Abstract
Inherited Alzheimer's detectable 20 years before dementia
Inherited forms of Alzheimer's disease may be detectable as many as 20 years before problems with memory and thinking develop, scientists will report July 20, 2011, at the Alzheimer's Association International Conference on Alzheimer's Disease in Paris.
Identifying Alzheimer's in its earliest stages is a top priority for researchers. Many think that by the time symptoms become apparent, Alzheimer's disease has already damaged the brain extensively, making it difficult or impossible to restore memory and other mental abilities.
“We want to prevent damage and loss of brain cells by intervening early in the disease process — even before outward symptoms are evident, because by then it may be too late,” says Alzheimer's researcher and physician Randall Bateman, MD, of Washington University School of Medicine in St. Louis and an associate director of the Dominantly Inherited Alzheimer's Network (DIAN), an international study of inherited forms of Alzheimer's.
Initial DIAN results confirm and expand upon earlier insights from studies of the more common sporadic forms of Alzheimer's, including data suggesting that changes in the levels of biological markers in the spinal fluid can be detected years before dementia.
Scientists say the results demonstrate the feasibility of clinical trials to prevent Alzheimer's in DIAN participants. Planning for those trials, which may start as early as next year, is currently under way.
“New treatments may have risks, so to treat patients prior to symptoms we must sure that we have a firm grasp on who will develop Alzheimer's dementia,” says DIAN director John C. Morris, MD, Harvey A. and Dorismae Hacker Friedman Professor of Neurology at Washington University. “If we can find a way to delay or prevent dementia symptoms in DIAN participants, that would be a tremendous success story and very helpful in our efforts to treat the much more common sporadic form of the illness.”
DIAN researchers are studying members of families who have mutations in one of three genes: amyloid precursor protein, presenilin 1 or presenilin 2. Participants with these mutations are certain to develop Alzheimer's disease early, with symptoms beginning in their 50s, 40s, or, in some rare cases, 30s.
DIAN, which includes research centers in the United States, the United Kingdom and Australia, is the largest study yet of these rare forms of dominantly inherited Alzheimer's. To date, 184 participants have been enrolled, nearly half the overall recruitment goal. This has allowed initial comparisons among participants who carry a genetic mutation for Alzheimer's but are still asymptomatic, those who have a mutation and have Alzheimer symptoms, and those who do not have a mutation and thus are unaffected.
By looking at the age of symptom onset in a parent who passed an Alzheimer's mutation to a DIAN participant, scientists can establish an estimated age of onset for a study participant. If a parent developed dementia at the age of 50, they would expect a child who inherited the mutation to develop dementia at roughly the same age. As a result, scientists can start amassing a detailed chronology of disease progression that covers the many years Alzheimer's is active in the brain but still before the onset of dementia.
“Based on what we see in our population, brain chemistry changes can be detected up to 20 years before the expected age of symptomatic onset,” Bateman says. “These Alzheimer' s-related changes can be specifically targeted for prevention trials in patients with inherited forms of Alzheimer's.”
Washington University researchers, including Bateman, Morris and Anne Fagan, PhD, research professor of neurology, will report initial results from DIAN, including confirmation of the value of disease indicators from cerebrospinal fluid analyses. Participants who carry the mutations but are still asymptomatic have significantly lower levels of amyloid beta and higher levels of tau protein in their cerebrospinal fluid than participants without the mutations.
Amyloid beta normally is cleared from the brain and into the spinal fluid. Scientists theorize that decreases in spinal fluid levels of amyloid beta reflect a buildup of this sticky protein fragment in the brain, where it forms Alzheimer's plaques. Tau protein is a structural component of central nervous system cells. Its increase in cerebrospinal fluid is thought to be a byproduct of damage to brain cells. (Source: EurekAlert! A service of AAAS and The Washington University School of Medicine).
Keeping up your overall health may keep dementia away
ST. PAUL, Minn. – Improving and maintaining health factors not traditionally associated with dementia, such as denture fit, vision and hearing, may lower a person's risk for developing dementia, according to a new study published in the July 13, 2011, online issue of Neurology®, the medical journal of the American Academy of Neurology.
“Our study suggests that rather than just paying attention to already known risk factors for dementia, such as diabetes or heart disease, keeping up with your general health may help reduce the risk for dementia,” said study author Kenneth Rockwood, MD, of Dalhousie University in Halifax, Nova Scotia, Canada.
The study included 7,239 people free of dementia ages 65 and older from the Canadian Study of Health and Aging. After five years and again after 10 years, they were evaluated for Alzheimer's disease and all types of dementia. Participants were asked questions about 19 health problems not previously reported to predict dementia. Problems included arthritis, trouble hearing or seeing, denture fit, chest or skin problems, stomach or bladder troubles, sinus issues, broken bones and feet or ankle conditions, among others.
After 10 years, 2,915 of the participants had died, 883 were cognitively healthy, 416 had Alzheimer's disease, 191 had other types of dementia, 677 had cognitive problems but no dementia, and the cognitive status of 1,023 people was not clear.
The study found that each health problem increased a person's odds of developing dementia by 3.2 percent compared to people without such health problems. Older adults without health problems at baseline had an 18 percent chance to become demented in 10 years, while such risk increased to 30 percent and 40 percent in those who had 8 and 12 health problems, respectively.
“More research needs to be done to confirm that these non-traditional health problems may indeed be linked to an increased risk of dementia, but if confirmed, the consequences of these findings could be significant and could lead to the development of preventive or curative strategies for Alzheimer's disease,” said Jean François Dartigues, MD, PhD, with the National Institute of Health and Medical Research (INSERM) in Paris, France, in an accompanying editorial. (Source: EurekAlert! A service of AAAS and The American Academy of Neurology).
Study demonstrates how memory can be preserved -- and forgetting prevented
BOSTON – As any student who's had to study for multiple exams can tell you, trying to learn two different sets of facts one after another is challenging. As you study for the physics exam, almost inevitably some of the information for the history exam is forgotten. It's been widely believed that this interference between memories develops because the brain simply doesn't have the capacity necessary to process both memories in quick succession. But is this truly the case?
A new study by researchers at Beth Israel Deaconess Medical Center (BIDMC) suggests that specific brain areas actively orchestrate competition between memories, and that by disrupting targeted brain areas through transcranial magnetic stimulation (TMS), you can preserve memory -- and prevent forgetting.
The findings are described in the June 26 Advance On-line issue of Nature Neuroscience.
“For the last 100 years, it has been appreciated that trying to learn facts and skills in quick succession can be a frustrating exercise,” explains Edwin Robertson, MD, DPhil, an Associate Professor of Neurology at Harvard Medical School and BIDMC. “Because no sooner has a new memory been acquired than its retention is jeopardized by learning another fact or skill.”
Robertson, together with BIDMC neurologist and coauthor Daniel Cohen, MD, studied a group of 120 college-age students who performed two concurrent memory tests. The first involved a finger-tapping motor skills task, the second a declarative memory task in which participants memorized a series of words. (Half of the group performed the tasks in this order, while a second group learned these same two tasks in reverse order.)
“The study subjects performed these back-to-back exercises in the morning,” he explains. “They then returned 12 hours later and re-performed the tests. As predicted, their recall for either the word list or the motor-skill task had decreased when they were re-tested.”
In the second part of the study, Robertson and Cohen administered TMS following the initial testing. TMS is a noninvasive technique that uses a magnetic simulator to generate a magnetic field that can create a flow of current in the brain.
“Because brain cells communicate through a process of chemical and electrical signals, applying a mild electrical current to the brain can influence the signals,” Robertson explains. In this case, the researchers targeted two specific brain regions, the dorsolateral prefrontal cortex and the primary motor cortex. They discovered that by applying TMS to specific brain areas, they were able to reduce the interference and competition between the motor skill and word-list tasks and both memories remained intact.
“This elegant study provides fundamental new insights into the way our brain copes with the challenge of learning multiple skills and making multiple memories,” says Alvaro Pascual-Leone, MD, PhD, Director of the Berenson-Allen Center for Noninvasive Brain Stimulation at BIDMC. “Specific brain structures seem to carefully balance how much we retain and how much we forget. Learning and remembering is a dynamic process and our brain devotes resources to keep the process flexible. By better understanding this process, we may be able to find novel approaches to help enhance learning and treat patients with memory problems and learning disabilities.”
“Our observations suggest that distinct mechanisms support the communication between different types of memory processing,” adds Robertson. “This provides a more dynamic and flexible account of memory organization than was previously believed. We've demonstrated that the interference between memories is actively mediated by brain areas and so may serve an important function that has previously been overlooked.” (Source: EurekAlert! A service of AAAS and The Beth Israel Deaconess Medical Center).
Advances in research into Alzheimer's disease
Transporter proteins at the blood CSF barrier and vitamin D may help prevent amyloid beta build-up in the brain
Advances in research into Alzheimer's disease: transporter proteins at the blood CSF barrier and vitamin D may help prevent amyloid β build up in the brain
Advancing age is a major risk factor for Alzheimer's disease and is associated with build- up of the peptide amyloid β in the brain. New research published in BioMed Central's open access journal Fluids and Barriers of the CNS shows that removal of amyloid β from the brain depends on vitamin D and also on an age-related alteration in the production of transporter proteins which move amyloid β in and out of the brain.
Low levels of vitamin D are thought to be involved in age-related decline in memory and cognition and are also associated with Alzheimer's disease. Researchers from Tohoku University, Japan, looked at the mechanism behind this and found that vitamin D injections improved the removal of amyloid β from the brain of mice.
Prof Tetsuya Terasaki said, “Vitamin D appears increase transport of amyloid β across the blood brain barrier (BBB) by regulating protein expression, via the vitamin D receptor, and also by regulating cell signaling via the MEK pathway. These results lead the way towards new therapeutic targets in the search for prevention of Alzheimer's disease.”
The transport of amyloid β across the BBB is known to be orchestrated by transporter proteins such as LRP-1 and P-gp, which move amyloid β out of the brain, and RAGE, which controls influx. Looking at the transport of amyloid β from blood to cerebrospinal fluid (CSF), and from CSF to blood, researchers from Rhode Island Hospital and The Warren Alpert Medical School, found that LRP-1 and P-gp at the blood-cerebrospinal fluid barrier (BCSFB), increased with age so increasing removal of amyloid β from the CSF and brain.
Prof Gerald Silverberg said, “While increased production of transporter proteins at the blood CSF barrier may help amyloid β removal from the older brain, production of these proteins eventually fails. This failure may be an important event in brain function as we age and for people with Alzheimer's disease.” (Source: EurekAlert! A service of AAAS and BioMed Central).
Study helps explain ‘sundowning,’ an anxiety syndrome in elderly dementia patients
COLUMBUS, Ohio – New research provides the best evidence to date that the late-day anxiety and agitation sometimes seen in older institutionalized adults, especially those with dementia, has a biological basis in the brain.
The findings could help explain “sundowning,” a syndrome in which older adults show high levels of anxiety, agitation, general activity and delirium in late afternoon and evening, before they would normally go to bed.
“It's a big problem for caregivers. Patients can get aggressive and very disruptive,” said Tracy Bedrosian, lead author of the study and a doctoral student in neuroscience at Ohio State University.
“There have been a few clinical studies documenting sundowning, but until now there hasn't been research in animals to see what's going on in the brain to explain this.”
The new study found that aged mice showed significantly more activity and more anxiety-like behaviors in the hours before they would normally sleep when compared to middle-aged mice – just like sundowning in humans.
In these aged mice, the researchers found changes in parts of their brain associated with attention, emotions, and arousal, all of which could be associated with the behavior seen in sundowning.
In addition, mice that were genetically engineered to have an Alzheimer's-like disease also showed more anxiety before sleep than did other mice.
“Some people have argued that sundowning could be explained just by a buildup of frustration of older people who couldn't communicate their needs over the course of the day, or by other factors,” said Randy Nelson, co-author of the study and professor of neuroscience and psychology at Ohio State.
“But our findings suggest there is a real phenomenon going on here that has a biological basis.”
The study will appear in the online Early Edition of the Proceedings of the National Academy of Sciences.
In the first experiment, researchers compared middle-aged adult mice (7 months old) with aged mice (29 months old) that would resemble humans in their 80s.
Results showed that the aged mice were significantly more active than middle-aged mice in the two to three hours before they would normally go to sleep.
“The middle-aged mice had a distinct pattern of activity, with three peaks of activity during their waking hours,” Bedrosian said.
“But the aged mice had a flattened rhythm in which they showed the same level of activity throughout their active period.”
That means that in the evening, when the middle aged mice would slow down compared to their peak activity levels, the aged mice kept going.
The mice were also tested for anxiety-like behaviors at two different times during their waking hours. The mice were placed in a maze where they were allowed to explore open areas – which are more anxiety-producing – or hide in enclosed areas.
The middle-aged mice showed consistent levels of anxiety at both times of the day. However, the aged mice showed more anxiety when tested soon before they would have gone to sleep, which is consistent with sundowning, Bedrosian said.
There were also differences in the brains of the aged mice when compared to the middle aged mice. The researchers looked specifically at the cholinergic system, because loss of function in that system is associated with dementia and many of the circadian changes associated with ageing.
Findings in aged mice showed greater expression of a certain enzyme – acetylcholinesterase – before sleep than earlier in the day. High levels of this enzyme are associated with anxiety and agitation.
However, in the middle-aged mice, there were no time-of-day differences in the expression of this enzyme.
Nelson noted that drugs used to control levels of acetylcholinesterase are sometimes used on dementia patients, although there has been no research evidence that it actually had an effect on sundowning.
“These drugs were prescribed for other purposes, but it also seemed to calm patients down. Now we have some evidence on why it works,” Nelson said.
The researchers also found differences in expression of two other proteins in the brains of the aged mice that are also associated with behavioral disturbances.
“All of these results converge to suggest there are changes in the cholinergic systems of aged mice that may be contributing to the anxiety and agitation symptoms that we documented,” Bedrosian said.
In another experiment, the researchers used mice that were genetically engineered to develop Alzheimer's-like disease in their brain. They were compared, at nine months of age, to similar wild-type mice of the same age.
The Alzheimer's-like mice showed more anxiety-type behaviors when tested before they would normally sleep than they did when tested earlier in their waking period. That is consistent with sundowning in humans, the researchers said.
However, the wild-type mice showed no differences in anxiety levels based on the time of day they were tested.
Nelson said one of the theories about sundowning is that it is tied to disruptions that often occur in the biological clocks of older people, where their sleep-wake cycles are fragmented.
To test this theory, the researchers also treated the aged mice with melatonin for four weeks in order to help consolidate their circadian rhythms. However, this treatment did not work to reduce anxiety issues in the mice.
Nelson said melatonin alone may not work because it doesn't deal with the disruptions in the cholinergic system that was identified in this study.
“We need to study whether treating cholinergic dysfunction alone or in combination with melatonin treatment will help deal with sundowning symptoms,” he said. (Source: EurekAlert! A service of AAAS and Ohio State University).
Alzheimer's prevention in your pantry
Tel Aviv University researcher discovers a cinnamon extract to inhibit progression of Alzheimer's disease
Alzheimer's, the degenerative brain disorder that disrupts memory, thought and behavior, is devastating to both patients and loved ones. According to the Alzheimer's Association, one in eight Americans over the age of 65 suffers from the disease. Now Tel Aviv University has discovered that an everyday spice in your kitchen cupboard could hold the key to Alzheimer's prevention.
An extract found in cinnamon bark, called CEppt, contains properties that can inhibit the development of the disease, according to Prof. Michael Ovadia of the Department of Zoology at Tel Aviv University. His research, conducted in collaboration with Prof. Ehud Gazit, Prof. Daniel Segal and Dr. Dan Frenkel, was recently published in the journal PLoS ONE.
Taking a cue from the ancient world
Prof. Ovadia was inspired to investigate the healing properties of cinnamon by a passage in the Bible. It describes high priests using the spice in a holy ointment, he explains, presumably meant to protect them from infectious diseases during sacrifices. After discovering that the cinnamon extract had antiviral properties, Prof. Ovadia empirically tested these properties in both laboratory and animal Alzheimer's models.
The researchers isolated CEppt by grinding cinnamon and extracting the substance into an aqueous buffer solution. They then introduced this solution into the drinking water of mice that had been genetically altered to develop an aggressive form of Alzheimer's disease, and fruit flies that had been mutated with a human gene that also stimulated Alzheimer's disease and shortened their lifespan.
After four months, the researchers discovered that development of the disease had slowed remarkably and the animals' activity levels and longevity were comparable to that of their healthy counterparts. The extract, explains Prof. Ovadia, inhibited the formation of toxic amyloid polypeptide oligomers and fibrils, which compose deposits of plaque found in the brains of Alzheimer's patients.
In the test-tube model, the substance was also found to break up amyloid fibers, similar to those collected in the brain to kill neurons. According to Prof. Ovadia, this finding indicates that CEppt may not just fight against the development of the disease, but may help to cure it after Alzheimer's molecules have already formed. In the future, he says, the team of researchers should work towards achieving the same result in animal models.
Adding a dash of cinnamon
Don't rush to your spice cabinet just yet, however. It would take far more than a toxic level of the spice — more than 10 grams of raw cinnamon a day — to reap the therapeutic benefits. The solution to this medical catch-22, Prof. Ovadia says, would be to extract the active substance from cinnamon, separating it from the toxic elements.
“The discovery is extremely exciting. While there are companies developing synthetic AD inhibiting substances, our extract would not be a drug with side effects, but a safe, natural substance that human beings have been consuming for millennia,” says Prof. Ovadia.
Though it can't yet be used to fight Alzheimer's, cinnamon still has its therapeutic benefits — it can also prevent viral infections when sprinkled into your morning tea. (Source: EurekAlert! A service of AAAS and American Friends of Tel Aviv University).
Natural Alzheimer's weapon suggests better treatment
AUGUSTA, Ga. – Scientists have shown a molecular chaperone is working like a waste management company to collect and detoxify high levels of toxic amyloid beta peptide found in Alzheimer's disease.
It was known that the molecular chaperone, HspB1, was present in the hallmark plaque of Alzheimer's patients but its role remained a mystery.
"What we have found is HspB1 is a protective mechanism that tries to get rid of the toxic oligomers or aggregates of amyloid beta that occur in Alzheimer's,” said Dr. Anil G. Cashikar, Biochemist at Georgia Health Sciences University's Center for Molecular Chaperones and Radiobiology. He is corresponding author of the study published in Molecular and Cellular Biology.
Amyloid beta peptide, or Abeta, is believed to start the cascade of events that leads to brain cell damage and death in Alzheimer's: as levels increase, the peptide starts clumping in the brain. In fact, high levels in the spinal fluid are a diagnostic marker for the disease. Molecular chaperones are known for their propensity to respond to disease-producing misfolded proteins, which is how the body views excessive Abeta.
While resulting plaques occupy prime real estate in the brain, it's still better than toxic Abeta killing neurons, Cashikar said. “We think maybe the system gets overwhelmed.”
Acknowledging much work remains, the scientist is excited about identifying the protective mechanism and exploring its treatment potential.
Earlier this year, a paper Cashikar published in PLoS One showed deleting genes with a similar function from a mouse model of Alzheimer's worsened disease symptoms. The new study also showed neurons from HspB1-deficient mice were more sensitive to the toxic ravages of Abeta.
“HspB1 is present because its function is to protect cells. The implication is if we can elevate the levels of this molecular chaperone, we may be able to handle the situation a little better,” Cashikar said.
He wants to exploit this natural system by developing a smaller version of the molecular chaperone that could be put into the bloodstream to leach excess Abeta from the brain. The brain has a natural protective mechanism that likely would prevent its direct application. However, the natural affinity of amyloid beta and HspB1 indicates a more distant approach could be effective. “We want to come up with smaller versions of HspB1 that can be put into the bloodstream so you can sop up the material from the brain into the blood where it can be cleared more efficiently.” He also wants to explore a way to increase brain cells' natural production of protective HspB1.
Neurons actually also make the Abeta believed to attack them in Alzheimer's. The peptide's normal function in the brain is not clear, but early evidence suggests it could be involved in synaptic pruning, which is essential for memory formation. Synapses connect neurons and some existing connections must be cut for new connections and memories to be made. Why neurons start making too much Abeta and how its overproduction can be controlled are million-dollar questions, Cashikar said.
A related ongoing debate is whether the amyloid plaques and neurofibrillarly tangles, insoluble globs of protein also found in Alzheimer's, are a cause or result of the disease. Cashikar's work as well as new studies on the neurofibrillarly tangles, suggest both are protective mechanisms. Also, there is evidence of both in the brains of some healthy, elderly individuals.
GHSU Graduate Student Juhi Ojha is first author on the paper. (Source: EurekAlert! A service of AAAS and Georgia Health Sciences University).
Dietary changes appear to affect levels of biomarkers associated with Alzheimer's disease
CHICAGO – Following a low–saturated fat and low–glycemic index diet appears to modulate the risk of developing dementia that proceeds to Alzheimer’s disease (AD), and making a switch to this dietary pattern may provide some benefit to those who are already experiencing cognitive difficulty, according to a report in the June issue of Archives of Neurology, one of the JAMA/Archives journals.
Previous research has suggested multiple links between diet and cognitive ability, the authors note as background information. Health conditions in which insulin resistance (the body’s inability to use insulin effectively) is a factor—obesity, type 2 diabetes, cardiovascular disease and high cholesterol levels—have also been associated with “pathological brain aging.” However, studies of specific foods have not found conclusive evidence of an influence on Alzheimer’s risk. “Thus,” the authors write, “a more promising approach to the study of dietary factors in AD might entail the use of whole-diet interventions, which have greater ecologic validity and preserve the nutritional milieu in which fat and carbohydrate consumption occurs.”
Jennifer L. Bayer-Carter, M.S., from Veterans Affairs Puget Sound Health Care System, Seattle, and colleagues sought to compare a high–saturated fat/high–simple carbohydrate diet (a macronutrient pattern associated with type 2 diabetes and insulin resistance) with a low–saturated fat/low–simple carbohydrate diet; the interventions were named HIGH and LOW, respectively. The authors evaluated the effects of these diets in 20 older adults who were healthy and 29 older adults who had amnestic mild cognitive impairment (aMCI), meaning they experienced some memory problems; the latter condition is often considered a precursor to AD. In a four-week randomized, controlled trial, 24 participants followed the HIGH diet and 25 followed the LOW diet. The researchers studied participants' performance on memory tests as well as their levels of biomarkers (biological substances indicative of AD), such as insulin, cholesterol, blood glucose levels, blood lipid levels and components of cerebrospinal fluid (CSF).
Results of the study were different for the group that had aMCI and the group of healthy participants. In the latter group, the LOW diet decreased some CSF biomarkers of AD as well as total cholesterol levels. However, among individuals with aMCI, the LOW diet increased levels of these biomarkers. Some changes to biomarkers, such as CSF insulin levels, were observed in both groups. Additionally, the LOW diet improved performance on delayed visual recall tests for both healthy and memory-impaired participants, but did not affect scores on other cognitive measures.
The findings indicate that “for healthy adults, the HIGH diet moved CSF biomarkers in a direction that may characterize a presymptomatic stage of AD,” explain the authors. They believe that the different results of the unhealthy diet in participants with aMCI may be due to the diet’s short duration. “The therapeutic effects of longer-term dietary intervention may be a promising avenue of exploration,” the authors conclude. “In addition, identification of the pathophysiologic changes underlying dietary effects may reveal important therapeutic targets that can be modulated through targeted dietary or pharmacologic intervention.” (Source: EurekAlert! A service of AAAS and JAMA and Archives Journals).