Posts tagged alzheimer's disease
Articles and news from the latest research reports.
Potential biomarkers for the diagnosis of Alzheimer’s disease
Drugs that modify DNA structure may be beneficial for treating Alzheimer’s Disease
In a study published this week in Nature Neuroscience, Bess Frost, PhD, and co-authors, identify abnormal expression of genes, resulting from DNA relaxation, that can be detected in the brain and blood of Alzheimer’s patients.
The protein tau is involved in a number of neurodegenerative disorders, including Alzheimer’s disease. Previous studies have implicated DNA damage as a cause of neuron, or cell, death in Alzheimer’s patients. Given that DNA damage can change the structure of DNA within cells, the researchers examined changes in DNA structure in tau-induced neurodegeneration. They used transgenic flies and mice expressing human tau to show that DNA is more relaxed in tauopathy. They then identified that the relaxation of tightly wound DNA and resulting abnormal gene expression are central events that cause neurons to die in Alzheimer’s disease.
The authors write, “Our work suggests that drugs that modify DNA structure may be beneficial for treating Alzheimer’s Disease.” The authors recommend, “A greater understanding of the pathway of DNA relaxation in tauopathies will allow us to identify the optimal target and explore the therapeutic potential of epigenetic-based drugs.”
(Source: eurekalert.org)
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.
Researchers discover an epigenetic lesion in the hippocampus of Alzheimer’s patients
Alzheimer’s disease can reach epidemic range in the coming decades, by the increasing average age of society. There are two key issues for Alzheimer’s disease: there is currently no effective treatment and it has been described very few associated genetic changes (mutations) which reduces the number of targets for future therapies.
Alzheimer’s disease
Pathologically, Alzheimer’s disease is characterized by the accumulation of protein deposits in the brain of patients. These deposits are formed by plates of a protein called amyloid-beta and rolled tangles of tau protein. The root cause of these lesions in most cases is unknown, but specific alterations in regulating genes expression might be involved.
Today, the prestigious international journal in neurology Hippocampus publishes an article led by Manel Esteller, Director of Epigenetics and Cancer Biology, Institute of Biomedical Research of Bellvitge (IDIBEL), ICREA researcher and Professor of Genetics at the University of Barcelona, with the collaboration of the Institute of Neuropathology IDIBELL led by Isidre Ferrer, demonstrating for the first time the existence of an epigenetic lesion in the hippocampus of the brain of patients with Alzheimer.
Switches in the hippocampus
"We first started studying 30,000 molecular switches that turn on and off genes in the hippocampal region in the brains of Alzheimer patients in different stages of disease and compared with that of healthy patients of the same age. We note that dusp22 gene switches off (methylates) as the disease advances" explained Manel Esteller, director of the study.
"But more importantly" continues "was the discovery that this gene regulates tau protein. Perhaps therefore the accumulation of tau protein produced in the brain of patients with Alzheimer results from dusp22 epigenetic inactivation".
According Esteller “the finding is relevant not only to determine the causes of the disease, but also to test potential treatments in the future to act on these epigenetic molecular switches”.
Cleveland Clinic identifies mechanism in Alzheimer’s-related memory loss
Cleveland Clinic researchers have identified a protein in the brain that plays a critical role in the memory loss seen in Alzheimer’s patients, according to a study to be published in the journal Nature Neuroscience and posted online today.
The protein – Neuroligin-1 (NLGN1) – is known to be involved in memory formation; this is the first time it’s been linked to amyloid-associated memory loss.
In Alzheimer’s disease, amyloid beta proteins accumulate in the brains of Alzheimer’s patients and induce inflammation. This inflammation leads to certain gene modifications that interrupt the functioning of synapses in the brain, leading to memory loss.
Using animal models, Cleveland Clinic researchers have discovered that during this neuroinflammatory process, the epigenetic modification of NLGN1 disrupts the synaptic network in the brain, which is responsible for developing and maintaining memories. Destroying this network can lead to the type of memory loss seen in Alzheimer’s patients.
"Alzheimer’s is a challenging disease that researchers have been approaching from all angles," said Mohamed Naguib, M.D., the Cleveland Clinic physician who lead the study. "This discovery could provide us with a new approach for preventing and treating Alzheimer’s disease."
Previous studies from this group of researchers have also identified a novel compound called MDA7, which can potentially stop the neuroinflammatory process that leads to the modification of NLGN1. Treatment with the compound restored cognition, memory and synaptic plasticity – a key neurological foundation of learning and memory – in an animal model. Significant preliminary work for the first-in-man study has been completed for MDA7 including in-vitro studies and preliminary clinical toxicology and pharmacokinetic work. The Cleveland Clinic plans to initiate Phase I human studies on the safety of this class of compounds in the near future.
Alzheimer’s disease is an irreversible, fatal brain disease that slowly destroys memory and thinking skills. About 5 million people in the United States have Alzheimer’s disease. With the aging of the population, and without successful treatment, there will be 16 million Americans and 106 million people worldwide with Alzheimer’s by 2050, according to the 2011 Alzheimer’s Disease Facts and Figures report from the Alzheimer’s Association.
(Source: eurekalert.org)
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%.
High good and low bad cholesterol levels are healthy for the brain, too
High levels of “good” cholesterol and low levels of “bad” cholesterol are correlated with lower levels of the amyloid plaque deposition in the brain that is a hallmark of Alzheimer’s disease, in a pattern that mirrors the relationship between good and bad cholesterol in cardiovascular disease, UC Davis researchers have found.
“Our study shows that both higher levels of HDL — good — and lower levels of LDL — bad — cholesterol in the bloodstream are associated with lower levels of amyloid plaque deposits in the brain,” said Bruce Reed, lead study author and associate director of the UC Davis Alzheimer’s Disease Center.
“Unhealthy patterns of cholesterol could be directly causing the higher levels of amyloid known to contribute to Alzheimer’s, in the same way that such patterns promote heart disease,” he said.
The relationship between elevated cholesterol and increased risk of Alzheimer’s disease has been known for some time, but the current study is the first to specifically link cholesterol to amyloid deposits in living human study participants, Reed said.
The study, “Associations Between Serum Cholesterol Levels and Cerebral Amyloidosis,” is published online today in JAMA Neurology.
In the United States, cholesterol levels are measured in milligrams (mg) of cholesterol per deciliter (dL) of blood. For HDL cholesterol, a level of 60 mg/dl or higher is best. For LDL cholesterol, a level of 70 mg/dL or lower is recommended for people at very high risk of heart disease.
Charles DeCarli, director of the Alzheimer’s Disease Center and an author of the study, said it is a wake-up call that, just as people can influence their late-life brain health by limiting vascular brain injury through controlling their blood pressure, the same is true of getting a handle on their serum cholesterol levels.
“If you have an LDL above 100 or an HDL that is less than 40, even if you’re taking a statin drug, you want to make sure that you are getting those numbers into alignment,” DeCarli said. “You have to get the HDL up and the LDL down.”
The study was conducted in 74 diverse male and female individuals 70 years and older who were recruited from California stroke clinics, support groups, senior facilities and the Alzheimer’s Disease Center. They included three individuals with mild dementia, 33 who were cognitively normal and 38 who had mild cognitive impairment.
The participants’ amyloid levels were obtained using a tracer that binds with amyloid plaques and imaging their brains using PET scans. Higher fasting levels of LDL and lower levels of HDL both were associated with greater brain amyloid — a first-time finding linking cholesterol fractions in the blood and amyloid deposition in the brain. The researchers did not study the mechanism for how cholesterol promotes amyloid deposits.
Recent guidelines instituted by the American College of Cardiology, the American Heart Association and the National Heart, Lung, and Blood Institute have suggested abandoning guidelines for LDL targets. Reed said that recommendation may be an instance in which the adage that “what’s good for the heart is good for the brain” does not apply.
“This study provides a reason to certainly continue cholesterol treatment in people who are developing memory loss, regardless of concerns regarding their cardiovascular health,” said Reed, a professor in the UC Davis Department of Neurology.
“It also suggests a method of lowering amyloid levels in people who are middle aged, when such build-up is just starting,” he said. “If modifying cholesterol levels in the brain early in life turns out to reduce amyloid deposits late in life, we could potentially make a significant difference in reducing the prevalence of Alzheimer’s, a goal of an enormous amount of research and drug development effort.”