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Alzheimer’s disease: First steps to stem the epidemic
CHICAGO—For the first time in 27 years, clinical diagnostic criteria for Alzheimer's disease (AD) dementia have been revised, and research guidelines for earlier stages of the disease have been characterized to reflect a deeper understanding of the disorder. The National Institute on Aging/Alzheimer's Association Diagnostic Guidelines for Alzheimer's Disease outline some new approaches for clinicians and provide scientists with more advanced guidelines for moving forward with research on diagnosis and treatments.
Dr. Maria Carrillo, senior director, medical and scientific relations at the Alzheimer's Association, refers to the current situation as an "epidemic" and a "crisis." Association figures show that while breast cancer, prostate cancer, heart disease, stroke and HIV have declined between 2000 and 2008 from 3 percent to 29 percent, AD has increased by 66 percent. In terms of research dollars, federal funding for cancer research is about $6 billion annually, cardiovascular disease research is about $4 billion and HIV/AIDS is about $3 billion each year, the association observes, while AD research funding in fiscal 2011 will be just $480 million.
Prospectively, Carrillo notes that the number of people afflicted with AD will likely triple from 3 million today to 9 million by 2050. And with AD, it is not just those with the disease who suffer, it's also their caregivers. In 2010, 14.9 million family and friends provided 17 billion hours of unpaid care to those with AD and other dementias. The economic value of this unpaid care totaled $202.6 billion. AD is the only cause of death among the top 10 in America without a way to prevent, cure or even slow its progression.
The new guidelines (see sidebar) represent the first updates since 1984, when the fear was that an Orwellian future lay in wait. They were developed by expert panels convened last year by the National Institute on Aging, part of the National Institutes of Health (NIH), and the Alzheimer's Association. Preliminary recommendations were announced at the association's International Conference on Alzheimer's Disease in July 2010, followed by a comment period. The panels purposefully left the guidelines flexible to allow for changes that could come from emerging technologies and advances in understanding of biomarkers and the disease process itself.
The original criteria were the first to address the disease and described only later stages, when symptoms of dementia are already evident. The assumption was that people free of dementia symptoms were disease-free. Diagnosis was confirmed only at autopsy, when the hallmarks of the disease, abnormal amounts of amyloid proteins forming plaques and tau proteins forming tangles, were found in the brain. The updated guidelines cover the full spectrum of the disease as it gradually changes over many years. They describe the earliest preclinical stages of the disease, mild cognitive impairment and dementia due to AD pathology. Importantly, the guidelines now address the use of imaging and biomarkers in blood and spinal fluid that may help determine whether changes in the brain and those in body fluids are due to AD. Biomarkers are increasingly employed in the research setting to detect onset of the disease and to track progression, but cannot yet be used routinely in clinical diagnosis without further testing and validation.
According to Carrillo, the Alzheimer's Association's Research Roundtable provided the original impetus to relook at the AD diagnostic criteria. The roundtable is a consortium of scientists from the pharmaceutical, biotechnology, diagnostics, imaging and cognitive testing industries and senior staff and advisors from the association. Begun in 2003 with four sponsors, the roundtable now includes more than 20 corporate sponsors, each of whom sends several senior scientists to the roundtable to benefit from the state-of-the-field scientific presentations, collegial interactions and networking opportunities. Additional attendees include investigators from academia and such government organizations as the U.S. Food and Drug Administration, the European Medicines Agency and the NIH.
Roundtable members explored a broad range of AD science topics, including: new data and technologies that may improve the diagnosis of AD, especially in its earliest and mildest stages; neuropsychological testing, genetic factors and biochemical and neuroimaging biomarkers that could contribute to an earlier and more accurate AD diagnosis; and lessons learned about clinical trial design that may help shape future clinical trials of drugs aimed at slowing or stopping the progression of AD. The outputs of roundtable meetings are published as articles in the Alzheimer's Association's journal, Alzheimer's & Dementia.
To facilitate clinical trials, the association's TrialMatch provides a free service by Internet and telephone that makes it easy for people with AD, caregivers, families and physicians to locate and connect to AD clinical trials based on personal criteria (diagnosis, stage of disease) and location. It is the first service of its kind in AD, Carrillo notes. More than 40,000 people have visited the website. Nearly 2,500 people have been referred to matched clinical study sites. As a result, there have been at least 101 new enrollments into AD clinical trials.
"We believe that the publication of these (guidelines) is a major milestone for the field," says Dr. William Thies, chief medical and scientific officer at the Alzheimer's Association. "Our vision is that this process will result in improved diagnosis and treatment of Alzheimer's, and will drive research that ultimately will enable us to detect and treat the disease earlier and more effectively. This would allow more people to live full, rich lives without—or with a minimum of—Alzheimer's symptoms."
Alzheimer's Disease: The new diagnostic criteria
To reflect what has been learned, the National Institute on Aging/Alzheimer's Association Diagnostic Guidelines for Alzheimer's Disease cover three distinct stages of the disease:
Preclinical: The stage for which the guidelines only apply in a research setting describes a phase in which brain changes, including amyloid buildup and other early nerve cell changes, may already be in process without evidence of clinical symptoms. In some people, amyloid buildup can be detected with positron emission tomography (PET) scans and cerebrospinal fluid (CSF) analysis, but it is unknown what the risk for progression to AD dementia is for these individuals. Use of these imaging and biomarker tests at this stage is recommended only for research. These biomarkers are still being developed and standardized and are not ready for use by clinicians in general practice.
Mild Cognitive Impairment (MCI): Primarily for research, the guidelines for the MCI stage also clarify existing guidelines for use in a clinical setting. The MCI stage is marked by symptoms of memory problems, enough to be noticed and measured, but not compromising a person's independence. People with MCI may or may not progress to AD dementia. Researchers will particularly focus on standardizing biomarkers for amyloid and for other possible signs of injury to the brain. Currently, biomarkers include elevated levels of tau or decreased levels of beta-amyloid in the CSF, reduced glucose uptake in the brain as determined by PET and atrophy of certain areas of the brain as seen with structural magnetic resonance imaging (MRI).
Alzheimer's Dementia: These criteria apply to the final stage of the disease, and are most relevant for doctors and patients. They outline ways clinicians should approach evaluating causes and progression of cognitive decline. The guidelines also expand the concept of AD dementia beyond memory loss as its most central characteristic. A decline in other aspects of cognition, such as word finding, vision/spatial issues and impaired reasoning or judgment may be the first symptom to be noticed. At this stage, biomarker test results may be used in some cases to increase or decrease the level of certainty about a diagnosis of AD dementia and to distinguish it from other dementias, even as the validity of such tests is still under study for application in everyday clinical practice.