News Article | March 16, 2016
In the 25 years that John Collinge has studied neurology, he has seen hundreds of human brains. But the ones he was looking at under the microscope in January 2015 were like nothing he had seen before. He and his team of pathologists were examining the autopsied brains of four people who had once received injections of growth hormone derived from human cadavers. It turned out that some of the preparations were contaminated with a misfolded protein — a prion — that causes a rare and deadly condition called Creutzfeldt–Jakob disease (CJD), and all four had died in their 40s or 50s as a result. But for Collinge, the reason that these brains looked extraordinary was not the damage wrought by prion disease; it was that they were scarred in another way. “It was very clear that something was there beyond what you'd expect,” he says. The brains were spotted with the whitish plaques typical of people with Alzheimer's disease. They looked, in other words, like young people with an old person's disease. For Collinge, this led to a worrying conclusion: that the plaques might have been transmitted, alongside the prions, in the injections of growth hormone — the first evidence that Alzheimer's could be transmitted from one person to another. If true, that could have far-reaching implications: the possibility that 'seeds' of the amyloid-β protein involved in Alzheimer's could be transferred during other procedures in which fluid or tissues from one person are introduced into another, such as blood transfusions, organ transplants and other common medical procedures. Collinge felt a duty to inform the public quickly. And that's what he did, publishing the study in Nature in September1, to headlines around the world. “Can you CATCH Alzheimer's?” asked Britain's Daily Mail, about the “potentially explosive new study”. Collinge has been careful to temper the alarm. “Our study does not mean that Alzheimer's is actually contagious,” he stresses. Carers won't catch it on the job, nor family members, however close. “But it raises concern that some medical procedures could be inadvertently transferring amyloid-β seeds.” Since then, the headlines have died away, but the academic work and discussion have taken off. Could seeds of amyloid-β proteins really be transmitted and, if so, are they harmless or do they cause disease? And could seeds of other related diseases involving misfolded proteins be transmitted in a similar way? In the past decade or so, evidence has been mounting for a controversial theory that rogue proteins, known collectively as amyloids and associated with diverse neurodegenerative diseases — from Alzheimer's to Parkinson's and Huntington's — might share some properties of prions, including their transmissibility. Collinge's data bolstered that theory. Urgent though these questions are, it could take years to find answers. The paper by Collinge and his colleagues has sparked a worldwide hunt for similar amyloid pathology in autopsied brains, and a small study2 published this January revealed a handful of related cases. Researchers are also trying to work out what the putative amyloid seeds look like, and whether different 'strains' of amyloids exist that are particularly damaging. Some researchers say that it is much too early to be alarmed. They point out that the number of patients in Collinge's study was tiny, that none had displayed symptoms of Alzheimer's disease before their death and that another toxic protein called tau also seems to be required to cause the condition. “We have to remember that there is no conclusive evidence that seeds of amyloids can transmit actual disease or that amyloids spread in the brain in a prion-like way,” says Pierluigi Nicotera, scientific director of the German Centre for Neurodegenerative Diseases in Bonn. “There may be other biological explanations.” Right now, there are few solid answers, but plenty of concerns. The sceptics worry that they might one day find themselves working under tight biosecurity regulations to handle proteins that they view as relatively innocuous. Others feel that the dangers may have been underestimated, and that scientists have a duty to investigate this as quickly as they can. “In my opinion, all amyloids should be considered dangerous until proven safe,” says prion and amyloid researcher Adriano Aguzzi at the University Hospital Zurich in Switzerland. A few decades ago, it was almost inconceivable that a protein, which has no genetic material or any other obvious way to self-replicate, could cause infectious disease. But that changed in 1982, when Stanley Prusiner, now at the University of California, San Francisco, introduced evidence for disease-causing prions, coining the term from the words 'proteinacious' and 'infectious'3. Prusiner showed that prion proteins (PrP) exist in a normal cellular form, and in a misfolded infectious form. The misfolded form causes the normal protein to also misfold, creating a cascade that overwhelms and kills cells4. It cause animal brains to turn into a spongy mess in scrapie, a disease of sheep, and in bovine spongiform encephalopathy (BSE or 'mad cow disease'), as well as in human prion diseases such as CJD. Prusiner and others also investigated how prions could spread. They showed that injecting brain extracts containing infectious prions into healthy animals seeds disease4. These prions can be so aggressive that in some cases, simply eating infected brains is sufficient to transmit disease. For example, many cases of variant CJD (vCJD) are now thought to have arisen in the United Kingdom in the 1990s after people ate meat from cattle that were infected with BSE. Since then, scientists have come to appreciate that many proteins associated with neurodegenerative diseases — including amyloid-β and tau in Alzheimer's disease and α-synuclein in Parkinson's disease — misfold catastrophically. Structural biologists call the entire family of misfolded proteins (including PrP) amyloids. Amyloid-β clumps into whitish plaques, tau forms ribbons called tangles and α-synuclein creates fibrous deposits called inclusions. A decade ago, these similarities prompted neuroscientist Mathias Jucker at the University of Tübingen in Germany to test whether injecting brain extracts containing misfolded amyloid-β into mice could seed an abnormal build-up of amyloid in the animals' brains. He found that it could, and that it also worked if he injected amyloids into the muscles5. “We saw no reason not to believe that if amyloid seeds entered the human brain, they would also cause amyloid pathology in the same way,” says Jucker. This didn't cause alarm at the time, because it wasn't clear how an amyloid seed from the brain of someone with Alzheimer's could be transferred into another person's body and find its way to their brain. To investigate that, what was needed was a group of people who had been injected with material from another person, and the opportunity to examine their brains in great detail, preferably when they were still relatively young and before they might have spontaneously developed early signs of Alzheimer's. The CJD brains provided just that opportunity. Between 1958 and 1985, around 30,000 people worldwide received injections of growth hormone derived from the pituitary glands of cadavers to treat growth problems. Some of the preparations were contaminated with the prion that causes CJD. Like all prion diseases, CJD has a very long incubation period, but once it gets going it rages through the brain, destroying all tissue in its wake and typically killing people from their late 40s onwards. According to 2012 statistics6, 226 people around the world have died from CJD as a result of prion-contaminated growth-hormone preparations. Collinge had not set out to find a link with Alzheimer's — it emerged as part of routine work at the National Prion Clinic in London, which he heads, and where around 70% of all people in the United Kingdom who die from prion-related causes are now autopsied. The clinic routinely looks for signs of all amyloid proteins in these brains to distinguish prion disease from other conditions. It was thanks to this routine work that the cluster of unusual cases emerged of people who had clearly died of CJD, but who also had obvious signs of amyloid pathology in their grey matter and cerebral blood vessels. As soon as he saw these brains, Collinge knew that he could get into stormy waters. Keen to strike a balance between warning of a possible public-health risk and causing unwarranted panic, he sketched a carefully worded press release that would go out from the National Prion Centre and set up hotlines for people who had been treated with growth hormone in the past. But no panic occurred: apart from one or two overwrought headlines, the news stories were fairly measured, he says. Only around ten people called the hotlines. For scientists, however, the paper was a red flag. “As soon as the paper came out we realized the health implications and started collecting slides and paraffin blocks from patients,” says Jiri Safar, director of the National Prion Disease Pathology Surveillance Center at Case Western Reserve University in Cleveland, Ohio. Like other pathologists in countries where people had died of CJD associated with medical procedures, he rushed to check the centre's archives of autopsied brains to see if any of them contained the ominous amyloid deposits. The answers are not yet in. Safar says that it has not proved easy to trace brain samples in the United States, but that he is working to do so with the National Institutes of Health and the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia. Charles Duyckaerts at the Pitié-Salpêtrière Hospital in Paris, France, has now examined brain tissues from around 24 patients and is likely to report the results later this year. A further 228 cases of CJD were caused by transplantation of prion-contaminated dura mater — the membrane surrounding the brain and spinal cord — prepared from cadavers around the world. Dura-mater preparations were regularly used in brain surgery as repair patches until the late 1990s. For the study2 published in January, Herbert Budka at the National Prion Diseases Reference Center at University Hospital Zurich and his colleagues examined the brains of seven such patients from Switzerland and Austria, and found that five had amyloid deposits in grey matter and blood vessels. In Japan, dementia researcher Masahito Yamada at Kanazawa University is making his way through a large number of such autopsy specimens and says that the 16 brains he has examined so far show signs of unusually high levels of amyloid deposition in cerebral blood vessels. Yet such case studies can only ever provide circumstantial evidence that seeds of amyloid-β were transferred during the treatments. And they cannot entirely rule out the possibility that the treatments themselves — or the patients' original medical conditions — caused the amyloid pathology. More-conclusive evidence would come from checking whether the original growth hormone and dura-mater preparations contained infectious amyloid seeds, by injecting them into animals and seeing whether this triggers disease. Most of these preparations, however, have long since disappeared. Collinge has access to some original samples of growth hormone stored by the UK Department of Health, and he is planning to analyse them for the presence of amyloid seeds and then inject them into mice. That work will take a couple of years to complete, he says. There is another hitch: no one knows for sure what size and shape the amyloid seeds might be. Jucker is hunting for them in an unusual source of human brain tissue that has nothing to do with CJD. A team in Bonn has collected frozen samples from more than 700 people with epilepsy who were operated on over the past 25 years to remove tissue that was driving their seizures. “It is the best source of fresh human brain tissue available at the moment,” says Jucker, who plans to scrutinize it carefully under the microscope for anything that might resemble tiny clumps or seeds of amyloid-β. The team also has records of the patients' cognitive skills, such as language and memory skills, before and at regular intervals after the operations. This should allow Jucker's team to correlate the presence of any amyloid-β seeds it finds with changes in the cognitive function of individual patients over time. Scientists have shown that tau and α-synuclein can also seed pathological features in mice. In two studies7, 8 from 2012, scientists injected fibrils of α-synuclein into the brains of mice already engineered to develop some of the characteristics of Parkinson's disease. This triggered the early onset of some of the signs and symptoms of Parkinson's, and eventually killed the animals. A third study9 showed that similar injections into normal mice caused some of the neurodegeneration typical of Parkinson's disease and the mice became less agile. In humans, α-synuclein would not necessarily turn out to be equally aggressive — mouse models of neurodegenerative diseases do not mimic human disease very closely — but scientists are taking the possibility seriously. If the transmissibility hypothesis proves true, the implications could be severe. Amyloids stick like glue to metal surgical instruments, and normal sterilization does not remove them, so amyloid seeds might possibly be transferred during surgery. The seeds might sit in the body for years or decades before spreading into plaques, and perhaps enabling the other pathological changes needed to induce Alzheimer's disease. Having amyloid plaques in cerebral blood vessels could be dangerous in another way, because they increase the risk that the vessel walls might break, leading to small strokes. But if common medical procedures really increased the risk of neurodegenerative disorders, then wouldn't that already have been detected? Not necessarily, says epidemiologist Roy Anderson at Imperial College London. “The proper epidemiological studies have not been done yet,” he says. They require very large and carefully curated databases of people with Alzheimer's disease, which include information about the development of symptoms and autopsy data. He and his team are now studying the handful of reliable databases that exist to tease out a signal that might associate medical procedures with Alzheimer's progression. The number of patients currently available may turn out to be too small to draw conclusions, he says, but a more definitive answer could emerge as the databases grow. Faced with so much uncertainty, some researchers and public-health agencies have adopted a wait-and-see approach. “We are right at the beginning of this story,” says Nicotera, “and if there is one message to come out right now it is that we need more work to see if this is a relevant mechanism.” The CDC and the European Centre for Disease Prevention and Control in Solna, Sweden, say that they are keeping a cautious eye on the issue. If further research does confirm that common neurodegenerative diseases are transmissible, what then? One immediate priority would be rigorous sterilization procedures for medical and surgical instruments that would destroy amyloids, in the way that extremely high temperatures and harsh chemicals destroy prions. Aguzzi says that funding agencies should put out calls now to researchers to develop cheap and simple sterilization methods. “It's not very sexy science, but it is urgently needed,” he says. He also worries about the safety of researchers working with amyloids — particularly α-synuclein. “I have nightmares that someone in my lab may catch Parkinson's,” he says. “While the story is in flux, our first duty is to protect lab workers.” The similarities between prions and other amyloids is throwing open other avenues of research. Prions can exist as distinct strains — proteins that have the same sequence of amino acids but misfold in different ways and have distinct biological behaviours10, much as different strains of a pathogenic virus can be aggressive or weak. The outbreak of vCJD in the United Kingdom in the 1990s was traced to BSE-contaminated meat because the prion strain was the same in both. Over the past few years, research in animals has shown that different strains of amyloid-β and α-synuclein exist11, 12. And a landmark paper13 in 2013 reported that strains of amyloid-β with different 3D structures were associated with different disease progression in two people with Alzheimer's. Structural biologist Robert Tycko, who led the work at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, is now looking at many more brain samples from such patients. Knowing the structures of pathological forms of amyloid seeds should help to design small molecules that bind to them and stop them doing damage, says biophysicist Ronald Melki at the Paris-Saclay Institute of Neuroscience, who works on α-synuclein strains. His lab is designing small peptides that target the seeds and mimic regions of 'chaperone' molecules, which usually bind to proteins and help them to fold correctly. Melki's small peptides mimic these binding regions, sticking to the amyloid proteins to stop them from aggregating further. In the research community, much of the agitation in response to Collinge's paper boils down to semantics. Some scientists do not like to use the word 'prion' in connection with the amyloids associated with common neurodegenerative diseases, or to describe any of their properties as 'prion-like' — because of its connotation of infectious, deadly disease. “The public has this perception of the word 'prion',” says Alzheimer's researcher Brad Hyman at Harvard Medical School in Boston, Massachusetts, and this matters, even if their ideas are wrong. “One of my patients told me that she wasn't getting any hugs any more from her husband who had read about the case in the media — that made me sad,” he says. Others, however, feel that it is helpful to consider prions and other amyloids as being part of a single spectrum of conditions involving proteins that misfold and misbehave. It means that researchers studying prion diseases and neurodegenerative diseases, who until recently had considered their disciplines to be separate, now find themselves tackling shared questions. Both fields are wary of raising premature alarm, even though they wonder what the future will bring. Jucker, only half-jokingly, says he could imagine a future in which people would go into hospital every ten years or so and get the amyloid seeds cleared out of their brains with antibodies. “You'd be good then to go for another decade.”
News Article | December 20, 2016
PHILADELPHIA--Tests that measure the sense of smell may soon become common in neurologists' offices. Scientists have been finding increasing evidence that the sense of smell declines sharply in the early stages of Alzheimer's, and now a new study from the Perelman School of Medicine at the University of Pennsylvania published today in the Journal of Alzheimer's Disease confirms that administering a simple "sniff test" can enhance the accuracy of diagnosing this dreaded disease. The sniff test also appears to be useful for diagnosing a pre-dementia condition called mild cognitive impairment (MCI), which often progresses to Alzheimer's dementia within a few years. Neurologists have been eager to find new ways to identify people who are at high risk of Alzheimer's dementia but do not yet show any symptoms. There is a widespread consensus that Alzheimer's medications now under development may not work after dementia has set in. "There's the exciting possibility here that a decline in the sense of smell can be used to identify people at risk years before they develop dementia," said principal investigator David R. Roalf, PhD, an assistant professor in the department of Psychiatry at Penn. Roalf and his colleagues used a simple, commercially available test known as the Sniffin' Sticks Odor Identification Test, in which subjects must try to identify 16 different odors. They administered the sniff test, and a standard cognitive test (the Montreal Cognitive Assessment), to 728 elderly people. The subjects had already been evaluated by doctors at Penn with an array of neurological methods, and according to expert consensus had been placed in one of three categories: "healthy older adult," "mild cognitive impairment," or "Alzheimer's dementia." Roalf and his team used the results from the cognitive test alone, or combined with the sniff test, to see how well they identified subjects in each category. As researchers report, the sniff test added significantly to diagnostic accuracy when combined with the cognitive test. For example, the cognitive test alone correctly classified only 75 percent of people with MCI, but that figure rose to 87 percent when the sniff test results were added. Combining the two tests also enabled more accurate identification of healthy older adults and those with Alzheimer's dementia. The combination even boosted accuracy in assigning people to milder or more advanced categories of MCI. "These results suggest that a simple odor identification test can be a useful supplementary tool for clinically categorizing MCI and Alzheimer's, and even for identifying people who are at the highest risk of worsening," Roalf said. Prompted by prior studies that have linked a weakening sense of smell to Alzheimer's, doctors in a few larger dementia clinics already have begun to use smell tests in their assessments of elderly patients. Part of the reason the practice has not yet become common is that the tests that seem most useful take too long to administer. Roalf and colleagues are now trying to develop a briefer test that works as well as the longer ones. "We're hoping to shorten the Sniffin' Sticks test, which normally takes 5 to 8 minutes, down to 3 minutes or so, and validate that shorter test's usefulness in diagnosing MCI and dementia--we think that will encourage more neurology clinics to do this type of screening," Roalf said. Roalf and his laboratory also plan to investigate whether protein markers of Alzheimer's, which are present in the olfactory region of the brain before dementia occurs, can be detected in nasal fluid to provide an even earlier warning of the disease process. Studies suggest that a high proportion of older adults who have cognitive impairment are not identified as such, in part due to lack of adequate screening. The study's first author was Penn's Megan Quarmley; the other co-authors were Paul J. Moberg, Dawn Mechanic-Hamilton, Sushila Kabadi, and David A. Wolk, all of Penn, and Steven E. Arnold of Harvard University and Massachusetts General Hospital. Data for this study was collected through the Penn Memory Center. Funding was provided by the National Institute of Mental Health (K01 497 MH102609), National Institute on Aging (P30 AG10124), and the Penn Center of Excellence for Research on Neurodegenerative Diseases. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania(founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.
News Article | October 31, 2016
The distinct structures of toxic protein aggregates that form in degenerating brains determine which type of dementia will occur, which regions of brain will be affected, and how quickly the disease will spread, according to a study from the Peter O'Donnell Jr. Brain Institute. The research helps explain the diversity of dementias linked to tau protein aggregation, which destroys brain cells of patients with Alzheimer's and other neurodegenerative syndromes. The study also has implications for earlier and more accurate diagnoses of various dementias through definition of the unique forms of tau associated with each. "In addition to providing a framework to understand why patients develop different types of neurodegeneration, this work has promise for the development of drugs to treat specific neurodegenerative diseases, and for how to accurately diagnose them. The findings indicate that a one-size-fits-all strategy for therapy may not work, and that we have to approach clinical trials and drug development with an awareness of which forms of tau we are targeting," said study author Dr. Marc Diamond, founding Director of the Center for Alzheimer's and Neurodegenerative Diseases, and Professor of Neurology and Neurotherapeutics with the O'Donnell Brain Institute at UT Southwestern Medical Center. Researchers used special cell systems to replicate distinct tau aggregate conformations. These different forms of pathological tau were then inoculated into the brains of mice. Each form created different pathological patterns, recapitulating the variation that occurs in diseases such as Alzheimer's, frontotemporal dementias, and traumatic encephalopathy. The different forms of tau caused pathology that spread at different rates through the brain, and affected specific brain regions. This experiment demonstrated that the structure of pathological tau aggregates alone is sufficient to account for most if not all the variation seen in human neurodegenerative diseases that are linked to this protein. The finding, published in Neuron, could have a notable impact on widespread efforts at the O'Donnell Brain Institute and elsewhere to develop treatments that eliminate tau and other toxic proteins from the brains of dementia patients. "The challenge for us now is to figure out how to rapidly and efficiently determine the forms of tau that are present in individual patients, and simultaneously, to develop specific therapies. This work says that it should be possible to predict patterns of disease in patients and responses to therapy based on knowledge of tau aggregate structure," said Dr. Diamond, who holds the Distinguished Chair in Basic Brain Injury and Repair. Dr. Diamond's lab, at the forefront of many notable findings relating to tau, had previously determined that tau acts like a prion -- an infectious protein that can self-replicate and spread like a virus through the brain. The lab has determined that tau protein in human brain can form many distinct strains, or self-replicating structures, and developed methods to reproduce them in the laboratory. This research led Dr. Diamond's team to the latest study to test whether these strains might account for different forms of dementia. To make this link, 18 distinct tau aggregate strains were replicated in the lab from human neurodegenerative disease brain samples, or were created from mouse models or other artificial sources. Researchers inoculated the strains into different brain regions of mice and found striking differences among them. While some strains had far reaching and rapid effects, others replicated only in limited parts of the brain, or caused widespread disease but did so very slowly. This surprising result answered a fundamental question that has dogged the field of neurodegenerative disease: Why are brain regions vulnerable in certain cases but not others, and why do some diseases progress more rapidly than others? For instance, in Alzheimer's disease, problems begin in brain memory centers before spreading to other areas that control functions such as language. Conversely, due to initial degeneration of frontal and temporal brain regions in frontotemporal dementia, the memory centers are relatively spared, and patients often first show changes in personality and behavior. The new study implies that with knowledge of tau aggregate structure in patients, or possibly even in healthy individuals, it should be possible to predict the brain regions most vulnerable to degeneration and the rate of disease progression. The study was funded by the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, National Institute on Aging, the Tau Consortium, and the Cure Alzheimer's Fund. At UT Southwestern the work was facilitated with help from the Neuro-Models Facility, Whole Brain Microscopy Facility, and the Moody Foundation Flow Cytometry Facility.
News Article | October 28, 2016
DALLAS - Oct.28, 2016 - The distinct structures of toxic protein aggregates that form in degenerating brains determine which type of dementia will occur, which regions of brain will be affected, and how quickly the disease will spread, according to a study from the Peter O'Donnell Jr. Brain Institute. The research helps explain the diversity of dementias linked to tau protein aggregation, which destroys brain cells of patients with Alzheimer's and other neurodegenerative syndromes. The study also has implications for earlier and more accurate diagnoses of various dementias through definition of the unique forms of tau associated with each. "In addition to providing a framework to understand why patients develop different types of neurodegeneration, this work has promise for the development of drugs to treat specific neurodegenerative diseases, and for how to accurately diagnose them. The findings indicate that a one-size-fits-all strategy for therapy may not work, and that we have to approach clinical trials and drug development with an awareness of which forms of tau we are targeting," said study author Dr. Marc Diamond, founding Director of the Center for Alzheimer's and Neurodegenerative Diseases, and Professor of Neurology and Neurotherapeutics with the O'Donnell Brain Institute at UT Southwestern Medical Center. Researchers used special cell systems to replicate distinct tau aggregate conformations. These different forms of pathological tau were then inoculated into the brains of mice. Each form created different pathological patterns, recapitulating the variation that occurs in diseases such as Alzheimer's, frontotemporal dementias, and traumatic encephalopathy. The different forms of tau caused pathology that spread at different rates through the brain, and affected specific brain regions. This experiment demonstrated that the structure of pathological tau aggregates alone is sufficient to account for most if not all the variation seen in human neurodegenerative diseases that are linked to this protein. The finding, published in Neuron, could have a notable impact on widespread efforts at the O'Donnell Brain Institute and elsewhere to develop treatments that eliminate tau and other toxic proteins from the brains of dementia patients. "The challenge for us now is to figure out how to rapidly and efficiently determine the forms of tau that are present in individual patients, and simultaneously, to develop specific therapies. This work says that it should be possible to predict patterns of disease in patients and responses to therapy based on knowledge of tau aggregate structure," said Dr. Diamond, who holds the Distinguished Chair in Basic Brain Injury and Repair. Dr. Diamond's lab, at the forefront of many notable findings relating to tau, had previously determined that tau acts like a prion - an infectious protein that can self-replicate and spread like a virus through the brain. The lab has determined that tau protein in human brain can form many distinct strains, or self-replicating structures, and developed methods to reproduce them in the laboratory. This research led Dr. Diamond's team to the latest study to test whether these strains might account for different forms of dementia. To make this link, 18 distinct tau aggregate strains were replicated in the lab from human neurodegenerative disease brain samples, or were created from mouse models or other artificial sources. Researchers inoculated the strains into different brain regions of mice and found striking differences among them. While some strains had far reaching and rapid effects, others replicated only in limited parts of the brain, or caused widespread disease but did so very slowly. This surprising result answered a fundamental question that has dogged the field of neurodegenerative disease: Why are brain regions vulnerable in certain cases but not others, and why do some diseases progress more rapidly than others? For instance, in Alzheimer's disease, problems begin in brain memory centers before spreading to other areas that control functions such as language. Conversely, due to initial degeneration of frontal and temporal brain regions in frontotemporal dementia, the memory centers are relatively spared, and patients often first show changes in personality and behavior. The new study implies that with knowledge of tau aggregate structure in patients, or possibly even in healthy individuals, it should be possible to predict the brain regions most vulnerable to degeneration and the rate of disease progression. The study was funded by the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, National Institute on Aging, the Tau Consortium, and the Cure Alzheimer's Fund. At UT Southwestern the work was facilitated with help from the Neuro-Models Facility, Whole Brain Microscopy Facility, and the Moody Foundation Flow Cytometry Facility. DALLAS - Recent efforts to develop a treatment for Alzheimer's disease and other dementias have focused heavily on removing toxic proteins from the brain. Here's a look at the tau protein and what we know about its role in the progression of dementia. A. The tau protein is known to bind microtubules in neurons. These structures enable transport of cellular components. But the protein becomes toxic in patients with Alzheimer's and other dementias, forming aggregates that progressively accumulate and lead to loss of neuron function and eventually to neurodegeneration. Q. How does tau spread in Alzheimer's patients? A. When the tau protein begins to form aggregates, it is toxic to neurons. It is unknown how these aggregates can escape cells. They may be released from living cells, or they may rupture the cell after causing its death. Once outside of cells the aggregates can be taken up by nearby cells. Once inside, they cause normal tau to begin to aggregate, and the process repeats itself. Remarkably, tau aggregates, which are highly ordered assemblies, can have different structures that will be precisely replicated over time within cells. These structures are referred to as "strains." A new study from the Peter O'Donnell Jr. Brain Institute shows the three-dimensional structure of a tau aggregate will determine which neurons are vulnerable to it, how readily it will create more pathology, and how quickly it will spread throughout the brain. A. Although no cure has been found for Alzheimer's or other dementias, many researchers believe removing toxic tau aggregates can help slow or stop the deterioration of the brain. Consequently, this is now a focus of drug development for most of the major pharmaceutical companies. Amyloid beta is another protein that also builds up in the brains of patients with Alzheimer's disease, and is thought to cause the accumulation of tau. Many clinical trials are now underway to test the protective effects of drugs designed to prevent the accumulation of each protein. It is hoped that they will slow or prevent cognitive decline. Q. How can people prevent tau from turning toxic? A. Scientists aren't sure, but since there is not yet a specific therapy, many believe the best course is to reduce the risk factors for dementia, which include high blood pressure, cholesterol and a sedentary lifestyle. Studies have shown cardiovascular health somehow affects the brain and that healthy diet and regular exercise can reduce the incidence of toxic protein buildup. An ongoing national study led by the O'Donnell Brain Institute is testing the combination of cholesterol-lowering medication and exercise on preserving brain function. UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. The faculty of almost 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in about 80 specialties to more than 100,000 hospitalized patients and oversee approximately 2.2 million outpatient visits a year. This news release is available on our website at http://www. . To automatically receive news releases from UT Southwestern via email, subscribe at http://www.
News Article | November 10, 2016
There are not a lot of things that could bring together people as far apart on the US political spectrum as Republican Newt Gingrich and Democrat Bob Kerrey. But in 2007, after leading a three-year commission that looked into the costs of care for elderly people, the political rivals came to full agreement on a common enemy: dementia. At the time, there were fewer than 30 million people worldwide diagnosed with the condition, but it was clear that the numbers were set to explode. By 2050, current predictions suggest, it could reach more than 130 million, at which point the cost to US health care alone from diseases such as Alzheimer’s will probably hit US$1 trillion per year in today’s dollars. “We looked at each other and said, ‘You know, if we don’t get a grip on Alzheimer’s, we can’t get anything done because it’s going to drown the system,’” recalls Gingrich, the former speaker of the US House of Representatives. He still feels that sense of urgency, and for good reason. Funding has not kept pace with the scale of the problem; targets for treatments are thin on the ground and poorly understood; and more than 200 clinical trials for Alzheimer’s therapies have been terminated because the treatments were ineffective. Of the few treatments available, none addresses the underlying disease process. “We’re faced with a tsunami and we’re trying to deal with it with a bucket,” says Gingrich. But this message has begun to reverberate around the world, which gives hope to the clinicians and scientists. Experts say that the coming wave can be calmed with the help of just three things: more money for research, better diagnostics and drugs, and a victory — however small — that would boost morale. “What we really need is a success,” says Ronald Petersen, a neurologist at Mayo Clinic in Rochester, Minnesota. After so many failures, one clinical win “would galvanize people’s interest that this isn’t a hopeless disorder”. Dementia is the fifth-biggest cause of death in high-income countries, but it is the most expensive disease to manage because patients require constant, costly care for years. And yet, research funding for dementia pales in comparison with that for many other diseases. At the US National Institutes of Health (NIH), for example, annual funding for dementia in 2015 was only around $700 million, compared with some $2 billion for cardiovascular disease and more than $5 billion for cancer. One problem is visibility. Other disease communities — most notably, people affected by breast cancer and HIV/AIDS — have successfully advocated for large pots of dedicated research funding. But “there simply wasn’t any comparable upswell of attention to Alzheimer’s”, says George Vradenburg, chair and co-founder of UsAgainstAlzheimer’s, a non-profit organization in Chevy Chase, Maryland. The biggest reason, he says, is that “the victims of the disease hide out”. Dementia mostly affects elderly people and is often misconstrued as a normal part of ageing; there is a stigma attached to the condition, and family care-givers are often overworked and exhausted. Few are motivated enough to speak up. However, social and political awareness has increased in the past five years. “We all started to work together a lot more, and that helps,” says Susan Peschin, chief executive at the Alliance for Aging Research in Washington DC, one of more than 50 non-profit groups in the Accelerate Cure/Treatments for Alzheimer’s Disease coalition. The impact can be seen in government investments. France took action first, creating a national plan for Alzheimer’s in 2008 that included €200 million (US$220 million) over five years for research. In 2009, the German Centre for Neurodegenerative Diseases in Bonn was created with a €66-million annual budget. And UK spending on dementia research more than doubled between 2010 and 2015, to £66 million (US$82 million). The European Union has been dishing out tens of millions of euros each year for dementia studies through the Innovative Medicines Initiative and the Joint Programming process, and Australia is now about halfway through doling out its Aus$200-million (US$150-million), five-year dementia-research fund. “This is a global challenge, and no one country will be able to solve the problem,” says Philippe Amouyel, a neurologist and geneticist at the University Hospital of Lille in France. Yet it’s the United States that has been the biggest backer by far, thanks in part to efforts by Gingrich and Kerrey. The NIH’s annual budget for Alzheimer’s and other dementias jumped in the past year to around $1 billion, and there is support for a target to double that figure in the next few years — even in the fractious US political landscape. “Alzheimer’s doesn’t care what political party you’re in,” says Kerrey. Two billion dollars is “a reasonable number”, says Petersen, who chairs the federal advisory board that came up with the target in 2012. Now, he adds, the research community just needs to work out “what are we going to do with it if in fact we get it?”. The answer could depend in large part on the fate of a drug called solanezumab, developed by Eli Lilly of Indianapolis, Indiana. This antibody-based treatment removes the protein amyloid-β, which clumps together to form sticky plaques in the brains of people with Alzheimer’s. By the end of this year, Lilly is expected to announce the results of a 2,100-person clinical trial testing whether the drug can slow cognitive decline in people with mild Alzheimer’s. It showed preliminary signs of cognitive benefit in this patient population in earlier trials (R. S. Doody et al. N. Engl. J. Med. 370, 311–321; 2014), but the benefits could disappear in this final stage of testing, as has happened for practically every other promising compound. No one is expecting a cure. If solanezumab does delay brain degradation, at best it might help people to perform 30–40% better on cognitive tests than those on a placebo. But even such a marginal gain would be a triumph. It would show scientists and the drug industry that a disease-modifying therapy is at least possible. By contrast, another setback could bring recent momentum in therapeutic development to a halt. “This is a fork in the road,” says John Hardy, a neurogeneticist at University College London. “This is going to be a very important outcome, way beyond the importance for Lilly and this particular drug.” On a scientific level, success for solanezumab could lend credence to the much-debated amyloid hypothesis, which posits that the build-up of amyloid-β in the brain is one of the triggers of Alzheimer’s disease. The previous failure of amyloid-clearing agents led many to conclude that plaques were a consequence of a process in the disease, rather than the cause of it. But those in favour of the amyloid hypothesis say that the failed drugs were given too late, or to people with no amyloid build-up — possibly those with a different form of dementia. For its latest solanezumab trial, Lilly sought out participants with mild cognitive impairment, and used brain scans and spinal-fluid analyses to confirm the presence of amyloid-β in their brains. Another company, Biogen in Cambridge, Massachusetts, took the same approach to screening participants in a trial of its amyloid-targeting drug aducanumab. Earlier this year, a 165-person study reported early signs that successfully clearing amyloid-β with the Biogen therapy correlated with slower cognitive decline (J. Sevigny et al. Nature 537, 50–56; 2016). If those results hold up to further scrutiny, “that will at least tell us that amyloid is sufficiently upstream in the cascade that it deserves being targeted and tackled pharmacologically”, says Giovanni Frisoni, a clinical neuroscientist at the University of Geneva in Switzerland who is involved in the drug’s testing. Although debate over the amyloid hypothesis continues, interest is growing in earlier intervention with drugs that clear the protein. Reisa Sperling, a neurologist at Brigham and Women’s Hospital in Boston, Massachusetts, worries that even mild dementia is a sign of irreparable brain-cell death. “You can suck all the amyloid out of the brain or stop it from further accumulating, but you’re not going to grow those neurons back.” That is why she is leading Anti-Amyloid Treatment in Asymptomatic Alzheimer’s, or A4, a $140-million, placebo-controlled solanezumab study that aims to treat people with elevated amyloid levels before they show any signs of cognitive impairment. And A4 is not her only trial. In March, she and neurologist Paul Aisen of the University of Southern California’s Alzheimer’s Therapeutic Research Institute in San Diego launched a trial in 1,650 asymptomatic people with early signs of amyloid-β build-up. It will test a pill from Johnson & Johnson that blocks β-secretase, an enzyme responsible for producing the toxic protein. These interventions are known as secondary prevention because they target people who are already developing amyloid plaques. Sperling and Aisen also plan to test what’s called primary prevention. In August, they received NIH funding to start treating people who have normal brain levels of amyloid-β and no signs of cognitive decline, but who have a high risk of developing Alzheimer’s — because of a combination of factors such as age and genetics. “The biggest impact we can have is in delaying the onset of the diseases,” says David Holtzman, a neurologist at Washington University School of Medicine in St. Louis, Missouri, and an investigator in the Dominantly Inherited Alzheimer Network, which is testing the benefits of giving either solanezumab or another anti-amyloid therapy to people who inherit gene mutations that predispose them to develop Alzheimer’s at an early age. Secondary prevention could eventually mean screening everyone past middle age for signs of amyloid-β, although the current testing methods are either expensive ($3,000 brain scans) or invasive (spinal taps). Researchers have flagged a dozen possible blood-based biomarkers, but none has yet panned out, says Dennis Selkoe, a Brigham and Women’s Hospital neurologist. Yet a cheap and easy diagnostic test for amyloid-β could ultimately prove unnecessary. In the same way that some have suggested giving cholesterol-lowering drugs to anyone at risk of heart disease, clinicians might eventually give anti-amyloid drugs to a broad set of people prone to Alzheimer’s — even if they are not already amyloid positive, says Sperling. Just as cholesterol is not the sole cause of heart disease, amyloid-β is not the only driver of Alzheimer’s. There’s also tau, a protein that causes tangles in the brains of most people with Alzheimer’s. Several pharmaceutical companies are targeting tau, but few large drug-makers have clinical candidates directed at other types of target. “They know how to modulate a specific target and keep looking under that lamp post, rather than venturing away from their comfort zones,” says Bernard Munos, an industry consultant and former Eli Lilly executive. That’s a problem, says Howard Fillit, chief science officer of the Alzheimer’s Drug Discovery Foundation in New York City. “We really need to increase the diversity of targets we’re tackling.” After amyloid and tau, the only target receiving much attention from researchers is neuroinflammation — the “third leg of the stool” in treating Alzheimer’s, according to neurogeneticist Rudy Tanzi at Massachusetts General Hospital in Boston. He likens Alzheimer’s disease to a wildfire in the brain. Plaques and tangles provide the initial brush fires, but it’s the accompanying neuroinflammation that fans the flames. Once the blaze is raging, Tanzi says, “putting out those brush fires that got you there isn’t good enough”. This could explain why anti-amyloid drugs failed when given to people with full-blown dementia. For these individuals, perhaps reducing the inflammatory activity of brain immune cells called microglia could help. Drug researchers are now focusing on two genes, CD33 and TREM2, that are involved in microglial function. But, says Tanzi, “there are two dozen other genes that deserve attention. Who knows if one of these new genes that no one is working on might lead to drug clues?” Many Alzheimer’s experts emphasize the need to develop better low-cost interventions that don’t require drug research. At the University of New South Wales in Sydney, Australia, for example, geriatric psychiatrist Henry Brodaty is testing whether an Internet coaching tool that focuses on diet, exercise, cognitive training and mood can postpone disease development. “We know that two-thirds of the world’s dementia is going to be in developing countries,” he says (see ‘The approaching wave’). Lifestyle interventions, he argues, could be more broadly scalable than expensive drugs. Researchers also need to look beyond Alzheimer’s, to the many other types of dementia. Injuries to the vessels that supply blood to the brain cause a form called vascular dementia. Clumps of a protein called α-synuclein underlie cognitive problems in people with Parkinson’s disease and also what’s called Lewy body dementia. Tau deposits are often behind the nerve-cell loss responsible for frontotemporal dementia. And there are many other, equally devastating, drivers of serious mental decline. “We should not be ignoring these other diseases,” says Nick Fox, a neurologist at University College London, especially given that many types of dementia share biological mechanisms. Tackling one disease could help inform treatment strategies for another. But perhaps the biggest hindrance to drug development today is more logistical than scientific, with clinical trials for dementia taking years to complete as investigators struggle to recruit sufficient numbers of study participants. “We need to get answers more quickly,” says Marilyn Albert, director of the Johns Hopkins Alzheimer’s Disease Research Center in Baltimore, Maryland. One solution is trial-ready registries. By enrolling people who are interested in taking part in a study before it actually exists, investigators can start a trial as soon as a drug comes along for testing. “We have to register humanity in the task of defeating this disease,” says Aisen. The 1,600-person COMPASS-ND registry is being funded through the Canadian Consortium on Neurodegeneration in Aging. Member Serge Gauthier, a neurologist at McGill University in Montreal, says that finding participants can be challenging. But he adds that around one-third of the people who come to memory clinics such as his have what’s known as subjective cognitive impairment — they might forget names or suffer from other ‘senior moments’, but they do not meet the clinical definition of dementia. They are perfect for trial-ready registries, says Gauthier: they are at an elevated risk of the disease, and they’ve demonstrated concern. Gauthier wants to find more people like them. He fits the profile himself, so he joined the Brain Health Registry, which has more than 40,000 participants so far and is led by researchers at the University of California, San Francisco. He takes regular cognitive tests, and could be asked to do more once potential diagnostic tools or therapies are ready for testing. “It’s a fun thing to do,” he says. Voluntarily or not, people will need to face up to dementia, because in just a few short decades, pretty much everyone is going to have a friend or loved one affected by the disease. It’s an alarming idea, and it should spur action, says Robert Egge, chief public policy officer of the Alzheimer’s Association in Chicago, Illinois. “We know where we’re heading,” he says. “The question is: are we going to get in front of it or not?”
News Article | April 20, 2016
An hour's drive from Kunming in southwestern China, past red clay embankments and sprawling forests, lies an unusual zoo. Inside the gated compound is a quiet, idyllic campus; a series of grey, cement animal houses stack up on the lush hillside, each with a clear plastic roof to let in the light. This is the Yunnan Key Laboratory of Primate Biomedical Research, and its inhabitants are some 1,500 monkeys, all bred for research. The serenity of the facility belies the bustle of activity within. Since it opened in 2011, this place has quickly become a Mecca for cutting-edge primate research, producing valuable disease models and seminal publications that have made its director, Ji Weizhi, a sought-after collaborator. Its campus houses a collection of gene-edited monkeys that serve as models of Duchenne muscular dystrophy, autism and Parkinson's disease. Ji plans to double the number of group leaders working there from 10 to 20 in the next 3 years, and to seek more international collaborations — he already works with scientists in Europe and the United States. “In terms of a technology platform, Ji is just way ahead,” says one collaborator, cardiologist Kenneth Chien at the Karolinska Institute in Stockholm. Ji is not alone in his ambitions for monkey research. With support from central and local governments, high-tech primate facilities have sprung up in Shenzhen, Hangzhou, Suzhou and Guangzhou over the past decade. Last month, the science ministry approved the launch of a facility at the Kunming Institute of Zoology that is expected to cost millions of dollars to build. These centres can provide scientists with monkeys in large numbers, and offer high-quality animal care and cutting-edge equipment with little red tape. A major brain project, expected to be announced in China soon, will focus much of its efforts on using monkeys to study disease. The enthusiasm stands in stark contrast to the climate in the West, where non-human-primate research is increasingly stymied by a tangle of regulatory hurdles, financial constraints and bioethical opposition. Between 2008 and 2011, the number of monkeys used in research in Europe declined by 28%, and some researchers have stopped trying to do such work in the West. Many have since sought refuge for their experiments in China by securing collaborators or setting up their own laboratories there. Some of the Chinese centres are even advertising themselves as primate-research hubs where scientists can fly in to take advantage of the latest tools, such as gene editing and advanced imaging. “It could be like CERN in Switzerland, where they set up a large facility and then people come from all over the world to get data,” says Stefan Treue, a neuroscientist who heads the German Primate Center in Göttingen, Germany. With China fast becoming a global centre for primate research, some scientists fear that it could hasten the atrophy of such science in the West and lead to a near monopoly, in which researchers become over-reliant on one country for essential disease research and drug testing. “Governments and politicians don't see this, but we face a huge risk,” says Erwan Bezard, who is director of the Institute of Neurodegenerative Diseases at the University of Bordeaux in France, and has set up his own primate-research company, Motac, in Beijing. Europe and the United States still have the lead in primate research, he says, but this could change as expertise migrates eastwards. “China will become the place where all therapeutic strategies will have to be validated. Do we want that? Or do we want to stay in control?” For decades, researchers have relied on monkeys to shed light on brain function and brain disease because of their similarity to humans. Growth in neuroscience research has increased demand, and although high costs and long reproductive cycles have limited the use of these animals in the past, new reproductive technologies and genetic-engineering techniques such as CRISPR–Cas9 are helping researchers to overcome these drawbacks, making monkeys a more efficient experimental tool. China has an abundance of macaques — the mainstay of non-human-primate scientific research. Although the population of wild rhesus macaques (Macaca mulatta) has declined, the number of farmed animals has risen. According to data from the Chinese State Forestry Administration, the number of businesses breeding macaques for laboratory use rose from 10 to 34 between 2004 and 2013, and the quota of animals that those companies could sell in China or overseas jumped from 9,868 to 35,385 over that time. Farm populations of marmosets, another popular research animal, are also on the rise. Most monkeys are shipped to pharmaceutical companies or researchers elsewhere in the world, but the growing appreciation among scientists of monkey models has prompted investment by local governments and private companies in dedicated research colonies. The country's 2011 five-year plan singled out primate disease models as a national goal; the science ministry followed up by pumping 25 million yuan (US$3.9 million) into the endeavour in 2014. Scientists visiting China are generally pleased with the care given to animals in these facilities, most of which have, or are trying to get, the gold-standard recognition of animal care — accreditation by AAALAC International. Ji's Yunnan Key Laboratory is the most active primate facility, but others are giving it competition. The new monkey facility at the Kunming Institute of Zoology was funded as part of the national development scheme for big science equipment that includes telescopes and supercomputers. The money will help the institute to double its colony of 2,500 cynomolgus monkeys (Macaca fascicularis) and rhesus macaques. Zhao Xudong, who runs the primate-research facility, says that the plan is to “set it up like a hospital, with separate departments for surgery, genetics and imaging”, and a conveyer belt to move monkeys between departments. There will be systems for measuring body temperature, heart rate and other physiological data, all to analyse the characteristics, or 'phenotypes', of animals, many of which will have had genes altered. “We are calling it the 'genotype versus phenotype analyser',” says Zhao. It will take ten years to finish, but he hopes to begin building this year and to start research within three. Other facilities, although smaller, are also expanding and diversifying. The Institute of Neuroscience in Shanghai plans to increase its population of 600 Old World monkeys to 800 next year and expand its 300-strong marmoset colony. Outside China, the numbers are heading in the opposite direction. Harvard Medical School closed its affiliated primate facility in May 2015 for 'strategic' reasons. Last December, the US National Institutes of Health decided to phase out non-human-primate experiments at one of its labs and subsequently announced that it would review all non-human-primate research that it funds. In Europe, researchers say, the climate is also growing colder for such research. Costs are a major disincentive. In 2008, Li Xiao-Jiang, a geneticist at Emory University in Atlanta, Georgia, helped to create the world's first transgenic monkey model of Huntington's disease1 with colleagues at Yerkes National Primate Research Centre. But Li says that it costs $6,000 to buy a monkey in the United States, and $20 per day to keep it, whereas the corresponding figures in China are $1,000 and $5 per day. “Because the cost is higher, you have to write a bigger grant, and then the bar will be higher when they judge it,” says Li. Funding agencies “really do not encourage large-animal research”. For Li, the solution was simple: go to China. He now has a joint position at the Institute of Genetics and Developmental Biology in Beijing, where he has access to around 3,000 cynomolgus monkeys at a farm in Guangzhou and some 400 rhesus monkeys at the Chinese Academy of Medical Sciences' monkey facility in Beijing. He has churned out a series of publications on monkeys with modified versions of the genes involved in Duchenne muscular dystrophy2 and Parkinson's disease3. Neuroscientist Anna Wang Roe says that red tape drove her to China. Roe's team at Vanderbilt University in Nashville, Tennessee, is attempting to work out how modules in the brain are connected, and she estimates that she and her colleagues have spent 25% of their time and a good deal of cash documenting the dosage and delivery-method for each drug they administered to their monkeys, as required by regulations. “We record something every 15 minutes,” she says. “It's not that it's wrong. It's just enormously time-consuming.” In 2013, impressed by the collaborative atmosphere at Zhejiang University in Hangzhou, she proposed that it build a neuroscience institute. The next day the university agreed, and she soon had a $25-million, 5-year budget. “Once the decision is made, you can start writing cheques,” she says. She is now closing her US laboratory to be the director of the Zhejiang Interdisciplinary Institute of Neuroscience and Technology, where she hopes to open a suite of the latest brain-analysis tools, including a powerful new 7-tesla functional magnetic resonance imaging device that she says will give images of the primate brain at unprecedented resolution. Bob Desimone was similarly impressed with the speed at which China moves. As a neuroscientist who heads the McGovern Institute for Brain Research at the Massachusetts Institute of Technology in Cambridge, in January 2014, he had a 'meet and greet' with the mayor of Shenzhen. In March, the mayor donated a building on the Shenzhen Institute of Advanced Technology campus for a monkey-research facility, and the centre's soon-to-be director, Liping Wang, promised that it would be ready by summer. Thinking that impossible, Desimone bet two bottles of China's prized mind-numbing liquor, maotai, that it wouldn't be done in time. He lost. The group raised most of the $10 million needed from city development grants, along with a small input from McGovern, and soon the first animals were being installed in the Brain Cognition and Brain Disorder Research Institute. “This place just makes things happen quickly,” Desimone says. But money and monkeys alone are not enough to lead to discovery. Researchers say that China is short on talented scientists to take advantage of the opportunities provided by animal research. That's why the organizers of the country's new primate centres hope to attract an influx of foreigners to permanent posts or as collaborators. So far, many of those moving to China have been Chinese or foreigners with a previous connection to the country, but others are expressing interest, says neuroscientist Guoping Feng, also at the McGovern Institute. Already, the Shenzhen primate centre has recruited from Europe and the United States, and Desimone says that it will be “an open technology base. Anyone who wants to work with monkeys can come.” The rapid spread of CRISPR–Cas9 and TALEN gene-editing tools is likely to accelerate demand for monkey research: they are turning the genetic modification of monkeys from a laborious and expensive task into a relatively quick, straightforward one. Unlike engineered mice, which can be bred and sent around the world, “monkeys are difficult to send, so it will be easier for the PI or postdoc to go there”, says Treue. Already, competition is fierce as researchers are racing for the low-hanging fruit — engineering genes with established roles in human disease or development. Almost all reports of gene-edited monkeys produced with these techniques have come from China. Desimone predicts that the pursuit of monkey disease models “could give China a unique niche to occupy in neuroscience”. The cages of Ji's facility are already full of the products of gene editing. One troop of animals has had a mutation genetically engineered into the MECP2 gene, which has been identified as the culprit in humans with Rett's syndrome, an autism spectrum disorder. An animal sits listless and unresponsive, holding tight to the bars of the cage as her normal twin sister crawls all over her. In another cage, a monkey with the mutation pumps its arm, reminiscent of repetitive behaviour seen in the human disorder. Some incessantly suck their thumbs. “I've never seen that in a monkey before — never so constant,” says Ji. Among the range of other disease models in Ji's menagerie are monkey versions of cardiovascular disease, which he is working on in collaboration with the Karolinska Institute. And last year, Ji made the world's first chimeric monkeys using embryonic stem cells4, an advance that could make the production of genetically modified animals even easier. The question now is whether these genetically modified monkeys will propel understanding of human brain function and dysfunction to a higher level. “You can't just knock out one gene and be sure you'll have human-like disease phenotype,” says Ji. Researchers see an opportunity to understand human evolution as well as disease. Su Bing, a geneticist at the Kunming Institute of Zoology, is working with Ji to engineer monkeys that carry the human version of a gene called SRGAP2, which is thought to endow the human brain with processing power by allowing the growth of connections between neurons. Su also plans to use CRISPR–Cas9 to introduce human versions of MCPH1, a gene related to brain size, and the human FOXP2 gene, which is thought to give humans unique language ability. “I don't think the monkey will all of a sudden start speaking, but will have some behavioural change,” predicts Su. Although the opportunities are great, there are still obstacles for scientists who choose to locate their animal research in China. Trying to keep a foot in two places can be challenging, says Grégoire Courtine, a spinal-cord-injury researcher based at the Swiss Federal Institute of Technology in Lausanne, who travels almost monthly to China to pursue his monkey research at Motac. He has even flown to Beijing, done a couple of operations on his experimental monkeys, then returned that night. “I'm 40 years old, I have energy in my body. But you need to really will it,” he says. Another downside, says Li, is that policies can change suddenly in China. “There is uncertainty. That makes us hesitate to commit,” says Li, who has retained his post at Emory University. And the immunity that China's primate researchers have had to animal-rights activism could start to erode, warns Deborah Cao, who researches law at Griffith University in Brisbane, Australia, and last year published a book on the use of animals in China5. People are starting to use Chinese social-media sites to voice outrage at the abuse of animals, Cao says. China has competition in its bid to dominate primate research, too. Japan has launched its own brain project focused on the marmoset as a model: the animal reaches sexual maturity in a year and a half, less than half the time it takes a macaque. Some research facilities in China are now building marmoset research colonies — but Japan is considered to be several years ahead. And some researchers want to ensure that such work continues outside Asia. Courtine says that he's “fighting to keep alive” a monkey-research programme he has at Fribourg, Switzerland, because he thinks it's important to have a division of labour. “Research that requires quantity, I'll do in China. I would like to do sophisticated work in Fribourg,” he says. Back at his primate centre in Yunnan, Ji is sure that such work is already taking place. His dream, he says is “to have an animal like a tool” for biomedical discovery. He knows there is a lot of competition in this field, especially in China. But he feels confident: “The field is wide, and there are many, many projects we can do.”
News Article | November 30, 2016
A drug that was seen as a major test of the leading theory behind Alzheimer’s disease has failed in a large trial of people with mild dementia. Critics of the ‘amyloid hypothesis’, which posits that the disease is triggered by a build-up of amyloid protein in the brain, have seized on the results as evidence of its weakness. But the jury is still out on whether the theory will eventually yield a treatment. Proponents of the theory note that the particular way in which solanezumab, the drug involved in the trial, works could have led to the failure, rather than a flaw in the hypothesis itself. And many trials are ongoing to test whether solanezumab — or others that target amyloid — could work in people at risk of the disease who have not yet shown symptoms, or even in people with Alzheimer’s, despite the latest negative result. “I’m extremely disappointed for patients, but this, for me, doesn’t change the way I think about the amyloid hypothesis,” says Reisa Sperling, a neurologist at the Brigham and Women’s Hospital in Boston, Massachusetts. She is leading one of several ongoing ‘prevention’ trials that is testing solanezumab, and other drugs that aim to reduce the build-up of amyloid ‘plaques’, in people at risk of developing Alzheimer’s. Solanezumab is an antibody that mops up amyloid proteins from the blood and cerebrospinal fluid. The proteins can go on to form plaques in the brain. Eli Lilly, the company that developed solanezumab, announced on 23 November that it would abandon the drug as a treatment for patients with mild dementia. The outcome adds to a long list of promising Alzheimer’s drugs that have flopped in the clinic, many of which, like solanezumab, targeted amyloid. The Lilly trial, known as EXPEDITION3, involved more than 2,100 people diagnosed with mild dementia due to Alzheimer’s disease. Half received monthly infusions of solanezumab and the other half a placebo. They were followed for 18 months and tested in a range of cognitive tasks. Analysis of people with comparable symptoms in earlier studies of solanezumab had seemed encouraging, but this latest trial indicated only small benefit, not enough to warrant marketing the drug. “We are disappointed for the millions of people waiting for a potential disease-modifying treatment for Alzheimer’s disease,” said Lilly’s chief executive, John Lechleiter, in a statement. At a press conference, the company said that it had spent around US$3 billion on Alzheimer’s research and development in the past 27 years. Lilly has also been running prevention trials to see whether solanezumab might help people at especially high risk of the disease. The company says it will now discuss with its trial partners whether to continue with those. Sperling’s trial is one of these, and tests solanezumab in people who have elevated amyloid levels in the brain but have not shown any symptoms of dementia. “An amyloid therapy has to be started before there’s significant neuronal loss,” she says. Researchers at Washington University in St Louis, Missouri, are also trialling solanezumab, and another similar antibody made by drug company Roche, in people who are currently healthy but are genetically at high risk of developing Alzheimer’s. Meanwhile, the Banner Alzheimer’s Institute in Phoenix, Arizona, is testing the effects of three therapies that target amyloid production, one of which is an antibody, in people at high genetic risk of Alzheimer’s. The Lilly outcome “doesn’t disprove the amyloid hypothesis, and it really increases the importance of these longer prevention trials”, says Eric Reiman, the institute’s executive director and leader of the trials. The latest negative finding, he says, “begs the question: Were we too little too late? And we’ll see.” Lilly’s result may say more about the characteristics of solanezumab than the accuracy of the underlying amyloid hypothesis, says Christian Haass, head of the Munich branch of the German Centre for Neurodegenerative Diseases. The antibody targets soluble forms of amyloid, he points out, so it “could be trapped in the blood without ever reaching the actual target in the brain in sufficient quantities”. Biogen, a company based in Cambridge, Massachusetts, is testing a different antibody called aducanumab, which targets amyloid plaques in the brain. In early clinical testing, the antibody showed signs of clearing amyloid and alleviating memory loss in people with mild Alzheimer's disease; results from phase III trials are expected in 2020. “Until the aducanumab data read out, we have not truly put amyloid to the test,” says Josh Schimmer, a biotechnology analyst at Piper Jaffray in New York City. Still, the negative trial findings have emboldened critics of the amyloid theory, who are weary of its failure to yield a treatment. “The amyloid hypothesis is dead,” says George Perry, a neuroscientist at the University of Texas at San Antonio. “It’s a very simplistic hypothesis that was reasonable to propose 25 years ago. It is not a reasonable hypothesis any longer.” “We’re flogging a dead horse,” adds Peter Davies, an Alzheimer’s researcher at the Feinstein Institute for Medical Research in Manhasset, New York. “There’s no sign of anybody getting better, even for a short period, and that suggests to me that you have the wrong mechanism.” Regardless of what Lilly decides about its other solanezumab trials, the company isn’t giving up on Alzheimer’s. In partnership with AstraZeneca, it is testing an inhibitor of an enzyme involved in the synthesis of amyloid, and is progressing with a handful of early-stage therapies aimed at other Alzheimer’s targets.
News Article | December 22, 2016
BORDEAUX, France/ December 22, 2016 - A French observational study in real life showed that dementia patients benefiting from occupational therapy sessions report relevant clinical benefits over the intervention period, according to a research study published in the Journal of Alzheimer's Disease this month. The research suggested the influence of occupational therapy on reducing behavioral troubles, caregivers' burden and amount of informal care over the intervention period and a stabilization over the 3-months period thereafter. France put a massive effort for improving dementia care through a national Alzheimer plan in 2008 and this effort was confirmed by the next government (Neurodegenerative Diseases Plan 2014-2019). Some new care models and interventions have been implemented such as integrated care, case management or occupational therapy. Occupational therapy has been spread nationwide through specialized Alzheimer team intervening at home with medical prescription. Even if efficacy of occupational therapy has been demonstrated in some clinical trials, its efficacy under routine care conditions was unknown and deserved to be investigated. The research was conducted on a network of 16 specialized Alzheimer team in Aquitaine, South West of France and was supported by the regional agency of Health (Agence Régionale de la Santé d'Aquitaine). Titled "Benefits of Occupational Therapy in Dementia Patients: Findings from a Real-World Observational Study," the study included 421 dementia patient who had been referred to occupational therapy by their general practionner or memory clinics and who had been followed up to 6 months. Research studied the clinical evolution of patients between inclusion and 3 month follow-up (end of the 15 home sessions) and between 3 and 6-month follow-up (no session planned over this timeframe). The study's results indicate that behavioral troubles, caregivers' burden, amount of informal care provided by caregivers and patients' quality of life were significantly reduced over the 3-month intervention period and remained stable thereafter. Cognitive performances remained stable over the 6-month study period and functional performances remained stable over the 3-month intervention period but were significantly reduced thereafter. Moreover, patients who had been diagnosed more recently and those with milder cognitive deficits may gain more benefits from occupational therapy in terms of functional decline or caregivers' burden decline. These findings suggest that occupational therapy should target early dementia stages in order to optimize its potential clinical benefits. In many Western countries, recent national guidelines have aimed at improving home dementia care. This study highlights the potential occupational therapy in terms of patients' and their caregivers' well-being. The findings also opens a new field of research on occupational therapy. Indeed, occupational therapy has been conceptualized as a short-term home intervention, but long-term benefits and consequences of disruption are unknown. "Future studies should explore more in detail which sub-groups of patients could gain more benefits from OT as well as its long-term clinical effects notably on global care quality and users' satisfaction" stated Clément Pimouguet. Moreover, strategies aiming to improve initial benefits of occupational therapy should be promoted. The French research team will conduct a randomized trial that aim to compare the maintenance of occupational therapy over an additional 4-month period and usual occupation therapy as recommended.
News Article | September 12, 2016
Our brains contain a surprising diversity of DNA. Even though we are taught that every cell in our body has the same DNA, in fact most cells in the brain have changes to their DNA that make each neuron a little different. Now researchers at the Salk Institute and their collaborators have shown that one source of this variation--called long interspersed nuclear elements or L1s--are present in 44 to 63 percent of healthy neurons and can not only insert DNA but also remove it. Previously, these L1s were known to be small bits of DNA called "jumping genes" that copy and paste themselves throughout the genome, but the researchers found that they also cause large deletions of entire genes. What's more, such variations can influence the expression of genes that are crucial for the developing brain. The findings, published September 12, 2016 in the journal Nature Neuroscience, may help explain what makes us each unique--why even identical twins can be so different from one other, for example--and how jumping genes can go awry and cause disease. "In 2013, we discovered that different neurons within the same brain have various complements of DNA, suggesting that they function slightly differently from each other even within the same person," says the study's senior investigator Rusty Gage, a professor in Salk's Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases. "This recent study reveals a new and surprising form of variation that will help us understand the role of L1s, not only in healthy brains but in those affected by schizophrenia and autism." In 2005, Gage's team discovered L1s as a mechanism of genome diversity in the brain. However, it was not until it became possible to sequence the entire genome of a single cell that scientists could get a handle on the amount and nature of these variations. Using single-cell sequencing detailed in a 2013 Science paper, Gage's group showed that large chunks of DNA were inserted--or deleted--into the genomes of the cells. But even in that study the mechanisms responsible for causing insertions and deletions were unclear, making it difficult to decipher whether specific regions of the genome were more or less likely to be altered, as well as whether jumping genes were related to the deletions. In the new study, Gage, co-first authors Jennifer Erwin and Apuã Paquola, and collaborators developed a method to better capture the L1-associated variants in healthy neurons for sequencing and created a computational algorithm to distinguish the variations with greater accuracy than before. Using stem cells that are coaxed to differentiate into neurons in a dish, the team found that L1s are prone to DNA breaks. That's because a specific enzyme that chews through L1 spots in the genome is particularly active during differentiation. People inherit some L1s from their parents, and the enzyme appears to cut near these spots, the group found. "The surprising part was that we thought all L1s could do was insert into new places. But the fact that they're causing deletions means that they're affecting the genome in a more significant way," says Erwin, a staff scientist in Gage's group. Gage believes that diversity can be good for the brain--after all, about half of our brain cells have large chunks of missing or inserted DNA caused by L1s alone--but that too much of it can cause disease. Recent evidence has shown that neurons derived from individuals with schizophrenia or the rare autism-associated disorder Rett syndrome harbor more than normal amount of L1 variations in their genomes. In the new study, the team examined a schizophrenia-associated gene called DLG2, in which introducing L1 variations can change the gene's expression and subsequent maturation of neurons. The group plans to explore the role of L1 variations in other genes and their effects on brain activity and disease.
News Article | November 29, 2016
Wiseguyreports.Com Adds “Apoptosis -Market Demand, Growth, Opportunities and analysis of Top Key Player Forecast to 2021” To Its Research Database Apoptosis Market research report gives an insight into Apoptosis Mechanism, by Molecular Pathways, Caspase Activators and Inhibitors, Protease/Proteasome Inhibitors, Bcl-2 Modulators, p53 Modulators and Other. The study also focuses on major diseases for which the treatment is based on apoptosis comprising Cancer, Neurodegenerative Diseases, Cardiovascular Diseases and other apoptosis based diseases including HIV infection, Organ Transplant Rejection and MODS. The study provides apoptosis market size related therapeutic products by the above apoptosis molecular pathways and also by the disease areas. The study includes estimates and projections for the total global apoptosis related therapeutic products market. Projections and estimates are also graphically illustrated by geographic regions encompassing North America, Europe, Asia-Pacific and Rest of World. Business profiles of 58 major companies are discussed in the report. The report serves as a guide to global apoptosis market, covering more than 555 companies that are engaged in apoptosis research, testing and supply of products and services. Major Contract Research Organizations and Universities serving apoptosis market are also covered in the Corporate Directory section of this report. Information related product developments, partnerships, collaborations, and mergers and acquisitions are also covered in the report. Compilation of Worldwide Patents and Research related to Apoptosis is provided. Over the past few years, availability of apoptosis related products (drugs, kits and reagents) has increased enormously. Global market for apoptosis related products is expected to grow at a high CAGR of 31.2% through 2005-2020, and the high growth is owing to increasing evidence of role of apoptosis in mechanism of action for large number of diseases such as Cancer; Neurodegenerative Diseases including Alzheimer's, Parkinson's, Multiple Sclerosis and Rheumatoid Arthritis; Cardiovascular Disease; and other apoptosis based diseases including organ transplant rejection and HIV infection. Cancer research has delivered outstanding progress in understanding the biology and genomics of cancer, in the last decade. Foremost of these progress areas is the recognition of apoptosis and its regulatory genes that have an effect on melanoma. In return, other oncogenical changes stimulate apoptosis and override apoptosis during multistage carcinogenesis by making selective pressures. Apoptosis associates cancer therapeutics with cancer genetics by providing conceptual structure, as well as similar changes that suppress apoptosis during tumor development. This report may help Strategists, Investors, Laboratories, Contract Research Organizations, Biotechnology & Healthcare Companies, Academic Professionals, Drug Approval Authorities, and Other Organizations to – Analytics and data presented in each report pertain to several parameters such as –