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    Medical Researchers Tackle Concussions

    Raised outside Green Bay, Wis., Ann McKee, MD, grew up “an enormous Packers fan.” But when her son entered high school, her husband nixed the idea of his playing football. Not for fear of concussions—this was about 10 years ago—but because of the chance of broken bones, torn ligaments, and damaged joints.

    Today McKee is the director of Boston University’s CTE Center and one of the nation’s most prominent researchers of progressive dementia, known as chronic traumatic encephalopathy (CTE). Given what scientists now know about the association between CTE and repetitive concussions, McKee advises parents to keep their children off the football field.

    “The evidence is just so clear,” said McKee, also a professor of neurology and pathology at Boston University School of Medicine. Youth football, she said, “is a danger to [children’s] brain health. Sports are hugely important for kids—for psychological and physical development, but I would suggest they play another sport.”

    But Uzma Samadani, MD, PhD, whose own son plays football, doesn’t think there is enough information to draw conclusions. Samadani is the Rockswold-Kaplan Endowed Chair for Traumatic Brain Injury Research at the Hennepin County Medical Center in Minneapolis. “No one has actually shown that your child is at increased risk of dementia if they play youth football.... That data doesn’t exist.”

    “In terms of the public health of the country, the biggest question is the one that parents are asking: What are the risks and benefits of allowing their children to play contact sports? We don’t have much data on that.”

    Walter J. Koroshetz, MD, National Institute of Neurological Disorders and Stroke

    Play football or not? The disagreement shows how much researchers still don’t know about concussion and how it may contribute to long-term cognitive decline. Aside from the continual abuse absorbed by boxers or pro football players, there are the concussions and mild head injuries some 2 million Americans experience annually—from elderly walkers to weekend jocks to the nation’s 7.8 million high school athletes. “In terms of the public health of the country, the biggest question is the one that parents are asking: What are the risks and benefits of allowing their children to play contact sports? We don’t have much data on that,” said Walter J. Koroshetz, MD, director of the National Institute of Neurological Disorders and Stroke.

    The connection between dementia and repeated blows to the head was recognized in the 1920s as dementia pugilistica, or punch-drunk syndrome. Boxers with the condition experienced slow movements, speech impairments, confusion, and tremors. Over time, dementia pugilistica was classified as a kind of CTE. But repeated head injuries weren’t taken seriously outside of the boxing ring. “People would have a concussion, and they’d go back and play again,” said Koroshetz.

    In 2002, forensic neuropathologist Bennet Omalu, MD, MBA, MPH, then working at the Allegheny County Coroner’s Office in Pittsburgh, announced that CTE was found in the brain of Pittsburgh Steelers center Mike Webster, who died at age 50. It was the first time CTE had been diagnosed in a football player. Diagnosis is currently possible only by autopsy. This news and subsequent autopsies showing CTE in National Football League (NFL) players began to spark concern “that repeated concussion can have consequences for the child’s health, school performance, and mood,” said Koroshetz.

    Vital research on the disease process and diagnostic tools

    Researchers started to discuss how to best collect meaningful data on the consequences of childhood concussion at an October 2016 workshop at the National Institutes of Health (NIH). At academic medical centers nationwide, investigators are trying to find biomarkers, or objective measurements of a condition, to better identify when a concussion has healed, develop imaging technology to confirm a concussion, and build portable eye-trackers and other monitors to detect concussion on the sidelines of athletic fields.

    Doctors also need a better way to diagnose and characterize concussions to see if there are different responses to interventions, said Wayne Gordon, PhD, director of the Brain Injury Research Center of Mount Sinai in New York. “We need to come up with a biomarker for concussion, and we don’t have that. We say that all brain injuries are different. They’re like snowflakes. But right now we have no way of classifying the injury. So we treat it as if it’s a uniform disease. But it’s not.”

    NIH, with supplemental financial support from the NFL, is funding eight projects to investigate brain injury. Two major projects focus on investigating brain injury resulting from CTE and better means to diagnose CTE.

    McKee is leading one of those CTE studies. One goal of McKee’s project is to expand a “brain bank” from patients who were exposed to both concussions and “subconcussive” injuries. So far, her team has acquired nearly 400 brains; they have diagnosed CTE in about 220 of them.

    “We wanted to understand the underpinnings of the disease at a pathologic level, understand the molecular changes that occur, even in the earliest or the youngest individuals [who] die,” McKee said. “We’re trying to figure out the key processes that cause [the disease] to progress, even though the person stopped being exposed to head trauma, usually years earlier.”

    “In and of itself, [a concussion] is not associated with CTE,” McKee stressed. “There’s no danger from a single isolated concussion or several individual concussions. But what the data is more and more pointing to is that these repetitive subclinical hits, these subconcussions can accumulate as an exposure that is a risk for CTE.”

    Robert Stern, PhD, McKee’s colleague and director of clinical research of the CTE Center at Boston University, this fall announced that technology developed by the biotechnology firm Quanterix detected elevated levels of tau proteins in the blood samples of former football players, opening the possibility that CTE can be diagnosed before death.

    Also this fall, Gordon and colleagues, in a study published in Translational Psychiatry, announced that they had developed a method that may be able to detect CTE in living patients through injecting chemicals that flow into the brain and are visible on a positron emission tomography scan.

    “We need to come up with a biomarker for concussion … we have no way of classifying the injury. So we treat it as if it’s a uniform disease. But it’s not.”

    Wayne Gordon, PhD, Brain Injury Research Center of Mount Sinai in New York

    Gordon, with support from another NIH grant, is studying the possibility as well that a single blow to the head can trigger CTE. He leads a team that is examining several hundred brains of people who suffered a single concussion for signs of amyloid and tau, hallmark proteins of CTE. In addition, the team is following about 80 patients from the Mount Sinai brain injury rehab program who have had a single moderate to severe brain injury. Researchers will examine their brains when they die to see if CTE can develop from a single brain injury.

    Risk in context

    A big challenge in research is assessing risk—the possible outcome for individuals and the likelihood that anything bad will happen at all.

    “There have really been no long-term longitudinal studies of folks who have been concussed,” said Gordon. “So if you are a high school football player or college football player, what happens to you over time?”

    Scientists recently learned that traumatic brain injury (TBI) resembles a chronic disease with long-lasting effects. “We just finished screening several thousand kids who are on probation or in jail in Texas. The surprising thing was not that the prevalence of TBI was high but that in the majority of kids with TBI, their TBI came before any criminal activity. There is one negative consequence right there,” Gordon said.

    A study published in August in PLOS Medicine showed similar prolonged effects from a single head injury. Researchers found that a single diagnosed concussion increased the likelihood that the patients would receive medical disability payments as adults. Patients were also more likely to seek mental health care, less likely to graduate from high school or attend college, and more likely to die prematurely.

    Samadani, who has published research on concussion and eye movement and the ineffectiveness of helmets in preventing concussions, remains skeptical that the risks of playing contact sports are significantly greater than those of engaging in a multitude of other activities. “If you look at other sports that kids do—for example, they ski, they bike, they skateboard. All of those things have risks slightly greater [than those from playing football]. Your child is about 14-fold less safe riding in a car than they are playing football,” she said. “The problem with work from [these pathologists] is that they’re not statisticians or epidemiologists. They’re looking at small numbers of professional athletes without controls and drawing conclusions that are not applicable to amateur youth athletics.”

    A realistic assessment of risk is important, she said, because while the population-scale correlation between contact sports and cognitive decline is tenuous, the benefits of athletic activities are not. “I’m not saying every kid has to play football, but if you really care about the health of your children, we need to be getting every kid in America out there playing sports, 30 minutes a day,” Samadani said.

    Given that kids will get injured, whether in football or another activity, researchers are continuing to look for biomarkers that show when the effects of a concussion have healed. For now, parents have little evidence on which to base a decision. “That’s a personal decision that the parents and the kid have to make,” says Koroshetz. “So to have evidence on when the brain is recovered I think would be really important to know. That’s another area of research we’re interested in pursuing.”