The first kickoff of the NFL season will take place tonight. The first tackle will not be far behind. During that event, the brain of both tackler and tackled will slosh against the inside of their respective skulls, setting in motion what might in many years culminate in a unique dementia syndrome that has resulted in the deaths of more than 100 NFL players to date.

It was dubbed dementia pugilistica by the great pathologist Harrison Martland in 1928 but came to be known as “punch-drunk syndrome” for the next eight decades. Today it is known by a different name, Chronic Traumatic Encephalopthy (CTE), and the poster child for the disease is no longer the scrappy pugilist taking his licks in the ring, but the football player taking hits on the gridiron.

CTE is a neurodegenerative disorder, meaning a condition in which brain cells die at an accelerated rate over time. Neurodegenerative disorders, like Alzheimer’s disease and Parkinson’s disease, each have their own classic symptoms, but they often end the same way – in the death of the afflicted. CTE acts differently than other neurodegenerative disorders in that it is characterized not only by cognitive impairment but by significant and often disturbing changes in behavior and mood.

The suicides of several high-profile professional athletes, beginning with NFL player Terry Luther Long in 2005, brought CTE into the public consciousness. And with more attention, more cases came to light. Expanding quickly beyond football, cases of CTE appeared in virtually every contact sport: ice hockey, professional wrestling, rugby, even water polo. But despite a proliferation of cases, research into the mechanisms of this disease has only begun to reveal the true causes and potential effects. Despite almost a century of experience with the condition, the gaps in our knowledge are vast. Here’s what we still don’t know:

We Don’t Know How To Diagnose CTE Until It Is Too late

Examine a piece of normal brain under a microscope, and you will see a field of pinkish uniform material punctuated by darker blue islands in a pattern that looks a bit like banana bread. The pink background is made up of the thousands of tails (axons) of neurons, coursing together to send and receive signals throughout the body. The blue islands are the cell bodies of neurons and their supporting cells known as glial cells.

But examine the brain of someone with CTE, and a new pattern emerges. When revealed by a special stain, dense deposits and tangles of a protein called hyperphosphorylated tau appear inside the neurons. These tangles can appear anywhere in the brain, but seem to aggregate at the base of the brain sulci – the bottom of those wrinkles that give the human brain its distinctive character (and power). These tangles appear to disrupt the neuron and are associated with the eventual death of the cells as well. But whether the tangles are the initiating event that leads to cell death or a marker of a cell going awry for another reason is yet another mystery.

These examinations take place at autopsy. The risks of taking a piece of living brain to make a diagnosis are simply too high. Without a test for CTE that can be used in living individuals, research has been severely hamstrung.

Several scientists are working on this very issue. The most promising approach seems to be to use a special type of brain scan called positron emission tomography (PET). PET scans inject a radioactive tracer into an individual which is designed to bind to a specific substance in the body. One investigatory tracer binds to tau protein, allowing us to see the deposition of these tangles without removing a piece of brain from the body. But to confirm that these tests are valid, we’ll need to scan patients while they are alive and follow-up with the gold-standard autopsy-based test after death. This will take some time.

We Don’t Know Why Tau Goes Bad

Tau protein, in its normal form, is critical for neurons to function. It helps stabilize microtubules, the “railroad tracks” of axons which transport proteins to and from the cell body to the distant axonal tail. Tau is a highly soluble protein – it dissolves easily in water – when it is properly folded. But mi-fold the protein, and it starts to stick to itself. Multiple copies of tau amalgamate creating those characteristic tangles. These proteinaceous globules do not function as they are supposed to and in fact disrupt the functioning of the neurons themselves, perhaps leading to their death.

But what initiates this misfolding event? Tau protein deposition is a prominent feature in several neurodegenerative diseases including Alzheimer’s, Parkinson’s, and Huntington’s diseases. In CTE, greater tau deposition is linked to greater number of concussions and more years of football playing, suggesting that repeated trauma is a precipitating event, but without understanding the real link between trauma and tau, it is unlikely that an effective treatment will be developed.

We Don’t Know How Common CTE Is

A highly publicized study appearing in the Journal of the American Medical Association documented that 99 percent of donated brains from NFL players had pathology consistent with CTE. Less reported data from that study showed that 21 percent of the brains donated by high-school football players and 91 percent of those donated by college football players had evidence of the disease. At face value, these numbers are truly damning. It would be ethically untenable to allow football to continue if one out of every five high school kids who plays has clear evidence of brain damage.

But a phenomenon known as selection bias is at play here. These brains were donated precisely because the individuals showed concerning symptoms before they died. They were selected from the true population of football players in a non-random way. Imagine if we tried to calculate how many cars had dirty oil filters by examining them at a Jiffy Lube – we’d vastly overestimate the true rate.

But because diagnosis can only be made after death we are extremely limited in our sampling. The true prevalence of CTE in American Professional Football Players could be 0.4 percent on the low end, still concerning, but perhaps tolerable. But most researchers suspect the number to be much higher.

We Don’t Know If CTE Is Truly Distinct From Other Degenerative Diseases

Despite the publicity, reported cases of CTE are few and far between. Almost all the case series come from two labs run by expert pathologists. This has led some to suggest that perhaps CTE is not a true disease entity at all. Perhaps the football players were simply suffering from Alzheimer’s disease or another dementia, and these pathologists are reading too much into their history of playing sports.

Anne McKee, a pathologist at Boston University, has collected the largest series of patients with CTE in the world. She is the lead author of that famous “99 percent” paper. I asked her if her team had independent pathologists review her diagnoses. They had not, but she notes that a new consortium promises to do just that – have multiple, independent pathologists make diagnoses based on the same slides in order to determine the rate of agreement. A high rate of agreement will be compelling evidence that CTE is its own disease, distinct from the multitude of other neurodegenerative disorders.

We Don’t Know If New Safety Procedures Help

Football apologists are quick to point out that most of the individuals diagnosed with CTE played football in an “earlier era” where safety was not as big a concern. In modern football, players tackle differently, use different equipment, and are protected by new rules such as those that require a play to be ended if a player’s helmet comes off. But there is little evidence to suggest that any of these changes will make a difference.

A 2014 study appearing in the American Journal of Sports Medicine found similar concussion rates among high school football players regardless of the helmet brand used. Tackling technique may not matter much when, as this NFL study shows, even well-anticipated tackles (such as those that occur during a kick return) can result in concussion.

In the End, We Just Don’t Know If Football Is Safe

We are deep into the realm of motivated reasoning here. Many of us want football to be safe, because we love the sport. While professional players clearly understand that there are risks associated with playing, there is an ocean of difference between knee injuries, broken fingers and a chronic, debilitating and degenerative brain disease. And while professional players are at least compensated financially, the same cannot be said for college and high school players. Calls to ban youth football are rare but increasing. And they will increase more, I suspect, as the science around chronic head injury develops.

It is a defining feature of the enterprise of science to admit what we don’t know. It is also the tendency of scientists to maintain the status quo in the face of uncertainty. Under those conditions, awaiting more data before we engage in efforts to prohibit youth football seems appropriate and reasonable. But personally, I have my doubts. The answers to these questions are coming. When they are answered, will we look back at the decisions we make now with regret?