title: The problem of axonal injury in the brains of veterans with histories of blast exposure.
abstract: BACKGROUND
  Blast injury to brain, a hundred-year old problem with poorly characterized neuropathology, has resurfaced as health concern in recent deployments in Iraq and Afghanistan. To characterize the neuropathology of blast injury, we examined the brains of veterans for the presence of amyloid precursor protein (APP)-positive axonal swellings typical of diffuse axonal injury (DAI) and compared them to healthy controls as well as controls with opiate overdose, anoxic-ischemic encephalopathy, and non-blast TBI (falls and motor vehicle crashes).
  
  
  RESULTS
  In cases with blast history, we found APP (+) axonal abnormalities in several brain sites, especially the medial dorsal frontal white matter. In white matter, these abnormalities were featured primarily by clusters of axonal spheroids or varicosities in a honeycomb pattern with perivascular distribution. Axonal abnormalities colocalized with IBA1 (+) reactive microglia and had an appearance that was distinct from classical DAI encountered in TBI due to motor vehicle crashes. Opiate overdose cases also showed APP (+) axonal abnormalities, but the intensity of these lesions was lower compared to cases with blast histories and there was no clear association of such lesions with microglial activation.
  
  
  CONCLUSIONS
  Our findings demonstrate that many cases with history of blast exposure are featured by APP (+) axonopathy that may be related to blast exposure, but an important role for opiate overdose, antemortem anoxia, and concurrent blunt TBI events in war theater or elsewhere cannot be discounted.
authors.affiliation: Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. jryu4@jhmi.edu.
authors.forename: Jiwon
authors.initials: J
authors.lastname: Ryu
authors.affiliation: Department of Neuropathology & Ophthalmic Pathology, Joint Pathology Center, Defense Health Agency, 606 Stephen Sitter Ave., Silver Spring, MD, 20910, USA. Iren.HorkayneSzakaly@us.army.mil.
authors.forename: Iren
authors.initials: I
authors.lastname: Horkayne-Szakaly
authors.affiliation: Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. lxu9@jhmi.edu.
authors.forename: Leyan
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. opletni1@jhmi.edu.
authors.forename: Olga
authors.initials: O
authors.lastname: Pletnikova
authors.affiliation: Department of Psychology, University of Guelph, Guelph, ON, N1G 2 W1, Canada. fleri@uoguelph.ca.
authors.forename: Francesco
authors.initials: F
authors.lastname: Leri
authors.affiliation: Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. ceberha@jhmi.edu.
authors.forename: Charles
authors.initials: C
authors.lastname: Eberhart
authors.affiliation: Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. troncoso@jhmi.edu.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.affiliation: Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. koliat@jhmi.edu.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. koliat@jhmi.edu.|Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. koliat@jhmi.edu.
authors.forename: Vassilis E
authors.initials: VE
authors.lastname: Koliatsos
mesh_terms: D000058:Accidental Falls; D000293:Adolescent; D000328:Adult; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D001369:Axons / Q000378:metabolism / Q000473:pathology; D001753:Blast Injuries / Q000150:complications*; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D020833:Diffuse Axonal Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D062787:Drug Overdose / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008840:Microfilament Proteins; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D018986:Motor Vehicles; D009293:Opioid-Related Disorders / Q000378:metabolism / Q000473:pathology; D014728:Veterans; D055815:Young Adult
chemical_list: C112986:AIF1 protein, human; C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins