Researchers have published a study which, they say, confirms the presence of chronic traumatic encephalopathy, or CTE, in a living person for the first time.
CTE — a degenerative brain disease that is thought to be caused by repeated brain trauma including concussions and sub-concussive hits — can currently only be diagnosed through direct examination of the patient’s brain tissue after death. However, scientists have been using PET scans to identify CTE-like patterns in living people for nearly five years, and this case — which was published in the journal Neurosurgery on Nov. 10 — is the first time that one of those scans has been verified postmortem. The confirmation could be a big step toward definitively diagnosing CTE in living people, which could allow doctors and patients to respond to the disease when it matters most.
Using a radioactive tracer called FDDNP, the researchers looked at a PET scan of the subject’s brain when he was 59 years old. The tracer, which binds to a protein called tau, appeared to identify clusters of the protein that are indicative of CTE. At the age of 63, the subject died and the researchers performed an autopsy that they claim has corroborated their findings. Although the subject was not named in the study, his family has confirmed that it is former Minnesota Vikings linebacker Fred McNeill.
Selected in the first round of the 1974 NFL Draft, McNeill played for 12 years in the league. According to the study, he played football for 22 years of his life, although he only had one reported concussion, which occurred in college. After he retired from the NFL, McNeill earned a law degree and began working as a lawyer, but he was dismissed from at least three firms as his performance progressively declined. When McNeill was 61, his wife noticed that he was having trouble performing simple motor tasks like buttoning his shirt or tying his shoes. At age 62, he was diagnosed with ALS, and he died 17 months later.
One of the challenges of studying CTE in living people is that it’s difficult to find subjects, like McNeill, who were at risk for CTE, scanned before death, and autopsied after death. And since tau tracers like FDDNP have only been around for half a decade, there simply hasn’t been much time for the subjects to pass away so the scans can be confirmed.
“It’s hard to find people who have had the exposure, it’s hard to find people that you think clinically on exam have CTE, it’s hard to get them scanned, and it’s hard for them die,” said Dr. Julian Bailes, a co-author of the study. “So, this is the best that science has to offer. This is a single case. That’s the way science begins a lot of times — just a single case.”
Indeed, a single case is exactly how CTE was discovered in the first place. In 2005, Dr. Bennet Omalu (who is also the lead author of the Neurosurgery study) uncovered the disease in former Pittsburgh Steelers center Mike Webster. Bailes, who was a former Steelers team doctor, reached out to Omalu and helped him bring CTE to the public’s attention. Bailes is now the co-director of NorthShore University HealthSystem’s Neurological Institute and the director of the department of neurosurgery, while Omalu is the chief medical examiner of San Joaquin County, Calif., a professor at UC Davis, and a partner in TauMark — the company that is trying to commercialize FDDNP.
Before FDDNP can be approved by the FDA for widespread diagnostic use, the tracer will have to be tested in a phase III clinical trial, which means that Omalu, Bailes, and the other researchers will likely have to confirm hundreds of CTE-positive scans through autopsy. That will require a lot of money — $5 million according to Bailes — although the rest of the framework is apparently in place.
“We have subjects, we have three centers that want to do the scanning, and we have the ability to make the isotope and deliver it,” Bailes said. “We just need the funding.”
Confirming CTE in hundreds of subjects will also require a substantial amount of time, but Bailes believes that it won’t take too long.
“We’d like to get this resolved within the next five years,” he said. “That’s just our projection, but it depends, of course, on several important aspects.”
One aspect is the progressive nature of the disease itself. Although CTE begins with “neurofibrillary tangles” of tau in specific areas of the brain, the protein can spread to many different brain regions when the disease reaches its later stages. That means that the tau pathology in the brain could be significantly more widespread during autopsy examination than it was during the original PET scan, making it more difficult to corroborate the findings. Still, Bailes says the presence of CTE will be apparent either way.
“We believe that, fundamentally, if it’s there on the scan, it’s going to be there when he dies,” he said. “It’s not going to disappear, and it didn’t disappear in this case.”
Another issue is that, unlike more recent tau tracers, FDDNP also binds strongly to a protein called amyloid. Since amyloid plaques are a pathological hallmark of Alzheimer’s disease, critics say that FDDNP could have trouble distinguishing CTE from Alzheimer’s. However, Bailes says that FDDNP’s ability to label amyloid is actually a good thing because 40 to 50 percent of CTE cases include amyloid deposits. He also says that years of PET scanning at UCLA’s Brain Research Institute has proven that FDDNP’s binding pattern is unique in CTE.
“It gives a very characteristic and unique picture which has not been seen at UCLA in, I think, nearly a thousand subjects they’ve scanned,” Bailes said. “So, it’s the pattern, the density of staining, and the location in the brain.”
In the case of McNeill, Bailes and his colleagues found no statistical correlation between the PET scan and the autopsy when it came to amyloid deposition, but that may simply be because he didn’t have any amyloid deposits. They did find a significant correlation when it came to tau, which, according to Bailes, is all that really matters.
“It’s kind of like you want a Coke or a Sprite and you open your refrigerator and you see Coke, so you grab it,” he said. “It doesn’t matter if there’s Sprite there or not. That’s kind of what’s happening in this case.”
Whether or not FDDNP is the best tau tracer is a matter of debate, but according to Bailes, it has the most published research to its name. Ultimately, a phase III trial and the FDA’s response will have to determine its effectiveness as a diagnostic tool.
“We’re very encouraged by what we see,” Bailes said. “We know it has the most experience of any marker. So, we’re encouraged about continuing to do the work, and we hope that we can get a phase III trial to either prove it or not.”
