This is Part 3 of a nine-part series. See also Part 1, Part 2, Part 4, Part 5, Part 6, Part 7, Part 8, Part 9. Download a PDF of the entire series.
28 February 2012. Thanks to amyloid-binding radiotracers and positron emission tomography (PET), research clinicians can now peer inside the living brain to see senile plaques that were once evident only at autopsy. Now available for research, amyloid PET may be approved for more routine clinical use this year. If that happens, doctors may order amyloid scans for their patients, and some people may demand them. However, it is unclear exactly what a positive scan means for a cognitively normal person, and the evidence for high risk of dementia in MCI patients is still emerging—all while preventive or disease-modifying treatments for AD remain elusive. Should cognitively normal people be told if they test positive for amyloid in the brain? Should they even be scanned? How about people with subtle memory problems? Should only specialists or also primary care physicians be able to order an amyloid scan? Will for-profit clinics sprout up that offer amyloid PET without appropriate safeguards?
Researchers are beginning to put considerable thought into the ethical questions that surround disclosure of a persons’ amyloid status. In light of longitudinal studies that increasingly link brain amyloid to subsequent cognitive decline, they wonder how that emerging knowledge is best handled in the clinic. Questions abound. Who should get a scan and who should be told the results? Is it appropriate to worry people over an illness they may not express for many years and for which there are no good treatment options? Does knowing give some peace to people who already worry because they sense their minds are slipping? If someone is to be told, how can the information be safely delivered? How should potential prevention trial participants be treated differently from patients in routine clinical practice?
At present, none of more than a dozen leading clinician-researchers contacted for this story routinely discloses amyloid status to cognitively normal people. Most researchers agreed that in future, plaque status should only be disclosed when a patient has symptoms, and that any information revealed should be tempered with pre- and post-test counseling. No formal guidelines have yet been issued on the matter, but initiatives are underway to put this consensus in writing in Europe and the U.S. (see below).
However the field decides to deal with disclosure, it needs to do so soon. For now, the original amyloid imaging agent Pittsburgh compound B (PIB) is exclusively used in research studies in which plaque status is almost universally withheld. PIB, labeled with carbon 11, has a short half-life, and is limited in use to centers that have a cyclotron for production and immediate use. But soon, longer-lived agents labeled with fluorine 18 may become available more broadly. One, florbetapir (see ARF related news story), sponsored by Avid Radiopharmaceuticals, now owned by Eli Lilly and Company, is under regulatory review. The company seeks approval of the tracer as a tool to support a clinical diagnosis in people with symptoms of dementia (see ARF related news story), and many researchers expect it to be approved this year.
"Amyloid imaging is probably going to be available soon," said David Knopman of the Mayo Clinic, Rochester, Minnesota. "It would be nice to have a consensus in the expert community about what to say about "positive scans" before that Pandora's box has been opened."
Whom to Tell?
Experts agree that plaque status should be revealed to people who can benefit from the information. Those include the fraction of AD patients who have a questionable diagnosis. Amyloid scans could help support or refute that diagnosis, said Bill Klunk, who co-developed PIB at the University of Pittsburgh in Pennsylvania. As more longitudinal data become available, clinicians may also be able to make better predictions about amyloid positivity in people with MCI, and use the scan to find out whether AD underlies their symptoms. "Most academics would agree that the usefulness of amyloid imaging would be in the differentiation of progressive from non-progressive MCI," said Giovanni Frisoni of the San Giovanni di Dio Fatebenefratelli Hospital in Brescia, Italy.
As a general rule, experts at this point counsel against scans for cognitively normal people. Data from current longitudinal studies, such as the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL), indicate that perhaps a third of cognitively normal people aged 60 and above are PIB-positive (see Rowe et al., 2010). In the ADNI study of older adults, that number is closer to 40 percent (see ARF related news story); numerous other aging cohorts have recently added amyloid imaging and are confirming increased incidence of amyloid positivity with advancing age. However, none of the studies has been ongoing long enough to determine whether these healthy amyloid-positive individuals progress to dementia. Therefore, all experts agreed, it is impossible at this point to make amyloid-based risk assessments for cognitively normal people. "We still need more information about what the implications are of a positive amyloid scan or of abnormal CSF AD markers," said Nick Fox, University College London, U.K. Many cognitively healthy people die of other causes with large Aβ accumulations in their brains. It is not clear whether or how quickly plaques become harmful (see ARF related news story). "Many of us feel that if a PIB-positive person were to live long enough, it would lead to cognitive decline, but we really don't know enough details about that now," Fox added.
Experts are concerned that people who test positive for brain amyloid could overinterpret the predictive value of the results, become depressed, make rash decisions—or even attempt suicide. "It is irresponsible in a clinical setting to infer something about cognitively healthy people's clinical course based on their amyloid status—we just don't have the data to support any conclusion," said Reisa Sperling of Brigham and Women's Hospital in Boston. "We are just at the beginning of our understanding," agreed Michael Weiner of the University of California, San Francisco, who leads the Alzheimer's Disease Neuroimaging Initiative (ADNI). "We have got to work as a community to develop proper guidelines."
The lack of an effective therapy that prevents or slows AD makes scan information even less useful for cognitively normal people. Once a treatment becomes available, the situation will change radically, said Klunk. "Then we'll start screening people, tell the ones who have amyloid in their brains, and suggest that they go on this preventive therapy," he said.
The Paternalistic Doctor?
What if some cognitively normal people are concerned about plaques—either because they have subjective memory complaints or a family history—and demand a scan? Some studies are beginning to show that people with subjective memory complaints are often right in their awareness that something is wrong (e.g., Perrotin et al., 2012). Should they be given a scan and its results? Opinion on this question diverges widely. Most clinician-researchers said they would refuse, but some counter that the patient has a right to know.
On rare occasions, participants who received scans as part of research have insisted on disclosure to the point of threatening to force it through a Freedom of Information Act request, researchers said. "Some individuals are extremely determined; they want to be in control of their future and I don't see why they should be denied knowledge of their brain amyloid status if they want it," said Christopher Rowe, Austin Hospital in Melbourne, Australia. "But it is essential that the significance of a positive versus a negative scan is explained clearly," said Rowe. Careful counseling to explain that a positive scan doesn't mean people will get Alzheimer's and a negative scan does not mean they are immune is crucial, most agreed. In the rare exceptions where clinician-researchers disclose, they couch amyloid positivity as a risk factor, not a deterministic finding. Amyloid status is not disclosed to subjects in the AIBL study, on which Rowe is a lead scientist. Other scientists have made exceptions for cognitively normal people with an autosomal-dominant family history of AD, who insisted on learning their status.
Studies of genetic testing related to ApoE and Huntington's disease suggest that people will not necessarily be flooding clinicians' offices for amyloid scans, said Scott Roberts, University of Michigan in Ann Arbor. Roberts is co-principal investigator on the series of REVEAL studies that examine the psychological and behavioral ramifications of disclosing people's ApoE status. "There's a self-selection process—people who come forward for the information tend to be ready to handle it, and people who are more vulnerable tend to stay away in the first place," said Roberts. REVEAL has found no evidence that people are psychologically harmed by a positive ApoE4 diagnosis (see ARF related news story). "People actually fare better than we often expect, assuming we give proper education and counseling support," he said. At the same time, Roberts conceded that the situation might be different for amyloid scans because brain plaque suggests a more imminent problem.
“People fear Alzheimer’s more than heart disease,” said Jason Karlawish of the University of Pennsylvania Medical School in Philadelphia at the Human Amyloid Imaging Conference held 12-13 January 2012 in Miami Beach, Florida. Karlawish specializes in ethical implications of Alzheimer’s research. “We have to respect that fear, and establish a process to safely and effectively communicate a predictive diagnosis. A stepwise process for disclosure is key.”
In fact, after pre-test counseling, many people decide they do not want to know after all, said John Morris, Washington University School of Medicine, St. Louis, Missouri. Morris does not disclose scan results in his studies, but is exploring whether and how to do that in the future. He asks interested research participants whether they would still want to know after considering, for instance, what the results might mean about family members' risk or the ability to purchase long-term care insurance. "Very often, when we start talking about what the implications are for individuals, they begin to reconsider," Morris said. Requests for results may also be curtailed by health insurance coverage for the scan, which may be limited.
Some researchers have already started disclosing scan results to a few study participants. Hermann-Josef Gertz, University of Leipzig, Germany, revealed plaque status to a handful of cognitively healthy patients who, after counseling, still wanted to know. They all seemed to take the results well and showed no adverse psychological effects, Gertz said. He attributes this, in part, to careful counseling that explained the uncertainty of the test, and that Alzheimer's progresses slowly with long, mild stages. "If we try to convey this view of AD, it may be less frightening," he said.
Another research study at the University of Munich in Germany employs counseling and reveals plaque status to participants with MCI if they wish to know it, said Alexander Kurz, one of the researchers involved in this study. Almost universally, these patients cope well with the results, in part because researchers point them toward interventions that may help somewhat: participation in preventative treatment trials, acetylcholinesterase inhibitors, or compensatory strategies to cope with the memory loss. "It doesn’t cause a lot of anxiety as long as you have something you can do for it," said Kurz.
There are catastrophic exceptions that even a careful process cannot prevent, however. At Kurz’s center, a woman with memory complaints insisted on a CSF biomarker test and disclosure even after going through more than six months of counseling. She committed suicide after receiving a CSF biomarker test that suggested Alzheimer's, Kurz said. The patient had a professional education, and a sister five years her senior was institutionalized with advanced AD. She had cleared an evaluation for depression but did not want to live with the disease. Despite this tragic outcome, Kurz takes the view that, in the end, it is a patient's decision to obtain this information. "Ultimately, every patient has the right to know," he said.
Initiatives to Forge Consensus
Several efforts are afoot to develop a framework for a unified approach to amyloid status disclosure. One headed by Gertz and Pieter Jelle Visser, University of Maastricht, The Netherlands, appears most advanced. These researchers are formulating a consensus statement within the European Alzheimer's Disease Consortium (EADC). The statement will outline for clinicians and researchers who should receive amyloid or biomarker testing in the course of diagnosis, and how the results should be used. Gertz, Visser, Frisoni, and other clinicians have discussed the issue, and Gertz has drafted a paper for presentation at an EADC meeting this coming May. The authors plan subsequent journal publication to help get researchers and clinicians on the same page until formal consensus guidelines become available. "This is an attempt to get a first European outline of future standardization," said Gertz.
More scientific study will be necessary to iron out disclosure issues, said Visser. "What we really need is a trial that discloses—or not—biomarker status to see what happens in terms of outcomes such as psychological well-being," he said. Jennifer Hagerty Lingler of the University of Pittsburgh, Pennsylvania, is heading in this direction. In a pilot trial, she is going through the motions of revealing plaque status to people with MCI, without doing any actual scanning. The patients know that it is a mock reveal. Lingler will conduct patient surveys during this study, asking patients and their study partners such things as, among others: Which counseling methods are most effective? How much information is enough? How well do you understand what you are being told? Do you prefer a study partner to be involved? Based on the results, Lingler plans to conduct a study in which volunteers with MCI undergo actual scans, and in which she uses her previously established methods to reveal their amyloid status. She plans extensive follow-up to monitor people's psychological state and evaluate potential benefits and drawbacks of disclosure.
"It's very important to prepare the field for managing disclosure sessions and delivering information in a comprehensible way," Lingler said.
This issue saw considerable discussion at the Human Amyloid Imaging Conference held 12-13 January 2012 in Miami, Florida. “The guiding principle that we have no obligation to disclose amyloid status so long as criteria for preclinical AD don’t directly affect clinical care will become less and less feasible in the near future,” Karlawish told the audience at HAI.
One such challenge awaits researchers for upcoming studies in which they intend to recruit cognitively healthy, amyloid-positive people into preventive anti-amyloid trials. Sperling and colleagues are preparing for one such study, the A4 trial (see ARF related news story), in which people will—by way of their participation—learn their amyloid status. “If you do a spinal tap or a PET scan to find out amyloid status and then are asked to join the study, you know your status,” Karlawish said. Sperling has partnered with Karlawish to come up with a standardized approach for disclosing amyloid status for A4 in an ethical and safe way. Designs using blinded placebo default groups avoid that, but they have practical disadvantages.
"We need to set up a process to assure that the information that participants get is understandable and is given in a way that minimizes harm," Karlawish told Alzforum. He and his colleagues will draw on best practices from genetic counseling for carriers of genes such as the ApoE4 allele, and do their own research as well. Assuming funding will come through, they hope to have a plan ready by early 2013.
With these initiatives to build consensus around how to bring amyloid PET—and diagnostic biomarkers in general—to patients, the community is trying to come to grips with the reality of a growing and expensive diagnostic armamentarium entering clinical care faster than disease-modifying therapies. “I predict that, as advances are made in AD therapeutics, disclosure practices will become less intensive,” Karlawish said at HAI. “Consider HIV/AIDS. Progress in treatments has led to more relaxed HIV testing guidelines, even home testing. You can now order the test and get your results over the phone. Eventually, that can happen in AD, too.”
But for now, these are early days. "There is no standard for disclosure whatsoever because we are all taking the first steps," said Gertz. "We are looking for a standard, trying to discuss and to find a common base, but we are very much at the beginning."—Gwyneth Dickey Zakaib.
This is Part 3 of a nine-part series. See also Part 1, Part 2, Part 4, , Part 5, Part 6, Part 7, Part 8, Part 9. Download a PDF of the entire series.