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New Concussion Test Keeps Athletes Safe

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CLEVELAND, Ohio (Ivanhoe Newswire) - About 400,000 high school and college athletes suffer a concussion each year. It's not surprising to find out that football players are most at risk. In fact, at least one player sustains a mild concussion in each game, but did you know that you can get hit hard, not sustain a concussion, and still put your brain at risk? Now, there's a new test that can show within seconds if a player should be pulled from the game even if they don't have a concussion.

College senior Zach Barley has taken some hard hits over the years.

"I've been hit hard hundreds or thousands of times," Zach Barley, Strong Safety #29 at Baldwin College, told Ivanhoe.

Number 29 was once pulled from a game after suffering a concussion, but you don't have to be hit that hard to damage your brain. There's now something called a sub-concussive hit.

Cleveland Clinic and the University of Rochester developed a blood test taken before, during, and after a game to find out if those hits can damage the blood brain barrier, the lining in each of the blood vessels in your brain that prevents harmful molecules from getting in. When a player is hit hard, that barrier is breached.

"The blood test is based on a molecule called S100B, which is present in the brain but not in blood. When the barrier breaches, the molecule shows up in the blood," Dr. Damir Janigro, Director in Cerebrovascular Research at Cleveland Clinic's Lerner Research Institute, told Ivanhoe.

And the immune system attacks it.

"The body believes there is a pathogen, bacteria, a fungus, or some other enemy to fight. So the body fights the enemy," Dr. Janigro said.

Then it goes into the brain and can attack brain tissue, similar to what happens with Alzheimer's patients.

Right now, Zach's brain is intact.

"But I'm not willing to risk my life over playing a game," Zach said.

This test could mean he and other players won't have to.

Before, doctors used MRI to see damage from concussion and sub-concussion, but it's not as sensitive as the blood test. Researchers hope to continue developing the blood test and one day have it used on the sidelines of every game.

RESEARCH SUMMARY

BACKGROUND:  A concussion is a traumatic brain injury that alters mental status and causes other symptoms.  Many people assume that they do not have a concussion if they have not lost consciousness, but significant injury can occur without losing consciousness at all.  When a concussion is suspected, a certified athletic trainer, a trained coach, or the team physician should immediately perform an initial "sideline" evaluation, which includes: symptoms list review, focused orientation exam that tests short-term memory recall like the event or play, focused neurological exam, assessment of athlete's ability to stay attentive to a complex task like reciting months backwards, and focused orientation exam that tests long term recall like their birth date.  If a concussion is left undiagnosed, a concussion could place an athlete at risk of developing second impact syndrome. (Source:http://www.stopsportsinjuries.org/concussion.aspx)

SYMPTOMS: Concussion symptoms can include:  balance problems, irritability, headache, difficulty communicating, dizziness, drowsiness, fatigue, feeling emotional, feeling mentally foggy, memory difficulties, nausea, nervousness, numbness or tingling, sadness, sensitivity to light or noise, sleeping more than usual or difficulty falling asleep, visual problems - blurry or double vision, and vomiting. (Source: http://www.stopsportsinjuries.org/concussion.aspx)

NEW TECHNOLOGY:  Concussions are the leading cause of brain damage in sports, especially football.  However, researchers at Cleveland Clinic and the University of Rochester found that football players suffer long-term brain changes even in the absence of concussion.  In a study of 67 college football players, researchers discovered that the more hits to the head a player had, the higher the levels of a particular brain protein that is known to leak into the bloodstream after a head injury.  None of the football players in the study had a concussion during the season, but four of them showed signs of an autoimmune response that has been associated with brain disorders.  "Much attention is being paid to concussions among football players and the big hits that cause them, but this research shows that more common, ‘sub-concussive' hits appear to cause damage too," Damir Janigro, PhD, Director of Cerebrovascular Research in Cleveland Clinic's Lerner Research Institute and study leader, was quoted as saying.  The study used several methods to assess brain injury, like brain scans, blood tests, and tests to measure memory, motor control, reaction time, impulse control and balance, in addition to extensive review of game video to assess head hits among the players in the study.  For the blood test, researchers drew blood from football players at Baldwin Wallace University, John Carroll University, and the University of Rochester before and after games, so that they could search for the S100B protein in the blood.  Usually S100B is found in the brain, finding S100B in the blood means that there has been damage to the blood-brain barrier.  Studies in Janigro's lab revealed that once in the bloodstream, S100B is seen by the immune system as a foreign invader, triggering an autoimmune response that releases auto-antibodies against S100B.  Four players out of the 27 for whom pre-season S100B blood levels were measured, showed signs of an autoimmune response to S100B.  Concussions can be difficult to diagnose, relying on player symptoms, cognitive tests or CT scans that cost thousands of dollars. The blood test offers an objective measure of whether a player has endured head trauma.  A blood test will be much less expensive (about $40) and could be performed anywhere, such as locker rooms or doctors' offices. (Source: www.clevelandclinic.org)  

INTERVIEW

Damir Janigro, PhD, Director of Cerebrovascular Research at Cleveland Clinic Lerner Research Institute, talks about a new test that could detect concussions.

Why do this study?

Dr. Janigro: We did this study for several reasons. One of the reasons is that everybody is aware of the risk of concussion in sports, especially in American football, but very few have actually looked at what a sub concussion episode does. Or in other words, how many sub concussions does it take to have the consequences of a real concussion.  This was very difficult to do because we didn't have at that time means to define a sub concussion. It's just an opinion, you can argue until the game is over whether this kid had a concussion or a sub concussion. So we came up with a blood test that is more objective than just observation. This blood test is interesting because instead of measuring brain damage or injury to the brain which would be appropriate for a concussion, it actually measures an event that is less traumatic but, in our opinion, equally significant, which is damage to the blood-brain barrier.

Can you tell me what the difference between a sub concussion and a concussion is?

Dr. Janigro: If you look at the definition of concussion on the Center for Disease Control, every head or event that has a consequence after you hit your head is considered to be a concussion. If you look at medical terminology or at textbooks, there is a variety of definitions of concussions. The most commonly used is the Glasgow Coma Scale, which is a very old way to see whether you are neurologically intact, but there is really not a good definition of concussion in sports other than self-reporting tests that are done on the sidelines by the trainers, coaches, or by a physician. Loss of consciousness is obviously always associated to a concussion. By definition if you lose consciousness you had a concussion, but there are a number of psychological changes that may be indicative of a concussion but are not recognized yet. When you study sub concussions it gets even murkier because a sub concussion is everything that is bad for you but is not a concussion. Since we have problems defining a concussion, we don't have much luck with a sub concussion either. I think the best definition for us was to look at people who had several hits to their head documented by cameras or self-reporting and follow these individuals for over a season and after a season, rule out those who had a concussion, and call the sub concussion those players who have any kind of long lasting consequences after playing football.

Can sub concussions be just as dangerous as concussions?

Dr. Janigro: In our hypothesis there are two fundamental differences. A concussion is an acute event that usually if it's diagnosed means that you will not play the next game, you will be pulled out of the game, and someone will take care of you. In a sub concussion this doesn't happen, so it's hard to tell because we don't know what the standard of treatment for sub concussions is or should be. Our hypothesis is that because of this reason, an unknown number of sub concussions may sum up to a real concussion sequelae. This was quite evident from the study we did where we followed players who did not have a real concussion and we divided them in groups based on a number of parameters. The simplest one to explain is how many hits to the head they had during one game, two games, and the whole season. We came up with a head hit index which was done by volunteers who were blinded, meaning they didn't know the players who were in the study and the players who were not in the study. They watched a lot of football games from fixed cameras and they counted these hits and scored them on intensity, severity, and left, right, front, back. At the end we had players, repeat offenders we called them, who always have a lot of head hits during any given game.

Are there certain positions that are worse?

Dr. Janigro:  Of course. It's predicted by position and the most common ones who would never have a head hit are the kicker and so forth. Then there are those guys who are in between, and this was the first way to divide them. If these guys were NFL players, there is actually a Pellman score that Dr. Pelmann came up with which is a number that gives you a risk for concussion based on position. For college players we don't have such a number so we just use the hit index.  Once this was done, we analyzed the blood samples that we took from the players in the study and the blood samples taken before the season, before a game, after a game, and at the end of the season. So each player had at least the beginning and the end of the season if they didn't play at all or two blood tests per game when they played even if they only played a few minutes. We compared the results of these blood tests to the head hit index. The blood test is based on a molecule called S100B, which is present primarily in the brain and is normally not present in blood except when the blood-brain barrier is breached because of a sub concussion. It's quantitative so we can tell you how much it went up compared to your pregame value. By analyzing all the changes in this molecule in every single game, we found out that there was a very striking correlation with the number of head hits. Players who never had head hits also never experienced a surge in this protein in blood while players who had the most head hits had the most of the protein and so on.

Does this molecule appear in people that are suffering neurological problems, Alzheimer's, dementia, or anything?

Dr. Janigro: This protein, which is really a reporter of blood-brain barrier integrity, is very useful for a variety of diseases. We have used in extensively as a marker of brain tumors, though not so much for primary brain tumors which are very rare; we can't scan everybody for a brain tumor because there would be too many false positives. It's also used in people who have breast cancer and lung cancer, primarily because they have a very high risk of brain metastasis and there is a premium in discovering these metastases early on. This test will tell you whether or not your blood-brain barrier has been breached by a tumor coming from your body. By the same token as Alzheimer's and dementia, they have found out that a lot of aging people at various levels of cognitive impairment also have damage to the blood-brain barrier. This is actually interesting for our study because what they found in Alzheimer's patients early on in the development of the disease were antibodies against S100B. So, not only was there a marker of blood-brain barrier dysfunction, there was also an immunological trail or memory of what happened earlier on. In other words, because this protein is not normally present in your blood, when it shows up repetitively the body believes there is a pathogen, bacterial, fungus, or some enemy to fight and the body fights these enemies by making antibodies. These antibodies persist in memory and it's like a vaccine; you're immunized against this protein for the rest of your life. Of course, if the protein never shows up again nothing will happen. The point is that you need to have a repeated sequence of events during early age when you're playing football or have many blood-brain barrier disruptions, and then the memories of these leakages of the barrier occur when you're aging and may cause an immunol response that could go after your brain. In our players we did not find any brain damage as you normally would define it, but we did find in elevated antibodies against S100B in a selective number of players. In the same players there were also changes on MRI scans that are indicative of some kind of brain dysfunction. I wouldn't call it brain damage, it's most likely transient but certainly it becomes yet another risk factor for football players.

There are a lot of studies into NFL player's brains right now saying that it could cause early Alzheimer's and brain damage. Could this be something different where you have this immune response attacking your brain so it's not Alzheimer's but something else attacking your brain?

Dr. Janigro: We don't know what causes dementia. I personally don't think that we have an answer, but one thing we do know is that it takes a long time. Even when you have an early onset Alzheimer's disease, we talk about tens of years of life before symptoms manifest. A possible explanation is that the brain is very big, and before you have symptoms you have to chew away a significant part of it. If this process starts early on in the life span because of an immune response, you predict that it will be a slow, almost imperceptible change over time until the first symptoms occur. You would also predict that these patients or these "almost patients", when they are getting there will have no symptoms because there is a critical volume of brain loss that is needed to have symptoms. Parkinson's disease is an example. We have many cells that produce dopamine to control tremor in our body and you need to lose a lot of these cells before you start to have symptoms of Parkinson's disease. Multiple Sclerosis is another example and in fact, in people who will develop Multiple Sclerosis you have antibodies against the brain before the onset of symptoms. I think it's a very intriguing hypothesis to look at the misguided immune response happening during a young age that then becomes a problem during aging.

What was the most surprising result from your blood test study?

Dr. Janigro: The most surprising result to me was that there were persistent changes. We scanned by MRI these players before the season, after the season, and then six months after the season was over, which is preseason for the next year. In four players out of the fifteen that we enrolled for this portion of the study, there were changes that were persistent after the season was completed.

Does that mean the changes continued to get worse?

Dr. Janigro: We didn't find any worsening, but we found persistence of whatever change. Many players had changes due to the game at the end of the season, but very few still had those changes six months later.

What you're saying is it's not reversible?

Dr. Janigro:  We don't know that. We really don't understand very well how the brain repairs itself or how long it takes. We need to find either an animal model or a surrogate study where people have repeated opening of the barrier and see what happens. We are looking at epilepsy because in epilepsy, in children especially, we have shown that this protein is actually increased before seizure onset and seizures can be triggered by an altered permeability of the blood-brain barrier. This is a paradigm we are pursuing with another group of individuals who don't play football but who do have a bona fide pathology that is characterized by these peaks and valleys of markers in blood and an autoimmune response.

Could this give coaches another tool to see which players need to be pulled from the game?

Dr. Janigro: The test comes in two flavors. One test is for the S100B protein, which is an acute test that ideally you would administer during the game.  It would be a marker of concussion or severe sub concussion.

It could be simple like diabetes test?

Dr. Janigro: If we had a point of care device, which we don't have yet, it could be done in a couple of minutes. The antibody test should be delivered at the end of the season, for example, and then we can start to talk to the players who have the highest markers and council them to perhaps change positions, play less, or stop playing altogether. This obviously goes beyond football. There are head injuries in hockey and obviously boxing is a concern. We don't know what levels of these markers should cause you to become worried about your professional career or your career as a sports person, so we are investigating that on bigger ponds of players.

Now this goes in to the MRI set though right?

Dr. Janigro: MRI is extremely sophisticated and it can be very sensitive. In our hands, MRI was not as sensitive as the blood test. In other words, there is no MRI sequence today that can see leakage of the blood-brain barrier at levels that the marker can see. MRIis also very expensive in addition to not being sensitive enough and you have to sit in a scanner for forty minutes. Furthermore, some of the agents used for MRI contrast agents can become toxic if you take them too often, so we are trying to develop a surrogate to MRI to scan only the players who have the top 10% of antibodies, for example, in their blood. So, not to scan everybody, which would be ideal but very cumbersome to do, but just scan those who have the highest risk.

You were talking about another study.

Dr. Janigro: Part of this study was to understand how to interpret these MRI changes. This is very hard to explain in a few words, but we were looking at a sequence called DTI, which stands for diffusion transfer imaging. Diffusion imaging transfer imaging primarily looks at white mater changes. Bundles of axons, of these wires that connect different parts of the brain, also connect the brain to the motor system and to the rest of the body. These bundles can be degenerating, in which case they become smaller or they can become swollen because of too much water or edema.

Then a concussion happens both ways? It can shrink and get bigger?

Dr. Janigro: Typically in a concussive acceleration injury, you first get the swelling then you have the disappearance of axon bundles. So, you get first swelling and then shrinkage. We found that there were bundles which were slightly smaller than they used to be or slightly bigger than they used to be, and after six months these changes stayed. They were very small changes however, and there was no indication by interviewing these players or analyzing their behavior that there was any real consequence at this point in time.

What could be the consequence if it continues?

Dr. Janigro:  If our hypothesis is correct, what happens is that it's a little bit like radiation damage. We have an allowance for a life span and before you really get sick from radiation exposure, you have to hit a certain number of rads. In my hypothesis, we have a sort of allowance for brain health before it becomes brain damage or brain deterioration depending on what you do, your lifestyle, whether you hit your head or not, whether you smoke, drink, and so forth. You will also damage your brain in part or substantially depending on how you do it; this is just yet another risk factor. It's not something that will certainly lead to pathology or a disease; it's just a risk factor.

So what do you do next? What is next for this study?

Dr. Janigro. This was funded by NINDS, the National Institute for Neurological Disorders and Stroke, and was a pilot two year study. We submitted a grant for a five year study and in this proposal, which was done together with the University of Rochester Medical Center and Dr. Jeff Bazarian, we will look at another feature that we can add to this mix. In our study we have primarily looked at hits as self-reported or as seen by a camera. In the next phase of the study, players have helmets which are instrumented in a way that measures intensity, direction, interval, and all the parameters associated with a hit. So, it gives much more information on the biomechanics of this event. This location of hits can be super imposed on an MRI to see whether there is a relationship between what side your head was hit, what the position of your neck was when the hit occurred, and the consequences that we observed on MRI and in blood tests. The other part is to keep these players enrolled in the study so we can follow them during the aging process, which of course is very difficult to do, but it has to be done at some point.

Why do you think this is such a hot topic right now?

Dr. Janigro: Because people love football and I think they are afraid that, because football can be dangerous, the game will be changed in a way that makes it unrecognizable. There are prior examples such as Rugby in Australia where they had a lot of neck snaps and a certain rule changed that, but the game didn't really change. People still go to the game, but no one got their neck snapped because they changed the rule and you get immediately ejected if you even try to do what used to be a legal move. In football we should probably do the same; keep the game as it is but put some more safeguards and also some metrics on when a player should retire and what is enough.

Like you said, it might change the game a little and you were explaining about the quarterback?

Dr. Janigro: The quarterback is obviously an interesting player because he's a player who has a selected number of hits and actually is the easiest player to follow in a study as in the one we did. The quarterbacks are different than the linemen, and linemen were obviously on the top of our scale for head hits. There is also the durability of their career; how many years is a person going to stay on the field, the body size, which is obviously different between the quarterback and other players, and the strength of your neck muscles are all factors as well. Very few players develop symptoms and the question is why is certain players will develop symptoms during aging and others will not even though the number of head hits was the same. We are trying to understand whether the immune tolerance of a player could be different from another, whether the size of the neck of a player is a predictor of good or poor outcome, and so on.

What is the blood-brain barrier?

Dr. Janigro: The blood-brain barrier is really an organ that you don't hear much about but is extremely important. There are three barriers primarily in our bodies. The fetal maternal barrier is one example and the testicular barrier in men is another example. These barriers usually tend to isolate a specific feature in case of the baby, or an organ in the case of the brain from the rest of the body. This is done for many reasons. In primates, the very important part of the blood-brain barrier is to keep water out of the brain. We have packed the brain with a lot of cells, but we have to protect the brain. So with every accumulation of water we cause a compression of the brain, which is not good for you. One of the tasks of the blood-brain barrier is to make sure that the water hemostasis is maintained so that you don't get brain edema even when you hit your head, or that if you get brain edema, it is short lived. So, the blood-brain barrier is really a homeostatic organ that maintains the status quo. Neurons, the brain cells, love to be in a status quo and work very poorly if you change their environment so it's a stabilizing factor that keeps the riff-raff out and gets the good guys in like glucose, nutrients, oxygen, and so forth.

You said it's an organ. An organ like the kidney?

Dr. Janigro: It's an organ made by only one cell type.

Where's it at?

Dr. Janigro: It's called the endothelium and it's the inner lining of every blood vessel in your brain. Unlike other blood vessels in your body, these blood vessels have a junction system that makes a zipper lock type of structure which isolates the in from the out. There are transporters that allow passage of things you want to go through, but in general stuff doesn't move across this tube. One of the things that are kept out is the immune system. There is an immune system in your body and there is some immunity in your brain, but they don't really talk to each other very much and don't actually know about each other until the blood-brain barrier opens up. In this case, there is communication coming from the blood to the brain and vice versa.

So there are millions of them?

Dr. Janigro: Cells? There are millions of the cells. The surface of exchange is several square yards. It's very important for drug delivery in that it keeps certain drugs out, but sometimes you want to breech the barrier to pump things like chemotherapy into the brain and other drugs you don't want to go in the brain. It's very complicated. In my career I started to work with the blood-brain barrier in 1992 I think, and very few were working in the field. Now it is really booming and there are meetings and conferences everywhere. It's really an important part that we have neglected for quite some time.

FOR MORE INFORMATION, PLEASE CONTACT:

Andrea Pacetti
Cleveland Clinic
(216) 316-3040
PACETTA@ccf.org

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