DNA damage as a marker of brain damage in individuals with history of concussions
Open accessAbstract
Mild traumatic brain injury (mTBI) is common in many populations, including athletes, veterans, and domestic abuse victims. mTBI can cause chronic symptoms, including depression, irritability, memory problems, and attention deficits. A history of repetitive mTBI has been epidemiologically associated with developing early-onset dementia and neurodegenerative diseases and, in particular, is thought to be the underlying cause of chronic traumatic encephalopathy (CTE)-a progressive tauopathy diagnosed by the presence of perivascular hyperphosphorylated tau protein (p-tau) in the depths of cortical sulci. However, the scarce and focal pathology often seen in CTE does not correlate with the severity of symptoms experienced by patients. This paper proposes accumulation of γH2AX, a marker of double-stranded DNA damage, as a novel pathological marker to identify brain damage post-mTBI. We present two cases of men with history of mTBI. Immunohistochemistry revealed extensive DNA damage throughout the frontal cortex, hippocampus, and brainstem areas. Furthermore, gene expression profiling showed increases of ataxia telangiectasia mutated (ATM) and checkpoint kinase 2 (CHEK2), two serine/threonine kinases recruited in response to double-strand breaks in the DNA damage response pathway. These cases highlight the complex pathophysiology of head trauma, and suggest DNA damage as the molecular mechanism behind mTBI-induced pathology and symptoms.
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The authors' lab has previously shown evidence of double-strand breaks in human brains with mTBI history.
“our lab has previously shown evidence of double-strand breaks (DSBs) in human brains with mTBI history [131, 132].”
From Early onset senescence and cognitive impairment in a murine model of repeated mTBI (2021) · cites this paper as [132]
Our own studies on human autopsy cases showed strong evidence of DSBs in brains of athletes with a history of rmTBI.
“Our own studies on human autopsy cases showed strong evidence of DSBs in brains of athletes with a history of rmTBI [131, 132].”
From Early onset senescence and cognitive impairment in a murine model of repeated mTBI (2021) · cites this paper as [132]
Previous work showed evidence of DNA damage in human cases with a history of acute and chronic mTBI.
“in our previous work, we have shown evidence of DNA damage in human cases with a history of acute and chronic mTBI [135].”
From DNA repair deficiency and senescence in concussed professional athletes involved in contact sports (2019) · cites this paper as [135]
In previous work, widespread accumulation of DNA damage and up-regulation of DDR signaling gene expression was presented in men with history of mTBI.
“In our previous work, we presented widespread accumulation of DNA damage and up-regulation of DDR signaling gene expression in men with history of mTBI [135].”
From DNA repair deficiency and senescence in concussed professional athletes involved in contact sports (2019) · cites this paper as [135]
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Self-citationRashno, M., Ghaderi, S., Nesari, A., Khorsandi, L., Farbood, Y., & Sarkaki, A. (2020) · Psychopharmacology · doi:10.1007/s00213-020-05482-3 · Cited by 43 · see citing works
RetractedEarly onset senescence and cognitive impairment in a murine model of repeated mTBI
Schwab, N., Ju, Y., & Hazrati, L.-N. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01190-x · Cited by 39 · see citing works
Self-citationCellular Senescence in Traumatic Brain Injury: Evidence and Perspectives
Schwab, N., Leung, E., & Hazrati, L. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.742632 · Cited by 33 · see citing works
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Chen, Y., Chen, Y., Chin, Y., Wang, C., Hwang, L.-L., Yang, L., & Lu, D. (2022) · Aging · doi:10.18632/aging.203958 · Cited by 14 · see citing works
Breast cancer type 1 and neurodegeneration: consequences of deficient DNA repair
Leung, E., & Hazrati, L. (2021) · Brain Communications · doi:10.1093/braincomms/fcab117 · Cited by 12 · see citing works
Self-citationUncaria tomentosa improves cognition, memory and learning in middle-aged rats
Castilhos, L. G., de Oliveira, J. S., Adefegha, S. A., Manzoni, A. G., Passos, D. F., Assmann, C. E., da Silveira, L. L., Trelles, K. B., Kronbauer, M., Doleski, P. H., et al. (2020) · Experimental Gerontology · doi:10.1016/j.exger.2020.111016 · Cited by 12 · see citing works
Brain pathology and symptoms linked to concussion history: beyond chronic traumatic encephalopathy
Taskina, D., Zhu, C., Schwab, N., & Hazrati, L. (2024) · Brain Communications · doi:10.1093/braincomms/fcad314 · Cited by 10 · see citing works
Self-citationErp57 facilitates ZIKV-induced DNA damage via NS2B/NS3 complex formation
Wang, Y., Song, D., Li, Y., Qin, L., Wan, Q., Hu, H., Wu, M., Feng, Y., Schang, L. M., Weiss, R. S., et al. (2024) · Emerging Microbes & Infections · doi:10.1080/22221751.2024.2417864 · Cited by 10 · see citing works
Cognitive Impairment and Dementia-Related Diagnoses in Chronic Traumatic Encephalopathy
LoBue, C., Bickart, K. C., Bieniek, K. F., Brett, B. L., Cabrera, H., Chiang, H., Sanotos, Y. D. L., Gonzales, M. M., Hart, J., Hernandez, R. S., et al. (2025) · Neurology · doi:10.1212/wnl.0000000000213934 · Cited by 8 · see citing works
The pathological potential of ependymal cells in mild traumatic brain injury
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Subcellular functions of tau mediate repair response and synaptic homeostasis in injury
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Exline, J. E., Volyanyuk, M., Lotesto, K. M., Segismundo, A. B., Byram, S. C., & Foecking, E. M. (2025) · Brain Research · doi:10.1016/j.brainres.2025.149611 · Cited by 3 · see citing works
Leung, E., Taskina, D., Schwab, N., & Hazrati, L. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1225226 · Cited by 3 · see citing works
Self-citationSelim, H. M. R. M., El-Gazar, A. A., Abdallah, D. M., Abo-Zalam, H. B., Ragab, G. M., Abdallah, A. N., El-Gazar, R. A., Alshehri, S., Yousef, E. M., Ballal, R., et al. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1622018 · Cited by 2 · see citing works
Siracusa, L. R., Park, E., Liu, E., & Baker, A. J. (2025) · Brain Research · doi:10.1016/j.brainres.2025.149559 · Cited by 1 · see citing works
Commentary: Type I Interferon Response Is Mediated by NLRX1-cGAS-STING Signaling in Brain Injury
McEntee, C. M., & LaRocca, T. J. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.947542 · Cited by 1 · see citing works
Twiss, E., McPherson, C., & Weaver, D. F. (2026) · Current Alzheimer Research · doi:10.2174/0115672050414496251124094000
Therapeutic potential of scutellarin in central nervous system: A comprehensive review
Ma, L., Chen, S., Jia, Q., Tian, R., Zeng, Y., Luo, K., Meng, X., & Yang, L. (2026) · Phytomedicine · doi:10.1016/j.phymed.2026.158506
Cellular senescence and senolytic therapy in traumatic brain injury
Brann, D. W., Singh, H. D., Wang, J., Lu, Y., Carr, C., & Dhandapani, K. M. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1862748
Baradie, Y., Najm, D. B., El-Makkawi, A., Cherfane, N., Murr, S. E., & Soueid, J. (2026) · Experimental Neurology · doi:10.1016/j.expneurol.2026.116056
- Authors
- Schwab, N., Tator, C., & Hazrati, L.-N.
- Affiliations
- University of Toronto (CA)
- University Health Network (CA)
- Corresponding author
- Hazrati, Lili-Naz
- Venue
- Laboratory Investigation
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 99
- Issue
- 7
- Pages
- 1008-1018
- ISSN
- 0023-6837 (ISSN-L)
- OpenAlex
- W2911754027
- Cited by
- 26
- References
- 78
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 2
- FWCI
- 1.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Laboratory Investigation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Road2Recovery
- Topics
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Automotive and Human Injury Biomechanics
- Keywords
- mild traumatic brain injury, chronic traumatic encephalopathy, DNA damage, γH2AX, DNA double-strand breaks, DNA damage response, ATM, CHEK2, tauopathy, repetitive head trauma, frontal cortex, hippocampus, brainstem
- MeSH terms
- Chronic Traumatic Encephalopathy, Adult, Aged, 80 and over, Brain, Brain Concussion, DNA Damage, Humans, Male, Biomarkers
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