Promising new natural treatment for Alzheimer's disease nears clinical trial

 

A promising new natural treatment for Alzheimer's disease is moving toward clinical trials. This will be a major step forward as there is nothing on the market that slows the progression of Alzheimer's.

Muraleedharan Nair, Michigan State University natural products chemist, has patented a botanical compound, withanamides. His spinoff company, Natural Therapeutics, will begin the trials as soon as funding is in place.

To date, none of the major pharmaceutical companies - Merck, Eli Lilly, Bristol-Myers Squibb - have been able to produce an effective treatment that passed human clinical trials, Nair said.

"This particular research has focused on Ashwagandha, an herbal remedy that's been used in Eastern medicines for centuries," he said. "Our compound withanamides may work to prevent Alzheimer's disease at the onset, and it also could prevent its progression."

While plants cannot be patented, compounds from it can. MSU holds the patent for withanamides, and earlier research revealed that the compound, found in the plants' seeds, proved to be a powerful anti-oxidant - double the strength of what's on today's market. The potent compound has shown that it can protect cells against damaging attacks by a rogue protein ¬- the earliest stage of Alzheimer's.

Alzheimer's begins when a specific protein starts breaking, or cleaving, at the wrong place to produce an unwanted fragment. This bad fragment, called BAP, stresses cells' membranes, sparks plaque formation and eventually kills the cells. This attack begins in the frontal lobe, erasing memories and continuing its unrelenting assault deeper into the brain.

A complicating factor is that the majority of protein cleaving is a natural, healthy process. Pharmaceutical companies, however, have focused their efforts on blocking the tiny faction of bad cleaving of the protein producing BAP.

Promising new natural treatment for Alzheimer's disease nears clinical trial

Rethinking of Alzheimer's Disease ?

So for the explanation for the Alzheimer's disease is "amyloid hypothesis", i.e., the disease results from of an accumulation of the peptide amyloid beta, the toxic protein fragments that deposit in the brain and become the sticky plaques that have defined Alzheimer's, this hypothesis has been accepted for 100 years. Something new explanation has been provided by George Bartzokis of UCLA professor of psychiatry and he says that a better working hypothesis is the "myelin model". He explains the model in the following lines :

Like insulation around wires, myelin is a fatty sheath that coats our nerve axons, allowing for efficient conduction of nerve impulses. It is key to the fast processing speeds that underlie our higher cognitive functions and encoding of memories. But the lifelong, extensive myelination of the human brain also makes it uniquely vulnerable to damage. The myelin model's central premise is that it is the normal, routine maintenance and repair of myelin throughout life that ultimately initiates the mechanisms that produce degenerative diseases like Alzheimer's. That is, the amyloid-beta peptide and the tau peptide, which is also implicated in Alzheimer's, as well as the signature clinical signs of the disease, such as memory loss and, ultimately, dementia, are all byproducts of the myelin breakdown and repair processes. The pervasive myelination of our brain is the single most unique aspect in which the human brain differs from other species.

Myelin is produced by oligodendrocytes, specialized glial cells that themselves become more vulnerable with age. Myelination of the brain follows an inverted U-shaped trajectory, growing strongly until our 50s, when it very slowly begins to unravel as we age. The myelin that is deposited in adulthood ensheaths increasing numbers of axons with smaller axon diameters and so spreads itself thinner and thinner. As a result, it becomes more susceptible to the ravages of age in the form of environmental and genetic insults and slowly begins to break down faster than it can be repaired.

The exclusive targeting of the amyloid-beta peptide for many years is understandable because the same genes and enzymes involved in controlling myelination and myelin repair are, ironically, also involved in the production of amyloid-beta proteins. Bartzokis' point is that the amyloid beta may actually develop as a result of the natural process of the repair and maintenance of myelin. So the breakdown that leads to Alzheimer's and other age-related brain diseases, such as Parkinson's, may begin much earlier, before the formation of the protein deposits that are used to define these diseases," Bartzokis said. Hope this explanation will lead to new innovative ideas for drug discoverers like rather than targeting amyloid-beta peptide !. Hoping for the better results....

Ref : http://newsroom.ucla.edu/portal/ucla/new-target-for-alzheimer-s-102065.aspx

BQCA improves symptoms of Alzheimer’s disease in rodents.....

The compound  benzylquinolone carboxylic acid (BQCA)  has been shown in earlier studies (rodent)  to lessen the occurrence and severity of the behavioral disturbances often symptomatic of Alzheimer's, such as hallucinations, delusions, paranoia and outbursts. But the important feature of this research lies in the fact that the compound, was able to change the way the brain works and whether or not it improved memory in our 'Alzheimer's mice,' which are experiencing progressive cognitive decline much like a person with Alzheimer's does.

Other attempts to identify such a specific treatment for Alzheimer's have failed, according to Dr.Michelle  Nicolle, the lead researcher. As per her claim "current treatments only treat the symptoms while the underlying disease is still progressing and  so recent research efforts are focusing on stopping disease progression instead of symptomatic treatment".

The researchers' findings suggest that  the compound BQCA,  could alter the progression of disease in mice and  ultimately  hold importance for humans as well.

BQCA activates a specific neurotransmitter receptor in the brain called the M1 muscarinic acetylcholine receptor. M1 receptors have been the focus of research into treatment of Alzheimer's disease because they affect the part of the brain that stimulates the memory and learning functions the disease inhibits. Until now, scientists have not found a treatment selective enough to activate the receptors without producing side effects such as nausea, vomiting and increased frequency of urination. As per the claim, BCQA is specific and BQCA also seemed to inhibit production of amyloid beta, one of the markers of Alzheimer's disease in the brain - perhaps key to the compound's potential for slowing the progression of the disease. Though detailed studies are still to be established its an interesting research. I found an interesting article in the same lines, those interested can read.

Ref : http://www.wfubmc.edu/News-Media-Resources/

Tiny doses of anti-HIV drug may be effective for treating Alzheimer's disease

In continuation of my update on efavirenz

For a promising pathway to treating Alzheimer's patients, "aim here." That's what National Institute of Standards of Technology (NIST) researchers advised collaborators hunting for molecules that, by linking to a normally occurring enzyme, rev up the brain's capacity for clearing cholesterol--a boost associated with improvements in memory and other benefits in animal studies.

The target pinpointed by the NIST scientists is where an approved anti-HIV drug -- efavirenz -- latches to the enzyme already responsible for about 80 percent of the cholesterol elimination from the human brain. Obtained with a cutting-edge atom-substitution technology called hydrogen-deuterium exchange (HDX), the molecular roadmap shows how small amounts of the drug can kick the enzyme, called CYP46A1, into higher gear.

With this information, a team led by Irina Pikuleva of Case Western Reserve University now has the full story behind the drug's mechanism of action, key evidence in their proposal to launch clinical trials of efavirenz as an Alzheimer's treatment. The analytical sleuthing that exposed the dynamics of the cholesterol-clearing connection was reported in a recent issue of the Journal of Biological Chemistry.

Analyses of NIST's HDX data and follow-on experiments helped to explain why, in studies of mice, tiny doses of efavirenz ramped up CYP46A1's cholesterol-removal capability while larger doses had an inhibiting effect.

The explanation: At low doses, efavirenz binds to a site on the enzyme that boosts cholesterol breakdown at another location on the enzyme, an increase enabled by changes in shape initiated by the drug. At higher doses, however, drug molecules begin to compete with cholesterol for the same site where cholesterol normally binds.

The shape-changing effect of efavirenz "is a classic example of a basic tenet of biology -- structure determines function," Pikuleva said. And the effect can be dramatic.

In mouse studies, the enzyme-drug connection triggered a 40 percent increase in cholesterol breakdown and removal from the brain. In people, the boost is likely to be significantly higher, Pikuleva said, since the enzyme plays a larger disposal role in the human brain than in the mouse's.

Studies of over the past 15 years persuaded Pikuleva's team to pursue an Alzheimer's treatment strategy focused on ratcheting up the cholesterol-clearing capabilities of CYP46A1, part of a large family of iron-containing enzymes that strongly influence how the body processes drugs.

Studies by other scientists that used genetic manipulations in mouse models of Alzheimer's disease showed that cranking up CYP46A1's activity reduced development of plaque, or clumps of protein pieces called beta amyloids. These studies also reported improvements in memory and learning. And, even in plaque-free, normal mice, increased cholesterol removal resulted in memory improvement.

Conversely, mouse studies also found that suppressing CYP46A1 led to learning deficiencies.Focusing on efavirenz as part of its strategy to "repurpose" already-approved drugs, the Case Western team set out to uncover how the drug stimulates the enzyme's activity. Computational simulations and modeling suggested more than 30 locations on the enzyme where efavirenz molecule might bind.

Seeking to winnow down the options, Pikuleva turned to Kyle Anderson and colleagues at the Institute for Bioscience and Biotechnology Research, a partnership between NIST and the University of Maryland.

In HDX analyses, proteins are immersed in "heavy water," in which normal hydrogen, containing a single proton in its nucleus, is replaced by deuterium, a rarer type of hydrogen whose nucleus holds both a proton and neutron. Protein and heavy water exchange hydrogen and deuterium. As the protein swaps out hydrogen for heavier deuterium, its mass increases. The process involves a series of steps that include quenching--or locking in the deuterium in the protein--and then breaking the protein into electrically charged fragments for analysis. With a device called a mass spectrometer, researchers can measure the mass of these fragments to determine how quickly these protein pieces exchange hydrogen for deuterium. A protein fragment that is largely exposed to water will have a fast exchange rate, but a fragment that comes from a site buried inside the protein or is covered up by a molecule binding to the protein will have a slower exchange rate.

"HDX mass spectrometry opens a window that allows you to look in on how proteins behave under physiologically relevant conditions," Anderson explained. "It provides the pieces to a puzzle that you can assemble to show how their three-dimensional shape changes over time."

The NIST team used HDX to compare and contrast CYP46A1 in four different states: alone, with cholesterol only, with efavirenz only, and with cholesterol and efavirenz. Subsequent analyses of the resulting torrents of experimental data--a computationally intensive process that Anderson performed in triplicate to ensure accuracy--revealed not only where the drug attached to the enzyme but also how the cholesterol-binding site adjusted in response. The structural changes enabled CYP46A1 to bind cholesterol molecules more tightly than in the absence of the drug.

Following up with a study using a different method, Pikuleva's team further confirmed the site of efavirenz binding as determined with HDX. The evidence strongly suggests, she said, at doses a hundred times lower than prescribed for treating HIV, efavirenz might be an effective therapy for stimulating cholesterol turnover from the brain and slowing or preventing Alzheimer's disease.

Pikuleva and colleagues now are seeking to obtain funding for a clinical trial on humans to investigate the effects of small doses of efavirenz.

Compound reverses symptoms of Alzheimer's disease in mice

"It reversed learning and memory deficits and brain inflammation in mice that are genetically engineered to model Alzheimer's disease," Farr said. "Our current findings suggest that the compound, which is called antisense oligonucleotide (OL-1), is a potential treatment for Alzheimer's disease."

Farr cautioned that the experiment was conducted in a mouse model. Like any drug, before an antisense compound could be tested in human clinical trials, toxicity tests need to be completed.

Antisense is a strand of molecules that bind to messenger RNA, launching a cascade of cellular events that turns off a certain gene.

In this case, OL-1 blocks the translation of RNA, which triggers a process that keeps excess amyloid beta protein from being produced. The specific antisense significantly decreased the over expression of a substance called amyloid beta protein precursor, which normalized the amount of amyloid beta protein in the body. Excess amyloid beta protein is believed to be partially responsible for the formation of plaque in
the brain of patients who have Alzheimer's disease.

Scientists tested OL-1 in a type of mouse that overexpresses a mutant form of the human amyloid beta precursor gene. Previously they had tested the substance in a mouse model that has a natural mutation causing it to overproduce mouse amyloid beta. Like people who have Alzheimer's disease, both types of mice have age-related impairments in learning and memory, elevated levels of amyloid beta protein that stay in the brain and increased inflammation and oxidative damage to the hippocampus  the part of the brain responsible for learning and memory.

"To be effective in humans, OL-1 would need to be effective at suppressing production of human amyloid beta protein," Farr said.

Scientists compared the mice that were genetically engineered to overproduce human amyloid beta protein with a wild strain, which served as the control. All of the wild strain received random antisense, while about half of the genetically engineered mice received random antisense and half received OL-1. 

The mice were given a series of tests designed to measure memory, learning and appropriate behavior, such as going through a maze, exploring an unfamiliar location and recognizing an object. 

Scientists found that learning and memory improved in the genetically engineered mice that received OL-1 compared to the genetically engineered mice that received random antisense. Learning and memory were the same among genetically engineered mice that received OL-1 and wild mice that received random antisense.

They also tested the effect of administering the drug through the central nervous system, so it crossed the blood brain barrier to enter the brain directly, and of giving it through a vein in the tail, so it circulated through the bloodstream in the body. They found where the drug was injected had little effect on learning and memory.

Ref http://iospress.metapress.com/content/px72758w0158103u/?issue=4&genre=article&spage=1005&issn=1387-2877&volume=40

1. 
   

1. 
   

Compound
reverses symptoms of Alzheimer's disease in mice  

Antihypertensive Drugs May Protect Against Alzheimer's Disease....

Researchers at Mount Sinai School of Medicine have found that the drug carvedilol (see structure), currently prescribed for the treatment of hypertension, may lessen the degenerative impact of Alzheimer's Disease and promote healthy memory functions.  

"These studies are certainly very exciting, and suggest for the first time that certain antihypertensive drugs already available to the public may independently influence memory functions while reducing degenerative pathological features of the Alzheimer’s disease brain," said study author Giulio Maria Pasinetti, MD, PhD, Saunders Family Professor of Neurology and Director of the Center of Excellence for Novel Approaches to Neurotherapeutics at Mount Sinai School of Medicine....

Dr. Pasinetti’s team found for the first time that carvedilol, a blood pressure lowering agent, is capable of exerting activities that significantly reduce Alzheimer’s disease-type brain and memory degeneration. This benefit was achieved without blood pressure lowering activity in mice genetically modified to develop Alzheimer’s disease brain degeneration and memory impairment.

They also found that carvedilol treatment was capable of promoting memory function, based on assessments of learning new tasks and information and recall of past information, which is already chemically stored in the brain. In the study, one group of mice received carvedilol treatment and the other group did not. The scientists conducted behavioral and learning tests with each group of mice, and determined that it took the mice in the carvedilol significantly less time to remember tasks than the other group.

Ongoing clinical research is in progress to test the benefits of carvedilol, which may prove to be an effective agent in the treatment of symptoms of Alzheimer’s disease,   hope they will come out with positive results...

Ref : http://www.j-alz.com/issues/21/vol21-2.html

Trial will evaluate resveratrol in Alzheimer's dementia

In continuation of my update on Resveratrol

Researchers at Georgetown University and 25 other U.S. academic institutions affiliated with the Alzheimer's Disease Cooperative Study will be conducting a phase II double-blinded, placebo-controlled trial that will test the effects of resveratrol in Alzheimer's disease patients. "This is the gold-standard for conducting a clinical study because it allows us to objectively determine if resveratrol is offering any benefits," stated Brigid Reynolds, NP, who is the lead researcher for the study's center at Georgetown.

The twelve-month trial, funded by the National Institute on Aging, will enroll men and women age 50 and over with mild to moderate dementia diagnosed as probable Alzheimer's disease and will require one caregiver or friend for each patient. Participants will be initially assigned to 500 milligrams resveratrol or a placebo daily, with dosage to be increased at 13 week intervals to a maximum of 1,000 milligrams twice per day. Lumbar punctures, brain magnetic resonance imaging (MRI) scans, and blood and urine tests will monitor the subjects' progress over the course of ten visits. The researchers hope to determine whether supplementation with resveratrol is helpful in delaying or altering the deterioration of memory and daily function that occurs in Alzheimer's disease.

"Most resveratrol studies showing any health benefits have been conducted in animal models, such as mice, and with doses that far exceed intake from sipping wine or nibbling on chocolate," stated R. Scott Turner, MD, PhD, who is the director of Georgetown University Medical Center's Memory Disorders Program and the national study's lead investigator. "With this clinical trial, we'll find out if daily doses of pure resveratrol can delay or alter memory deterioration and daily functioning in people with mild to moderate dementia due to Alzheimer's."

"During this study, we will also test whether resveratrol improves glucose and insulin metabolism in older individuals -- although those who already have diabetes will not be included in this study," he added....

Ref : http://explore.georgetown.edu/news/?ID=64145

TUM scientists develop molecules that could pave way for new treatments to fight Alzheimer's, diabetes

When proteins change their structure and clump together, formation of amyloid fibrils and plaques may occur. Such 'misfolding' and 'protein aggregation' processes damage cells and cause diseases such as Alzheimer's and type 2 diabetes. A team of scientists from the Technical University of Munich (TUM) headed by Professor Aphrodite Kapurniotu have now developed molecules that suppress protein aggregation and could pave the way for new treatments to combat Alzheimer's, type 2 diabetes and other cell-degenerative diseases.

The scientists designed and studied 16 different peptide molecules in order to find out which of them are able to impede the 'clumping' of the proteins amyloid beta (Aß) and islet amyloid polypeptide (IAPP), which are associated with Alzheimer's and type 2 diabetes.

The molecules were designed on the basis of scientific work that shows that the Aß and IAPP proteins interact with each other, and that this 'cross-amyloid interaction' suppresses their clumping. The researchers selected short sequences of the IAPP protein that correspond to the key regions involved in the interaction with the Alzheimer's protein. These "hot segments" were then chemically linked to each other by using specific peptide segments as 'linkers' in order to mimic and optimize the IAPP cross-amyloid interaction surface.

Ref : http://www.tum.de/en/about-tum/news/press-releases/short/article/32611/

TUM scientists develop molecules that could pave way for new treatments to fight Alzheimer's, diabetes

Researchers uncover mechanism by which anti-inflammatory processes may cause Alzheimer's

Inflammation has long been studied in Alzheimer's, but in a counterintuitive finding reported in a new paper, University of Florida researchers have uncovered the mechanism by which anti-inflammatory processes may trigger the disease.

This anti-inflammatory process might actually trigger the build-up of sticky clumps of protein that form plaques in the brain. These plaques block brain cells' ability to communicate and are a well-known characteristic of the illness.

The finding suggests that Alzheimer's treatments might need to be tailored to patients depending on which forms of Apolipoprotein E, a major risk factor for Alzheimer's disease, these patients carry in their genes.

The researchers have shown that the anti-inflammatory protein interleukin 10, or IL-10, can actually increase the amount of apolipoprotein E, or APOE, protein -- and thereby plaque -- that accumulates in the brain of a mouse model of Alzheimer's, according to the study, published online today (Jan. 22) in the journal Neuron.

Researchers uncover mechanism by which anti-inflammatory processes may cause Alzheimer's

Plant Sterols prove to be better cholesterol in Alzheimer`s disease

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

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

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

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

Ref : http://www.jneurosci.org/content/33/41/16072.full

        http://www.uni-saarland.de/nc/aktuelles/artikel/nr/9230.html

Plant Sterols prove to be better cholesterol in Alzheimer`s disease

Two research studies on new molecules could potentially treat Alzheimer's disease

This year, results have been published of two significant research studies about molecules that could potentially treat Alzheimer's disease. The chief researcher in both studies was the head of the Laboratory of Medical Chemistry and Bioinformatics at MIPT Yan Ivanenkov. Papers on the two new molecules were published in Molecular Pharmaceutics and Current Alyheimer Research. Mark Veselov, another MIPT employee, also participated in the second study.

Both papers cover the study of neuroprotectors - antagonists to the 5-HT6R receptor. The latest research confirms that this target has a high therapeutic potential in the treatment of Alzheimer's disease. Preclinical studies on lab animals have shown that the compounds have a high selectivity.

Alzheimer's is one of the most widespread diseases in elderly people. People over the age of 60 are at the greatest risk of developing the disease, but it can also occur at a younger age. Patients suffer from loss of memory and cognitive functions; they become socially detached and lose their independence, and the body can no longer function properly, which inevitably leads to death. According to medical statistics, Alzheimer's is the cause of two out of every three cases of dementia in the elderly and it is a huge economic problem in developed countries - the financial impact in the US, for example, is higher than for cancer or cardiovascular diseases.

Scientists have not yet succeeded in finding an effective cure for Alzheimer's. Despite the fact that we know how the disease develops, we cannot say that we are even close to a solution. Pharmaceutical studies are still being conducted in order to be able to reduce the symptoms of the disease.

In the first paper, specialists Alexander Ivashenko and Yan Lavrovsky from Alla Chem LLC, Avineuro Pharmaceuticals Inc. and R-Pharm Overseas Inc. (all US companies), in collaboration with MIPT's Yan Ivanenkov, worked on a 5-HT6R activity blocking compound. A similar task was investigated in Yan and Alexander's second study with another MIPT employee, Mark Veselov. 5-HT6R receptors were chosen because they are integrated into nerve cell membranes and are capable of reacting to certain external signals, which is why scientists consider them as targets for AD treatment. The antagonists to the receptor are able to ease the symptoms of the disease in a clinical environment.

Studying AVN-211

Scientists studied the pharmacokinetic features, activity, efficiency, and also the toxicity profile of AVN-211. First, a screening test was performed using recombinant human cells containing 5-HT6R to make sure that AVN-211 really is an antagonist. Another series of experiments with cell cultures demonstrated its ability to spread in a tissue and provided preliminary data about its state in the human body - metabolism, biochemical interactions, etc.

Tests were then performed on lab animals - mice, rats and monkeys to obtain the pharmacokinetic profile of a drug candidate in a real body. Observing concentration changes in the animals' blood after intake provided information about the compound's pharmacodynamics.

Memory disorder stress tests have shown that AVN-211 might be able to improve memory function. Rats and mice were taught to find an exit from a maze, while their cognition was imaired by drugs provoking memory loss. Animals who were given the drug demonstrated better results. In addition, healthy animals who received the new drug were better learners and could be trained more efficiently.

These results led the researchers to believe that AVN-211 will be able to combat cognitive dysfunction caused by AD.

Scientists also think that this compound can be used to treat certain mental disorders. Tests with chemicals that produce the same symptoms as psychosis have shown a possible antipsychotic and anxiolytic (reducing anxiety) effect. Such effects are used in treating schizophrenia and depression. It was also noticed that AVN has a comparable effect to haloperidol - a common antipsychotic drug.

In vitro studies revealed that this compound affects the 5-HT6R receptor more effectively and selectively compared to all other drugs, including those currently in clinical trials. Studies on lab animals showed that AVN-211 has low toxicity.

Studying AVN-322

The same tests were performed for AVN-322. Screening with the 5-HT6R receptor on human cell culture proved that the molecule is a highly effective antagonist. In vivo tests were performed on mice: the animals were taught how to get out of a maze and had to remember that a section of the floor was electrified. The results showed that mice that received low levels of AVN-322 performed better than after any existing neuroleptic drugs.

The pharmacokinetics of AVN-322 were analyzed in mice, rats, dogs and monkeys. During a 30-day intake monkeys did not have any toxic after-effects. A possible danger was noticed after a 180-day intake in rats - the substance can cause brachycardia and hypotension. However the exact after-effects are less serious than all other existing drugs. Pre-clinical data proves that AVN-322 also has a good pharmacokinetic profile - it is very digestible and passes well through the blood-brain barrier.

In conclusion, we can say that both compounds have a high pharmaceutical potential and low toxicity. The positive results of the studies mean that researchers can move on to clinical trials in order to verify the safety and effectiveness of a drug that could potentially treat one of the most serious diseases of our time.

Omega-3 fatty acids improve cognitive flexibility in older adults at risk of late-onset Alzheimer's disease

A study of older adults at risk of late-onset Alzheimer's disease found that those who consumed more omega-3 fatty acids did better than their peers on tests of cognitive flexibility -- the ability to efficiently switch between tasks -- and had a bigger anterior cingulate cortex, a brain region known to contribute to cognitive flexibility.

 

[alpha-linolenic acid (ALA), an essential omega-3 fatty acid, (18:3Δ9c,12c,15c, which means a chain of 18 carbons with 3 double bonds on carbons numbered 9, 12, and 15)].

The analysis suggests, but does not prove, that consuming DHA and EPA, two omega-3 fatty acids found in fish, enhanced cognitive flexibility in these adults in part by beefing up the anterior cingulate cortex, the researchers report in the journal Frontiers in Aging Neuroscience.

"Recent research suggests that there is a critical link between nutritional deficiencies and the incidence of both cognitive impairment and degenerative neurological disorders, such as Alzheimer's disease," said University of Illinois neuroscience, psychology, and speech and hearing science professor Aron Barbey, who led the study with M.D./Ph.D. student Marta Zamroziewicz. "Our findings add to the evidence that optimal nutrition helps preserve cognitive function, slow the progression of aging and reduce the incidence of debilitating diseases in healthy aging populations."

The researchers focused on aspects of brain function that are sometimes overlooked in research on aging, Zamroziewicz said. "A lot of work in cognitive aging focuses on memory, but in fact cognitive flexibility and other executive functions have been shown to better predict daily functioning than memory does," she said.

"Executive function" describes processes like planning, reasoning, paying attention, problem solving, impulse control and task switching.

"These functions tend to decline earlier than other cognitive functions in aging," Zamroziewicz said.

The new research built on previous studies that found associations between omega-3 fatty acid consumption, cognitive flexibility and the size of the anterior cingulate cortex.

"There's been some work to show that omega-3 fatty acids benefit cognitive flexibility, and there's also been work showing that cognitive flexibility is linked to this specific brain region, the anterior cingulate. But there's been very little work actually connecting these pieces," Zamroziewicz said.

The new study focused on 40 cognitively healthy older adults between the ages of 65 and 75 who are carriers of a gene variant (APOE e4) that is known to contribute to the risk of developing late-onset Alzheimer's disease.

The researchers tested participants' cognitive flexibility, measured levels of the fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) in their blood, and imaged their brains using MRI. Statistical analyses teased out the relationships between these factors.

"We wanted to confirm that higher omega-3 fatty acids related to better cognitive flexibility, and we did in fact see that," Zamroziewicz said. "We also wanted to confirm that higher omega-3 fatty acids related to higher volume in the anterior cingulate cortex, and we saw that. Finally, we were able to show that higher volume in the anterior cingulate cortex was an intermediary in the relationship between omega-3 fatty acids and cognitive flexibility."

 Docosahexaenoic acid

  Eicosapentaenoic acid

Omega-3 fatty acids improve cognitive flexibility in older adults at risk of late-onset Alzheimer's disease

FDA Panel Backs Amyvid (Florbetapir) Approval

FDA approve a new chemical, Florbetapir, E)-4-(2-(6-(2-(2-(2-([¹⁸F]-fluoroethoxy)ethoxy)ethoxy)- pyridin-3-yl)vinyl)-N-methyl benzenamine (see structure) that can highlight the telltale signs of Alzheimer's in brain scans may one day help doctors diagnose the neurodegenerative disease, experts said. Amyvid (trade name), with one critical caveat, however manufacturer Eli Lilly and Co. must demonstrate that standards for interpreting brain scans that show amyloid plaques illuminated by Amyvid can be made consistent enough to routinely guarantee an accurate diagnosis.

Amyvid (florbetapir) is injected into patients who then undergo a PET scan; a negative result can help rule out Alzheimer's, according to Lilly. Experts agreed that the test could become a critical part of spotting Alzheimer's before symptoms have taken hold, but they noted that the clinical reality of that is far from imminent.

"It may well be that amyloid imaging will join colonoscopy, mammography, etc. as mid-life surveillance tests, and that anti-amyloid interventions are most effective in the pre-symptomatic stages of Alzheimer's disease," said Dr. Sam Gandy, the Mount Sinai Chair in Alzheimer's Disease Research in New York City. However, this possibility is years away, he added..............

Ref : http://newsroom.lilly.com/releasedetail.cfm?ReleaseID=544894

Plant flavonols significantly reduce Alzheimer’s risk

A new study published in the journal Neurology in January 2020 concludes that increasing the intake of plant flavonols steeply reduces the risk of Alzheimer’s dementia (AD) by up to a half. In other words, AD could be prevented in many people simply by regularly eating and drinking more foods containing these compounds such as tea, oranges, and broccoli.

Alzheimer’s disease

AD is a progressive brain disorder in which the individual loses cognitive skills, including memory and thinking skills, and the ability to perform simple tasks. It is by far the leading cause of such disorders and affects over 5 million Americans.

One study was carried out on over 900 people, who were part of a community-wide ongoing larger research project called the Rush Memory and Aging (MAP) Project. These participants were assessed yearly for their neurologic health and dietary patterns, for an average of 6 years, but some for as long as 12 years. The average age was 81 years, and 3 out of 4 were female.

The findings

In the first study, 220/921 participants developed AD during the study. The risk of AD fell with a greater intake of flavonols. This finding held good even after the researchers adjusted for other health-associated factors – because those with the highest total flavonol intake were also the best educated, most active and took part in more cognitive activities. They also accounted for genetic factors like the presence of the APOE4 gene, and for cardiovascular risk factors that could influence the risk of AD, such as diabetes mellitus, history of heart attack, or stroke, or hypertension.

When classified into five groups based on decreasing flavonol intake, the participants in the first group (highest intake) consumed over 15 mg of flavonols a day. Compared to those in the lowest fifth (about 5 mg a day), these individuals showed an approximately 50% reduction in AD risk.

In concrete terms, 28 of 186 patients in the highest-intake group developed AD, vs. 54 of 182 in the lowest-intake group.

With respect to individual flavonols, kaempferol intake was linked to a reduction of almost 50%, and both myricetin and isorhamnetin by 40% each. A fourth flavonol, called quercetin, had no noticeable effect on AD risk.

Participants with the highest flavonol intake drank about one cup of black tea a day. Kale, and about a glass of red wine each day, could also supply flavonols.

Sources of flavonols

Kaempferol is richly present in green leafy vegetables, including spinach, broccoli, beans, tea and kale – and also in tea. Isorhamnetin-rich foods include olive oil, red wine, pears and tomato sauce. Myricetin is found in tea, kale, oranges, tomatoes and red wine.

Researcher Thomas Holland says, “More research is needed to confirm these results, but these are promising findings. Eating more fruits and vegetables and drinking more tea could be a fairly inexpensive and easy way for people to help stave off Alzheimer's dementia.”

Implications

Many scientists disagree with the emphasis on flavonols. Though these were thought to have antioxidant activity in the body, this theory was discredited many decades earlier. Antioxidant activity ceases when they are ingested and subjected to the activity of enzymes in the digestive tract.

They point out that flavonols are found in many plants, fruits and vegetables, which have been associated with good health for centuries. Nutritionists say that the AD-delaying effects of such foods are likely due to other plant chemicals which are relatively more abundant. On the other hand, taking flavonol pills or tea extracts is unlikely to produce the same healthful effect, and overdoses could be counterproductive.

This is not to say that eating more flavonol-rich foods or drinking a cup of black tea in the morning would hurt, since any foods containing these chemicals would also contain many more healthful compounds including vitamins, minerals and plant fiber. Holland makes a valid point with his conclusion: “'With the elderly population increasing worldwide, any decrease in the number of people with this devastating disease, or even delaying it for a few years, could have an enormous benefit on public health.”

https://n.neurology.org/content/early/2020/01/29/WNL.0000000000008981

Plant flavonols significantly reduce Alzheimer’s risk

New drugs to find the right target to fight Alzheimer's disease

A favorite Alzheimer's target: gamma secretase

The two next-generation classes of compound that are currently in clinical trials target an enzyme that cuts APP, known as gamma secretase. Until now, our understanding of the mechanism involved has been lacking. But with this work, the EPFL researchers were able to shed some more light on it by determining how the drug compounds affect gamma secretase and its cutting activity.

In most forms of Alzheimer's, abnormally large quantities of the long amyloid peptide 42 -- named like that because it contains 42 amino acids  are formed. The drug compounds change the location where gamma secretase cuts the APP protein, thus producing amyloid peptide 38 instead of 42, which is shorter and does not aggregate into neurotoxic plaques.

Compared to previous therapeutic efforts, this is considerable progress. In 2010, Phase III clinical trials had to be abandoned, because the compound being tested inhibited gamma-secretase's function across the board, meaning that the enzyme was also deactivated in essential cellular differentiation processes, resulting to side-effects like in gastrointestinal bleeding and skin cancer.

"Scientists have been trying to target gamma secretase to treat Alzheimer's for over a decade," explains Patrick Fraering, senior author on the study and Merck Serono Chair of Neurosciences at EPFL. "Our work suggests that next-generation molecules, by modulating rather than inhibiting the enzyme, could have few, if any, side-effects. It is tremendously encouraging."

Ref : http://www.nature.com/ncomms/2013/130802/ncomms3246/full/ncomms3246.html

New drugs to find the right target to fight Alzheimer's disease

Benzodiazepines linked to increased risk of death among Alzheimer’s disease patients

Benzodiazepine and related drug use is associated with a 40 per cent increase in mortality among persons with Alzheimer's disease, according to a new study from the University of Eastern Finland. The findings were published in the International Journal of Geriatric Psychiatry.

The study found that the risk of death was increased right from the initiation of benzodiazepine and related drug use. The increased risk of death may result from the adverse events of these drugs, including fall-related injuries, such as hip fractures, as well as pneumonia and stroke.

The study was based on the register-based MEDALZ (Medication Use and Alzheimer's Disease) cohort, which includes all persons diagnosed with Alzheimer's disease in Finland during 2005-2011. Persons who had used benzodiazepines and related drugs previously were excluded from this study, and therefore, the study population consisted of 10,380 new users of these drugs. They were compared with 20,760 persons who did not use these drugs.

Although several treatment guidelines state that non-pharmacological options are the first-line treatment of anxiety, agitation and insomnia in persons with dementia, benzodiazepines and related drugs are frequently used in the treatment of these symptoms. If benzodiazepine and related drug use is necessary, these drugs are recommended for short-term use only. These new results encourage more consideration for benzodiazepine and related drug use in persons with dementia.

Ref : https://www.uef.fi/en/-/bentsodiatsepiinit-lisaavat-kuolleisuutta-alzheimerin-tautia-sairastavilla

Benzodiazepines linked to increased risk of death among Alzheimer’s disease patients

Study: Prostate cancer drug stabilizes memory loss for a year in women with Alzheimer's disease

Women with Alzheimer's disease showed stable cognition for a year when a drug that is more commonly used to treat advanced prostate cancer was added to their drug regimen, according to a new study from researchers at the University of Wisconsin-Madison.

"This is the first time any therapy has been shown to stabilize memory loss over a year," says Dr. Craig Atwood, co-lead author of the study and associate professor of medicine at the UW School of Medicine and Public Health.

 

The study was published today in the Journal of Alzheimer's Disease and is available here: http://iospress.metapress.com/content/n207096671247200.

The clinical trial, initiated by Dr. Richard Bowen at the former Voyager Pharmaceutical Corporation, followed 109 women with mild to moderate Alzheimer's disease. Some were treated with the drug leuprolide acetate (Lupron Depot first above structure), used to treat cancer in men and severe endometriosis in women, and with an acetylcholineesterase inhibitor such as Aricept (second below structure), which improves mood in people with the condition but does little to slow memory loss. Others taking an acetylcholineesterase inhibitor received low-dose Lupron alone or a placebo.

Study: Prostate cancer drug stabilizes memory loss for a year in women with Alzheimer's disease

Case Western Reserve University - One of the nation's top universities and the best college in Ohio

Neuroscientists at Case Western Reserve University School of Medicine have made a dramatic breakthrough in their efforts to find a cure for Alzheimer's disease. The researchers' findings, published in the journalScience, show that use of a drug in mice appears to quickly reverse the pathological, cognitive and memory deficits caused by the onset of Alzheimer's. The results point to the significant potential that the medication, bexarotene, has to help the roughly 5.4 million Americans suffering from the progressive brain disease. 

Bexarotene has been approved for the treatment of cancer by the U.S. Food and Drug Administration for more than a decade. These experiments explored whether the medication might also be used to help patients with Alzheimer's disease, and the results were more than promising. Landreth and his colleagues chose to explore the effectiveness of bexarotene for increasing ApoE expression. The elevation of brain ApoE levels, in turn, speeds the clearance of amyloid beta from the brain. Bexarotene acts by stimulating retinoid X receptors (RXR), which control how much ApoE is produced.

In particular, the researchers were struck by the speed with which bexarotene improved memory deficits and behavior even as it also acted to reverse the pathology of Alzheimer's disease. The present view of the scientific community is that small soluble forms of amyloid beta cause the memory impairments seen in animal models and humans with the disease. Within six hours of administering bexarotene, however, soluble amyloid levels fell by 25 percent; even more impressive, the effect lasted as long as three days. Finally, this shift was correlated with rapid improvement in a broad range of behaviors in three different mouse models of Alzheimer's.

More...

Case Western Reserve University - One of the nation's top universities and the best college in Ohio

A Novel Neurotrophic Drug for Cognitive Enhancement and Alzheimer's Disease

A new drug candidate may be the first capable of halting the devastating mental decline of Alzheimer's disease.  The drug, known as J147 (above  structure), improved memory and prevented brain damage caused by the disease claims the researchers from Salk's Cellular Neurobiology Laboratory, lead by David Schubert. The new compound,  could be tested for treatment of the disease in humans in the near future.Researchers add that, J147 enhances memory in both normal and Alzheimer's mice and also protects the brain from the loss of synaptic connections.

Salk researchers went on to show that it prevented cognitive decline in animals with Alzheimer's and that mice and rats treated with the drug produced more of a protein called brain-derived neurotrophic factor (BDNF), a molecule that protects neurons from toxic insults, helps new neurons grow and connect with other brain cells, and is involved in memory formation.

Because of the broad ability of J147 to protect nerve cells, the researchers believe that it may also be effective for treating other neurological disorders, such as Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis (ALS), as well as stroke.

Although it is yet unknown whether the compound will prove safe and effective in humans, the Salk researchers' say their results suggest the drug may hold potential for treatment of people with Alzheimer's...

Ref : http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0027865

'Peanut butter' test can help diagnose Alzheimer's disease, researchers find

A dollop of peanut butter and a ruler can be used to confirm a diagnosis of early stage Alzheimer's disease, University of Florida Health researchers have found...

Of the 24 patients tested who had mild cognitive impairment, which sometimes signals Alzheimer's disease and sometimes turns out to be something else, about 10 patients showed a left nostril impairment and 14 patients did not. The researchers said more studies must be conducted to fully understand the implications.

"At the moment, we can use this test to confirm diagnosis," Stamps said. "But we plan to study patients with mild cognitive impairment to see if this test might be used to predict which patients are going to get Alzheimer's disease."

Stamps and Heilman point out that this test could be used by clinics that don't have access to the personnel or equipment to run other, more elaborate tests required for a specific diagnosis, which can lead to targeted treatment. At UF Health, the peanut butter test will be one more tool to add to a full suite of clinical tests for neurological function in patients with memory disorders.

'Peanut butter' test can help diagnose Alzheimer's disease, researchers find

Ref : http://dx.doi.org/10.1016/j.jns.2013.06.033