Thursday, January 9, 2014

How diabetes predisposes individuals to Alzheimer's disease

Diabetes and dementia are rising dramatically in the United States and worldwide. In the last few years, epidemiological data has accrued showing that older people with diabetes are significantly more likely to develop cognitive deterioration and increased susceptibility to onset of dementia related to Alzheimer's disease. Now, a research team led by Giulio Maria Pasinetti, MD, PhD, the Saunders Family Chair and Professor of Neurology at the Icahn School of Medicine at Mount Sinai, discovered a novel mechanism through which this may occur. The results are published online in the journal Diabetes.

Dr. Pasinetti and colleagues pinpointed changes in post-mortem brains of human subjects. They reported that gene expression was dysfunctional in the brains of diabetic human subjects, and this increase was associated with reduced expression of important molecules that play a critical role in maintaining the structural integrity of brain regions associated with learning.

Excited by this finding, Dr. Pasinetti reasoned that if the hypothesis was correct, similar conditions should be repeated in the laboratory by inducing diabetes in mice genetically predisposed to developing Alzheimer's type memory deterioration.

In fact, Dr. Pasinetti's laboratory confirmed this prediction in the mouse model, supporting the hypothesis that diabetes, through epigenetic changes in the brain, may casually promote onset and progression of Alzheimer's disease. Epigenetic changes are chemical changes in DNA that effect gene expression, but don't alter the actual genetic code.

"This new evidence is extremely intriguing, given that approximately 60 percent of Alzheimer's disease patients have at least one serious medical condition associated with diabetes," said Dr. Pasinetti. "What this adds is much needed insight into the potential mechanism that might explain the relationship between diabetes and Alzheimer's disease onset and progression by mechanisms through which DNA functions."

The discovery in Dr. Pasinetti's laboratory has staggering societal implications. More than 5 million are affected by Alzheimer's disease dementia, and the disease incidence is expected to skyrocket in the three decades as the population ages.

"The next question we must ask is how we can translate this into the development of novel disease prevention and treatment strategies," Dr. Pasinetti added. "If we can find out how DNA epigenetic modification can be manipulated pharmacologically, these studies will be instrumental in the formulation of novel treatments and possible preventative strategies in Alzheimer's disease.










How our brain resists temptation in preference of 'future rewards'

 When on a strict diet, it can be very hard to resist a bar of chocolate if it is right under your nose. Are you likely to eat it there and then? Or wait until the end of the week to intensify the satisfying experience? Whatever your answer, researchers now say they can explain the difference in people's ability to resist temptation.

According to researchers from the Brain and Spine Institute in Paris, activity in the hippocampus of the brain - an area of the brain involved in forming, storing and organizing memories - is crucial in making the decision to delay rewards.

Previous studies have analyzed human's temporal choices, with researchers conducting brain scans while participants are asked to make monetary choices, such as $10 now or $11 tomorrow.

"However, these paradigms miss an essential feature of the inter-temporal conflicts we have to face in everyday life," says Dr. Mathias Pessiglione of the Brain and Spine Institute and leader of the study.

"[...] immediate rewards can be perceived through our senses, whereas future rewards must be represented in our imagination."

To reach their findings, published in the journal PLOS Biology, the researchers conducted a series of experiments on volunteers using more natural rewards that people come across in everyday life. For example, participants were asked if they would like a beer today, or a bottle of champagne in a week's time.
Imagining future rewards

The participants were presented with choices between immediate rewards that were presented as pictures, or future rewards that were presented as text, meaning participants had to "imagine" the long-term rewards.

The researchers found that the ability to select future rewards was linked to the amount of activity in the hippocampus.

They then conducted the same experiments on a group of patients with hippocampus damage as a result of Alzheimer's disease, alongside patients with behavioral variant of frontotemporal dementia (bvFTD) as a result of prefrontal cortex degeneration. The prefrontal cortex of the brain is known to implement behavioral control.

Results showed that those with bvFTD demonstrated high impulsiveness in all choices, but those with Alzheimer's disease showed more bias towards immediate rewards when long-term rewards had to be imagined.

Dr. Pessiglione says the reason for these results is because the hippocampus plays an important role in imagining future situations by building details that makes long-term rewards appear more attractive.

Researchers demonstrate preventive effect of sterols in Alzheimer's disease

Plant sterols are present in various combinations in nuts, seeds and plant oils. As plant sterols are the equivalents of animal cholesterol, they can in principal influence metabolic processes, where cholesterol is involved," explained Marcus Grimm, Head of the Experimental Neurology Laboratory at Saarland University. "Because they also lower cholesterol levels, they are extensively used in the food industry and as dietary supplements."

High cholesterol levels have long been discussed to increase the risk of developing Alzheimer's disease. "Studies have already shown that cholesterol promotes the formation of so-called senile plaques," said Grimm. These plaques, which are composed of proteins, particularly beta-amyloid proteins, deposit at nerve cells within the brain and are regarded as one of the main causes of Alzheimer's disease.

The research team based at Saarland University's medical campus in Homburg collaborated with scientists from Bonn, Finland and the Netherlands to examine how the sterols that we ingest influence the formation of these plaque proteins. It was found that one sterol in particular, stigmasterol, actually inhibited protein formation. "Stigmasterol has an effect on a variety of molecular processes: it lowers enzyme activity, it inhibits the formation of proteins implicated in the development of Alzheimer's disease, and it alters the structure of the cell membrane," explained Dr Grimm. "Together, these effects synergistically reduce the production of beta-amyloid proteins." The research team has been able to confirm the positive effect of stigmasterol in tests on animals.

Overall, the researchers were able to demonstrate that the various plant sterols influence different cellular mechanisms and therefore have to be assessed individually. "Particularly in the case of Alzheimer's disease, it seems expedient to focus on the dietary intake of specific plant sterols rather than a mixture of sterols," explained Dr Grimm. In future studies, the research team wants to determine which other cellular processes in the brain are affected by phytosterols.


Scientists discover 11 new Alzheimer's risk genes

In what promises to be a major breakthrough in our understanding of Alzheimer's disease, an international group of scientists has discovered 11 previously unknown genes that increase people's risk of developing this most common cause of dementia.

The study, undertaken by the International Genomics Project (IGAP) and co-led by Cardiff University, Wales, UK, is published online this week in Nature Genetics.

The large group of four teams comes from 145 academic centers around the world and comprises most of the world's experts in the genetics of Alzheimer's.

They believe the discovery, which now brings the total number of genes known to raise the risk of developing Alzheimer's disease to 21, will open new avenues of research to improve our knowledge about the mechanisms that underpin the brain-wasting disease.

Prof. Julie Williams, head of neurodegeneration at Cardiff School of Medicine's Medical Research Council (MRC) Centre on Neuropsychiatric Genetics and Genomics, led one of the four international teams. She says:

"By combining the expertise and resources of geneticists across the globe, we have been able to overcome our natural competitive instincts to achieve a real breakthrough in identifying the genetic architecture that significantly contributes to our mapping of the disease."

The study builds on genome-wide association analysis work that, since 2009, has found the other 10 genes already known to be linked with Alzheimer's.

Prof. Williams, who is also chief scientific advisor for Wales, says the biggest surprise was finding out that several of the new genes involve the body's immune response in causing dementia.

However, she cautions that although we now have details of 21 genes known to increase risk of developing Alzheimer's, "a large portion of the genetic risk for the disease remains unexplained."

"Further research is still needed to locate the other genes involved before we can get a complete picture," she adds.
Discovery 'confirms' immune system's involvement

For the study, the teams gathered genome data from 74,076 people from 15 countries around the world to find the 11 new genes.

The researchers say one of the most significant findings relates to the HLA-DRB5/DRB1 major histocompatibility complex region of the genome. This discovery confirms that the immune system is somehow involved in the disease. This same region is associated with multiple sclerosis and Parkinson's disease.

The discoveries revolve around the most common, late-onset type of Alzheimer's.

Prof. Williams says they now want to turn their attention to people with the early-onset form of Alzheimer's, who get a more severe form of the disease in their 40s and 50s:

    "Their genetic architecture may hold the key to finding yet more genes involved in Alzheimer's. They carry a heavier genetic load than people who develop the condition in later life and will yield clues about what genetic markers we should be looking out for."

She says they will also be bringing together what has been found out about environmental factors that increase and decrease the risk of developing Alzheimer's disease.

Prof. Williams says these discoveries are greatly helped by the fact experts in the genetics of Alzheimer's set aside their urge to compete and instead come together in the large teams that are necessary to make these kinds of breakthroughs. Now the same needs to happen with the biologists, she adds:

"It would be greatly encouraging to also see the world's molecular biologists all pulling together, breaking out of their silos and uniting in their aim of unraveling disease and developing the treatments to tackle it."

The research was partly funded by the Medical Research Council, the Welsh Government and Alzheimer's Research UK.


The wrong levels of a protein linked with Alzheimer's disease can lead to dangerous blockages in brain cells

 Scientists have known for some time that a protein called presenilin plays a role in Alzheimer's disease, and a new study reveals one intriguing way this happens.

It has to do with how materials travel up and down brain cells, which are also called neurons.

In a paper in Human Molecular Genetics, University at Buffalo researchers report that presenilin works with an enzyme called GSK-3beta to control how fast materials - like proteins needed for cell survival - move through the cells.

"If you have too much presenilin or too little, it disrupts the activity of GSK-3ß, and the transport of cargo along neurons becomes uncoordinated," says lead researcher Shermali Gunawardena, PhD, an assistant professor of biological sciences at UB. "This can lead to dangerous blockages."
More than 150 mutations of presenilin have been found in Alzheimer's patients, and scientists have previously shown that the protein, when defective, can cause neuronal blockages by snipping another protein into pieces that accumulate in brain cells.

But this well-known mechanism isn't the only way presenilin fuels disease, as Gunawardena's new study shows.

"Our work elucidates how problems with presenilin could contribute to early problems observed in Alzheimer's disease," she says. "It highlights a potential pathway for early intervention through drugs - prior to neuronal loss and clinical manifestations of disease."

The study suggests that presenilin activates GSK-3ß. This is an important finding because the enzyme helps control the speed at which tiny, organic bubbles called vesicles ferry cargo along neuronal highways. (You can think of vesicles as trucks, each powered by little molecular motors called dyneins and kinesins.)

When researchers lowered the amount of presenilin in the neurons of fruit fly larvae, less GSK-3ß became activated and vesicles began speeding along cells in an uncontrolled manner.

Decreasing levels of both presenilin and GSK-3ß at once made things worse, resulting in "traffic jams" as the bubbles got stuck in neurons.

"Both GSK-3ß and presenilin have been shown to be involved in Alzheimer's disease, but how they are involved has not always been clear," Gunawardena says. "Our research provides new insight into this question."

Gunawardena proposes that GSK-3ß - short for glycogen synthase kinase-3beta - acts as an "on switch" for dynein and kynesin motors, telling them when to latch onto vesicles.

Dyneins carry vesicles toward the cell nucleus, while kinesins move in the other direction, toward the periphery of the cell. When all is well and GSK-3ß levels are normal, both types of motors bind to vesicles in carefully calibrated numbers, resulting in smooth traffic flow along neurons.

That's why it's so dangerous when GSK-3ß levels are off-kilter, she says.

When GSK-3ß levels are high, too many motors attach to the vesicles, leading to slow movement as motor activity loses coordination. Low GSK-3ß levels appear to have the opposite effect, causing fast, uncontrolled movement as too few motors latch onto vesicles.

Both scenarios -0 too much GSK-3ß or too little - can result in neuronal blockages.



FDA approves second brain imaging drug to help evaluate patients for Alzheimer's disease, dementia

The U.S. Food and Drug Administration has approved Vizamyl (flutemetamol F 18 injection), a radioactive diagnostic drug for use with positron emission tomography (PET) imaging of the brain in adults being evaluated for Alzheimer's disease (AD) and dementia.

Dementia is associated with diminishing brain functions such as memory, judgment, language and complex motor skills. The dementia caused by AD is associated with the accumulation in the brain of an abnormal protein called beta amyloid and damage or death of brain cells. However, beta amyloid can also be found in the brain of patients with other dementias and in elderly people without neurologic disease.

Vizamyl works by attaching to beta amyloid and producing a PET image of the brain that is used to evaluate the presence of beta amyloid. A negative Vizamyl scan means that there is little or no beta amyloid accumulation in the brain and the cause of the dementia is probably not due to AD. A positive scan means that there is probably a moderate or greater amount of amyloid in the brain, but it does not establish a diagnosis of AD or other dementia. Vizamyl does not replace other diagnostic tests used in the evaluation of AD and dementia.

"Many Americans are evaluated every year to determine the cause of diminishing neurologic functions, such as memory and judgment, that raise the possibility of Alzheimer's disease," said Shaw Chen, M.D., deputy director of the Office of Drug Evaluation IV in the FDA's Center for Drug Evaluation and Research. "Imaging drugs like Vizamyl provide physicians with important tools to help evaluate patients for AD and dementia."

Vizamyl is the second diagnostic drug available for visualizing beta amyloid on a PET scan of the brain. In 2012, FDA approved Amyvid (Florbetapir F 18 injection) to help evaluate adults for AD and other causes of cognitive decline.

Vizamyl's effectiveness was established in two clinical studies comprised of 384 participants with a range of cognitive function. All participants were injected with Vizamyl and were scanned. The images were interpreted by five independent readers masked to all clinical information. A portion of scan results were also confirmed by autopsy.

The study results demonstrate that Vizamyl correctly detects beta amyloid in the brain. The results also confirm that the scans are reproducible and trained readers can accurately interpret the scans. Vizamyl's safety was established in a total of 761 participants.

Vizamyl is not indicated to predict the development of AD or to check how patients respond to treatment for AD. Vizamyl PET images should be interpreted only by health care professionals who successfully complete training in an image interpretation program. The Vizamyl drug labeling includes information about image interpretation.

Safety risks associated with Vizamyl include hypersensitivity reactions and the risks associated with image misinterpretation and radiation exposure. Common side effects associated with Vizamyl include flushing, headache, increased blood pressure, nausea and dizziness.

Vizamyl is manufactured for GE Healthcare by Medi-Physics, Inc., based in Arlington Heights, Ill.


Specific molecules identified that could be targeted to treat Alzheimer's disease

Plaques and tangles made of proteins are believed to contribute to the debilitating progression of Alzheimer's disease. But proteins also play a positive role in important brain functions, like cell-to-cell communication and immunological response. Molecules called microRNAs regulate both good and bad protein levels in the brain, binding to messenger RNAs to prevent them from developing into proteins.

Now, Dr. Boaz Barak and a team of researchers in the lab of Prof. Uri Ashery of Tel Aviv University's Department of Neurobiology at the George S. Wise Faculty of Life Sciences and the Sagol School of Neuroscience have identified a specific set of microRNAs that detrimentally regulate protein levels in the brains of mice with Alzheimer's disease and beneficially regulate protein levels in the brains of other mice living in a stimulating environment.

"We were able to create two lists of microRNAs - those that contribute to brain performance and those that detract - depending on their levels in the brain," says Dr. Barak. "By targeting these molecules, we hope to move closer toward earlier detection and better treatment of Alzheimer's disease."

Prof. Daniel Michaelson of TAU's Department of Neurobiology in the George S. Wise Faculty of Life Sciences and the Sagol School of Neuroscience, Dr. Noam Shomron of TAU's Department of Cell and Developmental Biology and Sagol School of Neuroscience, Dr. Eitan Okun of Bar-Ilan University, and Dr. Mark Mattson of the National Institute on Aging collaborated on the study, published in Translational Psychiatry.
A double-edged sword

Alzheimer's disease is the most common form of dementia. Currently incurable, it increasingly impairs brain function over time, ultimately leading to death. The TAU researchers became interested in the disease while studying the brains of mice living in an "enriched environment" - an enlarged cage with running wheels, bedding and nesting material, a house, and frequently changing toys. Such environments have been shown to improve and maintain brain function in animals much as intellectual activity and physical fitness do in people.

The researchers ran a series of tests on a part of the mice's brains called the hippocampus, which plays a major role in memory and spatial navigation and is one of the earliest targets of Alzheimer's disease in humans. They found that, compared to mice in normal cages, the mice from the enriched environment developed higher levels of good proteins and lower levels of bad proteins. Then, for the first time, they identified the microRNAs responsible for regulating the expression of both good and bad proteins.

Armed with this new information, the researchers analyzed changes in the levels of microRNAs in the hippocampi of young, middle-aged, and old mice with an Alzheimer's-disease-like condition. They found that some of the microRNAs were expressed in exactly inverse amounts in mice with Alzheimer's disease as they were in mice from the enriched environment. The results were higher levels of bad proteins and lower levels of good proteins in the hippocampi of old mice with Alzheimer's disease. The microRNAs the researchers identified had already been shown or predicted to regulate the expression of proteins in ways that contributed to Alzheimer's disease. Their finding that the microRNAs are inversely regulated in mice from the enriched environment is important, because it suggests the molecules can be targeted by activities or drugs to preserve brain function.

Brain-busting potential

Two findings appear to have particular potential for treating people with Alzheimer's disease. In the brains of old mice with the disease, microRNA-325 was diminished, leading to higher levels of tomosyn, a protein that is well known to inhibit cellular communication in the brain. The researchers hope that eventually microRNA-325 can be used to create a drug to help Alzheimer's patients maintain low levels of tomosyn and preserve brain function. Additionally, the researchers found several important microRNAs at low levels starting in the brains of young mice. If the same can be found in humans, these microRNAs could be used as biomarker to detect Alzheimer's disease at a much earlier age than is now possible - at 30 years of age, for example, instead of 60.

"Our biggest hope is to be able to one day use microRNAs to detect Alzheimer's disease in people at a young age and begin a tailor-made


Link between RNA build-up and dementia, motor neuron disease

 new toxic entity associated with genetically inherited forms of dementia and motor neuron disease has been identified by scientists at the UCL Institute of Neurology. The toxin is the result of a genetic mutation that leads to the production of RNA molecules which could be responsible for the diseases. The findings are published in the journal Acta Neuropathologica.

Frontotemporal dementia and motor neuron disease are related neurodegenerative diseases that affect approximately 15,000 people in the UK. Frontotemporal dementia causes profound personality and behaviour changes. Motor neuron disease leads to muscle weakness and eventual paralysis.

The most common known cause for both frontotemporal dementia and motor neuron disease is an unusual genetic mutation in the C9orf72 gene. The mutation involves a small string of DNA letters at the beginning of the gene, which expand massively to produce thousands of copies.

The new research, funded by Alzheimer's Research UK and the Medical Research Council, has shown that this DNA expansion acts in a peculiar way, leading to the generation of unexpected RNA molecules that could cause the disease.

When a gene is turned on, an RNA copy of the gene's DNA is generated. The gene's DNA code has directionality, so that it is normally turned on in only one direction, termed the 'sense direction'. The new research shows that the DNA expansion is turned on in both directions.

This leads to the normal sense RNA being produced, as well as RNA in the opposite direction, termed 'antisense RNA'. Both RNA types accumulate into aggregates in the neurons of people with frontotemporal dementia.
Intriguingly, the research showed that people with more of these aggregates in their brains developed the disease earlier than people with less RNA aggregates. This correlation suggests that the build-up may be important in causing frontotemporal dementia and motor neuron disease, making the C9orf72 DNA expansion a potential target for therapy.

Dr Adrian Isaacs, lead researcher at the UCL Institute of Neurology, said: ""These findings identify new, potentially toxic molecules in diseases caused by DNA expansions. The next steps will be to determine how they might kill neurons and how to stop them building up."

Dr Simon Ridley, Head of Research at Alzheimer's Research UK, the UK's leading dementia research charity, said: "The discovery of the C9ORF72 gene was a major step forward for research into frontotemporal dementia and motor neuron disease, and it's positive to see researchers beginning to untangle how this gene may cause these diseases in some people.

"Alzheimer's Research UK is delighted to have supported this promising study. By unravelling some of the biological mechanisms at play, this research could take us further on the road to new treatments that are so desperately needed by the thousands of people with these devastating diseases. For these results to reach their full potential it's vital that we continue to invest in research."




Alzheimer's patients at increased risk for heart disease

Persons with Alzheimer's disease suffer from ischaemic heart diseases more frequently than others, yet they undergo related procedures and surgery less frequently than persons with no diagnosed AD, according to a nation-wide register-based study carried out at the University of Eastern Finland.

The study involved a total of 28,093 persons; that is every community-dwelling person with a diagnosed Alzheimer's disease living in Finland on 31 December 2005. According to the data obtained from the national hospital discharge register, persons with Alzheimer's disease were slightly more likely to suffer from ischaemic heart diseases than their matched control group with no existing AD diagnosis. Despite this, persons with Alzheimer's disease underwent significantly fewer procedures restoring cardiac circulation, such as coronary angioplasty and coronary artery bypass surgery, than the control group.

The results were not explained by medical treatment of cardiovascular diseases or by other related diseases such as stroke, diabetes, asthma, or cancer. Severely reduced cognitive function is a relative contraindication for coronary artery bypass surgery, but not for coronary angioplasty. However, the register-based data makes it difficult to assess whether the low number of coronary angioplasties performed on persons with Alzheimer's disease is indicative of their insufficient access to treatment.

The study constituted part of the register-based MEDALZ-2005 project, which focuses on the health of persons with Alzheimer's disease, their use of drugs and health services, and drug safety. The study was published in International Journal of Cardiology.

New hope for Alzheimer's disease offered by S14G-humanin

Humanin is a potential therapeutic agent for Alzheimer's disease, and its derivative, S14G-humanin, is 1 000-fold stronger in its neuroprotective effect against Alzheimer's disease-relevant insults.

Although effective, the detailed molecular mechanism through which S14G-humanin exerts its effects remains unclear.

A recent study by Xue Li and colleagues from Henan Provincial People's Hospital, China investigated the inhibitory effects of S14G-humanin on amyloid-beta protein-induced hippocampal neuronal injury, and data from this study showed that fibrillar amyloid-beta 40 disturbed cellular homeostasis through the cell membrane, increasing intracellular calcium, generating reactive oxygen species, and decreasing the mitochondrial membrane potential.

S14G-humanin blocked the effects of amyloid-beta 40 on the neuronal cell membrane, and restored the disturbed cellular homeostasis, thereby exhibiting a potential and effective treatment for Alzheimer's disease. These findings were

Specific brain regions can be trained by means of video games

Video gaming causes increases in the brain regions responsible for spatial orientation, memory formation and strategic planning as well as fine motor skills. This has been shown in a new study conducted at the Max Planck Institute for Human Development and Charite University Medicine St. Hedwig-Krankenhaus. The positive effects of video gaming may also prove relevant in therapeutic interventions targeting psychiatric disorders.

In order to investigate how video games affect the brain, scientists in Berlin have asked adults to play the video game "Super Mario 64" over a period of two months for 30 minutes a day. A control group did not play video games. Brain volume was quantified using magnetic resonance imaging (MRI). In comparison to the control group the video gaming group showed increases of grey matter, in which the cell bodies of the nerve cells of the brain are situated. These plasticity effects were observed in the right hippocampus, right prefrontal cortex and the cerebellum. These brain regions are involved in functions such as spatial navigation, memory formation, strategic planning and fine motor skills of the hands. Most interestingly, these changes were more pronounced the more desire the participants reported to play the video game.

"While previous studies have shown differences in brain structure of video gamers, the present study can demonstrate the direct causal link between video gaming and a volumetric brain increase. This proves that specific brain regions can be trained by means of video games", says study leader Simone Kühn, senior scientist at the Center for Lifespan Psychology at the Max Planck Institute for Human Development. Therefore Simone Kühn and her colleagues assume that video games could be therapeutically useful for patients with mental disorders in which brain regions are altered or reduced in size, e.g. schizophrenia, post-traumatic stress disorder or neurodegenerative diseases such as Alzheimer's dementia.

"Many patients will accept video games more readily than other medical interventions", adds the psychiatrist Jürgen Gallinat, co-author of the study at Charité University Medicine St. Hedwig-Krankenhaus. Further studies to investigate the effects of video gaming in patients with mental health issues are planned. A study on the effects of video gaming in the treatment of post-traumatic stress disorder is currently ongoing.

The next step in stroke prevention:

As growing numbers of America's baby boomers reach retirement, neuroscientists are expanding their efforts to understand and treat one of the leading health issues affecting this population: age-related neurological deterioration, including stroke and dementia.

One factor coming under increased study is cerebral microbleeds, experienced by nearly 20 percent of people by age 60 and nearly 40 percent by age 80. Research into these small areas of brain bleeding, caused by a breakdown of miniscule blood vessels, is shedding light on how the condition may contribute to these neurological changes.

With microbleeds common in older individuals, physicians need to take it into consideration when treating other brain-related issues, said Dr. Mark Fisher, professor of neurology, anatomy & neurobiology, and pathology & laboratory medicine at UC Irvine. This is especially important with stroke prevention measures, which often involve medications that interfere with blood clotting and could exacerbate microbleeds. Stroke risk escalates with age, especially after 55, making stroke one of the leading causes of disability and death in the elderly.

In two current papers published online in Frontiers in Neurology and Stroke, Fisher writes about the brain's intricate system to protect itself against hemorrhaging. This system seems to break down as we get older, resulting in microbleeds that develop spontaneously and become increasingly common with aging.

"The next step in stroke prevention will require that we address both blood clotting and protection of the blood vessels," he said. "This seems to be the best way to reduce the risk of microbleeds when it's necessary to limit blood clotting for stroke prevention."

In his Stroke article, Fisher describes how newer medications interfere with blood clotting (to protect against stroke) while at the same time protecting the blood vessel wall (to help prevent bleeding). And in Frontiers in Neurology, he suggests that MRI screening be used more strategically to identify patients with microbleeds, allowing their physicians to adjust treatments accordingly.

"With the prevalence of microbleeds, it's important that we better understand this neurological factor as we develop and proceed with brain-related treatments for the elderly," Fisher said. "Identifying and controlling microbleeds may be an important step in a therapeutic approach to maximize brain health during the process of aging. This is a critical issue requiring further study."

Amyloid beta-peptide may worsen cognitive impairment following cerebral ischemia-reperfusion injury

Amyloid beta-peptide, a major component of senile plaques in Alzheimer's disease, has been implicated in neuronal cell death and cognitive impairment.

Recently, studies have shown that the pathogenesis of cerebral ischemia is closely linked with Alzheimer's disease. According to a study, administration of amyloid β-peptide could further aggravate impairments to learning and memory and neuronal cell death in the hippocampus of rats subjected to cerebral ischemia-reperfusion injury.

The synergistic effect of amyloid β-peptide and cerebral ischemia-reperfusion injury exacerbated nerve damage by inducing glycogen synthase kinase 3β and protein phosphatase 2A activity, which resulted in the phosphorylation of tau protein.

This study by Dr. Bo Song and team from Research Center of Stem Cells and Regenerative Medicine, School of Medicine, Tsinghua University, China was published in Neural

Photo therapy may someday cure brain diseases such as Alzheimer's and Parkinson's

Researchers at Chalmers University of Technology in Sweden, together with researchers at the Polish Wroclaw University of Technology, have made a discovery that may lead to the curing of diseases such as Alzheimer's, Parkinson's and Creutzfeldt-Jakob disease (the so called mad cow disease) through photo therapy.

The researchers discovered, as they show in the journal Nature Photonics, that it is possible to distinguish aggregations of the proteins, believed to cause the diseases, from the the well-functioning proteins in the body by using multi-photon laser technique.

"Nobody has talked about using only light to treat these diseases until now. This is a totally new approach and we believe that this might become a breakthrough in the research of diseases such as Alzheimer's, Parkinson's and Creutzfeldt-Jakob disease. We have found a totally new way of discovering these structures using just laser light", says Piotr Hanczyc at Chalmers University of Technology.

If the protein aggregates are removed, the disease is in principle cured. The problem until now has been to detect and remove the aggregates.

The researchers now harbor high hopes that photo acoustic therapy, which is already used for tomography, may be used to remove the malfunctioning proteins. Today amyloid protein aggregates are treated with chemicals, both for detection as well as removal. These chemicals are highly toxic and harmful for those treated.

With multi photon laser the chemical treatment would be unnecessary. Nor would surgery be necessary for removing of aggregates. Due to this discovery it might, thus, be possible to remove the harmful protein without touching the surrounding tissue.

These diseases arise when amyloid beta protein are aggregated in large doses so they start to inhibit proper cellular processes.

Different proteins create different kinds of amyloids, but they generally have the same structure. This makes them different from the well-functioning proteins in the body, which can now be shown by multi photon laser technique.

Tau and amyloid-beta proteins in a preclinical model of Alzheimer's disease

Anavex Life Sciences Corp. announces that issue 38 (2013) of the international scientific journal Neuropsychopharmacology contains a report demonstrating that ANAVEX 2-73 dose-dependently blocks Tau and amyloid-beta ("amyloid") proteins and memory deficit in a mouse model of Alzheimer's disease (AD). A reduction in these two main hallmarks of Alzheimer's has the potential to stop, slow or reverse the disease. The report also suggests that, because it is targeting the mixed muscarinic and Sigma-1 receptors, ANAVEX 2-73 is able to achieve its effect further "upstream" in the Alzheimer's disease cascade. This compares to most other current AD clinical development compounds that are mainly downstream and single-targeted approaches, which might be limited by adverse effects. More interestingly, the mixed muscarinic and Sigma-1 agonist ANAVEX 2-73 exhibited powerful effects despite its moderate affinity for these receptors, emphasizing its great advantage for potential therapy in Alzheimer's disease.

Tangui Maurice, PhD, CNRS Research Director, Head of Team 2 'Endogenous Neuroprotection in Neurodegenerative Diseases', at the University of Montpellier and INSERM, and one of the study authors, said, "ANAVEX 2-73 also dose-dependently reduced C99 levels in the hippocampus, an effect which researchers are currently trying to achieve with BACE inhibitors. In the mouse model we also confirmed the central role of the kinase GSK-3 beta in Alzheimer's disease toxicity through drugs acting either directly as GSK-3 beta inhibitors, or indirectly, as mixed muscarinic and Sigma-1 ligands. Both can efficiently alleviate these two major alterations observed in the Alzheimer's animal model, as well as in Alzheimer's patient brains. However, by targeting GSK-3 beta indirectly as ANAVEX 2-73 does through muscarinic and Sigma-1 ligands, we could avoid the toxicity seen by directly targeting GSK-3 beta."

Christopher U. Missling, PhD, President and Chief Executive Officer of Anavex, said, "Using further upstream targets that efficiently block tau phosphorylation and amyloid overproduction might be a more comprehensive approach in successfully treating this complex disease. Together with previously confirmed findings demonstrating the ability of ANAVEX 2-73 to reduce mitochondrial oxidative stress, this publication strengthens the case for a potential pharmacological treatment for Alzheimer's disease."

The report, entitled "Blockade of Tau Hyperphosphorylation and Amyloid-beta1 - 42 Generation by the Aminotetrahydrofuran Derivative ANAVEX2-73, a Mixed Muscarinic and Sigma-1 Receptor Agonist, in a Nontransgenic Mouse Model of Alzheimer's Disease," is based on a scientific study conducted in France at the University of Montpellier and INSERM.