"Nanoparticles" of silver in common products could lead to Alzheimer"s

University of Southern Denmark

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Alzheimer's is characterized by an overproduction of free radicals in cells. That's why incredibly tiny "nanoparticles" of silver, found in supplements, cosmetics and food packaging, worry scientists. Hear their concerns, as well as products to avoid.

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Nanoparticles of silver, found in e.g. dietary supplements, cosmetics and food packaging, are worrying scientists. A trailblazing study from the University of Southern Denmark shows that nano-silver can penetrate our cells and cause damage.

Antibacterial Benefits

Silver has an antibacterial effect and therefore the food and cosmetic industry often coat their products with silver nanoparticles. Nano-silver can be found in:

1. Drinking bottles
2. Cosmetics
3. Band aids
4. Toothbrushes
5. Running socks
6. Refrigerators
7. Washing machines
8. Food packagings.

Cellular Changes

"Silver as a metal does not pose any danger, but when you break it down to nano-sizes, the particles become small enough to penetrate a cell wall. If nano-silver enters a human cell, it can cause changes in the cell," explain Associate Professor Frank Kjeldsen and PhD Thiago Verano-Braga, Department of Biochemistry and Molecular Biology at the University of Southern Denmark.

Together with their research colleagues they have just published the results of a study of such cell damages in the journal ACS Nano.

The researchers examined human intestinal cells, as they consider these to be most likely to come into contact with nano-silver, ingested with food.

Free Radicals in Cells

"We can confirm that nano-silver leads to the formation of harmful, so called free radicals in cells. We can also see that there are changes in the form and amount of proteins. This worries us," say Frank Kjeldsen and Thiago Verano-Braga.

A large number of serious diseases are characterized by the fact that there is an overproduction of free radicals in cells. This applies to cancer and neurological diseases such as Alzheimer's and Parkinson's.

Kjeldsen and Verano-Braga emphasizes that their research is conducted on human cells in a laboratory, not based on living people. They also point out that they do not know how large a dose of nano-silver, a person must be exposed to for the emergence of cellular changes.

"We don't know how much is needed, so we cannot conclude that nano-silver can make you sick. But we can say that we must be very cautious and worried when we see an overproduction of free radicals in human cells," they say.

Dietary Supplement

Nano-silver is also sold as a dietary supplement, promising to have an antibacterial, anti-flu and cancer-inhibatory effect. The nano-silver should also help against low blood counts and bad skin. In the EU, the marketing of dietary supplements and foods with claims to have medical effects is not allowed. But the nano-silver is easy to find and buy online.

In the wake of the Uiversity of Southern Denmark-research, the Danish Veterinary and Food Administration now warns against taking dietary supplements with nano-silver.

"The recent research strongly suggests that it can be dangerous," says Søren Langkilde from the Danish Veterinary and Food Administration to the Danish Broadcasting Corporation (DR).
University of Southern Denmark

Better drugs for Alzheimer's

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nepezil (Aricept)

MEDICATION: THE WORLD'S MOST POPULAR DEMENTIA-DRUG IS DONEPEZIL. Donepezil (Brand-name: Aricept®) boosts memory & thinking in Alzheimer's. More donepezil means more boost - along with intensified side-effects. Learn how it can be safely boosted when combined with solifenacin.

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IRVINE, California -- Donepezil helps Alzheimer's and other types of dementia. Doctors often minimize its use because it can have a variety of side-effects. Progressive research shows that by adding solifenacin to each pill of donepezil, a patient could potentially boost the dosage by as much as 400% without added side-effects.

How It Works

Here's a simplified explanation of how it works.

Early-to-Midstage Alzheimer's
Brand Name	Generic Name
Aricept®	donepezil
Exelon®	rivastigmine
Remynil or Razadyne®	galantamine
Drugs for Moderate-to-Severe Stage
Namenda® or Ebixa®	memantine

1. Acetylecholine is used by the brain to send messages from cell to cell.
2. If there is not enough acetylecholine in the brain, memory and thinking start to fail.
3. Alzheimer's often experiences dangerous drops in acetylcholine.
4. Donepezil helps boost the level of acetylcholine throughout the body.
5. This can help an Alzheimer's brain get back to normal. However, it can also overload other systems in the body, causing nausea, weight-loss and other side-effects.
6. The brain is separated from the rest of the body by the "blood-brain barrier".
7. A pill of donepezil travels from the stomach to the entire body. It passes through the blood-brain barrier, boosting acetylcholine in the brain.
8. Solifenacin is another drug that blocks donepezil. However, it CANNOT pass through the blood-brain barrier.
9. Therefore, it seems that solifenacin cannot get to the brain and as a result, cannot block donepezil in the brain.
10. At the same time, solifenacin can block donepezil everywhere else in the body, stopping side-effects like nausea in the stomach.
11. The result is no nausea or other side-effects in the body. The patient just gets the good effect in the brain.

New Combination

For now, researchers call this combination of donepezil-plus-solifenacin by the name CPC-201. The new combination will mean that the brain can get the benefits of a lot more donepezil with fewer side-effects.

Chase Pharmaceuticals Corporation (Chase) announced its results from a Phase 2 study of CPC-201.

400%

What Do Aricept, Exelon & Razadyne Do?

Teepa Snow
MEDICATION VIDEO
See Teepa Snow talk about the top medications for Alzheimer's & dementia. In plain English, she explores what they do and how they work. Get clarity on Aricept, Exelon and Razadyne (generic donepezil, rivastigmine and galantamine).

The CPC-201 Phase 2 results, presented by Thomas Chase, MD, chief scientific officer and co-founder of Chase, and the former Scientific Director and head of the Experimental Therapeutics Branch for the National Institute of Neurological Disorders and Stroke, confirmed that solifenacin attenuated donepezil adverse events, enabling the tolerable administration of doses of donepezil to as much as 400 percent of the current standard treatment of donepezil. Secondary endpoints provided signals of enhanced efficacy, as would be predicted from increased tolerable dosing of donepezil. The data were presented during an oral session at the 2016 Alzheimer’s Association Conference (AAIC) in Toronto, Canada (Abstract a12446).

The primary endpoint of this Phase 2 single-blind, crossover trial was to safely increase the tolerated dose of donepezil from 10 mg/day up to as much as 40 mg/day. This trial consisted of 41 moderate (MMSE 10-20) Alzheimer’s type subjects who were being successfully treated with 10 mg/day of donepezil. The anticholinergic solifenacin was first titrated to 15 mg/day and then donepezil escalated to each subject’s maximum tolerated dose or to the protocol limit of 40 mg/day. Subjects then continued for a three-month maintenance period. All subjects were able to tolerably maintain above the currently approved doses of donepezil and 85 percent of subjects reached and tolerated the maximum allowable donepezil dose of 40 mg/day. Moreover, in the maintenance phase of the trial, subjects experienced significantly less dose-limiting side effects than those that would be predicted for 10 mg/day of donepezil.

A Real Difference

Although this Phase 2 study was not designed nor powered to provide meaningful estimates of anti-dementia efficacy, both the ADAS-Cog and the CGI-I scales in the study yielded positive signals of enhanced efficacy.

During the dose maintenance phase, at a median donepezil dose of 40 mg/day, total gastrointestinal adverse events were greatly attenuated and about 80 percent below those predicted from trials of previously approved doses of 10 mg/day of donepezil. As would be expected with a cholinergic blocker that does not cross the blood-brain barrier, solifenacin had no effect on cognitive function and there were no drug-related serious adverse events (SAE) or clinically significant cardiovascular or laboratory abnormalities. There were no drug related drop­outs and no new AEs or evidence of solifenacin toxicity.

“Pre-clinical studies have repeatedly shown that there is a strong dose/efficacy relationship associated with AChEIs. Further, PET scan studies in humans show that at the typical dose of 10 mg/day of donepezil, the central enzymatic inhibition is no greater than about 30 percent, substantially lower than that which would be expected from optimal dosing. Yet, historically, it has not been possible to tolerably increase the dose of donepezil to meaningfully higher levels,” said Douglas Ingram, chief executive officer of Chase. “We believe we have the means to finally unlock the true potential of optimally dosed AChEIs. Moreover, we are employing an efficient development and regulatory pathway and plan to commence a superiority trial versus the current gold-standard treatment for Alzheimer’s, 10 mg/day of donepezil. If successful in Phase 3, CPC-201 could be the new standard for the symptomatic treatment of Alzheimer's disease and benefit millions of suffering patients.”

Technical Talk

“We believe that adverse events have long limited AChEI dosing to suboptimal levels, in turn limiting the efficacy of donepezil and other AChEIs,” said Thomas Chase, M.D. “Our Phase 2 findings, together with those from our earlier Phase 1 studies, robustly support our hypothesis that the co-formulation of a peripheral anticholinergic with donepezil enables the safe and tolerable administration of multiples of the current standard of care doses of AChEI such as donepezil.”

The mean change in ADAS-Cog over the course of the study showed improvement versus subject baseline and, adjusted for underlying disease progression using a multi-study meta-analysis, subjects showed a mean (± SEM) benefit of 2.45 points over 10 mg/day donepezil or 5.4 ± .84 points compared to predicted untreated disease progression. Combined Clinical Global Impression (CGI-I) scores from investigators and caregivers at 26 weeks averaged 3.1 ± .20 points, thus improving by .94 ± .20 points (p < .001; n = 16). The responder rate (as measured by those who either did not worsen or improved over the course of the study) was over 90 percent.

MORE INFORMATION:

About CPC-201
Chase’s lead candidate, CPC-201, is a patent-protected combination of donepezil (an AChEI), one of the few pharmaceuticals proven to improve cognition in Alzheimer’s patients, and solifenacin, a peripherally acting cholinergic blocker.

SOURCE:

About Chase
Chase Pharmaceuticals Corporation is a clinical-stage biopharmaceutical company focused on the development and commercialization of improved treatments for neurodegenerative disorders. Chase’s development program, if successful, will profoundly improve the symptomatic treatment of Alzheimer's disease. The company was co-founded by Thomas Chase, MD, the former Scientific Director and head of the Experimental Therapeutics Branch for the National Institute of Neurological Disorders and Stroke and Kathleen Clarence-Smith, MD, PhD, the former head of CNS development at each of Sanofi, Hoffmann-La Roche and Otsuka. Chase is led by its chief executive officer and president, Douglas Ingram, formerly the president of Allergan, Inc.

Chase has closed over $24 million in funding to date, with approximately $22 million through a Series B financing led by New Rhein Healthcare Investors, LLC and including, among others, Edmond de Rothschild Investment Partners, Cipla Ventures and Brain Trust Accelerator Fund.

EDITED BY:
Peter Berger

How to stop the new Alzheimer's problem?

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AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOG 

100 years ago, Dr. Alois Alzheimer's identified plaques and tangles as the hallmarks of Alzheimer's. In the search for a cure, scientists recently sharpened his discovery by revealing how tangles join end-to-end to create longer filaments. Drugs that can block this grouping may block Alzheimer's. Learn the latest.

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Early in the course of Alzheimer's disease--long before future patients begin to notice symptoms--neurofibrillary tangles composed of tau protein aggregates begin to form in their brain cells. How toxic these aggregates are and how well they spread depend on their size. However, scientists studying tangle formation have not been able to explain why different sizes of cable-like tau aggregates appear in disease.

Drugs to Inhibit Aggregation

But now, researchers at The Ohio State University have discovered that instead of adding just one protein at a time, fibrils of various lengths can join end-to-end to create one longer filament. The finding, which appears in the Journal of Biological Chemistry, helps explain how fibrils can grow to hundreds of nanometers and could also help researchers understand mechanisms of an emerging group of drug candidates designed to inhibit tau aggregation.

Two Proteins Bind, More Proteins Latch On

Scientists can use mathematical models to describe biological processes such as fibril formation. A common simple model of tau aggregation includes two steps. In the first step, two tau proteins bind slowly, and, in the second step, additional tau molecules latch on quickly.

Click to enlarge image, click again to shrink it (Source: Phys.org):

Biophysicists have discovered a new mechanism by which aggregates of tau protein, called fibrils, can grow. Two fibrils can attach end-to-end. This figure shows a fibril composed of smaller fibrils labeled in three colors. The researcher labeled tau proteins with three different fluorescent dyes and allowed them to aggregate in separate test tubes. Then she mixed these different colored fibrils together in a fourth test tube. Images taken with a super-resolution fluorescence microscope showed long fibrils with short sections of each color, indicating that fibrils from original test tubes must have joined ends to form longer fibrils. Credit: Carol Huseby/Ohio State University

First author Carol Huseby, a graduate student in the lab of Jeff Kuret, working in collaboration with Ralf Bundschuh, set out to expand this mathematical model to include other known ways that tau fibrils behave. Scientists have observed, for example, that sometimes one fibril fragments into two. Other times, a new fibril can nucleate in the middle of an existing fibril.

Simple Two-Step Model

The simple two-step model predicted that a test tube filled with purified tau protein would result in a large number of short fibrils. But Huseby knew that when researchers look at aggregated tau protein under a microscope, they see a smaller number of long fibrils. That discrepancy suggested that something was happening in the real world that hadn't been accounted for in the model. They hypothesized that perhaps short fibrils could attach end-to-end to get longer.

Huseby ran a series of experiments to test the hypothesis. In one, first she labeled tau proteins with three different fluorescent colors and allowed them to aggregate in separate test tubes. Then she mixed these different colored fibrils together in a fourth test tube.

Long Fibrils, Short Sections

Images taken with a super-resolution fluorescence microscope showed long fibrils with short sections of each color, indicating that fibrils from original test tubes must have joined ends to form longer fibrils. Control experiments established that this can't be explained by labeled molecules' preference for like labels.

After Huseby incorporated this new mechanism into the model, it produced a much better description of what purified tau proteins were really doing as they formed aggregates. This study is the first to show that the fibrils can elongate by more than a single tau protein at a time.

Tau Fibrils: Cause and Effect

Alzheimer's researchers are still trying to discern whether tau fibrils are a cause or simply an effect of the disease. One possibility is that transmission of fibrils from one cell to another may contribute to the spread of disease in the brain. A very long fibril, according to Kuret, is unlikely to spread in this way. "But once it's broken up into little pieces, those can diffuse, facilitating their movement from cell to cell."

This study used just one type of tau. Six isoforms of different length are known, and phosphorylation and other changes increase the protein's complexity. The researchers plan to incorporate these variables in future work, and to begin to use the model to understand how tau inhibitors change the protein aggregates' behavior.

SOURCE:

• AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY

SUPPORT:

• This research was funded by the National Institutes of Health.

How low Vitamin D increases Alzheimer's risk

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In the largest study of its kind, not getting enough vitamin D turned out to double the risk of developing dementia and Alzheimer’s. See why supplements may not be the answer. Find out which foods to eat.

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MINNEAPOLIS – In the largest study of its kind, researchers suggest that in older people, not getting enough vitamin D may double the risk of developing dementia and Alzheimer’s disease. The study is published in the online issue of Neurology®, the medical journal of the American Academy of Neurology.

Continued below video...

The study looked at blood levels of vitamin D, which includes vitamin D from food, supplements and sun exposure. Dietary vitamin D is found in:

• Fatty fish such as salmon, tuna or mackerel
• Milk
• Eggs
• Cheese

Twice as Strong

"We expected to find an association between low Vitamin D levels and the risk of dementia and Alzheimer's disease, but the results were surprising—we actually found that the association was twice as strong as we anticipated," said study author David J. Llewellyn, PhD, of the University of Exeter Medical School in the United Kingdom.

For the study, 1,658 people over the age of 65 who were dementia-free had their vitamin D blood levels tested. After an average of six years, 171 participants developed dementia and 102 had Alzheimer's disease.

Vitamin D Levels and Dementia Risk

The study found that people with low levels of vitamin D had a 53 percent increased risk of developing dementia and those who were severely deficient had a 125 percent increased risk compared to participants with normal levels of vitamin D.

People with lower levels of vitamin D were nearly 70 percent more likely to develop Alzheimer's disease and those who had severe deficiency were over 120 percent more likely to develop the disease.

The results remained the same after researchers adjusted for other factors that could affect risk of dementia, such as education, smoking and alcohol consumption
Clinical trials are now needed to establish whether eating foods such as oily fish or taking vitamin D supplements can delay or even prevent the onset of Alzheimer's disease and dementia. We need to be cautious at this early stage and our latest results do not demonstrate that low vitamin D levels cause dementia. That said, our findings are very encouraging, and even if a small number of people could benefit, this would have enormous public health implications given the devastating and costly nature of dementia," said Llewellyn.

MORE INFORMATION:
The study was supported by the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the Alzheimer's Association, the Mary Kinross Charitable Trust, the James Tudor Foundation, the Halpin Trust, the Age Related Diseases and Health Trust, the Norman Family Charitable Trust and the UK National Institute for Health Research. www.aan.com/patients.

The American Academy of Neurology, an association of more than 27,000 neurologists and neuroscience professionals, is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer's disease, stroke, migraine, multiple sclerosis, concussion, Parkinson's disease and epilepsy.

For more information about the American Academy of Neurology, visit http://www.aan.com or find us on Facebook, Twitter, Google+ and YouTube

How emotions affect those with Alzheimer's

Caregivers, and healthcare professionals,here is some great information

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EMOTIONAL STATES of individuals with Alzheimer's are profoundly influenced by Caregivers. Learn how.

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A new University of Iowa study further supports an inescapable message: caregivers have a profound influence -- good or bad -- on the emotional state of individuals with Alzheimer's disease. Patients may not remember a recent visit by a loved one or having been neglected by staff at a nursing home, but those actions can have a lasting impact on how they feel.
The findings of this study are published in the journal, Cognitive and Behavioral Neurology.

Sad and Happy Movies

UI researchers showed individuals with Alzheimer's disease clips of sad and happy movies. The patients experienced sustained states of sadness and happiness despite not being able to remember the movies.

Emotional Life is Alive and Well

"This confirms that the emotional life of an Alzheimer's patient is alive and well," says lead author Edmarie Guzmán-Vélez, a doctoral student in clinical psychology, a Dean's Graduate Research Fellow, and a National Science Foundation Graduate Research Fellow.

Guzmán-Vélez conducted the study with Daniel Tranel, UI professor of neurology and psychology, and Justin Feinstein, assistant professor at the University of Tulsa and the Laureate Institute for Brain Research.

Tranel and Feinstein published a paper in 2010 that predicted the importance of attending to the emotional needs of people with Alzheimer's, which is expected to affect as many as 16 million people in the United States by 2050 and cost an estimated $1.2 trillion.

Treating Patients, Teaching Caregivers

"It's extremely important to see data that support our previous prediction," Tranel says. "Edmarie's research has immediate implications for how we treat patients and how we teach caregivers."

Despite the considerable amount of research aimed at finding new treatments for Alzheimer's, no drug has succeeded at either preventing or substantially influencing the disease's progression. Against this foreboding backdrop, the results of this study highlight the need to develop new caregiving techniques aimed at improving the well-being and minimizing the suffering for the millions of individuals afflicted with Alzheimer's.

For this behavioral study, Guzmán-Vélez and her colleagues invited 17 patients with Alzheimer's disease and 17 healthy comparison participants to view 20 minutes of sad and then happy movies. These movie clips triggered the expected emotion: sorrow and tears during the sad films and laughter during the happy ones.

Remembering Scenes Vs. Remembering Feelings

About five minutes after watching the movies, the researchers gave participants a memory test to see if they could recall what they had just seen. As expected, the patients with Alzheimer's disease retained significantly less information about both the sad and happy films than the healthy people. In fact, four patients were unable to recall any factual information about the films, and one patient didn't even remember watching any movies.

Before and after seeing the films, participants answered questions to gauge their feelings. Patients with Alzheimer's disease reported elevated levels of either sadness or happiness for up to 30 minutes after viewing the films despite having little or no recollection of the movies.

Emotions Far Outlasted Memories

Quite strikingly, the less the patients remembered about the films, the longer their sadness lasted. While sadness tended to last a little longer than happiness, both emotions far outlasted the memory of the films.

The fact that forgotten events can continue to exert a profound influence on a patient's emotional life highlights the need for caregivers to avoid causing negative feelings and to try to induce positive feelings.

Empowering Caregivers

According to Guzmán-Vélez, simple things that can have a lasting emotional impact on a patient's quality of life and subjective well-being include:

• Frequent visits
• Social interactions
• Exercise
• Music
• Dance
• Jokes
• Serving patients their favorite foods.

Guzmán-Vélez says, "Our findings should empower caregivers by showing them that their actions toward patients really do matter."

Source:

• University of Iowa Health Care

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Journal Reference:

1. Edmarie Guzmán-Vélez, Justin S. Feinstein, Daniel Tranel. Feelings Without Memory in Alzheimer Disease. Cognitive And Behavioral Neurology, 2014; 27 (3): 117 DOI: 10.1097/WNN.0000000000000020