Butting Heads—Autopsies Fuel Debate on Football and Neurodegeneration

In American football, using your head may mean different things to different players. A top-class quarterback like Peyton Manning uses it for millisecond analysis of the state of play, but for a running back or a lineman it often doubles as a battering ram. Not surprisingly, football players suffer their fair share of concussions, despite the helmets. Do these mild traumas have long-term effects? Some recent autopsy data may re-energize the debate over the link between repetitive brain injuries and subsequent neurological decline, including depression and the development of Alzheimer-like pathologies, such as amyloid plaques and neurofibrillary tangles.

In last month’s Neurosurgery, Bennet Omalu and colleagues from the University of Pittsburgh, Pennsylvania, report autopsy data on retired National Football League (NFL) offensive guard Terry Long, who committed suicide in November 2005 at age 45 following a long battle with depression. They write that Long had chronic traumatic encephalopathy (CTE) accompanied by widespread neurofibrillary tangles and neuropil threads in the brain. The findings are reminiscent of an earlier autopsy on another ex-Pittsburgh Steeler, “Iron” Mike Webster. Omalu and colleagues, including University of Pittsburgh’s Steve DeKosky, had reported in July of 2005 that the 50-year-old Webster also had had CTE along with many diffuse amyloid plaques in his brain and sparse neurofibrillary tangles (Omalu et al., 2005). That earlier paper found itself hotly challenged by members of the NFL’s Mild Traumatic Brain Injury Committee, who asked for its retraction. The Committee’s rationale was not that the data was incorrect, but that Omalu and colleagues misinterpreted the definition of chronic traumatic encephalopathy. As far as this reporter has determined, the committee has not yet commented on Omalu’s new paper. Nor has it issued an official response to a story in the 18 January New York Times reporting that Omalu found similar neuropathology in the brain of a third former NFL player, Philadelphia Eagles defensive back Andre Waters, who committed suicide in November of 2006 at the age of 44.

In a telephone interview with Alzforum, Omalu said that though Waters’s complete brain had not been saved after autopsy, sufficient material was saved for histochemical analysis on more than 120 sections. “We found frequent density of neurofibrillary tangles and neuritic threads in the hippocampus, the neocortex, and the brainstem,” said Omalu. If the findings stand up to peer review, this will represent the third young ex-NFL player to exhibit pathologies normally associated with 70- and 80-year-old AD patients.

Three retrospective cases are hardly proof that football-related injuries precipitate AD-like pathologies in the prime of life. For this reason, Omalu and colleagues have called for a prospective, longitudinal study on a specified cohort of former professional contact-sport players, such as the NFL Hall of Famers. A preponderance of evidence from other studies suggests that the effects of repetitive mild traumatic brain injuries are cumulative. Kevin Guskiewicz and colleagues at the University of North Carolina, Chapel Hill, reported that NFL players who have received three or more concussions during their careers are five times more likely to suffer from mild cognitive impairment (Guskiewicz et al., 2005). The issue is a sensitive one for other professional sports, as well, such as boxing (Jordan, 2000).

Within the NFL, part of the debate surrounds the question of how quickly a player should play again after sustaining a concussion, and what medical attention is appropriate to prevent long-term consequences. But many neurodegeneration researchers may question whether any medical intervention is available to stem a long-term process of pathology buildup triggered by repetitive mild head trauma. These researchers are less surprised by a link between such trauma and neurofibrillary/amyloid pathologies than by the fact that this is news to society at large. Animal studies have documented this connection repeatedly (e.g., Yoshiyama et al., 2005; Uryu et al., 2002), and human data exist, as well (e.g., Jellinger, 2004).

“Recently there has been a major shift in scientific thought about the long-term sequelae of playing football. What we are finding out is that these repetitive concussions are cumulative over time and additive, and when players retire many years later they may have dementia-like disease,” said Omalu. Where do AD researchers stand on this issue? Are you letting your kids play high school football?—Tom Fagan

Comments

  1. A major contribution of this report is that it sharply focuses attention on the potentially deleterious effects of repeated head trauma in contact sports. The neuropathological findings are consistent with previous reports of what was termed "dementia pugilistica." It is certainly possible that the erratic fluctuations in mood and the severe depression with multiple suicide attempts relate to the widespread cortical and subcortical neuritic pathology. It also is possible that the abnormal behaviors in life resulted from unrelated psychopathology that may or may not have been exacerbated by steroid use. The authors correctly consider these alternatives, and make a much-needed call to systematically conduct clinico-pathological studies of individuals involved in these contact sports. The clear demonstration that neuropathological lesions can be associated with such sports underscores the paucity of data regarding the possible neuropsychiatric consequences. Full understanding of these consequences is needed to implement appropriate measures to ensure the safety of the participants.

    View all comments by John Morris

  2. We have argued for some years that neurofibrillary pathology, such as tangles and dystrophic neurites, are not particularly Alzheimer disease-specific, as they represent the prolonged aberrant reaction of nerve cells to ongoing or repeated structural injury (Vickers et al., 2000). In the case of “garden-variety” Alzheimer disease, we have proposed that plaque formation may cause enough compression of the neuropil to effectively squeeze axons. This would result in the stimulation of the stereotypical reaction to such interruption in axoplasmic flow, including the abnormal regenerative changes throughout the nerve cell that ultimately lead to classic neurofibrillary pathology.

    In this regard, any prolonged or repeated structural injury to axons, as you see in younger people with repeated head injury (e.g., Hof et al., 1991), would be predicted to have a similar outcome. This may be why the early axonal pathology associated with plaque formation is easy to model in experimental models involving axonal shear or transection (Dickson et al., 2000; Chung et al., 2005; Dickson et al., 2005). However, true neurofibrillary pathology may take a much longer time to develop, as it relies on the perikaryal response that builds up due to the prolonged or repeated axonal injury. In this regard, most neurofibrillary tangles in the neocortex in Alzheimer disease are still intracellular, further indicating a long period of time leading to degeneration. I would be interested in this report about more detail on the type of axonal pathology still present, and also if the tangles were largely intracellular.

    References:

    Dickson TC, Adlard PA, Vickers JC. Sequence of cellular changes following localized axotomy to cortical neurons in glia-free culture. J Neurotrauma. 2000 Nov;17(11):1095-103. PubMed.

    Dickson TC, Chuckowree JA, Chuah MI, West AK, Vickers JC. alpha-Internexin immunoreactivity reflects variable neuronal vulnerability in Alzheimer's disease and supports the role of the beta-amyloid plaques in inducing neuronal injury. Neurobiol Dis. 2005 Mar;18(2):286-95. PubMed.

    Chung RS, Staal JA, McCormack GH, Dickson TC, Cozens MA, Chuckowree JA, Quilty MC, Vickers JC. Mild axonal stretch injury in vitro induces a progressive series of neurofilament alterations ultimately leading to delayed axotomy. J Neurotrauma. 2005 Oct;22(10):1081-91. PubMed.

    Hof PR, Knabe R, Bovier P, Bouras C. Neuropathological observations in a case of autism presenting with self-injury behavior. Acta Neuropathol. 1991;82(4):321-6. PubMed.

    Vickers JC, Dickson TC, Adlard PA, Saunders HL, King CE, McCormack G. The cause of neuronal degeneration in Alzheimer's disease. Prog Neurobiol. 2000 Feb;60(2):139-65. PubMed.

    View all comments by James Vickers

  3. Repeated traumatic brain injury (TBI) in tau transgenic mice variably induces accelerated tangle formation. Moreover, the evidence that TBI is a robust risk factor for AD is very strong; see Yoshiyama et al., 2005.

    References:

    Yoshiyama Y, Uryu K, Higuchi M, Longhi L, Hoover R, Fujimoto S, McIntosh T, Lee VM, Trojanowski JQ. Enhanced neurofibrillary tangle formation, cerebral atrophy, and cognitive deficits induced by repetitive mild brain injury in a transgenic tauopathy mouse model. J Neurotrauma. 2005 Oct;22(10):1134-41. PubMed.

    View all comments by John Trojanowski

  4. Note from the Alzforum editor: Today's New York Times followed up its initial article of 18 January on neurodegenerative consequences of repeated concussions in professional football with the story of yet another player. According to the NYT, Ted Johnson, the New England Patriot's middle linebacker until his retirement in 2005, forgets people's names, misses appointments, and suffers from depression. Johnson sustained repeated concussions in close succession in 2002. The news article cites Johnson's neurologist as saying that Johnson shows the cognitive impairment that is characteristic of early Alzheimer disease. Johnson is 34 years old.

    View all comments by Gabrielle Strobel

  5. Given the similarities between Alzheimer disease and dementia pugilistica, we studied retired boxers in the late 1990s. We found that when we standardized for technical knockouts, boxers who were becoming demented were the ones who carried ApoE4 alleles, just as one might predict (Jordan et al., 1997). This raises the question of whether boxers and footballers should be genotyped before committing to a career in these sports. Neither the boxing nor football associations welcome this prospect.

    We also published a case report of a famous boxer, whose name we are not at liberty to disclose, who died of amyloid angiopathy (Jordan et al., 1995). From the perspective of the field of neurodegeneration research, the link between repeated mild brain trauma and degenerative changes in subsequent years is beyond dispute.

    References:

    Jordan BD, Relkin NR, Ravdin LD, Jacobs AR, Bennett A, Gandy S. Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. JAMA. 1997 Jul 9;278(2):136-40. PubMed.

    Jordan BD, Kanik AB, Horwich MS, Sweeney D, Relkin NR, Petito CK, Gandy S. Apolipoprotein E epsilon 4 and fatal cerebral amyloid angiopathy associated with dementia pugilistica. Ann Neurol. 1995 Oct;38(4):698-9. PubMed.

    View all comments by Sam Gandy

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References

Paper Citations

  1. Omalu BI, Dekosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH. Chronic traumatic encephalopathy in a National Football League player. Neurosurgery. 2005 Jul;57(1):128-34; discussion 128-34. PubMed.
  2. Guskiewicz KM, Marshall SW, Bailes J, McCrea M, Cantu RC, Randolph C, Jordan BD. Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurgery. 2005 Oct;57(4):719-26; discussion 719-26. PubMed.
  3. Jordan BD. Chronic traumatic brain injury associated with boxing. Semin Neurol. 2000;20(2):179-85. PubMed.
  4. Yoshiyama Y, Uryu K, Higuchi M, Longhi L, Hoover R, Fujimoto S, McIntosh T, Lee VM, Trojanowski JQ. Enhanced neurofibrillary tangle formation, cerebral atrophy, and cognitive deficits induced by repetitive mild brain injury in a transgenic tauopathy mouse model. J Neurotrauma. 2005 Oct;22(10):1134-41. PubMed.
  5. Uryu K, Laurer H, McIntosh T, Praticò D, Martinez D, Leight S, Lee VM, Trojanowski JQ. Repetitive mild brain trauma accelerates Abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis. J Neurosci. 2002 Jan 15;22(2):446-54. PubMed.
  6. Jellinger KA. Head injury and dementia. Curr Opin Neurol. 2004 Dec;17(6):719-23. PubMed.

External Citations

  1. 18 January New York Times

Further Reading

No Available Further Reading

Primary Papers

  1. Omalu BI, DeKosky ST, Hamilton RL, Minster RL, Kamboh MI, Shakir AM, Wecht CH. Chronic traumatic encephalopathy in a national football league player: part II. Neurosurgery. 2006 Nov 1;59(5):1086-92; discussion 1092-3. PubMed.

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