Abstract
Dementia: Cerebrolysin shows promise
Dementia patients may benefit from a promising new treatment called Cerebrolysin, according to the results of a systematic review published in The Cochrane Library. The authors brought together the most up-to-date evidence on Cerebrolysin as a treatment for vascular dementia.
Vascular dementia is a common form of dementia caused by damage to the network of blood vessels supplying the brain. Some of the symptoms are similar to those associated with Alzheimer's disease and stroke but in particular those with vascular dementia often experience difficulty thinking quickly, concentrating and communicating, as well as seizures and severe confusion.1 There is currently no definitive treatment for vascular dementia. Cerebrolysin is a drug treatment made from pig brain proteins that has produced positive results against vascular dementia, although inconsistently.
The researchers reviewed data from six randomized controlled trials involving 597 people in total. All were given Cerebrolysin intravenously in different daily concentrations and for different treatment periods, from a few weeks to three years, depending on the trial. Compared to standard care alone or placebos, Cerebrolysin significantly improved cognitive function, which was assessed with scales testing recall, arithmetic or other cognitive abilities. It had a small positive effect on patients' overall clinical state. There was also some suggestion that long-term treatment was associated with greater benefits, although only two trials looked at long-term effects.
“Our review suggests that Cerebrolysin can help improve cognitive and global function in patients with mild to moderate severity vascular dementia,” said researcher Li He of the Department of Neurology at Sichuan University in Sichuan, China. “The results are promising but due to low numbers of trials, inconsistencies between trials, risk of bias in the way some of the trials were conducted and lack of long-term follow-up, we cannot yet recommend Cerebrolysin as a routine treatment for vascular dementia.”
None of those involved in studies reported serious side effects due to taking the drug and non-serious side effects were no more common in those who took the drug compared to control groups. “This indicates to us that Cerebrolysin is safe and well tolerated by patients with vascular dementia,” said He. “But the fact that it has to be given in regular intravenous infusions means it could be impractical for use on a large scale.” (Source: EurekAlert! A service of AAAS and Wiley).
Study identifies protein that contributes to cognitive decline in Alzheimer's
Researchers at Columbia University Medical Center (CUMC) have demonstrated that a protein called caspase-2 is a key regulator of a signaling pathway that leads to cognitive decline in Alzheimer's disease. The findings, made in a mouse model of Alzheimer's, suggest that inhibiting this protein could prevent the neuronal damage and subsequent cognitive decline associated with the disease. The study was published this month in the online journal Nature Communications.
One of the earliest events in Alzheimer's is disruption of the brain's synapses (the small gaps across which nerve impulses are passed), which can lead to neuronal death. Although what drives this process has not been clear, studies have indicated that caspace-2 might be involved, according to senior author Michael Shelanski, MD, PhD, the Delafield Professor of Pathology & Cell Biology, chair of the Department of Pathology & Cell Biology, and co-director of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at CUMC.
Several years ago, in tissue culture studies of mouse neurons, Dr. Shelanski found that caspace-2 plays a critical role in the death of neurons in the presence of amyloid beta, the protein that accumulates in the neurons of people with Alzheimer's. Other researchers have shown that caspase-2 also contributes to the maintenance of normal synaptic functions.
Dr. Shelanski and his team hypothesized that aberrant activation of caspase-2 may cause synaptic changes in Alzheimer's disease. To test this hypothesis, the researchers crossed J20 transgenic mice (a common mouse model of Alzheimer's) with caspase-2 null mice (mice that lack caspase-2). They compared the animals' ability to negotiate a radial-arm water maze, a standard test of cognitive ability, with that of regular J20 mice and of normal mice at 4, 9, and 14 months of age.
The results for the three groups of mice were similar at the first two intervals. At 14 months, however, the J20/caspase-2 null mice did significantly better in the water maze test than the J20 mice and similarly to the normal mice. “We showed that removing caspase-2 from J20 mice prevented memory impairment—without significant changes in the level of soluble amyloid beta,” said co-lead author Roger Lefort, PhD, associate research scientist at CUMC.
Analysis of the neurons showed that the J20/caspase-2 null mice had a higher density of dendritic spines than the J20 mice. The more spines a neuron has, the more impulses it can transmit.
“The J20/caspase-2 null mice showed the same dendritic spine density and morphology as the normal mice—as opposed to the deficits in the J20 mice,” said co-lead author Julio Pozueta, PhD. “This strongly suggests that caspase-2 is a critical regulator in the memory decline associated with beta-amyloid in Alzheimer's disease.”
The researchers further validated the results in studies of rat neurons in tissue culture.
Finally, the researchers found that caspase-2 interacts with RhoA, a critical regulator of the morphology (form and structure) of dendritic spines. “It appears that in normal neurons, caspase-2 and RhoA form an inactive complex outside the dendritic spines,” said Dr. Lefort. “When the complex is exposed to amyloid beta, it breaks apart, activating the two components.” Once activated, caspase-2 and RhoA enter the dendritic spines and contribute to their demise, possibly by interacting with a third molecule, the enzyme ROCK-II.
“This raises the possibility that if you can inhibit one or all of these molecules, especially early in the course of Alzheimer's, you might be able to protect neurons and slow down the cognitive effects of the disease,” said Dr. Lefort. (Source: EurekAlert! A service of AAAS and Columbia University Medical Center).
Worming our way to new treatments for Alzheimer's disease
According to a 2012 World Health Organization report, over 35 million people worldwide currently have dementia, a number that is expected to double by 2030 (66 million) and triple by 2050 (115 million). Alzheimer's disease, the most common form of dementia, has no cure and there are currently only a handful of approved treatments that slow, but do not prevent, the progression of symptoms.
New drug development, no matter the disease, is a slow, expensive, and risky process. Thus, innovative techniques to study and assess the possibilities of already-existing drugs for different diseases can be used to alleviate the traditional burdens of cost and time. Detailed in their new article in Biological Psychiatry, researchers from the University of Washington, led by Dr. Brian Kraemer, have developed an exciting new approach to screening potential new treatments for Alzheimer's disease using C. elegans, a small transparent worm.
Their focus was on tau, a protein involved in maintaining brain cell structure. In Alzheimer's disease and related disorders, tau protein becomes abnormally modified and forms clumps of protein called aggregates. These aggregates are a hallmark of the dying nerve cells in Alzheimer's disease and other related disorders. Diseases with abnormal tau are called tauopathies.
Dr. Kraemer's lab previously developed a worm model for tauopathy by expressing human tau in C. elegans nerve cells. This model has behavioral abnormalities, accumulates abnormal tau protein, and exhibits loss of nerve cells—all of which are general features of Alzheimer's disease.
Using their worm model for this study, they screened a library of 1,120 drugs approved for human use and tested each at three different concentrations to identify compounds that suppress the effects of abnormal tau aggregation.
“We have identified six compounds capable of reliably alleviating tau induced behavioral abnormalities in our C. elegans model for tauopathy. In a human cultured cell model for abnormal tau protein, we have also seen that azaperone treatment can decrease the amount of abnormal tau,” said Kraemer.
Azaperone, an antipsychotic drug, normally binds to certain dopamine receptors found in nerve cells. They demonstrated that removing those receptors in either C. elegans or human cells has the same effect as azaperone treatment, indicating that azaperone and related drugs should alter abnormal tau accumulation. Other antipsychotic drugs also have a similar effect to azaperone.
Tests of these compounds for anti-tau properties are now underway in existing mouse models of Alzheimer's disease.
“This study is an exemplary instance of how a simple C. elegans model system may be used to rapidly screen drugs for diseases and evaluate mechanism of action,” said Drs. Sangeetha Iyer and Jonathan Pierce-Shimomura, authors of a commentary that accompanies this article.
Dr. John Krystal, Editor of Biological Psychiatry, agrees and added: “Studying the worm, C. elegans, has already provided us with fundamental insights into how the brain develops. The new approach described by McCormick and colleagues suggests that this animal model may be a powerful new approach to studying novel treatments that prevent its decline.” (Source: EurekAlert! A service of AAAS and Elsevier).
Alzheimer's disease protein controls movement in mice
Researchers in Berlin and Munich, Germany and Oxford, United Kingdom, have revealed that a protein well known for its role in Alzheimer's disease controls spindle development in muscle and leads to impaired movement in mice when the protein is absent or treated with inhibitors. The results, which are published in The EMBO Journal, suggest that drugs under development to target the beta-secretase-1 protein, which may be potential treatments for Alzheimer's disease, might produce unwanted side effects related to defective movement.
Alzheimer's disease is the most common form of dementia found in older adults. The World Health Organization estimates that approximately 18 million people worldwide have Alzheimer's disease. The number of people affected by the disease may increase to 34 million by 2025. Scientists know that the protein beta-secretase-1 or Bace1, a protease enzyme that breaks down proteins into smaller molecules, is involved in Alzheimer's disease. Bace1 cleaves the amyloid precursor protein and generates the damaging Abeta peptides that accumulate as plaques in the brain leading to disease. Now scientists have revealed in more detail how Bace1 works.
“Our results show that mice that lack Bace1 proteins or are treated with inhibitors of the enzyme have difficulties in coordination and walking and also show reduced muscle strength,” remarked Carmen Birchmeier, one of the authors of the paper, Professor at the Max-Delbrück-Center for Molecular Medicine in Berlin, Germany, and an EMBO Member. “In addition, we were able to show that the combined activities of Bace1 and another protein, neuregulin-1 or Nrg1, are needed to sustain the muscle spindles in mice and to maintain motor coordination.”
Muscle spindles are sensory organs that are found throughout the muscles of vertebrates. They are able to detect how muscles stretch and convey the perception of body position to the brain. The researchers used genetic analyses, biochemical studies and interference with pharmacological inhibitors to investigate how Bace1 works in mice. “If the signal strength of a specific form of neuregulin-1 known as IgNrg1 is gradually reduced, increasingly severe defects in the formation and maturation of muscle spindles are observed in mice. Furthermore, it appears that Bace1 is required for full IgNrg1 activity. The graded loss of IgNrg1 activity results in the animals having increasing difficulties with movement and coordination,” says Cyril Cheret, the first author of the work.
Drug developers are interested in stopping the Bace1 protein in its tracks because it represents a promising route to treat Alzheimer's disease. If the protein were inhibited, it would interfere with the generation of the smaller damaging proteins that accumulate in the brain as amyloid plaques and would therefore provide some level of protection from the effects of the disease. “Our data indicate that one unwanted side effect of the long-term inhibition of Bace1 might be the disruption of muscle spindle formation and impairment of movement. This finding is relevant to scientists looking for ways to develop drugs that target the Bace1 protein and should be considered,” says Birchmeier. Several Bace1 inhibitors are currently being tested in phase II and phase III clinical trials for the treatment of Alzheimer's disease. (Source: EurekAlert! A service of AAAS and European Molecular Biology Organization).
`Forrest Gump' mice show too much of a good thing, can be bad
A line of genetically modified mice that Western University scientists call “Forrest Gump” because, like the movie character, they can run far but they aren't smart, is furthering the understanding of a key neurotransmitter called acetylcholine (ACh). Marco Prado and his team at Robarts Research Institute say the mice show what happens when too much of this neurotransmitter becomes available in the brain. Boosting ACh is a therapeutic target for Alzheimer's disease because it's found in reduced amounts when there's cognitive failure. Prado's research is published in the Journal of Neuroscience.
“We wanted to know what happens if you have more of the gene which controls how much acetylcholine is secreted by neurons,” says Prado, a Robarts scientist and professor in the Departments of Physiology and Pharmacology and Anatomy and Cell Biology at Western's Schulich School of Medicine & Dentistry. “The response was the complete opposite of what we expected. It's not a good thing. Acetylcholine release was increased threefold in these mice, which seemed to disturb cognitive function. But put them on a treadmill and they can run twice as far as normal mice before tiring. They're super-athletes.” In addition to its function in modulating cognitive abilities, ACh drives muscle contraction which allowed for the marked improvement in motor endurance.
One of the tests the scientists, including first author Benjamin Kolisnyk, used is called the touch screen test for mice which uses technology similar to a tablet. After initiating the test, the mice have to scan five different spots on the touch screen to see a light flash, and then run and touch that area. If they get it right they get a reward. Compared to the control mice, the “Forrest Gump” mice failed miserably at the task. The researchers found the mice, which have the scientific name ChAT-ChR2-EYFP, had terrible attention spans, as well as dysfunction in working memory and spatial memory.
Prado interprets the research as showing ACh is very important for differentiating cues. So if your brain is presented with a lot of simultaneous information, it helps to pick what's important. But when you flood the brain with ACh, your brain loses the ability to discern what's relevant. This study was funded mainly by the Canadian Institutes of Health Research. (Source: EurekAlert! A service of AAAS and University of Western Ontario).
Stroke symptoms associated with developing memory and thinking problems
People who experience any stroke symptoms—but do not have a stroke—may also be more likely to develop problems with memory and thinking, according to new research published in the June 19, 2013, online issue of Neurology® , the medical journal of the American Academy of Neurology.
“‘Silent strokes' that cause small areas of brain damage have been tied to memory and thinking problems, but it has been difficult to study these ‘silent strokes' due to the cost and inconvenience of obtaining brain MRIs,” said study author Brendan J. Kelley, MD, of the University of Cincinnati and a member of the American Academy of Neurology. “With this study, we found that a quick, seven-question test can be a cost-effective tool to help identify people at increased risk of developing dementia.”
For the research, 23,830 people from the REGARDS study with an average age of 64 with no memory problems who had never had a stroke completed the stroke symptoms questionnaire at the start of the study and every six months for at least two years. The questionnaire asks about symptoms of stroke or transient ischemic attack (TIA), or a “mini-stroke” where symptoms resolve quickly with no permanent damage. The participants' memory and thinking skills were also tested yearly. During the study, 7,223 people had stroke symptoms.
The study found that people who had stroke symptoms were more likely to develop memory and thinking problems. Caucasians who had stroke symptoms were twice as likely to develop cognitive problems (11 percent) as Caucasians who did not have stroke symptoms (5 percent). African-Americans who had stroke symptoms were nearly 70 percent as likely to develop thinking problems (16 percent) as African-Americans who did not have stroke symptoms (about 10 percent).
“Our study highlights the importance of discussing stroke-like symptoms with your family doctor, even if they don't last long. These symptoms can be a warning sign that a person is at increased risk of stroke or problems with thinking or memory,” said Kelley. (Source: EurekAlert! A service of AAAS and the American Academy of Neurology).
Storytelling program helps change medical students' perspectives on dementia
Treating patients with dementia can be viewed as a difficult task for doctors, but Penn State College of Medicine researchers say that storytelling may be one way to improve medical students' perceptions of people affected by the condition. Participation in a creative storytelling program called TimeSlips creates a substantial improvement in student attitudes.
Daniel George, assistant professor of humanities, tested the effects of the TimeSlips program in an elective course he teaches at the college. Fourth-year medical students worked with patients at Country Meadows, a Hershey-based assisted living community. These patients are affected by advanced dementia and live in a memory-support unit requiring a locked environment.
Medical students commonly perceive persons with dementia as being challenging to work with.
“We currently lack effective drugs for dementia, and there's a sense that these are cases where students can't do much to benefit the patient,” George said. “The perception is that they're hard to extract information from, you don't know if that information is reliable, and there are often other complicated medical issues to deal with.”
TimeSlips is a non-pharmacological approach to dementia care that uses creative storytelling in a group setting and encourages participants to use their imagination rather than focusing on their inability to remember chronologically. Pictures with a staged, surreal image – for example, an elephant sitting on a park bench – are shared with all participants, who are encouraged to share their impressions of what is happening in the picture. As part of George's elective, medical students spent one month facilitating TimeSlips with groups of five to 10 residents and helping the residents build stories in poem form during their interactions.
“All comments made during a session – even ones that do not necessarily make logical sense – are validated and put into the poem because it is an attempt to express meaning,” George said. “The sessions become energetic and lively as the residents are able to communicate imaginatively, in a less linear way. In the process, students come to see dementia differently. It is very humanizing, revealing personality and remaining strengths where our culture tends to just focus on disease, decline and loss.”
Student attitudes were measured before and after the TimeSlips experience using a validated instrument called the Dementia Attitudes Scale. A significant improvement in overall attitude was observed over the course of the program, and students also demonstrated significant increases on sub-scales measuring comfort with people with dementia and knowledge about interacting with and treating these patients. Results were reported in the journal Academic Medicine.
“In talking with my students, they consistently express their anxieties about medical school training them to see patients as a diagnosis rather than as a fully-fledged person,” George said. “An activity like TimeSlips, which emphasizes the creative spirit in people with fairly advanced dementia, helps give students a richer sense of who the person was and what made them tick.”
At Penn State College of Medicine, which emphasizes the humanities in medical care and established the first Department of Humanities at a medical school in the nation, George hopes to expand TimeSlips volunteer opportunities to include all medical students and not exclusively fourth-year students. By reaching students earlier in their education and exposing them to a creative activity involving people with dementia, he hopes that TimeSlips could help nudge more trainees into geriatric medicine.
“As the incidence of dementia-related conditions is rising globally, the demand for high-quality, humanistic geriatric care is becoming more urgent,” George said.
There has already been an effort to extend TimeSlips volunteer opportunities to nurses, faculty, staff and patients.
“Several patients from our hospital, Penn State Milton S. Hershey Medical Center, have already begun taking part in the program,” he said. “Even though they are experiencing their own illnesses, they are able to find purpose in helping another vulnerable population through creative storytelling.” (Source: EurekAlert! A service of AAAS and Pennsylvania State University).
New Alzheimer’s research suggests possible cause: the interaction of proteins in the brain
For years, Alzheimer's researchers have focused on two proteins that accumulate in the brains of people with Alzheimer's and may contribute to the disease: plaques made up of the protein amyloid-beta, and tangles of another protein, called tau.
But for the first time, an Alzheimer's researcher has looked closely at not the two proteins independently, but at the interaction of the two proteins with each other—in the brain tissue of post-mortem Alzheimer's patients and in mouse brains with Alzheimer’s disease. The research found that the interaction between the two proteins might be the key: as these interactions increased, the progression of Alzheimer's disease worsened.
The research, by Hemachandra Reddy, Ph.D., an associate scientist at the Oregon National Primate Research Center at Oregon Health & Science University, is detailed in the June 2013 edition of the Journal of Alzheimer's Disease.
Reddy's paper suggests that when the interaction between the phosphorylated tau and the amyloid-beta—particularly in its toxic form—happens at brain synapses, it can damage those synapses. And that can lead to cognitive decline in Alzheimer's patients.
“This complex formation between amyloid-beta and tau—it is actually blocking the neural communication,” Reddy said. “If we could somehow find a molecule that could inhibit the binding of these two proteins at the synapses, that very well might be the cure to Alzheimer's disease.”
To conduct the research, Reddy and his team studied three different kinds of mice, who had been bred to have some of the brain characteristics of Alzheimer's disease, including having amyloid-beta and phosphorylated tau in their brains. Reddy also analyzed postmortem brain tissue from people who had Alzheimer's disease.
Using multiple antibodies that recognize amyloid-beta and phosphorylated tau, Reddy and Maria Manczak, Ph.D., a research associate in Reddy’s laboratory, specifically looked for the evidence of the amyloid-beta and phosphorylated tau interactions. They found amyloid-beta/tau complexes in the human Alzheimer’s brain tissue and in the Alzheimer’s disease mouse brains. The Reddy team also found much more of those amyloid-beta/tau complexes in brains where Alzheimer's disease had progressed the most.
Reddy found very little or no evidence of the same interaction in the “control” subjects—mice that did not have the Alzheimer's traits and human brain tissue of people who did not have Alzheimer's.
“So much Alzheimer's research has been done to look at amyloid-beta and tau,” Reddy said. “But ours is the first paper to strongly demonstrate that yes, there is an amyloid-beta/phosphorylated tau interaction. And that interaction might be causing the synaptic damage and cognitive decline in persons with Alzheimer’s disease.”
Reddy and his lab are already working on the next crucial questions. One is to define the binding site or sites and exactly where within the neuron the interaction of amyloid-beta and tau first occurs. The second is to find a way to inhibit that interaction—and thus maybe prevent or slow the progression of Alzheimer's. (Source: Oregon Health and Science University).
Concussion patients show Alzheimer's-like brain abnormalities
The distribution of white matter brain abnormalities in some patients after mild traumatic brain injury (MTBI) closely resembles that found in early Alzheimer's dementia, according to a new study published online in the journal Radiology.
“Findings of MTBI bear a striking resemblance to those seen in early Alzheimer's dementia,” said the study's lead author, Saeed Fakhran, M.D., assistant professor of radiology in the Division of Neuroradiology at the University of Pittsburgh School of Medicine. “Additional research may help further elucidate a link between these two disease processes.”
MTBI, or concussion, affects more than 1.7 million people in the United States annually. Despite the name, these injuries are by no means mild, with approximately 15 percent of concussion patients suffering persistent neurological symptoms.
“Sleep-wake disturbances are among the earliest findings of Alzheimer's patients, and are also seen in a subset of MTBI patients,” Dr. Fakhran said. “Furthermore, after concussion, many patients have difficulty filtering out white noise and concentrating on the important sounds, making it hard for them to understand the world around them. Hearing problems are not only an independent risk factor for developing Alzheimer's disease, but the same type of hearing problem seen in MTBI patients has been found to predict which patients with memory problems will go on to develop Alzheimer's disease.”
For the study, Dr. Fakhran and colleagues set out to determine if there was a relationship between white matter injury patterns and severity of post-concussion symptoms in MTBI patients with normal findings on conventional magnetic resonance imaging (MRI) exams. The researchers studied data from imaging exams performed on 64 MTBI patients and 15 control patients, using an advanced MRI technique called diffusion tensor imaging, which identifies microscopic changes in the brain's white matter.
The brain's white matter is composed of millions of nerve fibers called axons that act like communication cables connecting various regions of the brain. Diffusion tensor imaging produces a measurement, called fractional anisotropy, of the movement of water molecules along axons. In healthy white matter, the direction of water movement is fairly uniform and measures high in fractional anisotropy. When water movement is more random, fractional anisotropy values decrease.
Of the MTBI patients, 42 (65.6 percent) were men, and the mean age was 17. Sports injury was the reason for concussion in two-thirds of the patients. All patients underwent neurocognitive evaluation with Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT). The researchers analyzed correlation between fractional anisotropy values, the ImPACT total symptom score, and findings of sleep-wake disturbances.
Sleep-wake disturbances are among the most disabling post-concussive symptoms, directly decreasing quality of life and productivity and magnifying post-concussion memory and social dysfunction.
The results showed a significant correlation between high ImPACT total symptom score and reduced fractional anisotropy at the gray-white junction, most prominently in the auditory cortex. Significantly decreased fractional anisotropy was found in patients with sleep-wake disturbances in the parahippocampal gyri relative to patients without sleep-wake disturbances.
“When we sleep, the brain organizes our experiences into memories, storing them so that we can later find them,” Dr. Fakhran said. “The parahippocampus is important for this process, and involvement of the parahippocampus may, in part, explain the memory problems that occur in many patients after concussion.”
According to Dr. Fakhran, the results suggest that the true problem facing concussion patients may not be the injury itself, but rather the brain's response to that injury.
“Traditionally, it has been believed that patients with MTBI have symptoms because of abnormalities secondary to direct injury,” he said. “Simply put, they hit their head, damaged their brain at the point of trauma and thus have symptoms from that direct damage. Our preliminary findings suggest that the initial traumatic event that caused the concussion acts as a trigger for a sequence of degenerative changes in the brain that results in patient symptoms and that may be potentially prevented. Furthermore, these neurodegenerative changes are very similar to those seen in early Alzheimer's dementia.”
The researchers hope that these findings may lead to improved treatments in the future.
“The first step in developing a treatment for any disease is understanding what causes it,” Dr. Fakhran said. “If we can prove a link, or even a common pathway, between MTBI and Alzheimer's, this could potentially lead to treatment strategies that would be potentially efficacious in treating both diseases.” (Source: EurekAlert! A service of AAAS and the Radiological Society of North America).
Rare genomic mutations found in 10 families with early-onset, familial Alzheimer's disease
Although a family history of Alzheimer's disease is a primary risk factor for the devastating neurological disorder, mutations in only three genes – the amyloid precursor protein and presenilins 1 and 2 – have been established as causative for inherited, early-onset Alzheimer's, accounting for about half of such cases. Now Massachusetts General Hospital (MGH) researchers have discovered a type of mutation known as copy-number variants (CNVs) – deletions, duplications, or rearrangements of human genomic DNA – in affected members of 10 families with early-onset Alzheimer's. Notably, different genomic changes were identified in the Alzheimer's patients in each family.
The study was conducted as part of the Alzheimer's Genome Project – directed by Rudolph Tanzi, PhD, director of the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH) and a co-discoverer of the first three early-onset genes – and was supported by the Cure Alzheimer's Fund and the National Institute of Mental Health (NIMH).
“We found that the Alzheimer's-afflicted members of these families had duplications or deletions in genes with important roles in brain function, while their unaffected siblings had unaltered copies of those genes,” says Basavaraj Hooli, PhD, of the Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, lead author of a report that has been published online in Molecular Psychiatry. “Since our preliminary review of the affected genes has provided strong clues to a range of pathways associated with Alzheimer's disease and other forms of dementia, we believe that further research into the functional effects of these CNVs will provide new insights into Alzheimer's pathogenesis.” Hooli is a research fellow in Neurology at Harvard Medical School.
Most studies searching for genes contributing to Alzheimer's risk have looked for variants in a single nucleotide, and while thousands of such changes have been identified, each appears to have a very small impact on disease risk. Recently research has found that CNVs – in which DNA segments of varying lengths are deleted or duplicated – have a greater impact on genomic diversity than do single-nucleotide changes. This led Tanzi and his team to search for large CNVs in affected members of families with inherited Alzheimer's disease. “These are the first new early-onset familial Alzheimer's disease gene mutations to be reported since 1995, when we co-discovered the presenilins. As with those original genes, we hope to use the information gained from studies of the new Alzheimer's mutations to guide the development of novel therapies aimed at preventing and treating this devastating disease.” Tanzi explains.
The investigators reviewed genomic data from two sources – the NIMH Alzheimer's Disease Genetics Initiative and the National Cell Repository for Alzheimer's Disease – and focused on 261 families with at least one member who developed Alzheimer's before the age of 65. Using a novel algorithm they had developed for analyzing CNVs, the researchers identified deletions or duplications that appeared only in affected members of these families. Two of these families had CNVs that included the well-established amyloid precursor protein gene, but 10 others were found to have novel Alzheimer's-associated CNVs, with different gene segments being affected in each family.
While none of the novel variants have previously been associated with Alzheimer's disease, most of them affect genes believed to be essential to normal neuronal function, and several have been previously associated with other forms of dementia. For example, one of the identified CNVs involves deletion of a gene called CHMP2B, mutations of which can cause ALS. In another family, affected members had three copies of the gene MAPT, which encodes the tau protein found in the neurofibrillary tangles characteristic of Alzheimer's. Mutations in MAPT also cause frontotemporal dementia.
Hooli explains, “Potential clinical application of the findings of this study are not yet clear and require two additional pieces of information: similar studies in larger groups of families with inherited Alzheimer's to establish the prevalence of these CNVs and whether the presence of one ensures development of the disease, and a better understanding of how these variants affect neuronal pathways leading to the early-onset form of Alzheimer's disease.”
“In a broader sense,” Tanzi adds, “the advent of affordable, advanced whole-genome sequencing will lead to the identification of novel, rare mutations that lead to many human disorders. In the future, diagnosis and prognosis may rely more on disease genetics than on traditional laboratory results and behavioral effects. If knowing the exact genetic causes of these disorders leads to more effective and efficient treatment strategies targeted to specific defects, the consequences of this approach would be enormous.” (Source: EurekAlert! A service of AAAS and Massachusetts General Hospital).
Sanford-Burnham researchers develop new drug that reverses loss of brain connections in Alzheimer's
The first experimental drug to boost brain synapses lost in Alzheimer's disease has been developed by researchers at Sanford-Burnham Medical Research Institute. The drug, called NitroMemantine, combines two FDA-approved medicines to stop the destructive cascade of changes in the brain that destroys the connections between neurons, leading to memory loss and cognitive decline.
The decade-long study, led by Stuart A. Lipton, M.D., Ph.D., professor and director of the Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, who is also a practicing clinical neurologist, shows that NitroMemantine can restore synapses, representing the connections between nerve cells (neurons) that have been lost during the progression of Alzheimer's in the brain. The research findings are described in a paper published June 17 by the Proceedings of the National Academy of Sciences of the United States of America (PNAS).
The focus on a downstream target to treat Alzheimer's, rather than on amyloid beta plaques and neurofibrillary tangles—approaches which have shown little success—“is very exciting because everyone is now looking for an earlier treatment of the disease,” Lipton said. “These findings actually mean that you might be able to intercede not only early but also a bit later.” And that means that an Alzheimer's patient may be able to have synaptic connections restored even with plaques and tangles already in his or her brain.
Targeting lost synapses
In their study, conducted in animal models as well as brain cells derived from human stem cells, Lipton and his team mapped the pathway that leads to synaptic damage in Alzheimer's. They found that amyloid beta peptides, which were once thought to injure synapses directly, actually induce the release of excessive amounts of the neurotransmitter glutamate from brain cells called astrocytes that are located adjacent to the nerve cells.
Normal levels of glutamate promote memory and learning, but excessive levels are harmful. In patients suffering from Alzheimer's disease, excessive glutamate activates extrasynaptic receptors, designated eNMDA receptors (NMDA stands for N-methyl-D-aspartate), which get hyperactivated and in turn lead to synaptic loss.
How NitroMemantine works
Lipton's lab had previously discovered how a drug called memantine can be targeted to eNMDA receptors to slow the hyperactivity seen in Alzheimer's. This patented work contributed to the FDA approval of memantine in 2003 for the treatment of moderate to severe Alzheimer's disease. However, memantine's effectiveness has been limited. The reason, the researchers found, was that memantine—a positively charged molecule—is repelled by a similar charge inside diseased neurons; therefore, memantine gets repelled from its intended eNMDA receptor target on the neuronal surface.
In their study, the researchers found that a fragment of the molecule nitroglycerin—a second FDA-approved drug commonly used to treat episodes of chest pain or angina in people with coronary heart disease—could bind to another site that the Lipton group discovered on NMDA receptors. The new drug represents a novel synthesis connecting this fragment of nitroglycerin to memantine, thus representing two FDA-approved drugs connected together. Because memantine rather selectively binds to eNMDA receptors, it also functions to target nitroglycerin to the receptor. Therefore, by combining the two, Lipton's lab created a new, dual-function drug. The researchers developed 37 derivatives of the combined drug before they found one that worked, Lipton said.
By shutting down hyperactive eNMDA receptors on diseased neurons, NitroMemantine restores synapses between those neurons. “We show in this paper that memantine's ability to protect synapses is limited,” Lipton said, “but NitroMemantine brings the number of synapses all the way back to normal within a few months of treatment in mouse models of Alzheimer's disease. In fact, the new drug really starts to work within hours.”
To date, therapies that attack amyloid plaques and neurofibrillary tangles have failed. “It's quite disappointing because I see really sick patients with dementia. However, I'm now optimistic that NitroMemantine will be effective as we advance to human trials, bringing new hope to both early and later-stage Alzheimer's patients,” Lipton said. (Source: EurekAlert! A service of AAAS and Sanford-Burnham Medical Research Institute).
Commonly-prescribed drugs may influence the onset and progression of Alzheimer's disease
Multiple drug classes commonly prescribed for common medical conditions are capable of influencing the onset and progression of Alzheimer's disease, according to researchers at The Mount Sinai Medical Center. The findings are published online in the journal PLoS One.
Led by Giulio Maria Pasinetti, MD, PhD, the Saunders Family Chair and Professor in Neurology at Mount Sinai, a research team used a computer algorithm to screen 1,600 commercially-available medications to assess their impact on the brain accumulation of beta-amyloid, a protein abnormally accumulated in the brain of Alzheimer's disease and implicated in neurodegeneration. They found that currently-available medications prescribed for conditions such as hypertension, depression, and insomnia were found to either to block or to enhance the accumulation of beta-amyloid, the component of amyloid plaques.
“This line of investigation will soon lead to the identification of common medications that might potentially trigger conditions associated with the prevention, or conversely the onset, of Alzheimer's disease,” said Dr. Pasinetti. “They may be a novel reference for physicians to consider when prescribing the most appropriate drug, particularly in subjects at high risk for Alzheimer's disease.”
To validate the screening protocol, Dr. Pasinetti and his colleagues administered these drugs in mice that were genetically engineered to develop the hallmark amyloid plaques associated with Alzheimer's disease. After six months of treatment with blood pressure medicines, amyloid plaques and neurodegeneration were significantly reduced in the mice. One such medicine was Carvedilol, now under clinical investigation in Alzheimer's disease with the intent to slow down memory deterioration.
“In recent years, amyloid plaques have become one of the main focal points in the search to understand and to treat Alzheimer's disease,” said Dr. Pasinetti. “Thus, identifying novel drug treatments that prevent harmful beta-amyloid generation will help in the development of treatments for Alzheimer's disease. For example, one very exciting finding of our study is that Carvedilol, already approved for treatment of hypertension, may immediately become a promising drug for the treatment of Alzheimer's as well.”
The authors discuss the limitations of the research, noting that studies must be immediately verified in human-safety studies that examine the effects of the drugs independent of the original indication. Dr. Pasinetti hopes these findings will lead to multiple clinical trials in the future to identify preventive drugs, which will need to be prescribed at tolerable dosages.
“If we can repurpose drugs currently used for different indications, such as lowering blood pressure, this could have dramatic implications for this population,” said Dr. Pasinetti. (Source: EurekAlert! A service of AAAS and The Mount Sinai Hospital / Mount Sinai School of Medicine).