Abstract
Blood test for Alzheimer's
MUHC study identifies procedure that detects early stages
Montreal May 4, 2011 – A new blood test that will diagnose Alzheimer's disease may soon hit the market, thanks to an innovative study from the Research Institute of the McGill University Health Centre (MUHC). Their findings have characterized a unique biochemical diagnosis, which identifies patients with this devastating disorder. This research, published in the month's issue of the Journal of Alzheimer's Disease, has implications for the half-a-million Canadian sufferers and many millions more worldwide.
“Until now, there has been no definitive diagnostic tool for Alzheimer's, other than postmortem analysis of brain tissue,” says senior author Dr. Vassilios Papadopoulos, director of the MUHC Research Institute. “Our clinical study shows that a non-invasive blood test, based on a biochemical process, may be successfully used to diagnose Alzheimer's at an early stage and differentiate it from other types of dementia.”
The biochemistry behind the test
Papadopoulos and colleagues based the Alzheimer's blood test on the production of a brain hormone called dehydroepiandrosterone (DHEA). This hormone is present at high levels in the brain where it has a wide range of biological effects.
The researchers were able to promote the production of DHEA, using a chemical process called oxidation, in blood taken from non-Alzheimer's patients. However, oxidation of blood from Alzheimer's patients did not result in an increase of DHEA.
“There is a clear correlation between the lack of ability to produce DHEA through oxidation in the blood and the degree of cognitive impairment found in Alzheimer's disease,” says Papadopoulos. “We demonstrated we could accurately and repetitively detect Alzheimer's disease, with small samples of blood. This test also allowed for differential diagnosis of early stages of Alzheimer's disease, suggesting this can be used as a test to diagnose the disease in its infancy.”
Treatment implications
“There are many candidate disease-modifying therapies that target the underlying development of Alzheimer's disease, which are in clinical trials,” adds Papadopoulos. “However, the implementation of any therapy is dependant on the reliability of the diagnosis.”
Currently the diagnosis of Alzheimer's follows the sequence of family history, information, mental assessment and the physical exam, focusing on neurological signs.
“An accurate, easy and specific non-invasive biochemical test that correlates with clinical findings is vital. We believe our results demonstrate that the DHEA-oxidation blood test can be used to diagnose Alzheimer's at a very early stage and monitor the effect of therapies and the evolution of the disease.” (Source: EurekAlert! A service of AAAS and McGill University Health Centre).
Researchers induce Alzheimer's neurons from pluripotent stem cells
First-ever feat provides new method to understand cause of disease, develop drugs
Led by researchers at the University of California, San Diego School of Medicine, scientists have, for the first time, created stem cell-derived, in vitro models of sporadic and hereditary Alzheimer's disease (AD), using induced pluripotent stem cells from patients with the much-dreaded neurodegenerative disorder.
“Creating highly purified and functional human Alzheimer's neurons in a dish – this has never been done before,” said senior study author Lawrence Goldstein, PhD, professor in the Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute Investigator and director of the UC San Diego Stem Cell Program. “It's a first step. These aren't perfect models. They're proof of concept. But now we know how to make them. It requires extraordinary care and diligence, really rigorous quality controls to induce consistent behavior, but we can do it.”
The feat, published in the January 25 online edition of the journal Nature, represents a new and much-needed method for studying the causes of AD, a progressive dementia that afflicts approximately 5.4 million Americans. More importantly, the living cells provide an unprecedented tool for developing and testing drugs to treat the disorder.
“We're dealing with the human brain. You can't just do a biopsy on living patients,” said Goldstein. “Instead, researchers have had to work around, mimicking some aspects of the disease in non-neuronal human cells or using limited animal models. Neither approach is really satisfactory.”
Goldstein and colleagues extracted primary fibroblasts from skin tissues taken from two patients with familial AD (a rare, early-onset form of the disease associated with a genetic predisposition), two patients with sporadic AD (the common form whose cause is not known) and two persons with no known neurological problems. They reprogrammed the fibroblasts into induced pluripotent stem cells (iPSCs) that then differentiated into working neurons.
The iPSC-derived neurons from the Alzheimer's patients exhibited normal electrophysiological activity, formed functional synaptic contacts and, critically, displayed tell-tale indicators of AD. Specifically, they possessed higher-than-normal levels of proteins associated with the disorder.
With the in vitro Alzheimer's neurons, scientists can more deeply investigate how AD begins and chart the biochemical processes that eventually destroy brain cells associated with elemental cognitive functions like memory. Currently, AD research depends heavily upon studies of post-mortem tissues, long after the damage has been done.
“The differences between a healthy neuron and an Alzheimer's neuron are subtle,” said Goldstein. “It basically comes down to low-level mischief accumulating over a very long time, with catastrophic results.”
The researchers have already produced some surprising findings. “In this work, we show that one of the early changes in Alzheimer's neurons thought to be an initiating event in the course of the disease turns out not to be that significant,” Goldstein said, adding that they discovered a different early event plays a bigger role.
The scientists also found that neurons derived from one of the two patients with sporadic AD exhibited biochemical changes possibly linked to the disease. The discovery suggests that there may be sub-categories of the disorder and that, in the future, potential therapies might be targeted to specific groups of AD patients.
Though just a beginning, Goldstein emphasized the iPSC-derived Alzheimer's neurons present a huge opportunity in a desperate fight. “At the end of the day, we need to use cells like these to better understand Alzheimer's and find drugs to treat it. We need to do everything we can because the cost of this disease is just too heavy and horrible to contemplate. Without solutions, it will bankrupt us – emotionally and financially.” (Source: EurekAlert! A service of AAAS and University of California - San Diego).
Protein in Brain Could Be a Key Target in Controlling Alzheimer’s
(Jan. 25, 2012) — A protein recently discovered in the brain could play a key role in regulating the creation of amyloid beta, the major component of plaques implicated in the development of Alzheimer's disease, according to researchers at Temple University's School of Medicine.
A group led by Domenico Pratico, professor of pharmacology and microbiology and immunology at Temple, discovered the presence of the protein, called 12/15-Lipoxygenase, in the brain three years ago.
“We found this protein to be very active in the brains of people who have Alzheimer's disease,” said Pratico. “But three years ago, we didn't know the role it played in the development of the disease.”
Following two years of study, the Temple researchers have found that the protein is at the top of a pathway and controls a biochemical chain reaction that begins the development of Alzheimer's.
Pratico said that their research has shown that 12/15-Lipoxygenase controls Beta secretase (BACE-1), an enzyme that is key to the development of amyloid plaques in Alzheimer's patients.
“For reasons we don't yet know, in some people, 12/15-Lipoxygenase starts to work too much,” he said. “By working too much, it sends the wrong message to the Beta secretase, which in turn starts to produce more amyloid Beta. This initially results in cognitive impairment, memory impairment and, later, an increase of amyloid plaque.”
BACE-1 has long been a biological target for researchers seeking to create a drug against Alzheimer's disease, said Pratico. But because little has been known about how it functions, they have been unsuccessful developing a molecule that could reach the brain and block it.
“We now know much better how Beta secretase works because we have found that the 12/15-Lipoxygenase protein is a controller of BACE functions,” he said. “You don't need to target the Beta secretase directly because the 12/15-Lipoxygenase is really the system in the brain that tells BACE to work more or work less.”
Pratico said that they have validated 12/15-Lipoxygenase as a target for a potential Alzheimer drug or therapy.
“By modulating BACE levels and activity through controlling the 12/15-Lipoxygenase, we can potentially improve the cognitive part of the phenotype of the disease, and prevent the accumulation of amyloid beta inside the neurons, which will eventually translate into less of those plaques,” he said. “This is a totally new mechanism for controlling BACE.”
Pratico said his group has looked at an experimental compound that blocks 12/15-Lipoxygenase function as a potential therapy to inhibit BACE function in the brain. In their lab, using animal models, they saw the drug's ability to restore some cognitive function, as well as improve learning and memory ability.
“There is an opportunity here to study this molecule and develop an even stronger molecule to target 12/15-Lipoxygenase function in the brain,” he said.
The study was funded by the National Institutes of Health and the Alzheimer's Association. (Source: Science Daily and TempleUniversity).
People with dementia less likely to return home after stroke
ST. PAUL, Minn. – New research shows people with dementia who have a stroke are more likely to become disabled and not return home compared to people who didn't have dementia at the time they had a stroke. The study is published in the November 1, 2011, issue of Neurology ®, the medical journal of the American Academy of Neurology.
“Our findings represent a growing challenge for the health care system as baby boomers age and their risk of stroke and dementia increases,” said lead study author Gustavo Saposnik, MD, MSc, of the University of Toronto in Canada and member of the American Academy of Neurology.
The study involved 9,304 people who had a stroke between 2003 and 2008. Of the group, 702 people had dementia at the time they had a stroke.
Researchers found the people with dementia who had a stroke were three times more likely to have greater disability at discharge from the hospital compared to people without dementia who had a stroke, with 81 percent of those with dementia having moderate to severe disability compared to 57 percent of those without dementia. In addition, only 24 percent of the people in the dementia group returned to the place they lived prior to the stroke compared to 45 percent of people without dementia.
People with dementia were also more likely to have severe stroke and an abnormal heart rhythm and less likely to receive tPA, a clot-busting drug used to treat stroke.
“How to best manage stroke patients with pre-existing dementia is under debate and raises several diagnostic, management and ethical issues as some facilities may limit access to specialized stroke care for dementia patients unless the care is likely to improve outcomes,” said Saposnik. “The lack of established guidelines for the management and treatment of stroke patients with dementia contributes to this uncertainty.” Another study is underway to determine whether dementia or other comorbid conditions (e.g. hypertension, diabetes, atrial fibrillation, smoking) are responsible for the observed outcomes. (Source: EurekAlert! A service of AAAS and the American Academy of Neurology).
Biologists a step nearer to solving the Parkinson's conundrum
Scientists at the University of York have made a significant step forward in isolating the cause of Parkinson's disease in younger adults.
Research by a team in the University's Department of Biology found evidence that movement disorders, including tremor and slowness of movement (bradykinesia), associated with Parkinson's disease (PD) may be due to a defect in energy production in the nervous system. The advance may help to identify young adults who may be susceptible to the disease.
Parkinson's, the second most common form of neurodegenerative disease, principally affects people aged over 60, but some forms – known as juvenile PD – usually start in the 30-40 age group. One in 20 people diagnosed with Parkinson's are under 40 and such early onset PD is often inherited. Previous research has identified the genes which cause the disease and found them to be linked in a common pathway to failure of the mitochondria – the power source within each cell.
In the latest research, part-funded by leading research charity Parkinson's UK and published in Human Molecular Genetics, scientists at York studied the effect that parkin, one of the genes which cause juvenile PD, has on the larva of the fruit fly, Drosophila.
They discovered that parkin faithfully models the locomotory defects of PD with a marked reduction in speed, and slower muscle contractions, reminiscent of bradykinesia.
Dr Chris Elliott, who led the study, said: “Our experimental evidence confirmed that this was due to a defect in the nervous system. This was important because previous work had suggested a big impact on the muscles, but PD is associated with neuronal failure.”
The research team, which included undergraduate and postgraduate students, found that oxygen consumption and the production of ATP (the chief supply of energy inside cells) were drastically reduced. In response, lactate was increased.
The researchers also discovered that parkin larvae showed oxidative stress due to high levels of reactive oxygen species (ROS; also known as free radicals, such as hydrogen peroxide) which have been suggested as a key component of PD. The study suggested that relieving the ROS had only a marginal effect on mitigating slowed locomotion.
Dr Elliott added: “These findings show drastic failure in energy production by parkin larvae, and suggest that biochemicals related to lactate may be worth investigating as biomarkers for the progress of PD.
“We believe that the larval bradykinesia is a consequence of neuronal energy deficit, which leads to failure in neural communication. Oxidative stress is a consequence, rather than cause, of PD.”
Dr Kieran Breen, Director of Research and Innovation at Parkinson's UK, comments:
“This study shows just how vital models like the fruit fly are in helping us understand what happens to the nerve cells that are affected in Parkinson's.
“We already knew that mitochondria were important in Parkinson's but this research suggests that mitochondrial problems may be the root cause of the problems that lead to nerve cell death.
“So finding ways to protect and enhance the mitochondria may be the key to treatments that can slow or even stop Parkinson's in its tracks.” (Source: EurekAlert! A service of AAAS and the University of York).
How Fast You Walk and Your Grip in Middle Age May Predict Dementia, Stroke Risk
NEW ORLEANS – Simple tests such as walking speed and hand grip strength may help doctors determine how likely it is a middle-aged person will develop dementia or stroke. That’s according to new research that was released today and will be presented at the American Academy of Neurology’s 64th Annual Meeting in New Orleans April 21 to April 28, 2012.
“These are basic office tests which can provide insight into risk of dementia and stroke and can be easily performed by a neurologist or general practitioner,” said Erica C. Camargo, MD, MSc, PhD, with Boston Medical Center.
More than 2,400 men and women with an average age of 62 underwent tests for walking speed, hand grip strength and cognitive function. Brain scans were also performed. During the follow-up period of up to 11 years, 34 people developed dementia and 70 people had a stroke.
The study found people with a slower walking speed in middle age were one-and-a-half times more likely to develop dementia compared to people with faster walking speed. Stronger hand grip strength was associated with a 42 percent lower risk of stroke or transient ischemic attack (TIA) in people over age 65 compared to those with weaker hand grip strength. This was not the case, however, for people in the study under age 65.
“While frailty and lower physical performance in elderly people have been associated with an increased risk of dementia, we weren’t sure until now how it impacted people of middle age,” said Camargo.
Researchers also found that slower walking speed was associated with lower total cerebral brain volume and poorer performance on memory, language and decision-making tests. Stronger hand grip strength was associated with larger total cerebral brain volume as well as better performance on cognitive tests asking people to identify similarities among objects. “Further research is needed to understand why this is happening and whether preclinical disease could cause slow walking and decreased strength,” said Camargo. (Source: Newswise and the American Academy of Neurology).
Overeating May Double Risk of Memory Loss
NEW ORLEANS – New research suggests that consuming between 2,100 and 6,000 calories per day may double the risk of memory loss, or mild cognitive impairment (MCI), among people age 70 and older. The study was released today and will be presented at the American Academy of Neurology’s 64th Annual Meeting in New Orleans April 21 to April 28, 2012. MCI is the stage between normal memory loss that comes with aging and early Alzheimer’s disease.
“We observed a dose-response pattern which simply means; the higher the amount of calories consumed each day, the higher the risk of MCI,” said study author Yonas E. Geda, MD, MSc, with the Mayo Clinic in Scottsdale, Arizona and a member of the American Academy of Neurology.
The study involved 1,233 people between the ages of 70 and 89 and free of dementia residing in Olmsted County, Minn. Of those, 163 had MCI. Participants reported the amount of calories they ate or drank in a food questionnaire and were divided into three equal groups based on their daily caloric consumption. One-third of the participants consumed between 600 and 1,526 calories per day, one-third between 1,526 and 2,143 and one-third consumed between 2,143 and 6,000 calories per day.
The odds of having MCI more than doubled for those in the highest calorie-consuming group compared to those in the lowest calorie-consuming group. The results were the same after adjusting for history of stroke, diabetes, amount of education, and other factors that can affect risk of memory loss. There was no significant difference in risk for the middle group.
“Cutting calories and eating foods that make up a healthy diet may be a simpler way to prevent memory loss as we age,” said Geda. (Source: Newswise and the American Academy of Neurology).
Study Shows Alzheimer’s Disease May Spread by ‘Jumping’ from One Brain Region to Another
Findings open new opportunities for studying Alzheimer’s and testing potential therapies
New York, NY (February 1, 2012) — For decades, researchers have debated whether Alzheimer’s disease starts independently in vulnerable brain regions at different times, or if it begins in one region and then spreads to neuroanatomically connected areas. A new study by Columbia University Medical Center (CUMC) researchers strongly supports the latter, demonstrating that abnormal tau protein, a key feature of the neurofibrillary tangles seen in the brains of those with Alzheimer’s, propagates along linked brain circuits, “jumping” from neuron to neuron.
The findings, published today in the online journal PloS One, open new opportunities for gaining a greater understanding of Alzheimer’s disease and other neurological diseases and for developing therapies to halt its progression, according to senior author Karen E. Duff, PhD, professor of pathology (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.
Alzheimer’s disease, the most common form of dementia, is characterized by the accumulation of plaques (composed of amyloid-beta protein) and fibrous tangles (composed of abnormal tau) in brain cells called neurons. Postmortem studies of human brains and neuroimaging studies have suggested that the disease, especially the neurofibrillary tangle pathology, begins in the entorhinal cortex, which plays a key role in memory. Then as Alzheimer’s progresses, the disease appears in anatomically linked higher brain regions.
“Earlier research, including functional MRI studies in humans, have also supported this pattern of spread,” said study coauthor Scott A. Small, MD, professor of neurology in the Sergievsky Center and in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at CUMC. “But these various findings do not definitively show that Alzheimer’s spreads directly from one brain region to another.”
To look further into this issue, the CUMC researchers developed a novel transgenic mouse in which the gene for abnormal human tau is expressed predominantly in the entorhinal cortex. The brains of the mice were analyzed at different time points over 22 months to map the spread of abnormal tau protein.
The researchers found that as the mice aged, the abnormal human tau spread along a linked anatomical pathway, from the entorhinal cortex to the hippocampus to the neocortex. “This pattern very much follows the staging that we see at the earliest stages of human Alzheimer’s disease,” said Dr. Duff.
The researchers also found evidence suggesting that the abnormal tau protein was moving from neuron to neuron across synapses, the junctions that these cells use to communicate with each other.
The findings of the study have important implications for therapy.
“If, as our data suggest, tau pathology starts in the entorhinal cortex and emanates from there, the most effective approach may be to treat Alzheimer’s the way we treat cancer—through early detection and treatment, before it has a chance to spread,” said Dr. Small. “The best way to cure Alzheimer’s may be to identify and treat it when it is just beginning, to halt progression. It is during this early stage that the disease will be most amenable to treatment. That is the exciting clinical promise down the road.”
Treatments could conceivably target tau during it extracellular phase, as it moves from cell to cell, added Dr. Duff. “If we can find the mechanism by which tau spreads from one cell to another, we could potentially stop it from jumping across the synapses — perhaps using some type of immunotherapy. This would prevent the disease from spreading to other regions of the brain, which is associated with more severe dementia.” (Source: Newswise and Columbia University Medical Center).