title: Differential susceptibility to axonopathy in necrotic and non-necrotic perinatal white matter injury.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239-3098, USA.
authors.forename: Art
authors.initials: A
authors.lastname: Riddle
authors.forename: Jennifer
authors.initials: J
authors.lastname: Maire
authors.forename: Xi
authors.initials: X
authors.lastname: Gong
authors.forename: Kevin X
authors.initials: KX
authors.lastname: Chen
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Kroenke
authors.forename: A Roger
authors.initials: AR
authors.lastname: Hohimer
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Back
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology*; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology*; D009336:Necrosis / Q000378:metabolism / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology*; D016900:Neurofilament Proteins / Q000378:metabolism; D011247:Pregnancy; D012756:Sheep
chemical_list: D016564:Amyloid beta-Protein Precursor; D016900:Neurofilament Proteins
references.citation: Acta Neuropathol. 2007 Dec;114(6):619-31
references.pmid: 17912538
references.citation: Pediatr Res. 2001 Apr;49(4):453-7
references.pmid: 11264425
references.citation: Nature. 2005 Dec 22;438(7071):1167-71
references.pmid: 16372012
references.citation: J Neurocytol. 2003 Nov;32(9):1165-79
references.pmid: 15044847
references.citation: Brain Res. 2009 Dec 8;1301:100-9
references.pmid: 19747899
references.citation: Ann Neurol. 2008 Apr;63(4):520-30
references.pmid: 18393269
references.citation: J Neuropathol Exp Neurol. 2004 Aug;63(8):872-81
references.pmid: 15330341
references.citation: JAMA. 2006 Oct 4;296(13):1602-8
references.pmid: 17018805
references.citation: Arch Neurol. 1962 Nov;7:386-410
references.pmid: 13966380
references.citation: J Anat. 2010 Oct;217(4):429-35
references.pmid: 20408904
references.citation: Lancet Neurol. 2009 Nov;8(11):1042-55
references.pmid: 19800293
references.citation: Clin Perinatol. 2008 Dec;35(4):735-48, vi-vii
references.pmid: 19026337
references.citation: J Neuropathol Exp Neurol. 1997 Mar;56(3):219-35
references.pmid: 9056536
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11555-60
references.pmid: 20534434
references.citation: Clin Neuropathol. 2001 Mar-Apr;20(2):87-91
references.pmid: 11327303
references.citation: Pediatr Res. 2003 Aug;54(2):263-9
references.pmid: 12736386
references.citation: J Neurophysiol. 1998 Jan;79(1):95-105
references.pmid: 9425180
references.citation: Cereb Cortex. 2009 Dec;19(12):2916-29
references.pmid: 19363145
references.citation: J Cereb Blood Flow Metab. 2007 Feb;27(2):334-47
references.pmid: 16757980
references.citation: Ann Neurol. 2012 Jan;71(1):93-109
references.pmid: 22275256
references.citation: J Neurosci. 2000 Jan 1;20(1):34-42
references.pmid: 10627578
references.citation: J Child Neurol. 2006 Jul;21(7):580-1
references.pmid: 16970847
references.citation: Neuroimage. 2005 May 1;25(4):1205-13
references.pmid: 15850738
references.citation: Semin Pediatr Neurol. 1998 Sep;5(3):180-9
references.pmid: 9777676
references.citation: Ann N Y Acad Sci. 2010 Jan;1184:68-86
references.pmid: 20146691
references.citation: Neurochem Int. 2010 Nov;57(4):359-66
references.pmid: 20380859
references.citation: Pediatr Neurol. 1997 May;16(4):296-300
references.pmid: 9258961
references.citation: Ann Neurol. 2011 Sep;70(3):493-507
references.pmid: 21796666
references.citation: Nat Med. 2005 Sep;11(9):966-72
references.pmid: 16086023
references.citation: J Neurosci. 2006 Mar 15;26(11):3045-55
references.pmid: 16540583
references.citation: Ann Neurol. 2009 Nov;66(5):682-93
references.pmid: 19938170
references.citation: Ann Neurol. 2005 Jul;58(1):108-20
references.pmid: 15984031
references.citation: Curr Opin Neurobiol. 2006 Oct;16(5):508-14
references.pmid: 16945520
references.citation: Pediatr Neurol. 1995 Sep;13(2):161-3
references.pmid: 8534283
references.citation: J Neurosci. 2002 Jan 15;22(2):455-63
references.pmid: 11784790
references.citation: Pediatr Res. 2008 Jun;63(6):656-61
references.pmid: 18520330
references.citation: N Engl J Med. 2004 Nov 4;351(19):1985-95
references.pmid: 15525724
references.citation: J Neurosci. 2007 Mar 28;27(13):3416-28
references.pmid: 17392458
references.citation: Pediatr Res. 2005 Jun;57(6):865-72
references.pmid: 15774844