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Neurology Today:
doi: 10.1097/01.NT.0000265822.43283.38
Article

Football Concussions Linked to Depression, Cognitive Impairment—Experts Seek Prospective Studies

Cajigal, Stephanie

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The football season is over, but what's happening on the sidelines may be just as important. Several articles in the New York Times have questioned whether National Football League (NFL) players who have had multiple concussions are at greater risk for neurological problems than those who have had one or none.

Figure. New reports ...
Figure. New reports ...
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In a Jan. 18 article, University of Pittsburgh neuropathologist Bennet Omalu, MD, claimed that the successive concussions experienced by former Philadelphia Eagles defensive back Andre Waters led to his depression and eventual suicide in November. He also reported that Waters' brain had degenerated to resemble that of an 85-year-old man with pathology similar to early Alzheimer disease (AD). Waters was only 44 when he died.

Two weeks later, Ted Johnson, 34, revealed to the newspaper that he suffers depression and symptoms of mild cognitive impairment that started with two concussions he sustained four days apart as a former middle linebacker for the New England Patriots.

While these accounts are compelling, the scientific evidence suggesting that NFL players are at increased risk for these conditions is less clear, boiling down to only a handful of studies.

Dr. Omalu's work on Waters has not yet been published, but he told Neurology Today that he plans to submit a paper soon for scientific review. In mid-December he obtained brain slices with permission from the athlete's family. He said he discovered the tau-positive neurofibrillary tangles and neuritic threads that are associated with Alzheimer disease and other types of dementias. The findings, he said, were consistent with chronic traumatic encephalopathy (CTE). Whereas Alzheimer disease pathology begins in the hippocampus and involves the neocortex in later stages, CTE begins in the neocortex and then progresses to the hippocampus, according to Dr. Omalu.

“In a man of Waters' age you should not see any neurofibrillary tangles,” he said.

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PRELIMINARY RESEARCH

In 2005 Dr. Omalu and colleagues at the University of Pittsburgh reported the first documented CTE case (Neurosurgery 57;128–134). Hall of Famer and Pittsburgh Steelers center Mike Webster died in 2002 at the age of 50 from a myocardial infarction. According to telephone interviews between researchers and the family, Webster had a neuropsychiatric history that resembled dysthymic disorder, including symptoms of depression, poor concentration, and feelings of hopelessness. According to the Neurosurgery paper, Webster also had problems with memory, judgment, and parkinsonism. Autopsy revealed many diffuse extracellular amyloid plaques, neuritic threads, and neurofibrillary tangles.

One year later, the research team reported a second case of CTE, this time in former Steelers' guard Terry Long who in 2004 committed suicide at the age of 45 (Neurosurgery 59;1086–1093). Like Webster, Long had a major depressive disorder in retirement and autopsy showed neurofibrillary tangles and neurophil threads in all regions of the brain, researchers reported. However, Long did not have amyloid plaques. His apolipoprotein APOE4 genotype, which is linked to AD, was also different; Webster and Waters had the allele for E3 while Long had the allele for E4.

Dr. Omalu, who referred to his research as “hard-core primary evidence,” said the disease model for these cases might be similar to that of asbestos infection. “People are exposed to asbestos and 20, 30, 40 years later they develop mesothelioma. In these three cases we've seen a latency period from several years to over 15 years.”

He hopes his work leads to more prospective, longitudinal studies. These findings, he said, “are just the tip of the iceberg.”

More convincing might be a 2005 study from the Center for Retired Athletes at the University of North Carolina-Chapel Hill (Neurosurgery 57;719–726). Researchers there culled data from a general health questionnaire completed by 2,552 retired NFL players who were, on average, 53.8 years old and had played professional football for an average of 6.6 years. A follow-up questionnaire focusing on issues related to memory and mild cognitive impairment (MCI) was completed by 758 retired players. The results were cross-tabulated with results from the original health questionnaire. Of the former players, 61 percent had sustained at least one concussion during their NFL career, and 24 percent had three or more concussions.

Retired players with three or more reported concussions had a fivefold prevalence of diagnosed MCI (p=0.02) and a three-fold prevalence of reported serious memory problems (p=0.001) compared with retirees without a history of concussion. There was no association between concussion and Alzheimer disease, but researchers found that AD had an earlier onset among the NFL retirees than in the general population.

Figure. Dr. Bennet O...
Figure. Dr. Bennet O...
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Principal investigator Kevin M. Guskiewicz, PhD, professor and chair of the department of exercise and sport science and director of the Sports Medicine Research Laboratory at the University of North Carolina, told Neurology Today that in future studies he would like to compare 20 to 30 retired players with MCI to retired players without MCI. He also hopes to determine whether players with the APOE4 allele are at greater risk of developing cognitive impairment, and whether the number of their concussions increases their risk.

“We are much better positioned today to answer these questions than we were ten years ago,” he said. People are more willing to participate in some of these studies because they realize concussion needs to be taken seriously.

“We've done a good job at getting the message out to players that they can't take head injuries lightly,” he continued. “We're trying to eliminate terms like ‘ding’ or ‘bell ringer’ because when coaches hear those words, they assume it's something mild and negligible. But we've learned that mild traumatic brain injuries can have a lasting effect, especially in a cumulative manner.”

Dr. Guskiewicz said his team completed a study showing an association between the number of concussions and depression in retired players, but couldn't comment in depth because the paper is under review for publication. “When we begin to look at those with two, three, four, five concussions, compared to those in the general population without concussion, clearly, there's an increased likelihood of being diagnosed with it [depression],” he said.

A 2003 study led by Dr. Guskiewiecz reported similar findings (Med Sci Sports Exerc 35(5):S50). Again, 2,488 retired NFL players completed a general health questionnaire; 263 had been diagnosed with clinical depression. Retired players with five or more previous concussions had nearly a three-fold risk of incident depression, and those with three to four previous concussions had a two-fold risk of incident depression, compared to retired players with no history of concussion.

“At the very least, there's enough writing on the wall here to suggest that single concussion is a transient neurologic event followed by a rapid and complete recovery, but when a person is exposed to multiple concussions, all bets are off,” said Michael McCrea, PhD, executive director of the ProHealth Care Neuroscience Center at Waukesha Memorial Hospital, and associate professor of neurology at the Medical College of Wisconsin. Dr. McCrea worked on the 2005 study from the Center for Retired Athletes and their most recent study on depression.

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PROSPECTIVE STUDIES

But he, like Drs. Guskiewicz and Omalu, emphasized that more conclusive evidence would need to be garnered from studies that follow athletes for a lifetime after their playing careers.

Dr. Omalu said the NIH and NFL should fund an independent, multisite, multidisciplinary study. According to Dr. Omalu's proposal, NFL players would choose a study site where they would receive neuropsychiatric testing about twice a year, and when they died, their brains would be examined neuropathologically. “With sufficient empirical data we can at least begin to understand this disease better, and find out who is at risk of developing CTE,” he said.

According to Dr. Guskiewicz, the NFL Charities — an organization of the member clubs of the NFL that awards sports-related medical research grants — has denied several applications he had submitted for prospective studies. “The NFL appears to have its own research agenda, some of which is very good, but some of those individuals have chosen to ignore our findings.”

And that, he said, is nothing more than a fumble. “Our findings are also important in terms of what they mean to younger athletes playing the same sport. It's important that we create this awareness to parents, players, and coaches that some of these links have been found and it's not too early to begin thinking about some of the long-term complications.”

The NFL, however, stands behind an ongoing series of studies from its mild traumatic brain injury committee that followed active players from 1996 through 2001. One of these reports found that players who experienced three or more concussions did not demonstrate evidence of neurocognitive decline (Neurosurgery 2004;55(6):1290–1305).

Figure. Dr. Kevin M....
Figure. Dr. Kevin M....
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Marc R. Lovell, PhD, director of the University of Pittsburgh Medical Center Sports Medicine Concussion Program, said he is one of several independent researchers working on a study that the NFL began about eight years ago that will track hundreds of players through retirement, focusing on evidence of long-term brain damage. The results will most likely be published when “there's enough data to make a reasonable scientific statement,” he said.

He is also working on a study initiated last year that is looking for neurocognitive effects in about 160 retired players, he said.

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IMPLICATIONS FOR THE SPORT

James P. Kelly, MD, co-author of the 1997 sport concussion guidelines by the AAN Quality Standards Committee, said that unlike boxing, which has been extensively linked to brain damage, evidence associating football with neurological deficits is scant. Dr. Kelly is a visiting professor of neurosurgery at the University of Colorado at Denver and Health Sciences Center.

Long-term studies should address genetic predisposition, length of time playing the sport, number of concussions, and severity of the concussions, he said. “It's something that needs to be closely watched and that we need to worry about.”

Dr. McCrea said the issue is somewhat of a new concern. “It's only in the last decade or so that concussion had really been addressed systematically and scientifically.”

Existing concussion guidelines are probably sufficient as long as coaches, trainers, and medical personnel adhere to them, he said. “In general, I think that as long as a player is given adequate recovery time and measures are taken to make certain he has made a complete recovery before he returns to competition, you not only reduce the likelihood of a repeat concussion, but you also reduce the risk of long-term or late-life problems associated with those repeat concussions.”

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ARTICLE IN BRIEF

✓ In January, a neuropathologist reported that a brain autopsy of former Philadelphia Eagles defensive back Andre Waters was consistent with chronic traumatic encephalopathy, adding to evidence of a link between multiple concussions and neurological problems in NFL players.

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REFERENCES

• Omalu BI, DeKosky ST, Minster RL, Kamboh AI, Hamilton RL, and Wecht CH. “Chronic Traumatic Encephalopathy in a National Football League Player.” Neurosurgery 2005;57:128–134.

• Omalu BI, DeKosky ST, Hamilton RL, et al. “Chronic Traumatic Encephalopathy in a National Football League Player: Part II.” Neurosurgery 2006;59:1086–1093.

• Guskiewicz KM, Marshall SW, Bailes Julian, et al. “Association Between Recurrent Concussion and Late-Life Cognitive Impairment in Retired Professional Football Players.” Neurosurgery 2005;57:719–726.

• Guskiewicz KM, Bailes J, Cantu RC, and Marshall S. “Recurrent Sport-Related Concussion Linked to Clinical Depression.” Med Sci Sports Exerc 2003;35(5):S50.

• Pellman EJ, Viano DC, Casson IR, Arfken C, Feuer H. “Concussion in professional football: players returning to the same game — part 6.” Neurosurgery 2004;55(6):1290–1305.

©2007 American Academy of Neurology

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