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What We Know About the NFL's Bogeyman, CTE

Chronic traumatic encephalopathy has been a known condition since the 1920s, but it remains one of medical science's great mysteries.

If you do not repeatedly suffer head trauma, you will not get chronic traumatic encephalopathy (CTE). Unfortunately, that's about it for clear facts about CTE. How many concussions cause CTE? How many sub-concussive hits? Does it matter at what age brain trauma begins? Are there genetic components? How big a role do they play? Why are some NFL retirees cognitively falling apart before 50, while some appear to be high-functioning individuals?


The easiest way to answer any of these questions is with a clear double-blind study. Take a few hundred people, randomize them into different groups, control and record the force and location of the blows, have neurologists analyze their cognitive abilities over the years, and eventually get a look at everyone's brains after they pass away. Of course, that's nearly as immoral as intentionally misleading your employees on the risks they face in employment and then abandoning them to mounting ill health and medical bills.

Read More: The NFL Concussion Settlement Is Pure Evil

Another fact to keep in mind is that CTE is nowhere near new. Medically, we've had a recognized diagnosis for decades now, although it's more nebulous than most. Best to start with the things we absolutely, 100 percent know. Every single known case of CTE was found in an individual with a history of repetitive head trauma. Every single one. While the early literature mostly looks at boxers, it's also seen in football players, hockey players, soccer players, military veterans, abuse victims, and patients with self-harming behavior.

I'll get into what actually happens in your brain, but it'll be easier to start with the clinical presentation. Coming back to that nebulous description earlier, it's worth noting that strictly defining illnesses with behavioral and cognitive components is hard. There are no simple baselines.


While there are a few different proposed criteria for the clinical diagnosis of CTE, they share some significant overlap. All include changes in four domains: mood, behavior, cognition, and motor. These can include depression, irritability, impulsivity, aggression, memory impairment, executive dysfunction, dementia, and chronic headache, among others. All horrible, horrible stuff. The criteria themselves help tease out the specific combinations of these which point to possibly underlying CTE.

The first mention of CTE was in a 1928 paper titled "Punch Drunk" by Dr. Harrison Martland who wrote:

For some time fight fans and promoters have recognized a peculiar condition occurring among prize fighters which, in ring parlance, they speak of as "punch drunk." Fighters in whom the early symptoms are well recognized are said by the fans to "cuckoo," "goofy," "cutting paper dolls," or "slug nutty."

Punch drunk most often affects fighters of the slugging type, who are usually poor boxers and who take considerable head punishment, seeking only to land a knockout blow. It is also common in second rate fighters used for training purposes, who may be knocked down several times a day. Frequently it takes a fighter from one or two hours to recover from a severe blow to the head or jaw. In some cases consciousness may be lost for a considerable period of time.

The early symptoms of punch drunk usually appear in the extremities. There may be only an occasional and very slight flopping of one foot or leg in walking, noticeable only at intervals; or a slight unsteadiness in gait or uncertainty in equilibrium. These may not seriously interfere with fighting. In fact, many who have only these early symptoms fight extremely well, and the slight staggering may be noticed only as they walk to their corners.2


You're likely drawing the connection to Muhammad Ali. Clinically, this is entirely reasonable, but Ali's doctors have long maintained he suffers from Parkinson's disease. I'm not a neurologist specializing in movement disorders, and any clinical differentiation between Parkinson's and CTE is far too complicated to discuss here, but Parkinson's disease, like CTE and Alzheimer's, is a clinical diagnosis that can only be confirmed with autopsy. We'll talk about why in a little bit.

First, it's worth noting a fascinating but morbid discovery that has come in comparing early and modern CTE cases. Turns out boxers and football players display consistently different symptoms. Research has shown that rotational head injury (like when a vicious hook connects with a boxer's chin) does more damage to the midbrain and cerebellum than the acceleration/deceleration trauma of football hits. Midbrain and cerebellum damage lead to Parkinson's disease-like symptoms such as ataxia (wobbly, unsteady movement) and dysarthria (difficulty using the muscles necessary for speech).1 Boxers tend to exhibit Parkinsonism, while football players tend to show behavioral and mood symptoms.

It also appears there are at least two subtypes within modern CTE (meaning non-boxing related). One has mood and behavioral symptoms presenting around age 35 and progressing to include cognitive impairment. The second has cognitive impairment presenting around age 60 which may then progress to include mood and behavioral symptoms.3


So what actually happens to your brain? And why does it require repetitive brain trauma?

I'll try and work from the big picture down. Think of the brain as a huge collection of neuronal cells. These neurons (pictured above) form an insanely complicated and jumbled network—imagine trying to map out deep space at a microscopic level and you've got a rough idea. The impossibly complex patterns arising in the signals flying through these networks run the show. For the system to work, and for you to be you, both the structure and function of these neurons must remain intact. If the structure breaks down and connections are broken, signals get lost and the pattern falls apart.

Neurons hold their shape and form with microtubules, strings of tubulin proteins. It's not unreasonable to picture them as scaffolding. Furthermore, neurons are elongated cells with tube-like extensions. Essential molecules (neurotransmitters, nutrients, etc.) are in a constant flux of production, transport, use, and degradation. Microtubules act as guide-rails for this transport within the cell. The vital importance of these processes is even more dramatically demonstrated as a frequent target of neurodegenerative disease.

Quick aside, this molecular transport process is mind-blowing. These microtubule tracts have little walking proteins which carry organelles and all kinds of things along. Watch this video, it's a minute long:


Throughout the brain, a small protein called tau can be found bound to tubulin, both promoting assembly and stabilizing structure by cross-linking microtubules within bundles. Tau protein plays the major role in CTE development once the brain trauma component comes into play.

Then we introduce brain trauma. Sudden acceleration/deceleration trauma deforms individual cells and alters membrane permeability, ion channels, ion flow, and blood supply. This is a major problem. Ion flow (positively charged sodium in this case) across membranes is the driving force of signal encoding, transportation, and eventual cerebral processing into our thoughts, actions, sights, scents, etc. Working normally, blood brings energy and supplies to these cells which then use a system of channels, ion flow, and membrane pumps to both send messages and reset the system to baseline to prepare to send more.

The mechanical force of brain trauma hijacks this system, but not in any recognizable pattern. Cells stretch, small vessels rupture, small neurons tear, ions are released en masse, and the system breaks down. To attempt and correct these new imbalances, membrane pumps kick into high gear, which ramps up glucose metabolism (think of this as energy requirement).6 This particular supply and demand problem is hypothesized to be a contributor to the mental symptoms after a concussion. Traumatized regions need more energy to try and render themselves functional again, and this same trauma has disrupted blood supply. Until the ion balance and efficiency of the signaling system is restored, a region of your brain isn't as good at its job. I should note, your brain staggering back into shape is a best case scenario. If these cells die, that's it. No replacements.


Now, repeat that trauma over and over again: some huge hits, more moderate hits, and a lifetime of small hits. Then… something happens. And tau protein begins to pathologically aggregate in sheets within cells. This gap in knowledge explains some of the oddly vague speech you'll hear some people, especially medical professionals, use concerning brain trauma, concussions, and CTE development. We don't know exactly how the acute damage of these impacts, repetitively and over time, develops into the later pathology. Again, we do know that every time we've seen the clinical symptoms and confirmed CTE in autopsy, the patient had a history of repetitive brain trauma.

Tau deposition begins perivascularly (next to blood vessels) and deep inside the grooves on the surface of the brain. This deposition leads to neuronal death and gliosis (think of this as brain scarring). Remember, tau protein stabilizes microtubules, and therefore neuronal function. We need this protein fulfilling its role.

This cross-section is a visually dramatic case, but still. Look at that. This late stage of degeneration shows widespread neuronal loss, enlargement of the ventricles (the empty spaces near the middle of the brain which hold cerebrospinal fluid), and a variety of equally devastating but not as easily described damage.

You can't discuss CTE without talking about the NFL's longstanding habit of denying or downplaying the dangers of head trauma. Please read Deadspin's thorough coverage of the NFL's historical denials of concussion science and Patrick Hruby's ongoing coverage of the debacle that is the NFL's offered health care settlements (I only linked Hruby's most recent, but all of his settlement coverage both here and at Sports on Earth should be required reading). Remember, especially while reading Deadspin's rundown linked above, that we've had medical articles in major journals concerning CTE since the 1920s.


Despite all this, we really don't know enough. The NFL is right to say there's much to learn and clarify, but drawing all the wrong conclusions (shockingly, their conclusions tend to save them a pile of money, deemphasize the long-term risks of concussions, and shaft retirees' health care). What we really need is prevalence values and an accurate way to diagnose CTE while a patient is still alive.

Prevalence refers to the percentage of individuals within a given population who have a disease (for example, you could have prevalence of heart disease in smokers, diabetes in the morbidly obese, arthritis in those older than 80, really anything in any group). We need to know just how many NFL retirees actually have CTE. Once we have this data, we can start teasing out which traits, comorbidities, and historical trends affect the likelihood of CTE development following repetitive brain trauma.

This kind of "hold on everybody, calm down, we don't know enough" mindset has been brought up before concerning CTE (excellently here by Dr. Matt McCarthy) and it's very easy to see why it gets people riled up. If you don't read carefully, it sounds a lot like the NFL's version of "hold on everybody, calm down, we don't know enough" and can be easily misunderstood as the vague "we don't know FOR SURE it's football" defense. The medical concern here is that, without prevalence data, the unprecedented public attention being heaped on CTE can actually be harmful. We've seen some horrible, tragic cases. Wonderful, caring human beings whose families, and then the rest of us, watch them fall into a chaotic mix of depression, impulsivity, aggression, confusion, and occasionally suicide.


While CTE makes for an easy armchair diagnosis in such cases, roughly 20 percent of people suffer from a major depressive episode at some point in their lifetime—regardless of any history of brain trauma or lack thereof. That's 1 of every 5 people spending at least two weeks with some combination of depressed mood most of nearly every day, loss of interest in previously pleasurable activities, significant weight loss, insomnia/hypersomnia, psychomotor agitation/retardation, fatigue, feelings of worthlessness or excessive guilt, inability to concentrate, and recurrent thoughts of death. Furthermore, recurrent concussions have also been linked to depression later in life in NFL players.5

This raises some countervailing possibilities: What if CTE's prevalence is only 1 percent? What if it's .1 percent in those who play less than 4 years? It might be 20 or 50 or 100 or 1,000 times more likely that an NFL player is experiencing a major depressive episode rather than CTE, Alzheimer's, or another deeply terrifying possibility. It may be that he could see his primary care doctor, learn about depression, receive the same treatment as millions of others, and that his entire situation would turn around. But instead he looks around and sees nothing but CTE this and Alzheimer's that, and the fear and uncertainty can make seeking treatment a seemingly insurmountable obstacle.

We just don't know enough.


In response, there's usually a chorus of "Look at the stats though! Boston University's phenomenal CTE center has found CTE in damn near every brain they've examined posthumously." The problem here is both small sample size and selection bias. We're learning tons of invaluable information from the phenomenally important work they've been doing, but it is irresponsible to extrapolate prevalence from that data.

The next big step forward will be in vivo (meaning in a live person) imaging of tau protein deposited in the brain. We will learn from watching CTE's development and begin screening at-risk populations. This could eventually lead to better screening, diagnosis, and ways to follow treatment efficacy. I'm getting way ahead of myself here, but progress is being made.

There's a considerable amount of neuropathological overlap between CTE and other neurodegenerative disorders. Alzheimer's, frontotemporal lobe degeneration, Down's syndrome, Guam Parkinsonism-dementia complex, progressive supranuclear palsy, and corticobasal degeneration all share with CTE pathological accumulation of tau protein.5 This means that further advances in imaging will both have implications for diagnosing and treating a myriad of diseases and be more complicated. While these diseases all have distinct patterns of tau deposition and neuronal damage, the more similar they are, the more accurate and detailed imaging data must be to differentiate between them.


We look in living people's brains all the time. We can scan your brain and quickly have a 3-dimensional model of the network of blood vessels supplying your brain. Why don't we just look at the pathological tau protein? Attach some fluorescent or irradiated tracer or look really carefully at an MRI? Doctors are guilty of this way of thinking, maybe even more so than most people. We assume the PhD nerds will take care of it. This next bit will get a little complicated, but bear with me; the reasons tau visualization is especially difficult are fascinating.

Tau protein aggregates form intracellularly and are found in six different isoforms (or subtypes). These isoforms undergo further modifications, introducing even more variety. Remember, all healthy brains have tau proteins bound to microtubules. Our hypothetical ideal tracer needs to pass through cell membranes easily, bind only to pathologically deposited tau in its many different forms, and do all of this without harming a patient. Not at all easy.

However, once we do start successfully visualizing disease progression, we can include the various clinical evaluation criteria. These two can then be compared to brain tissue at autopsy, and fine-tuned until we can accurately identify and follow degeneration as it progresses. Hopefully, this will allow us to improve treatment efficacy both with individualized treatments and more accurate prediction, screening, and earlier identification.

None of this will happen overnight. It's honestly amazing we're as close as we are to figuring this imaging problem out, and the potential applications are expansive. This could be a huge step in our understanding of a vast array of devastating neurodegenerative illnesses.

In the meantime: If you play football and want to minimize your risk of developing CTE, stop playing football.

CTE is a horrible, devastating illness with a clear link to repetitive brain trauma. The scientific community will keep making progress toward identifying and treating this disease. Hopefully, enterprises with billions in annual profits will show a shred of human decency, and go out of their way to support their employees who suffer from not just CTE, but a whole host of crippling ailments. As usual, though, the smart money is on the scientific community stepping up.

1.Baugh, C.M., Robbins, C.A., Stern, R.A., McKee, A.C. (2014). Current Understanding of Chronic Traumatic Encephalopathy. Current Treatment Options Neurology. 16:306.

2.Martland, H.S. (1928). Punch Drunk. JAMA. 91:1103-1107.

3.Stern, R.A., Daneshvar, D.H., Baugh, C.M., Seichepine, D.R., Montenigro, P.H., Riley, D.O., et al. (2013). Clinical Presentation of Chronic Traumatic Encephalopathy. Neurology. 81:1122-1129.

4.Sendek, A., Fuller, H.R., Hayre, N.R., Singh, R.R.P., Cox, D.L. (2014). Simulated Cytoskeletal Collapse via Tau Degradation. PLOS ONE. 9(8): e104965.

5.Villemagne, V.L., Okamura, N. (2014). In vivo tau imaging: Obstacles and progress. Alzheimer's & Dementia. S254-S264.