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Cited by 63Traumatic Brain Injury ResearchAlzheimer's disease research and treatmentsTraumatic Brain Injury and Neurovascular Disturbances

Mild Chronic Traumatic Encephalopathy Neuropathology in People With No Known Participation in Contact Sports or History of Repetitive Neurotrauma

Open access
Iverson, Grant L, Luoto, Teemu M, Karhunen, Pekka J, Castellani, Rudolph J·2019·Journal of Neuropathology & Experimental Neurology
DOI 10.1093/jnen/nlz045PMC PMC6581557
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Abstract

It has been asserted that chronic traumatic encephalopathy (CTE) pathology is only present in former athletes and others who have been exposed to repetitive concussions, subconcussive blows, or both. We hypothesized that CTE pathology would be present in men who had no known history of repetitive neurotrauma. Comprehensive medical record reviews and health surveys completed by a family member were available for the 8 men in this case series, none of whom had known exposure to repetitive neurotrauma but 2 of whom had a history of traumatic brain injury (TBI). Postmortem tissue was immunostained for hyperphosphorylated tau (p-tau) to assess for CTE pathology, Braak stage, and aging-related p-tau. The neuropathologist was blind to age, personal history, and clinical history. Six of the 8 cases (75%) showed p-tau in neurons, astrocytes, and cell processes around small blood vessels in an irregular pattern at the depths of the cortical sulci. The changes were focal and limited in terms of overall extent, and some of the cases had a clearer pattern of pathology and some could be considered equivocal. Two of the 8 cases had a history of TBI and one of them showed CTE pathology. Five of the 6 cases with no known history of neurotrauma appeared to meet consensus criteria for CTE. This study adds to the emerging literature indicating that CTE pathology is present in people not known to have experienced multiple concussions or subconcussive blows to the head.

AI snapshot

Written from the paper’s full text.

TL;DR

In an autopsy case series of 8 men with no known participation in contact or collision sports, 6 (75%) showed p-tau pathology meeting the required consensus criterion for CTE, including 5 of 6 men with no known neurotrauma. The pathology was focal and limited, sometimes equivocal, and the authors conclude CTE-like pathology is not unique to people with repetitive neurotrauma.

Key findings

  • Six of 8 cases (75%) showed p-tau in neurons, astrocytes, and cell processes around small blood vessels in an irregular pattern at the depths of cortical sulci; 5 of the 6 men with no known history of neurotrauma appeared to meet consensus criteria for CTE (83%).
  • Two of 8 men had a documented TBI history, and one of them showed CTE pathology; cases 4 and 8 did not have CTE pathology in the depths of sulci.
  • Braak stage ranged from I to V; 4 cases showed Braak III–IV neurofibrillary change with no or at most sparse amyloid-β, consistent with PART, and also showed variable ARTAG. One case (case 2) had intermediate AD neuropathologic change sufficient to explain dementia.
  • TDP-43 immunostains showed grains, threads, and cytoplasmic inclusions including NFT in the medial temporal lobe in all cases, varying from minimal/sparse to moderate.

Methods

  • Embedded in the Tampere Sudden Death Study: a consecutive sample of 12 men aged 49–82 who died out of hospital in 2014–2015; family health surveys were returned for 8 men aged 56–82, who formed this case series. None had known contact/collision sport participation; 2 had TBI documented in medical records.
  • Data included autopsy findings, large brain tissue samples, centralized electronic medical record review, mail survey by a relative/family member, and blood samples.
  • Postmortem tissue was immunostained for p-tau (AT8), amyloid-β, TDP-43, α-synuclein, neurofilament protein, and APP, with Bielschowsky silver impregnation; the neuropathologist was blind to age, personal history, and clinical history. Cases were assessed using 2016 consensus criteria for CTE, Braak stage, PART/ARTAG, and NIA-AA 2012 AD guidelines.

Limitations

  • The paper states that some men likely experienced concussions that were not medically documented, and some may have played contact sports briefly without family knowledge; these limitations are inherent in virtually all neuropathology studies of this type.
  • The paper states there is no defined lower bound for classifying CTE pathology, that there can be disagreements about what constitutes a specific immunostaining pattern, and that the small amounts of CTE pathology found were presumed clinically inconsequential.
  • The paper states that sledge microtome, free-floating immunohistochemical preparations were not performed, so negative cases might have been positive using that technique; evident from the text, the study is a very small case series of 8 men with no control comparison and relies on retrospective family surveys and medical records to establish exposure history.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1093/jnen/nlz045

Cites

58 of 58 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 36 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    No recent or remote structural brain injury attributable to neurotrauma was noted in the tissue examined in the case series, with the exception of case 8.

    “No recent or remote structural brain injury attributable to neurotrauma was noted in the tissue examined in the case series, with the exception of case 8.”
    Quote in the paperSubstantial claim
  • Findingown data

    Four cases showed Braak III to IV neurofibrillary change with either no or at most sparse amyloid-b limited to neocortex, consistent with PART.

    “Four cases showed Braak III to IV neurofibrillary change with either no or at most sparse amyloid-b limited to neocortex, consistent with PART.”
    Quote in the paperSubstantial claim
  • Findingown data

    Changes suggestive of traumatic axonal injury were generally absent, aside from encephalomalacia from the remote contusion in case 8.

    “Changes suggestive of traumatic axonal injury were generally absent, aside from encephalomalacia from the remote contusion in case 8.”
    Quote in the paperSubstantial claim
  • Findingown data

    Two of the 8 men had a history of a single traumatic brain injury (TBI) documented in their medical records.

    “2 of whom had a history of traumatic brain injury (TBI)”
    • Also stated in: § Case Ascertainment · plain
      “Two of the 8 cases had a history of traumatic brain injury (TBI) documented in their medical records.”
    • Also stated in: § DISCUSSION · plain
      “Two of the 8 men had a history of a single TBI”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Family surveys and medical record reviews accurately capture the men's history of contact sports and repetitive neurotrauma.
  • Findingown data

    Five of the 6 cases with no known history of neurotrauma appeared to meet consensus criteria for CTE.

    “Five of the 6 cases with no known history of neurotrauma appeared to meet consensus criteria for CTE.”
    • Also stated in: § DISCUSSION · plain
      “Of the 6 men with no known history of neurotrauma, 5 met consensus criteria for having CTE (83%).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Family surveys and medical record reviews accurately capture the men's history of contact sports and repetitive neurotrauma.
  • May combine two claims. 10
  • Classified as probably not a substantial claim. 14

  • May combine two claims.

    Findingown data

    Each of these 4 cases also showed variable astrocytic tau disposed in thorny astrocytes in subpial, subependymal, and/or perivascular areas, and occasional astrocytic plaques, consistent with ARTAG.

    “Each of these 4 cases also showed variable astrocytic tau disposed in thorny astrocytes in subpial, subependymal, and/or perivascular areas, and occasional astrocytic plaques, consistent with ARTAG.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Findingnone given

    The authors' subjects had small amounts of CTE pathology that they presumed to be clinically inconsequential.

    “We too found that our subjects had small amounts of CTE pathology that we presumed to be clinically inconsequential.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The neuropathologist was blind to age, personal history, and clinical history.

    “The neuropathologist was blind to age, personal history, and clinical history.”
    • Also stated in: § Autopsy Study Procedures · plain
      “The neuropathologist did not know the personal or medical history of any of the cases, including the age of the decedent.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    When CTE pathology is found in studies that do not involve former collision or contact sport athletes, it is usually, but not always, reported that the subjects had a history of at least 1 brain injury, or the authors speculate that the subjects could have experienced undocumented brain injuries.

    “When CTE pathology is found in studies that do not involve former collision or contact sport athletes, it is usually, but not always, reported that the subjects had a history of at least 1 brain injury (23), or the authors speculate that the subjects could have experienced injuries to their brains that were not documented, such as in falls (22).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23] Ling, 2015, Histological evidence of chronic traumatic encephalopathy in a large series of neurodegenerative diseases, Acta Neuropathol source

      Not checked in the free run.

    • cites [22] Koga, 2016, Chronic traumatic encephalopathy pathology in multiple system atrophy, J Neuropathol Exp Neurol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Prior to 2016, there were no agreed upon neuropathological criteria for CTE, and the criteria published by the 2 leading research groups in the United States differed substantially.

    “Prior to 2016, there were no agreed upon neuropathological criteria for CTE, and the criteria published by the 2 leading research groups in the United States differed substantially (7,14).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Omalu, 2011, Emerging histomorphologic phenotypes of chronic traumatic encephalopathy in American athletes, Neurosurgery source

      Not checked in the free run.

    • cites [14] McKee, 2013, The spectrum of disease in chronic traumatic encephalopathy, Brain source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Cerebellum, midbrain, medulla, and occipital cortex were not available for study.

    “recognizing that cerebellum, midbrain, medulla, and occipital cortex were not available for study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All immunohistochemical stains were performed using an automated immunostainer and antigen retrieval, along with positive and negative controls.

    “All immunohistochemical stains were performed using an automated immunostainer and antigen retrieval, along with positive and negative (omission of primary antibody) controls.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    It has been reported that sledge microtome technique may detect CTE pathology in 20% of cases that is otherwise not detectable by routine histopathological and immunohistochemical methods for dementia diagnosis.

    “It has been reported that this technique may detect CTE pathology in 20% of cases that is otherwise not detectable by routine histopathological and immunohistochemical methods for dementia diagnosis (15).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] McKee, 2016, The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy, Acta Neuropathol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study did not perform sledge microtome, free-floating immunohistochemical preparations.

    “Finally, we did not perform sledge microtome, free-floating immunohistochemical preparations for this study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Concussions are very common in men in the general population.

    “Concussions are very common in men in the general population”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Sosin, 1996, Incidence of mild and moderate brain injury in the United States, 1991, Brain Inj source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Other studies indicate that neuroinflammation, b-amyloid deposition, and accumulation of TDP-43 and p-tau can arise following a single moderate-severe TBI, and there is emerging evidence that multiple types of neuropathology can be present following repetitive mild TBI.

    “There are other studies, however, indicating that different types of neuropathology, such as neuroinflammation (36), b-amyloid deposition (37), and accumulation of TDP-43 (38) and p-tau (37, 39, 40) can and do arise following a single moderate-severe TBI (41)(42)(43), and there is emerging evidence that multiple types of neuropathology can be present following repetitive mild TBI (43,44).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [36] Frugier, 2010, In situ detection of inflammatory mediators in post mortem human brain tissue after traumatic injury, J Neurotrauma source

      Not checked in the free run.

    • cites [37] Johnson, 2012, Widespread tau and amyloid-beta pathology many years after a single traumatic brain injury in humans, Brain Pathol source

      Not checked in the free run.

    • cites [38] Johnson, 2011, Acute and chronically increased immunoreactivity to phosphorylation-independent but not pathological TDP-43 after a single traumatic brain injury in humans, Acta Neuropathol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The amount of CTE pathology in terms of the required criterion in these cases was limited, likely mostly stage I and stage II, although the staging is not entirely clear.

    “The amount of CTE pathology in terms of the required criterion in these cases was limited, likely mostly stage I and stage II, although the staging is not entirely clear.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Noy et al noted that there is no lower bound for classifying Stage I CTE pathology, so if one includes sparse pathology characteristic of Stage I, an additional 34 cases were identified (30.6% of their sample).

    “However, they noted that there is no lower bound for classifying Stage I CTE pathology, so if one includes sparse pathology characteristic of Stage I, an additional 34 cases were identified (30.6% of their sample).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Noy, 2016, Chronic traumatic encephalopathy-like abnormalities in a routine neuropathology service, J Neuropathol Exp Neurol source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Noy et al examined 111 brains for CTE pathology, from adults between the ages of 18 and 60, in a routine neuropathology service in Canada.

    “Noy et al examined 111 brains for CTE pathology, from adults between the ages of 18 and 60, in a routine neuropathology service in Canada (24).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Noy, 2016, Chronic traumatic encephalopathy-like abnormalities in a routine neuropathology service, J Neuropathol Exp Neurol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    There currently is no lower bound for identifying CTE pathology.

    “There currently is no lower bound, which is problematic because it is thus possible to diagnose someone has having CTE when they have only a tiny amount of signature pathology-even late in life.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The consensus group did not define a lower bound of pathology for classifying a person as having CTE.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    It is possible that some of the men in the case series played contact sports, at least briefly, during their lives and that their family members did not know about this.

    “Second, it is also possible that some of them played contact sports, at least briefly, during their lives and that their family members did not know about this.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The results of this study are striking in that 75% of the small case series met neuropathological criteria for CTE, but none of the men had a known history of participation in contact sports, collision sports, or multiple concussions.

    “The results of this study are striking in that 75% of our small case series met neuropathological criteria for CTE, but none of the men had a known history of participation in contact sports, collision sports, or multiple concussions (Table 5).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Family surveys and medical record reviews accurately capture the men's history of contact sports and repetitive neurotrauma.

  • May combine two claims.

    Premisecitation

    CTE pathology has been identified in women and men who do not have neurological disorders, and in people with substance abuse histories.

    “CTE pathology has been identified in women (23) and men (23,24) who do not have neurological disorders, and in people with substance abuse histories (24).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] Ling, 2015, Histological evidence of chronic traumatic encephalopathy in a large series of neurodegenerative diseases, Acta Neuropathol source

      Not checked in the free run.

    • cites [24] Noy, 2016, Chronic traumatic encephalopathy-like abnormalities in a routine neuropathology service, J Neuropathol Exp Neurol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Leading CTE researchers have indicated that a single concussion does not lead to CTE.

    “Leading CTE researchers have clearly indicated that a single concussion does not lead to CTE (33).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Stein, 2015, Concussion in chronic traumatic encephalopathy, Curr Pain Headache Rep source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The prevailing theory of CTE, often expressed in articles as fact, is that it is a distinct and unique neurodegenerative disease.

    “In conclusion, the prevailing theory of CTE, often expressed in articles as fact, is that it is a distinct (1, 3, 9-11) and unique (10) neurodegenerative disease (9-13).”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [1] Gavett, 2011, Chronic traumatic encephalopathy: A potential late effect of sport-related concussive and subconcussive head trauma, Clin Sports Med source

      Not checked in the free run.

    • cites [3] McKee, 2009, Chronic traumatic encephalopathy in athletes: Progressive tauopathy after repetitive head injury, J Neuropathol Exp Neurol source

      Not checked in the free run.

    • cites [9] Baugh, 2012, Chronic traumatic encephalopathy: Neurodegeneration following repetitive concussive and subconcussive brain trauma, Brain Imaging Behav source

      Not checked in the free run.

    • cites [10] Baugh, 2014, Current understanding of chronic traumatic encephalopathy, Curr Treat Opt Neurol source

      Not checked in the free run.

    • cites [11] Mez, 2013, Chronic traumatic encephalopathy: Where are we and where are we going?, Curr Neurol Neurosci Rep source

      Not checked in the free run.

    • cites [12] Gavett, 2011, Clinical appraisal of chronic traumatic encephalopathy. Current perspectives and future directions, Curr Opin Neurol source

      Not checked in the free run.

    • cites [13] McKee, 2014, The neuropathology of sport, Acta Neuropathol source

      Not checked in the free run.

20 of 20

  • The authors state this as an assumption.

    It is reasonable to assume that CTE-like pathology might be more common in older adult control subjects, such as our sample, than middle-aged and younger control subjects.

    “It is reasonable to assume that CTE-like pathology might be more common in older adult control subjects, such as our sample, than middle-aged and younger control subjects.”

  • The paper relies on this without support.

    Family surveys and medical record reviews accurately capture the men's history of contact sports and repetitive neurotrauma.

    “According to the family surveys, none of the 8 men had a history of participation in contact or collision sports.”
    “Two of the 8 cases had a history of traumatic brain injury (TBI) documented in their medical records.”

  • The paper relies on this without support.

    The consensus group did not define a lower bound of pathology for classifying a person as having CTE.

    “The consensus group did not define a lower bound of pathology for classifying a person as having CTE”

  • The paper relies on this without support.

    There are no longitudinal or epidemiological studies that support the assertions that CTE is a distinct and unique neurodegenerative disease.

    “there are no longitudinal or epidemiological studies that support these assertions”
4 of 4

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?

  • CTE-consistent pathology has been reported in cases with no history of head trauma, indicating that it may be a common pathology within the general population and not specific to the aftermath of mTBI.

    “It is also important to note that CTE-consistent pathology has been reported in cases with no history of head trauma, further indicating that it may be a common pathology within the general population and not specific to the aftermath of mTBI [55, 69, 89, 119].”

    From DNA repair deficiency and senescence in concussed professional athletes involved in contact sports (2019) · cites this paper as [69]

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Related

Authors
Iverson, G. L., Luoto, T. M., Karhunen, P. J., & Castellani, R. J.
Affiliations
  • Harvard University (US)
  • Tampere University Hospital (FI)
  • Tampere University (FI)
  • West Virginia University (US)
Corresponding author
Iverson, Grant L
ORCID
Venue
Journal of Neuropathology & Experimental Neurology
Publisher
Oxford University Press (OUP)
Published
2019-06-06
Volume
78
Issue
7
Pages
615-625
ISSN
  • 0022-3069 (ISSN-L)
  • 1554-6578
DOI
10.1093/jnen/nlz045
PMC
PMC6581557
OpenAlex
W2952010976
Cited by
63
References
58
Citations by year
2026: 1 · 2025: 19 · 2024: 3 · 2023: 5 · 2022: 9 · 2021: 7 · 2020: 13 · 2019: 6
FWCI
6.66
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Journal of Neuropathology & Experimental Neurology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Western Michigan University School of Medicine
  • NIH
  • Western Michigan University
Topics
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords
chronic traumatic encephalopathy, hyperphosphorylated tau, traumatic brain injury, non-contact sports, Braak stages, postmortem neuropathology, men
MeSH terms
Chronic Traumatic Encephalopathy, Aged, Aged, 80 and over, Aging, Astrocytes, Autopsy, Brain Diseases, Chronic Disease, Humans, Immunohistochemistry, Male, Middle Aged, Neurons, Phosphorylation, Sports, tau Proteins

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