Introduction

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

Transcript:

Participants: J. Lucy Boyd, Boyd Intellectual Properties; Ira Casson, Long Island Jewish Medical Center; Steve DeKosky, University of Pittsburgh; Hank Feuer, Indiana University; Sam Gandy, Mount Sinai School of Medicine; Ann McKee, Boston University; Zaven Khachaturian, Lou Ruvo Institute; June Kinoshita, Alzheimer Research Forum; Vincent Marchesi, Yale University; Brenda Nowinski; Christopher Nowinski, Sports Legacy Institute; Norman Relkin, Weill Cornell Medical Center; Daniel Perl, Mount Sinai School of Medicine; Dushyant Purohit, Mount Sinai; Mark A. Smith, Case Western Reserve University; Gabrielle Strobel, Alzheimer Research Forum; Junming Wang, University of Mississippi Medical Center; Henrik Zetterberg, Sahlgrenska University.

Note: Transcript has been edited for clarity and accuracy.

Gabrielle Strobel
I look forward to this. Sam, Norm, hi. Check out the brand-new comment by Zaven Khachaturian on the Live Discussion page. You all might be able to follow up at the Lou Ruvo Institute if you want.

Sam Gandy
Yes, Zaven just e-mailed me. That would be great! Zaven is joining us here for the first 30 minutes.

Sam Gandy
Hi Ann, welcome. Hi Henrik. Glad you could join us. Hi Chris. Hi Dan.

Henrik Zetterberg
Hi, great being here.

Gabrielle Strobel
Hi Chris, Henrik, Ann, Dan, great to have you all!

Christopher Nowinski
Hi Sam, Dan, and all. I enjoyed your presentations and appreciate being included on the panel.

Gabrielle Strobel
It's an honor to have you, Chris.

Sam Gandy
Chris, you bring a unique perspective. Delighted that you were willing to participate.

Gabrielle Strobel
Hi Zaven, it's wonderful that you are joining us. That is great news that you are interested in supporting this.

Junming Wang
By way of introduction, I was in Robbie Brinton’s lab at USC and started my lab this year at the University of Mississippi Medical Center.

Sam Gandy
Welcome, Junming.

Gabrielle Strobel
Our panel is complete save for Steve DeKosky, who’s running late. I'd like to welcome you all and thank you for coming. Thank you to the panelists for recording these video presentations—they are a great entry to the topic for future readers of this discussion who had a conflict during this hour. Let's get started. We have lots of questions to get through. I'll pose these to the panel and invite the audience to participate as well. First, though, I'd like to give Zaven the opportunity to make a statement about this topic, as I understand he has to leave soon. Zaven?

Zaven Khachaturian
Gabrielle, this is an incredibly important topic not only by itself but also for better understanding of what is happening in AD in general.

Gabrielle Strobel
Do you think that concussions/head trauma contribute significantly to AD in the general population, not just athletes?

Zaven Khachaturian
Probably not directly, but the general idea of disrupting or damaging the microvessels or blood-brain barrier may play a significant role in being an initial triggering factor. Organizing a large-scale, population-based longitudinal study will allow us to answer your question and develop new hypotheses about what is going on.

Sam Gandy
Just a note to everyone to read Zaven's comment on this Live Discussion page on the ARF site and proposal for a way to move forward.

Sam Gandy
I think that to a great extent, we are preaching to the choir. Most or all of us here (I think) believe that there is a significant issue that is largely overlooked. In my mind, the question is how to gauge the extent of CTE. TBI has received much more attention than CTE. I think that we all agree that the extent of the problem needs some systematic definition. For example (as I was just discussing with Dan in person), what is the minimal injury that can produce late sequelae?

Steven DeKosky
Hello, everyone, sorry to be a bit late.

Gabrielle Strobel
Welcome, Steve; we are just starting. Let's address the questions we set out in the text. We saw two separate areas: public health questions and research questions. The first issue we were going to discuss is, Do the scientific data about risk from repeated concussions translate into a public health message? Can we state this message simply? All members of the panel, what do you think? Not to cut you off, Sam; you and I were typing simultaneously. We can have both these question in the room.

Daniel Perl
Until we know the scope of the problem, especially the minimum degree of trauma leading to further sequelae (plus can one episode of head trauma do this?) I don’t think we can make any specific public health pronouncements.

Christopher Nowinski
As the person on the panel who has likely suffered the most concussions, I think we are reaching the point where there is a clear public health message—multiple concussions dramatically increase your risk of late-onset neurological sequelae. The public health recommendation in my mind is less clear scientifically. Is it don't get many concussions? Is it rest long enough after your concussions? Is it don't participate in head trauma sports for more than X number of years?

Sam Gandy
Gabrielle, I don’t think that we have a rigorous enough database to make much public comment beyond the extremes. However, even the extremes (dementia pugilistica, Chris Benoit, etc.) deserve greater visibility. And the problem will grow as Iraqi vets return with CTE and PTSD. I agree with Chris that even what is blatantly obvious to most of us would be unknown to most people.

Zaven Khachaturian
Gabrielle, the public health and research questions you had posted in the discussion backgrounder are all very good ones and should be the topic of discussion. Unfortunately, I do not see how we can address these questions without data. Thus, we need to focus on how to organize and fund such a large-scale study knowing that no single agency alone will be able or interested in funding such a mega-study.

Sam Gandy
Zaven, I'm not even sure that "a" study will have sufficient scope, which is why I wondered whether your ADRC model might pertain.

Steven DeKosky
A major issue for smaller injuries will be ascertainment. Minor injuries are not recalled (by their nature), and in sports it is not in the interest of the individual or team to report them. While smaller injuries do surely have effects, remember that the “bar” above which risk of AD can be identified as a risk factor for head trauma is unconsciousness lasting greater than half an hour. A proposal to study this in the population (for more minor injuries) will have to include a very good ascertainment measure....

Sam Gandy
Steve, there are certainly challenges to be overcome, but do you agree with expanding the scale of the inquiry?

Steven DeKosky
Absolutely.

Sam Gandy
Steve, do you like the ADRC model? The cluster of clinical, pathological, and outreach cores coupled with fundamental research would seem appropriate to this problem (blatant pandering to Zaven!). Or would the DoD be more responsive?

Steven DeKosky
DoD is a good idea; they have great interest in both very mild and severe TBI. This would be a different model than repetitive injury in sport, of course.

Zaven Khachaturian
Sam, I agree that no single study will be adequate to answer all the questions. Yes, the ADRC model, but organized differently and funded differently will be an approach. Namely, you would have to organize a number of core facilities, e.g., biomarker, neuropath, imaging, clinical neurological, genetic, proteomic, etc. These core facilities, unlike ADRC, do not need to be in a single location. Essentially I am proposing a virtual center model with an executive committee to coordinate the study.

Vincent Marchesi
All, has anyone measured anti-Aβ autoantibodies in people with post-traumatic injury who also have an ApoE4 genotype?

Sam Gandy
Vincent, not that I have seen.

Norman Relkin
Vincent, no, I do not believe that has been done to date.

Gabrielle Strobel
Vincent, Tony Wyss-Coray is working on Aβ autoantibodies these days.

Vincent Marchesi
If anyone has such serum samples, I'd like to make those measurements. I have found that AD patients with ApoE4/4 have elevated auto-anti-aβ antibodies that were assayed with a peptide fragment of Aβ derived from the juxtamembrane region of APP.

Gabrielle Strobel
Has a reasonably comprehensive study ever been done on retired NFL players, for example? That would seem to be straightforward.

Steven DeKosky
I had proposed such a study to the NFL Hall of Fame. They did not respond. The issue was one of what would be expanded disability claims, I believe. I made the proposal after getting involved in the Webster case, and had been asked to get involved by the Alzheimer’s Association.

Gabrielle Strobel
I believe we have a participant here who has published with the NFL. Hank Feuer, would you like to comment on this issue?

J. Lucy Boyd
There is also a possibility that age makes a difference: that the same injury to a 13-year-old will have a different long-term effect than one received by a 30-year-old.

Christopher Nowinski
Gabrielle, there have been retrospective surveys done with more than 2,500 NFL players with over three years’ experience by the Center for the Study of Retired Athletes at UNC—Kevin Guskiewicz and Julian Bailes.

Sam Gandy
Chris, would you elaborate?

Gabrielle Strobel
Chris, are these published?

Christopher Nowinski
Sam, certainly—CSRA at UNC independently surveyed the health of retired NFL players. Neurological status was included. Found that those who remembered having three or more concussions had triple the rate of depression and self-reported memory impairment, about 20 percent, versus those who remembered zero. While the “number” of concussions they remember may not be perfect, those who sustained more of them appeared to be in worse shape. But that is the best large population data out there. See Guskiewicz et al., 2005 and Guskiewicz et al., 2007.

Steven DeKosky
Right, those are very informative data from the CSRA study. The group that had me involved wanted to study the “later life” risk—specifically in people 20-30 years out because of the risk of what we know to be two separate later complications: AD and CTE.

Norman Relkin
I think the ascertainment issue that Steve brought up before is quite important relative to choosing the right populations to study.

Sam Gandy
Dan Perl is going to enter via my keyboard. Dan? I think such studies need to include neuropathology. Also, automobile accidents are another huge setting for survival with major head trauma. Another group to look at.

Gabrielle Strobel
All, Henrik is with Kaj Blennow, a leading Swedish group in CSF biomarkers. See his comment on CSF tau and neurofilament protein detection in amateur boxers and soccer players. Henrik, I understand you are doing CSF biomarker work in soldiers. Can you tell us what you found?

Henrik Zetterberg
One question with regards to post-traumatic stress disorders has been that high-impact blows from firing heavy weapons might cause brain damage. In a standardized setting we did not find any such evidence using the same sensitive markers (neurofilament light protein, tau, GFAP, etc.) as we did when we discovered the very clear evidence of acute axonal injury in post-fight amateur boxers.

Gabrielle Strobel
Henrik, was that impact just blowback from firing weapons or impact sustained in war? And did you measure CSF Aβ in the soldiers, boxers, soccer players?

Henrik Zetterberg
Gabrielle, the impact was from firing heavy weapons in an experimental setting, not a war situation.

June Kinoshita
It seems that if the concern is about public health implications of head injury in amateur sport, particularly among younger people, one would want to collaborate with children's hospitals about tracking concussion in young athletes.

Henrik Zetterberg
I believe some sports, such as amateur boxing, are advertised as healthy and good both for physical and social training. The results on the pronounced increases in axonal proteins in CSF after mild head blows (e.g., in amateur boxing with head gear and softer gloves) call for caution with allowing children to perform such sports.

Steven DeKosky
One thing that is clear from the wealth of ideas is that different types of studies, requiring different resources and skills, are necessary. For example, following up people in late life is a different design than tracking young athletes. This would not be a one-size-fits-all project, but could be a series of specifically targeted desired datasets.

Christopher Nowinski
Sam, later-life risk is the data needed. The NFL just funded a plan, called the 88 Plan, to pay for care for any former NFL athlete with dementia, regardless of the source. Once the program was publicized, I believe media reports indicated the NFL were quite surprised by the number of families that reached out and by the young age of some of them. That list exists somewhere....

Gabrielle Strobel
Here is a news link on the response to the 88 plan.

Norman Relkin
We have looked at NFL players before retirement, and active boxers. While frank dementia isn't expected, relative cognitive impairments and other neurologic findings can be detected, particularly in ApoE4 carriers.

Daniel Perl
We are likely talking about a 20- or more year latency period. The childhood head trauma cases won't likely show anything until much later in life.

Steven DeKosky
Agree with Dan. The reason the NFL Hall of Fame group had raised the question was because they had "follow-up" observing people every year at Canton. When people retired from the NFL they would not have the same kinds of gatherings where they would be repeatedly seen.

June Kinoshita
That's true about the latency between childhood head trauma and later consequences, but if you are talking about intervention, or prevention, it might be a good idea to try to understand possible mechanisms.

Zaven Khachaturian
Dear all, unfortunately I have to log off. This is a very informative exchange, but we need to have a face-to-face meeting to adequately address these issues and develop a viable action plan. Please feel free to communicate with me offline if there is a way I might be able to help you in this endeavor.

Sam Gandy
Zaven, thank you for the offer. We will get started organizing after we log off!

Gabrielle Strobel
Zaven, it was great to have you. Steve, would it not be straightforward to identify retired NFL players, I mean players who retired 10, 20 years ago, and invite them into an independently funded study without active involvement from the NFL? After all, they are retired.

Steven DeKosky
That is what I proposed to the Hall of Fame committee several years ago. They did not respond. Of course, at that time I thought they would want to support the investigation, and I now understand the reasons that it was not something they were prepared to do because of the liability/cost issues. Now that the NFL has responded with the 88 plan, it may be a better time to do that.

Christopher Nowinski
Gabrielle, that would be possible. There are unaffiliated retired athlete groups available to discuss.

Norman Relkin
Gabrielle, studying active players prospectively would be a very worthwhile endeavor, and they are very easy to locate!

Sam Gandy
My concern is that we will never get organized sports on board. That we have to back into that area via something less politically and financially charged. Maybe veterans and DoD? Or the motor vehicle accident victims like Dan suggests.

Sam Gandy
Steve, what encouragement did you receive from the NFL? Curiously, the rugby association is actually giving out grants to look at CTE/TBI in ruggers.

Steven DeKosky
I was not in contact with the NFL. The NFL Hall of Fame is a separate corporation. They were the ones to whom I responded following the request that came through the Alzheimer's Association.

Steven DeKosky
It was coincidental, I think, that the Webster case (and our autopsy study) came to us at the same time.

Sam Gandy
Steve, where does the NFL HoF project stand? That is new to me.

Steven DeKosky
In the five cases we looked at here and published, the neuropathologist, Ron Hamilton, immediately suspected dementia pugilistica. For me, the experience of seeing no medial temporal tangles but abundant cortical tangles was the major finding....

Norman Relkin
There is a big problem with studying retired players, namely, an ascertainment bias—it is not easy to quantify head trauma from records or recollections.

Sam Gandy
I think that you eventually have to look prospectively to get truly reliable prevalence data

Norman Relkin
Agreed, Steve, and that is one of several reasons why studying active players prospectively may be more productive.

Steven DeKosky
Norm, I agree but think that both studies should be done. A study of the later life athletes would help to identify things to study in the prospective group....

Gabrielle Strobel
Sam and Norm, how would you do that? Enroll the highest-exposed people (boxers perhaps) and follow them?

Norman Relkin
Gabrielle, I would want to draw upon a full range of exposures to permit comparisons, as well as varied ages and genetic backgrounds.

Sam Gandy
Gabrielle, that would be the general idea. Choice of sport would be important because of the SES and other confounds, I think. Not sure whether boxers are "clean" (i.e., of recreational substances) enough, in large numbers. But maybe this bias is not true.

Vincent Marchesi
What are people going to be looking for in living survivors?

Sam Gandy
I think that serial neuropsych exams and neuroimaging would be the place to start. In other words, an ADNI for TBI/CTE.

Christopher Nowinski
It appears we've been joined by Ira Casson, M.D., the Chair of the NFL's Committee on Mild Traumatic Brain Injury, if you have any questions for him. Hi, Ira. Good to see you again.

Gabrielle Strobel
Welcome, Dr. Casson. Great to have you. Dr. Casson, what is the most current stance of the NFL on long-term neurologic sequelae after professional football? Is there support for systematic study of long-retired athletes?

Ira Casson
Gabrielle, we are currently performing a study on a large group of retired NFL players.

Gabrielle Strobel
Dr. Casson, is this study conducted by the NFL itself or by independent investigators?

Sam Gandy
Another issue (yet another issue) is how many diseases we are talking about, or maybe that is genetically specified. Some dementia pugilistica has amyloid, some is tangle only, yes?

Steven DeKosky
That was going to be my major point. CTE, the classic dementia pugilistica, does not have plaque sufficient to make the call of AD. TBI is also a risk factor for AD—and these cases look like classic AD. So there are two different entities at autopsy.

Henrik Zetterberg
Steven, the original hypothesis when we designed the amateur boxing study was that boxers might have the relatively AD-specific changes of elevated P-tau and low Aβ42 in CSF. However, they did not display these changes at all. Instead, we found pronounced damage to subcortical axons and glia cells.

Ann McKee
Gabrielle and Steve, I think that many cases of late-life CTE are misdiagnosed as AD. Although there are considerable overlaps, they have clear distinctions that can be parsed out. The issue of Aβ deposition in older age groups always complicates the issue. I also agree with Dan from my own experience with a large brain bank, that a single head injury, such as from a motor vehicle accident, can result in CTE.

Steven DeKosky
Ann, I understand that is a risk. But if you look at what is published, it is not a lot, and comes from very good places.

Daniel Perl
Finding the cases misdiagnosed as AD is not straightforward and has not been done. The key is the distribution of the NFTs, and you have to know what you are looking for to find it.

Steven DeKosky
I agree, Norm. You would have to study them in comparison to matched groups to determine prevalence in them.

Ann McKee
Steve and Dan, I agree—you have to look for the differences, and if you don't think to do that, you could miss the distinction.

Steven DeKosky
We've always known that ApoE has two brain “risks”: one for decreased clearance of β amyloid and the other the decrease in repair abilities that have been demonstrated in mice. That difference may be what leads to either CTE path or facilitates AD. Or it may just be the loss of brain reserve that comes with serious injury.

Junming Wang
Steve, we saw neurogenesis deficits in as early as three-month-old 3xTg mouse hippocampus. I think this lower rate of producing new, healthy cells is an important factor. A biomarker of neural progenitor cell proliferation may help.

Steven DeKosky
Junming, it would help for animal studies but not for human. I was referring to decreased sprouting after injury. Both mechanisms, of course, may be interfering with recovery....

Vincent Marchesi
Does anybody have any comment of the observation of Laskowitz that a 17-amino-acid fragment of ApoE improves the rate of recovery of experimental head injuries? Laskowitz et al., 2007; Wang et al., 2007.

J. Lucy Boyd
Would it be possible to assume professional football players of 10 or more years have had more head trauma than the general population? That would solve the ascertainment issue.

Vincent Marchesi
What are people going to be looking for?

Norman Relkin
J. Lucy Boyd, that is a reasonable assumption, but would still not permit assessment of differences in cumulative expsore. Several studies have failed to find such a correlation.

Sam Gandy
Dan and I are agreeing here that defining minimal exposure and maximal latency would be key parameters to define before initiating a study with any chance of being close to comprehensive. Agreed, anyone?

Gabrielle Strobel
Our next agenda question was, Assuming we agree on the minimal public health message Chris spelled out, then how broad is it beyond professional football? Wrestling? Soccer? Hockey? College? High school sports? Do we have data to say anything beyond a general message of concern?

Christopher Nowinski
New splinter question—when do we believe athletes are most likely laying the groundwork for long-term progressive brain damage? Is it even through all years of sports? More risk when trauma is received ages five-10? 10-20? 20+? Any thoughts? I am curious.

Sam Gandy
Great question, Chris. I have no clue.

J. Lucy Boyd
Chris, I am very curious about that also.

Gabrielle Strobel
Sam, panel, is the age and latency question where ApoE comes in? Less capacity to repair damage over time?

Sam Gandy
I wish that I could say that I knew anything for sure. The sample sizes are too small to be sure. Dan is commenting here that ApoE genotype may specify how quickly cognition declines, i.e., like the age at onset in AD. Here it would be modulating latency.

Steven DeKosky
Chris's question is a key one. Just as we believe AD “emerges” on the background of an aging brain, it may be that the injuries are present but not clinically detectable until combined with age-related change....

Sam Gandy
Steve, one thing that might speak to this issue is that some mid-life risks for AD can persist into old age despite resolution of the risk factor per se. For example, mid-life obesity that remains a risk later even if the obesity is gone.

Norman Relkin
Chris, one very interesting window on the question you ask is the phenomenon of sudden death from massive brain edema after serial concussions close in time. Called Second Impact syndrome, this is unfortunately seen in young (Sam Gandy
Norm, the catastrophic edema reaction extends to children, maybe babies.

Norman Relkin
In terms of public health messages, the Second Impact syndrome is a good example of a post-traumatic neurologic syndrome that is relatively poorly publicized and catastrophic when it occurs.

Sam Gandy
Second Impact, latency are both issues that we all recognize but not even the general medical population is aware of.

Gabrielle Strobel
There was an extraordinary cover story a while back in the Sunday New York Times describing second impact deaths in high school football players. It was heartrending.

Gabrielle Strobel
All, in light of latency of disease process and age, does sitting out more games, or resting a week or two instead of three days, make a difference for the athlete?

Christopher Nowinski
Gabrielle, I just returned from a UCLA conference with Dave Hovda and Chris Giza, and their groups' studies in the rat model consistently seem to show that rats who don't “rest” after brain trauma, physical and/or cognitively, have more physical brain damage/neuronal dropout. So longer rest after concussion also should theoretically have a major impact on long-term sequelae.

Daniel Perl
There is no human data I am aware of that resting in between multiple concussions is protective against the neurodegenerative sequelae. It may be protective against malignant cerebral edema but not the late stuff.

Christopher Nowinski
Regarding public health message on sports, I think we also have to agree first whether it is “concussions” alone or cumulative trauma that is responsible for CTE. Is it safer to get knocked out once every five years or take 10,000 sub-concussive blows to the head in the same time but have zero concussions? When we have that answered, we'll have a better idea of which sports are most dangerous for the brain. Any thoughts?

Steven DeKosky
Chris's question is the excellent reason to do the prospective study carefully....

Mark A. Smith
Regarding Chris's question, is there any data from animal studies looking at repetitive low-level injury?

Ira Casson
The evidence from boxing indicates that CTE is related to length of career and number of bouts, not the number of times the boxer was knocked out.

Gabrielle Strobel
That would argue for cumulative effect of sub-threshold impact, not just full concussions. Any data like that from the NFL study?

Ira Casson
Gabrielle, we are looking at this as part of our study. Dr Trojanowski's group worked with a group in China and reported a study of the effects of a number of relatively low-level head impacts on a group of genetically identical lab rats (a few years ago).

Norman Relkin
Gabrielle, a substantial component of a boxer’s exposure to head trauma comes from sparring rather than actual bouts.

Sam Gandy
Practice injuries in football too, Norm.

Daniel Perl
In the NC study there were nearly as many concussions during practice as during games.

Mark A. Smith
Having played soccer (30+ years) and rugby (10 years), this is clearly a question of self-interest!

Christopher Nowinski
Mark, I like it. The former pro wrestler in me thinks maybe we should give all researchers concussions so they have a greater motivation to solve the problem. I know some people (laugh). Thoughts?

Norman Relkin
Chris, we get hit over the head by the NIH all the time....

Steven DeKosky
Ah, we have agreement! Norm, any information from autopsies? Any suggestion of factors that would lead to AD or to CTE at pathology?

Norman Relkin
Good, question, Steve, but there are too few autopsy series to answer that.

Sam Gandy
Before people begin to drop out, please take a look at Zaven's suggestion on the main discussion page. See you in Vegas?

Norman Relkin
There are a lot of boxers in Vegas—great place to meet!

Sam Gandy
I think that Zaven's suggestions are terrific. We and other stakeholders of all sorts should get together and try to agree on what the questions are. Then we can move on to how to answer them.

Gabrielle Strobel
In terms of agenda items to discuss in Vegas, how about a genetic study looking for frequency of genes implicated in AD and PD (all listed in AlzGene and PDGene) in retired athletes and correlating that with their neurologic health? Doable? Too complex?

Sam Gandy
Gabrielle, I think that that might be an eventual goal, but I’m not sure we're ready until we know how many clinical and neuropathological "bins" there are. We could certainly look at the "usual suspects," though.

Gabrielle Strobel
Sam, AlzGene has 350 genes alone, but a pretty solid top-20 list. Someone could make a chip for those.

J. Lucy Boyd
I believe that 100 years from now, the understanding will be that the human brain is fragile, more fragile than we want it to be. Just as today we know "don't shake a baby." We don't say, don't shake a baby harder than x, or longer than x, or more times than x. In the future, I believe it will become clear (with better imaging, testing, and studies) that all brain trauma is negative and probably creates some long-term effect.

Mark A. Smith
J. Lucy Boyd, I agree...the question is whether these are avoidable and or worth it on an individual or societal level. In other words, are the rewards (often huge) worth the risks (even if high)?

Sam Gandy
In my slides, there's a citation to a recent paper in Acta Neuropath Scand about E4, falls without head injury (shakes), and late cognitive decline. The results looked superficially like what you would predict (I didn’t scrutinize the paper that carefully so there could be some flaws that I missed, but at the least the concept is there).

Henrik Zetterberg
J. Lucy Boyd, a comment on that. We were actually surprised that amateur boxers who took 15 or more hits to their heads (without being knocked out) but felt fine afterwards had neurofilament light protein levels in their CSF similar to what we see after minor brain infarctions. I agree with you completely that the brain is more fragile than we want it to be and particularly susceptible to shaking.

Norman Relkin
Henrik, I thought that was a very compelling finding. Wasn't it difficult, though, to get athletes to agree to undergo spinal taps?

Henrik Zetterberg
No it was not. But perhaps that has to do with the fact that we perform spinal taps much more often than in the U.S. For instance, every patient who seeks medical advice for memory problems undergoes a spinal tap to exclude neuroborreliosis and assess AD biomarkers, and if not, he or she (or relatives) might argue that it was a careless physician and ask for a second opinion.

Norman Relkin
Thanks, Henrik. I do think professional athletes might be more reticent out of concern about negative after-effects, but I have not approached any recently to ask....

Gabrielle Strobel
Henrik, can you teach the U.S. how to adopt that attitude here? Reluctance to do spinal taps, and fear of them, holds back some of the most innovative AD research here.

Henrik Zetterberg
Gabrielle, it is just to be persistent. If people are willing to undergo colonoscopy on a regular basis, which is very likely to be much more troublesome, it should be possible to perform one or two spinal taps.

Henrik Zetterberg
Dear all, many thanks for a nice discussion. I have to leave. Please let me know if there is any way our lab could assist in the future.

Gabrielle Strobel
Thanks for coming at your dinnertime!

Gabrielle Strobel
We were going to discuss whether we are ready to recommend ApoE genotyping. Given that GINA does not cover life and long-term care insurance (see ARF news story GINA No Genie), do I sense consensus that the answer may be "still no"? Panel, all?

Norman Relkin
Gabrielle, I do not think there is sufficient evidence at this time to recommend the use of ApoE genotyping as a marker for risk of neurologic sequelae in athletes. Unfortunately, I'm being called away. Thanks, Gabrielle, Nico, and all—very interesting discussion!

Gabrielle Strobel
Bye, Norm—many thanks!

Sam Gandy
I agree with Norm. I think the issue is how to build the database to say anything concrete. The old "if your child had an E4 allele, would you let him/her play contact sports in high school?" Is it desirable to look for the answer to that question?

Christopher Nowinski
I thought Norm said it well in his video presentation. Too early for all, but will help some. Maybe an easier question is, If your child played contact sports and received a few concussions, would you have him or her tested for E4 and then include that in a decision of whether to retire early? I think that is a yes, and people should be informed of that option. There is nothing worse than finding out after the fact that you should have known better.

Gabrielle Strobel
Chris, your framework makes sense at a gut level. There would have to have been an event already that causes one to worry, rather than just a totally pre-emptive genetic test.

Sam Gandy
But Chris, do you think you have the knowledge base to make that decision or are you just being ultra-cautious? A problem with this message is that it implies that the E4 non-carriers will not dement, and that's the wrong message.

Christopher Nowinski
One of the worst aspects of my retirement experience was discovering that doctors believed I wasn't smart or mature enough (at 24) to be told that research exists that shows concussions have long-term detrimental consequences, just in case I overreacted. So if the data are the data, then I say tell people and let them make their own choices. And no, I don't believe that telling people E4 increases risks tells others they can be careless. The CTE cases I've been involved with haven't involved E4 for the most part. It just takes good education.

Gabrielle Strobel
So Chris, do you see the generally negative stance toward ApoE testing as a kind of paternalism by physicians?

Christopher Nowinski
Gabrielle, thanks for the loaded question.... The interpretation of my experience was that they didn't want to tell me things that would scare me or change my behavior much. While not everyone has the capacity to interpret reams of medical research, and I don' t have the experience of being a clinician, I think in some cases you've got to lay the cards on the table and let people choose for themselves.

J. Lucy Boyd
Chris, I agree.

Sam Gandy
The paternalism/condescension thing bugs me, too, Chris.

Christopher Nowinski
Thanks so much everyone. This has been amazing, but I have to run as well. I have to get on the road to New York for a dinner with eight current NFL players. Guess what I'll be discussing.... I'll send them all your best and let you know we are looking out for them!

Sam Gandy
Thanks, Chris. We'll be in touch. See you in Vegas.

Gabrielle Strobel
Goodbye, Chris. Thanks so much for weighing in on this. Sam, have Zaven invite Chris's dinner guests to Vegas....

Sam Gandy
Absolutely. I think that there should be an advocacy/public policy piece to the meeting. Since Norm has gone, I will suggest that we begin thinking about organizing something along the lines of what he and I did for the Alzheimer's Association ApoE Genotyping Consensus in 1995ish. A praecis was published in The Lancet and longer papers were collated into a volume of Annals NYAS. Zaven has volunteered his journal to play that role, but I think that we might want to get The Lancet on board again up front.

Gabrielle Strobel
I think the time for that would be good, Sam.

Mark A. Smith
Any thoughts on the influence of performance-enhancing drugs, which are likely common in professional (and amateur) sports?

Gabrielle Strobel
On performance-enhancing drugs, I'd like to ask Dan and Ann and all neuropathologists here, Can you distinguish a difference between their impact on brain ("steroid brain") and the impact of blows to head?

Sam Gandy
Gabrielle, that's another confound to define, I think.

Ann McKee
Although steroids have been shown to augment Aβ and tau pathology in animal models, I am not aware of any human study specifically demonstrating that chronic steroid use results in anything remotely similar to CTE.

Mark A. Smith
Ann, I was thinking more along the lines of a double whammy—a two-hit type of thing (Zhu et al., 2004).

Gabrielle Strobel
Ann, pathologically speaking, is there such a thing as "steroid brain"? I heard that reference in a CNN story about TBI.

Ann McKee
I've seen the references in the lay press as well, but as far as I know there is a neuropsychological aspect to chronic steroid use but not a neuropathological one characterized by abnormalities of tau, although animal studies suggest that steroid use might potentially accentuate the tau abnormalities.

Dushyant Purohit
To all pathologists here, considering there are few autopsies of TBI in individual centers, a collective brain bank could be a good idea. It will be immediately useful for a study, because clinical cases recruitment and follow-ups would take a much longer time to get any significant results.

Ira Casson
Ann, can you tell us where to find the animal studies that show neuropathological effects of steroids on the brain?

Sam Gandy
Glucocorticoids are toxic to hippocampal neurons. Read anything that Bruce McEwen has published over the past 30 years.

Ira Casson
I have discussed this with Dr McEwen. He told me that no one has studied the relationship between steroids and tau.

Sam Gandy
If that's what Bruce said, I would not challenge. GCs do kill neurons and increase Aβ generation and accumulation. (Wow! Took me 80 minutes to mention Aβ! That must be a record!)

Ann McKee
Ira, Frank LaFerla's group published a recent paper showing increased Aβ and tau with glucosteroids in the triple transgenic animal model of AD. The paper is Kim et al., 2006.

Ann McKee
Gabrielle, my take on this issue of CTE is, as mentioned early on, that it is much more prevalent than realized, and that it may also in fact also accelerate what we consider to be AD (perhaps along the lines of the double-hit hypothesis). Although Steve mentioned that his CTE cases had no medial temporal neurofibrillary tangles, my experience would be the opposite—that there is considerable medial temporal lobe, especially amygdala pathology.

Daniel Perl
I agree with Ann (as usual); our cases had very heavy medial temporal pathology, including involvement of amygdala.

Gabrielle Strobel
All, if memory serves, Hank Feuer is a coauthor on NFL papers about return to play by concussed players. Perhaps you have a question? We'd love to hear from him.

Hank Feuer
Enjoyed the chat. Education and communication have been the hallmarks of my care of the concussed athlete and all those involved.

Steven DeKosky
Great discussion. Thanks, all. I have to leave.

Gabrielle Strobel
I would like to invite the panelists to make a closing statement before they have to log out. In keeping with the structure of the discussion, perhaps tell us what you think we know with reasonable certainty now and what you would like to study next if money was available.

Steven DeKosky
Here’s my concluding statement: just as our discussion today showed what a complex area this is, the manner in which we address it in experimentation and data gathering can also vary. While I need more time to digest the suggestions of information provided, my view at present is that there are several biological questions that I would be very interested in trying to answer. A major one is after a lifetime in which there were several or multiple blows to the head, or even one significant injury, what leads to either chronic traumatic encephalopathy (dementia pugilistica pathology) or classical Alzheimer disease pathology? They are certainly very different. This would be the reason to study people in late life who have or do not have cognitive impairment but were matched for experience in, for example, professional sports. The other would be the initiation of a prospective study, with public health implications, of younger people playing sports and looking to see what the short- to intermediate-term effects on cognition are. This latter may be more difficult because of reluctance or unwillingness to have such things documented (especially if they are done during sports and might precipitate the loss of a player). These are difficulties known to all of us. But a central discussion might evolve a very good way to do this. I believe the first study I propose would be somewhat easier to initiate. It is not the only way to do it. Working with the Department of Defense and the VA on subjects who have had head trauma would also provide very useful data.

Variables to be considered in devising studies: severe injury one time versus multiple smaller injuries, age at which injuries occurred (young children playing sports versus professional football players versus soldiers), and how long after the exposure one would look—short- to intermediate-term, long-term/late life.

In addition to the fact that we will learn something with significant implications for public health, I also think we will answer fundamental question about how injury affects the brain. I am fascinated by the idea that what appear at this point to be similar injuries may lead to either chronic traumatic encephalopathy or to Alzheimer disease. One has neurofibrillary tangles in a different distribution than Alzheimer's, the other has tangles and amyloid plaque. What determines which pathology emerges? We have the ability to make progress in a variety of ways here as well as do good things for public health.

Gabrielle Strobel
Steve, many thanks. I am very glad you came!! Last call for comments, all!

Ira Casson
I enjoyed reading all your comments and discussion.

Gabrielle Strobel
Ira, did you take anything away from this discussion? Did it change your mind in any way?

Ira Casson
Gabrielle, I always enjoy hearing other perspectives and always keep an open mind. My opinions are always based on solid scientific research.

Gabrielle Strobel
You listened to some of the best scientific minds in the field of Alzheimer and CTE research today.

Sam Gandy
My final comment is that we don't yet have enough real data to make much of a fuss vis-à-vis public policy, but we should not ignore the problem to the extent that it has been in the past. Operations Iraqi Freedom and Enduring Freedom (OIF/OEF) vets with TBI certainly represent another population that merits representation at the table.

Gabrielle Strobel
Thank you for all your work on this Sam. Clearly there'll be follow-up.

Sam Gandy
We've covered a lot in 90 minutes and in a fairly coherent manner! Check out the Alzheimer's Association ApoE consensus in The Lancet for something that we might use as an organizational template or springboard.

Sam Gandy
Ciao, all.

Gabrielle Strobel
Goodbye and thanks to all.

Background

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

1. • Henrik Zetterberg
     University of Gothenburg
   • Posted: 25 Jun 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 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. PubMed.

   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. PubMed.

   View all comments by Henrik Zetterberg
2. • Zaven Khachaturian
     Alzheimer's & Dementia
   • Posted: 26 Jun 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 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
3. • Christopher Nowinski
     Sports Legacy Institute
   • Posted: 03 Jul 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 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

Make a Comment

To make a comment you must login or register.

References

News Citations

1. Alzheimer Activism: How To Modernize Clinical Trials? 31 Mar 2008
2. GINA No Genie for Alzheimer Disease Patients and Relatives 27 Jun 2008

Webinar Citations

1. Susceptibility Testing and Risk Assessment in Alzheimer Disease 1 May 2007
2. Sports Concussions, Dementia, and APOE Genotyping: What Can Scientists Tell the Public? What’s Up for Research? 9 Jun 2008

Paper Citations

1. Katzman R, Galasko DR, Saitoh T, Chen X, Pay MM, Booth A, Thomas RG. Apolipoprotein-epsilon4 and head trauma: Synergistic or additive risks?. Neurology. 1996 Mar;46(3):889-91. PubMed.
2. Relkin NR, Kwon YJ, Tsai J, Gandy S. The National Institute on Aging/Alzheimer's Association recommendations on the application of apolipoprotein E genotyping to Alzheimer's disease. Ann N Y Acad Sci. 1996 Dec 16;802:149-76. PubMed.
3. Eckert SL, Katzen H, Roberts JS, Barber M, Ravdin LD, Relkin NR, Whitehouse PJ, Green RC. Recall of disclosed apolipoprotein E genotype and lifetime risk estimate for Alzheimer's disease: the REVEAL Study. Genet Med. 2006 Dec;8(12):746-51. PubMed.
4. Roberts JS, Cupples LA, Relkin NR, Whitehouse PJ, Green RC, . Genetic risk assessment for adult children of people with Alzheimer's disease: the Risk Evaluation and Education for Alzheimer's Disease (REVEAL) study. J Geriatr Psychiatry Neurol. 2005 Dec;18(4):250-5. PubMed.
5. LaRusse S, Roberts JS, Marteau TM, Katzen H, Linnenbringer EL, Barber M, Whitehouse P, Quaid K, Brown T, Green RC, Relkin NR. Genetic susceptibility testing versus family history-based risk assessment: Impact on perceived risk of Alzheimer disease. Genet Med. 2005 Jan;7(1):48-53. PubMed.
6. 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.
7. Guskiewicz KM, Marshall SW, Bailes J, McCrea M, Harding HP, Matthews A, Mihalik JR, Cantu RC. Recurrent concussion and risk of depression in retired professional football players. Med Sci Sports Exerc. 2007 Jun;39(6):903-9. PubMed.
8. Laskowitz DT, McKenna SE, Song P, Wang H, Durham L, Yeung N, Christensen D, Vitek MP. COG1410, a novel apolipoprotein E-based peptide, improves functional recovery in a murine model of traumatic brain injury. J Neurotrauma. 2007 Jul;24(7):1093-107. PubMed.
9. Wang H, Durham L, Dawson H, Song P, Warner DS, Sullivan PM, Vitek MP, Laskowitz DT. An apolipoprotein E-based therapeutic improves outcome and reduces Alzheimer's disease pathology following closed head injury: evidence of pharmacogenomic interaction. Neuroscience. 2007 Feb 23;144(4):1324-33. PubMed.
10. Zhu X, Raina AK, Perry G, Smith MA. Alzheimer's disease: the two-hit hypothesis. Lancet Neurol. 2004 Apr;3(4):219-26. PubMed.
11. Green KN, Billings LM, Roozendaal B, McGaugh JL, Laferla FM. Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer's disease. J Neurosci. 2006 Aug 30;26(35):9047-56. PubMed.

Other Citations

1. Gabrielle Strobel

External Citations

1. CNN clip
2. NYT story
3. Justin Strzelczyk
4. Chris Benoit
5. NYT story
6. ESPN story
7. U.S. Senate Committee hearing
8. Genetic Information Non-discrimination Act
9. Alzheimer disease
10. Parkinson disease
11. Sports Legacy Institute
12. Head Games: Football’s Concussion Crisis
13. Listen to Radio Story
14. news link

Further Reading