Sam Gandy Christopher Nowinski Norman Relkin Steven T. DeKosky Ann McKee Daniel Perl

This live discussion was held on 26 June 2008 with Sam Gandy, Mount Sinai School of Medicine, New York; Steven T. DeKosky, University of Pittsburgh; Christopher Nowinski, President, Sports Legacy Institute, Author, Head Games: Football’s Concussion Crisis; Norman Relkin, Weill Cornell Medical College, New York; Ann McKee, Boston University; and Daniel Perl, Mount Sinai School of Medicine. View Videoclip Presentations Listen to Radio Story

View Transcript of Live Discussion — Posted 11 November 2008

Background Text
By Gabrielle Strobel and Sam Gandy

Over the past year, the national media featured reports of sports celebrities whose early, tragic deaths were linked to brain damage from repeated concussions the athletes had sustained years earlier during their careers in professional football or simulated wrestling. The stories presented a new twist to a larger issue that has troubled neurologists for the past decade; that is: just what are the lasting consequences for the brain of repeated blows to the head? Can an athlete shake off those “dings” and be fine, or will they come back to haunt him or her down the road? In the recent news coverage, representatives of the NFL or WWE expressed concern about the issue, but invariably pointed to disagreements among scientists, and lack of proof, as reasons why no major changes are warranted at this point (see, for example, CNN clip). Lying below the surface of the public debate is an evolving genetic component, whereby certain people may well be more vulnerable to developing long-term brain damage from multiple concussions than others, but genetic testing for the one identified risky genotype comes with its own uncertainties such as a fear of insurance discrimination. To set the stage for discussion, this background text will

• define the current debate about long-term effects of sports concussions;
• distinguish points on which there is strong scientific consensus from issues that remain unclear;
• make suggestions for research initiatives that could address the open questions.

The authors and the Alzforum editors cordially invite you to join the discussion.

What’s Old—What’s New?
That repeated knockout blows to the head are bad for the brain is common sense to most people. Professional boxing is most extreme in this regard, and the terms “dementia pugilistica,” “punch-drunk syndrome,” “chronic traumatic encephalopathy/CTE” are various terms for the same collection of brain pathologies. Immediate neurological damage and long-term brain damage both are scientifically established as common outcomes, and medical associations around the world, including the American Academy of Neurology, have long called for a ban on boxing. The issue of long-term consequences of sports-related head injury surfaced again last year with the deaths of former Philadelphia Eagles safety Andre Waters, former Pittsburgh Steelers offensive lineman Mike Webster, and linebacker Terry Long (see NYT story), and Justin Strzelczyk, as well as former WWE wrestler Chris Benoit, who killed his family and himself. In the years before their deaths, these men had shown symptoms of depression, erratic behavior, or cognitive impairment, and postmortem analysis of their brains showed evidence of extensive brain damage including the classic pathologies of Alzheimer disease (AD). By the age of 34, former New England Patriots linebacker and Super Bowl champion Ted Johnson suffered from depression and cognitive impairment consistent with incipient Alzheimer disease, reportedly linked to multiple concussions (see NYT story). And Bill Bridgwater, a former telecommunications executive who, since his diagnosis of early-onset AD four years ago at age 48 has become a dignified advocate for more awareness and research, said at a conference in March 2008 that he sustained some 30 concussions while playing high school and college football.

New to the current debate is the notion that far beyond the concussion symptoms that are apparent at the time of the trauma, or days later, molecular cascades of pathogenic changes can continue inside the concussed brain even after the initial symptoms of blurred vision, headache, etc., subside and the athlete appears normal again. A majority of scientists in Alzheimer disease research agree that molecular brain changes build up “silently” for years before the disease symptoms manifest themselves. In essence, the idea is that repeated hits to the head may touch off and accelerate a silent neurodegenerative process, leading to overt disease in mid-life rather than in old age as is usually the case in non-concussed, more typical dementia patients. Scientists cannot predict who among any given group of contact athletes will develop long-term damage, or from which type of neurodegenerative disease they may suffer. That depends on a number of genetic predispositions, of which only one is well studied to date (see below). This is an area where new research needs to be done. But there is strong consensus among neurologists and neurodegenerative disease experts that repeated knockout concussions greatly increase some people’s risk for serious, progressive neurological disease years later.

Currently, team doctors and coaches make decisions about when to send concussed players back on the field or in the ring based primarily on functional neurological tests, but the decision is not generally informed by scientific knowledge of slowly progressive neurodegenerative disease processes. Moreover, decisions about return to play typically concern a period of days or at most weeks; they are not driven by the prospect of truly delayed consequences such as dementia. The NFL is conducting its own investigation of the consequences of concussion, though questions have been raised about its independence (see ESPN story). Meanwhile, NFL Hall of Fame player, coach, and sportscaster Mike Ditka has taken up the cause of ex-players’ pensions, and as part of that raised his concern about concussions at a U.S. Senate Committee hearing last fall.

How vulnerable a given athlete is to long-term consequences from brain trauma depends primarily on the severity of the injury, but his or her genetic makeup plays a significant role as well. One gene that is well understood is APOE. A particular variant of this gene, the E4 allele, occurs in roughly 15 percent of the population and increases a person’s risk of developing Alzheimer disease up to 15-fold. The risk shoots up further when an APOE4 carrier sustains a traumatic brain injury (TBI), as APOE genotype and head trauma interact (e.g., Katzman et al., 1996), probably by mechanisms that include both diminishing the brain’s capacity to repair damage and by driving amyloid deposition. Would an athlete change anything—choose a different sport, wear extra headgear—if (s)he knew (s)he carried APOE4? How would coaches and team doctors make use of this information? Would parents permit their child to take up high school football or choose boxing as a hobby? When genetic testing (genotyping) for APOE became possible in the early 1990s, leading professional groups including the Alzheimer’s Association formally discouraged APOE genotyping except in research studies, and discouraged telling people their genotypes in all settings, including research. Some of the leaders of this discussion co-authored such a consensus recommendation (Relkin et al., 1996). (These recommendations were not intended to apply specifically to a person’s susceptibility to brain trauma or its long-term outcomes; they were developed to protect people from the uncertainties of a relative risk prediction for AD, a non-preventable disease.)

Science does not have the data in hand to predict precisely which of the repeatedly concussed football players and boxers are most likely to develop dementia. But should they not begin to accumulate the data upon which we might reliably estimate the lifetime risk associated with APOE ε4 in teenagers or adults who take up concussion-prone contact sports? Is protection against the psychological harm of forced genotype disclosure more important than delaying or preventing dementia? In light of the results of REVEAL, which set out to study the effects of such disclosure on people, it is not clear to this panel that the current conventional position of discouraging disclosure serves people’s needs better than offering disclosure with adequate safeguards (Eckert, 2006; Roberts et al., 2005; LaRusse et al., 2005). (For detailed information on REVEAL and APOE genotyping, see Live Discussion and lay summary.) In this context, it is worth noting that the Genetic Information Non-discrimination Act, aka GINA, was signed into law on 21 May 2008, after more than a decade of congressional debate. Meant to protect people against discrimination by employers and insurers, the new law could help remove an obstacle that had been holding back wider use of available genetic testing for a variety of diseases, including Alzheimer’s. Clearly, research is required to see whether the predicted enhanced risk of APOE ε4 alleles combined with long-term concussive sports participation is borne out, but shouldn't we at least find out whether APOE ε4 carriers should be counseled against concussive sports?

Beyond APOE, many other genes have been implicated to contribute to AD risk, albeit more weakly. It would be worth looking for some of those alleles in athletes who have suffered long-term consequences of repeated concussions. Importantly, to start gathering the data, establishing a network of research centers or programs on traumatic brain injuries in athletes would be a strong first step. This could include brain banking, DNA banking, serial clinical/neuropsychological testing, and brain imaging.

Suggested public health questions are as follows:

• Do the scientific data about risk from repeated concussions translate into a public health message? Can we state this message simply?
• How broad is the message? Professional football? Wrestling? Soccer? Hockey?
• Can we ascertain what role age plays in the risk? What are the implications for college and high school sports?
• Current debate focuses on the length of rest periods after concussion. Does sitting out more games/practices eliminate the long-term risk?
• How do we educate coaches and players without causing undue alarm?
• Are we ready to recommend APOE genotyping? For adults? For minors?

Suggested research questions are as follows:

• Systematic study of people involved in contact sport is clearly needed. What mechanisms exist already to support the creation of a data, DNA, and tissue bank (like that of the Alzheimer Disease Research Centers) that would enable study of long-term cognitive sequelae of sports TBI on a national scale?
• Ditto for a national registry.
• Can we put together a genetic research study for retired players, players with CTE or other neurologic symptoms? Beyond APOE, does it make sense to look for the top 10 gene variants implicated in association studies for Alzheimer disease and Parkinson disease?
• TBI in which sports should be studied? Which level?
• Are there other populations (e.g., Iraq war veterans) where TBI may cause similar long-term neurological consequences?

See Further Reading: Lay Articles
See Further Reading: Scientific Articles

	Comments on Live Discussion
	Comment by:  Henrik Zetterberg
	Submitted 25 June 2008  |  Permalink	Posted 25 June 2008
	Not Just the Pros: Neurochemical Aftermath of Amateur Boxing We determined that amateur boxers who sustained 15 or more punches to the head, or were groggy after the bout, showed pronounced increases in their cerebrospinal fluid (CSF) levels of neurofilament light protein, tau protein, and glial fibrillary acidic protein seven to 10 days after the fight. These results suggest acute damage to axons and astroglial cells in the brain as a direct consequence of participation in an amateur boxing bout. All boxers were followed up after the summer rest, during which no fights occurred, with most of the protein changes returning to normal or close to normal levels. Importantly, none of the boxers in our study was knocked out. Together, these results, published in the September 2006 issue of the Archives of Neurology (Zetterberg et al., 2006), show that relatively mild traumatic brain injury through repeated head punches in amateur boxing results in the release of brain-specific proteins to the CSF that indicate structural injury to the brain. The molecular changes detected...  Read more Not Just the Pros: Neurochemical Aftermath of Amateur Boxing We determined that amateur boxers who sustained 15 or more punches to the head, or were groggy after the bout, showed pronounced increases in their cerebrospinal fluid (CSF) levels of neurofilament light protein, tau protein, and glial fibrillary acidic protein seven to 10 days after the fight. These results suggest acute damage to axons and astroglial cells in the brain as a direct consequence of participation in an amateur boxing bout. All boxers were followed up after the summer rest, during which no fights occurred, with most of the protein changes returning to normal or close to normal levels. Importantly, none of the boxers in our study was knocked out. Together, these results, published in the September 2006 issue of the Archives of Neurology (Zetterberg et al., 2006), show that relatively mild traumatic brain injury through repeated head punches in amateur boxing results in the release of brain-specific proteins to the CSF that indicate structural injury to the brain. The molecular changes detected are likely to be even more pronounced in professional boxers and in boxers who have received a knockout punch. In contrast, using the same diagnostic tests and a similar experimental set-up with lumbar puncture seven to 10 days after exposure to a large number of standardized headings, we have shown that headings in soccer are not associated with any biochemical signs of neuronal or astroglial injury. We conclude that the biomechanical effect on the brain of heading in soccer is quite different from that caused by head punches in boxing (Zetterberg et al., 2007). Most likely, part of the differing results can be explained by how well the sportsman is able to stabilize his/her head with the neck muscles during the force exposure. If you lose tension of the neck when receiving a series of head punches during a boxing bout, you are very likely to contract such a severe brain injury that you lose consciousness (and the match…). References: Zetterberg H, Hietala MA, Jonsson M, Andreasen N, Styrud E, Karlsson I, Edman A, Popa C, Rasulzada A, Wahlund LO, Mehta PD, Rosengren L, Blennow K, Wallin A. Neurochemical aftermath of amateur boxing. Arch Neurol. 2006 Sep;63(9):1277-80. Abstract Zetterberg H, Jonsson M, Rasulzada A, Popa C, Styrud E, Hietala MA, Rosengren L, Wallin A, Blennow K. No neurochemical evidence for brain injury caused by heading in soccer. Br J Sports Med. 2007 Sep;41(9):574-7. Abstract View all comments by Henrik Zetterberg
	Comment by:  Zaven Khachaturian, ARF Advisor (Disclosure)
	Submitted 26 June 2008  |  Permalink	Posted 26 June 2008
	Comments by Zaven Khachaturian The public health and research questions concerning TBI, such as those posted in this live discussion, beg for a major multi-site collaborative study. The only way to answer all of these questions is through a well-powered study that would provide a longitudinal systematic assessment of a large cohort. The support for such a large and expensive study may not necessarily require the creation of a new funding mechanism if such a study could be added as supplementary projects to ongoing funded research programs ( e.g., PO1s, ADRCs/ADCCs, ADNI etc.) that may have relevant or appropriate ‘specific aims’ or core resources, such as neuropath core or clinical core or biomarker core. As a next step, the conveners of this live online discussion should consider organizing a face to face ‘research planning’ think-tank meeting to define the key parameters for such a study, e.g. sample size, inclusion/exclusion criteria, domains of measurements, duration of the study, number of sites - criteria for inclusion, budget, resources needed, and potential...  Read more Comments by Zaven Khachaturian The public health and research questions concerning TBI, such as those posted in this live discussion, beg for a major multi-site collaborative study. The only way to answer all of these questions is through a well-powered study that would provide a longitudinal systematic assessment of a large cohort. The support for such a large and expensive study may not necessarily require the creation of a new funding mechanism if such a study could be added as supplementary projects to ongoing funded research programs ( e.g., PO1s, ADRCs/ADCCs, ADNI etc.) that may have relevant or appropriate ‘specific aims’ or core resources, such as neuropath core or clinical core or biomarker core. As a next step, the conveners of this live online discussion should consider organizing a face to face ‘research planning’ think-tank meeting to define the key parameters for such a study, e.g. sample size, inclusion/exclusion criteria, domains of measurements, duration of the study, number of sites - criteria for inclusion, budget, resources needed, and potential sources of funding etc. This next step of planning/discussion is very difficult to conduct in a live chat room format, which is an excellent mechanism for assessing the range of perspectives, but less well suited for detailed analysis of the scope of the problem strategic planning. The Lou Ruvo Brain Institute will be pleased to sponsor such a ‘think- tank’ meeting to plan the next steps for mobilizing a national cooperative research effort that could be funded by multiple agencies, foundations or sponsors. I doubt that any single agency would be able to carry the full load. View all comments by Zaven Khachaturian
	Comment by:  Christopher Nowinski
	Submitted 3 July 2008  |  Permalink	Posted 3 July 2008
	Thank you to ARF, my fellow panelists, and all who were involved in this discussion. It is wonderful to see that the Alzheimer’s research community is taking such an interest in the long-term consequences of MTBI. One of the reasons I’ve worked so hard over the last few years to raise awareness on concussions is to get your attention focused on this issue. I have always been excited about how much scientists have learned about the brain. But I was surprised during the forum to see how much the experts said we still don’t know about why or how CTE develops. With that in mind, I hope the experts realize that while very few cases of CTE have been positively identified (and the literature has less than 100), that is because we’ve never looked before. With my work with the researchers at the Sports Legacy Institute, I have yet to be involved with a postmortem neuropathological examination that wasn’t positive for CTE, and everyone has been less than 50 years old and symptomatic prior to early death. So we believe CTE is likely a much larger public health problem than is...  Read more Thank you to ARF, my fellow panelists, and all who were involved in this discussion. It is wonderful to see that the Alzheimer’s research community is taking such an interest in the long-term consequences of MTBI. One of the reasons I’ve worked so hard over the last few years to raise awareness on concussions is to get your attention focused on this issue. I have always been excited about how much scientists have learned about the brain. But I was surprised during the forum to see how much the experts said we still don’t know about why or how CTE develops. With that in mind, I hope the experts realize that while very few cases of CTE have been positively identified (and the literature has less than 100), that is because we’ve never looked before. With my work with the researchers at the Sports Legacy Institute, I have yet to be involved with a postmortem neuropathological examination that wasn’t positive for CTE, and everyone has been less than 50 years old and symptomatic prior to early death. So we believe CTE is likely a much larger public health problem than is recognized, but prior to now it has likely been misdiagnosed as other neurodegenerative diseases because we haven’t known what to look for. So as someone who suffered numerous concussions over 11 years of collision sports, I hope that as we carve CTE out as a unique disorder, we give it the attention and resources that those of us closest to it know it deserves. View all comments by Christopher Nowinski

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