title: Localized cortical chronic traumatic encephalopathy pathology after single, severe axonal injury in human brain.
abstract: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild impact traumatic brain injury from contact sports. Recently, a consensus panel defined the pathognomonic lesion for CTE as accumulations of abnormally hyperphosphorylated tau (p-tau) in neurons (neurofibrillary tangles), astrocytes and cell processes distributed around small blood vessels at sulcal depths in irregular patterns within the cortex. The pathophysiological mechanism for this lesion is unknown. Moreover, a subset of CTE cases harbors cortical β-amyloid plaques. In this study, we analyzed postmortem brain tissues from five institutionalized patients with schizophrenia and history of surgical leucotomy with subsequent survival of at least another 40 years. Because leucotomy involves severing axons bilaterally in prefrontal cortex, this surgical procedure represents a human model of single traumatic brain injury with severe axonal damage and no external impact. We examined cortical tissues at the leucotomy site and at both prefrontal cortex rostral and frontal cortex caudal to the leucotomy site. For comparison, we analyzed brain tissues at equivalent neuroanatomical sites from non-leucotomized patients with schizophrenia, matched in age and gender. All five leucotomy cases revealed severe white matter damage with dense astrogliosis at the axotomy site and also neurofibrillary tangles and p-tau immunoreactive neurites in the overlying gray matter. Four cases displayed p-tau immunoreactivity in neurons, astrocytes and cell processes encompassing blood vessels at cortical sulcal depths in irregular patterns, similar to CTE. The three cases with apolipoprotein E ε4 haplotype showed scattered β-amyloid plaques in the overlying gray matter, but not the two cases with apolipoprotein E ε3/3 genotype. Brain tissue samples from prefrontal cortex rostral and frontal cortex caudal to the leucotomy site, and all cortical samples from the non-leucotomized patients, showed minimal p-tau and β-amyloid pathology. These findings suggest that chronic axonal damage contributes to the unique pathology of CTE over time.
authors.affiliation: Department of Pathology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.|Center for Neuroscience and Regenerative Medicine, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.|Henry M. Jackson Foundation for the Advancement of Military Medicine, 6720 Rockledge Drive, Bethesda, MD, 20817, USA.
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Shively
authors.affiliation: Center for Neuroscience and Regenerative Medicine, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.|Henry M. Jackson Foundation for the Advancement of Military Medicine, 6720 Rockledge Drive, Bethesda, MD, 20817, USA.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Edgerton
authors.affiliation: Department of Pathology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.|Center for Neuroscience and Regenerative Medicine, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.|Henry M. Jackson Foundation for the Advancement of Military Medicine, 6720 Rockledge Drive, Bethesda, MD, 20817, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Iacono
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY, 10029, USA.
authors.forename: Dushyant P
authors.initials: DP
authors.lastname: Purohit
authors.affiliation: Center for Neuroscience and Regenerative Medicine, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.|Department of Neurology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
authors.forename: Bao-Xi
authors.initials: BX
authors.lastname: Qu
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY, 10029, USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY, 10029, USA.|Mental Illness Research Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA.
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY, 10029, USA.|Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY, 10029, USA.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Davis
authors.affiliation: Center for Neuroscience and Regenerative Medicine, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.|Department of Neurology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
authors.forename: Ramon
authors.initials: R
authors.lastname: Diaz-Arrastia
authors.affiliation: Department of Pathology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA. daniel.perl@usuhs.edu.|Center for Neuroscience and Regenerative Medicine, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA. daniel.perl@usuhs.edu.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Perl
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D002540:Cerebral Cortex / Q000473:pathology*; D000070627:Chronic Traumatic Encephalopathy / Q000473:pathology*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008297:Male; D016874:Neurofibrillary Tangles / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000473:pathology*; D011612:Psychosurgery; D012559:Schizophrenia / Q000150:complications / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001057:Apolipoproteins E; D005904:Glial Fibrillary Acidic Protein; D016875:tau Proteins; C067980:CD68 antigen, human; D000097382:CD68 Molecule
keywords: Axonal injury; Chronic traumatic encephalopathy; Neurofibrillary tangle; Tau; Traumatic brain injury; β-Amyloid plaque