Differential susceptibility to axonopathy in necrotic and non-necrotic perinatal white matter injury

Art Riddle, Jennifer Maire, Xi Gong, Kevin X. Chen, Christopher (Chris) Kroenke, Alan (Roger) Hohimer, Stephen Back

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Background and Purpose-: White matter injury (WMI) is the leading cause of brain injury in preterm survivors and Results in myelination failure. Although axonal degeneration occurs in necrotic lesions, the role of axonopathy in myelination failure remains controversial for diffuse non-necrotic WMI, which is currently the major form of WMI. We determined the burden of axonopathy in diffuse lesions. Methods-: We analyzed WMI in a preterm fetal sheep model of global cerebral ischemia that replicates the relative burden of necrotic and non-necrotic human WMI. WMI was analyzed at 1 or 2 weeks after ischemia and identified by ex vivo high-field (11.7 Tesla) magnetic resonance imaging of fixed brain tissue. Axonal integrity was analyzed by immunohistochemical detection of axon injury markers and by transmission electron microscopy to quantify axon loss and degeneration in magnetic resonance imaging-defined lesions. Results-: Axonal degeneration, defined by staining for neurofilament protein and β-amyloid precursor protein, was restricted to discrete necrotic foci with robust microglial activation. Unexpectedly, axonal degeneration was not visualized in the major form of WMI, which comprised large non-necrotic lesions with diffuse reactive astrogliosis. In these major lesions, quantitative electron microscopy studies confirmed no significant differences in the density of intact and degenerating axons or in the distribution of axon diameters relative to controls. Conclusions-: The mechanism of myelination failure differs significantly in perinatal WMI dependent on the burden of necrosis. Axonopathy is associated with focal necrotic injury but not with primary diffuse non-necrotic lesions, which supports that intact axons in the primary lesions are potential targets for myelination.

Original languageEnglish (US)
Pages (from-to)178-184
Number of pages7
JournalStroke
Volume43
Issue number1
DOIs
StatePublished - Jan 2012

Fingerprint

Wounds and Injuries
Axons
Magnetic Resonance Imaging
White Matter
Neurofilament Proteins
Amyloidogenic Proteins
Protein Precursors
Brain Ischemia
Transmission Electron Microscopy
Brain Injuries
Sheep
Electron Microscopy
Necrosis
Ischemia
Staining and Labeling
Brain

Keywords

  • axonal injury
  • electron microscopy
  • hypoxia-ischemia
  • prematurity
  • white matter injury

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialized Nursing

Cite this

Differential susceptibility to axonopathy in necrotic and non-necrotic perinatal white matter injury. / Riddle, Art; Maire, Jennifer; Gong, Xi; Chen, Kevin X.; Kroenke, Christopher (Chris); Hohimer, Alan (Roger); Back, Stephen.

In: Stroke, Vol. 43, No. 1, 01.2012, p. 178-184.

Research output: Contribution to journalArticle

Riddle, Art ; Maire, Jennifer ; Gong, Xi ; Chen, Kevin X. ; Kroenke, Christopher (Chris) ; Hohimer, Alan (Roger) ; Back, Stephen. / Differential susceptibility to axonopathy in necrotic and non-necrotic perinatal white matter injury. In: Stroke. 2012 ; Vol. 43, No. 1. pp. 178-184.
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