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Neurology Now:
doi: 10.1097/01.NNN.0000451324.82915.54
Features: Traumatic Brain Injury

Tracking Traumatic Brain Injury: What new biomarkers may reveal about concussion over the short and long term.

Shaw, Gina

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If you fall from a ladder and hit your head, which test can definitively tell the doctor whether or not you've sustained a traumatic brain injury/concussion?

  • 1. A computed tomography (CT) scan
  • 2. A magnetic resonance imaging (MRI) scan
  • 3. A computerized neurocognitive test

The answer? None of the above.

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Despite years of research into traumatic brain injury (TBI), the tests currently available to neurologists, emergency physicians, and other experts can't reliably identify who has sustained a TBI after a blow to the head, and who has not. (See box, “Traumatic Brain Injury: The Basics.”)

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Traumatic Brain Injury: The Basics

What is traumatic brain injury?

Traumatic brain injury (TBI) occurs when a sudden trauma—such as a violent blow or jolt to the head or body—causes damage to the brain. TBI can be caused by closed head injury (when the head suddenly and violently hits an object but the skull remains intact) or by penetrating head injury (when the object pierces the skull and enters brain tissue). The most common form of TBI is concussion, caused by a bump, blow, or jolt to the head that can alter the way an individual's brain normally works. It can also occur from a fall or a blow to the body that causes the head and brain to move quickly back and forth.

“Concussions are caused by a rapid acceleration and deceleration of the head. This is commonly caused by an impact to the head, but there doesn't have to be impact,” says Michael Lipton, M.D., Ph.D., associate director of the Gruss Magnetic Resonance Research Center at Albert Einstein College of Medicine in New York City.

“Think of the brain as sitting inside the hard skull, floating in fluid. If that brain is moved quickly enough, it can disrupt the signals between neurons,” explains Jeffrey Kutcher, M.D., member of the American Academy of Neurology (AAN), director of Michigan Neurosport, and associate professor of neurology at the University of Michigan.

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What are the symptoms of traumatic brain injury?

With mild TBI, the individual may lose consciousness for a few seconds or minutes, but not always. The person may also continue to feel dazed for days to weeks after the injury. Additional symptoms may include trouble with memory, attention, concentration, or thinking; confusion; headache or lightheadedness; blurred vision or tired eyes; ringing in the ears; fatigue; behavioral or mood changes; or altered sleep patterns.

Moderate or severe TBI may causes the same symptoms, but headache may persist or worsen. In addition, the person may experience repeated vomiting or nausea, dilation of the pupils, numbness or weakness in the extremities, inability to wake from sleep, slurred speech, loss of coordination, increased confusion, restlessness, and agitation.

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What causes traumatic brain injury?

The most common causes of TBI in people under 75 are automobile, motorcycle, or bicycle accidents. Falls are the most common cause in people over 75. Nearly one-fifth of all TBIs are due to violence (such as firearm assaults or child abuse) and about 3 percent are from sports injury. Half of all TBIs involve alcohol abuse.

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How is traumatic brain injury treated?

In the case of severe TBI, call 911 so that a trained medical professional can stabilize the person to avoid further injury. For a mild brain injury, the only real treatment is rest. The person should be monitored continuously for any changes or worsening symptoms and may require follow-up appointments with a physician. People with moderate to severe TBI should receive rehabilitation that may include physical therapy, occupational therapy, speech and language therapy, physiatry, psychology and psychiatry, as well as social support.

SOURCES: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE, MAYO CLINIC, NEUROLOGY NOW

“We're still stuck at step one, even in 2014,” says Jeffrey Bazarian, M.D., M.P.H., associate professor of emergency medicine, neurology, and neurosurgery at the Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY. “When someone experiences a blow to the head, the way we diagnose him or her with a TBI is by asking, ‘Did you get knocked out? Is there a period of time you don't remember?'” (But see “The Latest Concussion Research,” page 12 of this issue, for a potential improvement in diagnosis using a vision-based test.)

What about a CT scan? Many hospital emergency departments still use them—a combination of x-rays taken at many different angles to create a cross-sectional image of bones and soft tissue—to rule out a TBI. But CT scans can only show damage to blood vessels, not to nerve cells (neurons) in the brain. Damage to neurons occurring after a mild to moderate TBI—called axonal injury—is not revealed on these scans. “Most mild TBI doesn't appear on CT scans,” says American Academy of Neurology (AAN) member Christopher Giza, M.D., professor of pediatric neurology and neurosurgery at the University of California Los Angeles (UCLA) Brain Injury Research Center and Mattel Children's Hospital-UCLA. “CT scans should really only be relied on if something more serious is suspected, such as bleeding in the brain,” Dr. Giza explains.

In addition, it's almost impossible to know who will recover quickly from these injuries, who will have more long-term symptoms, and who will go on to develop more progressive cognitive problems, such as chronic traumatic encephalopathy (CTE), a degenerative brain disease found in athletes and others with a history of repetitive brain trauma.

“Traditionally, we thought that people with severe TBI go through a period where they have serious symptoms and may even be comatose, after which they improve,” says Ramon Diaz-Arrastia, M.D., Ph.D., Fellow of the AAN, director of clinical research at the Center for Neuroscience and Regenerative Medicine at the Uniformed Services University of the Health Sciences in Bethesda, MD. “For many people, that is still true. And most of the time, people with milder TBI recover 100 percent. But now we know that some people do not recover fully, and others, after a period of recovery, start to decline cognitively. Some studies indicate that having had even a ‘mild' TBI in early or midlife may increase the risk for dementia in late life, probably at least twofold.”

As we learn more about the long-term risks of repeated TBI, experts say we must identify biomarkers that reveal signs of damage to the brain, indicate whether the brain is recovering or not, and predict who is at risk of long-term decline later in life as a result of a TBI. (See box, “What Is a Biomarker?”)

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What Is a Biomarker?

A biomarker is an objective measurement of either normal or diseased processes in the body. Some biomarkers can be measured in physical samples from the body, such as urine, spinal fluid, or blood. For example, cholesterol is a biomarker for cardiovascular disease, and S100β may be a biomarker for TBI. Other biomarkers are measured with imaging tools, such as magnetic resonance imaging (MRI). For example, an MRI of a woman's breast can be used to measure a tumor's response to chemotherapy, and functional MRI might be used to measure TBI.

A good biomarker has a few important characteristics. It should be:

  • ▸ Safe and easy to measure
  • ▸ Inexpensive
  • ▸ Consistent across men and women and ethnic groups

In December, the National Institutes of Health (NIH) announced that it will fund eight new projects—two large, multi-million dollar cooperative agreements and six smaller pilot projects—aimed at answering some of these questions. The projects are funded by the Sports and Health Research Program, a partnership among the NIH, the National Football League, and the Foundation for the National Institutes of Health.

“We need to be able to predict which patterns of injury are rapidly reversible and which are not. This program will help researchers get closer to answering some of the important questions about concussion for our youth who play sports and their parents,” said Story Landis, Ph.D., director of the National Institute of Neurological Disorders and Stroke, in a statement.

It's not just young athletes and their families who may benefit, but anyone who has sustained a TBI—in military service, from a car accident, or from any other kind of injury.

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CHEMICAL IMBALANCES IN THE BRAIN

Since a mild to moderate concussion does disrupt the brain's structure and chemistry on a cellular level (axonal injury), researchers hope that detecting certain proteins that signal axonal injury can become a reliable test for these injuries.

One such test is already on the market in Europe. A protein called S100β, found in the glial cells that support neurons in the brain, appears to be a reliable biomarker of brain injury. Because this protein is typically found only in the brain, detecting it in someone's blood indicates probable damage to the blood-brain barrier. (The blood-brain barrier, which is formed by tightly-connected cells in the brain, allows some but not all materials in the bloodstream to cross. It protects the brain from foreign substances in the blood that may injure the brain.)

The presence of S100β in the bloodstream can also trigger an autoimmune response. The immune system may see it as a foreign invader and release antibodies that can seep back through the damaged blood-brain barrier, leading to long-term brain damage.

“A test for this protein, marketed by Roche, is now an official part of the Scandinavian guidelines for who should receive a CT scan and who should not,” says Dr. Bazarian. The Scandinavian guidelines for head injury management, published in 2013, note that “studies consistently show that low S100β levels can be used to select patients who do not need a CT scan.” [Disclosure: Dr. Bazarian has received consulting fees from Banyan Biomarkers and Roche Diagnostics.]

The U.S. Department of Defense recently funded a large study of a test for two other proteins that might play a similar role in diagnosing TBI, developed by Florida-based Banyan Biomarkers.

These biomarker tests are mostly useful right after someone has sustained a blow to the head, experts say. For example, they could be used on the playing field to immediately diagnose, with a simple finger-stick, whether or not the defensive lineman who's just taken a bone-crunching tackle that rattled his helmet actually sustained a TBI or not.

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SEEING TBI MORE CLEARLY

Once a person has sustained a TBI, a physician will want to know how well the brain is recovering and what the risk for long-term problems might be. Right now, the primary way they do this is by asking the patient, “Are you still feeling dizzy? Having headaches? Are you more irritable or moody than usual?”

But several types of imaging tests may better measure recovery from TBI—and predict who's at greater risk down the road.

One such test is functional magnetic resonance imaging (fMRI), which measures the activation of various regions of the brain when a person performs a certain task—anything from moving a pinky finger to remembering a series of numbers.

Scientists know that a person with TBI typically has to use more regions of their brain to accomplish a task than someone who has not had such an injury. Let's say you ask two people—one who had a TBI six weeks ago, and one who did not—to remember a list of 10 names. They might both repeat the list of names to you equally well. You might never know, just from listening to them, that there was any difference in what their brains were doing to repeat the list. But an fMRI would.

“While someone with a TBI may be able to complete a task just as well as someone without a TBI, they will use a larger part of the same area of the brain to do it. They may also use other areas of the brain to accomplish it,” explains Stacy Suskauer, M.D., director of Brain Injury Rehabilitation Programs at Kennedy Krieger Institute in Baltimore, MD. “Even if you've had a mild concussion, this appears to be true.”

Dr. Suskauer has used fMRI to study children with mild to moderate TBI within a few months after the injury. She has found that the children who perform best on difficult coordination tasks seem to have linked the attention networks (areas that control attention-demanding mental tasks) in their brains with their motor networks (brain cell pathways that control movement) much more than children without TBI. “We typically describe these children with relatively mild injuries as having recovered because they're doing very well, but the imaging suggests that it is compensatory brain activity that allows them to do so well.”

Now, Dr. Suskauer and her team are starting to look at information from later on in the children's recovery—up to a year after the injury. “Using fMRI could eventually have huge implications for clinical care—such as how we decide if a child is ready to go back to playing soccer or football,” she says. “We'd also like to know what happens after multiple TBIs. Can we predict which children are more likely to have trouble after the next one?”

That's one of the biggest questions about TBI: how can we figure out who is at the greatest risk of long-term damage to their brain function?

In 2013, researchers from the University of Pittsburgh School of Medicine reported that the brains of people with mild TBI showed damaged white matter and elevated levels of amyloid, the brain protein that accumulates into the characteristic plaques of AD. Using an advanced form of MRI known as diffusion tensor imaging (DTI), which Dr. Bazarian calls “MRI on steroids,” the researchers found that these individuals' brains looked very similar to those of people with AD.

“This happens very soon after injury,” says AAN member Sam Gandy, M.D., Ph.D., director of the Mount Sinai Center for Cognitive Health and director of the NFL Neurological Center at the Mount Sinai School of Medicine in New York City. “The difference is that after a TBI, the amyloid tends to be deposited primarily at the site of impact, whereas in AD, it's distributed throughout the cortex [the thin sheet of tissue on the surface of the brain, associated with everything from interpreting sensory input to abstract thought and language] and the hippocampus [the part of the brain that is associated with memory]. For most people with milder TBI, the amyloid appears to clear after a month or so. But we've had a number of patients now turn up with increased amyloid levels even six months later.”

While researchers are not sure if these changes will result in dementia later in life, Dr. Gandy suggests that these patients may be ideal candidates for medications that are already available to reduce amyloid buildup. “These medications have been developed for AD, but the challenge is that amyloid accumulation begins many years before the symptoms of AD begin. That's hard to identify. But if we could spot people with a TBI who have increased amyloid deposition and give them amyloid-reducing therapy, we might reduce their risk of developing AD or CTE later on.”

DTI might also be a powerful way to assess TBI recovery. This type of imaging is particularly good at picturing the brain's white matter, which contains the fibers connecting nerve cells—fibers that tear when the brain twists as a result of a TBI.

“DTI may be able to detect the subtle cellular damage that occurs with TBI and assess whether it gets better or worse with time,” says Dr. Giza. A particular DTI measure called fractional anisotropy shows how organized or disorganized connecting fibers in the brain are. “The higher the fractional anisotropy number, the more organized the wiring is in a particular area of the brain. A lower number shows less organization—the kind of thing that happens after severe TBI. Fibers can become less organized after an injury, then stabilize, and then partially recover.”

But it's still not entirely clear what abnormal DTI findings may mean about a TBI. “At four months after an injury, most patients' symptoms have gotten better, even though they still have abnormalities on DTI,” says Dr. Giza.

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PORTABLE SCANNING TOOLS

Most of these biomarkers are still in the experimental stage, but some may be close to ready for use. One of these is a tool called Ahead M-100, which assesses brainwave activity using a portable electroencephalography (EEG) device.

“EEG has been around forever, but what's limited its use in TBI is having some portable form that you can use, for example, on the sidelines at a football game,” says Dr. Bazarian, who has collaborated with the developers of Ahead M-100 (BrainScope) on a device that's about the size of the signing tablet you get from a FedEx carrier. A cable attached to the device connects to EEG leads placed on the patient's forehead. After a 10-minute reading of electrical activity in the brain, the device compares its findings with a database of thousands of brainwave recordings, from people without and with known TBI.

“Not only is this device good at saying whether you've sustained a TBI or not, it can then track your recovery and see when your brain activity gets back to what healthy people in the database look like,” says Dr. Bazarian. BrainScope recently won an award from General Electric and the National Football League for further study; he predicts it will go to the FDA for approval soon.

Another interesting approach is eye-tracking technology pioneered by Jamshid Ghajar, M.D., Ph.D., chief of neurosurgery at Jamaica Hospital-Cornell Trauma Center in New York City. When a person sustains a TBI, the part of the brain that controls eye movement is thrown out of whack. “You shine a light on the inside of the glasses, the injured person tries to follow the light, and peripheral cameras track eye movement,” Dr. Bazarian explains. Called Eye-TRAC, the device is now being studied by Army researchers to diagnose TBI among soldiers in combat.

“There is so much going on in this field, and a lot that is very promising,” says Dr. Giza. But he cautions that most of it is still in the experimental stage. “There's the potential down the line for it to be very helpful, but right now, outside of a research study, most people will not benefit from tests with all these bells and whistles.”

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FOR MORE INFORMATION

  • ▸ For more Neurology Now articles on traumatic brain injury (TBI), go to bit.ly/1hjZ9SK
  • ▸ For articles on TBI in Neurology Today, go to bit.ly/1q1WxxQ
  • ▸ For articles on TBI in Neurology: Clinical Practice (and a free podcast), go to bit.ly/1kvlktm and bit.ly/QnJo4D
  • ▸ For a patient summary (in English and Spanish) of the American Academy of Neurology's guideline for the evaluation and treatment of sports concussion, go to bit.ly/1nJg9VT

© 2014 American Academy of Neurology

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