Michael L. Alosco (left) and Thor Stein are among the BU CTE Center researchers launching a major new study, Bank CTE, to accelerate efforts to diagnose the neurodegenerative disease in life.

CTE Series: Part 2

“It Will Make CTE a Treatable Disease”: The Race for a Diagnosis in Life

CTE can only be diagnosed after death, but BU researchers are pushing closer to a breakthrough—one that could give patients answers before it’s too late

When you’re not feeling yourself, you hope your doctor can provide some answers. Maybe they can tell you what’s wrong, why it’s happening, and what can be done about it. Or, if they can’t zero in on a diagnosis, perhaps tests—blood work, scans, samples—can help fill in the gaps.

But what if a diagnosis never comes? What if you remain a medical mystery? For those worried that they might have chronic traumatic encephalopathy (CTE), a neurodegenerative disease caused by repeated hits to the head, a definitive resolution may remain out of reach.

CTE has become synonymous with collision-heavy sports like football and linked to a jumble of symptoms—memory loss, confusion, aggression, poor impulse control, slow movement, and more—but there is currently no way of diagnosing it in life. The only way to confirm if someone had the progressive disease is to examine their brain after death. That’s not much consolation if you suspect you or a loved one is suffering with it today.

In an age when brain scans can help identify Alzheimer’s disease, blood tests can spot cancer, and a clinical interview is all it takes to assess many psychiatric disorders, why does identifying CTE in the living remain so elusive?

“That’s a complicated question,” says Thor Stein, a Boston University Chobanian & Avedisian School of Medicine associate professor of pathology and laboratory medicine. He points to that long list of symptoms, which makes it easy to confuse CTE with a host of other conditions. “It’s like a lot of neurodegenerative diseases—Alzheimer’s, too, has been difficult to pin down and definitively diagnose. I think it’s harder for CTE because it’s rarer.”

But with a clearer picture of how to diagnose CTE in life, researchers could turn their attention to studying potential treatments and better prevention options—though some of the latter are already clear, like changing the way certain sports are played to reduce head impacts.

At the BU CTE Center, home to one of the largest tissue banks in the world dedicated to studying traumatic brain injury, researchers are pushing closer to a lifetime diagnosis. By analyzing the brains of deceased contact sports athletes and armed forces personnel, they’ve shown how CTE changes the brain, messing with its proteins, wiring, and structure. “By looking at the brains, by examining the tissue after people pass, we’ve been able to identify what the pathology is, where it occurs,” says Stein, who’s also director of molecular research at the CTE Center.

Now, with a major new study, Bank CTE, the center will be looking for clues to the disease in 1,000 living participants. One focus: Can they uncover traces, or biomarkers, of CTE in blood that could one day be spotted with a simple test?

Researchers will follow people aged over 40 who’ve played contact sports or served in the military, surveying their health, taking blood samples, then studying their brain after death.

“We can correlate what we find in terms of the blood and the surveys with what we actually find in the brain—the ground truth,” says Michael L. Alosco, a BU medical school associate professor of neurology. “That’s hopefully the best way to validate the signs, symptoms, and biomarkers of different diseases like CTE.”

According to Chris Nowinski, cofounder and CEO of the Concussion Legacy Foundation, a lifetime diagnosis would be a game changer.

“That would be the most important inflection point in this discussion,” says Nowinski, whose foundation is a longtime partner of the CTE Center. “It will let people know where they stand. It will let people know the public health burden of this disease. It will make CTE a treatable disease. It will provide endpoints we can measure interventions against.”

Why CTE Can’t Be Diagnosed in Life—Yet

If scientists have a fair idea of CTE’s symptoms and causes, it’s perhaps surprising that someone at risk—say, a former hard-hitting pro football star who’s concerned something is wrong—can’t be diagnosed: football career + memory loss + poor impulse control = CTE. The trouble for clinicians and researchers is that most of CTE’s symptoms aren’t unique to the disease.

“A lot of the symptoms overlap with diseases like Alzheimer’s, psychiatric disorders, or sometimes even more rare degenerative diseases, like frontotemporal dementias,” says Stein. “The heterogeneity of the symptoms makes it very difficult to clinically point out, ‘Here’s the pattern that’s specific for CTE.’”

In one recent study of 481 deceased athletes, the CTE Center found that what may have looked like Parkinson’s symptoms in life—tremor, slow movement, stiffness—were actually caused by CTE.

“Neurodegenerative diseases rarely occur in isolation,” adds Alosco, the CTE Center’s codirector of clinical research. “They often occur together and it’s often their combination that drives symptoms.” Although he and his colleagues have seen CTE in more than 90 percent of ex-NFL players studied, they’ve also discovered football brings a greater risk of a host of other disorders, from amyotrophic lateral sclerosis (ALS) to cognitive impairment.

Scrutinizing MRI Scans and Blood Samples for Signs of CTE

The disease’s inscrutability doesn’t mean researchers haven’t made progress. BU experts have charted the distinctive marks, or pathologies, CTE has left behind in the brain postmortem, such as degenerated tissue and the buildup of an abnormal protein called tau. And knowing what the disease looks like in the brain, says Alosco, is a crucial first step on the path to diagnosing CTE in life.

“It’s a complicated process,” he says, “but we have the framework of Alzheimer’s disease to follow, where you first have to learn what are the specific signs and symptoms, then identify a biomarker that can help detect the biological processes that are going on in the brain.”

Today, spinal taps and magnetic resonance imaging (MRI) are key tools for diagnosing Alzheimer’s, and scientists are close to perfecting a blood test to confirm it; at BU, researchers are even developing AI programs and apps that could diagnose, perhaps predict, the disease. “We’ve been able to utilize the road map and the findings of Alzheimer’s research—which has had many decades of study—to accelerate our understanding of CTE,” says Stein. “We still have a ways to go, but we’re moving very fast when you compare it to other neurodegenerative diseases.”

In a 2021 study published in the journal Alzheimer’s Research & Therapy, for example, BU researchers showed MRI had the potential to highlight traces of CTE in the brain. They looked at MRI scans from 55 patients who’d later had CTE confirmed postmortem and saw indications of brain shrinkage not visible in healthy controls.

“We found that people with CTE had more shrinkage of the frontal and temporal lobes, as well as [being] more likely to have a tear in the tissue—called the cavum septum pellucidum—that separates the ventricles,” says Alosco. The next stage in that research is to distinguish more firmly the patterns of shrinkage they saw in brains with CTE from patterns seen in brains diagnosed with other neurodegenerative diseases, including Alzheimer’s.

In separate studies, center researchers have also examined blood and cerebrospinal fluid samples taken soon after death in their hunt for possible CTE biomarkers. “We have collected blood from people at the time of death—it’s not ideal, but it can still tell you something, tell you if maybe these pathologies in the brain can get into the blood,” says Stein. “That’s a study we haven’t published yet.” Bank CTE, he says, will take that work to the next level.

Following People in Life

Bank CTE is still in the recruitment phase, but the researchers are excited about its potential, particularly the opportunity it’ll bring “to follow people in life and do a more longitudinal study,” says Stein. He hopes that pairing their existing knowledge of CTE in postmortem brains with more robust clinical data could lead to a breakthrough.

“A blood test and clinical tests taken at some point in life, then matching those with the pathology to see if we can predict what might develop in the brain years before significant symptoms,” says Stein. “I think that’s the way we’re going to be able to move forward.”

That work might also be fast-tracked by advances in artificial intelligence and machine learning, which Stein says could help them evaluate more data and spot new patterns.

Both Alosco and Stein enjoy watching sports—and are former players themselves. Alosco played lacrosse, Stein football.

“A lot of my passion comes from playing sports and being a sports fan,” says Alosco. “So, doing the work to hopefully create a future that’s safer for all athletes—that’s a motivating factor for me.”

But what about those suffering with symptoms today and wondering if they have CTE? Is there any hope, any relief, for them?

“We have a lot of patients on the younger side, and they have a lot of psychiatric symptoms,” says Alosco. “And we always stress, we’re not sure what’s causing those symptoms, but we can manage them, we have treatments for them. We really focus on what we can take care of.”

Bank CTE is funded by the National Institute of Neurological Disorders and Stroke and the National Institute on Aging. The study is recruiting people aged over 40 who played an organized contact or collision sport or served in the military, as well as control participants. You can check your eligibility and sign up online.