Biosynthetic Grape Derived Compound Prevents Progression of Alzheimer's

This group of researchers found that certain grape seeds extracts, comprised of a complex mixture of naturally occurring polyphenols, were capable of lessening cognitive deterioration and reducing brain neuropathology.

+Alzheimer's Reading Room

Mount Sinai School of Medicine researchers have succeeded in developing a biosynthetic polyphenol that improves cognitive function in mice with Alzheimer's disease (AD). The findings, published in a recent issue of the Journal of Neuroscience, provide insight in determining the feasibility of biosynthetic polyphenols as a possible therapy for AD in humans, a progressive neurodegenerative disease for which there is currently no cure.

Polyphenols, which occur naturally in grapes, fruits, and vegetables, have been shown to prevent the cognitive decline associated with AD in a mouse model, but the molecules are very complex and are extensively metabolized in the body.

This is the first study to determine which specific subfraction of these molecules penetrates the animal brain, and demonstrate that a drug compound similar to polyphenols can exert similar bioactivities.

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Biosynthetic grape-derived compound prevents progression of Alzheimer's disease in mice

A research group led by Giulio Maria Pasinetti, MD, PhD, Saunders Family Professor and Chair in Neurology at Mount Sinai School of Medicine, has been exploring the application of specific grape-derived polyphenols for the treatment of AD. Previously, this group found that certain grape-seeds extracts, comprised of a complex mixture of naturally occurring polyphenols, were capable of lessening cognitive deterioration and reducing brain neuropathology in an animal model of AD, but they did not know how to manipulate the natural extract into a pharmaceutical compound that could be used by the brain.

"My team, along with many members of the scientific community, did not know how we could harness the efficacy of naturally occurring polyphenols in food for treatment of Alzheimer's disease," Dr. Pasinetti said. "We were skeptical that these naturally occurring polyphenols would reach the brain because they are extensively metabolized following ingestion."

The researchers separated the natural occurring polyphenols from grapes, sorted them by size, and administered each for five months through drinking water to mice genetically altered to develop AD, after which they assessed brain neuropathology and cognitive function of the mice. They identified a specific grape polyphenol metabolite that was capable of selectively reaching and accumulating in the brain. This compound reduced the neuropathology of AD in the brain by preventing the accumulation of abnormal proteins in the brain, a hallmark of AD.

Dr. Pasinetti's team analyzed the structure of this polyphenol by nuclear magnetic resonance imaging and recreated it biosynthetically in the laboratory. Dr. Pasinetti and his collaborators discovered that the synthetic polyphenol generated in the laboratory also promoted plasticity and benefits in learning and memory functions in the brains of the mice.

"While this is an exciting development, we have a lot to discover and many years of testing before this agent can be considered in humans," said Dr. Pasinetti. "I look forward to further studying this compound to determine its feasibility as a treatment for Alzheimer's disease."

Dr. Pasinetti is currently exploring the possibility of delivering biosynthetic polyphenols nasally or subcutaneously, thereby preventing them from being metabolized in the liver.

Mount Sinai researchers are supported by a grant from the National Institutes of Health. Dr. Giulio Maria Pasinetti is a named inventor of a pending patent application filed by Mount Sinai School of Medicine (MSSM) related to the study of Alzheimer's disease. In the event the pending or issued patent is licensed, Dr. Pasinetti would be entitled to a share of any proceeds MSSM receives from the licensee.
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About The Mount Sinai Medical Center

The Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and Mount Sinai School of Medicine. The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation's oldest, largest and most-respected voluntary hospitals.

For more information, visit http://www.mountsinai.org.

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Understanding of the Tau Mechanism in Alzheimer's Disease Progression

Mount Sinai scientists have determined how a pathological brain protein called tau contributes to the progression of Alzheimer's disease.

Alzheimer's Reading Room

Researchers at Mount Sinai School of Medicine have gained insight into the mechanism by which a pathological brain protein called tau contributes to the progression of Alzheimer's disease (AD) and other neurodegenerative disorders.

This finding, published in the most recent issue of the Journal of Biological Chemistry, may provide the basis for future investigations on how to prevent tau from damaging brain circuits involved in cognitive function.

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Researchers Gain Better Understanding of the Mechanism Behind Alzheimer's Disease Progression

Giulio Maria Pasinetti

Previous studies have shown that the abnormal folding, or misfolding, and buildup of tau are key neuropathological features of many neurodegenerative disorders, including AD. Some research has demonstrated that AD-type tau neuropathology spreads in the brain, seemingly moving from one brain cell to another.

A research group led by Giulio Maria Pasinetti, MD, PhD, Saunders Family Chair in Neurology at Mount Sinai School of Medicine, explored whether misfolded tau released by neurons from the human brain – also known as paired helical filaments (PHFs) – could actually be taken up by surrounding cells and promote the spread of tau neuropathology. The evidence was gathered by treating human neuronal cell lines with human Alzheimer's disease-derived PHFs. The researchers found that not only did the cells in fact internalize the human PHFs, the abnormal tau then propagated its abnormal state to the native, normal tau protein in the cells.

"While these findings are potentially important for possibly opening new therapeutic avenues in Alzheimer's disease, they also shed light on a new therapeutic target for a wide variety of disorders sharing pathological features with Alzheimer's disease, for which there are currently no cures," said Dr. Pasinetti. "Such diseases include Progressive Supranuclear Palsy, frontotemporal dementia, and other devastating neurodegenerative disorders in which misfolded tau forms aggregates in the brain."

Next the researchers treated the same cell lines with a grape-seed extract enriched in polyphenols, which are natural compounds found in grapes, fruits, and vegetables, based on 2011 research showing the efficacy of this extract in preventing the progression of AD in mice. Dr. Pasinetti's group found that a subfraction of this natural grape-seed extract enriched in polyphenols was able to prevent the cell-to-cell spread of tau pathology in the same human neuronal cell lines.

"Pathology in neurodegenerative disorders is thought to be initiated decades before disease onset," said Dr. Pasinetti. "While further research is needed in humans, we hypothesize that this grape-derived compound may be a promising therapy for not only treating but preventing neurodegenerative disorders involving tau neuropathology."

Dr. Pasinetti and Jun Wang, PhD, Assistant Professor of Neurology at Mount Sinai, are named inventors of a pending application filed by Mount Sinai School of Medicine titled "Methods Preventing Neurodegenerative Disease" related to the use of grape-seed extracts for the treatment of neurodegenerative diseases and may benefit financially from this patent.

About The Mount Sinai Medical Center

The Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and Mount Sinai School of Medicine. Established in 1968, Mount Sinai School of Medicine is one of the leading medical schools in the United States.

For more information, visit http://www.mountsinai.org.

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Alzheimer's Drug Memantine Fails to Reduce Significant Agitation, Does Help with Behavior and Psychological Symptoms

I read the study presented below with great interest. It is my personal belief that we turned the behavior corner when Dotty was started on the combination of Aricept and Namenda (memantine).

By Bob DeMarco
Alzheimer's Reading Room

Malaz Boustani

If you read the report below you will notice the findings state that memantine "does not ease clinically significant agitation in patients".

The researchers did report signficant improvement in cognitive function and for overall neuropsychiatric symptoms for the group given memantine, but no statistically significant difference in terms of the severe agitation that was the primary focus of the study. The key words here are "severe agitation".

I would say that Dotty was less moody, did improve in cognitive function, and was easier to work with once on memantine (brand name Namenda in the U.S.).

The study indicates that memantine does, can, have real benefits for patients in later stages of Alzheimer's disease.

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Alzheimer's drug fails to reduce significant agitation

A drug prescribed for Alzheimer’s disease does not ease clinically significant agitation in patients, according to a new study conducted by researchers from the U.K., U.S. and Norway. This is the first randomized controlled trial designed to assess the effectiveness of the drug (generic name memantine) for significant agitation in Alzheimer’s patients.

Previous studies suggested memantine could help reduce agitation and improve cognitive functions such as memory. Led by the University of East Anglia in the U.K., the new research found that while memantine does improve cognitive functioning and neuropsychiatric symptoms such as delusion, mood and anxiety, it is no more effective in reducing significant agitation than a placebo.

“Memantine is quite commonly prescribed for Alzheimer’s disease in the U.S. Despite the negative findings regarding agitation, this trial opens a door of hope,” said Regenstrief Institute investigator Malaz Boustani, M.D., MPH, associate professor of medicine at the Indiana University School of Medicine and associate director of the IU Center for Aging Research. “Memantine does appear to help with other behavioral and psychological symptoms of Alzheimer’s disease.”

Dr. Boustani, a co-author of the study, is also the medical and research director of the Healthy Aging Brain Center at Wishard Health Services.

“Efficacy of memantine for agitation in Alzheimer's dementia: a randomized double-blind placebo controlled trial” published in PLoS ONE on May 2. Authors of the study are from Indiana University; the University of East Anglia, University College London, University of Kent, Aston University, Oxleas National Health Service Foundation Trust and Kings College London, all in the U.K.; and the University of Stavanger in Norway.

An estimated 5.4 million Americans have Alzheimer’s disease according to the Alzheimer’s Association. Many are agitated. They may, for example, pace continually, become physically or verbally aggressive or scream persistently. In addition to harming quality of life for the patient, agitation places enormous strain on relationships with family members and care providers, and often results in institutionalization.

“People who have mild symptoms [of agitation] often respond to changes in the environment or psychological treatment, but these methods are impractical in severe agitation," said Chris Fox, M.D., of Norwich Medical School at University of East Anglia, who led the research. "Our findings regarding memantine are disappointing with respect to severe agitation -- particularly as the alternative antipsychotic medications can have significant side effects such as increased rates of stroke and death. However, we hope our study will highlight the urgent need for investment in safe and effective new treatments for this growing disease.”

The team of researchers studied 153 nursing home residents and hospital inpatients with severe Alzheimer’s from September 2007 to May 2010. All the study participants displayed significant agitation requiring clinical treatment. Half were given memantine, and half received a placebo. The researchers reported signficant improvement in cognitive function and for overall neuropsychiatric symptoms for the group given memantine, but no statistically significant difference in terms of the severe agitation that was the primary focus of the study.

Memantine is approved by the U.S. Food and Drug Administration for Alzheimer’s disease. The trial was sponsored by East Kent Hospitals University National Health Service Foundation Trust in the U.K. The study was funded by Lundbeck, a manufacturer of memantine.

“This research suggests that even though memantine can have real benefits for people in the later stages of Alzheimer’s, it may not have all the answers," said Anne Corbett, research manager at the Alzheimer’s Society of the U.K., which was not involved in the research. "However, prescribers should not see the only alternative as being to hand out antipsychotics. These overprescribed drugs double the risk of death and treble the risk of stroke and should always be a last resort for people with dementia.”

"Efficacy of memantine for agitation in Alzheimer's dementia: a randomized double-blind placebo controlled trial" by C. Fox (UEA), M. Crugel (Oxleas NHS Foundation Trust), S. Coulton (University of Kent), I. Maidment (Aston University), B.H. Auestad (University of Stavanger, Norway), A. Treloar (Oxleas NHS Foundation Trust), C. Ballard (Kings College London), M. Boustani (Indiana University and the Regenstrief Institute, USA), C. Katona (University College London) and G. Livingston (University College London) is available online at http://dx.plos.org/10.1371/journal.pone.003

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Our Brains Are What We Eat

Can diet affect your risk of Alzheimer's, or reduce those risks?

Alzheimer's Reading Room

Gene Bowman

Higher blood levels of omega-3 fatty acids, vitamin B, vitamin C, vitamin D and vitamin E are associated with better mental functioning and less brain shrinkage in older people.

This study caught my attention because the average of a participant was 87 years old.

The research behind the study was published in the journal Neurology and showed that people with healthier diets — rich in omega-3 fatty acids and a variety of vitamins — had bigger brains and better cognitive function than those whose diets were unhealthier on the whole.

This study does differ from previous studies around these issues. See the explanation below.

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OUR BRAINS ARE WHAT WE EAT - IN A WAY

That was the finding from a study led by OHSU’s Gene Bowman. And the results from the interesting and innovative study, published Dec. 28 in Neurology, have received a lot of national attention.

The study found that elderly people with diets high in vitamins B, C, D, and E and in omega 3 fatty acids are less likely to have the brain shrinkage and other abnormalities associated with Alzheimer’s disease than people whose diets aren't high in those nutrients.

People taking in the good nutrients also had higher scores on mental thinking tests than those with diets low in the good nutrients.

And, the study found, our bad eating catches up to us in other ways as well. It found that people with diets high in trans fats - often found in fast, frozen and processed foods and in baked goods - were more likely to have brain shrinkage and lower scores on thinking and memory tests.

Previous studies have relied on the study participants to recall foods eaten over the last year. But the OHSU study measured the nutrients in study participants' blood as an objective reflection of dietary intake. The study also identified nutrient combinations that may have synergistic effects on brain health.

The average age of study participants was 87.

Layton Aging & Alzheimer’s Disease Center

The study was funded by the National Institutes of Health, the National Institute on Aging, the National Center for Complementary and Alternative Medicine and the U.S. Department of Veteran Affairs, Portland VA Medical Center.

***I'll add that Dotty does get a vitamin B12 shot each month, we get vitamin C from orange juice, broccoli and other dark green vegetables, vitamin D from bright sunlight, and we take Omega-3 twice a day, and we eat salmon and tuna twice a week. Basically we try to get these nutrients by eating as opposed to taking supplements.


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Original content Bob DeMarco, the Alzheimer's Reading Room