles/PMC8410082/ /pubmed/34369386 http://dx.doi.org/10.1172/jci.insight.149227 Text en © 2021 Desimone et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Desimone, Alexa Hong, James Brockie, Sydney T. Yu, Wenru Laliberte, Alex M. Fehlings, Michael G. The influence of ApoE4 on the clinical outcomes and pathophysiology of degenerative cervical myelopathy |
title | The influence of ApoE4 on the clinical outcomes and pathophysiology of degenerative cervical myelopathy |
title_full | The influence of ApoE4 on the clinical outcomes and pathophysiology of degenerative cervical myelopathy |
title_fullStr | The influence of ApoE4 on the clinical outcomes and pathophysiology of degenerative cervical myelopathy |
title_full_unstemmed | The influence of ApoE4 on the clinical outcomes and pathophysiology of degenerative cervical myelopathy |
title_short | The influence of ApoE4 on the clinical outcomes and pathophysiology of degenerative cervical myelopathy |
title_sort | influence of apoe4 on the clinical outcomes and pathophysiology of degenerative cervical myelopathy |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410082/ https://www.ncbi.nlm.nih.gov/pubmed/34369386 http://dx.doi.org/10.1172/jci.insight.149227 |
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