April 19, 2011 — New diagnostic criteria for Alzheimer's disease (AD), including mild cognitive impairment (MCI) due to AD and a new "for research purposes only" category of preclinical AD, are now published.
Draft criteria were first presented last summer at the International Conference on Alzheimer's Disease and were subject to feedback from the research and practice community. They are now published in 3 final documents, along with an introductory summary, online April 19 in Alzheimer's & Dementia: The Journal of the Alzheimer's Association.
The 3 working groups were convened by the National Institute on Aging (NIA) and the Alzheimer's Association to update criteria established by the National Institute of Neurological Disorders and Stroke/Alzheimer's Disease and Related Disorders Association — now the Alzheimer's Association — in 1984.
The guidelines published today were "extensively revised" from those presented last summer, Creighton H. Phelps, director of the Alzheimer's Disease Centers Program at NIA, told reporters during a press teleconference Monday.
"The revised guidelines that we're presenting today address particularly the difference between information that can be used in clinical practice and that which is intended for use only in research settings," Dr. Phelps said. "They also present a distinction between the underlying disease process and clinically observable disease states."
"Special attention" is paid in the new document to how biomarkers may be used to add levels of confidence to clinical findings in MCI and AD, primarily in the research setting, he added.
In fact, the take on biomarkers appears to be one of the biggest changes from last summer's presentation. The working groups had developed these documents in isolation from each other and had come to somewhat divergent positions on the use of biomarkers, such as advanced imaging and cerebrospinal fluid (CSF) markers of disease. The working group on MCI had urged their inclusion at least in the research setting, for example, whereas the AD working group had not addressed the use of biomarkers at all.
Clifford R. Jack Jr., from the Department of Radiology at Mayo Clinic in Rochester, Minnesota, lead author of the overview document, said that a small working committee was formed specifically to harmonize the documents.
They worked to make not only the terminology for biomarkers more consistent, Dr. Jack said, "but also the concepts and what they actually measure — in other words, what pathology individual biomarkers that are discussed map onto and also the business of how they should be used.
"So there was that effort, and we think we were successful by and large in harmonizing those aspects of biomarkers as they are treated in the 3 documents," he added.
"Another thing that we tried to do in revision of these documents after last summer was to make it a little clearer what was there for clinical use now vs what is a research agenda for the future," Dr. Phelps told Medscape Medical News. "I think that's come out in discussion fairly well today, but that was a little murky last summer."
Dementia Due to AD
Guy McKhann, MD, from Johns Hopkins University School of Medicine in Baltimore, Maryland, who chaired the Alzheimer's Disease Dementia Workgroup, was instrumental to the definition of the 1984 diagnostic criteria and headed the working group on dementia due to AD.
During the briefing, Dr. McKhann pointed out that the diagnosis of AD is still a clinical one in this document. "Primarily, we're asking the physician, with the help of an informant — members of the family, even the patient — to make a judgment as to whether or not dementia has occurred or is occurring."
Biomarkers can assist in the diagnosis of AD but are not essential; rather they are used in research studies to augment certainty about a given diagnosis, he said. "But for the practicing physician — and I would caution that people who see these folks first are not necessarily neurologists or psychiatrists; they are people who are geriatricians, general practitioners, internists — the people who see these people first, are first making this distinction on clinical grounds."
They aimed to make the diagnostic criteria sufficiently flexible to serve both general healthcare providers without access to imaging, CSF measures, or neuropsychological testing, as well as specialized investigators in clinical trial settings, the study authors note.
The working group retained the framework of probable AD dementia from the 1984 criteria, but "on the basis of the past 27 years of experience," made several changes to the clinical criteria for the diagnosis. They also retained the term "possible AD dementia," they write, "but redefined it in a manner more focused than before."
Biomarker evidence was incorporated after all into diagnostic formulations for probable and possible AD at least for research settings, they note. "The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia," they write. "Much work lies ahead for validating the biomarker diagnosis of AD dementia."
Also incorporated are the concepts of a continuum of disease and the distinction between AD and other types of dementia or mixed dementias, Dr. McKhann noted.
MCI Due to AD
The MCI working group was chaired by Marilyn Albert, MD, also from Johns Hopkins University School of Medicine, who presented their findings here. The term MCI has been in use in the field since about 2000, largely based on the work of Ron Peterson, MD, from the Mayo Clinic, Rochester, Minnesota, she said.
"What this term has come to mean is people who have mild progressive symptoms, changes in mental abilities — usually memory but not always memory — and that these become progressive over time," Dr. Albert said. "What has been learned in the field in the last 10 or so years is a very large number of these individuals — although certainly not all of them — ultimately will progress to have Alzheimer's dementia."
As in the AD document, for the purposes of clinical practice, the diagnostic criteria for MCI are not much changed and are meant to be used by physicians in any setting.
"There are some very minor differences that have to do with who can provide the source of information about whether or not there have been changes [in cognition] and whether or not these changes have some minor impact on functional ability, but overall, the clinical criteria that we're describing are extremely similar to what's been used for the last 10 years in the field," Dr. Albert noted.
The big change has been the discussion of biomarkers to increase diagnostic certainty, she noted, "but the use of biomarkers is recommended currently now only in research settings because there's an enormous amount we still have to learn about them."
That is a somewhat more circumspect view than she took last summer, when she suggested that although "we recognize that there's much more that needs to be learned about all of these biomarkers to be able to move them out into community settings, but we believe the time is right, and we urge everyone to move ahead."
In the new document, the MCI working group actually developed 2 sets of criteria: 1 outlining "core clinical criteria" for use by providers without access to advanced imaging or CSF analysis and 1 describing research criteria that incorporate biomarkers for use in research and clinical trials settings, even though, they note, "considerable work is needed to validate the criteria that use biomarkers and to standardize biomarker analysis for the use in community settings.
"The final set of criteria for mild cognitive impairment due to AD has 4 levels of certainty, depending on the presence and nature of the biomarker findings," they write. These are as follows:
1. Concern regarding a change in cognition: This concern can now be identified by the patient, an informant, or a skilled clinician, they note. In previous criteria, the patient had to express concern and then be corroborated by an informant.
2. Impairment in one or more cognitive domains: Performance should be lower than would be expected for the patients' age and education, they note, and if repeat assessments are available, should show decline over time. Although impairments may begin in any cognitive domain, including executive function, language, attention. or visuospatial skills, impairment in episodic memory occurs most often in those who progress to AD.
3. Preservation of independence in functional abilities: Those with MCI may take more time, be less efficient, and make more errors in daily tasks, such as paying bills and preparing a meal, but they generally maintain independence of function with minimal assistance.
4. Not demented: Changes should be sufficiently mild that there is no evidence of social or occupational impairment.
Preclinical AD Working Group
Finally, the third group, chaired by Reisa Sperling, MD, from Harvard Medical School in Boston, Massachusetts, outlined a preclinical stage of AD.
There's converging evidence that the pathophysiologic process of AD begins years, probably more than a decade, before the time that we make a diagnosis of dementia, Dr. Sperling said. "This long preclinical phase of AD provides a critical opportunity for potential intervention with disease-modifying therapy."
The document and the writers of the document were both clear, though, that there is no utility of this classification for the purposes of day to day practice. "I want to emphasize since the preclinical might be the most controversial that we are really proposing our guidelines for research purposes only, and at this time they really do not have any use in clinical practice," Dr. Sperling said.
"The main conceptual point that our group felt we wanted to work towards was to define AD on the basis of underlying brain changes rather than just requiring clinical symptoms."
For many chronic conditions, including cancer, heart disease, diabetes, and osteoporosis, there are factors associated with risk for the disease, such as high cholesterol or blood glucose levels, the presence of which help to define a higher-risk population but that do not mean that the individual at risk will develop the disease with 100% certainty. However, at a population level, screening and treating those with evidence of early disease can significantly reduce mortality, Dr. Sperling noted.
"So we propose a staging framework to try to better define individuals at the greatest risk for going on towards clinical impairment," she said.
The stages include the following:
- Stage 1 — asymptomatic cerebral amyloidosis;
- Stage 2 — amyloidosis plus evidence of "downstream" neurodegeneration; and
- Stage 3 — amyloidosis, neuronal injury, plus subtle cognitive/behavioral decline.
"The main change in our criteria from what we published last July is the idea that we acknowledge that these individuals may or may not progress to the clinical stage of the disease but that we've tried to make a research framework that will allow us to best test these hypotheses," Dr. Sperling noted.
"We've now included some subtle behavioral symptoms, such as apathy, which may precede the clinical symptoms of MCI by a few years, and tried to come up with a very specific way of staging individuals who are at most risk for Alzheimer's disease dementia in the future," she added.
William Thies, PhD, chief medical and scientific officer at the Alzheimer's Association in Chicago, Illinois, pointed out that the new criteria will result in little change in current clinical practice.
"However, the expanded recognition of the course of Alzheimer's disease will have more immediate importance in the research area," he said. "In the future, the new criteria will drive research into earlier diagnosis, better treatment, and a better understanding of the public health impact of Alzheimer's disease."
The criteria will be validated during the next few years, he added. Further research will require identification of further markers of early pathology and allow development of drugs "that will prevent that early pathology from causing the catastrophic symptoms of full-blown disease."