cte: what we don’t know

Sunday, July 31, 2016

The press has not been kind to Gary Bettman this week and this time, the press is wrong. The NHL Commissioner wrote a letter in response to questions asked by Connecticut Senator, Richard Blumenthal, that outlined the league’s position regarding concussion and the long term effects of head injury. The New York Times called out his “reluctance to link hits to the head in hockey with a degenerative brain disease”.  Sports Illustrated wrote of the “refusal to acknowledge a possible link between concussions and CTE has proved to be controversial.”

“I was surprised and appalled, because I thought the response would be more receptive,” Blumenthal told SI.com via telephone from Philadelphia. “I would’ve welcomed an acknowledgement for stronger action and a commitment to determining whether the game is causing these heartrending injuries with such painful consequences, rather than dismissing the link between hockey and CTE.” 

Mr. Bettman’s 24-page letter acknowledged the potential for head injury and concussion in all contact sports and also summarized the medical literature that has yet to prove that chronic traumatic encephalopathy (CTE) is caused by concussion. While it seems intuitive that CTE is caused by trauma, there are major questions that remain unanswered.

Association v. Causation

There is no doubt that there is an association between traumatic brain injury and CTE, but the research is just beginning as to what causes some people to develop CTE and others to be spared. Or have they been? With todays’ science and technology, CTE can only be diagnosed after death by autopsy, and then only if the brain is dissected and special stains are used to look at cells under the microscope. Of the athletes whose brains have been studied, there seems to be a correlation between the many concussions that they had sustained and CTE findings in the lab. Unfortunately, there is a problem with the statistics.

For a cause and effect to be found, brains from different groups of athletes need to be studied:

  • Those who had no concussion history and no signs or symptoms of depression or dementia
  • Those who had no concussion history but developed signs or symptoms of depression or dementia
  • Those who had a concussion history and had no signs or symptoms of depression or dementia.

As of now, researchers have mostly studied those who have had a history of concussion and developed signs of mental illness and/or dementia.

What do we know?

There is evidence that there is a link exists between a severe traumatic brain injury and the eventual development of dementia. There also may be a dose relationship, meaning the more severe the head injury, the more likely dementia becomes a future possibility.  However, there is not necessarily that same link that connects repetitive minor head injuries with CTE. Lots of small concussions does not necessarily equal one major head injury.

…specifically for rTBI (recurrent mild traumatic brain injury), there has been an unavoidable case-selection bias and a virtual absence of control material from uninjured cases in reports of CTE, rendering interpretations of the incidence of this pathology meaningless in the context of exposure to repetitive mild injury. –  Hay J, et al. Annual Review of Pathology. May 2016

While the public is hearing about brain chemistry and anatomy, including tau proteins and neurofibrillary tangles, other research is ongoing looking at other markers of brain injury. These include amyloid deposits, DNA binding proteins, neuroinflammtion, brain white matter degradation and neuron (brain cell) loss. Chromosome research may offer some clues to CTE development, with certain genes more likely to be associated  CTE after a brain injury and others that might injure the brain by activating certain enzymes. 

What don’t we know?

Traumatic brain injury is known to be the biggest risk factor for developing dementia. The question is how much brain trauma is needed to cause CTE.

  • Does it take one or multiple concussions?
  • Are concussions spaced closer together more dangerous? Or does the same damage occur even when they are spaced years apart.
  • Is concussion in children and teenagers more important than later in life? or are their brains better able to adapt and heal themselves?
  • Do brains heal themselves and become pristine after a period of time, or is the concussion damage permanent?
  • Why do some concussion patients develop depression and dementia, while other do not?

The bottom line is that while a relationship exists between head injury and degenerative brain disease, scientific research has yet to prove that concussion causes CTE. There are many next steps for research to take, including being able to diagnose CTE in live patients without having to wait until they die to perform an autopsy. For now, we know that we don’t know a lot.

There are known knowns. These are things we know that we know. There are known unknowns. That is to say, there are things that we know we don’t know. But there are also unknown unknowns. There are things we don’t know we don’t know. – Donald Rumsfeld.

 

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the pathology of CTE

Monday, December 3, 2012

With more and more players suing the NFL for downplaying the risk of head injury in the sport, it seems time that science is slowly catching up to the events in the courtroom. While more than 3,000 players allege that they were kept in the dark about the consequences of repeated concussions, it is only this month that pathologists, doctors who study the dead to teach the living, have published research that starts to categorize the changes in the brain seen with Chronic Traumatic Encephalopathy or CTE.

CTE has made the news recently when structural changes in the brain were discovered at autopsy of pro football players who had committed suicide. Though the symptoms of a punch drunk fighter had been described in the 1920s, the term CTE was introduced in the 19650s. The standards to make the clinical diagnosis were established only a couple of years ago and talked about personality changes with irritability, aggression, depression and increased risk of suicide that would occur a decade after pro athlete had sustained multiple mild traumatic brain injuries. It’s important to remember that mild brain injuries are defined as those where the patient may or may not be knocked unconscious but returns to normal function within a couple of hours and has no bleeding or swelling of the brain.

The latest study of CTE was published in the December 2012 journal Brain, A Journal of Neurology by researchers from Boston University. 85 families donated the brains of their loved ones who had passed away. Not only did the pathologists dissect the brains, but they also spent time learning about the lives that had been lived.  17 brains of patients who had not had a history of concussion were also examined to use as controls. They were looking for the abnormal tau proteins in the brain, a marker for brain damaged associated with head injury. Other markers of CTE included abnormal tangles of brain cells in specific regions of the brain. These could be distinguished from the findings in other brain degeneration diseases like Alzheimer Disease.

The results: In the control group patients with no history of head trauma, no evidence of the CTE protein and abnormal brain cells could be found. Interestingly, 17 of the 85 athletes who had sustained multiple minor head injuries also showed no evidence of CTE on brain dissection. The other 68 athlete brains showed CTE damage.  The more severe the clinical symptoms displayed by the athlete, the more damage found in the brain. The majority of athletes studied were former high school, college or pro football players. As well, more than a third of those wit hCTE also had other degenerative brain illnesses including Parkinsonism and Alzheimer Disease.The findings allowed the researchers to define 4 categories of CTE, with increasing symptoms associated with increased brain damage From the published paper:

Category 1 – headache and loss of attention and concentration

Category 2 – depression and mood swings, explosivity, loss of attention and concentration, headache and short-term memory lossHeadaches, short term memory loss, depression and mood swings

Category 3 – cognitive impairment with memory loss, executive dysfunction, loss of attention and concentration, depression, explosivity and visuospatial abnormalities. 75% were cognitively impaired.

Category 4 – dementia with profound short-term memory loss, executive dysfunction, attention and concentration loss, explosivity and aggression. Most also showed paranoia, depression, impulsivity and visuospatial abnormalities

 

So what did we learn?

  • Chronic traumatic encephalopathy occurs as a consequence of so called minor head injuries. None of the non-athlete patients had any of the brain findings for CTE on autopsy.
  • A decade after the injury, CTE symptoms begin to appear. They may be progressive and over time the most severe consequences include major depression, aggressiveness and dementia.
  • The more severe the symptoms, the more damage found in the brain at autopsy.

And what don’t we know?

  • Why did 17 of 85 athletes with multiple concussions have no symptoms of brain injury, normal brains on autopsy and escaped the consequences of CTE?
  • Is one big concussion worse than numerous small ones?
  • Does resting the brain after an injury make a difference? And how long should the rest period be?

Whats next?

  • Take hundreds of NFL football players and follow them for the rest of their lives, assessing their physical, emotional and psychiatric status.
  • Take hundreds of “normal” people to use as controls and watch them as well.
  • When they die, examine the brains, compare the lives lived to the findings on death and see what’s what.
  • Hope that medicine progresses quickly in the next few years so that the brain can be studied safely while the patient is still alive…and treatment may occur before any damage becomes permanent.

Science moves very slowly. Eureka moments are rare and even when they do occur, the results need to be validated and reproduced. For CTE, once the pathology of the brain can be understood, researchers can work backwards to find out who is at risk for developing the disease and perhaps prevent it. Is there a genetic component that makes an athlete more prone to brain damage, or perhaps it’s a gene that protects the brain. What we do know is that we don’t know. It will be interesting to see  if the courts can explain that to the NFL and the players.

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