Friday, May 24, 2013

Alzheimer's Cause Found In Trigger Of Brain Protein Malfunction

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Medical News Today
 
In a new breakthrough to find the cause of Alzheimer's disease, scientists have pinpointed a molecule that appears to trigger a chain reaction of protein malfunction that eventually clogs up and kills brain cells.
The teams, from the University of Cambridge in the UK and Lund University in Sweden, write about their findings in a paper due to be published online first this week in the Proceedings of the National Academy of Sciences.

Tuomas Knowles, one of the study leaders, runs a group based at Cambridge that studies the physical aspects of protein molecule self-assembly. In a statement about the study, he says current therapies for Alzheimer's and
dementia are limited, they don't address the disease, only the symptoms:

"We have to solve what happens at the molecular level before we can progress and have real impact," he adds.

And that is what the researchers on this study did: they dug deep into molecular behavior and produced a detailed map of the pathway that produces the malformed proteins that are at the root of neurodegenerative disorders like Alzheimer's.

They believe their breakthrough is an important step toward earlier diagnosis of neurological disorders like Alzheimer's and Parkinson's.

And by revealing molecular clues about the earliest stages of Alzheimer's, they say the findings also open new avenues for developing drugs that target these pathways in the early stages of the disease.

Misfolding Proteins and Amyloid Fibrils

When proteins made in brain cells start to misfold and take on structures that cause them to malfunction, the end result is neurodegenerative diseases like Alzheimer's.

Proteins are important molecules for carrying out essential jobs in and around cells. To make a protein, the cell assembles amino acids according to patterns encoded in its DNA. The assembled protein is a long thin chain that is then folded into a complex, tightly packed and precise structure so it can carry out its tasks correctly.

Things start to go wrong when proteins misfold. These can then snag surrounding proteins, even if they are normal, producing clumps that can build up to millions of protein molecules, forming unwieldy tendrils called "amyloid fibrils".

Amyloid fibrils are what produce the large protein deposits or "plaques" found in the brains of people with Alzheimer's. These were thought to be the primary cause of the disease, until another senior author of this latest study, Christopher Dobson, a professor of Chemistry at Cambridge, and his team discovered "toxic oligomers" about ten years ago.

Toxic Oligomers and Juvenile Tendrils

When the abnormal amyloid fibrils that lead to plaques start to grow, the tendrils grow outwards around the starting or focal point. This is known as "nucleation".

When these were first discovered, it was thought that the key to the cause of Alzheimer's was this nucleation process. But that is only part of the story.

What this study shows is that once a small but critical amount of malfunctioning protein clumps together, it triggers a runaway chain reaction that leads to rapid formation of new clumps, activating new focal points through "nucleation".

And it appears it is these secondary nucleations that create juvenile tendrils that at first have just a few clusters containing a handful of protein molecules, or "toxic oligomers". (An oligomer, comprising only a few molecular units, is a much shorter version of a polymer, a repeating chain of units that can almost go on for ever).

These "toxic oligomers" are soluble and small enough, unlike the bigger, insoluble and denser plaques (which have more of a knotted polymer structure), to travel around the brain and wreak havoc by interacting harmfully with other molecules. The result is the gradual death of neurons that cause loss of memory and the other known symptoms of dementia.

Before this study scientists knew that toxic oligomers were more likely to be the cause of Alzheimer's, but were mystified about where they came from.

Knowles says:

"We've now established the pathway that shows how the toxic species that cause cell death, the oligomers, are formed. This is the key pathway to detect, target and intervene - the molecular catalyst that underlies the pathology."

Recreating the Crime Scene at the Root of Alzheimer's

The researchers brought together tools commonly used in other areas of chemistry and physics, but this study is the first time they have been used to their full potential to look at misfolding proteins.

"Increasingly, using quantitative experimental tools and rigorous theoretical analysis to understand complex biological processes are leading to exciting and game-changing results," says Knowles.

He explains that they are essentially borrowing tools from chemistry and physics to look at a biomolecular problem: to map the networks of processes and "recreate the crime scene" that is at the molecular root of Alzheimer's.

"With a disease like Alzheimer's, you have to intervene in a highly specific manner to prevent the formation of the toxic agents. Now we've found how the oligomers are created, we know what process we need to turn off," he adds.

In another breakthrough study published recently researchers suggest
new Alzheimer's treatment may come from discovering how plaques lead to tangles.

Written by Catharine Paddock PhD
Copyright: Medical News Today

Wednesday, May 22, 2013

Top activities for those with dementia on Memorial day



Caregivers, and healthcare professionals, here is some great information


Here is a great dementia resource for caregivers and healthcare professinals,


Your residents will love the Amazon Kindle Fire




Here is information on being the best caregiver you can be


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The Dementia Caregiver's Little Book of Hope [Kindle Edition]

  • Veterans who suffer from various forms of dementia, including Alzheimer disease, often have very specific care needs. It is important that these veterans are cared for by people who understand their condition and have the appropriate instruction and skills. Therefore encourage family members of veterans to gain the training they need to care for their loved one with dementia.

  • For those in nursing homes and other institutions, make sure veterans with dementia are visited often. All people, including those with memory loss, need human contact. They need to be hugged. They need to hear your voice. They may not know you but as long as you know who they are, that's all that matters.

  • Talk to them about their service to our country. Often they will share stories with you because their time in the service made a huge impression on them 

  • Tell them how proud you are of them. Thank them for their service. This is sure to make them feel good. Most likely, it will make them smile

  • Smile with a veteran. Laughter is wonderful medicine.

  • Sing patriotic songs with a veteran with dementia. Often they will be able o sing many familiar songs even though, they may not be able to speak.

  • Read to them. Have them read to you. Large simple statements are best.
  • Share pictures with them, especially large colorful ones

  • Make a visitor's packet for them.

  • For more ideas on things you can do with a veteran or anyone with dementia on this Memorial Day or any day, read the book, Adorable Photographs of Our Baby-Meaningful, Mind-Stimulating Activities and More for the Memory Challenged, 
  • Their Loved Ones, and Involved Professionals 

  • So please remember all our veterans on Memorial Day including those with dementia




Friday, May 10, 2013

Diet may improve Alzheimer's

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News Fix
 
A study suggests that a high fat, low carbohydrate diet can help improve Alzheimer’s disease in mice.
It’s been previously suggested that a high fat diet may predispose the brain to Alzheimer’s disease, perhaps by clogging up the arteries. Researchers in Colorado seem to be suggesting the opposite – at least from animal studies.

They have been looking at a group of mice with the equivalent of Alzheimer’s disease. Giving the animals a diet that is high in fat, low in carbohydrate, reduces the amount of beta-amyloid, the brain protein deposits which are the hallmarks of Alzheimer’s disease. The researchers explain their results suggesting that insulin and insulin-related growth factor may be involved. In this kind of diet, insulin seems to be able to break up the amyloid deposits. Other studies have looked at fat in the presence of high carbohydrate. When the carbohydrates are reduced, insulin may behave in a more positive way.
 

Wednesday, May 8, 2013

Aspiration Pneumonia Risks Premature Death in Alzheimer's

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Medscape Today
 
Taipei, Taiwan — The risk of dying of aspiration pneumonia among people with Alzheimer's disease and related dementias (ADRD) is higher for men than women and, in the United States, is higher for younger elderly compared with those 85 years or older, according to a survey of death certificates.
Presenting his analysis here at the Alzheimer's Disease International (ADI) 28th International Conference, Tsung-Hsueh Lu, MD, PhD, from the Department of Public Health at National Cheng Kung University Hospital in Tainan, Taiwan, told delegates that death certificates list a disease or condition directly leading to death and then other antecedent conditions as contributing causes, but often those latter causes are lost in analyses.
For example, a death certificate may list sepsis as the direct cause, but if aspiration pneumonia and Alzheimer's disease are listed as antecedent causes, only sepsis may be considered for purposes of vital statistics. So he and a colleague looked for occurrences of listings of aspiration pneumonia, which can be a preventable cause of premature death, with ADRD.
Between 2002 and 2009, 6% of death certificates in the United States and 3.6% of those in Taiwan that listed ADRD as a cause of death also listed aspiration pneumonia.
Table. Aspiration Pneumonia on Death Certificates Listing ADRD (2002 to 2009)
Endpoint United States (n = 2,002,957) (%) Taiwan (n = 9143) (%)
Total6.03.6
Sex  
  Men8.44.5
  Women4.82.8
Age  
  65 - 74 y7.53.2
  75 - 84 y6.63.7
  ≥85 y5.53.6
 
Men in the United States were at a 78% greater risk for aspiration pneumonia if they had ADRD than were women (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.776 - 1.80). Similarly, men in Taiwan were 71% more likely than women there to die with aspiration pneumonia with ADRD (OR, 1.71; 95% CI, 1.36 - 2.14).
Compared with people aged 65 to 74 years in the United States, residents with ADRD had a decreasing risk for aspiration pneumonia as they aged (at 75 to 84 years: OR, 0.92 [95% CI, 0.90 - 0.94]; at ≥85 years: OR, 0.84 [95% CI, 0.82 - 0.86]). An interesting finding that Dr. Lu could not explain was that Taiwan residents trended in the direction of a nonsignificant increased risk with age.
In both countries, the proportion of people dying with aspiration pneumonia and ADRD decreased during the study period, from 6.9% in 2002 to 2003 to 5.0% in 2008 to 2009 in the United States (OR, 0.72 [95% CI, 0.70 - 0.73] for later period vs earlier) and (nonsignificantly) from 3.9% to 3.5% in Taiwan for the same periods (OR, 0.86 [95% CI, 0.63 - 1.17]).
Dr. Lu cautioned that aspiration pneumonia may be underreported as a cause of death, so the true figures may be even higher than that found from death certificates. And in the United States, different states may have different systems for determining and reporting the causes of deaths.
Preventing Premature Death
Aspiration of food is a major cause of pneumonia, but the risk can be reduced. "Speech therapists should be consulted to evaluate the swallowing ability in such a patient, training of the swallowing, or preparing of food to prevent this premature death," Dr. Lu advised.
Session moderator David Troxel, MPH, a long-term care consultant and writer in the field of dementia in Sacramento, California, commented to Medscape Medical News that swallowing issues and food aspiration are recognized as big problems among elderly patients with dementia.
"Where I'd say we aren't doing a good job is I think that families don't know to go to a speech pathologist. Doctors may not think about referring to a speech pathologist who can maybe help with that and assess [the patient]," he said. "Certainly in home settings I doubt families know much about how to prepare foods
 Go to different kinds of puréed foods."
He said he believes families are not getting much support in this area, so problems persist. He suggests that professionals in the elder care field talk to physicians about recognizing problems contributing to aspiration, about referring to speech pathologists, and "to really do more education with the families about different dos and don'ts about food."
Mr. Troxel is a dementia consultant to Atria Senior Living, Home Instead, American Baptist Homes of the West, and Prestige Care, and he previously consulted for Genentech Roche.
Alzheimer's Disease International (ADI) 28th International Conference. Abstract OC024. Presented April 19, 2013.
 

Thursday, May 2, 2013

Alzheimer's Disease Symptoms Reversed in Mice (part 2)

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Scientific American
 
by Gary Stix
 
The study also provides the most compelling evidence to date of how the biggest risk factor for Alzheimer's later in life—having the so-called Apolipoprotein E (APOE) gene, identified in the early 1990s—might yield a strategy for new therapies. The gene for apolipoprotein E comes in three versions, one of which, the e4 variant, confers a significantly higher risk of getting the disease—a roughly 60 percent chance at age 80 for those who carry a copy from both their mother and father, as against a less than 10 percent overall risk at that age in the general population. The gene variant, known informally as the Alzheimer's gene, is common: about 20 percent of the U.S. population has at least one copy. The e4 carriers may be vulnerable to Alzheimer's because they have a diminished ability to clear amyloid, a hypothesis that seems to be reinforced by this Case Western study.
Jumping the gun?
That idea, though, is not universally endorsed. Some experiments have shown that the e4 version may also impair the brain in other ways, perhaps by bollixing the biochemical functioning at the synapses, the connection points between neurons, or by producing toxic fragments of the lipoprotein that damage neurons. If so, increasing the production of this form of apolipoprotein E could actually worsen the pathology of the disease and would complicate greatly bexarotene's development.

This potential hurdle does not dissuade one researcher experienced in Alzheimer's clinical trials. "I am not particularly concerned" about potential toxic effects of extra e4 production, says Paul Aisen of the University of California, San Diego, who heads the Alzheimer's Disease Cooperative Study, which organizes clinical trials for drugs to combat the illness. "If it significantly enhances amyloid clearance and reduces the burden of brain amyloid, there is a good chance it will succeed." David Holtzman, a prominent Alzheimer's researcher from Washington University in Saint Louis, echoes the sentiment about bexarotene's prospects: "I do think it is promising to go into humans."
Landreth and Cramer certainly think so. They have formed a company called ReXceptor Therapeutics that intends to begin a preliminary trial in humans in the next few months to determine whether the drug crosses the blood–brain barrier and clears amyloid, as it does in mice. If those processes occur, clinical trials on the drug's effectiveness in humans could begin even this year, and they would probably last from 18 months to three years. The drug loses patent protection for cancer this year, but Case Western has filed for patents for its use in Alzheimer's.
Many unknowns
Despite their optimism, scientists say it's important not to overplay the progress. After all, drugs that work in mice do not necessarily help humans. Moreover, the genetically engineered version of mice used in this study do not recapitulate every aspect of the human disease. For instance, the mice do not experience the effects of dying neurons (despite having impaired cognition), and they do not go on to develop a hallmark characteristic of a later disease stage in humans—namely, the accretion of so-called tau proteins that seem to abet the killing of nerve cells. "Transgenic mouse experiments have not reliably predicted therapeutic effects in humans," Aisen says, "so caution is essential until human studies confirm target engagement," that is, the removal of amyloid plaques.

And bexarotene does not come without risk: it raises levels of triglycerides, blood fats implicated in cardiovascular disease and diabetes. The Case Western mouse work suggests that Alzheimer's patients may benefit with doses lower than those ingested for cancer treatment, which might produce less of an effect on fat levels. Whether the drug remains effective over time is another question. The levels of amyloid plaques—although not the apparently more toxic soluble form of the peptide—rose after 90 days, a suggestion that the drug may be metabolized differently after ingestion over long periods.
The enthusiasm generated for a mouse study stems from the desperation for new ideas as the number of Alzheimer's cases, now at 5.4 million in the U.S., is expected to more than double by the year 2050 as the nation's demographic profile continues to gray. A better understanding of the disease process—the knowledge that pathology begins 10 or 20 years before the first symptom—has shifted focus toward earlier drug trials. New technologies that combine brain imaging and spinal fluid tests might identify at-risk patients and test new drugs. A relatively inexpensive drug that can be ingested orally, such as bexarotene, could then be prescribed to at-risk but symptom-free patients, who would take them over the course of their lifetimes, like a cholesterol-lowering drug.
As ReXceptor moves forward with its clinical trial plans, it will inevitably have to contend with the demands of the families of Alzheimer's patients. Landreth emphasizes that calling your physician after reading an article like this one is a bad idea. "Don't try this at home," he cautions, "because we don't know we what dose to give, we don't know how frequently to give it, and there are a few nuances to its administration. So one shouldn't be prescribing it off-label." It is also unclear whether a drug like bexarotene would work at a middle or advanced stage of the disease, when neurodegenerative processes have already set in.
Bexarotene's genesis as an Alzheimer's treatment comes as an outgrowth of Landreth's long-time fundamental work on cell receptors. If it succeeds, it will demonstrate that new ideas for treating this seemingly intractable disease may come from beyond the sometimes narrowly focused strategies of large pharmaceutical companies.
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