Expert

Concussions, Traumatic Brain Injuries and Alzheimer’s Risk

Illustration showing a concussion's impact on the brain
Learn what traumatic brain injury is and how it can increase the risk of developing Alzheimer’s disease.

What is Traumatic Brain Injury?

Traumatic brain injury (TBI) occurs when a physical force acts on the head, leading to altered brain function. Examples of trauma-induced abnormalities include a decrease or loss in consciousness, persistent headaches, sleep disturbances and changes in mental functions like memory and attention.1 TBI is a leading cause of disability and death among young people and is most often associated with falls, motor vehicle accidents, assaults, military service and engagement in contact sports (like football, boxing, and hockey).2

TBI severity can range from mild to severe injury. A “mild” TBI is often used interchangeably with “concussion,” and most cases (60-80%) of TBI are mild.3 In general, injury severity is classified based on clinical symptoms such as the level of consciousness, as measured by the Glasgow Coma Scale, which remains the gold standard for moderate and severe TBI. Mild TBI and concussion, however, is more challenging to diagnose, and objective measures including neuroimaging and blood biomarkers tests are actively being studied to better diagnose mild TBI and concussion.

TBI and Dementia

In addition to possible death and long-term disabilities, individuals that sustain a moderate to severe TBI are reported to be two to five times more likely to develop dementia, including Alzheimer’s disease (AD), later in life when compared to uninjured individuals.4-6 It is less clear whether mild injuries are also associated with this increased risk.

How Does TBI Affect the Brain?

Disrupted function of brain cells (“neurons”) and their connections (“axons”) after TBI are believed to be caused by the vigorous mechanical strains and deformations that are sustained during impact.7 Experimental data from animal model studies by our group, as well as others, show that concussions induce the inflammatory response in the brain as soon as a few hours after injury.8 These inflammatory signals activate immune cells, which may persist for months in the brain, creating a sustained chronic inflammatory environment.9 Whereas acute inflammation is necessary for tissue healing and repair, chronic inflammation of the brain may result in prolonged injury to neurons and axons. This may eventually trigger degeneration of the brain and thus lead to dementia.10,11

In addition to chronic inflammation, injured neurons also undergo cellular stress and disrupted metabolism that may result in an abnormal production and/or inefficiency in the clearance of toxic proteins, leading to their accumulation in the brain. One such toxic protein is phosphorylated tau (p-tau).

Recent studies that have examined autopsy brains from retired contact sport athletes suggest that multiple concussions sustained over a career may be associated with a brain degenerative condition called chronic traumatic encephalopathy (CTE).12,13 CTE brains are characterized by shrinkage, or atrophy, of brain tissue and accumulation of p-tau around blood vessels, particularly at the bottom of the folds in the brain.14 Moreover, p-tau is also one of the major pathological accumulations in other brain degenerative diseases, including AD.15 These findings suggest that TBI and brain degeneration may share overlapping pathways, such as chronic brain inflammation and accumulation of toxic proteins.

Genetic Risk Factors and TBI

Several research studies have been performed to investigate genetic risk factors that would negatively impact TBI outcomes. One of the potential gene candidates is called APOE. In humans, there are three common genetic variants of the APOE gene: APOE2, APOE3, and APOE4.16 Under normal circumstances, the protein products of this gene (called apolipoprotein E or apoE) play an integral role in essential aspects like cholesterol metabolism, neuronal repair and the clearance of a toxic substance called A-beta, the accumulation of which is associated with the development of AD.

Clinical studies have established APOE4 as the strongest genetic risk factor for AD, and thus whether APOE variants underlie a potential association between TBI and the later development of AD is of intense interest. In studies using genetically engineered animals, the APOE4 gene is associated with accumulation of A-beta and disruption of brain blood vessel health after TBI.17,18 Human clinical studies, however, do not have a conclusive finding. Some studies suggest that APOE4 may be associated with poorer long-term recovery after TBI.19,20 Other studies showed that APOE4 does not significantly increase risk of concussion or risk of developing CTE.21-23 Overall, the link between APOE and TBI outcome still requires further investigation.

Predicting Diagnosis and Recovery from TBI

Another major avenue in TBI research is the development of fluid biomarkers. Biomarkers are important because they can assist in diagnosis and can also be used to predict recovery. Currently, there are still no fully validated TBI biomarkers.24 However, we know that damaged brain cells release trace amounts of molecules which leak into cerebrospinal fluid (CSF) and the bloodstream. Improved technology now allows us to measure these molecules in both CSF and blood.

In recent years, a protein called glial fibrillary acidic protein (GFAP) has risen as a potentially important concussion biomarker candidate. GFAP is found in brain cells called astrocytes, and is shown to be present in much higher amounts in blood samples taken from athletes who had concussions compared to athletes who did not.25

Neurofilament light (NF-L) chain, a protein released from damaged axons, is also present at much higher levels in blood from concussion patients. Both GFAP and NF-L may prove to be useful to monitor recovery and predict TBI outcomes.26

Summary

TBI research is very complex, as TBI can happen to any person at any time of life, by many causes. Currently, there is no cure for TBI. However, with recent advancements in technology and research, we now have better tools to monitor TBI and predict its outcomes. We are also gaining more insights into how traumatic injury may trigger or exacerbate mechanisms known to be involved in neurodegeneration.

In the future, we hope to be able to identify risk factors for TBI and help improve management strategies. The ultimate goal is, of course, to develop effective treatments for TBI. However, as TBI involves damage to different types of brain cells, disruption of brain blood vessels, accumulation of toxic proteins, chronic inflammation, and brain atrophy, it is unlikely that we will come up with one single magic bullet. The more likely scenario is that we will develop different therapeutic approaches to target different aspects of TBI in a patient-centered approach.

Contributing Authors:

Drs. Wai Hang Cheng, David Baron, Jasmine Gill, and Yu Hang Kang.

Resources:

You May Also Be Interested In:

References:

  1. Menon, D. K. et al. Position statement: definition of traumatic brain injury. Archives of physical medicine and rehabilitation 91, 1637-1640, doi:10.1016/j.apmr.2010.05.017 (2010).
  2. Popescu, C., Anghelescu, A., Daia, C. & Onose, G. Actual data on epidemiological evolution and prevention endeavours regarding traumatic brain injury. J Med Life 8, 272-277 (2015).
  3. Bruns, J., Jr. & Hauser, W. A. The epidemiology of traumatic brain injury: a review. Epilepsia 44 Suppl 10, 2-10 (2003).
  4. Gardner, R. C. et al. Dementia risk after traumatic brain injury vs nonbrain trauma: the role of age and severity. JAMA Neurol 71, 1490-1497, doi:10.1001/jamaneurol.2014.2668 (2014).
  5. Mortimer, J. A. et al. Head trauma as a risk factor for Alzheimer’s disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group. Int J Epidemiol 20 Suppl 2, S28-35 (1991).
  6. Fleminger, S., Oliver, D. L., Lovestone, S., Rabe-Hesketh, S. & Giora, A. Head injury as a risk factor for Alzheimer’s disease: the evidence 10 years on; a partial replication. J Neurol Neurosurg Psychiatry 74, 857-862 (2003).
  7. Schmitt, K. U. N., P.F.; Cronin, D.S.; Muser, M.H.; Walz, F. in Trauma Biomechanics. An Introduction to Injury Biomechanics. Fourth Edition. (Springer, 2014).
  8. Namjoshi, D. R. et al. Defining the biomechanical and biological threshold of murine mild traumatic brain injury using CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration). Exp Neurol, doi:10.1016/j.expneurol.2017.03.003 (2017).
  9. Cheng, W. H. et al. CHIMERA repetitive mild traumatic brain injury induces chronic behavioural and neuropathological phenotypes in wild-type and APP/PS1 mice. Alzheimers Res Ther 11, 6, doi:10.1186/s13195-018-0461-0 (2019).
  10. Kokiko-Cochran, O. N. & Godbout, J. P. The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease. Front Immunol 9, 672, doi:10.3389/fimmu.2018.00672 (2018).
  11. Vonder Haar, C. et al. Repetitive closed-head impact model of engineered rotational acceleration (CHIMERA) injury in rats increases impulsivity, decreases dopaminergic innervation in the olfactory tubercle and generates white matter inflammation, tau phosphorylation and degeneration. Exp Neurol 317, 87-99, doi:10.1016/j.expneurol.2019.02.012 (2019).
  12. McKee, A. C. et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 68, 709-735, doi:10.1097/NEN.0b013e3181a9d503 (2009).
  13. Omalu, B. I. et al. Chronic traumatic encephalopathy in a National Football League player. Neurosurgery 57, 128-134; discussion 128-134 (2005).
  14. McKee, A. C. et al. The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol 131, 75-86, doi:10.1007/s00401-015-1515-z (2016).
  15. Kovacs, G. G. Tauopathies. Handb Clin Neurol 145, 355-368, doi:10.1016/B978-0-12-802395-2.00025-0 (2017).
  16. Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C. C. & Bu, G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol 15, 501-518, doi:10.1038/s41582-019-0228-7 (2019).
  17. Main, B. S. et al. Apolipoprotein E4 impairs spontaneous blood brain barrier repair following traumatic brain injury. Mol Neurodegener 13, 17, doi:10.1186/s13024-018-0249-5 (2018).
  18. Washington, P. M. & Burns, M. P. The Effect of the APOE4 Gene on Accumulation of Abeta40 After Brain Injury Cannot Be Reversed by Increasing apoE4 Protein. J Neuropathol Exp Neurol 75, 770-778, doi:10.1093/jnen/nlw049 (2016).
  19. Kassam, I., Gagnon, F. & Cusimano, M. D. Association of the APOE-epsilon4 allele with outcome of traumatic brain injury in children and youth: a meta-analysis and meta-regression. J Neurol Neurosurg Psychiatry 87, 433-440, doi:10.1136/jnnp-2015-310500 (2016).
  20. Li, L. et al. The Association Between Apolipoprotein E and Functional Outcome After Traumatic Brain Injury: A Meta-Analysis. Medicine (Baltimore) 94, e2028, doi:10.1097/MD.0000000000002028 (2015).
  21. Maroon, J. C. et al. Chronic traumatic encephalopathy in contact sports: a systematic review of all reported pathological cases. PLoS One 10, e0117338, doi:10.1371/journal.pone.0117338 (2015).
  22. McKee, A. C. et al. The spectrum of disease in chronic traumatic encephalopathy. Brain 136, 43-64, doi:10.1093/brain/aws307 (2013).
  23. Panenka, W. J. et al. Systematic Review of Genetic Risk Factors for Sustaining a Mild Traumatic Brain Injury. J Neurotrauma, doi:10.1089/neu.2016.4833 (2017).
  24. Wang, K. K. et al. An update on diagnostic and prognostic biomarkers for traumatic brain injury. Expert Rev Mol Diagn 18, 165-180, doi:10.1080/14737159.2018.1428089 (2018).
  25. McCrea, M. et al. Association of Blood Biomarkers With Acute Sport-Related Concussion in Collegiate Athletes: Findings From the NCAA and Department of Defense CARE Consortium. JAMA Netw Open 3, e1919771, doi:10.1001/jamanetworkopen.2019.19771 (2020).
  26. Hossain, I. et al. Early Levels of Glial Fibrillary Acidic Protein and Neurofilament Light Protein in Predicting the Outcome of Mild Traumatic Brain Injury. J Neurotrauma 36, 1551-1560, doi:10.1089/neu.2018.5952 (2019).

 

This content was first posted on: October 6, 2020

The information provided here is a public service of the BrightFocus Foundation and should not in any way substitute for personalized advice of a qualified healthcare professional; it is not intended to constitute medical advice. Please consult your physician for personalized medical advice. BrightFocus Foundation does not endorse any medical product, therapy, or resources mentioned or listed in this article. All medications and supplements should only be taken under medical supervision. Also, although we make every effort to keep the medical information on our website updated, we cannot guarantee that the posted information reflects the most up-to-date research.

These articles do not imply an endorsement of BrightFocus by the author or their institution, nor do they imply an endorsement of the institution or author by BrightFocus.

Some of the content may be adapted from other sources, which will be clearly identified within the article.

More Like This

  • Accessible Voting Machine
    Expert

    Making an Accessible Voting Plan

    As the 2020 election is quickly approaching on Tuesday, November 3rd, now is a great time to make your voting plan. In addition to reviewing the dates, deadlines, locations, and requirements for in-person or absentee voting in your state, for people with disabilities and impairments, it’s also important to know what your options are for accessible voting.

    October 14, 2020
  • Abstract illustration of the brain depicting various paths that Alzheimer's can take
    Expert

    The Three Stages of Alzheimer’s Disease

    Patients, families and clinicians all want to know how far Alzheimer’s disease has progressed and what the future is likely to hold. Learn about the symptoms associated with the three stages of the disease.

    September 7, 2020
Don't miss out.
Receive research updates, inspiring stories, and expert advice
Please enter your first name.
Please enter your last name.
Keep me informed about: *
Please select at least one.
You must select at least one disease category.