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Cited by 1,273Traumatic Brain Injury and Neurovascular DisturbancesTraumatic Brain Injury ResearchAutomotive and Human Injury Biomechanics

Axonal pathology in traumatic brain injury

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Johnson, Victoria E., Stewart, William, Smith, Douglas H.·2013·Experimental Neurology
DOI 10.1016/j.expneurol.2012.01.013PMC PMC3979341
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Abstract

Over the past 70 years, diffuse axonal injury (DAI) has emerged as one of the most common and important pathological features of traumatic brain injury (TBI). Axons in the white matter appear to be especially vulnerable to injury due to the mechanical loading of the brain during TBI. As such, DAI has been found in all severities of TBI and may represent a key pathologic substrate of mild TBI (concussion). Pathologically, DAI encompasses a spectrum of effects from primary mechanical breaking of the axonal cytoskeleton, to transport interruption, swelling and proteolysis, through secondary physiological changes. Depending on the severity and extent of injury, these changes can manifest acutely as immediate loss of consciousness or confusion and persist as coma and/or cognitive dysfunction. In addition, recent evidence suggests that TBI may induce long-term neurodegenerative processes, such as insidiously progressive axonal pathology. Indeed, axonal degeneration has been found to continue even years after injury in humans, and appears to play a role in the development of Alzheimer’s disease-like pathological changes. Here we review the current understanding of DAI as a uniquely mechanical injury, its histopathological identification, and its acute and chronic pathogenesis following TBI.

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Crossref · 10.1016/j.expneurol.2012.01.013

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  • Concussion is thought to be a type of DAI because axons may be injured due to stretching.

    “As a neuropathological definition, concussion is thought to be a type of DAI because axons may be injured due to stretching (104, 105).”

    From Pituitary Dysfunction After Traumatic Brain Injury: A Clinical and Pathophysiological Approach (2015) · cites this paper as [105]

    The Introduction describes DAI as occurring across severities of closed-head injury, and the Conclusions say axonal damage may contribute to dysfunction in mild TBI. The section on primary mechanical damage explains how rapid stretch can injure axons. These passages support a possible role for stretch-related axonal injury in concussion, but they do not define concussion itself as a type of DAI. Page numbers were not available in our copy. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • DAI is the primary neuropathology of TBI that is caused by the shearing of fragile axons by acceleration/deceleration forces from head trauma.

    “DAI is the primary neuropathology of TBI that is caused by the shearing of fragile axons (disruption of axonal fibers and myelin sheaths) by acceleration/deceleration forces from the head trauma (105, 106).”

    From Pituitary Dysfunction After Traumatic Brain Injury: A Clinical and Pathophysiological Approach (2015) · cites this paper as [105]

    The Introduction calls DAI one of the most common neuropathological consequences of TBI and links it to mechanical loading during rapid head acceleration; it does not call DAI the primary neuropathology. The section “Potential Primary Mechanical Damage due to Axonal Trauma” also says immediate shearing apart of axons is relatively rare and that disconnection usually develops secondarily after cytoskeletal damage, so the claim oversimplifies the mechanism. Page numbers were not available in our copy. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • DAI can be identified within hours after head trauma and is characterized by sequential changes with an initial shearing of axons that causes disrupted axonal transport, secondary axonal disconnection, and eventually Wallerian degeneration.

    “By using histopathological techniques, DAI can be identified within hours after head trauma and is characterized by sequential changes with an initial shearing of axons that causes disrupted axonal transport, secondary axonal disconnection, and eventually, Wallerian degeneration (105, 110).”

    From Pituitary Dysfunction After Traumatic Brain Injury: A Clinical and Pathophysiological Approach (2015) · cites this paper as [105]

    The paper’s “DAI: Pathological Features and Identification” section says APP staining can detect damaged axons within two hours of injury. “Potential Primary Mechanical Damage due to Axonal Trauma” describes cytoskeletal damage, interrupted transport, secondary disconnection and Wallerian degeneration, but says immediate severing of axons is relatively rare—not the usual initial step implied by “initial shearing of axons.” (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Concussion is the most frequent type of acute TBI in sports-related head trauma, and DAI is the primary pathophysiology of TBI.

    “As we discussed above, concussion is the most frequent type of acute TBI in sports-related head trauma, and DAI, which is caused by the shearing of fragile axons, is the primary pathophysiology of TBI (105).”

    From Pituitary Dysfunction After Traumatic Brain Injury: A Clinical and Pathophysiological Approach (2015) · cites this paper as [105]

    The Introduction describes DAI as one of the most common pathological consequences of closed-head TBI, and the section on DAI genesis describes shear strains as a mechanism. The paper does not establish that concussion is the most frequent acute sports-related TBI or that DAI is the primary pathophysiology of all TBI. The section on primary mechanical damage also says immediate axonal disconnection is relatively rare, so describing DAI simply as shearing of fragile axons oversimplifies the mechanism. Page numbers were not available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Cites

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Research works printed but not linked: 14

  1. [2]Adams JH D D Ford I Gennarelli TA Graham DI McLellan DR 1989 Diffuse axonal injury in head injury: definition, diagnosis and grading Histopathology 15 49 59 2767623
  2. [3]Adams JH Doyle D Ford I Gennarelli TA Graham DI McClellan DR 1989 Diffuse axonal injury in head injury: definition, diagnosis, and grading Histopathol 15 49 59 2767623
  3. [4]Adams JH Doyle D Ford I Gennarelli TA Graham DI McLellan DR 1989 Diffuse axonal injury in head injury: definition, diagnosis and grading Histopathology 15 49 59 2767623
  4. [8]Adams JH Graham DI Murray LS Scott G 1982 Diffuse axonal injury due to nonmissile head injury in humans: An analysis of 45 cases Ann Neurol 12 557 563 7159059
  5. [26]Chen XH Johnson VE Uryu K Trojanowski JQ Smith DH 2009 A lack of amyloid beta plaques despite persistent accumulation of amyloid beta in axons of long-term survivors of traumatic brain injury Brain Pathol 19 214 223 18492093 PMC3014260
  6. [27]Chen XH Meaney DF Xu BN Nonaka M McIntosh TK Wolf JA Saatman KE Smith DH 1999 Evolution of neurofilament subtype accumulation in axons following diffuse brain injury in the pig J Neuropathol Exp Neurol 58 588 596 10374749
  7. [68]Johnson VE Stewart W Smith DH 2011 Amyloid and Tau Pathologies Many Years Following Single Traumatic Brain Injury in Humans Brain Pathology In Press PMC3979351 21714827
  8. [69]Johnson VE Stewart W Smith DH 2011 Widespread Amyloid and Tau Pathologies Following a Single Traumatic Brain Injury in Humans Brain Pathol (Accepted) PMC3979351 21714827
  9. [114]Povlishock JT Becker DP 1985 Fate of reactive axonal swellings induced by head injury Lab Invest 52 540 552 2581065
  10. [117]Povlishock JT Buki A Koiziumi H Stone J Okonkwo DO 1999 Initiating mechanisms involved in the pathobiology of traumatically induced axonal injury and interventions targeted at blunting their progression Acta Neurochir Suppl 73 15 20 10494336
  11. [139]Smith DH Chen XH Xu BN McIntosh TK Gennarelli TA Meaney DF 1997 Characterization of diffuse axonal pathology and selective hippocampal damage following inertial brain trauma in the pig Journal of Neuropathology & Experimental Neurology 56 822 834 9210879
  12. [144]Smith DH Meaney DF Shull WS 2003 Diffuse axonal injury in head trauma J Head Trauma Rehab 18 307 316 16222127
  13. [148]Smith DH Wolf JA Lusardi TA Lee VM-Y Meaney DF 1999 High tolerance and delayed elastic response of cultured axons to dynamic stretch injury J Neurosci 19 4263 4269 10341230 PMC6782601
  14. [162]Tokuda T Ikeda S Yanagisawa N Ihara Y Glenner GG 1991 Re-examination of ex-boxers’ brains using immunohistochemistry with antibodies to amyloid beta-protein and tau protein Acta Neuropathol 82 280 285 1759560

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Authors
Johnson, V. E., Stewart, W., & Smith, D. H.
Affiliations
University of Pennsylvania (US)
Corresponding author
Smith, Douglas H.
ORCID
Venue
Experimental Neurology
Publisher
Elsevier BV
Published
2013-08
Volume
246
Pages
35-43
ISSN
0014-4886 (ISSN-L)
DOI
10.1016/j.expneurol.2012.01.013
PMC
PMC3979341
OpenAlex
W2170921124
Semantic Scholar
6fdff07fcccb6429453f06a8aae43cdaad508837
Cited by
1,273
References
162
Citations by year
2026: 82 · 2025: 88 · 2024: 86 · 2023: 106 · 2022: 105 · 2021: 123 · 2020: 102 · 2019: 98 · 2018: 93 · 2017: 113 · 2016: 92 · 2015: 89 · 2014: 37 · 2013: 44 · 2012: 14
FWCI
8.26
Type
journal article
Language
en
Open access
Locations
  • Experimental Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (R03AG038911)
  • National Institute of Neurological Disorders and Stroke (NS-038104, R01NS038104, P01NS056202, NS 056202)
Topics
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Automotive and Human Injury Biomechanics
Keywords
diffuse axonal injury, traumatic brain injury, axonal pathology, white matter, mild traumatic brain injury, concussion, axonal cytoskeleton, axonal transport, axonal swellings, proteolysis, secondary injury, Alzheimer's disease, histopathology, pathogenesis
MeSH terms
Animals, Axons, Brain Injuries, Coma, Humans, Nerve Degeneration, Nerve Fibers, Myelinated, Diffuse Axonal Injury

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