In July 2010, at the annual Alzheimer's Association International Conference on Alzheimer's Disease, the working groups presented preliminary reports. The proposed criteria have two components: (1) clinical and cognitive criteria, which are almost identical to the approach that is being used in the field at the present time, and (2) criteria that involve the use of measures known as biomarkers. The second component of these criteria call for extensive testing of emerging techniques, such as neuroimaging and measures of proteins in cerebrospinal fluid. For this reason, the proposed revisions related to imaging and biomarkers primarily focus on use in a research setting. Some physicians in specialized medical centers may elect to use biomarkers as another tool in diagnosing patients with symptoms of Alzheimer's dementia, even as the techniques are being validated for broader use in a clinical setting, but this is not generally recommended since there is limited standardization of these methods and appropriate cut-offs have not been identified for use in clinical practice.
Now, the project's organizers are seeking comment from a larger community with interests in Alzheimer's disease, aging, and health. The working group reports can be viewed and comments on the proposed revisions can be submitted through the Alzheimer's Association website at www.alz.org/research/diagnostic_criteria/. Comments are due by August 31, 2010. After the working groups and organizers review and integrate the comments into final reports, recommendations will be published in a peer reviewed medical journal for broad distribution to scientists and clinicians. The organizers aim for journal publication early next year.
Going forward, the three sets of diagnostic criteria recommended will be subject to periodic re-appraisal and revision. As we learn more through comment and validation - especially about new testing and imaging methods - that new knowledge will be incorporated into the diagnostic criteria as they continue to evolve.
Why was this effort undertaken?
The current criteria for the diagnosis of Alzheimer's were established by the National Institute of Neurological Communicative Disorders and Stroke (NINCDS)/Alzheimer's Disease and Related Disorders Association (ADRDA) workgroup in 1984. The criteria were universally adopted and have been in use, without modification, for more than 25 years.
Since those criteria were established, however, understanding has increased significantly regarding genetics and the course of Alzheimer's disease, including some of the very early brain and body fluid changes that might occur at various points in the disease process. A most important advance is knowledge of how the Alzheimer's process progresses over time, which is often described as having three phases. It is hypothesized to start in a pre-symptomatic, or preclinical, phase many years prior to the diagnosis of dementia. In mid-course, there is a symptomatic phase currently usually referred to as mild cognitive impairment (MCI), characterized by mild problems in the ability to think, learn, and remember; some people with MCI progress to dementia, but some do not. At its most advanced, the disease is Alzheimer's dementia, which is reflected by a loss of the ability to function independently and a substantial impairment in cognitive function.
The current effort led by the National Institute on Aging at NIH and the Alzheimer's Association seeks to incorporate this new knowledge of a disease spectrum into updated diagnostic criteria. Three working groups were established, one for each proposed phase of the disease. The proposals involving preclinical phases of the disease outline a research plan for testing and validating approaches at this earliest time in the disease process. Guidelines suggested for MCI and Alzheimer's dementia are directed toward different audiences in research and clinical practice. They provide clarification of existing clinical guidelines for use by doctors in the community, and offer new guidelines for use only by the research community to test experimental approaches for detecting disease or adding greater certainty to the diagnosis of Alzheimer's dementia. In the long term, the overall goal is to provide standards for research scientists and practicing physicians that move the field farther in the direction of early detection and treatment.
Currently, Alzheimer therapies are in development that may be able to slow or stop the progression of the disease. By improving early detection and risk evaluation for Alzheimer's now, we will better be able to test potential therapies and eventually prescribe them for people most at risk. Ultimately, this approach envisions what is now common practice in cardiovascular disease, where early signs of risk - for example, in genetic markers or in blood cholesterol and/or blood pressure levels -- can be treated to reduce the chances of heart attack or stroke later on.
What is being proposed? The proposed changes to Alzheimer's diagnostic criteria aim to better address the course of the disease from its very earliest stages. Current criteria for the most part focus on reliable diagnosis when signs of problems in thinking, learning, and memory are noticeable to an individual, family, and friends. But research now tells us that Alzheimer's likely begins years, perhaps even decades, before symptoms appear.
The workgroup proposals refer to three phases of disease progression over time:
- Preclinical - changes that may indicate the very earliest signs of disease. Currently, there are no diagnostic criteria for this phase. The proposed approaches suggested by the workgroup are meant for research; they propose schema for data collection, to see if a "preclinical" stage of the disease can be defined, so that eventually people who will develop Alzheimer's dementia can be distinguished from those who will not. This experimental approach calls for measurement of certain proteins in blood and cerebrospinal fluid - so-called "biomarkers" - as well as neuroimaging tests to characterize brain changes that may be predictive of Alzheimer's disease. They also may include new assessments to tease out the very earliest and subtle clinical signs of decline.
- Mild cognitive impairment (MCI) - mild changes in memory and thinking abilities, enough to be noticed and measured, but not impairment that compromises independence in going about everyday activities. This impairment increasingly can be measured in research and is gradually being recognized in medical or specialty practice. However, much more work is needed to distinguish those with MCI who will go on to develop Alzheimer's dementia from those who will not. In this area, the workgroup focused on the potential added benefit of biomarkers, as they become validated, to help increase diagnostic accuracy in research settings.
- Alzheimer's dementia - cognitive and behavioral symptoms that impair an individual's ability to function independently. The working group for this phase of disease emphasized the continuing need and importance to rule out other causes of cognitive decline and of documenting progressive decline over time. The group also noted that the diagnosis of Alzheimer's dementia may not always have memory impairment as its most central characteristic; a decline in other aspects of cognition (such as word-finding, vision/spatial issues, and impaired reasoning, judgment, and problem solving), may be the presenting or most prominent symptoms at first. For research purposes, the workgroup proposes that diagnostic certainty might be improved by incorporation of certain biomarker measures, although the usefulness and reliability of these tests in everyday medical practice still needs to be tested.
The proposals under discussion consider how biomarkers in cerebrospinal fluid and neuroimaging might be applied. Regarding biomarkers, for example, two of the hallmarks of Alzheimer's disease are amyloid plaques and tau-promoted tangles. A recent major advance is the ability to view the accumulation of amyloid in the brain by non-invasive imaging techniques. Also, evidence of beta amyloid and tau proteins in cerebrospinal fluid has been shown to predict progression of patients with MCI to Alzheimer's in research settings.
The proposed criteria call for extensive testing of these emerging techniques. Biomarker tests need to be standardized for use, even among research groups, and transition points have yet to be developed in which readings determine evidence - or not - of disease. For the earliest stages, much more investigation is needed to determine the usefulness and validity of biomarkers to predict who will develop Alzheimer's dementia.
When could the proposed diagnostic criteria be implemented?
These are initial proposals, and there is a careful path planned for review, comment, and validation of the proposed criteria by the scientific and medical communities. Planned next steps are publication in a peer reviewed medical journal followed by systematic validation of the new proposals through incorporation of the criteria into research projects. Only by doing clinical studies with these proposed new diagnostic guidelines will the specific data needed for their use in research and clinical practice be obtained.
Are any changes going to impact current diagnosis of Alzheimer's?
In medical practice, the proposed changes represent refinements of existing criteria for Alzheimer's dementia. They suggest, for example, that physicians recognize that memory complaints may not always be the presenting symptom. Adding biomarker testing to Alzheimer's diagnosis in clinical practice would be limited; clinicians at specialized medical centers may try to employ the measures to enhance diagnosis, following best practice guidelines, with the understanding that these measures have yet to be fully validated and standardized for use in a clinical setting.
Will the new criteria impact the number of people with Alzheimer's?
It is estimated that as many as 5.1 million Americans live with Alzheimer's disease; many are undiagnosed. At this time, these proposed criteria will not change the number of people who are thought to have Alzheimer's disease. However, the revisions, if validated by further research, may offer an opportunity to identify Alzheimer's disease earlier in the process. This could impact future estimates of the number of people with the potential to develop Alzheimer's dementia, in addition to offering opportunities for earlier treatment, as treatments become available.
Why would it be important to identify the disease process early if there are limited opportunities for intervention?
The last two decades of intensive research into Alzheimer's disease have provided important insights into its development, but currently there are no treatments for delaying the progress of the disease or preventing Alzheimer's entirely. Still, moving to earlier diagnosis, if scientifically validated, is important.
It is now known that the pathology of Alzheimer's disease starts well before signs and symptoms of cognitive decline are noticeable in an individual. Based on new understandings in the biology of the disease, drugs are now being designed and tested in clinical trials to intervene at earlier stages in the disease process. The goal is to slow or stop the progression of cognitive and behavioral decline and enable more years with higher levels of brain function. Updating criteria and moving forward now with their validation should help improve the pace and progress of research toward the goal of earlier intervention.
For individuals and families, improved ways to diagnose Alzheimer's disease, in all of its phases, will provide important benefits. Families often express some relief with diagnosis because it helps explain what is causing changes they are already seeing in themselves or loved ones. Knowing a diagnosis also can help individuals and families with personal, legal, and financial planning for the future. It allows them to access information and support services in the community, and to work together as a family. Learning about Alzheimer's disease, its symptoms and stages, and how to best provide care across the course of the disease can reduce stress and anxiety for caregivers and family members.
Source: American Alzheimer's Association