Why We Need Better Tests for Concussions

Ken Willis wrote a wonderful series of articles in the Daytona Beach News-Journal entitled NASCAR and Concussions: An Old Problem, a New Concern. He starts with Dale Earnhardt, Jr., but touches on the long history of drivers now suffering the effects of hard hits: Jerry Nadeau, Bobby Allison, and Fred Lorenzen. He also interviews drivers with more recent experience with concussions like Geoff Bodine, Randy LaJoie and Florida racer David Rogers.

Willis mentions that Earnhardt, Jr. recently pledged his brain to science — the only current driver to do so, although Fred Lorenzen also has. Lorenzen is 82 and suffers from dementia and suspected Chronic Traumatic Encephalopathy (CTE). If evidence of CTE is found, he would be the first NASCAR driver with documented CTE.

CTE diagnosis can’t be made until a person has died because the criteria for what constitutes CTE requires examining the inside of the brain. The figure below shows the brain of former University of Texas defensive tackle Greg Ploetz, who passed at age 66 and was found to have stage IV CTE. (There are four stages, the highest number being the most serious.)

A study in the Journal of the American Medical Association (July 25, 2017) reported the status of the brains of 202 men who had played football at professional, semi-professional, college or high-school levels. They found:

• Out of all 202 men, 177 showed evidence of CTE
• Out of 111 NFL players
  • 110 (99%) of them had CTE
  • 79 (71%) had severe CTE

(Some, including the NFL have questioned this study. I’ll explain more about that below.)

They correlated CTE to symptoms like memory loss, attention and language deficit, impulsivity, depression, apathy and anxiety in many of the cases.

But not everyone who has those symptoms has CTE. You can’t diagnose the disease from the symptoms.

What is CTE?

The brown areas on the brain with CTE are tangles of the Tau protein. This protein collects around blood vessels and in the deep creases of the brain. Tau proteins normally help hold our brain cells (aka neurons) together.

The most fragile part of a neuron is the skinniest part: the axon. The axon diameter is about a hundred times smaller than the diameter of a human hair (i.e. an axon is about 1 micrometer is diameter). A hard hit to the head, especially a rotation, damages these structures. The axons are the wiring in your brain, so a damaged axon doesn’t relay signals properly.

Damaged axons release tau proteins, which form clumps and tangles (and yes, those are the technical terms) that mess up the brain’s ability to send and receive messages.

The diagram at right comes from Alzheimer’s News Today. The same tau tangles responsible for CTE show up in Alzheimer’s, too.

Being able to see the disease only at it’s endpoint means we can’t answer a number of very important questions like:

• How do the clumps and tangles form?
• How fast does the disease develop?
• What are the differences between Alzheimer’s and CTE?
• Do treatments work?
• Why do some people who have had repeated concussions never develop CTE? (Willis cites Buddy Baker as an example.)

There are an estimated 3.8 million sports-related concussions annually in the U.S. In addition to sports-related injuries, concussions are major issues for the military and for victims of domestic abuse. Anywhere between 3.2 to 5.3 million people live with the serious, long-term consequences of traumatic brain injury.

You need to know if you’ve have a concussion so it can be treated. It’s especially important to know because having a second concussion while you’re still recovering from a first concussion exacerbates brain damage. We need a fast way to tell when you’ve had a concussion, how serious a concussion it was, and to monitor your recovery from concussion.

Current State of the Art:PET

Positron Emission Tomography (PET) can’t see tau tangles directly, but it can see chemicals that bind to the Tau protein. You can see a significant different in the PET scans from control brains and those of two NFL players. Yellow and red signal high concentration of tau proteins.

Advantages

• PET scans can be done on living people.
• PET scans work at a molecular level. CT (Computerized Tomography) is essentially a highly detailed 3D x-ray. It can screen for bigger issues, like internal bleeding, but it isn’t capable of finding Tau tangles.

Disadvantages

• You need a molecule that binds to tau proteins, but doesn’t bind to other things. It has to bind efficiently enough to detect small quantities of the protein.
• PET requires injecting a very small dose of a radioactive chemical into the body. PET is usually used to diagnose people who have had heart attacks, or are fighting cancer. It’s not a technique to track disease in a person over twenty or thirty years.
• PET scanners (and people who know how to use them and interpret the results) are not ubiquitous. It’s estimated there are only about 400 PET scanners worldwide.
• The radioactive tracer chemical is expensive and difficult to produce and transport because it become non-radioactive fairly quickly.
• PET scans are very expensive.

In short, this technique isn’t useful for a chronic diseases like CTE. Its expense and risk preclude many people from using it.

The Future: Biomarkers

A blood work up usually included Total Serum Protein. This test detects proteins like albumin, which carries medicine and hormones throughout your body and helps with healing, and globulin, which are a group of proteins that are made by you liver and immune system to help fight infection and transport nutrients.

Biomarkers

A biomarker is an objective indication of a medical state. Pulse, blood pressure, albumin level, globulin level are all biomarkers. Some biomarkers are very specific. (The HER-2 marker for breast cancer, for example). Others can indicate more than one possible issue and need the presence of other biomarkers for a definitive diagnosis.

Biomarkers are important because they are not self-reported symptoms. As I’ve written about before, concussion victims can hide symptoms if they don’t want to be parked.

A number of biomarker molecules have been identified for concussions, including proteins and enzymes. Biomarkers are found in three types of fluids:

• Saliva, Urine & Tears
• Blood
• Cerebrospinal fluid

I’ve listed these in the order of easiest to get to hardest to get, but I’ll consider them in order of least-likely-to-be-useful to most-likely-to-be-useful.

Saliva, Urine and Tears

Sounds like the name of a heavy metal band, doesn’t it?

These fluids rid the body of things it doesn’t want. Some proteins produced by concussions may be discarded through one of these fluids. They’re easy to get. The problem is that the concentration of concussion biomarkers is very small and research thus far doesn’t suggest there’s a correlation between how much is detected and how much is actually present in the brain.

Cerebrospinal Fluid

Cerebrospinal Fluid (CSF) is a colorless, clear fluid in the brain and spinal cord. Your body has about 150 milliliters of CSF. A medical professional extracts it by putting a very long needle into the lower spine, under local anesthetic. (You can also take the fluid directly from the brain, but this requires drilling a hole into the skull.)

You have a much higher chance of finding biomarkers in CSF because they are much more concentrated. On the negative side, a professional must collect the fluid. Although tests of the CSF are useful for research and learning about concussion, they’re not likely to become routine tests for concussions.

Blood

One of your body’s greatest defenses makes detecting biomarkers in the blood a great challenge.

The Blood-Brain Barrier (BBB). Biomarkers have a hard time getting from the CSF into the blood. The blood-brain barrier is a semi-porous membrane that keeps circulating blood away from the CSF. The BBB is our brain’s safety fence, letting oxygen, glucose and amino acids in and out, but keeping larger molecules (like bacteria and neurotoxins and proteins) from passing through. You may have Tau proteins in your brain, but they may not be able to get into the bloodsteam in detectable amounts until there has already been significant damage.

Advantages

• Blood is easy to get; it’s relatively painless and doesn’t require a lot of skill.
• There many handheld blood-analysis devices on the market (or soon to come onto the market). These are similar to the glucose testing devices, but can be adapted for other types of analyses. This allows the possibility for a future in which the infield care center had every driver who had a hard hit stick their finger in a device and get an instant reading of whether they need followup testing for concussion.
• There are also much more sensitive tests available in laboratories using standard blood-analysis techniques

Disadvantages

• The brain has about 150 milliliters of cerebrospinal fluid. Only a fraction of the proteins released into the cerebrospinal fluid after a concussion get into the bloodstream. Those that do rapidly diffuse throughout the 4 Liters of blood in your body. Imagine putting a grain of sand in a quart of water compared to putting the same grain of sand in 666 gallons of water.
• The Blood-Brain Barrier
• Measuring the biomarkers is a challenge
  • Assays must be able to measure not only small amounts of the biomarker, but small changes in small amounts
  • You have to be sure you’re measuring the biomarker and not other molecules that look similar to the biomarker.
  • The measurement must be done quickly.

Recent advance, however, suggest that we are on the verge of overcoming these difficulties. There are a number of cases in which the concussion can temporarily disrupt the BBB. That’s not necessarily good, but it may allow biomarker molecules to escape into the blood, which would allow them to be detected.

 i-STAT

Abbott Labs’ i-STAT is a handheld real-time blood analyzer. Hospitals already use i-STAT for routine blood work. Abbott has partnered with the Department of Defense, who have a decade of research into biomarkers they think would be useful to treating their soldiers. In May, DoD gave Abbott a 11.2 million dollar contract to develop a portable blood analysis device that would detect mild brain injury. Over 360,000 service members have suffered traumatic brain injury since 2000.

They hope to deploy a device that can test for one or both of two biomarkers in 15 minutes or less in the next two years.

Track-TBI

While the i-STAT people have zeroed in on two particular biomarkers, the TRACK-TBI team is trying to figure out which biomarkers might be the most accurate for detecting and monitoring concussions by looking at over 3,000 patients in 18 different cities. It’s one of the largest studies of concussion biomarkers. This gets to the question of not just ‘can we measure it’, but ‘what do the numbers we measure really mean for the patient?’

Astrocytes

Astrocytes are star-shaped glial cells that help sustain and repair the central nervous system. Just last October, a UCLA research group found that astrocytes release four biomarkers into the cerebrospinal fluid when they rupture.

Astrocytes connect to capillaries and blood vessels, so it’s possible the biomarkers might make it out into the blood stream due to those ruptures. (Researchers at Boston University are taking advantage of a similar mechanism, using a biomarker protein called CLL11 they think sneaks into the blood stream when tiny blood vessels that carry oxygen into the brain rupture.)

The UCLA group could detect three of the four biomarkers as soon as one hour after injury. They found the biomarkers even when a CT scan showed no macroscopic damage.

BUT…

You won’t be seeing any of these methods used in NASCAR next year. Why?

Hype. I found five or six reports, all on different research, all with titles like “For the first time, researchers may be able to diagnose concussions with a simple blood test.” In an attempt to make the results easy to understand and click-worthy, results are often inflated in the transition from the research paper to the newspaper.

Lab vs. Racetrack. There’s a big difference between a Ph.D. biochemist measuring something in the lab and being able to translate that into the hands of the assistant football coach at Joe Schlobotik High School (or the nurse at the infield care center).

Two years ago, everyone developing devices said they expected they would be available by the end of 2017. The same people are now saying it’ll be another two years. This is how science works, folks. You solve one problem only to find more.

Finding it vs. Knowing What It Means. It’s one thing to measure a biomarker. It’s another thing to understand how to use it. Researchers need long-term (meaning years or decades) clinical trials involving large numbers of people to correlate the amount of biomarker measured to the severity of the injury.

Red Tape/ The FDA must approve any device that claims to make a medical diagnosis. The company will have to prove that an average user can get meaningful, correct results. The first blood tests for concussion will likely be done in a laboratory and not on-site. That slows down the process, but is better than current technology. The same 2015 stories that predicted the hand-held device would be on the market about now also said that this test could be approved within 6 months. We’re still waiting.

What are the Chances of Getting CTE?

We don’t know.

I mentioned that the NFL has taken issue with some of the CTE research. One of the problems researchers acknowledge is that the people most likely to donate their brains (or undergo PET or other tests you can do while alive…) are the ones who believe they’ve had concussion-related damage. It looks really bad when 110 out of 111 brains showed CTE, but it doesn’t mean that 99% of all football players are going to have CTE. The position you play also makes a difference, as do individual variations in your biochemistry. If they’d included brains from people who had no sign of mental degradation, it may have been 110 out of 300. That’s not to say it’s not a problem. It’s saying we don’t know how much of a problem it is.

Researchers need to examine “normal” brains, not just brains from people we’re already pretty sure are affected. We currently have no way to even estimate the chances of getting CTE from a particular sport. We know concussions are worse when they happen to developing brains, and they’re worse if you have a lot of them. But we don’t know how much worse, or if some people are more likely to be affected than others. Youth football participating is going down: some NFL players have walked away. There’s no way to give people informed consent about what they are getting into.

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Related

• NASCAR’s Concussion Policy
• NASCAR Concussions II: A Screening Test
• Driving Concussed