Posts tagged dementia
Articles and news from the latest research reports.
An Amazing Village Designed Just For People With Dementia
Centuries after Shakespeare wrote about King Lear’s symptoms, there’s still no perfect way to care for sufferers of dementia and Alzheimer’s. In the Netherlands, however, a radical idea is being tested: Self-contained “villages” where people with dementia shop, cook, and live together—safely.
We, as a population, are aging rapidly. According to the Alzheimer’s Association, one in three seniors today dies with dementia. The process of finding—and paying for—long-term care can be very confusing, unfortunately, and difficult for both loved ones and patients. Most caretakers are underpaid, overworked, and must drive far distances to their jobs—giving away some 17 billion unpaid hours of care a year. And it’s just going to get worse: Alzheimer’s has increased by an incredible 68 percent since 2000, and the cost of caring for sufferers will increase from $203 billion last year to $1.2 trillion by 2050.
In short, we’re not prepared for the future that awaits us—financially, infrastructurally, or even socially. But in the small town of Weesp, in Holland—that bastion of social progressivism—at a dementia-focused living center called De Hogeweyk, aka Dementiavillage, the relationship between patients and their care is serving as a model for the rest of the world.
Natural plant compound prevents Alzheimer’s disease in mice
A chemical that’s found in fruits and vegetables from strawberries to cucumbers appears to stop memory loss that accompanies Alzheimer’s disease in mice, scientists at the Salk Institute for Biological Studies have discovered. In experiments on mice that normally develop Alzheimer’s symptoms less than a year after birth, a daily dose of the compound—a flavonol called fisetin—prevented the progressive memory and learning impairments. The drug, however, did not alter the formation of amyloid plaques in the brain, accumulations of proteins which are commonly blamed for Alzheimer’s disease. The new finding suggests a way to treat Alzheimer’s symptoms independently of targeting amyloid plaques.
"We had already shown that in normal animals, fisetin can improve memory," says Pamela Maher, a senior staff scientist in Salk’s Cellular Neurobiology Laboratory who led the new study. "What we showed here is that it also can have an effect on animals prone to Alzheimer’s."
More than a decade ago, Maher discovered that fisetin helps protect neurons in the brain from the effects of aging. She and her colleagues have since—in both isolated cell cultures and mouse studies—probed how the compound has both antioxidant and anti-inflammatory effects on cells in the brain. Most recently, they found that fisetin turns on a cellular pathway known to be involved in memory.
"What we realized is that fisetin has a number of properties that we thought might be beneficial when it comes to Alzheimer’s," says Maher.
So Maher—who works with Dave Schubert, the head of the Cellular Neurobiology Lab—turned to a strain of mice that have mutations in two genes linked to Alzheimer’s disease. The researchers took a subset of these mice and, when they were only three months old, began adding fisetin to their food. As the mice aged, the researchers tested their memory and learning skills with water mazes. By nine months of age, mice that hadn’t received fisetin began performing more poorly in the mazes. Mice that had gotten a daily dose of the compound, however, performed as well as normal mice, at both nine months and a year old.
"Even as the disease would have been progressing, the fisetin was able to continue preventing symptoms," Maher says.
In collaboration with scientists at the University of California, San Diego, Maher’s team next tested the levels of different molecules in the brains of mice that had received doses of fisetin and those that hadn’t. In mice with Alzheimer’s symptoms, they found, pathways involved in cellular inflammation were turned on. In the animals that had taken fisetin, those pathways were dampened and anti-inflammatory molecules were present instead. One protein in particular—known as p35—was blocked from being cleaved into a shorter version when fisetin was taken. The shortened version of p35 is known to turn on and off many other molecular pathways. The results were published December 17, 2013, in the journal Aging Cell.
Studies on isolated tissue had hinted that fisetin might also decrease the number of amyloid plaques in Alzheimer’s affected brains. However, that observation didn’t hold up in the mice studies. “Fisetin didn’t affect the plaques,” says Maher. “It seems to act on other pathways that haven’t been seriously investigated in the past as therapeutic targets.”
Next, Maher’s team hopes to understand more of the molecular details on how fisetin affects memory, including whether there are targets other than p35.
"It may be that compounds like this that have more than one target are most effective at treating Alzheimer’s disease," says Maher, "because it’s a complex disease where there are a lot of things going wrong."
They also aim to develop new studies to look at how the timing of fisetin doses affect its influence on Alzheimer’s.
"The model that we used here was a preventive model," explains Maher. "We started the mice on the drugs before they had any memory loss. But obviously human patients don’t go to the doctor until they are already having memory problems." So the next step in moving the discovery toward the clinic, she says, is to test whether fisetin can reverse declines in memory once they have already appeared.
(Source: salk.edu)
Infections damage our ability to form spatial memories
Increased inflammation following an infection impairs the brain’s ability to form spatial memories – according to new research. The impairment results from a decrease in glucose metabolism in the brain’s memory centre, disrupting the neural circuits involved in learning and memory.
Inflammation has long been linked to disorders of memory like Alzheimer’s disease. Severe infections can also impair cognitive function in healthy elderly individuals. The new findings published in the journal Biological Psychiatry help explain why inflammation impairs memory and could spur the development of new drugs targeting the immune system to treat dementia.
In the first trial to image how inflammation impairs human memory, the team at Brighton and Sussex Medical School scanned 20 participants before and after either a benign salty water injection or typhoid vaccination, used to induce inflammation. Positron emission tomography (PET) was used to measure the effects of inflammation on the consumption of glucose in the brain and after each scan participants tested their spatial memory by performing a series of tasks in a virtual reality.
A reduction in glucose metabolism within the brain’s memory centre, known as the Medial Temporal Lobe (MTL), was seen following inflammation. Participants also performed less well in spatial memory tasks, an effect that appeared to be directly mediated by the change in MTL metabolism.
"We have known for some time that severe infections can lead to long-term cognitive impairment in the elderly. Infections are also a common trigger for acute decline in function in patients with dementia and Alzheimer’s disease," explains Dr Neil Harrison, a Wellcome Trust Intermediate Clinical Fellow at BSMS who led the study. "This study suggests that catching a cold or the flu, which leads to inflammation in the brain, could impair our memory."
Infections are unlikely to cause long-term detrimental impact in the young and healthy but the findings are of great significance in the elderly. The team now plan to investigate the role of inflammation in dementia, including insight into how acute infections such as influenza influence the rate of progression and decline.
"Our findings suggest that the brain’s memory circuits are particularly sensitive to inflammation and help clarify the association between inflammation and decline in dementia," says Dr Harrison. "If we can control levels of inflammation, we may be able to reduce the rate of decline in patients’ cognition."
(Source: eurekalert.org)
Can Fish Oil Help Preserve Brain Cells?
People with higher levels of the omega-3 fatty acids found in fish oil may also have larger brain volumes in old age equivalent to preserving one to two years of brain health, according to a study published in the January 22, 2014, online issue of Neurology®, the medical journal of the American Academy of Neurology. Shrinking brain volume is a sign of Alzheimer’s disease as well as normal aging.
For the study, the levels of omega-3 fatty acids EPA+DHA in red blood cells were tested in 1,111 women who were part of the Women’s Health Initiative Memory Study. Eight years later, when the women were an average age of 78, MRI scans were taken to measure their brain volume.
Those with higher levels of omega-3s had larger total brain volumes eight years later. Those with twice as high levels of fatty acids (7.5 vs. 3.4 percent) had a 0.7 percent larger brain volume.
“These higher levels of fatty acids can be achieved through diet and the use of supplements, and the results suggest that the effect on brain volume is the equivalent of delaying the normal loss of brain cells that comes with aging by one to two years,” said study author James V. Pottala, PhD, of the University of South Dakota in Sioux Falls and Health Diagnostic Laboratory, Inc., in Richmond, Va.
Those with higher levels of omega-3s also had a 2.7 percent larger volume in the hippocampus area of the brain, which plays an important role in memory. In Alzheimer’s disease, the hippocampus begins to atrophy even before symptoms appear.
Alzheimer’s drugs fail, but lessons are learned
After the failure of two novel drugs using antibodies to fight the buildup of brain plaque in Alzheimer’s patients, scientists said on Wednesday they have learned lessons for the future.
The biologic drugs solanezumab, by pharmaceutical giant Eli Lilly, and bapineuzumab, by Johnson and Johnson, made it to phase III trials and were taken by thousands of patients, according to a full report on the research published in the New England Journal of Medicine.
Alzheimer’s disease: 15-minute test could spot early sign of dementia
A simple 15-minute test which can be taken at home can spot the early signs of Alzheimer’s disease, researchers claim.
The exam which can be completed online or by hand, tests language ability, reasoning, problem solving skills and memory.
Results can then be shared with doctors to help spot early symptoms of cognitive issues such as early dementia or Alzheimer’s disease.
The research was published in The Journal of Neuropsychiatry and Clinical Neurosciences.
Vitamin E slows Alzheimer’s progression
Patients with mild to moderate Alzheimer’s disease were able to care for themselves longer and needed less help performing everyday chores when they took a daily capsule containing 200 IUs of alpha tocopherol, or vitamin E, a study has found.
Compared with subjects who took placebo pills, those who took daily supplements of the antioxidant vitamin E and were followed for an average of two years and three months delayed their loss of function by a little over six months on average, a 19% improvement. And the vitamin E group’s increased need for caregiver help was the lowest of several groups, including those taking the Alzheimer’s drug memantine, those taking memantine and vitamin E, and those taking a placebo pill.
The new research, published Tuesday in the Journal of the American Medical Assn. (JAMA), also cast doubt on earlier findings suggesting that vitamin E supplements hastened death in those with Alzheimer’s. The study found that subjects taking vitamin E were no more likely to die of any cause during the study period than those taking memantine or a placebo.
The findings offer a slim ray of hope that the progressive memory loss and mental confusion that characterizes Alzheimer’s can at least be slowed by an agent that is inexpensive and easily accessible. Far more expensive drugs that come with greater risks and more side effects have failed to do as well in altering the trajectory of the disease.
The authors of the study called the outcomes seen among those who took vitamin E “a meaningful treatment effect” that was on a par with those seen in clinical trials of prescription drugs approved by the Food and Drug Administration. They expressed surprise that those taking memantine along with vitamin E did not show a delay in functional loss. Possibly, the researchers noted, memantine may disrupt or hinder the metabolism or absorption of vitamin E.
"For people who are in the early stage of Alzheimer’s disease, I think any delay in the rate of progression is meaningful and important," said Maurice W. Dysken, the study’s lead author.
While memantine has shown itself effective in slowing loss of function among patients with moderate to severe Alzheimer’s, its effectiveness in earlier stages of the disease has been less well explored.
In an accompanying editorial in JAMA, Dr. Denis A. Evans, a neurologist at Rush University Medical Center, called the effects of vitamin E “modest” in that it appeared to ameliorate symptoms rather than disrupt or reverse the inexorable march of the disease. Given the expected swelling numbers of those at risk and the discouraging record of progress in finding therapies that could reverse or cure Alzheimer’s, Evans wrote, a shift in emphasis toward the prevention “seems warranted.”
The study is one of the largest and longest to track participants with mild to moderate Alzheimer’s. It followed 561 patients, 97% of them men, from 14 Veterans Affairs medical centers around the country. Researchers tracked each subject for as little as six months and as long as four years after diagnosis with possible or probable Alzheimer’s disease of mild to moderate severity.
Subjects were assigned randomly to one of four groups: 139 subjects got a hard-gelatin, liquid-filled capsule of 200 IUs of DL-alpha-tocopherol acetate (“synthetic” vitamin E) and a maintenance dose of 10 mg. of memantine; 140 got the vitamin E capsule and a memantine placebo; 142 got a placebo vitamin E capsule and memantine; and 140 got placebo vitamin E and placebo memantine.
Using a 78-point inventory of “activities of daily living,” researchers evaluated subjects’ function every six months, and asked caregivers to report on dementia-related behavioral problems and how much assistance the subjects needed in six major areas of activity. They also assessed subjects’ memory, language, gait and general mental function.
While subjects on memantine and those on the placebo required increased caregiver assistance ranging from 2.2% to 2.43% annually, caregivers of those taking vitamin E reported their time spent assisting the patient increased annually by 1.48%.
Study Shows Where Alzheimer’s Starts and How It Spreads
Using high-resolution functional MRI (fMRI) imaging in patients with Alzheimer’s disease and in mouse models of the disease, Columbia University Medical Center (CUMC) researchers have clarified three fundamental issues about Alzheimer’s: where it starts, why it starts there, and how it spreads. In addition to advancing understanding of Alzheimer’s, the findings could improve early detection of the disease, when drugs may be most effective. The study was published today in the online edition of the journal Nature Neuroscience.
“It has been known for years that Alzheimer’s starts in a brain region known as the entorhinal cortex,” said co-senior author Scott A. Small, MD, Boris and Rose Katz Professor of Neurology, professor of radiology, and director of the Alzheimer’s Disease Research Center. “But this study is the first to show in living patients that it begins specifically in the lateral entorhinal cortex, or LEC. The LEC is considered to be a gateway to the hippocampus, which plays a key role in the consolidation of long-term memory, among other functions. If the LEC is affected, other aspects of the hippocampus will also be affected.”
The study also shows that, over time, Alzheimer’s spreads from the LEC directly to other areas of the cerebral cortex, in particular, the parietal cortex, a brain region involved in various functions, including spatial orientation and navigation. The researchers suspect that Alzheimer’s spreads “functionally,” that is, by compromising the function of neurons in the LEC, which then compromises the integrity of neurons in adjoining areas.
A third major finding of the study is that LEC dysfunction occurs when changes in tau and amyloid precursor protein (APP) co-exist. “The LEC is especially vulnerable to Alzheimer’s because it normally accumulates tau, which sensitizes the LEC to the accumulation of APP. Together, these two proteins damage neurons in the LEC, setting the stage for Alzheimer’s,” said co-senior author Karen E. Duff, PhD, professor of pathology and cell biology (in psychiatry and in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain) at CUMC and at the New York State Psychiatric Institute.
In the study, the researchers used a high-resolution variant of fMRI to map metabolic defects in the brains of 96 adults enrolled in the Washington Heights-Inwood Columbia Aging Project (WHICAP). All of the adults were free of dementia at the time of enrollment.
“Dr. Richard Mayeux’s WHICAP study enables us to follow a large group of healthy elderly individuals, some of whom have gone on to develop Alzheimer’s disease,” said Dr. Small. “This study has given us a unique opportunity to image and characterize patients with Alzheimer’s in its earliest, preclinical stage.”
The 96 adults were followed for an average of 3.5 years, at which time 12 individuals were found to have progressed to mild Alzheimer’s disease. An analysis of the baseline fMRI images of those 12 individuals found significant decreases in cerebral blood volume (CBV) — a measure of metabolic activity — in the LEC compared with that of the 84 adults who were free of dementia.
A second part of the study addressed the role of tau and APP in LEC dysfunction. While previous studies have suggested that entorhinal cortex dysfunction is associated with both tau and APP abnormalities, it was not known how these proteins interact to drive this dysfunction, particularly in preclinical Alzheimer’s.
To answer this question, explained first author Usman Khan, an MD-PhD student based in Dr. Small’s lab, the team created three mouse models, one with elevated levels of tau in the LEC, one with elevated levels of APP, and one with elevated levels of both proteins. The researchers found that the LEC dysfunction occurred only in the mice with both tau and APP.
The study has implications for both research and treatment. “Now that we’ve pinpointed where Alzheimer’s starts, and shown that those changes are observable using fMRI, we may be able to detect Alzheimer’s at its earliest preclinical stage, when the disease might be more treatable and before it spreads to other brain regions,” said Dr. Small. In addition, say the researchers, the new imaging method could be used to assess the efficacy of promising Alzheimer’s drugs during the disease’s early stages.
Study breaks blood-brain barriers to understanding Alzheimer’s
A study in mice shows a breakdown of the brain’s blood vessels may amplify or cause problems associated with Alzheimer’s disease. The results published in Nature Communications suggest that blood vessel cells called pericytes may provide novel targets for treatments and diagnoses.
“This study helps show how the brain’s vascular system may contribute to the development of Alzheimer’s disease,” said study leader Berislav V. Zlokovic, M.D. Ph.D., director of the Zilkha Neurogenetic Institute at the Keck School of Medicine of the University of Southern California, Los Angeles. The study was co-funded by the National Institute of Neurological Diseases and Stroke (NINDS) and the National Institute on Aging (NIA), parts of the National Institutes of Health
Alzheimer’s disease is the leading cause of dementia. It is an age-related disease that gradually erodes a person’s memory, thinking, and ability to perform everyday tasks. Brains from Alzheimer’s patients typically have abnormally high levels of plaques made up of accumulations of beta-amyloid protein next to brain cells, tau protein that clumps together to form neurofibrillary tangles inside neurons, and extensive neuron loss.
Vascular dementias, the second leading cause of dementia, are a diverse group of brain disorders caused by a range of blood vessel problems. Brains from Alzheimer’s patients often show evidence of vascular disease, including ischemic stroke, small hemorrhages, and diffuse white matter disease, plus a buildup of beta-amyloid protein in vessel walls. Furthermore, previous studies suggest that APOE4, a genetic risk factor for Alzheimer’s disease, is linked to brain blood vessel health and integrity.
“This study may provide a better understanding of the overlap between Alzheimer’s disease and vascular dementia,” said Roderick Corriveau, Ph.D., a program director at NINDS.
One hypothesis about Alzheimer’s disease states that increases in beta-amyloid lead to nerve cell damage. This is supported by genetic studies that link familial forms of the disease to mutations in amyloid precursor protein (APP), the larger protein from which plaque-forming beta-amyloid molecules are derived. Nonetheless, previous studies on mice showed that increased beta-amyloid levels reproduce some of the problems associated with Alzheimer’s. The animals have memory problems, beta-amyloid plaques in the brain and vascular damage but none of the neurofibrillary tangles and neuron loss that are hallmarks of the disease.
In this study, the researchers show that pericytes may be a key to whether increased beta-amyloid leads to tangles and neuron loss.
Pericytes are cells that surround the outside of blood vessels. Many are found in a brain plumbing system, called the blood-brain barrier. It is a network that exquisitely controls the movement of cells and molecules between the blood and the interstitial fluid that surrounds the brain’s nerve cells. Pericytes work with other blood-brain barrier cells to transport nutrients and waste molecules between the blood and the interstitial brain fluid.
To study how pericytes influence Alzheimer’s disease, Dr. Zlokovic and his colleagues crossbred mice genetically engineered to have a form of APP linked to familial Alzheimer’s with ones that have reduced levels of platelet-derived growth factor beta receptor (PDGFR-beta), a protein known to control pericyte growth and survival. Previous studies showed that PDGFR-beta mutant mice have fewer pericytes than normal, decreased brain blood flow, and damage to the blood-brain barrier.
“Pericytes act like the gatekeepers of the blood-brain barrier,” said Dr. Zlokovic.
Both the APP and PDGFR-beta mutant mice had problems with learning and memory. Crossbreeding the mice slightly enhanced these problems. The mice also had increased beta-amyloid plaque deposition near brain cells and along brain blood vessels. Surprisingly, the brains of the crossbred mice had enhanced neuronal cell death and extensive neurofibrillary tangles in the hippocampus and cerebral cortex, regions that are typically affected during Alzheimer’s.
“Our results suggest that damage to the vascular system may be a critical step in the development of full-blown Alzheimer’s disease pathology,” said Dr. Zlokovic.
Further experiments suggested that pericytes may transport beta-amyloid across the blood-brain barrier into the blood and showed that crossbreeding the mice slowed the rate at which beta-amyloid was cleared away from nerve cells in the brain.
Next, the researchers addressed how beta-amyloid may affect the vascular system. The crossbred mutants had more pericyte death and more damage to the blood-brain barrier than the PDGFR-beta mutant mice, suggesting beta-amyloid may enhance vascular damage. The investigators also confirmed previous findings showing that beta-amyloid accumulation leads to pericyte death.
Dr. Zlokovic and his colleagues concluded that their results support a two-hit vascular hypothesis of Alzheimer’s. The hypothesis states that the toxic effects of increased beta-amyloid deposition on pericytes in aged blood vessels leads to a breakdown of the blood-brain barrier and a reduced ability to clear amyloid from the brain. In turn, the progressive accumulation of beta-amyloid in the brain and death of pericytes may become a damaging feedback loop that causes dementia. If true, then pericytes and other blood-brain barrier cells may be new therapeutic targets for treating Alzheimer’s disease.
(Source: ninds.nih.gov)
New gene discovery sheds more light on Alzheimer’s risk
A research team from The University of Nottingham has helped uncover a second rare genetic mutation which strongly increases the risk of Alzheimer’s disease in later life.
In an international collaboration, the University’s Translational Cell Sciences Human Genetics research group has pinpointed a rare coding variation in the Phospholipase D3 (PLD3) gene which is more common in people with late-onset Alzheimer’s than non-sufferers.
The discovery is an important milestone on the road to early diagnosis of the disease and eventual improved treatment. Having surveyed the human genome for common variants associated with Alzheimer’s, geneticists are now turning the spotlight on rare mutations which may be even stronger risk factors.
More than 820,000 people in the UK have dementia and the number is rising as the population ages. The condition, of which Alzheimer’s disease is the predominant cause, costs the UK economy £23 billion per year, much more than other diseases like cancer and heart disease.
Nottingham’s genetic experts have been working with long-term partners from Washington University, St Louis, USA and University College, London, to carry out next-generation whole exome sequencing on families where Alzheimer’s affects several members.
Earlier this year the collaboration uncovered the first ever rare genetic mutation implicated in disease risk, linking the TREM2 gene to a higher risk of Alzheimer’s (published in the New England Journal of Medicine). Now, in a new study published today in the international journal, Nature, the team reveal that after analysis of the genes of around 2,000 people with Alzheimer’s, a second genetic variation has been found, in the PLD3 gene.
PLD3 influences processing of amyloid precursor protein which results in the generation of the characteristic amyloid plaques seen in AD brain tissue, suggesting that it may be a potential therapeutic target.
The international research team used Nottingham’s Alzheimer’s Research UK DNA bank, one of the largest collections of DNA from Alzheimer’s patients, to completely sequence the entire coding region (exome) of the PLD3 gene. The results showed several mutations in the gene occurred more frequently in people who had the disease than in non-sufferers. Carriers of PLD3 coding variants showed a two-fold increased risk for the disease.
Leading the team at Nottingham, Professor of Human Genomics and Molecular Genetics, Kevin Morgan, said:
“This second crucial discovery has confirmed that this latest scientific approach does deliver, it is able to find these clues. However, it is also inferring that there are lots more AD-significant variations out there and before we can use it for diagnosis we need to find all of the other genetic variations involved in Alzheimer’s too.
“Our research is forming the basis of potential diagnostics later on and more importantly it shows pathways that can be diagnostic targets which could lead to therapeutic interventions in the future.
“The next step will be to examine how this particular rare gene variant functions in the cell and see if it can be targeted, to see if there are any benefits to finding out how this gene operates in both normal and diseased cells. If we can do this, we may be able eventually to correct the defect with drug therapy. Here in Nottingham we will keep looking for more rare gene variations.
“Even if we could eventually slow or halt the progress of the disease with new drugs rather than curing it completely, the benefits would be huge in terms of the real impact on patients’ lives and also in vast savings to the health economy. The group The University of Nottingham has played a significant role in all of the recent AD genetics discoveries that have highlighted 20 new regions of interest in the genome in the last five years and we will continue to do so into the future.”
Rebecca Wood, Chief Executive of Alzheimer’s Research UK, the UK’s leading dementia research charity, said: “Advances in genetic technology are allowing researchers to understand more than ever about the genetic risk factors for the most common form of Alzheimer’s. This announcement, made just off the back of the G8 dementia research summit, is a timely reminder of the progress that can be made by worldwide collaboration. We know that late-onset Alzheimer’s is caused by a complex mix of risk factors, including both genetic and lifestyle. Understanding all of these risk factors and how they work together to affect someone’s likelihood of developing Alzheimer’s is incredibly important for developing interventions to slow the onset of the disease. Alzheimer’s Research UK is proud to have contributed to this discovery, both by funding researchers and through the establishment of a DNA collection that has been used in many of the recent genetic discoveries in Alzheimer’s.”
(Source: nottingham.ac.uk)