Blots on a Field? (A modern story of unethical research related to Alzheimer's)

Charles Pillar

Science Magazine

Originally posted 21 JUL 22

Here is an excerpt:

A 6-month investigation by Science provided strong support for Schrag’s suspicions and raised questions about Lesné’s research. A leading independent image analyst and several top Alzheimer’s researchers—including George Perry of the University of Texas, San Antonio, and John Forsayeth of the University of California, San Francisco (UCSF)—reviewed most of Schrag’s findings at Science’s request. They concurred with his overall conclusions, which cast doubt on hundreds of images, including more than 70 in Lesné’s papers. Some look like “shockingly blatant” examples of image tampering, says Donna Wilcock, an Alzheimer’s expert at the University of Kentucky.

The authors “appeared to have composed figures by piecing together parts of photos from different experiments,” says Elisabeth Bik, a molecular biologist and well-known forensic image consultant. “The obtained experimental results might not have been the desired results, and that data might have been changed to … better fit a hypothesis.”

Early this year, Schrag raised his doubts with NIH and journals including Nature; two, including Nature last week, have published expressions of concern about papers by Lesné. Schrag’s work, done independently of Vanderbilt and its medical center, implies millions of federal dollars may have been misspent on the research—and much more on related efforts. Some Alzheimer’s experts now suspect Lesné’s studies have misdirected Alzheimer’s research for 16 years.

“The immediate, obvious damage is wasted NIH funding and wasted thinking in the field because people are using these results as a starting point for their own experiments,” says Stanford University neuroscientist Thomas Südhof, a Nobel laureate and expert on Alzheimer’s and related conditions.

Lesné did not respond to requests for comment. A UMN spokesperson says the university is reviewing complaints about his work.

To Schrag, the two disputed threads of Aβ research raise far-reaching questions about scientific integrity in the struggle to understand and cure Alzheimer’s. Some adherents of the amyloid hypothesis are too uncritical of work that seems to support it, he says. “Even if misconduct is rare, false ideas inserted into key nodes in our body of scientific knowledge can warp our understanding.”

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The paper provided an “important boost” to the amyloid and toxic oligomer hypotheses when they faced rising doubts, Südhof says. “Proponents loved it, because it seemed to be an independent validation of what they have been proposing for a long time.”

“That was a really big finding that kind of turned the field on its head,” partly because of Ashe’s impeccable imprimatur, Wilcock says. “It drove a lot of other investigators to … go looking for these [heavier] oligomer species.”

As Ashe’s star burned more brightly, Lesné’s rose. He joined UMN with his own NIH-funded lab in 2009. Aβ*56 remained a primary research focus. Megan Larson, who worked as a junior scientist for Lesné and is now a product manager at Bio-Techne, a biosciences supply company, calls him passionate, hardworking, and charismatic. She and others in the lab often ran experiments and produced Western blots, Larson says, but in their papers together, Lesné prepared all the images for publication.

The info is here.

Would I Give Aducanumab to My Mother?

Dena S. Davis

The Hastings Center

Originally published 11 June 21

Here is an excerpt:

First, it is not at all clear that the drug works, in terms of affecting cognition and slowing decline. As Jason Karlawish explains in an incisive piece in STAT, crucial scientific steps were missed, and the current data are inconclusive and contradictory. 

Side effects include possible brain swelling and bleeds (which appear to be severe in about 6% of patients), headache, falls, diarrhea, and what Biogen describes as “confusion/delirium/altered mental status/disorientation.”  Wait a minute!  I thought the reason to take this drug was that one already had altered mental status and confusion.

Before someone is even considered eligible for aducanumab, they must take a PET scan to ascertain that they have elevated levels of amyloid and then an MRI to make sure they don’t already have brain swelling. MRIs have to be repeated regularly while people are on the drug. I know perfectly competent adults who are freaked out by MRI’s.  How do you explain this to someone with dementia?  Or do you sedate them, thus adding to the risk? Furthermore, the drug itself is not a pill, but a monthly infusion. 

Put that all together, and it just doesn’t add up. How would my mother’s life change for the better? There is little evidence of the drug’s efficacy. Meanwhile, her peaceful life in her rural home with her dedicated caregiver would now be punctuated by trips to the hospital for MRI’s, and monthly struggles to start infusions in her 90-year-old body, with its tiny veins and paper-thin skin. Aducanumab is apparently best suited to people in the early stages of Alzheimer’s, but even in the earliest stage my mother refused to accept that she had a problem. I cannot imagine successfully explaining that we were taking these measures in the faint hope of combatting a problem she insisted she didn’t have. And in the absence of an explanation she could understand, surely the frequent hospital trips would feel to her like unpleasant, even scary, invasions.

The entire info is here.

A Debate Over ‘Rational Suicide’

Paula Span
The New York Times
Originally posted August 31, 2018

Here is an excerpt:

Is suicide by older adults ever a rational choice? It’s a topic many older people discuss among themselves, quietly or loudly — and one that physicians increasingly encounter, too. Yet most have scant training or experience in how to respond, said Dr. Meera Balasubramaniam, a geriatric psychiatrist at the New York University School of Medicine.

“I found myself coming across individuals who were very old, doing well, and shared that they wanted to end their lives at some point,” said Dr. Balasubramaniam. “So many of our patients are confronting this in their heads.”

She has not taken a position on whether suicide can be rational — her views are “evolving,” she said. But hoping to generate more medical discussion, she and a co-editor explored the issue in a 2017 anthology, “Rational Suicide in the Elderly,” and she revisited it recently in an article in the Journal of the American Geriatrics Society.

The Hastings Center, the ethics institute in Garrison, N.Y., also devoted much of its latest Hastings Center Report to a debate over “voluntary death” to forestall dementia.

Every part of this idea, including the very phrase “rational suicide,” remains intensely controversial. (Let’s leave aside the related but separate issue of physician aid in dying, currently legal in seven states and the District of Columbia, which applies only to mentally competent people likely to die of a terminal illness within six months.)

The info is here.

Is It Immoral for Me to Dictate an Accelerated Death for My Future Demented Self?

By Norman L. Cantor
Harvard Law Blog
Originally posted December 2, 2015

I am obsessed with avoiding severe dementia. As a person who has always valued intellectual function, the prospect of lingering in a dysfunctional cognitive state is distasteful — an intolerable indignity. For me, such mental debilitation soils the remembrances to be left with my survivors and undermines the life narrative as a vibrant, thinking, and articulate figure that I assiduously cultivated. (Burdening others is also a distasteful prospect, but it is the vision of intolerable indignity that drives my planning of how to respond to a diagnosis of progressive dementia such as Alzheimers).

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I suggest that while a demented persona no longer recalls the values underlying the AD and cannot now be offended by breaches of value-based instructions, those considered instructions are still worthy of respect. As noted, the well established mechanism — an AD – is intended to enable a person to govern the medical handling of their future demented self. And the values and principles underlying advance instructions can certainly include factors beyond the patient’s contemporaneous well being.

The entire blog post is here.

Physicians and Euthanasia: What about Psychiatric Illness, Dementia and Weltschmerz?

By Eva Bolt
BMJ Blogs
Originally posted on February 18, 2015

Here is an excerpt:

Concluding, while most Dutch physicians can conceive of granting requests for euthanasia from patients suffering from cancer or other severe physical diseases, this is not the case in patients suffering from psychiatric disease, dementia or being tired of living. This distinction is partly related to the criteria for due care. For instance, some physicians describe that it is impossible to determine the presence of unbearable suffering in a patient with advanced dementia. Other explanations for the distinction are not related to the criteria for due care. For instance, it is understandable that physicians do not agree with performing euthanasia in a patient with advanced dementia who does not fully understand what is happening, even if the patient has a clear advanced euthanasia directive.

The entire article is here.

The article in the Journal of Medical Ethics is here.

Alzheimer's Blood Test Raises Ethical Questions

By Jon Hamilton
NPR News
Originally posted March 9, 2014

Here is an excerpt:

But the biggest concern about Alzheimer's testing probably has to do with questions of stigma and identity, Karlawish says. "How will other people interact with you if they learn that you have this information?" he says. "And how will you think about your own brain and your sort of sense of self?"

The stigma and fear surrounding Alzheimer's may decrease, though, as our understanding of the disease changes, Karlawish says. Right now, people still tend to think that "Either you have Alzheimer's disease dementia or you're normal, you don't have it," he says.

The entire story is here.

How the FDA forgot the evidence: the case of donepezil 23 mg

By Lisa M Schwartz & Steven Woloshin
British Journal of Medicine
Published March 22, 2012

What is the difference between 20 and 23? If you said three, you are off by millions—of dollars in sales, that is—at least from the perspective of Eisai, the manufacturer of donepezil (marketed as Aricept by Pfizer).

A little context helps make the maths clearer. Donepezil, the biggest player in the lucrative market for Alzheimer’s disease treatments, was a blockbuster, with over $2bn in annual sales in the United States alone. But the drug, first approved in 1996, had reached the end of the road: the patent expired in November 2010. Investors call this “going over the cliff,” an anxious reference to plummeting sales as market share is lost to generic competitors. Necessity, however, is the mother of invention. Just four months before the expiry of the patent, the US Food and Drug Administration (FDA) approved a new dose for moderate to severe Alzheimer’s disease: donepezil 23 mg. Is 23 an odd number? Not really, when you consider that you cannot get to 23 mg using the 5 mg and 10 mg doses that were going generic. The “new” 23 mg product would be patent protected for three more years.

Now it was time for the marketing to begin. In addition to their sales force, the manufacturers deployed dedicated teams of “Aricept 23 mg clinical nurse educators” to reach prescribers. They focused particularly on “priority targets”—neurologists and high volume facilities for the long term care of people with Alzheimer’s disease—to promote the idea that “there are no ‘stable’ AD [Alzheimer’s disease] patients—therefore aggressive treatment is required.

The entire story is here.

Thanks to Ken Pope for the information.