Thursday, January 24, 2013

The Ethics of Public Diagnosis Using an Unvalidated Method

The last post covered a new study claiming to identify markers of chronic traumatic encephalopathy (CTE) in living patients using a method called FDDNP PET (Small et al., 2013). Previously, the disease could only be diagnosed at autopsy due to the requirement to process post mortem tissue for the presence of tau protein. The paper made a big splash in the media because the patients in the study were five former NFL football players.

Combining the journal article with two different news reports, I was able to identify the following information about the players and their brains (which are shown in the figure above):
  • NFL1: Fred McNeill, 59-year-old former Vikings linebacker - mild cognitive impairment, experienced momentary loss of consciousness after each of two concussions
  • NFL2: Wayne Clark, 64-year-old former backup quarterback - no symptoms except age-consistent memory impairment, experienced momentary loss of consciousness and 24-hour amnesia following one concussion
  • NFL3: 73-year-old former guard - dementia and depression, suffered brief loss of consciousness after 20 concussions and a 12-hour coma after one concussion
  • NFL4: 50-year-old former defensive lineman - mild cognitive impairment and depression, suffered two concussions w/ loss consciousness for 10 min after one of them
  • NFL5: 45-year-old former center - mild cognitive impairment, sustained 10 concussions and complained of light sensitivity, irritability, and decreased concentration after the last two
ESPN identified two players by name and the others by position and age. The San Francisco Chronicle identified the players by position and symptoms. The actual journal article reported the symptoms along with histories of concussion.

Mr. Clark, who has been doing quite well in his post-football life, was quoted in ESPN:
Clark, now 65, said in an interview that he was exposed to limited contact and sustained only one major concussion during his career. During a 1972 game at Miami, he was holding on a field goal attempt that was blocked and was injured while trying to make the tackle.

Film of the play failed to show how the injury occurred, and Clark didn't remember. "It was a total blackout," he said.

Clark, who ran a Southern California video services business and officiated high school football games after his playing career ended, said he reacted with "interest, not alarm," after being told that he had signs of CTE.

"I don't feel like I'm suffering from any real symptoms at this point, and didn't have any sense of anything going on except normal age-related issues," he said. He decided to participate in the hope that "it could help other people and maybe help me."

What are the ethics of telling Mr. Clark that he has "signs of CTE" after a undergoing a scan that has not been validated to accurately diagnose CTE? It seems unethical to me. I imagine it would be quite surprising to be told you have this terrible disease that has devastated so many other former players, especially if your mood and cognitive function are essentially normal.

One objection I raised previously was that FDDNP is not specfiic for tau; it also labels beta amyloid and prion proteins. If you take a look at the NFL3 brain above, it shows extensive signs of atrophy.1 He is the oldest participant, and his lifetime injuries were the most severe. But it's not clear whether this former player has Alzheimer's disease, CTE, or another neurodegenerative disorder.

ESPN says the evidence in favor of CTE is definitive, however:
CTE found in living ex-NFL players

By Steve Fainaru and Mark Fainaru-Wada 

Brain scans performed on five former NFL players revealed images of the protein that causes football-related brain damage -- the first time researchers have identified signs of the crippling disease in living players.

Researchers who conducted the pilot study at UCLA described the findings as a significant step toward being able to diagnose the disease known as chronic traumatic encephalopathy, or CTE, in living patients.

The SF Chronicle was a little more circumspect:
A clue to brain disorder - before death

By Drew Joseph 

For the first time, scientists think they have detected in living patients a protein that accumulates in the brains of people suffering from chronic traumatic encephalopathy, a neurodegenerative disorder tied to repeated brain injuries that afflicts football players and military veterans.

. . .

The study was limited by the small number of participants, and the scientists could not definitively determine the protein was tau.

That article also quoted an outside expert, UCSF neurosurgery professor Dr. Geoffrey Manley:
More to be done
Researchers cannot be sure if the protein was tau because the chemical marker binds to other proteins as well. Dr. Geoffrey Manley, a neurosurgery professor at UCSF and chief of neurosurgery at San Francisco General, said the study raises interesting ideas but cautioned that the findings need to be verified.

"We need to make sure that all the basic science behind this is solid and we know beyond a shadow of a doubt that we're looking at tau," he said.

Nonetheless, the bulk of the coverage has already diagnosed these men with CTE. It seems that Dr. Gary Small, study coauthor and FDDNP patent holder, has also diagnosed these patients, according to CNN:
"We found (the tau) in their brains, it lit up," said Dr. Gary Small, professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA and lead author of the study, published Tuesday in the American Journal of Geriatric Psychiatry.

What was startling, said Small, was the specific pattern of the tau they found: "It was identical to what's seen in a condition called chronic traumatic encephalopathy, CTE, that has only been diagnosed at autopsy." [NOTE: no, it's not.2]

As I said before, I could be wrong about all of this and maybe FDDNP PET does provide a definitive diagnosis of CTE (the definition of which may need amending). But don't you want to be sure before breaking the news to one of your patients?


1 It's very easy to see enlargement of the ventricles and widening of the cortical sulci on this scan.

2 In post mortem brain tissue, McKee et al. (2012) found neurofibrillary tangles (NFTs) in "focal epicentres in cerebral cortex, usually frontal lobe" in CTE stages I–II. It was not until CTE stages III-IV that they found "High densities of NFTs in thalamus, hypothalamus, mammillary bodies, brainstem." Presumably NFL1, NFL2, NFL4, and NFL5 are not showing advanced signs of pathology, given their mild (or non-existent) symptoms.


McKee, A., Stein, T., Nowinski, C., Stern, R., Daneshvar, D., Alvarez, V., Lee, H., Hall, G., Wojtowicz, S., Baugh, C., Riley, D., Kubilus, C., Cormier, K., Jacobs, M., Martin, B., Abraham, C., Ikezu, T., Reichard, R., Wolozin, B., Budson, A., Goldstein, L., Kowall, N., & Cantu, R. (2012). The spectrum of disease in chronic traumatic encephalopathy. Brain.

Gary W. Small, Vladimir Kepe, Prabha Siddarth, Linda M. Ercoli, David A. Merrill, Natacha Donoghue, Susan Y. Bookheimer, Jacqueline Martinez, Bennet Omalu, Julian Bailes, Jorge R. Barrio (2013). PET Scanning of Brain Tau in Retired National Football League Players: Preliminary Findings. Am J Geriatr Psychiatry, 21.

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At January 28, 2013 7:20 PM, Anonymous Anonymous said...

If you're talking about unvalidated (and undescribed!) methods, I think this is the new winner. I'm more than a bit surprised that it made it into the NY Times.

Dr. Daniel Amen, a brain disorder specialist who has done extensive studies on football players, made the initial diagnosis of Dempsey. He said he was astonished by the amount of damage he noticed in his brain after getting back the results of some scans.

At January 29, 2013 9:02 AM, Blogger The Neurocritic said...

Thanks for pointing out that NYT article, I hadn't seen it. I'm pretty sure Dr. Amen used SPECT for this:

"The emergency that Amen spoke of was visible holes, three of them, in the front part of Dempsey’s brain."

I guess the article didn't say what type of dementia, because that pattern wouldn't be the most typical of Alzheimer's. At least they didn't say CTE...


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