What Do Clinicians Say? Peers Welcome Revised Criteria
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A comprehensive proposal of new diagnostic criteria—the first official revision of the current NINDS/ADRDA criteria published a quarter-century ago (McKhann et al., 1984)—marked a highlight at the International Conference on Alzheimer’s Disease held 10-15 July 2010 in Honolulu, Hawaii. The criteria drew mixed responses in the media (see Part 1), some of which missed the point that the more ambitious proposals are meant to guide research and therapeutic studies (see Part 2). Those readers who saw media stories but were not at ICAD, or were in a parallel session, may want to know how the research community at the conference reacted to the presentations. In a packed session, Guy McKhann of Johns Hopkins Medical School in Baltimore, Maryland, introduced the criteria for Alzheimer Disease Dementia, Marilyn Albert of Hopkins summarized criteria for MCI of the Alzheimer’s Type, Reisa Sperling of Harvard Medical School presented criteria for preclinical AD, and Steven DeKosky of the University of Virginia Medical School added clinical perspective. In an open-mike discussion after these talks and in hallway and phone conversations with a reporter afterward, ICAD attendees expressed mostly positive feedback interspersed with a few concerns. Unlike the media, some scientists thought the changes did not go far enough. Below is a summary of views. For further perspective, see commentary below by William Jagust at the University of California, Berkeley, Dave Holtzman of Washington University, St. Louis, and Sperling herself (see comment).
Overall, clinicians from different centers across the world commended the effort to evolve current criteria by defining the entire natural history of AD from its asymptomatic beginning to full-blown dementia. Most welcomed a biomarker-enhanced staging of MCI as opposed to the prior clinical definition. Others welcomed the inclusion of atypical presentations of Alzheimer disease that tend to be overlooked by the current criteria. Some clinicians remarked on the opposite, i.e., that diseases that are not AD sometimes get misdiagnosed as such because, to most non-specialists, AD is the best known of the age-related dementias. These clinician-researchers welcomed the inclusion of biomarkers and genetic tests, for example, for tau or even serum progranulin, to help clinicians avoid labeling people as having AD when in fact they have a different disease. Some noted the need for biomarkers for α-synuclein to help delineate those diseases and to provide a more detailed roadmap to navigate the different forms of dementia they see in their clinics.
Several clinicians particularly welcomed the proposed guidelines’ recognition of mixed pathologies. For example, if a patient showed symptoms of parkinsonism, the revised criteria recommend consideration of dementia with Lewy bodies; if a patient has disinhibition, the criteria recommend looking into frontotemporal dementia. Some clinicians were pleased at the recognition of vascular factors in the proposed guidelines, and called for finer-grained distinctions of vascular and mixed dementias to help them with differential diagnosis.
In the way of constructive criticism, some scientists pointed to confusing terminology that arises chiefly because the three work groups have so far worked largely independently of each other. The group did not harmonize their language before rolling out the draft criteria. This, some commentators said, creates apparent paradoxes at the borders of the separate stages. For example, the most advanced “preclinical” patients have symptoms, and the most advanced MCI patients are labeled as having “prodromal Alzheimer’s dementia,” but by definition cannot have dementia if they fall into the MCI group. One scientist pointed out that, as per the AD dementia group’s criteria, patients who meet clinical criteria but have had biomarker tests that came back negative are still considered to have “possible AD dementia,” whereas the MCI workgroup places patients with negative biomarker results in a group called “MCI of the neurodegenerative etiology,” where the likelihood that the underlying process is AD is considered low.
Some clinicians pointed to the high cost of a full neuropsychology workup. In response, DeKosky noted to a reporter that as computerized cognitive tests become more validated and widely available, some of that can be done easily by the patients themselves as they wait to be seen.
One theme echoed through conversations with scientists at ICAD and beyond. It is that the set of proposed criteria devised individually for each of three separate phases of AD appears to many to be quite complex. In particular, several scientists picked up on a question Jesse Cedarbaum of Elan Pharmaceuticals in South San Francisco had asked during the scientific session. Cedarbaum complimented the staging system proposed for the preclinical period, and asked if it could be extended across the entire disease continuum to reflect the progressive nature of Alzheimer disease. Cedarbaum noted that in cancer, continuous staging has proven useful, even though cancer, too, comes in many different forms. A paper published recently in the Journal of Nutrition, Health, and Aging formalized this suggestion with a staging scheme stretching from “No clinical or biomarker evidence” (Stage 0) through to “Incapacitating cognitive and functional decline (Stage 5, see Cedarbaum et al., 2010). Like the criteria of Dubois et al., this proposal, too, is geared primarily toward facilitating clinical trials in early AD.
It is not the first time a continuous staging system has been suggested, others pointed out. Barry Reisberg of New York University and, more recently, David Bennett of Rush University Medical Center, Chicago, have done so before. Several ICAD attendees said that it might deserve another look. “Jesse’s paper proposing a staging system as opposed to three sets of criteria for preclinical, MCI, and AD is, I believe, a better way of thinking of the disease. In fact, that is basically what we do now in our own research studies. We use the clinical dementia rating scale in combination with making a clinical diagnosis in combination with biomarkers,” David Holtzman of Washington University in St. Louis, Missouri, wrote to ARF (for additional comment, see below). For her part, Sperling wrote to ARF: “The idea of a staging system from asymptomatic to early symptoms to MCI to dementia makes sense. Our group tried to operationalize the preclinical stages for research purposes and to lay out a hypothetical model and conceptual framework to test these hypotheses. We might want to consider seven stages overall instead of the five Jesse published, but would need to discuss with the three workgroups before making any specific recommendations” (see full Sperling comment below).
Finally, some commentators noted that multiple groups have established their own diagnostic nomenclature for AD. Some of those are undergoing their own revision. They include the DSM, the WHO’s International Classification of Diseases (ICD-10), and the AAGP. Each use their own terminology, and they do not at present speak to each other in a formal way to explore if they could harmonize their language. Of these four sets of diagnostic schemes, the NIA/Alzheimer’s Association one appears the most biologically oriented; the approaches by Dubois et al. and Cedarbaum et al. carry the reliance on biologic markers further still. In an indication of how sensitive this discussion is, most commentators for this story requested anonymity on any disagreement they might have with the proposed criteria, or with the views of their colleagues in psychiatry. But despite quibbles about language and about how many categories there need to be, the overall tenor among AD scientists was resoundingly this: “Like it or not, biomarker-supported early diagnosis is where the field has to go.” What do you think? We value your feedback. Write your comment in the box below.—Gabrielle Strobel.
References
News Citations
- Noisy Response Greets Revised Diagnostic Criteria for AD
- Revised Criteria for Preclinical AD, Exactly as Presented
Paper Citations
- McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939-44. PubMed.
- Cedarbaum JM, Crans G, Grundman M. Seeing with new eyes: finding a path to early intervention trials in Alzheimer's disease. J Nutr Health Aging. 2010 Apr;14(4):306-9. PubMed.
Other Citations
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Comments
Washington University
There is currently no effective treatment for Alzheimer disease. The new proposed diagnostic criteria for preclinical and very mildly impaired individuals AD are research criteria. They were written to benefit development of new therapeutics so that individuals who have AD pathology could be identified at different stages of disease that occur prior to symptoms or just after symptom onset. They are not criteria for implementation in “patients” at this time. They should be useful for improving sensitivity and specificity of diagnosis, even at the asymptomatic and very mild clinical stages of disease, for entry into clinical trials and for research studies. Many of the comments to the The New York Times article that criticize the new criteria are likely because the article did not mention the new criteria were research criteria, not yet for us in patients. Amyloid imaging is not even approved for use in patients at this time.
Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School
I chaired the Preclinical Alzheimer’s Disease committee. The main confusion in the coverage of this issue so far is that some lay press, perhaps without reading the proposed criteria, made the leap that we were suggesting these criteria for clinical practice. We explicitly state that these are for research purposes only.
Perhaps this misunderstanding happened because the original press release before the presentation bundled together the three groups under the common theme of revising the diagnostic criteria from 1984, so the leap seemed to be that we were proposing clinical diagnostic criteria. However the press release also stated clearly that the preclinical group was proposing a research framework. I sincerely hope this confusion will not dilute what many colleagues consider to be an important conceptual step forward.
We are proposing a research framework to answer exactly the questions that the lay press has been discussing. The lay press keeps asking why we would want to diagnose early AD if we can't do anything about it. The key point to understand here is that this research agenda was proposed specifically so that we can understand the prognostic value (or lack thereof) of these markers at a stage of the disease for which we have the greatest likelihood of altering the subsequent clinical course with treatment. We need to diagnose early AD in a research setting so that we can then test what we can do about early AD, not the other way around. Both animal studies and disappointing clinical trial results suggest we may have to treat earlier to slow the disease course. This is common wisdom in almost every other field of medicine. For example, consider mammograms for breast cancer: Most drugs don't work at the stage of metastatic cancer. Or colonoscopy for polyps: Many polyps may never result in cancer. Or cholesterol: The prognostic value for an individual is poor, but treating elevated cholesterol has reduced the public health burden for both cardiac disease and stroke. Finally, in bone density scans for osteoporosis, the point is not waiting for someone to fall and have a fracture.
True, we have not yet fully elucidated the link between the earliest pathological markers of AD (CSF A-beta/tau and PET amyloid imaging) and the emergence of clinical symptoms. Much research needs to be done, both longitudinal studies to understand the prognostic value of these markers and the factors that may influence the progression of the pathophysiological process and the emergence of clinical symptoms. We also have much work to do on the standardization of the biomarkers, and learning about optimal "cut-off" values. We have to develop the diagnostic criteria for the subjects who will come into these presymptomatic trials, and we have to learn what the actual risk of developing AD is for an asymptomatic amyloid-positive individual, so that we can make informed decisions about the risk-benefit ratios.
Here’s my worry: If we don't start this research now, we will still be having the same debate in the lay press 10 years from now.
The proposed preclinical research criteria have no clear prognostic value for an individual person at this point, and we do not advocate that physicians obtain testing on normal individuals. Our committee was charged with reviewing the current state of knowledge and making recommendations for future research to fill in the knowledge gaps about the earliest stages of AD. We developed these recommendations in order to move the research field forward towards earlier diagnosis and eventually initiating treatment at the point when we are most likely to have success in altering the course of Alzheimer disease.
It is important to convey to the public that we do have emerging evidence that the pathophysiological process of Alzheimer disease begins many years before dementia. This long preclinical phase provides a critical potential opportunity for therapeutic intervention and maximal impact on public health burden. There is still much unknown, however, about the pathophysiological sequence, the factors (both positive and negative) which may influence rate of progression and the emergence of the earliest clinical symptoms. We must work towards defining these earlier stages of AD, and fortunately, now have biomarkers as promising research tools to begin this research. It will be several years, perhaps a decade, before we are ready to translate this research into recommendations for clinicians. Hopefully, we can move forward sooner in planning clinical trials for presymptomatic individuals, both genetic at-risk groups and for older individuals with evidence of early AD pathologic changes, but we desperately need additional information to develop inclusion criteria and outcome markers for trials in these preclinical phases of AD.
The response from the research community has been been very positive, praising our ‘forward thinking’. We have already had excellent suggestions for refining our recommendations, which we will work to incorporate. Interestingly, some of the research community felt that our recommendations sounded too cautious, and that we should be more forthright in charting a research agenda for the next decade. Hopefully we will find the right balance to move the field forward without raising unrealistic expectations for patients and physicians.
I believe that as a patient becomes more impaired, the amyloid biomarkers will be less important and may serve primarily in negative predictive value. For example, if a dementia patient has no evidence of amyloid pathology, a clinician or researcher should consider other diagnoses. In contrast, at the stage of MCI or preclinical, these biomarkers hopefully will prove to have positive predictive value, such that the presence of amyloid markers will help predict who will decline towards dementia (and eventually receive treatment). Similarly, in clinical trials, I would not advocate screening all mild to moderate AD patients with amyloid markers; however, for an early MCI trial for a drug aimed at amyloid lowering, I would suggest requiring evidence of amyloid markers for study entry.
Three sets of criteria, each different for each stage of the disease process, appears complicated. However, exactly the issues that have been raised in the press emphasize the need to consider the differential use of criteria. So I think we should publish three sets of recommendations. But we will work to harmonize the terminology to emphasize that both the pathophysiological process and the clinical course of AD are best conceptualized as continuums, or as two parallel trajectories with a temporal lag, which we hypothesize may be up to a decade.
I was a member of the MCI committee and helped define the biomarker criteria in that draft document, so am biased in this sense. In light of some of the media coverage, a few points seem worth noting:
1. The criteria are designed to be multipurpose, that is, to serve clinicians at multiple levels, clinical researchers, and industry for clinical trials. Trying to be all things to all people is always difficult, and that is surely one of the limitations we are grappling with. So in contrast to the ideas proposed by Jesse Cedarbaum and Mike Grundman, which are very thoughtful and reasonable, I think we had to use biomarkers differently at different disease stages and for multiple purposes. The Cedarbaum et al. scheme is, in contrast, expressly designed for clinical trials.
For example, in AD, patients with a typical presentation and documented decline can have probable AD (i.e. the highest certainty) without testing for biomarkers, although absent documented decline, biomarkers can establish this level of certainty. Similarly for MCI, levels of certainty are available without testing for biomarkers or differently for different types of biomarkers. I think this is a good compromise so that, for example, a community physician can diagnose AD simply on the basis of a good history and physical with some follow up and no need for expensive testing. As the symptoms move earlier, there is more reliance on biomarkers.
I should note that the op-ed piece in the New York Times was quite misinformed about this, suggesting that these tests were necessary to diagnose AD. They are not, they are only required at stages where symptoms are more subtle or non-existent if more information is deemed necessary by a clinician or scientist.
2. I do think it is fair and reasonable to discuss the costs/benefits of the new criteria. But again, based on the way they are written they do not require expensive testing in all situations. If a patient presents with symptoms of MCI, it is up to a physician or researcher to decide how far to pursue this. One could omit biomarkers, perform only an MRI scan, or do extensive testing with amyloid imaging or CSF and the level of certainty of AD would be based on the amount of testing. We are not saying that one or another of these approaches is required; it depends on the clinical or scientific needs. So for example, a clinician who has determined that testing will not affect the management of a patient may decide to do minimal or no testing. Conversely, if there are important clinical or lifestyle decisions to be made there may be an indication for more extensive evaluation so that a diagnosis of “prodromal Alzheimer’s dementia” could be established. Clinical trials are another obvious situation in which more testing may be needed. Finally, of course we have tried to create a pathway for future studies and guidelines that will be useful if/when effective therapy is available. We hope that this may occur in the near future and in that situation one would expect that more aggressive testing to establish a diagnosis will be indicated.
3. “Pushing the envelope” to encompass preclinical AD is of course controversial. Again, no one in this workgroup is recommending routine measurement of biomarkers in older people. In fact, the current document specifically states that the purpose of these criteria is to serve clinical research and clinical trials and not diagnostic clinical criteria exactly because we do not yet understand the clinical significance of positive biomarkers absent cognitive impairment. The problem is here whether we want to acknowledge the situation or ignore it. Amyloid imaging will grow in its availability to the community. CSF testing is already available, and many older people are aware of and concerned about Alzheimer disease and their own cognitive function. These criteria offer a framework for thinking about the problem clearly based on our current knowledge of biomarkers. As Steve DeKosky pointed out, the length of the documents was directly related to the disease stage, and this was the longest – there are acknowledged to be many unknowns in this stage. So I think that proposing ways of thinking about and categorizing subjects for research purposes is an advance that is nevertheless complex at present.
4. A final word about the length/complexity. Much of these documents are background designed to explain the reasoning for the approach to diagnostic criteria and categorization. Again, I think this is because we hope these will serve as working documents for revision with time. The actual criteria are pretty short and straightforward and in most cases can be distilled into little more than a page.
Yale University School of Medicine
Few would disagree with the view that knowing the cause of a disease greatly enhances the prospect of designing effective therapies. Antibiotics for specific infectious agents are one obvious example. Recognizing the presence of dementia is rarely a problem in the advanced stages of the disease, and now we have technologies that can detect individuals who seem to be minimally impaired, the so-called MCI state. Does this now equip us to test new therapies on these patients, given the reasonable assumption that therapies are likely to be most effective at the earliest stages of the disease before irreversible changes develop?
A serious concern is whether amyloid deposits in brains at any stage of the disease represent a consequence of the disease rather than a primary cause. There is a commonly held view among AD investigators that pathogenic factors that lead to clinical dementia begin decades before clinical symptoms, even though we have as yet no idea what these processes might be. It is an unproven assumption that amyloid deposits acting alone are the most important pathogenic agents. Given this uncertainty, amyloid-scanning approaches may not reveal the start of the AD process at a stage when it might be most treatable. We have hints as to how aggregated forms of Aβ may damage cultured neurons, but the data are too inconclusive to guide therapy.
I do believe that the evidence linking Aβ peptides to pathogenesis is too strong to ignore, and scans for detecting amyloid deposits in living brains are a great step forward, but the question as to whether they detect the earliest stages of the disease remains unanswered. It should also be pointed out that the widespread use of brain scans for amyloid detection has the potential disadvantage of focusing too much attention (and resources) on amyloid as the sole or major cause of the disease, thereby discouraging efforts to explore other contributing causes, among them oxidative damage and inflammatory processes.
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