Noisy Response Greets Revised Diagnostic Criteria for AD
Updated 5 August 2010
Following a media call hosted by Alzheimer's Association, The New York Times ran a second story on the revised diagnostic guidelines.
Every newspaper editor knows it: dare tinker with the established look and feel of the paper, and some readers’ initial response will be irritated, even vituperative, no matter how carefully the modernization was done. Something similar—though on a deeper, more serious issue—happened to perhaps the biggest news story of the International Conference on Alzheimer’s Disease, hosted 10-15 July 2010 at the Hawai’i Convention Center in Honolulu. There, three expert groups convened by the National Institute on Aging and the Alzheimer’s Association presented to the assembled research and clinical community draft results of their ongoing, year-long effort to incorporate scientific advances of the past quarter-century into a revision of the current diagnostic criteria for Alzheimer disease (AD). Published in 1984, these criteria predate much of what’s now known about imaging and biomarker research, about genetics, related diseases, and, indeed, the molecular pathophysiology underlying early AD. They are widely used and have never been formally updated.
In Honolulu, a panel of leading scientists addressed nearly 1,000 of their colleagues in the main lecture hall, and then spoke with attending reporters. For its part, the Association had issued a press release and made the revised criteria—all 30 pages of them—freely available to reporters and the public. Even so, the story spun out of control. Some press reports implied, erroneously, that biomarker testing would triple the number of diagnoses starting this fall, driving up costs while needlessly upsetting people who would never get dementia and for whom nothing could be done anyhow. The issue prompted public concern among Alzheimer disease scientists who question the amyloid hypothesis, among medical practitioners, and among psychiatrists who questioned the wisdom of attempting a diagnosis when the person feels no “dis-ease,” i.e., is still at ease.
What happened? Most of all, what were the scientists really trying to say? And what do their colleagues think of the new criteria?
The scientific workgroups had broken the task of revising diagnostic criteria into three parts. One group, led by Guy McKhann of Johns Hopkins University in Baltimore, Maryland, took on Alzheimer’s dementia. A second group, led by Marilyn Albert, also of Hopkins, dealt with mild cognitive impairment due to AD, and a third, led by Reisa Sperling of Harvard Medical School, tackled preclinical AD. Stating that the underlying Alzheimer disease process advances continuously starting with a decade-long or maybe even longer asymptomatic period, the three sets of new guidelines each incorporate biomarker measurements. The guidelines gradually rely on biomarkers more and more the earlier in the disease process one goes. The workgroups posted them on the Web, and invite fellow clinicians to engage in a period of feedback throughout the month of August, before the guidelines are published in a peer-reviewed journal.
The key point of misunderstanding lay in the fact that the biomarker portions in the criteria for all three phases of AD are strictly for research purposes. At this point and for some years to come, the biomarker-driven criteria serve as a conceptual framework for testing and to facilitate therapeutic trials in secondary prevention. They are not meant for community physicians any time soon.
Can You Hear Me?
This was said explicitly. “I want to put a clear bright line between those criteria intended for general use by clinicians, and those criteria intended to be used as research criteria. These research criteria are not even available to us as we go over to the clinic to diagnose! This is hugely important with respect to how the world hears this issue,” Steven DeKosky of the University of Virginia told both scientists and the media. “We want to get out the message that we are trying to find ways to diagnose and treat earlier.” Alas, this was not universally heard. Some news stories mixed up what’s ready for prime time and what’s not, and lumped the recommendations for clinical use in with those for research use. And truth be told, the threesome of presentations at ICAD left this a bit vague. While the entirety of the preclinical criteria are meant for research only, and were unequivocally presented as such, there was less clarity at ICAD about the criteria for the MCI and dementia phases of the disease. For those two, the portion of each set of criteria dealing with biomarkers is also intended primarily for research, whereas their clinical and cognitive portions were indeed written to be broadly applicable in clinics around the country.
“The clinical and cognitive parts of the AD dementia and MCI criteria are for community use now. But throughout all three sets of criteria, anything that has to do with biomarkers has to be evaluated in research,” Albert told ARF.
Those esteemed readers who missed the hullabaloo may want to grab a cup of coffee and catch up on how the issue played in news reports and in the blogosphere before they read on for a summary of the actual ICAD presentation in Honolulu. Here’s a sampling: One article widely cited as accurate appeared in Medscape Medical News, one that caused head-scratching among scientists, and a slew of angry comments appeared in The New York Times. This was followed by a New York Times Op-Ed. Coverage appeared on ABC News, CBS News, Forbes.com (see also guest reply below the blog), and blogs by clinicians, for example, The Health Care Blog. Some of the coverage prompted Maria Carrillo from the Alzheimer’s Association to clarify the purpose of the draft criteria on CNN. And the Association is holding a media briefing today to do so again.
Resistance against these biomedicine-inspired diagnoses stirred in the psychiatric community, as well, for example, an article in PsychiatricTimes. In an invited independent comment, Allen Frances, professor emeritus at Duke University School of Medicine in Durham, North Carolina, called the guidelines suggested at ICAD a “dreadful mistake”; see comment below. Frances lead the American Psychiatric Division’s DSM-IV task force. In an earlier article about unintended consequences of changing diagnostic criteria in mental illnesses, Frances had similarly critiqued the upcoming DSM-V, which has proposed its own separate set of draft diagnostic guidelines for AD. (If this link pulls up a registration wall, Google “Allen Frances, a warning sign”.) In a response on behalf of the DSM-V’s psychosis group, William Carpenter of the University of Maryland School of Medicine in Baltimore notes, “The field is moving towards early detection, secondary prevention, and more robust therapeutic results,” echoing a similar trend in the AD field.
Taken together, public criticism voiced so far argues against moving toward a pathophysiology-inspired definition of AD in the absence of a cure. But some criticism also comes from the opposite direction. For some researchers in the AD field, the revisions did not go far enough, though most scientists find common ground around the concept that early detection in a research setting is a means towards finding better drugs. For more, see Part 2 and Part 3 of this series.—Gabrielle Strobel.
This is Part 1 of a three-part series. See Part 2 and Part 3.
- Revised Criteria for Preclinical AD, Exactly as Presented
- What Do Clinicians Say? Peers Welcome Revised Criteria
No Available Further Reading
New Guidelines for Diagnosing Alzheimer's—Wishful Thinking, Dangerous Consequences
Previously, I have been quite critical of the DSM-V suggestion to introduce a new diagnosis—Minor Neurocognitive Disorder—on the grounds that it would create a large false-positive problem and would lead to unnecessary worry and cost with no useful intervention. Even more ambitious and dangerous are the recently suggested diagnostic guidelines for Alzheimer's created by a panel jointly sponsored by the National Institute on Aging and the Alzheimer's Association. The proposal is a clear case of narrowly focused experts getting far ahead of the available technology to suggest what will be an enormously costly public health experiment with dire unintended consequences.
The goal of the proposed guidelines is laudable—to identify those at risk for Alzheimer's even before they have developed clinical symptoms and to intervene preventively before the damage is done. The suggested guidelines would divide Alzheimer's into three groups of ascending severity and clarity of presentation: 1) preclinical, i.e., no symptoms, but positive laboratory findings; 2) mild impairment; and 3) classic dementia. The guidelines would recommend laboratory studies to make the diagnosis in the first two groups, neither of which is currently considered an official diagnosis.
If we had well-established diagnostic tools to identify preclinical and mild presentations, the guidelines would make great sense. Unfortunately, however, we do not yet have proven tests, and guidelines that pretend we do are premature and reckless. Laboratory studies for Alzheimer's are of recent vintage, tested only in small, selected samples, will probably have huge false-positive rates in the general population, are expensive, and carry medical risks. None is nearly ready to be used in routine clinical practice, particularly in the general population.
To make matters worse (and the suggested guidelines even more ridiculous), there is no effective treatment for Alzheimer's in any of its stages. So finding out that you are (only possibly) at risk for developing Alzheimer's would provide little or no benefit—but would create needless worry, testing, treatment, expense, risk, and insurance and disability issues. The attempt to provide early identification with fallible tests and no effective treatment serves no useful purpose and can cause great harm, not only to individuals, but also to public health policy. Scarce health dollars should not be wasted on what would amount to a frivolous public health experiment. First, let's do the research necessary to prove the tests are sufficiently specific and to find medications that work.
How could such a bad idea be forwarded by renowned experts sponsored by august organizations? I have in earlier pieces written on the tunnel vision of experts in any given area and their natural enthusiasm for pushing the boundaries of their disorder of interest. No doubt the premature emergence of these guidelines results from the great frustration we all feel at the slow pace of development of diagnostic and treatment tools for Alzheimer's. Most of us expected there to be a well-established laboratory test by now, and drug discovery has also been disappointingly slow. My guess is that the guideline makers hope to jumpstart the field by highlighting the potential of early identification. But this is definitely putting the cart before the horse. Guidelines that will have great influence on how people live their lives and how the country will spend limited healthcare dollars must follow well-established science and an inclusive public policy debate, not lead it.
I am convinced from my experience with experts that they act from naïve good faith that expanding their field of interest will be good for patients. They tend to be blind to false-positive problems and societal costs because they are not trained to think in these terms, not because of conflicts of interest. But such naïve goodwill does not motivate the corporations that market drugs and diagnostic tests. There will be an explosion of testing and treatment if these guidelines are approved, much or all of it unnecessary and expensive, some of it downright harmful. The medical/industrial complex will have a field day.
The suggested guidelines for Alzheimer's are not yet official, so there is still hope. Given the great impact they will have on public health policy, they should not become official until there is a wide public policy debate with input and monitoring that reaches beyond the narrow group of experts in the field. Decisions on Alzheimer's are too important to patients and public policy to be made exclusively by experts on Alzheimer's.
Alzheimer's Tests: A Research Tool Not Ready for Clinical Use
In July, panels sponsored jointly by the National Institute of Aging and the Alzheimer's Association presented controversial proposed guidelines for diagnosing Alzheimer's at three different stages of its progression:
1) preclinical, 2) mild cognitive impairment, and, 3) classic dementia. The preclinical panel stated that laboratory testing (i.e., PET or MRI scans, spinal taps, or blood tests) before the appearance of symptoms was meant to be purely for research. But the other two panels seemed to suggest that laboratory testing was ready, or soon would be ready, to be used in routine clinical practice in diagnosing mild cognitive impairment or dementia. Faced with widespread skepticism, the panels held a conference call to clarify their position. As reported by Gina Kolata in The New York Times, there is reassuring new information. The panels recognize that laboratory testing is still only a research tool and will not be recommending that it be included as part of current clinical diagnosis. This makes great sense. All the available tests are at an early stage of development and are not nearly ready for routine use.
Rapid strides are being made in the study of Alzheimer disease, with powerful new methods leading us closer to understanding its causes and mechanisms. But let's not jump the gun and mislead ourselves and the public into the false beliefs that a diagnostic breakthrough has already been made and that a treatment breakthrough is possible in the near future.
It is easy to show that a promising laboratory procedure yields different group mean values when comparing Alzheimer's to a control group. It is difficult to prove that it has sufficient reliability, accuracy, clinical utility, and cost effectiveness to become a useful diagnostic test worthy of use in routine clinical practice. It will require years of testing in very varied populations before we will learn if any of the currently available candidates is indeed the long-awaited diagnostic test for Alzheimer's.
It is understandable that Alzheimer's experts have a strong desire to become preventively proactive. Can amyloid be the early marker of Alzheimer's, in analogy to cholesterol and heart disease? Can early identification and early intervention prevent the ravages of the disease? The problem is that you cannot skip the middle steps. Do the research first—then publish the guidelines.
We should also be cautious in our expectations for a treatment breakthrough. It is possible that learning more about the mechanisms of Alzheimer's may eventually lead to the development of a rational cure or preventive—but it is equally possible that it will not. The general experience in medicine over the past three decades is that an exponential explosion in knowledge about a disease does not often lead to any immediate miracle cure. The lack of success to date in developing medications for Alzheimer's does not inspire confidence. The available drugs—although they have been highly profitable to the drug companies—have little, if any, efficacy for patients. Attempts to develop a new generation of effective drugs have so far failed despite considerable investment. There does not appear to be any low-hanging fruit.
We should have and encourage reasonable hope regarding advances in Alzheimer's. Progress will be steady, but probably much slower than suggested by the recent excitement.
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