Six new genetic risk factors for Parkinson’s found

Using data from over 18,000 patients, scientists have identified more than two dozen genetic risk factors involved in Parkinson’s disease, including six that had not been previously reported. The study, published in Nature Genetics, was partially funded by the National Institutes of Health (NIH) and led by scientists working in NIH laboratories.”Unraveling the genetic underpinnings of Parkinson’s is vital to understanding the multiple mechanisms involved in this complex disease, and hopefully, may one day lead to effective therapies,” said Andrew Singleton, Ph.D., a scientist at the NIH’s National Institute on Aging (NIA) and senior author of the study.Dr. Singleton and his colleagues collected and combined data from existing genome-wide association studies (GWAS), which allow scientists to find common variants, or subtle differences, in the genetic codes of large groups of individuals. The combined data included approximately 13,708 Parkinson’s disease cases and 95,282 controls, all of European ancestry.The investigators identified potential genetic risk variants, which increase the chances that a person may develop Parkinson’s disease. Their results suggested that the more variants a person has, the greater the risk, up to three times higher, for developing the disorder in some cases.”The study brought together a large international group of investigators from both public and private institutions who were interested in sharing data to accelerate the discovery of genetic risk factors for Parkinson’s disease,” said Margaret Sutherland, Ph.D., a program director at the National Institute of Neurological Disorders and Stroke (NINDS), part of NIH. “The advantage of this collaborative approach is highlighted in the identification of pathways and gene networks that may significantly increase our understanding of Parkinson’s disease.”To obtain the data, the researchers collaborated with multiple public and private organizations, including the U.S. Department of Defense, the Michael J. Fox Foundation, 23andMe and many international investigators.Affecting millions of people worldwide, Parkinson’s disease is a degenerative disorder that causes movement problems, including trembling of the hands, arms, or legs, stiffness of limbs and trunk, slowed movements and problems with posture. Over time, patients may have difficulty walking, talking, or completing other simple tasks. Although nine genes have been shown to cause rare forms of Parkinson’s disease, scientists continue to search for genetic risk factors to provide a complete genetic picture of the disorder.The researchers confirmed the results in another sample of subjects, including 5,353 patients and 5,551 controls. …

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Anti-inflammatory drug can prevent neuron loss in Parkinson’s model

An experimental anti-inflammatory drug can protect vulnerable neurons and reduce motor deficits in a rat model of Parkinson’s disease, researchers at Emory University School of Medicine have shown.The results were published Thursday, July 24 in the Journal of Parkinson’s Disease.The findings demonstrate that the drug, called XPro1595, can reach the brain at sufficient levels and have beneficial effects when administered by subcutaneous injection, like an insulin shot. Previous studies of XPro1595 in animals tested more invasive modes of delivery, such as direct injection into the brain.”This is an important step forward for anti-inflammatory therapies for Parkinson’s disease,” says Malu Tansey, PhD, associate professor of physiology at Emory University School of Medicine. “Our results provide a compelling rationale for moving toward a clinical trial in early Parkinson’s disease patients.”The new research on subcutaneous administration of XPro1595 was funded by the Michael J. Fox Foundation for Parkinson’s Research (MJFF). XPro1595 is licensed by FPRT Bio, and is seeking funding for a clinical trial to test its efficacy in the early stages of Parkinson’s disease.”We are proud to have supported this work and glad to see positive pre-clinical results,” said Marco Baptista, PhD, MJFF associate director of research programs. “A therapy that could slow Parkinson’s progression would be a game changer for the millions living with this disease, and this study is a step in that direction.”In addition, Tansey and Yoland Smith, PhD, from Yerkes National Primate Research Center, were awarded a grant this week from the Parkinson’s Disease Foundation to test XPro1595 in a non-human primate model of Parkinson’s.Evidence has been piling up that inflammation is an important mechanism driving the progression of Parkinson’s disease. XPro1595 targets tumor necrosis factor (TNF), a critical inflammatory signaling molecule, and is specific to the soluble form of TNF. This specificity would avoid compromising immunity to infections, a known side effect of existing anti-TNF drugs used to treat disorders such as rheumatoid arthritis.”Inflammation is probably not the initiating event in Parkinson’s disease, but it is important for the neurodegeneration that follows,” Tansey says. “That’s why we believe that an anti-inflammatory agent, such as one that counteracts soluble TNF, could substantially slow the progression of the disease.”Postdoctoral fellow Christopher Barnum, PhD and colleagues used a model of Parkinson’s disease in rats in which the neurotoxin 6-hydroxydopamine (6-OHDA) is injected into only one side of the brain. This reproduces some aspects of Parkinson’s disease: neurons that produce dopamine in the injected side of the brain die, leading to impaired movement on the opposite side of the body.When XPro1595 is given to the animals 3 days after 6-OHDA injection, just 15 percent of the dopamine-producing neurons were lost five weeks later. …

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Slow walking speed, memory complaints can predict dementia

A study involving nearly 27,000 older adults on five continents found that nearly 1 in 10 met criteria for pre-dementia based on a simple test that measures how fast people walk and whether they have cognitive complaints. People who tested positive for pre-dementia were twice as likely as others to develop dementia within 12 years. The study, led by scientists at Albert Einstein College of Medicine of Yeshiva University and Montefiore Medical Center, was published online on July 16, 2014 in Neurology, the medical journal of the American Academy of Neurology.The new test diagnoses motoric cognitive risk syndrome (MCR). Testing for the newly described syndrome relies on measuring gait speed (our manner of walking) and asking a few simple questions about a patient’s cognitive abilities, both of which take just seconds. The test is not reliant on the latest medical technology and can be done in a clinical setting, diagnosing people in the early stages of the dementia process. Early diagnosis is critical because it allows time to identify and possibly treat the underlying causes of the disease, which may delay or even prevent the onset of dementia in some cases.”In many clinical and community settings, people don’t have access to the sophisticated tests — biomarker assays, cognitive tests or neuroimaging studies — used to diagnose people at risk for developing dementia,” said Joe Verghese, M.B.B.S., professor in the Saul R. Korey Department of Neurology and of medicine at Einstein, chief of geriatrics at Einstein and Montefiore, and senior author of the Neurology paper. “Our assessment method could enable many more people to learn if they’re at risk for dementia, since it avoids the need for complex testing and doesn’t require that the test be administered by a neurologist. The potential payoff could be tremendous — not only for individuals and their families, but also in terms of healthcare savings for society. All that’s needed to assess MCR is a stopwatch and a few questions, so primary care physicians could easily incorporate it into examinations of their older patients.”The U.S. …

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New EMS system dramatically improves survival from cardiac arrest

A new system that sent patients to designated cardiac receiving centers dramatically increased the survival rate of victims of sudden cardiac arrest in Arizona, according to a study published online in Annals of Emergency Medicine.”We knew lives would be saved if the hospitals implemented the latest cutting edge guidelines for post-cardiac arrest care and we were able to get cardiac arrest patients to those hospitals, similar to what is done for Level 1 trauma patients,” said lead study author Daniel Spaite, MD, Director of EMS Research at the University of Arizona Emergency Medicine Research Center in Phoenix and Tucson and a professor and distinguished chair of emergency medicine at the University of Arizona College of Medicine. “Taking these patients directly to a hospital optimally prepared to treat cardiac arrest gave patients a better chance of survival and of preventing neurologic damage, a common result of these cardiac events.”Under the study, 31 hospitals, serving about 80 percent of the state’s population, were designated as cardiac receiving centers between December 2007 and November 2010. Approximately 55 emergency medicine service agencies also participated in the study.The study shows that the survival rate increased by more than 60 percent during the four-year period of the study, from 2007 to 2010. More importantly, when the results were adjusted for the various factors that significantly impact survival (such as age and how quickly the EMS system got to the patients after their arrest), the likelihood of surviving an arrest more than doubled. In addition, the likelihood of surviving with good neurological status also more than doubled.This statewide effort was accomplished through the Save Hearts Arizona Registry and Education-SHARE Program, a partnership involving the Arizona Department of Health Services, the University of Arizona, over 30 hospitals and more than 100 fire departments and EMS agencies. The SHARE Program is part of a network of statewide cardiac resuscitation programs dedicated to improving cardiac arrest survival and working together as the HeartRescue Project.”We worked closely with the hospitals around the state to implement these Guidelines and then formally recognized the hospitals as Cardiac Receiving Centers (CRCs) ,” said Ben Bobrow, MD, Medical Director of the Bureau of Emergency Medicine Services and Trauma System for the Arizona Department of Health Services in Phoenix, Ariz. “We then developed protocols for our EMS agencies to transport post-cardiac arrest patients to those centers. Our overarching goal was to have more cardiac arrest victims leave the hospital in good shape and be able to return to their families and careers. As we suspected, ‘regionalizing’ the care for these critically-ill patients markedly increased their likelihood of survival and good neurologic outcome.”Dr. Bobrow, who is also a professor of emergency medicine at the University of Arizona College of Medicine-Phoenix and an emergency physician at Maricopa Medical Center, said the study shows that just transporting these patients to the nearest emergency department does not maximize the likelihood of a positive outcome. …

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Epigenetic changes can drive cancer, study shows

Cancer has long been thought to be primarily a genetic disease, but in recent decades scientists have come to believe that epigenetic changes — which don’t change the DNA sequence but how it is ‘read’ — also play a role in cancer. In particular DNA methylation, the addition of a methyl group (or molecule), is an epigenetic switch that can stably turn off genes, suggesting the potential to cause cancer just as a genetic mutation can. Until now, however, direct evidence that DNA methylation drives cancer formation was lacking.Researchers at the USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine and Texas Children’s Hospital have now created a mouse model providing the first in vivo evidence that epigenetic alterations alone can cause cancer. Their report appears in the Journal of Clinical Investigation.”We knew that epigenetic changes are associated with cancer, but didn’t know whether these were a cause or consequence of cancer. Developing this new approach for ‘epigenetic engineering’ allowed us to test whether DNA methylation changes alone can drive cancer,” said Dr. Lanlan Shen, associate professor of pediatrics at Baylor and senior author of the study.Shen and colleagues focused on p16, a gene that normally functions to prevent cancer but is commonly methylated in a broad spectrum of human cancers. They devised an approach to engineer DNA methylation specifically to the mouse p16 regulatory region (promoter). As intended, the engineered p16 promoter acted as a ‘methylation magnet’. As the mice reached adulthood, gradually increasing p16 methylation led to a higher incidence of spontaneous cancers, and reduced survival.”This is not only the first in vivo evidence that epigenetic alteration alone can cause cancer,” said Shen. “This also has profound implications for future studies, because epigenetic changes are potentially reversible. …

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New brain pathways for understanding type 2 diabetes and obesity uncovered

Researchers at UT Southwestern Medical Center have identified neural pathways that increase understanding of how the brain regulates body weight, energy expenditure, and blood glucose levels — a discovery that can lead to new therapies for treating Type 2 diabetes and obesity.The study, published in Nature Neuroscience, found that melanocortin 4 receptors (MC4Rs) expressed by neurons that control the autonomic nervous system are key in regulating glucose metabolism and energy expenditure, said senior author Dr. Joel Elmquist, Director of the Division of Hypothalamic Research, and Professor of Internal Medicine, Pharmacology, and Psychiatry.”A number of previous studies have demonstrated that MC4Rs are key regulators of energy expenditure and glucose homeostasis, but the key neurons required to regulate these responses were unclear,” said Dr. Elmquist, who holds the Carl H. Westcott Distinguished Chair in Medical Research, and the Maclin Family Distinguished Professorship in Medical Science, in Honor of Dr. Roy A. Brinkley. “In the current study, we found that expression of these receptors by neurons that control the sympathetic nervous system, seem to be key regulators of metabolism. In particular, these cells regulate blood glucose levels and the ability of white fat to become ‘brown or beige’ fat.”Using mouse models, the team of researchers, including co-first authors Dr. Eric Berglund, Assistant Professor in the Advanced Imaging Research Center and Pharmacology, and Dr. Tiemin Liu, a postdoctoral research fellow in Internal Medicine, deleted MC4Rs in neurons controlling the sympathetic nervous system. …

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