Abstract
Dementia incidence in less-developed countries could be double that of previous estimates
Conventional estimates of dementia incidence in middle-income countries have been too optimistic, suggests one of the largest studies of dementia incidence to date, published Online First in The Lancet. New estimates generated using a cross-culturally validated algorithm that is sensitive to more mild to moderate cases indicate that dementia incidence in middle-income might be much the same as in higher-income countries. Moreover, this is the first study to demonstrate that in less developed countries, as in developed nations, education offers substantial protection against dementia.
Our studies provide supportive evidence for the cognitive reserve hypothesis—that better brain development can mitigate the effects of neurodegeneration in later-life. Our findings suggest that early life influences, education and learning to read and write, may be particularly important for reducing the risk of dementia in late life. We need to understand more about cognitive reserve, how to measure it, and how it is stimulated across cultures, explains Martin Prince from King's College London who led the research. “The high incidence of dementia in less developed countries reminds us that we are facing a global epidemic, and there needs to be more focus on prevention.”
Previous studies using conventional western diagnostic approaches such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV criteria, have indicated that the incidence of dementia (the number of new dementia cases over a given time) might be considerably lower in low- and middle-income countries compared with high-income countries.
A recently developed alternative approach to diagnosing dementia (the 10/66 Dementia Diagnosis) that uses methods developed and validated in 25 low- and middle–income countries, has been shown to provide accurate diagnoses even in those with little or no education.
Unlike many previous studies, restricted to single sites, this research applied both the 10/66 and standard DSM-IV criteria to nearly 12 800 people aged 65 years and older, across nine rural and urban sites in Cuba, the Dominican Republic, Venezuela, Peru, Mexico, and China to compare the incidence of dementia, and to determine whether factors such as education and literacy are protective against the development of dementia.
The new figures indicate that 10/66 dementia incidence is 1.5-.5 times higher than that calculated using standard DSM-IV criteria. After standardization for age, 10/66 dementia incidence was consistently similar to, or higher than, dementia incidence previously observed in European studies.
Individuals with dementia at the start of the study had a nearly three-fold greater risk of dying compared with those who were dementia-free.
The findings also showed that 10/66 dementia incidence was independently associated with increased age, being female, and low education, but not with occupational attainment.
The authors conclude: “The protective effects of education seem to extend to settings where many older people have little or no formal education, and literacy confers an additional independent benefit. These findings…support the notion that cognitive reserve might counter the effects of neurodegeneration later in life.”
In a linked Comment, Kathleen Hall and Hugh Hendrie from Indiana University School of Medicine in the USA say: “The most vexing question posed by Prince and colleagues is that, if the link is substantial, why is incidence of dementia not higher in middle-income countries and even higher in low-income countries than in the high-income countries? One explanation they suggest is that the high case mortality associated with dementia in middle-income countries results in an underestimate of incident cases. [But there is another possible explanation]…that low education may simply be a marker for socioeconomic deprivation including poverty, malnutrition, and toxic environmental exposures…These factors, incidentally, have also been implicated as risk factors for dementia.” (Source: EurekAlert! A service of AAAS and Lancet).
Alcohol intake in the elderly affects risk of cognitive decline and dementia
Alzheimer's disease (AD) and other types of dementia are most common in the very elderly, and are associated with huge health costs. With a rapidly ageing population throughout the world, factors that affect the risk of cognitive decline and dementia are of great importance. A review paper by Kim JW et al published in Psychiatry Investig 2012;9:8-16 on the association between alcohol consumption and cognition in the elderly provides an excellent summary of the potential ways in which alcohol may affect cognitive function and the risk of dementia, both adversely and favorably as alcohol may have both a neuro toxic and neuro protective effect, depending on the dose and drinking pattern. Longitudinal and brain imaging studies in the elderly show that excessive alcohol consumption may increase the risk of cognitive dysfunction and dementia, but regular low to moderate alcohol intake may protect against cognitive decline and dementia and provide cardiovascular benefits.
Studies published from 1971 to 2011 related to alcohol and cognition in the elderly were reviewed using a PubMed search. At present, there are no proven agents to prevent cognitive decline or dementia, although a number of prospective epidemiologic studies have shown a lower risk of such conditions among light to moderate drinkers in comparison with non-drinkers. Other studies have found that beneficial effects are seen only among certain sub-groups of subjects. A recent meta-analysis by Peters et al of subjects over the age of 65 in longitudinal studies concluded that light-to-moderate alcohol consumption, in comparison with abstinence, was associated with approximately 35-45% lower risk of cognitive decline or dementia.
This paper provides a summary of what is known about the mechanisms by which alcohol consumption, especially heavy drinking, can be neurotoxic, and how light-to-moderate drinking may help protect against cognitive decline and dementia. The authors state that their intent is to determine if there is an “optimal pattern of drinking” that may protect the elderly against such conditions.
At present, the mechanisms by which the moderate intake of wine and other alcoholic beverages reduces the risk of cardiovascular diseases are much better defined than they are for cognition. Forum members agree with the authors that further research is needed to evaluate a potential role that alcohol may play in reducing the risk of dementia.
Forum members also agree that, at present, the specific mechanisms of such putative protection are not well defined, and it would be premature to recommend light-to-moderate drinking for reducing the risk of dementia. On the other hand, current biomedical data supports the concept that regular, moderate intake of ethanol is not simply less dangerous for cognitive function, but is positively protective. This is the same conclusion reached by epidemiologic studies. (Source: EurekAlert! A service of AAAS and Boston University Medical Center).
Individuals with dementia more likely to die at home than in nursing homes
INDIANAPOLIS — A new study from the Regenstrief Institute and Indiana University has found that, at time of death, individuals with dementia are more likely to be living at home than in a nursing home. This contradicts the commonly held view that most individuals with dementia in the United States eventually move to nursing homes and die there.
“Transitions in Care for Older Adults With and Without Dementia” appears online in advance of publication in the May 2012 issue of the Journal of the American Geriatrics Society.
Most individuals with dementia, even advanced dementia, die of a physical condition such as heart disease, cancer or pneumonia. This study is the first to track movement of individuals with dementia until death regardless of whether the cause of death was recorded as dementia or as another condition.
The study follows these individuals to determine where they receive care and in what order. Rather than finding individuals with dementia progressing on a straight line from home to hospital to nursing home as presumed, the researchers found that individuals with dementia go back and forth. The number and direction of transitions in care can be numerous and follow no determined path.
“This is a study on what it is like to live with dementia over a five- to 10-year period,” said Regenstrief Institute investigator Christopher Callahan, M.D., Cornelius and Yvonne Pettinga Professor in Aging Research at Indiana University School of Medicine and director of the Indiana University Center for Aging Research. “You probably won't proceed on a straight line from home to hospital to nursing home. You will experience multiple transitions as you progress from mild to moderate to advanced dementia.”
While 74 percent of the time individuals with dementia go to a nursing home after hospitalization, they don't remain there. Approximately a quarter will return to the hospital in less than a month. Many of the remainder will return home.
The researchers determined that a majority of care for those with dementia, even advanced dementia, is provided in the community by families.
“These results challenge previous assumptions,” said Dr. Callahan, who founded the IU Center for Aging Research in 1997. “Our findings will provide important information for all those concerned with managing the care of older adults — families, physicians, social workers, policy-makers, Medicare and Medicaid, insurance companies, hospital and nursing home administrators, as well as aging individuals. Caring for people living with dementia requires the attention of our entire health care system.” (Source: EurekAlert! A service of AAAS and Indiana University School of Medicine).
NIH-funded research provides new clues on how ApoE4 affects Alzheimer's risk
Common variants of the ApoE gene are strongly associated with the risk of developing late-onset Alzheimer's disease, but the gene's role in the disease has been unclear. Now, researchers funded by the National Institutes of Health have found that in mice, having the most risky variant of ApoE damages the blood vessels that feed the brain.
The researchers found that the high-risk variant, ApoE4, triggers an inflammatory reaction that weakens the blood-brain barrier, a network of cells and other components that lines brain's brain vessels. Normally, this barrier allows nutrients into the brain and keeps harmful substances out.
The study appears today in Nature, and was led by Berislav Zlokovic, M.D., Ph.D., director of the Center for Neurodegeneration and Regeneration at the Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles.
“Understanding the role of ApoE4 in Alzheimer's disease may be one of the most important avenues to a new therapy,” Dr.Zlokovic said. “Our study shows that ApoE4 triggers a cascade of events that damages the brain's vascular system,” he said, referring to the system of blood vessels that supply the brain.
The ApoE gene encodes a protein that helps regulate the levels and distribution of cholesterol and other lipids in the body. The gene exists in three varieties. ApoE2 is thought to play a protective role against both Alzheimer's and heart disease, ApoE3 is believed to be neutral, and ApoE4 confers a higher risk for both conditions. Outside the brain, the ApoE4 protein appears to be less effective than other versions at clearing away cholesterol; however, inside the brain, exactly how ApoE4 contributes to Alzheimer's disease has been a mystery.
Dr. Zlokovic and his team studied several lines of genetically engineered mice, including one that lacks the ApoE gene and three other lines that produce only human ApoE2, ApoE3 or ApoE4. Mice normally have only a single version of ApoE. The researchers found that mice whose bodies made only ApoE4, or made no ApoE at all, had a leaky blood-brain barrier. With the barrier compromised, harmful proteins in the blood made their way into the mice's brains, and after several weeks, the researchers were able to detect loss of small blood vessels, changes in brain function, and a loss of connections between brain cells.
“The study demonstrates that damage to the brain's vascular system may play a key role in Alzheimer's disease, and highlights growing recognition of potential links between stroke and Alzheimer's-type dementia,” said Roderick Corriveau, Ph.D., a program director at NIH's National Institute of Neurological Disorders and Stroke (NINDS), which helped fund the research. “It also suggests that we might be able to decrease the risk of Alzheimer's disease among ApoE4 carriers by improving their vascular health.”
The researchers also found that ApoE2 and ApoE3 help control the levels of an inflammatory molecule called cyclophilin A (CypA), but ApoE4 does not. Levels of CypA were raised about five-fold in blood vessels of mice that produce only ApoE4. The excess CypA then activated an enzyme, called MMP-9, which destroys protein components of the blood-brain barrier. Treatment with the immunosuppressant drug cyclosporine A, which inhibits CypA, preserved the integrity of the blood-brain barrier and lessened damage to the brain. An inhibitor of the MMP-9 enzyme had similar beneficial effects. In prior studies, inhibitors of this enzyme have been shown to reduce brain damage after stroke in animal models.
“These findings point to cyclophilin A as a potential new drug target for Alzheimer's disease,” said Suzana Petanceska, Ph.D., a program director at NIH's National Institute on Aging (NIA), which also funded Dr. Zlokovic's study. “Many population studies have shown an association between vascular risk factors in mid-life, such as high blood pressure and diabetes, and the risk for Alzheimer's in late-life. We need more research aimed at deepening our understanding of the mechanisms involved and to test whether treatments that reduce vascular risk factors may be helpful against Alzheimer's.”
Alzheimer's disease is the most common cause of dementia in older adults, and affects more than 5 million Americans. A hallmark of the disease is a toxic protein fragment called beta-amyloid that accumulates in clumps, or plaques, within the brain. Gene variations that cause higher levels of beta-amyloid are associated with a rare type of Alzheimer's that appears early in life, between age 30 and 60.
However, it is the ApoE4 gene variant that is most strongly tied to the more common, late-onset type of Alzheimer's disease. Inheriting a single copy of ApoE4 from a parent increases the risk of Alzheimer's disease by about three-fold. Inheriting two copies, one from each parent, increases the risk by about 12-fold.
Dr. Zlokovic's study and others point to a complex interplay between beta-amyloid and ApoE4. On the one hand, beta-amyloid is known to build up in and damage blood vessels and cause bleeding into the brain. On the other hand, Dr. Zlokovic's data suggest that ApoE4 can damage the vascular system independently of beta-amyloid. He theorizes that this damage makes it harder to clear beta-amyloid from the brain. Some therapies under investigation for Alzheimer's focus on destroying amyloid plaques, but therapies designed to compensate for ApoE4 might help prevent the plaques from forming, he said. (Source: EurekAlert! A service of AAAS and NIH/National Institute of Neurological Disorders and Stroke).
Researchers gain better understanding of mechanism behind tau spreading in the brain and the progression of Alzheimer's disease
Researchers at Mount Sinai School of Medicine have gained insight into the mechanism by which a pathological brain protein called tau contributes to the progression of Alzheimer's disease (AD) and other neurodegenerative disorders. This finding, published in the most recent issue of the Journal of Biological Chemistry, may provide the basis for future investigations on how to prevent tau from damaging brain circuits involved in cognitive function.
Previous studies have shown that the abnormal folding, or misfolding, and buildup of tau are key neuropathological features of many neurodegenerative disorders, including AD. Some research has demonstrated that AD-type tau neuropathology spreads in the brain, seemingly moving from one brain cell to another.
A research group led by Giulio Maria Pasinetti, MD, PhD, Saunders Family Chair in Neurology at Mount Sinai School of Medicine, explored whether misfolded tau released by neurons from the human brain – also known as paired helical filaments (PHFs) – could actually be taken up by surrounding cells and promote the spread of tau neuropathology. The evidence was gathered by treating human neuronal cell lines with human Alzheimer's disease-derived PHFs. The researchers found that not only did the cells in fact internalize the human PHFs, the abnormal tau then propagated its abnormal state to the native, normal tau protein in the cells.
“While these findings are potentially important for possibly opening new therapeutic avenues in Alzheimer's disease, they also shed light on a new therapeutic target for a wide variety of disorders sharing pathological features with Alzheimer's disease, for which there are currently no cures,” said Dr. Pasinetti. “Such diseases include Progressive Supranuclear Palsy, frontotemporal dementia, and other devastating neurodegenerative disorders in which misfolded tau forms aggregates in the brain.”
Next the researchers treated the same cell lines with a grape-seed extract enriched in polyphenols, which are natural compounds found in grapes, fruits, and vegetables, based on 2011 research showing the efficacy of this extract in preventing the progression of AD in mice. Dr. Pasinetti's group found that a subfraction of this natural grape-seed extract enriched in polyphenols was able to prevent the cell-to-cell spread of tau pathology in the same human neuronal cell lines.
“Pathology in neurodegenerative disorders is thought to be initiated decades before disease onset,” said Dr. Pasinetti. “While further research is needed in humans, we hypothesize that this grape-derived compound may be a promising therapy for not only treating but preventing neurodegenerative disorders involving tau neuropathology.”
Dr. Pasinetti and Jun Wang, PhD, Assistant Professor of Neurology at Mount Sinai, are named inventors of a pending application filed by Mount Sinai School of Medicine titled “Methods Preventing Neurodegenerative Disease” related to the use of grape-seed extracts for the treatment of neurodegenerative diseases and may benefit financially from this patent. (Source: EurekAlert! A service of AAAS and The Mount Sinai Hospital / Mount Sinai School of Medicine).
Eating more berries may reduce cognitive decline in the elderly
Flavonoid-rich blueberries and strawberries offer most benefit
Blueberries and strawberries, which are high in flavonoids, appear to reduce cognitive decline in older adults according to a new study published today in Annals of Neurology, a journal of the American Neurological Association and Child Neurology Society. The study results suggest that cognitive aging could be delayed by up to 2.5 years in elderly who consume greater amounts of the flavonoid-rich berries.
Flavonoids are compounds found in plants that generally have powerful antioxidant and anti-inflammatory properties. Experts believe that stress and inflammation contribute to cognitive impairment and that increasing consumption of flavonoids could mitigate the harmful effects. Previous studies of the positive effects of flavonoids, particularly anthocyanidins, are limited to animal models or very small trials in older persons, but have shown greater consumption of foods with these compounds improve cognitive function.
According to the 2010 U.S. Census, elderly Americans—those 65 years of age and older—increased by 15% between 2000 and 2010, faster than the total U.S. population, which saw a 9.7% increase during the same time period. “As the U.S. population ages, understanding the health issues facing this group becomes increasingly important,” said Dr. Elizabeth Devore with Brigham and Women's Hospital and Harvard Medical School in Boston, Mass. “Our study examined whether greater intake of berries could slow rates of cognitive decline.”
The research team used data from the Nurses' Health Study—a cohort of 121,700 female, registered nurses between the ages of 30 and 55 who completed health and lifestyle questionnaires beginning in 1976. Since 1980 participants were surveyed every four years regarding their frequency of food consumption. Between 1995 and 2001, cognitive function was measured in 16,010 subjects over the age of 70 years, at 2-year intervals. Women included in the present study had a mean age of 74 and mean body mass index of 26.
Findings show that increased consumption of blueberries and strawberries appear to slow cognitive decline in older women. A greater intake of anthocyanidins and total flavonoids was also associated with reduce cognitive degeneration. Researchers observed that women who had higher berry intake delayed cognitive aging by up to 2.5 years. The authors caution that while they did control for other health factors in the modeling, they cannot rule out the possibility that the preserved cognition in those who eat more berries may be also influenced by other lifestyle choices, such as exercising more.
“We provide the first epidemiologic evidence that berries may slow progression of cognitive decline in elderly women,” notes Dr. Devore. “Our findings have significant public health implications as increasing berry intake is a fairly simple dietary modification to test cognition protection in older adults.” (Source: EurekAlert! A service of AAAS and Wiley-Blackwell).
Reduction of excess brain activity improves memory in amnestic mild cognitive impairment
Research published by Cell Press in the May 10th issue of the journal Neuron, describes a potential new therapeutic approach for improving memory and modifying disease progression in patients with amnestic mild cognitive impairment. The study finds that excess brain activity may be doing more harm than good in some conditions that cause mild cognitive decline and memory impairment.
Elevated activity in specific parts of the hippocampus, a brain region involved in memory, is often seen in disorders associated with an increased risk for Alzheimer's disease. Amnestic mild cognitive impairment (aMCI), where memory is worse than would be expected for a person's age, is one such disorder. “In the case of early aMCI, it has been suggested that the increased hippocampal activation may serve a beneficial function by recruiting additional neural resources to compensate for those that are lost,” explains senior study author, Dr. Michela Gallagher, from Johns Hopkins University. “However, animal studies have raised the alternative view that this excess activation may be contributing to memory impairment.”
Dr. Gallagher and colleagues tested how a reduction of hippocampal activity would impact human patients with aMCI. The researchers used a low dose of a drug used clinically to treat epilepsy, for the purpose of reducing hippocampal activity in subjects with aMCI to levels that were similar to activity levels in healthy, age-matched subjects in a control group. The researchers found that treatment with the drug improved performance on a memory task. These findings point to the therapeutic potential of reducing excess activation in the hippocampus in aMCI.
The results also have broader significance as elevated activity in the hippocampus is also observed in other conditions that are thought to precede Alzheimer's disease, and may be one of the underlying mechanisms of neurodegeneration. “Apart from a direct role in memory impairment, there is concern that elevated activity in vulnerable neural networks could be causing additional damage and, possibly, widespread disease-related degeneration that underlies cognitive decline and the conversion to Alzheimer's disease,” concludes Dr. Gallagher. “Therefore, reducing the elevated activity in the hippocampus may help to restore memory and protect the brain.” (Source: EurekAlert! A service of AAAS and Cell Press).