This is Part 2 of a three-part series. For intro and media reaction, see Part 1. See also Part 3.
4 August 2010. At the International Conference on Alzheimer’s Disease held 10-15 July 2010 in Honolulu, three workgroups of clinicians from the U.S. and Europe appointed by the National Institute on Aging and the Alzheimer’s Association offered new guidelines for the diagnosis of AD, making them freely available for download and feedback. The guidelines span a conceptual continuum beginning with a preclinical stage—and they sparked intense reactions in the media and medical circles (see Part 1). Confused? Perhaps a detailed summary of exactly what was actually presented at ICAD will help inform the debate.
The basics have been widely publicized and are available through the draft documents themselves. In brief, Creighton Phelps from the National Institute on Aging in the summer of 2009 set up three workgroups. The initiative grew out of ongoing discussion at prior meetings convened by the Alzheimer’s Association, which itself was spurred in part by the publication of a widely noticed paper redefining early AD (Dubois et al., 2007). In essence, these European-American authors defined a large subset of the heterogeneous group of people who would otherwise be diagnosed as having mild cognitive impairment as indeed having prodromal AD. Their method combined a cognitive test probing attention and delayed word learning with an AD marker such as MRI brain volumetry, PET imaging, or spinal fluid biochemistry. Only people who do not have prodromal AD by way of these tests are then considered to have the clinical syndrome of MCI. These research criteria are being used in Europe and in some U.S. therapeutic trials.
How do the criteria of Dubois et al. and the new NIA/AA sets relate to each other? “Our three workgroups attempted to be more detailed and comprehensive. Our criteria span the entire disease continuum. They contain guidance for community physicians who have no access to neuropsychology or biomarkers, for clinicians who have some access, as well as for tertiary care settings where these markers are being studied and clinical trials conducted,” said Phelps.
Because it was the third set of criteria—for preclinical AD—that touched off the lion’s share of controversy, this news account continues with a detailed transcript of the presentation by its leader, Reisa Sperling of Harvard Medical School in Boston. It will conclude with highlights of the ensuing scientific discussion at ICAD for all those who were unable to be there (Part 3).
The Preclinical Criteria—A Work in Progress
Phelps introduced Sperling as having the hardest task because her workgroup was charged with breaking new ground. On behalf of her group, Sperling told the audience: “We think it is time to define this stage because converging evidence suggests that the pathological process of AD begins years, perhaps more than a decade, prior to the diagnosis of dementia. This long preclinical phase provides a critical opportunity for potential intervention with disease-modifying therapy. We need to elucidate the link between the pathophysiological disease process and the emergence of the clinical syndrome further and determine the best predictors of clinical decline.” The draft research criteria, she said, aim to enable exactly this research. The workgroup dealt with the factors that predict decline to MCI and dementia due to the brain pathology of AD, even though many other factors clearly intersect with the AD pathway, for example, cerebrovascular and Lewy body diseases. But to facilitate the design of secondary prevention trials, the workgroup looked for factors they considered central to the core AD process in the decade prior to MCI and dementia symptoms, Sperling said.
What to call the stage before MCI? Asymptomatic? Presymptomatic? Latent? Pre-MCI? “We did some arm wrestling about that but then decided to use the term ‘preclinical.’ This term captures the continuum from an asymptomatic individual to one with very early symptoms that do not rise to the level of MCI,” Sperling said.
Evidence of this preclinical decade is mounting, though it is not ready for broad clinical use, Sperling stressed. It includes data from brain imaging, CSF assays, and other biomarkers that point to AD pathologic changes in vivo. Epidemiologic and cognitive research, too, have pointed to risk factors and subtle cognitive changes years before a person meets criteria for MCI.
Acknowledging controversy around that concept, Sperling encouraged the field to look beyond its own borders to other areas of medicine, where the concept of a preclinical stage of disease finds wide acceptance. Examples include carcinoma in situ, or coronary artery disease detected on cardiac catheterization. Quite often, symptoms are not required to diagnose disease. For example, renal insufficiency or liver cirrhosis can be detected by blood tests, and subsequent treatment can then prevent the emergence of symptoms. Regarding concerns about false-positive test results, Sperling noted that in hypercholesterolemia, not all individuals later develop atherosclerosis; even so, blood cholesterol testing and control are still considered useful.
Compared to those diseases, one glaring difference is that AD lacks proven disease-modifying drugs. But this is the point of research diagnoses: it may be more feasible to develop these with a biomarker-based diagnosis of preclinical AD than in mild to moderate AD as per the 1984 NINDS/ADRDA criteria.
The other big knowledge gap yet to fill in AD is that scientists lack widely reproduced, definitive evidence linking the pathologic process to the emergence of symptoms, Sperling said. This is the leading edge of ongoing research in many laboratories at present (e.g., ARF Toronto story, ARF St. Louis imaging story, ARF St. Louis biomarker story, ARF Toronto abstracts). The working hypothesis holds that Aβ accumulation is an early inciting event that is necessary but may not be sufficient to cause the clinical syndrome of AD, Sperling said. Multiple factors—possibly different ones in different people—mediate the relationship from AD pathology to clinical manifestation.
Evidence to date in this research area suggests that clinically “normal” people who have brain amyloid as per PET imaging or CSF Aβ42 measurement tend to have dysfunctional synapses in AD-relevant areas on functional MRI and FDG-PET, as well as elevated CSF tau/phospho-tau and a thinning of the cortex and atrophy of the hippocampus as seen with MRI. Studies are beginning to report subtle decrements in cortical connectivity by BOLD fMRI and in cognitive performance. This is early data, Sperling acknowledged; it needs to be followed up longitudinally and confirmed independently. Limiting caveats at this point include that many of the data come from highly select, or self-selected cohorts that over-represent people with advanced education or concerns about memory or family history. Also, the current Aβ biomarkers likely reflect monomeric or fibrillar Aβ, not its oligomeric forms.
Still, the overall data gave the workgroup confidence to devise draft operational research criteria for preclinical AD. They offer a common language, and a framework, for researchers who conduct longitudinal natural history studies to determine whether the presence of Aβ, either alone or with markers of neurodegeneration, predicts cognitive decline. One step beyond that, Sperling said, is that the criteria can support clinical trials of candidate disease-modifying agents in this phase of AD. The criteria start from the twin postulates that AD represents a sequence of biological events that begins far in advance of clinical dementia with cerebral amyloidosis and that having this biomarker affects a person’s future clinical decline and responsiveness to treatment.
Before laying out the group’s criteria themselves, Sperling again emphasized that they are not intended for routine clinical use in the near future. For that to become appropriate, further research must first determine that the requisite biomarkers indeed predict an individual person’s future clinical decline. For practical reasons, the research criteria cut the spectrum of preclinical AD into discrete stages, because stages can be more easily tailored to the goals of a given study, Sperling said. For example, some FDA clinical trials might enroll people in a late preclinical stage to ensure rapid progression to MCI within the duration of the trial, whereas other therapeutic strategies might be most successful if started earlier, many years prior to MCI.
With this qualified introduction, Sperling then unveiled the draft criteria. Stage I represents asymptomatic amyloidosis, whereby people have low CSF Aβ42 or elevated brain amyloid by PET imaging, but normal cognition for their age and education. Stage II is still defined by normal cognition but requires an added AD-like pattern of abnormality on downstream markers. These could be synaptic dysfunction as per FDG hypometabolism or functional connectivity MRI, increased CSF tau/phospho-tau, or MRI findings of cortical thinning or atrophy in the hippocampus or entorhinal cortex. By Stage III, symptoms start to encroach. This can be evident in the form of subtle cognitive decline over time but still within the normal range, or by low performance on certain sensitive cognitive measures. Or it could be a person’s subjective complaint that memory is slipping, which stays below the threshold for MCI.
Sperling said that these stages may change once alterations prior to Aβ become more widely documented; at present, some cohort studies in ApoE4 carriers suggest that synaptic dysfunction may actually precede Aβ markers. On the practical side, the field at large has to clear the significant hurdle of standardization. It has to set cutoffs and validate all biomarkers involved. One such initiative is underway (see story on Quality Control Initiative), and initial data were reported in a separate talk at ICAD, where, indeed, one entire session dealt with the challenge of how to standardize biomarkers and brain imaging. The current draft criteria can actually facilitate the standardized collection of new biomarker data, Sperling noted. On a different front, the cognitive measures suitable for tracking progression toward MCI are not fully worked out; studies to establish them must take care to recruit cohorts that represent a cross-section of the general population.
Sperling ended her presentation with a note of urgency for the field to get started, because definitive studies to prove or disprove these hypotheses may take a decade. The risk/benefit equation of cognitively normal people taking potential disease-modifying drugs, with their likely side effects, has been intensely discussed in general terms for some years. To be able to move beyond the abstract and weigh this issue quantitatively, the field needs to obtain a closer numerical grip on how likely a given person is to progress to MCI, Sperling added. Finally, she pointed to initiatives that are already planning secondary prevention trials in preclinical populations at various levels of risk, for example, DIAN, API, and the ADCS’s A4 trial.
Compared to the preclinical criteria, the proposed criteria for Alzheimer disease dementia sparked little controversy. They, too, are described in downloadable PDFs, so this story only highlights the main points in brief. Guy McKhann of Johns Hopkins University in Baltimore, Maryland, who already led development of the widely used current criteria (McKhann et al, 1984), told the ICAD audience that research since then has laid bare some shortcomings of these criteria. For example, the long pre-symptomatic and the middle MCI phase were poorly understood at the time, as were the deficits in cognitive domains such as executive function, visuospatial function, and language that are quite common in AD. Nothing at all was known about biomarkers and little about other dementing conditions such as dementia with Lewy bodies or corticobasal degeneration, to pick but two examples. Awareness of early-onset AD has rendered the age cutoffs largely obsolete, some genetic information is available, and the category of “possible” dementia has been difficult to pin down in practice all along, McKhann said.
The new guidelines retain the core of the previous dementia diagnosis, i.e., that there has to be evidence of a performance decrement in two domains and of a progressive decline. “In their essence, the old criteria were, and still are, extremely durable,” said Steven DeKosky of the University of Virginia School of Medicine in Charlottesville. The new guidelines refine existing categories to incorporate new knowledge in the research areas named above. They are intended for clinics everywhere. Indeed, the workgroup purposely kept them flexible so they would be useful in many countries and cultural contexts, McKhann said. For example, they make it possible to diagnose AD dementia clinically without use of neuropsychology testing or biomarkers in settings where those services are unavailable, or for large multinational clinical trials; they also recommend the use of biomarkers to add certainty to a questionable diagnosis in settings where this is doable.
On the middle phase of the disease process, Marilyn Albert of Johns Hopkins said to the assembled audience that after months of intensive work, the group settled on the term “MCI due to AD.” Terminology is important—and frequently contentious—in efforts to define diagnostic criteria. Gone from the new proposed vocabulary are the words “amnestic MCI (aMCI)” or “conversion,” reflecting consensus that the disease worsens progressively rather than stepping over a discrete threshold.
The criteria for MCI due to AD remain similar to the old MCI criteria in that they require a cognitive concern and impairment in one or more domains. They are different in that they broaden the domains in which the cognitive deficit can occur to now include language, visuospatial function, or executive functions such as reasoning and problem solving, as did the AD Dementia workgroup. They also require a higher level of functional independence. Importantly, the draft criteria incorporate biomarker measurements in various ways for research purposes. They distinguish amyloid evidence—which is considered evidence that Alzheimer’s, rather than a different disease, is ongoing—from downstream measures of structural or functional change. The proposed MCI due to AD criteria fall into three types, with increasing levels of certainty bestowed, in part, by increasing biomarker/imaging data. In short, the criteria focus on what other groups call prodromal AD. They describe other conditions to the extent that they assist the differential diagnosis. The biggest news lies in their use of biomarkers to increase the certainty of the diagnosis.
These draft criteria ultimately are also intended to be helpful throughout the world, not just in tertiary care centers, Albert said. But she added a caution. “Although we are trying to incorporate biomarkers, we still think there is much to be learned about them. Todd Golde, in his plenary lecture here at ICAD, called the use of biomarkers in AD diagnosis a paradigm shift, and we agree. It would be premature to ask all clinicians in community settings to shift toward using them at this point.” The draft criteria will evolve as new biomarker data come in, Albert added.—Gabrielle Strobel.
This is Part 2 of a three-part series. For intro and media reaction, see Part 1. See also Part 3.