Dementia Four Times More Likely in Pro Football Players

Players who spent at least five seasons battling it out in the National Football League (NFL) are three times more likely to die of a neurodegenerative disease than is the general population. Their risk for dying with dementia or amyotrophic lateral sclerosis hits fourfold. These sobering statistics appeared in the September 5 Neurology online. “Those are very high numbers,” said lead author Everett Lehman, National Institute for Occupational Safety and Health (NIOSH), Cincinnati, Ohio. “We conduct a lot of mortality studies, and we do not see such high risks very often,” he told Alzforum. (Uranium miners are one group that comes close.)

“The data support a notion that many of us have had: that playing a contact sport for a good chunk of your life at a high level is a risk for a variety of neurodegenerative disorders,” said Jeffrey Kutcher, University of Michigan, Ann Arbor. Kutcher did not participate in this study.

Growing evidence links sports-related head injuries, mostly concussions, to neurological problems and neurodegeneration later on in life (see ARF related news story). The medical field now recognizes chronic traumatic encephalopathy (CTE) as a major problem among football players, boxers, and other participants in contact sports. Against that backdrop, these new figures do not necessarily come as a huge surprise, said Lehman. Robert Cantu, Co-Director of the Center for the Study of Traumatic Encephalopathy at Boston University, agreed. “The BU center stores more than 100 donated brains, of which 30 are from deceased NFL players, and all had CTE,” Cantu told Alzforum. He was quick to point out that his may not be a representative sample, as the donations came predominantly from players who took their own lives or had severe problems later in life. “But we know CTE is out there, we just don’t know the prevalence and incidence,” he said.

Lehman and colleagues tried to address that issue in what Cantu considered pioneering work. The NIOSH researchers focused on more than 3,400 football professionals who played in the NFL between 1959 and 1988. Lehman followed them through 2007, documenting mortality. By then, 334 of them had died at an average age of 54. The good news is that, overall, the NFL retirees were half as likely to die during this period as were members of the general population. “As you can imagine, these are very fit individuals who received excellent medical attention,” said Lehman. Alas, how they died told another story. On standard death certificates, neurodegenerative disease, including Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis (ALS), turned up three times as often as underlying and contributing causes of death as it did for non-players. Narrowing that down, deaths related to dementia/AD and ALS were 3.86- and 4.31-fold higher, respectively. Both these diseases share pathologies found in CTE, including deposits of hyperphosphorylated tau and the RNA-binding protein TDP-43 (see ARF related news story). "Most of the existing data aimed at estimating the prevalence of major neurodegenerative diseases (AD, CTE, ALS) are postmortem and unavoidably biased. This study is unusual and important in the inclusion of ‘all-cause’ mortality data,” noted Sam Gandy, Mount Sinai Medical Center, New York, in an e-mail to Alzforum.

Other researchers contacted by Alzforum said that while these numbers are high, they are probably underestimates. Doctors often don’t record dementia as a contributing cause of death, especially in 50-year-olds, agreed Lehman (ARF related news story). Cantu noted that people with CTE can be asymptomatic for as long as 20 years, and without biopsy data a diagnosis of neurodegeneration may be missed. CTE was not even a recognized condition when many of these players passed away.

Underestimates or not, there are limitations to the study, as Lehman pointed out. Data on injuries and concussions were unavailable, and cause and effect cannot be established in this retrospective analysis. “We can presume impact led to these [mortality] rates being higher, but there are other variables to consider as well, including genetics and lifestyles that might put NFL players at risk, said Kutcher. A hint of the importance of impact comes from breaking down the data by player position. Defensive and offensive linemen fared best, being 1.6 times as likely as a non-NFL player to die of a neurodegenerative disease. That number jumped to 4.74 for players who tackle or are tackled at speed (including linebackers, running backs, quarterbacks, tight ends, and most other positions). The likelihood a physician noted dementia/AD or ALS on a “speed” position player’s death certificate was sixfold higher than normal.

"An important follow-up to this study would be to hunt for identifiable familial/genetic risk alleles that might enable the prospective prediction of those at highest risk," wrote Gandy. He noted that the increase in risk in the NFL players is roughly equivalent to that associated with a single ApoE4 allele, but that the combination of an ApoE4 allele and a serious traumatic brain injury with loss of consciousness could increase the risk for AD by 10-fold.

What do these data mean for the NFL? League spokesperson Greg Aiello sent Alzforum a prepared statement (see below) that outlined recent steps the league has taken to reduce player injuries. They include new rules that penalize for helmet-to-helmet contact. The league has also invested in research and care. Though the NFL dragged its heels in recognizing the seriousness of head trauma in years past (see ARF related news story), researchers now see signs that it is moving in the right direction. “I think since 2010, no other organization, professional or amateur, has done even a fraction of the amount of good toward protecting its participants with regard to head trauma as the NFL,” said Cantu. Kutcher agreed that the changes implemented by the NFL will help. “The big question is whether we can quantify that,” he said. “Where it will end up, we don’t know,” said Cantu, “but I don’t believe they can ever make [football] completely safe.”—Tom Fagan

Comments

  1. Well before this study was released, the NFL took significant steps to address head injuries in football, provide medical and financial assistance to our retired players, and raise awareness of the most effective ways to prevent, manage, and treat concussions. The NFL has strengthened its playing rules to remove unnecessary hits to the head and better protect players in speed and defenseless positions. The study underscores the continuing need to invest in research, education, and advocacy; strengthen and enforce our rules on player safety; and do all we can to make our game safer. As the science on head injuries continues to evolve, and as doctors and scientists continue to learn more about the causes and effects of concussions, we will be in a better position to take further appropriate action to protect players and reduce the potential risk of any long-term consequences associated with concussions. We remain committed to doing all that we can to promote player health and safety.

    Background on NFL programs that address neurological issues:

    • 88 Plan—Distributed more than $18 million since 2007 to former players with dementia, Alzheimer’s, ALS, or Parkinson’s disease (no requirement to establish causation).
    • Neurological Care Program—Retired players have access to evaluations at six medical centers across the country.
    • Dr. David Satcher (former U.S. Surgeon General) program of mental health forums for retired players and their families.
    • Neurocognitive disability benefit in CBA (new benefit in 2011 CBA for vested inactive players who have not yet taken their pension).
    • CDC education partnership on concussions for youth sports coaches, leaders, parents, and athletes.
    • NFL Player Care Foundation, funded in part by the NFL, provides financial support for players who need neurological care but cannot afford it.
    • NFL advocacy for Lystedt law now passed in 39 states and DC. Requires concussion education for parents, athletes, and coaches, and medical clearance before a young athlete can return to play after suffering a concussion.
    View all comments by Greg Aiello

  2. The science of concussion and chronic traumatic encephalopathy (CTE) is still emerging. Here are some findings from the literature.

    Christopher Giza at the University of California, Los Angeles, has published on the neurometabolic cascade of concussion. Following concussion, cerebral pathophysiology includes abrupt neuronal depolarization, release of excitatory neurotransmitters, ionic shifts, changes in glucose metabolism, altered cerebral blood flow, and impaired axonal function (1).

    His work from an animal model has focused on activated N-methyl-D-aspartate receptor (NMDA) changes after traumatic brain injury (TBI) (2).

    Following activated NMDA receptors, excess intracellular calcium may be sequestered in the mitochondria, resulting in impaired oxidative metabolism and, ultimately, energy failure (3).

    After an initial period of hyperglycolysis, cerebral glucose use is diminished by 24 hours post-injury and remains low for five to 10 days in experimental animals, and is demonstrated by PET scanning in humans that may last two to four weeks post-TBI (4).

    Accelerated glycolysis leads to increased lactate production. The impairment of mitochondrial function can lead to reduced ATP production and lactate production concurrent with a decrease in lactate metabolism, resulting in lactate accumulation. Increased levels of lactate after TBI may leave neurons more vulnerable to a secondary ischemic injury (1).

    Reduction in magnesium, diffuse axonal injury, delayed cell death, persistent calcium accumulation, and neurotransmitter alteration (NMDA, adrenergic and cholinergic system post-concussion receptor) have been described (1).

    The results of repeated concussion (CTE) have been found in the brains of a number of former football players who have suffered from TBI and taken their lives. It has recently been described upon autopsy in the press and Scientific American. Football is not alone, as rugby, soccer, and hockey players; boxers; wrestlers; soldiers; and victims of physical abuse have also been reported (5).

    Examination of these victims’ brains leaves a signature somewhat analogous to Alzheimer’s but distinct: microscopic clumps of tau proteins. Patients with CTE don’t have the extensive plaques characteristic of Alzheimer’s, and their tau clumps tend to be patchier. McKee and her colleagues published a review in the Journal of Neuropathology and Experimental Neurology (6).

    The treatment of mild post-concussion syndrome is in its infancy, with early recognition, psychological testing, and taking the victim out of the game and resting the brain. The only FDA-approved OTC, acetaminophen (paracetamol), has been studied for mild concussion headaches. A potent N-type calcium channel blocker (SNX-111), NMDA receptor blockers (MK-801 and HU-211), and a synthetic cannabinoid with pharmacological profile of an NMDA receptor antagonist have been reported in experimental models (1).

    The increased awareness of post-concussion syndrome and now CTE is a perfect storm for both NFL-funded, NIH-sponsored, military, big pharma, and biotech research.

    References:

    Giza CC, Hovda DA. The Neurometabolic Cascade of Concussion. J Athl Train. 2001 Sep;36(3):228-235. PubMed.

    Giza CC, Maria NS, Hovda DA. N-methyl-D-aspartate receptor subunit changes after traumatic injury to the developing brain. J Neurotrauma. 2006 Jun;23(6):950-61. PubMed.

    Verweij BH, Muizelaar JP, Vinas FC, Peterson PL, Xiong Y, Lee CP. Mitochondrial dysfunction after experimental and human brain injury and its possible reversal with a selective N-type calcium channel antagonist (SNX-111). Neurol Res. 1997 Jun;19(3):334-9. PubMed.

    Bergsneider M, Hovda DA, Lee SM, Kelly DF, McArthur DL, Vespa PM, Lee JH, Huang SC, Martin NA, Phelps ME, Becker DP. Dissociation of cerebral glucose metabolism and level of consciousness during the period of metabolic depression following human traumatic brain injury. J Neurotrauma. 2000 May;17(5):389-401. PubMed.

    Wilyard C. Brain damage on the playing field. Sci Am. Feb 24, 2011.

    McKee AC, Gavett BE, Stern RA, Nowinski CJ, Cantu RC, Kowall NW, Perl DP, Hedley-Whyte ET, Price B, Sullivan C, Morin P, Lee HS, Kubilus CA, Daneshvar DH, Wulff M, Budson AE. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol. 2010 Sep;69(9):918-29. PubMed.

    View all comments by Trent Nichols

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References

News Citations

  1. Butting Heads—Autopsies Fuel Debate on Football and Neurodegeneration
  2. TDP-43 and Tau Entangle Athletes’ Nerves in Rare Motor Neuron Disease
  3. Research Brief: Many Alzheimer Deaths Go Unreported
  4. NFL Does About Face on Head Injury, Funds Researchers

Further Reading

Primary Papers

  1. Lehman EJ, Hein MJ, Baron SL, Gersic CM. Neurodegenerative causes of death among retired National Football League players. Neurology. 2012 Nov 6;79(19):1970-4. PubMed.

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