AAIC Press Release
New Research Reported at the Alzheimer's Association International Conference Advances Validation of New Diagnostic Guidelines
VANCOUVER, July 18, 2012 – In April 2011, the U.S. National Institute on Aging (NIA) and the Alzheimer's Association® published new criteria and guidelines for the diagnosis of Alzheimer's disease. These guidelines separate the progression of Alzheimer's into three phases: (1) pre-clinical (or pre-symptomatic) Alzheimer's disease, (2) mild cognitive impairment (MCI) due to Alzheimer's disease, and (3) Alzheimer's disease dementia. Phases (1) and (2) were clearly described as research criteria in need of validation, especially for their first-time incorporation of biomarkers* into the diagnostic process.
* A biomarker is something in the body that can be objectively measured as an indicator of normal biological processes, disease processes, or responses to therapy. For example, blood cholesterol levels are a biomarker for heart disease. A variety of imaging (amyloid PET, whole brain and hippocampal MRI) and fluid (amyloid and tau protein levels in blood and cerebrospinal fluid) biomarkers are under investigation in Alzheimer's disease.
Two scientific abstracts reported at the Alzheimer's Association International Conference® 2012 (AAIC® 2012) in Vancouver by scientists with the Mayo Clinic Study of Aging (MCSA) provide encouraging data on their attempts to validate phases (1) and (2) of the new diagnostic criteria and guidelines. MCSA is a population-based study of more than 3,000 people age 70 to 89 at the time of enrollment living in Olmsted County, MN, created to investigate the prevalence, incidence and risk factors for MCI and dementia.
"The NIA-Alzheimer's Association guidelines proposed diagnostic criteria for what has become known as the ‘Alzheimer's disease spectrum.' The most advanced phase – dementia due to Alzheimer's – is characteristic of what had been called Alzheimer's in previous years," said Ronald Petersen, PhD, MD, MCSA principal investigator and Director of the Mayo Clinic Alzheimer's Disease Research Center in Rochester, MN. Petersen is a member of the Alzheimer's Association Board of Directors.
"The spectrum now has expanded to include milder cases, such as those people found to have MCI due to Alzheimer's, and to the preclinical phase of Alzheimer's, when people do not have any outwardly measureable cognitive impairment but may have biological changes related to Alzheimer's," Petersen said.
"It is now generally accepted that Alzheimer's begins years, perhaps even decades, before symptoms are noticeable. Before the proposal of these new diagnostic guidelines, there was is no single, generally accepted way to identify the disease in its earliest phases – before symptoms are evident. As these two new reports show, we are making good progress in that direction," said William Thies, PhD, Alzheimer's Association chief medical and scientific officer.
"Earlier detection of people at highest risk for Alzheimer's and those who have the earliest forms of the disease will help us identify the right people for risk reduction and prevention trials, and will move the field further in the direction of early detection and treatment," Thies said.
NIA-AA MCI Alzheimer's Diagnostic Guidelines Applied to the Mayo Clinic Study of Aging
The proposed NIA-Alzheimer's Association diagnostic criteria for MCI due to Alzheimer's are based on the clinical presentation of people with MCI and are augmented by various biomarkers, the goal of which is to enhance the likelihood that the observed symptoms are due to underlying physical and biological changes caused by Alzheimer's disease. Three levels of certainty have been introduced in the new criteria – uninformative, intermediate and highest – which are ordered according to the availability of biomarkers. The applicability of these proposed new criteria in the general population has not been widely evaluated.
Petersen and colleagues assessed the MCI criteria by applying them to 156 participants with MCI in the MCSA. For the purpose of this study, the participants were evaluated with various imaging technologies such as quantitative MRI scans, FDG PET scans, and amyloid imaging using C11 Pittsburgh Compound B (PiB) PET scans.
The researchers found that:
- Approximately 16% of subjects with a clinical diagnosis of MCI did not have any evidence for positive imaging biomarkers.
- Another 12% had evidence for the presence of amyloid on PiB scanning but no other signs of neurodegeneration.
- An additional 55% of the subjects had evidence for both amyloid deposition on PiB scanning and either atrophy on MRI or an FDG PET scan indicative of hypometabolism, or both.
- Finally, 17% of the subjects had evidence of neurodegeneration, atrophy on MRI, hypometabolism on FDG PET or both, without having evidence for amyloid deposition.
- The frequency of Apolipoprotein E4 carrier status was highly correlated with the presence of amyloid.
In sum, the researchers found that the majority of study subjects with MCI had evidence for amyloid deposition, neurodegeneration or both. However, some subjects classified as having MCI had no evidence of the presence of Alzheimer's biomarkers.
"These results indicate that the new diagnostic criteria for MCI due to Alzheimer's work quite well," Petersen said. "Sixty-seven percent of the participants had evidence for either amyloid deposition or amyloid plus a marker for neurodegeneration. As such, about two-thirds of the participants were thought to be highly likely to develop the dementia due to Alzheimer's. Ultimately, the validity of these new criteria will be determined by the long-term outcome of these subjects."
"Interestingly, a significant number of participants had no evidence of any biomarker positivity, and another group had evidence of brain cell loss but no amyloid. The latter group likely represents non-Alzheimer's causes of MCI, such as vascular disease," Petersen said.
Examination of the NIA-AA Proposed Diagnostic Guidelines for Preclinical Alzheimer's Disease
The proposed NIA-Alzheimer's Association diagnostic guidelines for preclinical Alzheimer's disease are based on the presence of abnormal levels of beta-amyloid biomarkers. Beta-amyloid is the main component of amyloid plaques, which are sticky deposits found in the brains of people with Alzheimer's; plaques are one of the two hallmark brain lesions of Alzheimer's (the other are known as tau tangles).
Three stages are proposed within the preclinical Alzheimer's disease pathway:
- Stage 1 – detection of abnormal levels of beta-amyloid.
- Stage 2 – stage 1 plus evidence of brain neurodegeneration.
- Stage 3 – stage 2 plus subtle cognitive changes.
David Knopman, MD, and colleagues examined 443 cognitively normal subjects from the MCSA who underwent brain magnetic resonance (MR) scans, 18Fluorodeoxyglucose (FDG) and Pittsburgh compound B (PiB) positron emission tomography (PET) scans, and full clinical and diagnostic assessments. Features evaluated by structural MR included hippocampal volume, white matter hyperintensity (WMH) volume and number of infarcts.**
** The hippocampus is a brain region involved in memory that is known to deteriorate in people with Alzheimer's. WMH and infarcts (strokes seen on MR scans) are measures of cerebrovascular disease. Hippocampal atrophy and glucose hypometabolism in regions on FDG PET are common in Alzheimer's, though they may occur due to other brain diseases.
The researchers identified a group of study participants didn't fit any of the three proposed stages – they had normal beta-amyloid biomarkers and abnormal levels of neurodegeneration. They were assigned to a group labeled "suspected non-Alzheimer pathophysiology" (sNAP).
They found that:
- 189 (43%) had no abnormal imaging biomarkers.
- 137 (31%) fell into stages 1 to 3 of the preclinical Alzheimer's pathway.
- 102 (23%) were in the sNAP group.
- 15 (3%) were unclassified.
According to the researchers, people in the preclinical Alzheimer's pathway (stages 1-3) were more likely to progress to cognitive impairment than the biomarker negative group (p<0.001). Those in Alzheimer's preclinical stages 2 and 3 were more likely to progress than the sNAP group (p=0.04). There was no difference in outcome between the sNAP group and the biomarker negative group.
"The NIA-AA preclinical Alzheimer's guidelines identify a group of cognitively normal persons who are at risk for cognitive decline. Those who had abnormal beta-amyloid imaging results with neurodegeneration carried a higher risk than neurodegeneration alone," Knopman said. "The use of these advanced imaging tools to explore the earliest brain changes in cognitively normal persons offers us an exciting new window to identify the markers that may eventually lead to dementia."
"We were surprised by the number of people that fell into the sNAP group and wished to learn more about them," Knopman added.
According to Knopman, they found that the sNAP group and those with Alzheimer's preclinical stages 2 and 3 were similar with one exception: the sNAP group had a lower proportion (14%) of people who carried the Alzheimer's risk gene, APOE-e4, than the preclinical Alzheimer's phases 2 & 3. Otherwise, the sNAP group and those people in preclinical Alzheimer's stages 2 and 3 had similar patterns of structure, function and association with clinical features.
"In this group of cognitively normal people, it was not necessary to have abnormal levels of beta-amyloid in the brain to produce slowdowns in energy processing and physical atrophy comparable to what we usually see in the presence of high levels of brain beta amyloid," Knopman said.
The Alzheimer's Association International Conference® (AAIC) is the world's largest conference of its kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders. As a part of the Alzheimer's Association's research program, AAIC serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.
About the Alzheimer's Association®
The Alzheimer's Association is the world's leading voluntary health organization in Alzheimer's care, support and research. Our mission is to eliminate Alzheimer's through the advancement of research, to provide and enhance care and support for all affected, and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. Visit www.alz.org or call 800-272-3900.
- Ronald Petersen, et al. NIA-AA MCI Criteria Applied to the Mayo Clinic Study of Aging. (Funders: National Institute on Aging, Robert H. and Clarice Smith, Abigail Van Buren Alzheimer's Disease Research Program)
- David Knopman, et al. Clinical Outcomes for Stages of NIA-AA Preclinical Alzheimer's Disease. (Funders: National Institute on Aging, Robert H. and Clarice Smith, Abigail Van Buren Alzheimer's Disease Research Program)
O4-08-05 Wednesday, July 18 / Oral, 3:30-5 pm
20-Year alcohol consumption patterns and cognitive impairment in older women
Tina Hoang1, Deborah Barnes2, Amy Byers3, Kristine Yaffe3
1NCIRE, San Francisco, California, United States; 2University of California, San Francisco, California, United States; 3University of California, San Francisco; San Francisco Veterans Affairs Medical Center, California, United States
Presenting author e-mail: email@example.com
Background: The association between moderate alcohol consumption and cognitive impairment in late-life is controversial with several studies suggesting a protective effect. Few studies have considered patterns of alcohol consumption over time, especially in very late-life.
Methods: We studied 1306 women ≥ 65 years old, enrolled in a prospective cohort study and followed for 20 years. Frequency of current and past alcohol use was assessed by self report at baseline and current use reassessed at midpoint (years 6 and 8) and late phases (years 10 and 16) of follow-up. Clinically significant cognitive impairment (mild cognitive impairment and dementia) was adjudicated by an expert panel at year 20.
Results: At baseline, mean age of participants was 68.3(SD=2.8); 40.6% were nondrinkers, 50.4% were light drinkers (0 to 7 drinks/week), and 9.0% were moderate drinkers (≥7 and ‰¤ 14 drinks/week). Heavy drinkers, >14 drinks/week were excluded, n=10 (0.8%). Women who reported drinking more in the past than at baseline were at increased risk of developing cognitive impairment (adjusted OR [aOR]=1.30, 95% CI 1.02-1.65). Moderate drinkers at baseline or at midpoint had similar risk of cognitive impairment compared to non-drinkers; however, moderate drinkers in the late phase were more likely to develop cognitive impairment (aOR=1.62, 95% CI 1.14-2.32). Women who changed from nondrinking to drinking over the follow-up period also had an increased risk of cognitive impairment (aOR=3.07, 95% CI 1.39-6.76), while transitioning from drinking to nondrinking over time was not associated with cognitive impairment.
Conclusions: In this older female cohort, moderate alcohol consumption was not protective. We found that heavier use earlier in life, moderate use in late-life, and transitioning to drinking in late-life were associated with an increased risk of developing cognitive impairment. These findings suggest that alcohol use in late-life may not be beneficial for cognitive function in older women.
O4-08-06 Wednesday, July18 / Oral, 3:30-5 pm
Heavy Episodic Drinking and Risk of Cognitive Decline in Older Adults
Iain Lang1, Kenneth Langa2, Robert Wallace3, David Llewellyn1
1Peninsula College of Medicine and Dentistry, Exeter, United Kingdom; 2University of Michigan, Ann Arbor, Michigan, United States; 3University of Iowa, Iowa City, Iowa, United States
Presenting author e-mail: firstname.lastname@example.org
Background: Although the consequences for cognitive function of overall levels of alcohol consumption have been studied little is known about the possible harmful effects of heavy episodic ("binge") drinking in older people. The purpose of this study was to assess the effects of heavy episodic drinking in older people in the United States on cognitive decline and depressive symptoms.
Methods: Secondary analysis of data from 5,075 participants aged ≥65 years in the Health and Retirement Study (HRS), a biennial, longitudinal, nationally representative survey of US adults aged over 50. Baseline data were collected in 2002 and participants were followed up for eight years. Overall level of alcohol consumption and level of heavy episodic drinking (consumption of four or more drinks on one occasion) were assessed at baseline and models were adjusted for age, sex, mean number of drinks/day, baseline cognitive function score, race, level of education, household wealth, and smoking status. Outcomes were change in cognitive function and memory (assessed using the Telephone Interview of Cognitive Status).
Results: Binge drinking on average once a month or more frequently was reported by 8.3% of men and 1.5% of women, and binge drinking on average twice a month or more was reported by 4.3% of men and 0.5% of women. In participants who reported heavy episodic drinking once per month or more the odds ratios (OR) of being in the group experiencing the greatest 10% of decline in cognitive function were 1.62 (95% Confidence Interval (CI) 0.99 to 2.65) and of decline in memory were 1.27 (95% CI 0.71 to 2.28). In those reporting heavy episodic drinking twice per month or more the OR of being in the group experiencing the greatest 10% of decline in cognitive function were 2.47 (95% CI 1.31 to 4.60) and of decline in memory were 2.49 (95% CI 1.19 to 5.21). Outcomes were similar in men and women when analyzed separately.
Conclusions: In community-dwelling older adults, heavy episodic drinking is associated with an increased risk of cognitive decline.
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