Potential new drug for neurodegenerative diseases

A research team has identified a small molecule that helps human cells get rid of the misfolded, disfigured proteins implicated in Alzheimer's disease and other neurodegenerative ailments.

potential drug could have applications for other conditions as well.

Cells create and discard proteins continuously, a process that relies on a balance between the speed with which new proteins are created and damaged ones destroyed. Protein destruction occurs through a sophisticated system that marks proteins for disposal by tagging them with a small molecule called ubiquitin.

Ubiquitin latches onto these proteins, often forming long chains. The cell9s protein waste-disposal system, the proteasome, recognizes these ubiquitinated proteins and breaks them down.

If that finely tuned system malfunctions, damaged or misfolded proteins begin to accumulate in the cell and may become toxic. A number of ailments, including Parkinson's, Creutzfeldt-Jakob and Alzheimer9s have been linked to this build up of misfolded proteins.

To better understand just what causes this malfunction, a research team led by Harvard Medical School researchers Daniel Finley, professor of cell biology, and Randall King, associate professor of cell biology, zeroed in on an enzyme called Usp14.

They found that, when activated, Usp14 disassembles the ubiquitin chain, slowing down the proteasome's ability to rid the cell of bad proteins. As a result, the cell makes new proteins faster than it rids itself of the old ones, leading to a build-up of misfolded proteins.

The researchers wanted to see if they could find a molecule that inhibited Usp14, thus allowing the proteosome to work effectively. To identify such a selective inhibitor, Byung-Hoon Lee, a postdoctoral researcher, developed a special screening assay with assistance from the Institute of Chemistry and Cell Biology-Longwood Screening Facility at HMS.

Lee screened 63,000 compounds, looking for molecules that inhibited only Usp14 and could easily infiltrate the cell. The strongest candidate was a small molecule they named IU1.

Experimenting in both human and mouse cell cultures, Min Jae Lee, also a postdoctoral researcher, and his co-workers found that IU1 inhibited Usp14 and allowed the proteasome to dispose of proteins more quickly. In other words, adding IU1 to cells boosted proteasome activity.

Though scientists are still investigating just how IU1 works, it appears that the molecule suppresses Usp14's ability to trim the ubiquitin chain.

In addition to discovering IU1, this research has also shed light on an aspect of proteasome function that was not previously understood, King says.

Scientists had thought that the proteasome was not involved in regulating the speed of protein degradation, but that other proteins work with ubiquitin to modulate the process.

"Our work suggests that there is another level of control where the rate at which the proteasome can degrade these ubiquinated proteins is also controlled. It looks like there are multiple control steps along the way in this pathway," King said.

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New theory of Alzheimer's explains drug failures

Brain plaques, long considered the chief killer of brain cells and the cause of Alzheimer's disease, may actually play a protective role under a new theory that is changing the way researchers think about the disease.

Instead of sticky plaques, free-floating bits of a toxic protein called amyloid beta may be what's killing off brain cells in Alzheimer's patients, U.S. researchers say.

If the theory is right, then drugs that target plaque, including bapineuzumab -- being developed by Pfizer, Johnson & Johnson and Elan -- may be aiming at the wrong target, they say.

"The plaque is not the main culprit in terms of toxicity," said Dr. Scott McGinnis of Harvard Medical School and Brigham and Women's Hospital in Boston, who treats Alzheimer's patients and runs clinical trials testing new Alzheimer's drugs.

For more than two decades, the prevailing plan of attack for researchers and drug companies has been to find a way to remove sticky clumps of a protein called amyloid beta from the brain.

But several recent studies in mice and rats now suggest that floating pieces of amyloid beta called oligomers are the real bad actors in Alzheimer's disease.

And instead of being the chief toxin, several teams suspect, the plaques may be the body's way of trapping and neutralizing oligomers.

"If you say Alzheimer's, everyone immediately thinks that it's the plaques that actually cause the disease. That couldn't be further from the truth," Andrew Dillin, of the Salk Institute in California and the Howard Hughes Medical Institute, told reporters in London this week at a conference on aging.

"The data actually suggest these plaques are a form of protection that the body tries to put on. So this is a sign that your brain was trying to do something very useful and helpful to you, and the remnant was the formation of amyloid plaques," Dillin said.

A Good Thing?

Adrian Ivinson, who directs the Harvard NeuroDiscovery Center in Boston, a drug discovery center affiliated with Harvard Medical School working on new Alzheimer's drugs, said scientists are beginning to think plaque is a good thing.

"It actually sequesters all of that amyloid," he said, adding that oligomers are "the really toxic substance."

In the latest study, a team led by Dr. Sam Gandy of the Alzheimer's Disease Research Center at Mount Sinai School of Medicine in New York genetically engineered mice that form only oligomers, but never brain plaques.

They found these mice developed the same level of memory and thinking problems as genetically engineered mice that get both plaques and oligomers.

And when the team added a gene that converted the oligomers to plaques, the mice got no worse.

"That suggests that plaques were not necessary and the addition of plaque did not make the oligomer-induced memory problems any worse," said Gandy, whose study appeared last month in the Annals of Neurology.

The findings may help explain the stunning failure of drugs designed to remove plaques from the brain of patients, which do little to improve thinking in Alzheimer's patients.

Alzheimer's is the most common form of dementia in which patients progressively lose their ability to think and care for themselves. Current drugs only treat symptoms.

Lack of Effects

Gandy points to a recent imaging study in Lancet Neurology looking at the drug bapineuzumab -- now in late-stage clinical trials.

The team used an imaging agent called Pittsburgh Compound B or PiB that can be used in brain scans to identify amyloid plaques. Using these scans in 28 patients, the team found that bapineuzumab shrank brain plaques by 25 percent, but Gandy said the drug had no effect on patients' ability to think and reason.

"We don't know whether bapineuzumab sees oligomers or not," Gandy said in a telephone interview.

And because PiB can only see amyloid deposits and not floating clumps of oligomers, there is no way to know whether the drug is having any effect.

Gandy said the Lancet Neurology study may simply mean that patients need to be treated longer to benefit from bapineuzumab. Or, it may mean that the drug -- an engineered immune-system molecule called a monoclonal antibody -- is targeting the wrong thing.

Bapineuzumab has had mixed results in a mid-stage clinical trial, and some researchers were encouraged by the Lancet Neurology study because it reduced plaque levels in patients.

But Dillin said the drug, like several others aimed at trying to stop plaques from forming, is destined to fail.

"This hypothesis is actually completely wrong, and we need a new way to start looking at this disease. This is actually not a viable therapeutic avenue," Dillin said.

Pfizer this month said results of its U.S. phase 3 trials would be released in mid-2012 and the European phase 3 trials would be done in 2014, a bit later than analysts had expected.

Many investors have already written off bapineuzumab, but since Alzheimer's afflicts 26 million people worldwide, any success could mean billions of dollars in revenue.

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New treatments address unmet needs in Alzheimer's and epilepsy

A number of leading drug makers used this year's meeting of the American Academy of Neurology to present new data for promising pipeline candidates. Despite promising results, however, Datamonitor believes that the epilepsy drugs will struggle to find their place in the market. Moreover, the positive Phase II data for Baxter’s potential Alzheimer’s therapy Gammagard do not guarantee later success.

Alzheimer's disease: hope remains despite setbacks

There remains an enormous unmet need in the treatment of Alzheimer's disease. For the millions of elderly people worldwide, there are just four drugs available that can only offer a modest symptomatic effect. Even so, these treatments cannot slow or modify the course of this neurodegenerative disease, which is the ultimate goal in Alzheimer's therapy. While it was announced in March 2010 that in a Phase III trial Medivation/Pfizer's Dimebon (latrepirdine) failed to meet any of its clinical endpoints, there remains hope in the pipeline for Alzheimer's sufferers and their caregivers. One such drug, Baxter's Gammagard (intravenous immune globulin; IGIV), is actively recruiting for a Phase III trial, and at the American Academy of Neurology Annual Meeting (AAN 2010) the company presented new data from the extension phase of its Phase II trial.

Gammagard is a human antibody preparation already launched for the treatment of primary immunodeficiency diseases in the US and Western Europe. The drug is currently being assessed in Phase III clinical trials in patients with mild-to-moderate Alzheimer's disease. At AAN 2010, Baxter presented clinical trial results for the first time measuring function and cognition in patients who received uninterrupted Gammagard for a period of 18 months for mild-to-moderate Alzheimer's disease. After 18 months, patients who received Gammagard continuously averaged approximately 1.36 points higher than patients who initially received placebo on the Alzheimer's disease Cooperative Study-Clinical Global Impression of Change rating (ADCS-CGIC).

While clarifying that the study involved only a very small number of patients, Baxter is clearly encouraged by these data and has stated that it plans to initiate a second, concurrent Phase III study of the drug in this patient population. However, in light of the recent setback with Dimebon and other numerous late-stage trial failures in the last 10 years, Datamonitor remains cautious about Gammagard's prospects until Q3 2011 when results of the 360-patient Phase III study are expected.

Epilepsy: long-term data for new drugs the highlight

The second half of 2008 and first half of 2009 saw a flood of generic second-generation anticonvulsants enter the US market as Lamictal (lamotrigine; GlaxoSmithKline), Keppra (levetiracetam; UCB), Depakote IR and ER (valproate semisodium; Abbott) and Topamax (topiramate; Johnson & Johnson) lost patent protection. As the market environment for new and prospective drug candidates becomes increasingly price-sensitive and competitive, both Valeant/GlaxoSmithKline and UCB presented long-term safety and efficacy data for their respective novel anti-epileptic candidates in order to support their positions in the growing treatment arsenal.

Valeant's retigabine is a first-in-class anti-epileptic drug that reduces neuronal excitability by enhancing the activity of neuronal KCNQ (Kv7) potassium channels and through its gamma aminobutyric acid type A (GABA-A) receptor agonistic properties. In August 2008, Valeant entered into an exclusive worldwide collaboration agreement for retigabine with GlaxoSmithKline, and in October 2009 the companies filed a New Drug Application (NDA) in the US and a Marketing Authorization Application (MAA) in Europe for the adjunctive treatment of partial-onset seizures in adults with refractory epilepsy.

The efficacy and safety of retigabine in patients with refractory partial-onset epilepsy was demonstrated in two pivotal Phase III trials, RESTORE 1 and RESTORE 2. At AAN 2010, Valeant provided insight into the maintenance of efficacy and the safety profile of retigabine at doses of 600mg-1,200mg/day, as demonstrated in the long-term open-label extensions of the trials. With 81% of patients transitioning from RESTORE 1 and 92% doing so from RESTORE 2, median percent reduction in 28-day total partial-seizure frequency was 57% and 53%, respectively. Furthermore, safety assessments supported what Valeant called an acceptable safety profile for an adjunctive therapy.

With both US and EU regulatory bodies currently appraising the drug, Datamonitor believes that the inconvenient dosing regimen and reasonably high level of treatment-related side effects will deter some treatment-refractory epilepsy patients and their physicians from using retigabine, despite the strong efficacy data demonstrated thus far.

UCB's Vimpat (lacosamide) was the subject of numerous studies and analyses at this year's AAN conference. Indicated as an adjunct therapy for the treatment of partial-onset seizures in adults with epilepsy, Vimpat was approved in the EU in September 2008 and shortly after in October in the US, making it one of the most recent novel entrants to the epilepsy market. Although monotherapy trial data is anticipated by mid-2011, long-term analysis from adjunct trials presented on the conference provides additional support to Vimpat's growing safety and efficacy profile.

Data presented during the meeting focused largely on providing long-term safety/tolerability and efficacy of Vimpat from Phase II-III double-blind and/or open-label extension trials. While one study reported the efficacy of Vimpat in cohorts of patients completing successively longer durations of lacosamide exposure, another indicated that lacosamide improved 50% responder rates and reduced median seizure frequencies by up to 42% and 86% for complex partial seizures and secondarily generalized seizures (the two most commonly reported seizure types), respectively. A third poster provided insight into the drug's long-term safety profile; an important consideration for a drug dosed in such a chronic fashion.

However, with questions previously raised regarding the drug's side-effect profile in comparison to first-line treatments like levetiracetam and lamotrigine, Vimpat is likely to encounter difficulty in taking significant market share from its well-tolerated competitors. Datamonitor predicts that potential future indication expansions in pediatric patients as well as primary generalized tonic-clonic seizures will hold the key for Vimpat's commercial success in epilepsy.

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Are You At Risk For Getting Alzheimer's Disease?

Introduction

Alzheimer's disease is a progressive condition that damages areas of the brain involved in intelligence, memory, behavior, judgment, and language. It is the most common form of mental decline in older adults.

Alzheimer's gets worse over time, but the course of the disease varies from person to person. Some people may still be able to function relatively well until late stages of Alzheimers disease. Others may lose the ability to do daily activities in earlier stages. Over time, Alzheimer's disease causes severe mental and functional problems and eventually results in death.

Causes

Scientists do not yet fully understand the causes of Alzheimer's disease. There probably is not one single cause, but several factors that affect each person differently.

Recent studies indicate that amyloid beta protein may cause Alzheimer's disease.

In healthy people, this protein can cross the blood-brain barrier (the wall of blood vessels that feed the brain and regulate the entry and exit of brain chemicals) and leave the brain. In people with Alzheimers disease, amyloid beta protein can't pass through that barrier. As more amyloid beta protein accumulates in a person's brain, they become more and more mentally disabled.

Research has recently revealed that consumption of sugar could be one of the biggest threats to our overall health - especially when it comes to age related diseases such as Alzheimer's. One of the major problems stemming from sugar over-consumption is a chemical process called glycation.

Glycation refers to the combination of a sugar and a protein molecule and occurs in your body when glucose in your blood combines with the amino acids tryptophan, lysine or arginine. This reaction releases byproducts called Advanced Glycation Endproducts (appropriately given the acronym AGE).

The formation of AGEs is accelerated when you have lower levels of antioxidants in your system and when your kidneys are weak or malfunctioning. The formation is also accelerated when blood sugar levels are high. Researchers now believe that glycation and the formation of AGEs lie at the heart of the alteration of proteins in the brain that cause Alzheimer's disease.

Risk Factors

Age is the most important known risk factor for Alzheimer's disease. The number of people with the disease doubles every 5 years beyond age 65.

Blood sugar problems that cause excess glucose in the blood, such as diabetes, has now been added to the list of risk factors for Alzheimer's, given the role of glycation.

Family history is another risk factor, depending on the type of Alzheimer's . Familial Alzheimer's Disease, a rare form of Alzheimer's that usually occurs between the ages of 30 and 60, is inherited - so family history is a big risk factor.

The more common form of Alzheimers disease is known as late-onset Alzheimer's. It occurs later in life, and no obvious inheritance pattern is seen.

Relationship to Aluminum

Since 1965, researchers have suspected that Alzheimers disease is related to accumulations of aluminum in the brain. A relationship between aluminum in drinking water and Alzheimer's has now been established.

Additionally, a study looked at the association of Alzheimer's and lifetime exposure to aluminum in antiperspirants and antacids. Scientists found a direct correlation. The more antiperspirant that was used, the more likely the person would develop Alzheimers disease.

The same held true for aluminum antacids. It is hard to deny that environmental exposure to aluminum is at least related to Alzheimer's.

Symptoms and Cures

Alzheimer's disease is a progressive disease for which there is no known cure. However, various therapies and treatments can slow the progression of Alzheimer's. Therefore, it is important to know the warning signs for each stage of Alzheimer's and detect the condition early. If caught early, alpha lipoic acid and other Alzheimer's treatments can be used to slow (and possibly stop) the progression of the disease.

by: William Doyle
Source : www.articlecity.com

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New Alzheimer's Gene Is Pinpointed

New research has pinpointed a gene that could improve predictions of who will develop Alzheimer's and at what age.

Allen Roses, director of Duke University's Deane Drug Discovery Institute, said that if other researchers get the same findings, it could mean a drastic improvement in the accuracy of predictions about the disease as well as the approximate age within a five-to-seven-year window when individuals might begin noticing symptoms. And if drugs to slow the course of Alzheimer's become available, the gene could help identify who should begin taking those drugs earlier.


In 1993, Dr. Roses reported that people who have a variant of the ApoE gene have an unusually high risk of developing Alzheimer's. Despite facing initial skepticism, his findings have since been replicated by a number of independent scientists. Testing for the gene variant, called ApoE4, has become accepted as a way of identifying individuals at high genetic risk for Alzheimer's.

But investigators haven't found drugs that slow the disease in these ApoE4-positive individuals; they have only been able to identify their risk of getting the disease. Also, the ApoE4 findings don't explain why many people with the most common version of the gene, ApoE3, also get the disease.

In research presented Sunday at the International Conference on Alzheimer's Disease in Vienna, Dr. Roses and his team looked at the area of DNA surrounding the ApoE gene. They found that a gene linked to ApoE called TOMM40 had mutations that involved a small number of extra copies of a particular building block of DNA in some individuals and a large number of extra copies in others.

Individuals with the large number of extra copies -- known as the "long repeat" version of TOMM40 -- coupled with ApoE3 develop Alzheimer's an average of seven years earlier -- about age 70 -- compared with ApoE3 individuals with a "short repeat" version of TOMM40.

"What you need is the information on the repeat in order to make sense of what type [of ApoE3] you have," said Dr. Roses, who started a company, Zinfandel Pharmaceuticals, to help fund the research.

The researchers used several pools of people with and without Alzheimer's to identify and confirm the genetic findings, including a small group who agreed to have their brain autopsied upon their deaths.

Some scientists urged caution about the new findings. "Before I get too excited about it, I'd like to see it confirmed in more patient populations," said William Thies, president of the Alzheimer's Association, which is sponsoring the conference. With any single study, it is important to make sure the results aren't a result of "statistical anomaly," Dr. Thies said.

The TOMM40 gene is related to how easily molecules can get into and out of the surface of the mitochondria, the energy center of cells. Some researchers propose that this permeability is part of Alzheimer's disease, according to Dr. Thies. One experimental drug called Dimebon, which is being studied by Medivation Inc. and its partner Pfizer Inc., may be a therapy that acts through that mechanism, Dr. Thies said.

Zaven Khachaturian -- the former director of Alzheimer's research at the National Institutes of Health who currently runs Khachaturian Radebaugh & Associates Inc., an international consulting group on Alzheimer's and aging -- called the findings "quite significant."

"I do get excited about the possibility of having a good genetic marker that's going to tell us with greater precision who's going to get it and within a time window," Dr. Khachaturian said. "I also have skepticism that we need to validate with larger numbers before we go public."

Source : online.wsj.com

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Study: Coffee may reduce or reverse Alzheimer's disease

diseaseDaily coffee consumption may help delay the progress of Alzheimer's disease or reverse the condition, according to a study in Sunday's online edition the Journal of Alzheimer's Disease.

Drinking coffee has previously been linked to a lower risk of developing Alzheimer's, but this is the first study to suggest that caffeine can directly target the disease itself.

Researchers from the University of South Florida studied 55 mice that had been genetically engineered to develop dementia symptoms identical to those of Alzheimer's as they aged.Alzheimer's occurs when sticky clumps of abnormal protein in the brain called beta-amyloid build up to form plaques, impairing cognitive function.

Half the animals were given a daily dose of caffeine in their drinking water, while the other half continued to drink ordinary water.

By the end of the two-month study, the caffeine-drinking mice were performing far better on tests of memory and thinking than mice given water.

Their memories were as sharp as those of healthy older mice without dementia.The study found that caffeine cut by half the mice's excessive blood and brain levels of beta amyloid."The new findings provide evidence that caffeine could be a viable 'treatment' for established Alzheimer's disease, and not simply a protective strategy," lead author Gary Arendash, a University of South Florida neuroscientist, said in a news release. "That's important because caffeine is a safe drug for most people, it easily enters the brain, and it appears to directly affect the disease process."

The researchers hoped that caffeine could present a safe, inexpensive treatment for dementia and wished to conduct human patient trials as soon as possible."The findings provide evidence that caffeine could be a viable treatment for established Alzheimer’s disease and not simply a protective strategy," said Arendash.

A study in 2002 found that people who consumed caffeine in mid-life were 60 percent less likely to develop the disease.

Source : www.articlealley.com

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New drug to combat Alzheimer's may be possible

Scientists say that a cluster of peptides may be the toxic agent in Alzheimer's disease and from the discovery, new drugs may be possible.

In an article published this week in Nature Chemistry, the researchers explain the process in which the toxic Amyloid Beta 42 peptides aggregate, and outline the new technology they use to study these peptides. The findings come out of the laboratory of Michael T. Bowers, professor of chemistry and biochemistry at UCSB.

"We believe that we have put a face, a structure, on the molecular assembly that is responsible for Alzheimer's disease," said Bowers. His research group used an innovative technology called ion mobility-based mass spectroscopy, a method that allows researchers to investigate the structure, aggregation, and energetics of protein and peptide systems.

The Amyloid Beta (AB) 42 peptide is clipped from a much larger protein, the amyloid precursor protein (APP), and is composed of 42 amino acid residues. A second peptide, AB40, is 10 times more abundant than AB42 in healthy human brains and is also clipped from APP. It is identical to AB42 except it is missing the last two amino acids. Both peptides aggregate, but AB42 more so than AB40.

AB40 never grows beyond a tetramer -- a cluster of four AB40 peptides. As a consequence, it is nontoxic. By contrast, AB42 grows to form rings of six units each. Two of these "six-mer" rings stack to form a dodecamer, or "twelve-mer," according to Bowers, and then the aggregation stops. These dodecamer clusters are long-lived, but may eventually rearrange to form so-called B-sheet structures, which lead to the large fibrils that form the plaques found in the brains of those with Alzheimer's disease and other neurodegenerative diseases.

In related studies, transgenic mice, implanted with the gene that expresses human APP (and hence able to form AB42 in their brains), are found to quickly develop memory deficits -- as if they have Alzheimer's disease. Since mice have a much faster metabolism than humans, the disease progresses more quickly. Of importance is the fact that the only AB species found in the brains of the transgenic mice correlates with the dodecamer of AB42 characterized in the Bowers lab experiments. These two pieces of data together strongly implicate the dodecamer of AB42 as the toxic agent in Alzheimer's disease.

"Our group, along with our collaborators, are searching for drug candidates that can prevent AB42 from aggregating to form the toxic dodecamer," said Bowers. "While it is early in the search, we are hopeful good candidates can be found. As a consequence, there is a need to find an early marker for Alzheimer's disease so that we can use these drugs to radically slow down the disease progression."

Bowers explained that this research method is new, but is gaining acceptance in the biological community. He said that to fully understand the disease, effects of the oligomerization process would have to be observed at the cellular level, however.

"These latest results are a very hopeful thing," said Bowers. "I'm more hopeful now than I have ever been that we can make some real progress on this terrible disease."

Source : www.axcessnews.com

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How To Distinguish Between Alzheimer Demens And Regular Dementia Or Dement

Dementia becomes a problem for many elderly citizens. Dozens of millions of people from all over the world are being affected by this illness to some degree. Apart from other causes, Dementia is mainly caused by dying brain cells. The destruction of brain cells is generally caused by strokes, tumors or head injuries. Dementia, or demens, dement as it is widely known across the globe, can also be hereditary, so all people should check their family history to see if there were cases of dementia in their family, as a way to help prevent as much as possible dementia. Demens, Dement alters the personality, and it leads to mood swings and ultimately leads to erratic behavior. Those who become ill with Dement or Demens are not able to realize the fact that they are ill, because the disease slowly alters their personality, so it does not seem as they are behaving differently, at least to themselves.

While many studies in the past concluded that Demens and Alzheimer are two completely different illnesses that have no connection to each other, recent studies performed by the American Alzheimer Foundation revealed that almost three quarters of the people suffering from demens or dementia are actually suffering from an illness called Alzheimer Demens or Alzheimer’s Dementia. Dement or Dementia is often times considered to be one of the precursors for more serious illnesses such as Huntington, Parkinson, or Alzheimer. For some people dementia or demens is not hereditary or a precursor to more serious diseases, but simply a byproduct of strokes. The Alzheimer Dement’s primary characteristic is forgetfulness. Because the ones that suffer from this illness are generally older people, the first signs are not cause for concern. However, with time, this symptom keeps aggravating, and it ultimately leads to the patient forgetting more and more each day, from daily routines and to even the names and faces of their loved ones.

The Alzheimer disease is generally affecting people in their sixties. This disease disrupts to normal function of the part of the brain that controls the memory and thought processes along with the language. Because Alzheimer Dement differs from the other forms of demens, its causes have not yet been fully discovered. However it is easily recognizable by expert doctors, which after a battery of tests are able to determine correctly if the patient is suffering Alzheimer Demens, regular Dement or Dementia, or is simply being affected more seriously by the most known illness to the elderly, senility. So the visit to the expert physician is necessary to determine whether the patient is suffering from Dementia or is simply becoming senile. The most common Dement or Demens symptoms are memory deficiencies, orientation problems.

Source : www.amazines.com

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Alzheimer’s Drugs Increase Risk for Falls, Hip Fracture, Pacemakers

One of the major abnormalities in Alzheimer's dementia is that the brain lacks enough acetylcholine, a neurotransmitter associated with short term memory. Drugs that help remedy this deficit have been on the market for many years. While it was known that these drugs also can have effects on the heart, the extent of the risk has not been fully appreciated. A new study documents a clear and important risk from these medications.

The Problem

Neurotransmitters last only seconds. Acetylcholine is dissolved by an esterase. Aricept, Exelon, and Razadyne all work the same way. These dementia drugs block the esterase, allowing the acetylcholine to last longer, so it has more “punch” even if there is less of it.

The problem is that acetylcholine is also an important transmitter in other parts of the body. In parts of the body where there is no deficit of acetylcholine, giving it more punch with these drugs can cause an excess of acetylcholine effect. In the heart, this leads to slow heart rate—bradycardia—which can decrease the heart’s pumping action.

Inadequate heart pumping leads to less oxygen delivered to the brain, then fainting. Fainting leads to falls, and falls lead to hip fracture, a very serious event, especially in older people.

Even if bradycardia does not lead to falls, it can lead to an Emergency Room visit or a hospital admission and insertion of a cardiac pacemaker. In most studies evaluating a new drug, otherwise healthy people are subjects. How often these undesirable events occur in real-world (unselected) populations had not been systematically studied.

The Study

Researchers looked at data from records of older people with dementia in Ontario, Canada. They identified over 19,000 people who were treated with one of these drugs, and compared them to over 61,000 age-matched people who were not.

The outcomes they felt might be associated with drug use were:

Syncope (fainting)
Bradycardia (excessively slow heart rate)
Placement of a permanent heart pacemaker
Hip fracture (which was associated with falling)
Subjects who received one of the drugs were about 75% more likely to have syncope (adjusted hazard ratio [HR] 1.75); 70% more likely to have bradycardia (HR 1.69); about half again as likely to need a pacemaker (HR 1.49); and about 20% more likely to suffer a hip fracture (HR 1.18).

Implications

Many believe these drugs are useful for Alzheimer’s dementia, but the extent of their value is often debated. The researchers who did this study remind readers that “Treatment decisions [for dementia] need to be individualized and should involve a discussion with patients and their caregivers about the expected benefits and potential risks of treatment.”


Source : seniors-health-medicare.suite101.com

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New drug may alter Alzheimer's, Huntington's care

The Chief Executive of Medivation Inc said on Friday experimental drug Dimebon has the potential to transform care for both Alzheimer's and Huntington's disease and achieve blockbuster sales.

David Hung said Dimebon has shown impressive results in clinical studies in stabilizing the thinking and memory of patients with Alzheimer's disease for a year or longer and improving the memory of those with Huntington's, a hereditary disease that causes loss of brain cells and mental deterioration.

By contrast, Hung said most current Alzheimer's treatments only help patients about 12 weeks before the condition worsens and the only approved medicine for Huntington's actually worsens cognition.
"If we can get a drug out onto the market that is really effective and safe, that will probably increase the incentive of doctors to diagnose Alzheimer's early on and to treat it," Hung said in an interview.

That could greatly bolster the current $5 billion a year market for Alzheimer's drugs. The category is now dominated by Pfizer Inc's Aricept -- a drug deemed minimally effective in improving the symptoms of patients with the degenerative brain disease.

Medivation signed a partnership last year with Pfizer, the world's largest drugmaker, which entitles the tiny San Francisco-based biotechnology company to 40 percent of U.S. profits from Dimebon and an undisclosed royalty on overseas sales.

Hung said Dimebon met its primary goal in one pivotal study, as well as all four secondary goals, and raised no safety concerns.

That stands in contrast to a highly watched experimental drug for Alzheimer's being developed by Wyeth, called bapineuzumab, which failed to meet its primary goal in a mid-stage trial and caused brain swelling at higher doses.

"And for Huntington's disease, there were fewer adverse events with Dimebon than with placebo," Hung said.

Medivation licensed Dimebon from a privately held Russian company that had sold it as an antihistamine. But Hung said the drug seems to help Alzheimer's and Huntington's patients by preventing damage to mitochondria: tiny units of all cells that supply energy.

"A number of neuro-degenerative diseases appear to be caused by different things that harm mitochondria," he said, and cells, including neurons, become sick and die.

"If we can inhibit neuron injury or death, it's better to do it sooner than later" by attempting to diagnose Alzheimer's and Huntington's as early as possible and begin treatment.

Hung added that U.S. regulators are requiring Medivation to complete another successful pivotal trial before Dimebon can be approved for treatment of mild to moderate Alzheimer's. Several such trials are expected to be underway later this year.

Hung also expressed confidence in a second Medivation drug, called MDV3100, now being tested among patients with advanced prostate cancer who failed to benefit from standard treatment.

He said the drug has dramatically reduced the number of lingering cancer cells after surgery -- so-called circulating tumor cells -- a sign it may be able to prolong survival in planned late-stage studies.

Source : www.guardian.co.uk

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Neurological Care of CNY is a test site for new Alzheimer drug

The new drug trial by Elan Pharmaceuticals is ICARA or Investigatational, Clinical, Amyloid, Research in Alzheimer. It is also commonly known as the Bapi study, which is evaluating the safety and effectiveness of a new drug, bapineuzamab ,which involves a new approach to dealing with Alzheimer Disease (AD).

There is still no known cure, but this drug is aimed at slowing down the disease progression and will be used in tandem with the current Alzheimer drugs on the market Aricep (Exelon, Razadyne) and Namenda.

There are 200 trial sites around the United States and Canada with one in CNY. Dr. Smita Kittur of Nuerologial Care of Central New York in Syracuse has been selected to test 16 patients. There are already eight enrolled in the trial.

- The new drug is an antibody to the amyloid protein, which when given by Intravenous infusion, will attach itself to the amyloid,¡± Kittur said.

It is hoped that it will then remove the amyloid from the cell, and will also prevent the development of further amyloid proteins forming within that cell.

- They found in mice that it removed the already deposited protein and helped to prevent the progression,¡± she said.

Kittur said, when people talk about memory problems or dementia, 90 percent is AD. Non-AD-dementia could be caused by a problem with B12 absorption, stroke or an aneurysm.

"The patient interested in inclusion in this trial will be evaluated for Alzheimer¡¯s Disease by performing a memory or psychological test,¡± Kittur said. ¡°And also, a blood test and MRI, which is mainly to rule out other diseases.¡±

She said this drug differs greatly from Aricep, Exelon or Razadyne, which all work the same by helping to maximize brain activity. And, also the latest drug on the market, Namenda, is more for protection of the brain cells caused by calcium that grows inside the cells.

- When we learn something new, at that time a channel opens inside the brain cell and not close, which will result in a flood of calcium,¡± Kittur said.

- These are better than not taking anything,¡± she said and will be continued during the trial.

The current medications are mostly aimed at maximizing the brain activity; The ICARA study is evaluating the safety and effectiveness of a new drug aimed at slowing down the disease progression and possibly even helping with prevention.

The conditions of the trial include:
- A caregiver must be present at all treatments.
- Participant between the ages of 50 and 88.
- Must pass a test that determines presence of AD.
- Damage to the brain, such as a stroke or an aneurysm ¨C will disqualify the patient.
- Other significant neurological disease or major psychiatric disorder will disqualify the patient.
- Persons interested in the study will remain on their current AD medications throughout.
- There is a 60-percent chance of receiving the drug and a 40-percent chance of receiving a placebo.
- A woman can not be of childbearing potential

How can participants benefit?
Clinical research is necessary to determine whether this new drug works and if it is safe. There is no guarantee, but the information gathered from this study could help future AD patients.
¡ñ Participants will receive the investigational drug, physical exams, as well as laboratory services and tests. Throughout the study, participants will be monitored by a medical team including a nurse (or study coordinator) and a physician.

What the trial will entail?
- There will be no charge to participate.
- The procedure is a 45 minutes infusion, for a total of six times with 13 weeks in between each infusion.
- There is also a four-hour monitoring of the patient immediately following the first infusion and then two-hour monitoring at the subsequent five infusions.
- Because this is an antibody, the doctor is making sure there isn¡¯t a negative reaction during the monitoring period. If there is an immune system reaction, she has drugs to counteract this, but also the patient will not be allowed to continue.

Those interested in participating should call 701-4554. For more information visit icarastudy.com or call 1-888-770-6366 (memory).

Alzheimer disease facts:
- There is no current cure for AD
- 90 percent of all dementia is AD.
- One in two people by age 85 will have AD.
- More than 5 million people in the US have been diagnosed.
- The national annual cost is $1,000,000,000.
- Typically a patient can cost a household up to $36,000 a year.

Source : www.cnylink.com

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