This concludes a three-part series. See Part 1 and Part 2.
4 August 2010. 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.
See Part 1 and Part 2.