The influence of ApoE4 on the clinical outcomes and pathophysiology of degenerative cervical myelopathy

Autor: Wen-Ru Yu, James Hong, Alexa Desimone, Michael G. Fehlings, Sydney T. Brockie, Alex M. Laliberte
Rok vydání: 2021
Předmět:
Male
Aging
medicine.medical_specialty
Apolipoprotein E4
Models
Neurological
Hindlimb
Mouse models
Proinflammatory cytokine
Mice
03 medical and health sciences
Myelopathy
Grip strength
Postoperative Complications
0302 clinical medicine
Internal medicine
medicine
Animals
Humans
Spinal cord injury
Alleles
030304 developmental biology
Neurologic Examination
0303 health sciences
business.industry
Cervical Cord
Genetic Variation
Neurodegenerative Diseases
Recovery of Function
General Medicine
Middle Aged
Decompression
Surgical
medicine.disease
Pathophysiology
3. Good health
Astrogliosis
Disease Models
Animal
medicine.anatomical_structure
Disease Progression
Cardiology
Surgery
Female
lipids (amino acids
peptides
and proteins)
Symptom Assessment
Forelimb
business
human activities
030217 neurology & neurosurgery
Research Article
Neuroscience
Zdroj: JCI Insight
ISSN: 2379-3708
DOI: 10.1172/jci.insight.149227
Popis: 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.
Databáze: OpenAIRE
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