In his search for a blood test for concussions, an alumnus also investigates the long-term consequences of chronic repetitive blows to the head.
By Michael Wentzel
An emergency medicine physician sees all kinds of illnesses and injuries, but Jeffrey Bazarian, M.D., M.P.H. (M ’87, R ’90, MPH ’02), chose to investigate blows to the head and concussions, now a more than 15-year pursuit that has taken him from a search for a blood test for concussions to suspicions of an epidemic.
“I saw many people coming into emergency with blows to the head and I couldn’t be certain if they really had an injury,” he said. “If they didn’t seem to be obviously brain-injured, I sent them home. But I was never really sure they would be OK. To me, this seemed odd as we had diagnostic aids for most other injuries and illness that came into the E.D., but not for concussion.”
A head CT scan was used most often with injured patients, but the scans almost always were normal. In the early 1990s, a number of investigators showed that concussions result in subtle, but measurable, injury to the brain and this injury almost never shows up on a CT scan, Bazarian said.
“From my standpoint, I was trying to evaluate an injury to something as important as the brain and the only tool I had – a CT scan – was no good,” he said. “As the number of head-injured patients coming into the E.D. grew, I realized we were dealing with an unmet need. We needed an accurate and quick way to diagnose a brain injury after a concussion – a blood test for concussion. That seemed like a reasonable goal.”
But Bazarian, associate professor of emergency medicine at the University of Rochester Medical Center, now sees a blood test as just a first step in unraveling a threat to the viability of the brain.
“I started out thinking concussion was bad, that it causes brain injury that lasts forever and we need a blood test to diagnose and treat it,” he said. “Now, it looks like not everyone who has a concussion has an injury. If they do, the injury may be transient and resolve with little intervention. It’s the multiple concussions or multiple sub-concussive blows that may represent the real threat to the long-term viability of the brain, even leading to early-onset dementia. I’m talking about the football lineman, for example, who thinks he is fine, but his brain isn’t fine. The consequences of multiple hits are what we are trying to understand, prevent and/or treat. That is the really silent epidemic.”
The path of Bazarian’s studies illustrates not only the nature of research but also his persistence.
“It might seem like my research stopped at times, but it never did,” he said. “I’ve been working on this a long time. I’ve changed directions a few times but it was always in the direction the data took me. It’s a journey. It really is.”
Inspiration and an injured teenage girl
Bazarian’s fascination with neurology goes back to his School of Medicine and Dentistry student days when he was inspired by the teaching of David Felten, M.D., Ph.D, then a professor of neurobiology and anatomy at Rochester.
While in medical school, Bazarian also spent two summers working in the lab of German neurologist Claus Meier, M.D., at the University Hospital of Berne, or Inselspital, in Switzerland. But he eventually chose emergency medicine.
“I didn’t think then I was cut out for neurology,” Bazarian said. “I did an internal medicine residency but discovered that I really liked taking care of critically ill and injured patients the best. Emergency medicine was so new back then that you could move right into it.”
He was further motivated to pursue his neurology interest in 1993 when his father died of a head injury after falling down a flight of stairs. But Bazarian’s research started slowly as funding for his target was sometimes scarce. In 1997, a foundation grant supported a small study of patients who visited the emergency department and reported blows to the head.
“I did a study using pen-and-paper cognitive testing right in the E.D.,” he said. “If concussed patients said they were OK, how well were their brains working? Many patients were cognitively quite abnormal. This study started to tell us there was more than meets the eye with concussions.”
In 2002, with a $560,000 National Institutes of Health grant, Bazarian began the nation’s first emergency department-based traumatic brain injury registry. His project collected detailed information – plus a blood sample – from every brain-injury patient brought to Strong Memorial Hospital’s emergency department for two years. Where and how did the injury happen? Was a sport involved? Was the patient intoxicated? Was the patient wearing a seatbelt or helmet? What tests were performed before treatment?
“These data, plus all the collected serum, are available, and we continue to go back and dip into that and look at serum samples,” Bazarian said. “But this study was even more valuable because it forced me to realize that, in many E.D. patients, it was impossible to determine if they met the clinical definition of concussion. Many patients just couldn’t tell us if they lost consciousness, blacked out or were confused at the time of injury. I guess I shouldn’t have been surprised. In effect, we were asking a patient who may have had a brain injury that disrupts their ability to remember – to remember the details of their accident! When I came to this realization, I had to change the course of my research. It moved me away from research focused on describing the epidemiology of concussion, and toward research attempting to improve the diagnosis of concussion through the use of objective aids, such as a blood test.”
At the same time, as a project for his master’s degree in public health, Bazarian and colleagues analyzed a sample of crashes reported to the National Highway Traffic Safety Administration in 2000 to determine the risk for brain injuries.
“The project was driven by a patient, an 18-year-old girl who was brought to the emergency department,” said Bazarian, who lives in Honeoye Falls, south of Rochester. “She had been wearing a seat belt. The car in which she was riding sideswiped a tree. She died in the E.D. from her head injury. It was hard for me to understand how she died. And she was from the town where I live.”
Bazarian’s analysis of the national accident reports showed that occupants of automobiles involved in side-impact crashes were three times more likely to suffer a traumatic brain injury than people involved in head-on or other types of collisions. Females were found to be at a higher risk of brain injuries.
The researchers saw their analysis as the first population-based study to find that a side-impact crash is a risk factor for traumatic brain injury.
“Cars were not well-protected then from side impacts,” Bazarian said. “With side protection, we thought many fatal and non-fatal injuries could be prevented. Most cars now have side-impact airbags.”
Even a mild or moderate head injury also might be a risk factor for early-onset dementia or Alzheimer’s disease, Bazarian had come to believe. A blood test would help doctors diagnose axonal injury, a type of brain injury that often occurs after a concussion but does not show up on a CT scan of the brain, and begin quick treatment.
But in order to develop a surrogate marker for brain injury using a blood test, Bazarian realized he needed to know which concussion patients had brain injury. In the mid 2000s, a new test called diffusion tensor imaging (DTI) was found to be an accurate reflection of brain injury in animal models, but it had not been well studied in humans.
In a pilot study, Bazarian and his colleagues investigated whether DTI could detect axonal damage from a concussion. The DTI scans of six E.D. patients with mild concussions were compared with scans of six non-injured brains. The DTI showed subtle axon swelling, which is known to occur when the axons are over-stretched. The axonal swelling correlated with the patients who were having trouble processing information or remembering things as well as before the injury.
The data from the pilot study enabled Bazarian in 2007 to receive a $1.5 million R01 award from the National Institutes of Health to use DTI to develop a blood test for concussions.
About 40 adults who sought emergency treatment for head injuries were enrolled in the NIH R01 study, along with a similar number of control patients who received treatment for orthopedic injuries. All patients received three sets of DTI scans, blood tests and cognitive tests.
“How does the brain injury we’re picking up on the DTI scan correlate to brain-related proteins in the test and how well the brain functions, and how does that compare to someone who just hurt a wrist? Is the brain injury were seeing in the scan reflected by elevations of brain-related proteins in the in the blood?” Bazarian said. “The scans and blood tests were taken over a month. What happens over that month’s time? Does the brain injury go away?Â Does it get worse? We’re asking pretty fundamental questions about concussion.”
Bazarian and his colleagues are still analyzing the data. During the study, however, they discovered limits to their project.
“We were comparing E.D. patients with concussions and controls who were unrelated to them,” Bazarian said. “However, there is so much variation in the brain structure from person to person that it was hard to know if the group differences were due to injury or just natural variation. This variation creates an obstacle to analyzing data using group comparisons. We wondered how we could get around this obstacle. That’s when athletes came to mind. Athletes are unique in that they give us the opportunity to look at the brain before injury and compare that to its appearance after injury. This helps reduce much of the variation that clouds analysis if brain images using group comparisons.”
An unsettling football finding
Nine Rochester area high school athletes and six students as controls volunteered to take part in the research funded by the Medical Center’s Center for Aging during the 2006-2007 sports season. Among the nine athletes, who recorded their estimate of hits in diaries, only one was diagnosed with a sports-related concussion that season. Measurements showed many changes in the brain of the player with the diagnosed concussion.
“The control group had no damage, which was expected because they were not engaged in sports of any kind,” Bazarian said. “What was surprising to us was that the eight other athletes also had damage. They never suffered a concussion but the DTI scans showed damage, and this damage correlated to the number of times they say they got hit. The more they said they were hit, the more damage we saw on the scans.”
The finding unsettled Bazarian and his collaborators.
“We thought about the hundreds of thousands of youths playing football – from Pop Warner to high school and college teams – getting hit in every practice and in every game,” he said. “It’s one thing to assert that brain injury results from frank concussions. That’s a big problem, but relatively manageable in scope. It’s quite another to assert that brain injury occurs in every athlete undergoing repetitive head hits, whether they have a concussion or not. That would be a major public health problem. We felt we had to chase this as fast as we could.”
Bazarian and his collaborators successfully applied to the National Football League for funding for research that would provide more precise and more definitive information about chronic repetitive head hits and brain injury. Ten University of Rochester football players agreed to wear specially designed helmets with sensors that detect the number of hits a player receives and the velocity and angle of the hits. Each player received a DTI scan before the season began, after the season and then after six months. None of the 10 players suffered a concussion, but the hit statistics were significant. The player with the most in the season had 1,850 detected hits. The lowest number of hits was 500.
“All the players, including the one with the most the most hits, are OK clinically, although we have not yet analyzed the DTI scans,” Bazarian said. “But the issue is not how they are doing now. It is how they will be doing years from now. Does the low-level brain injury we expect to see on the scans build up with year after year of playing to form the substrate for cognitive problems down the line? Or does the injury go away with rest? These are fundamental questions we are asking, but they could give us insight into the development of chronic traumatic encephalopathy we’re been seeing in NFL players.”
The traumatic brain injury research group at the Medical Center includes Bazarian, Tong Zhu, Ph.D., research assistant professor of imaging sciences, Jianhui Zhong, Ph.D., professor of imaging sciences, Brian J. Blyth, M.D., assistant professor of emergency medicine, and Jason H. Huang, M.D., associate professor of neurosurgery.
The researchers now are following about 300 University of Rochester and Rochester Institute of Technology athletes, conducting detailed tests, taking blood samples and performing scans when they are injured. Bazarian believes he and his collaborators are very close to reporting a verifiable blood test for concussions.
Bazarian also is part of the Medical Center’s sports concussion program, with Mark H. Mirabelli, M.D., and E. James Swenson, M.D., both assistant professors of orthopaedics and family medicine. He sees at least 10 patients a week and the number is growing.
“I use my research experience when I talk to families,” Bazarian said. “I tell them there may be a link between concussions and neurodegeneration. That can be scary to hear, but it is important to know. But we have to tighten and better define that link to describe what happens to an athlete during a career or a soldier who is subject to multiple bomb blasts and how and whether they develop dementia. Then we can investigate whether there is a point where you can stop playing and not develop dementia and whether there is a point where we can intervene.
“I believe chronic repetitive hits is the real public health problem, the real threat to the neurologic viability of the brain. But the blood test is a first step. We can’t say what will happen 10 years from now if we don’t know what has happened to you now, if we don’t know if you have an injury to begin with. This is so fundamental. We can’t really skip over it. We can’t talk about preventing a major public health problem until we know who is getting injured in the first place.”
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