Localized cortical chronic traumatic encephalopathy pathology after single, severe axonal injury in human brain
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the context of traumatic brain injury, post-mortem human brains after blast exposure show astrogliosis in sub-pial regions, specifically surrounding the grey-white matter junctions, in the subpial area and lining of ventricles.
“In the context of traumatic brain injury, post-mortem human brains after blast exposure show astrogliosis in sub-pial regions, specifically surrounding the grey-white matter junctions, in the subpial area and lining of ventricles [139].”
From DNA repair deficiency and senescence in concussed professional athletes involved in contact sports (2019) · cites this paper as [139]
The morphology of astrocytes in these blast-exposure cases was similar to the cases illustrated here, in which astrocytic cell bodies are swollen and cellular processes are beaded.
“The morphology of astrocytes in these cases was similar to the cases illustrated here, in which astrocytic cell bodies are swollen and cellular processes are beaded (see figure 1 in reference [139]).”
From DNA repair deficiency and senescence in concussed professional athletes involved in contact sports (2019) · cites this paper as [139]
Astrogliosis in these individuals was thought to be the basis of post-traumatic stress disorder (PTSD) in soldiers who had suffered blast exposure-related mTBI.
“Furthermore, astrogliosis in these individuals was thought to be the basis of post-traumatic stress disorder (PTSD) in soldiers who had suffered blast exposure-related mTBI [139].”
From DNA repair deficiency and senescence in concussed professional athletes involved in contact sports (2019) · cites this paper as [139]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359 · see citing works
Iliff, J. J., Wang, M., Liao, Y., Plogg, B. A., Peng, W., Gundersen, G. A., Benveniste, H., Vates, G. E., Deane, R., Goldman, S. A., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003748 · Cited by 5,824 · see citing works
Structural and functional features of central nervous system lymphatic vessels
Louveau, A., Smirnov, I., Keyes, T. J., Eccles, J. D., Rouhani, S. J., Peske, J. D., Derecki, N. C., Castle, D., Mandell, J. W., Lee, K. S., et al. (2015) · Nature · doi:10.1038/nature14432 · Cited by 4,413 · see citing works
Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
Liu, C.-C., Kanekiyo, T., Xu, H., & Bu, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.263 · Cited by 3,459 · see citing works
Chronic traumatic encephalopathy in athletes: Progressive tauopathy after repetitive head injury
McKee, A. C., Cantu, R. C., Nowinski, C. J., Hedley-Whyte, E. T., Gavett, B. E., Budson, A. E., Santini, V. E., Lee, H.-S., Kubilus, C. A., & Stern, R. A. (2009) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181a9d503 · Cited by 2,295 · see citing works
A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules
Aspelund, A., Antila, S., Proulx, S. T., Karlsen, T. V., Karaman, S., Detmar, M., Wiig, H., & Alitalo, K. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20142290 · Cited by 2,198 · see citing works
The spectrum of disease in chronic traumatic encephalopathy
McKee, A. C., Stein, T. D., Nowinski, C. J., Stern, R. A., Daneshvar, D. H., Alvarez, V. E., Lee, H.-S., Hall, G., Wojtowicz, S. M., Baugh, C. M., et al. (2013) · Brain · doi:10.1093/brain/aws307 · Cited by 2,098 · see citing works
Axonal pathology in traumatic brain injury
Johnson, V. E., Stewart, W., & Smith, D. H. (2013) · Experimental Neurology · doi:10.1016/j.expneurol.2012.01.013 · Cited by 1,273 · see citing works
Impairment of Glymphatic Pathway Function Promotes Tau Pathology after Traumatic Brain Injury
Iliff, J. J., Chen, M. J., Plog, B. A., Zeppenfeld, D. M., Soltero, M., Yang, L., Singh, I., Deane, R., & Nedergaard, M. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.3020-14.2014 · Cited by 1,159 · see citing works
Inflammation and white matter degeneration persist for years after a single traumatic brain injury
Johnson, V. E., Stewart, J. E., Begbie, F. D., Trojanowski, J. Q., Smith, D. H., & Stewart, W. (2013) · Brain · doi:10.1093/brain/aws322 · Cited by 1,045 · see citing works
Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias
Plassman, B. L., Havlik, R. J., Steffens, D. C., Helms, M. J., Newman, T. N., Drosdick, D., Phillips, C., Gau, B. A., Welsh–Bohmer, K. A., Burke, J. R., et al. (2000) · Neurology · doi:10.1212/wnl.55.8.1158 · Cited by 896 · see citing works
the TBI/CTE group, McKee, A. C., Cairns, N. J., Dickson, D. W., Folkerth, R. D., Dirk Keene, C., Litvan, I., Perl, D. P., Stein, T. D., Vonsattel, J.-P., et al. (2016) · Acta Neuropathologica · doi:10.1007/s00401-015-1515-z · Cited by 885 · see citing works
Self-citationCorsellis, J. A. N., Bruton, C. J., & Freeman-Browne, D. (1973) · Psychological Medicine · doi:10.1017/s0033291700049588 · Cited by 836 · see citing works
MARTLAND, H. S. (1928) · Journal of the American Medical Association · doi:10.1001/jama.1928.02700150029009 · Cited by 774 · see citing works
DIFFUSE DEGENERATION OF THE CEREBRAL WHITE MATTER IN SEVERE DEMENTIA FOLLOWING HEAD INJURY
Strich, S. J. (1956) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.19.3.163 · Cited by 728 · see citing works
Nedergaard, M. (2013) · Science · doi:10.1126/science.1240514 · Cited by 704 · see citing works
Chronic neuropathologies of single and repetitive TBI: substrates of dementia?
Smith, D. H., Johnson, V. E., & Stewart, W. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2013.29 · Cited by 699 · see citing works
Association of apolipoprotein E polymorphism with outcome after head injury
Teasdale, G. M., Nicoll, J. A. R., Murray, G. D., & Fiddes, M. (1997) · The Lancet · doi:10.1016/s0140-6736(97)04318-3 · Cited by 683 · see citing works
Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing
Jordan, B. D. (1997) · JAMA · doi:10.1001/jama.278.2.136 · Cited by 659 · see citing works
Widespread tau and amyloid-beta pathology many years after a single traumatic brain injury in humans
Johnson, V. E., Stewart, W., & Smith, D. H. (2012) · Brain Pathology · doi:10.1111/j.1750-3639.2011.00513.x · Cited by 620 · see citing works
Mayeux, R., Ottman, R., Maestre, G., Ngai, C., Tang, M., Ginsberg, H., Chun, M., Tycko, B., & Shelanski, M. (1995) · Neurology · doi:10.1212/wnl.45.3.555 · Cited by 597 · see citing works
Mortimer, J. A., Van Duijn, C. M., Chandra, V, Fratiglioni, L., Graves, A. B., Heyman, A., Jorm, A. F., Kokmen, E., Kondo, K., Rocca, W. A., et al. (1991) · International Journal of Epidemiology · doi:10.1093/ije/20.supplement_2.s28 · Cited by 594 · see citing works
Traumatic brain injury and amyloid-β pathology: a link to Alzheimer's disease?
Johnson, V. E., Stewart, W., & Smith, D. H. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2808 · Cited by 587 · see citing works
Roberts, G. W., Gentleman, S. M., Lynch, A., Murray, L., Landon, M., & Graham, D. I. (1994) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.57.4.419 · Cited by 569 · see citing works
Clinical presentation of chronic traumatic encephalopathy
Stern, R. A., Daneshvar, D. H., Baugh, C. M., Seichepine, D. R., Montenigro, P. H., Riley, D. O., Fritts, N. G., Stamm, J. M., Robbins, C. A., McHale, L., et al. (2013) · Neurology · doi:10.1212/wnl.0b013e3182a55f7f · Cited by 564 · see citing works
Aging-related tau astrogliopathy (ARTAG): Harmonized evaluation strategy
Kovacs, G. G., Ferrer, I., Grinberg, L. T., Alafuzoff, I., Attems, J., Budka, H., Cairns, N. J., Crary, J. F., Duyckaerts, C., Ghetti, B., et al. (2016) · Acta Neuropathologica · doi:10.1007/s00401-015-1509-x · Cited by 532 · see citing works
The occult aftermath of boxing.
Roberts, G. W., Allsop, D., & Bruton, C. (1990) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.53.5.373 · Cited by 518 · see citing works
Head injury and the risk of AD in the MIRAGE study
Guo, Z., Cupples, L. A., Kurz, A., Auerbach, S. H., Volicer, L., Chui, H., Green, R. C., Sadovnick, A. D., Duara, R., DeCarli, C., et al. (2000) · Neurology · doi:10.1212/wnl.54.6.1316 · Cited by 506 · see citing works
Microscopic lesions in the brain following head injury.
Oppenheimer, D. R. (1968) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.31.4.299 · Cited by 501 · see citing works
Apolipoprotein E ε4 allele is associated with deposition of amyloid β-protein following head injury
Nicoll, J. A. R., Roberts, G. W., & Graham, D. I. (1995) · Nature Medicine · doi:10.1038/nm0295-135 · Cited by 486 · see citing works
βA4 amyloid protein deposition in brain after head trauma
Roberts, G., Gentleman, S., Lynch, A., & Graham, D. I. (1991) · The Lancet · doi:10.1016/0140-6736(91)92724-g · Cited by 440 · see citing works
Apolipoprotein E-ε4 genotype predicts a poor outcome in survivors of traumatic brain injury
Friedman, G., Froom, P., Sazbon, L., Grinblatt, I., Shochina, M., Tsenter, J., Babaey, S., Yehuda, A. B., & Groswasser, Z. (1999) · Neurology · doi:10.1212/wnl.52.2.244 · Cited by 437 · see citing works
Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance
Zhao, Z., Sagare, A. P., Ma, Q., Halliday, M. R., Kong, P., Kisler, K., Winkler, E. A., Ramanathan, A., Kanekiyo, T., Bu, G., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4025 · Cited by 410 · see citing works
Alzheimer's pathology in human temporal cortex surgically excised after severe brain injury
Ikonomovic, M. D., Uryu, K., Abrahamson, E. E., Ciallella, J. R., Trojanowski, J. Q., Lee, V. M.-Y., Clark, R. S., Marion, D. W., Wisniewski, S. R., & DeKosky, S. T. (2004) · Experimental Neurology · doi:10.1016/j.expneurol.2004.06.011 · Cited by 399 · see citing works
Blood Biomarkers for Brain Injury in Concussed Professional Ice Hockey Players
Shahim, P., Tegner, Y., Wilson, D. H., Randall, J., Skillbäck, T. B., Pazooki, D., Kallberg, B., Blennow, K., & Zetterberg, H. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2014.367 · Cited by 389 · see citing works
Emerging histomorphologic phenotypes of chronic traumatic encephalopathy in American athletes
Omalu, B., Bailes, J., Hamilton, R. L., Kamboh, M. I., Hammers, J., Case, M., & Fitzsimmons, R. (2011) · Neurosurgery · doi:10.1227/neu.0b013e318212bc7b · Cited by 381 · see citing works
Uryu, K., Chen, X.-H., Martinez, D., Browne, K. D., Johnson, V. E., Graham, D. I., Lee, V. M.-Y., Trojanowski, J. Q., & Smith, D. H. (2007) · Experimental Neurology · doi:10.1016/j.expneurol.2007.06.018 · Cited by 360 · see citing works
Neurochemical Aftermath of Amateur Boxing
Zetterberg, H., Hietala, M. A., Jonsson, M. A. G., Andreasen, N., Styrud, E., Karlsson, I., Edman, Å., Popa, C., Rasulzada, A., Wahlund, L., et al. (2006) · Archives of Neurology · doi:10.1001/archneur.63.9.1277 · Cited by 355 · see citing works
Beta-amyloid deposition in chronic traumatic encephalopathy
Stein, T. D., Montenigro, P. H., Alvarez, V. E., Xia, W., Crary, J. F., Tripodis, Y., Daneshvar, D. H., Mez, J., Solomon, T., Meng, G., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1435-y · Cited by 291 · see citing works
CSF-Biomarkers in Olympic Boxing: Diagnosis and Effects of Repetitive Head Trauma
Neselius, S., Brisby, H., Theodorsson, A., Blennow, K., Zetterberg, H., & Marcusson, J. O. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033606 · Cited by 274 · see citing works
Chen, X., Johnson, V. E., Uryu, K., Trojanowski, J. Q., & Smith, D. H. (2009) · Brain Pathology · doi:10.1111/j.1750-3639.2008.00176.x · Cited by 267 · see citing works
Zlokovic, B. V., Deane, R., Sagare, A. P., Bell, R. D., & Winkler, E. A. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.07002.x · Cited by 261 · see citing works
Tokuda, T., Ikeda, S., Yanagisawa, N., Ihara, Y., & Glenner, G. G. (1991) · Acta Neuropathologica · doi:10.1007/bf00308813 · Cited by 197 · see citing works
Implications of the discovery of brain lymphatic pathways
Iliff, J. J., Goldman, S. A., & Nedergaard, M. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)00221-5 · Cited by 186 · see citing works
Purohit, D. P., Perl, D. P., Haroutunian, V., Powchik, P., Davidson, M., & Davis, K. L. (1998) · Archives of General Psychiatry · doi:10.1001/archpsyc.55.3.205 · Cited by 185 · see citing works
Self-citationLower Cognitive Performance of Older Football Players Possessing Apolipoprotein E ε4
Kutner, K. C., Erlanger, D. M., Tsai, J., Jordan, B. D., & Relkin, N. R. (2000) · Neurosurgery · doi:10.1097/00006123-200009000-00026 · Cited by 170 · see citing works
Psychosurgery in the Treatment of Mental Disorders and Intractable Pain
Freeman, W. (1952) · Southern Medical Journal · doi:10.1097/00007611-195203000-00024 · Cited by 116 · see citing works
Calero, O., Hortigüela, R., Bullido, M. J., & Calero, M. (2009) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2009.06.033 · Cited by 116 · see citing works
β‐Amyloid (Aβ)42(43), Aβ42, Aβ40 and apoE immunostaining of plaques in fatal head injury
Horsburgh, K. J., Cole, G. M., Yang, F., Savage, M. J., Greenberg, B., Gentleman, S. M., Graham, D. I., & Nicoll, J. A. R. (2000) · Neuropathology and Applied Neurobiology · doi:10.1046/j.1365-2990.2000.026002124.x · Cited by 88 · see citing works
Cerebral amyloid angiopathy in traumatic brain injury: association with apolipoprotein E genotype
Leclercq, P. D. (2005) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2003.025528 · Cited by 46 · see citing works
Rapp, M. A., Beeri, M. S., Purohit, D. P., Reichenberg, A., McGurk, S. R., Haroutunian, V. H., & Harvey, P. D. (2009) · Schizophrenia Research · doi:10.1016/j.schres.2009.10.013 · Cited by 39 · see citing works
Self-citationHirano, A., & Zimmerman, H. M. (1962) · Archives of Neurology · doi:10.1001/archneur.1962.00450200028003 · Cited by 39 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
McKee, A. C., Stein, T. D., Huber, B. R., Crary, J. F., Bieniek, K., Dickson, D., Alvarez, V. E., Cherry, J. D., Farrell, K., Butler, M., et al. (2023) · Acta Neuropathologica · doi:10.1007/s00401-023-02540-w · Cited by 244 · see citing works
Iverson, G. L., Luoto, T. M., Karhunen, P. J., & Castellani, R. J. (2019) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlz045 · Cited by 63 · see citing works
DNA repair deficiency and senescence in concussed professional athletes involved in contact sports
Schwab, N., Grenier, K., & Hazrati, L.-N. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0822-3 · Cited by 47 · see citing works
DNA damage as a marker of brain damage in individuals with history of concussions
Schwab, N., Tator, C., & Hazrati, L.-N. (2019) · Laboratory Investigation · doi:10.1038/s41374-019-0199-8 · Cited by 26 · see citing works
- Authors
- Shively, S. B., Edgerton, S. L., Iacono, D., Purohit, D. P., Qu, B.-X., Haroutunian, V., Davis, K. L., Diaz-Arrastia, R., & Perl, D. P.
- Affiliations
- Henry M. Jackson Foundation (US)
- Icahn School of Medicine at Mount Sinai (US)
- Uniformed Services University of the Health Sciences (US)
- James J. Peters VA Medical Center (US)
- Corresponding author
- Perl, Daniel P.
- ORCID
- Venue
- Acta Neuropathologica
- Published
- 2016-11-24
- Volume
- 133
- Issue
- 3
- Pages
- 353-366
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC5325841
- OpenAlex
- W2552018811
- Cited by
- 52
- References
- 52
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 3 · 2023: 8 · 2022: 5 · 2021: 3 · 2020: 5 · 2019: 13 · 2018: 5 · 2017: 2
- FWCI
- 6.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH45212, MH064673)
- Defense Health Agency
- Topics
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- chronic traumatic encephalopathy, axonal injury, leucotomy, hyperphosphorylated tau, neurofibrillary tangles, amyloid plaques, APOE ε4, astrocyte activation, white matter injury, prefrontal cortex, schizophrenia, postmortem neuropathology
- MeSH terms
- Chronic Traumatic Encephalopathy, CD68 Molecule, Aged, Aged, 80 and over, Apolipoproteins E, Cerebral Cortex, Female, Glial Fibrillary Acidic Protein, Humans, Male, Neurons, Psychosurgery, Schizophrenia, Antigens, Differentiation, Myelomonocytic, Antigens, CD, Neurofibrillary Tangles, tau Proteins, Plaque, Amyloid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
