title: Histopathological correlates of magnetic resonance imaging-defined chronic perinatal white matter injury.
abstract: OBJECTIVE
  Although magnetic resonance imaging (MRI) is the optimal imaging modality to define cerebral white-matter injury (WMI) in preterm survivors, the histopathological features of MRI-defined chronic lesions are poorly defined. We hypothesized that chronic WMI is related to a combination of delayed oligodendrocyte (OL) lineage cell death and arrested maturation of preoligodendrocytes (preOLs). We determined whether ex vivo MRI can distinguish distinct microglial and astroglial responses related to WMI progression and arrested preOL differentiation.
  
  
  METHODS
  We employed a preterm fetal sheep model of global cerebral ischemia in which acute WMI results in selective preOL degeneration. We developed novel algorithms to register histopathologically-defined lesions with contrast-weighted and diffusion-weighted high-field ex vivo MRI data.
  
  
  RESULTS
  Despite mild delayed preOL degeneration, preOL density recovered to control levels by 7 days after ischemia and was ~2 fold greater at 14 days. However, premyelinating OLs were significantly diminished at 7 and 14 days. WMI evolved to mostly gliotic lesions where arrested preOL differentiation was directly proportional to the magnitude of astrogliosis. A reduction in cerebral WM volume was accompanied by four classes of MRI-defined lesions. Each lesion type displayed unique astroglial and microglial responses that corresponded to distinct forms of necrotic or non-necrotic injury. High-field MRI defined 2 novel hypointense signal abnormalities on T(2) -weighted images that coincided with microscopic necrosis or identified astrogliosis with high sensitivity and specificity.
  
  
  CONCLUSIONS
  These studies support the potential of high-field MRI for early identification of microscopic necrosis and gliosis with preOL maturation arrest, a common form of WMI in preterm survivors.
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: Justin
authors.initials: J
authors.lastname: Dean
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Buser
authors.forename: Xi
authors.initials: X
authors.lastname: Gong
authors.forename: Jennifer
authors.initials: J
authors.lastname: Maire
authors.forename: Kevin
authors.initials: K
authors.lastname: Chen
authors.forename: Tahir
authors.initials: T
authors.lastname: Ahmad
authors.forename: Victor
authors.initials: V
authors.lastname: Cai
authors.forename: Thuan
authors.initials: T
authors.lastname: Nguyen
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: D000465:Algorithms; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001921:Brain / Q000254:growth & development / Q000473:pathology*; D001925:Brain Damage, Chronic / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology; D002135:Calcium-Binding Proteins; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D018450:Disease Progression; D004574:Electromagnetic Fields; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D005333:Fetus / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008840:Microfilament Proteins; D058953:Neural Stem Cells / Q000473:pathology; D009836:Oligodendroglia / Q000473:pathology; D011247:Pregnancy; D012756:Sheep; D016707:Tissue Fixation
chemical_list: C112986:AIF1 protein, human; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D053148:Caspase 3