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. …

Read more

Two forms of Parkinson’s disease identified

Oct. 11, 2013 — Why can the symptoms of Parkinson’s disease vary so greatly from one patient to another? A consortium of researchers, headed by a team from the Laboratoire CNRS d’Enzymologie et Biochimie Structurales, is well on the way to providing an explanation. Parkinson’s disease is caused by a protein known as alpha-synuclein, which forms aggregates within neurons, killing them eventually. The researchers have succeeded in characterizing and producing two different types of alpha-synuclein aggregates. Better still, they have shown that one of these two forms is much more toxic than the other and has a greater capacity to invade neurons. This discovery takes account, at the molecular scale, of the existence of alpha-synuclein accumulation profiles that differ from one patient to the next. These results, published on October 10 in Nature Communications, represent a notable advance in our understanding of Parkinson’s disease and pave the way for the development of specific therapies targeting each form of the disease.Parkinson’s disease, which is the second most frequent neurodegenerative disease after Alzheimer’s, affects some 150,000 people in France. According to those suffering from the disease, it can manifest itself in the form of uncontrollable shaking (in 60% of patients) or by less-localized symptoms such as depression, behavioral and motor disorders. These differences in symptoms point to different forms of Parkinson’s disease.This condition, for which no curative treatment currently exists, is caused by the aggregation in the form of fibrillar deposits of alpha-synuclein, a protein that is naturally abundant at neuron junctions. …

Read more

Early-onset Parkinson’s disease linked to genetic deletion

Sep. 9, 2013 — Scientists at the Centre for Addiction and Mental Health (CAMH) and University Health Network (UHN) have found a new link between early-onset Parkinson’s disease and a piece of DNA missing from chromosome 22. The findings help shed new light on the molecular changes that lead to Parkinson’s disease.The study appears online today in JAMA Neurology.Among people aged 35 to 64 who were missing DNA from a specific part of chromosome 22, the research team found a marked increase in the number of cases of Parkinson’s disease, compared to expected rates of Parkinson’s disease in the general population from the same age group.The deletion, which occurs when a person is born with about 50 genes missing on one chromosome 22, is associated with 22q11.2 deletion syndrome. People with this condition may have heart or other birth defects, learning or speech difficulties, and some develop schizophrenia. It occurs in an estimated 1 in 2,000 to 4,000 births, but is believed to be under-diagnosed.”22q11.2 deletion syndrome has been fairly well studied in childhood and adolescence, but less is known about its effects as people age,” said Dr. Anne Bassett, Director of CAMH’s Clinical Genetics Research Program and Director of the Dalglish Family Hearts and Minds Clinic at UHN, the world’s first clinic dedicated to adults with 22q11.2 deletion syndrome. A few cases of patients with the syndrome who had Parkinson’s disease symptoms had been previously reported, which suggested that the two conditions might be linked.Parkinson’s disease is one of the most common neurodegenerative disorders worldwide, typically affecting people over the age of 65. Earlier onset of Parkinson’s disease, before age 50, is rare and has been associated with several other genetic changes that are not on chromosome 22.The researchers studied 159 adults with 22q11.2 deletion syndrome to discover how many had been clinically diagnosed with Parkinson’s disease. For three individuals with the deletion and Parkinson’s disease who were deceased, brain tissue was also examined.”Through a post-mortem examination, we were able to show that all three patients had a loss of neurons that was typical of that seen in Parkinson’s disease. The examination also helped to show that the symptoms of Parkinson’s disease were not related to side effects of the medications commonly used to treat schizophrenia,” added Dr.Rasmus Kiehl, neuropathologist in UHN’s Laboratory Medicine Program, who co-authored the report with CAMH graduate student Nancy Butcher. …

Read more

TB and Parkinson’s disease linked by unique protein

Sep. 4, 2013 — A protein at the center of Parkinson’s disease research now also has been found to play a key role in causing the destruction of bacteria that cause tuberculosis, according to scientists led by UC San Francisco microbiologist and tuberculosis expert Jeffery Cox, PhD.The protein, named Parkin, already is the focus of intense investigation in Parkinson’s disease, in which its malfunction is associated with a loss of nerve cells. Cox and colleagues now report that Parkin also acts on tuberculosis, triggering destruction of the bacteria by immune cells known as macrophages. Results appear online today (September 4, 2013) in the journal Nature.The finding suggests that disease-fighting strategies already under investigation in pre-clinical studies for Parkinson’s disease might also prove useful in fighting tuberculosis, according to Cox. Cox is investigating ways to ramp up Parkin activity in mice infected with tuberculosis using a strategy similar to one being explored by his UCSF colleague Kevan Shokat, PhD, as a way to ward off neurodegeneration in Parkinson’s disease.Globally, tuberculosis kills 1.4 million people each year, spreading from person to person through the air. Parkinson’s disease, the most common neurodegenerative movement disorder, also affects millions of mostly elderly people worldwide.Cox homed in on the enzyme Parkin as a common element in Parkinson’s and tuberculosis through his investigations of how macrophages engulf and destroy bacteria. In a sense the macrophage — which translates from Greek as “big eater” — gobbles down foreign bacteria, through a process scientists call xenophagy.Mycobacterium tuberculosis, along with a few other types of bacteria, including Salmonella and leprosy-causing Mycobacterium leprae, are different from other kinds of bacteria in that, like viruses, they need to get inside cells to mount a successful infection.The battle between macrophage and mycobacterium can be especially intense. M. tuberculosis invades the macrophage, but then becomes engulfed in a sac within the macrophage that is pinched off from the cell’s outer membrane. The bacteria often escape this intracellular jail by secreting a protein that degrades the sac, only to be targeted yet again by molecular chains made from a protein called ubiquitin. …

Read more

Comprehensive Parkinson’s biomarker test has prognostic and diagnostic value

Aug. 26, 2013 — Perelman School of Medicine researchers at the University of Pennsylvania report the first biomarker results reported from the Parkinson’s Progression Markers Initiative (PPMI), showing that a comprehensive test of protein biomarkers in spinal fluid have prognostic and diagnostic value in early stages of Parkinson’s disease.The study is reported in JAMA Neurology.Compared to healthy adults, the study found that people with early Parkinson’s had lower levels of amyloid beta, tau and alpha synuclein in their spinal fluid. In addition, those with lower concentrations of tau and alpha synuclein had greater motor dysfunction. And early Parkinson’s patients with low levels of amyloid beta and tau were more likely to be classified as having the postural instability-gait disturbance- dominant (PIGD) motor type of disease, where falling, freezing, and walking difficulty are common.”Biomarkers for Parkinson’s disease such as these could help us diagnose patients earlier, and we’ve now shown that the simultaneous measurement of a variety of neurodegenerative disease proteins is valuable,” said study senior author Leslie M. Shaw, PhD, professor of Pathology and Laboratory Medicine at Penn Medicine. Dr. Shaw and John Q. Trojanowski, MD, PhD, director of the Penn Udall Center for Parkinson’s Research, are co-leaders of the Bioanalytics Core for the Parkinson’s Progression Markers Initiative, an international observational clinical study sponsored by The Michael J. Fox Foundation for Parkinson’s Research.The team evaluated spinal fluid collected from baseline visits of the first 102 PPMI participants — 63 with early, untreated Parkinson’s disease and 39 healthy controls. The spinal fluid was evaluated for levels of five biomarkers: amyloid beta, total tau, phosphorylated tau, alpha synuclein and the ratio of total tau to amyloid beta. …

Read more

Receptor may aid spread of Alzheimer’s and Parkinson’s in brain

Aug. 23, 2013 — Scientists at Washington University School of Medicine in St. Louis have found a way that corrupted, disease-causing proteins spread in the brain, potentially contributing to Alzheimer’s disease, Parkinson’s disease and other brain-damaging disorders.The research identifies a specific type of receptor and suggests that blocking it may aid treatment of theses illnesses. The receptors are called heparan sulfate proteoglycans (HSPGs).”Many of the enzymes that create HSPGs or otherwise help them function are good targets for drug treatments,” said senior author Marc I. Diamond, MD, the David Clayson Professor of Neurology. “We ultimately should be able to hit these enzymes with drugs and potentially disrupt several neurodegenerative conditions.”The study is available online in the Proceedings of the National Academy of Sciences.Over the last decade, Diamond has gathered evidence that Alzheimer’s disease and other neurodegenerative diseases spread through the brain in a fashion similar to conditions such as mad cow disease, which are caused by misfolded proteins known as prions.Proteins are long chains of amino acids that perform many basic biological functions. A protein’s abilities are partially determined by the way it folds into a 3-D shape. Prions are proteins that have become folded in a fashion that makes them harmful.Prions spread across the brain by causing other copies of the same protein to misfold.Among the most infamous prion diseases are mad cow disease, which rapidly destroys the brain in cows, and a similar, inherited condition in humans called Creutzfeldt-Jakob disease.Diamond and his colleagues have shown that a part of nerve cells’ inner structure known as tau protein can misfold into a configuration called an amyloid. These corrupted versions of tau stick to each other in clumps within the cells. Like prions, the clumps spread from one cell to another, seeding further spread by causing copies of tau protein in the new cell to become amyloids.In the new study, first author Brandon Holmes, an MD/PhD student, showed that HSPGs are essential for binding, internalizing and spreading clumps of tau. …

Read more

A new wrinkle in Parkinson’s disease research: Skin cream ingredient may stop effects of Parkinson’s on brain cells

Aug. 15, 2013 — The active ingredient in an over-the-counter skin cream might do more than prevent wrinkles. Scientists have discovered that the drug, called kinetin, also slows or stops the effects of Parkinson’s disease on brain cells.Scientists identified the link through biochemical and cellular studies, but the research team is now testing the drug in animal models of Parkinson’s. The research is published in the August 15, 2013 issue of the journal Cell.”Kinetin is a great molecule to pursue because it’s already sold in drugstores as a topical anti-wrinkle cream,” says HHMI investigator Kevan Shokat of the University of California, San Francisco. “So it’s a drug we know has been in people and is safe.”Parkinson’s disease is a degenerative disease that causes the death of neurons in the brain. Initially, the disease affects one’s movement and causes tremors, difficulty walking, and slurred speech. Later stages of the disease can cause dementia and broader health problems. In 2004, researchers studying an Italian family with a high prevalence of early-onset Parkinson’s disease discovered mutations in a protein called PINK1 associated with the inherited form of the disease.Since then, studies have shown that PINK1 normally wedges into the membrane of damaged mitochondria inside cells that causes another protein, Parkin, to be recruited to the mitochondria, which are organelles responsible for energy generation. Neurons require high levels of energy production, therefore when mitochondrial damage occurs, it can lead to neuronal death. However, when Parkin is present on damaged mitochondria, studding the mitochondrial surface, the cell is able to survive the damage. …

Read more

Genetic mutations linked to Parkinson’s disease

Aug. 11, 2013 — Researchers have discovered how genetic mutations linked to Parkinson’s disease might play a key role in the death of brain cells, potentially paving the way for the development of more effective drug treatments.In the new study, published in Nature Neuroscience, a team of researchers from UCL, the University of Cambridge and the University of Sheffield showed how defects in the Parkinson’s gene Fbxo7 cause problems with ‘mitaphagy’ — an essential process through which our bodies are able to get rid of damaged cells.Mitochondria are the ‘energy powerhouses’ of cells. Their function is vital in nerve cells which require a great deal of energy in order to function and survive. Dysfunctional mitochondria are potentially very harmful and, normally, cells dispose of the damaged mitchondria by self-eating them, a process called mitophagy.Most of what we know about the mitophagy process comes from the study of the familial forms of Parkinson’s, one of the most common diseases of the brain. Over the last three years, two genes associated with familial Parkinson’s disease, PINK1 and Parkin, have been reported to play a role in mitophagy.This new study shows just how central the role of mitophagy is and how mutations in Fbxo7 are also linked with the disease and interfere with the PINK1-Parkin pathway. In people with Parkinson’s, genetic mutations cause defects in mitophagy, leading to a build-up of dysfunctional mitochondria. This is likely to explain, at least partially, the death of brain cells in Parkinson’s patients with these mutations.One of the lead authors, Dr Helene Plun-Favreau from the UCL Institute of Neurology, said: “These findings suggest that treatment strategies that target mitophagy might be developed to benefit patients with Parkinson’s disease in the future.Dr Plun-Favreau, who was recently awarded a grant from the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, said: “What makes the study so robust is the confirmation of defective mitophagy in a number of different Parkinson’s models, including cells of patients who carry a mutation in the Fbxo7 gene.”Co-author Dr Heike Laman, University of Cambridge, said: “This research focuses the attention of the PD community on the importance of the proper maintenance of mitochondria for the health of neurons. We are really only at the very beginning of this work, but perhaps we can use this information to enable earlier diagnosis for Parkinson’s disease patients or design therapies aimed at supporting mitochondrial health.”Professor Nicholas Wood, Neuroscience programme director for the NIHR University College London Hospitals BRC, said: “It is very exciting to see how detailed biological work of this type can highlight a single pathway that contributes to Parkinson’s disease. This presents the opportunity of more rationale drug design for many forms of parkinsonism.”Professor Hugh Perry, chair of the Neurosciences and Mental Health Board at the Medical Research Council who part-funded the study, said: “This study raises interesting questions about precisely how brain cells die in a Parkinson’s patient: the process which is key to understanding the disease’s progression. The more we understand about the basic molecular events which contribute to the onset and progression of Parkinson’s disease, the better placed we will be to develop treatments to stop it in its tracks.”The work was funded by the Medical Research Council, the Wellcome Trust and The NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London.

Read more

Genetics: More than merely a mutated gene

Aug. 1, 2013 — If two women have the same genetic mutation that puts them at higher-than-average risk for a disease such as breast cancer, why does only one develop the disease?In the current issue of PLoS Genetics, Michigan State University genetic scientists have begun to understand how the rest of the genome interacts with such mutations to cause the differences we see among individuals.”It’s been known for a while that genetic mutations can modify each other’s effects,” said Ian Dworkin, MSU associate professor of zoology and co-author of the paper. “And we also know that the subtle differences in an individual’s genome — what scientists call wild type genetic background — also affects how mutations are manifested.”Dworkin and Sudarshan Chari, zoology doctoral student and the paper’s lead author, wanted to know how common it was for wild type genetic background to alter the way genetic mutations interact with each other. This is the first time that it’s been examined in a systematic manner, Dworkin added.Using the fruit fly genome, the researchers found that wild type genetic background affected the outcomes of interactions between genetic mutations about 75 percent of the time. This could have huge implications in how scientists construct genetic networks — maps of how genes interact with each other.”It may be that some crucial portions of genetic networks are missing,” he said. “It also seems that network descriptions are more fluid than we thought.”Fruit flies have been called humans with wings, genetically speaking, due to their similarities. By focusing on wings and a genetic mutation that alters them, the researchers demonstrated the influence of wild type genetic background was actually quite common.The broader implication for humans is that even for diseases with a simple genetic basis, variation in the genome may matter for both understanding and treatment, Dworkin said.This new insight explains how, in an example like breast cancer, every woman’s genetic background is likely influencing how the mutation is expressed, causing different disease outcomes. The research also may help explain why some people benefit from a specific treatment for a disease, while others get no benefits or become resistant to a drug after a short time.It’s likely that most diseases with a suspected genetic component, such as cancer, asthma or Parkinson’s, involve reactions between more than one set of genes. For Dworkin and Chari, the next step is to tease apart the intricacies of what’s happening.”Is it just the two pairs of genes that are interacting?” Dworkin asked. “Or is it that the two genes are interacting and then many other genes are modifying that reaction? …

Read more

Sudden decline in testosterone may cause Parkinson’s disease symptoms in men

July 26, 2013 — The results of a new study by neurological researchers at Rush University Medical Center show that a sudden decrease of testosterone, the male sex hormone, may cause Parkinson’s like symptoms in male mice. The findings were recently published in the Journal of Biological Chemistry.One of the major roadblocks for discovering drugs against Parkinson’s disease is the unavailability of a reliable animal model for this disease.”While scientists use different toxins and a number of complex genetic approaches to model Parkinson’s disease in mice, we have found that the sudden drop in the levels of testosterone following castration is sufficient to cause persistent Parkinson’s like pathology and symptoms in male mice,” said Dr. Kalipada Pahan, lead author of the study and the Floyd A. Davis endowed professor of neurology at Rush. “We found that the supplementation of testosterone in the form of 5-alpha dihydrotestosterone (DHT) pellets reverses Parkinson’s pathology in male mice.””In men, testosterone levels are intimately coupled to many disease processes,” said Pahan. Typically, in healthy males, testosterone level is the maximum in the mid-30s, which then drop about one percent each year. However, testosterone levels may dip drastically due to stress or sudden turn of other life events, which may make somebody more vulnerable to Parkinson’s disease.”Therefore, preservation of testosterone in males may be an important step to become resistant to Parkinson’s disease,” said Pahan.Understanding how the disease works is important to developing effective drugs that protect the brain and stop the progression of Parkinson’s disease. Nitric oxide is an important molecule for our brain and the body.”However, when nitric oxide is produced within the brain in excess by a protein called inducible nitric oxide synthase, neurons start dying,” said Pahan.”This study has become more fascinating than we thought,” said Pahan. “After castration, levels of inducible nitric oxide synthase (iNOS) and nitric oxide go up in the brain dramatically. Interestingly, castration does not cause Parkinson’s like symptoms in male mice deficient in iNOS gene, indicating that loss of testosterone causes symptoms via increased nitric oxide production.””Further research must be conducted to see how we could potentially target testosterone levels in human males in order to find a viable treatment,” said Pahan.Other researchers at Rush involved in this study were Saurabh Khasnavis, PhD, student, Anamitra Ghosh, PhD, student, and Avik Roy, PhD, research assistant professor.This research was supported by a grant from the National Institutes of Health that received the highest score for its scientific merit in the particular cycle it was reviewed.Parkinson’s is a slowly progressive disease that affects a small area of cells within the mid-brain known as the substantia nigra. …

Read more

Stopping cholesterol drugs may be associated with increased risk of Parkinson’s

July 24, 2013 — People who stop taking cholesterol drugs may be at an increased risk for developing Parkinson’s disease, according to research that appears in the July 24, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology. Previous studies on the relationship between cholesterol drugs called statins and the risk of Parkinson’s disease have had inconsistent results.The current study involved 43,810 people in Taiwan who were taking statins and did not have Parkinson’s disease. Taiwan’s compulsory national health insurance program reimbursement policy requests that doctors stop prescribing statins once the patient’s cholesterol reaches the treatment goal, which is contrary to standard treatment in the United States. “This policy allowed us to see whether there was any difference in the risk of Parkinson’s in people who stopped taking statins compared to the ones who kept taking them,” said study author Jou-Wei Lin, MD, PhD, of National Taiwan University in Taipei.The study found a difference between two types of statins. The use of lipophilic, or fat-soluble, statins such as simvastatin and atorvastatin was associated with a reduced risk of Parkinson’s, while no such association was found for hydrophilic, or water-soluble, statins such as pravastatin and rosuvastatin.Those who stopped taking the fat-soluble statins were 58 percent more likely to develop Parkinson’s disease than those who kept taking the drugs, an absolute risk of 2.65 cases per one million person-days. This result was consistent even after adjusting for other conditions such as diabetes and high blood pressure.The study also looked at how many people taking the two types of statins developed Parkinson’s disease, compared to the number of person-days spent on the medication to come up with an incidence rate. A total of 25 people taking fat-soluble statins developed Parkinson’s from a total of nearly 15 million person-days on the drugs, for a rate of 1.68 cases per one million person-days on the drugs. For the water-soluble statins, 14 people developed Parkinson’s from nearly four million person-days on the drugs, for a rate of 3.52 cases per one million person-days on the drugs.”The fat-soluble statins are better able to cross the blood-brain barrier than the water-soluble statins,” Lin said.The study was supported by the Taiwan Ministry of Education.

Read more

Potential cause of Parkinson’s disease points to new therapeutic strategy

July 24, 2013 — Biologists at The Scripps Research Institute (TSRI) have made a significant discovery that could lead to a new therapeutic strategy for Parkinson’s disease.The findings, recently published online ahead of print in the journal Molecular and Cell Biology, focus on an enzyme known as parkin, whose absence causes an early-onset form of Parkinson’s disease. Precisely how the loss of this enzyme leads to the deaths of neurons has been unclear. But the TSRI researchers showed that parkin’s loss sharply reduces the level of another protein that normally helps protect neurons from stress.”We now have a good model for how parkin loss can lead to the deaths of neurons under stress,” said TSRI Professor Steven I. Reed, who was senior author of the new study. “This also suggests a therapeutic strategy that might work against Parkinson’s and other neurodegenerative diseases.”Genetic CluesParkinson’s is the world’s second-most common neurodegenerative disease, affecting about one million people in the United States alone. The disease is usually diagnosed after the appearance of the characteristic motor symptoms, which include tremor, muscle rigidity and slowness of movements. These symptoms are caused by the loss of neurons in the substantia nigra, a brain region that normally supplies the neurotransmitter dopamine to other regions that regulate muscle movements.Most cases of Parkinson’s are considered “sporadic” and are thought to be caused by a variable mix of factors including advanced age, subtle genetic influences, chronic neuroinflammation and exposure to pesticides and other toxins. But between 5 and 15 percent of cases arise specifically from inherited gene mutations. Among these, mutations to the parkin gene are relatively common. Patients who have no functional parkin gene typically develop Parkinson’s-like symptoms before age 40.Parkin belongs to a family of enzymes called ubiquitin ligases, whose main function is to regulate the levels of other proteins. …

Read more

Vascular link in Alzheimer’s disease with cognition

July 10, 2013 — Researchers in the Perelman School of Medicine at the University of Pennsylvania found that, across a variety of neurodegenerative diseases, cerebrovascular disease affecting circulation of blood in the brain was significantly associated with dementia. The researchers contend that people already exhibiting clinical features of Alzheimer’s disease and other memory impairments may benefit from effective therapies currently available to reduce vascular problems. Thus, early management of vascular risk factors, such as high blood pressure and cholesterol, and adopting a ‘heart healthy’ diet as well as exercise and other lifestyles in midlife may delay or prevent the onset of dementia due to Alzheimer’s and Parkinson’s disease.The link between cerebrovascular disease was strongest with Alzheimer’s disease — as compared to other neurodegenerative diseases including frontotemporal lobar degeneration, Lou Gehrig’s disease or ALS and Parkinson’s disease — and had the most pronounced effect in younger Alzheimer’s patients, according to the study, published in the July 10 issue of Brain.”While there was evidence already to suggest that vascular disease could play a role in neurodegenerative disease, this is the first study to compare the burden of vascular disease across neurodegenerative diseases with multiple, distinct or different origins,” said senior author John Q. Trojanowski, MD, PhD, director of the National Institute on Aging-funded Alzheimer’s Disease Core Center at the University of Pennsylvania and professor of Pathology and Laboratory Medicine. “We were surprised to find such a strong link to vascular disease in Alzheimer’s disease, especially in younger patients, in comparison to individuals with other neurodegenerative diseases.”Penn researchers analyzed 5715 cases from the National Alzheimer’s Coordinating Center (NACC) database, which have been collected from 35 past and present NIA-funded Alzheimer’s centers across the US since NACC was started in 1999. This is the first study to compare the presence of cerebrovascular disease across the whole spectrum of neurogenerative diseases.Nearly 80 percent of the more than 4600 Alzheimer’s disease patients showed some degree of vascular pathology — defined as hardened or blocked blood vessels, tissue death due to lack of blood supply, or bleeding — in the brain, as compared to 67 percent in the control group of people with no remarkable brain disease pathology, and 66 percent in the Parkinson’s pathology group.”In the absence of any disease modifying therapies to change the course of the Alzheimer’s and Parkinson’s, we hope that the diligent use of existing treatments for vascular conditions and the implementation of campaigns promoting healthy lifestyles in young and middle aged people may have a positive impact on preventing or reducing dementia symptoms in Alzheimer’s and Parkinson’s disease ” said lead study author Jon B. Toledo, MD, postdoctoral researcher at the University of Pennsylvania Perelman School of Medicine.The study has implications from a public health perspective and for the design of clinical study cohorts that better represent the general population of people with cognitive impairment. In addition, drugs tested for Alzheimer’s disease and other related dementias should consider the impact of the frequent concident presence of cerebrovascular disease on the treatment response of new therapies for Alzheimer’s, as most current trials exclude patients with vascular risk factors or cardiovascular disease. Given the prevalence of vascular problems, the researchers note that this large subset of dementia patients should be included in clinical trials to accurately represent the true population dealing with these neurodegenerative diseases, or, at least considered when predicting the clinical impact on patients in a real world population.Additional members of the Penn study team include Steven Arnold, MD, co-director of Penn’s Alzheimer’s Disease Core Center and Murray Grossman, MD, EdD, director of the Penn Frontotemporal Disease Center; Kevin Raible and Johanness Brettschneider from the Center for Neurodegenerative Disease Research; and Sharon Xie, from the Department of Biostatics and Epidemiology. Colleagues at the National Alzheimer’s Coordinating Center at the University of Washington also contributed to this report.Funding was provided by the National Institute on Aging (U01 AG016976 and P30 AG010124), with additional support from the Fundacion Alfonso Martin Escudero.

Read more

Shape-shifting disease proteins may explain neurodegenerative variation

July 3, 2013 — Neurodegenerative diseases are not all alike. Two individuals suffering from the same disease may experience very different age of onset, symptoms, severity, and constellation of impairments, as well as different rates of disease progression. Researchers in the Perelman School of Medicine at the University of Pennsylvania have shown one disease protein can morph into different strains and promote misfolding of other disease proteins commonly found in Alzheimer’s, Parkinson’s and other related neurodegenerative diseases.Virginia M.Y. Lee, PhD, MBA, professor of Pathology and Laboratory Medicine and director of the Center for Neurodegenerative Disease Research, with co-director, John Q. Trojanowski MD, PhD, postdoctoral fellow Jing L. Guo, PhD, and colleagues, discovered that alpha-synuclein, a protein that forms sticky clumps in the neurons of Parkinson’s disease patients, can exist in at least two different structural shapes, or “strains,” when it clumps into fibrils, despite having precisely the same chemical composition.These two strains differ in their ability to promote fibril formation of normal alpha-synuclein, as well as the protein tau, which forms neurofibrillary tangles in individuals with Alzheimer’s disease.Importantly, these alpha-synuclein strains are not static; they somehow evolve, such that fibrils that initially cannot promote tau tangles acquire that ability after multiple rounds of “seeded” fibril formation in test tubes.The findings appear in the July 3rd issue of Cell.Morphed Misfolding Proteins Found In Overlapping Neurodegenerative DiseasesTau and alpha-synuclein protein clumps are hallmarks of separate diseases — Alzheimer’s and Parkinson’s, respectively. Yet these two proteins are often found entangled in diseased brains of patients who may manifest symptoms of both disorders.One possible explanation for this convergence of Alzheimer’s and Parkinson’s disease pathology in the same patient is a global disruption in protein folding. But, Guo and Lee showed that one strain of alpha-synuclein fibrils which cannot promote tau fibrillization actually evolved into another strain that could efficiently cause tau to fibrillize in cultured neurons, although both strains are identical at the amino acid sequence level. Guo and Lee called the starting conformation “Strain A,” and the evolved conformation, “Strain B.”To figure out how A and B differ, Guo showed that the two strains folded into different shapes, as indicated by their differential reactivity to antibodies and sensitivity to protein-degrading enzymes. The two strains also differed in their ability to promote tau fibrillization and pathology in mouse brains, mimicking the results from cultured cells. …

Read more

Brain-imaging technique can help diagnose movement disorders

June 13, 2013 — A new University of Florida study suggests a promising brain-imaging technique has the potential to improve diagnoses for the millions of people with movement disorders such as Parkinson’s disease.Utilizing the diffusion tensor imaging technique, as it is known, could allow clinicians to assess people earlier, leading to improved treatment interventions and therapies for patients.The three-year study looked at 72 patients, each with a clinically defined movement disorder diagnosis. Using a technique called diffusion tensor imaging, the researchers successfully separated the patients into disorder groups with a high degree of accuracy.The study is being published in the journal Movement Disorders.”The purpose of this study is to identify markers in the brain that differentiate movement disorders which have clinical symptoms that overlap, making [the disorders] difficult to distinguish,” said David Vaillancourt, associate professor in the department of applied physiology and kinesiology and the study’s principal investigator.”No other imaging, cerebrospinal fluid or blood marker has been this successful at differentiating these disorders,” he said. “The results are very promising.”Movement disorders such as Parkinson’s disease, essential tremor, multiple system atrophy and progressive supranuclear palsy exhibit similar symptoms in the early stages, which can make it challenging to assign a specific diagnosis. Often, the original diagnosis changes as the disease progresses, Vaillancourt said.Diffusion tensor imaging, known as DTI, is a non-invasive method that examines the diffusion of water molecules within the brain and can identify key areas that have been affected as a result of damage to gray matter and white matter in the brain. Vaillancourt and his team measured areas of the basal ganglia and cerebellum in individuals, and used a statistical approach to predict group classification. By asking different questions within the data and comparing different groups to one another, they were able to show distinct separation among disorders.”Our goal was to use these measures to accurately predict the original disease classification,” Vaillancourt said. “The idea being that if a new patient came in with an unknown diagnosis, you might be able to apply this algorithm to that individual.He compared the process to a cholesterol test.”If you have high cholesterol, it raises your chances of developing heart disease in the future,” he said. “There are tests like those that give a probability or likelihood scenario of a particular disease group. We’re going a step further and trying to utilize information to predict the classification of specific tremor and Parkinsonian diseases.”Vaillancourt and his team are part of the National Institute of Neurological Disorders and Stroke Parkinson’s Disease Biomarkers Program, an effort that was launched in 2012 and awarded nine grants to scientists across the U.S., totaling more than $5 million in the first year. The program gives researchers access to a much broader community of individuals and patients as part of a biomarker initiative for Parkinson’s disease.Vaillancourt’s team is engaged in a longitudinal study at UF that will assess between 150 and 180 people over the next few years. …

Read more

Age-related smelling loss significantly worse in African-Americans

June 12, 2013 — The ability to distinguish between odors declines steadily with age, but a new study shows that African-Americans have a much greater decrease in their sense of smell than Caucasians. This can have serious consequences. Olfactory loss often leads to impaired nutrition. It also may be an early warning sign of neurodegenerative diseases, such as Alzheimer’s or Parkinson’s, and can predict death.The study, published early online in the Journal of Gerontology: Medical Sciences, found that as they aged, African-Americans and Hispanics had comparable deficits. For Hispanics, many of whom are recent immigrants, social and cultural factors, such as disparities in education and household assets and health-related cognitive problems, accounted for the sensory loss. For African-Americans, however, premature presbyosmia — age-related declines in the ability to smell — could not be explained by social, environmental or medical factors.”We have long known that men begin to lose their sense of smell some years sooner than women, but this is the first study to point to racial or ethnic differences,” said study author Jayant Pinto, MD, associate professor of surgery at the University of Chicago. “What surprised us was the magnitude of the difference. The racial disparity was almost twice as large as the well-documented difference between men and women.”Although many people live long lives with only minor age-related declines in the ability to smell, about 24 percent of Americans 55 years or older have a measurable problem with their sense of smell, according to data from the National Institute on Aging. That rises to about 30 percent for those ages 70 to 80, and to more than 60 percent for those over age 80.This study was one component of the University of Chicago-based National Social Life, Health and Aging Project (NSHAP), the first in-home study of social relationships and health in a large, nationally representative sample of older adults, ages 57 to 85.For this project, conducted from 2005 to 2006, survey teams from the National Opinion Research Center used a standard, well-validated test to assess the ability of 3,005 older participants to identify five common odors. The scents were presented one at a time. …

Read more

Dance of the atoms: Clustering of atoms observed

June 10, 2013 — Lone people standing in a ballroom don’t tend to move a lot. It’s only when they find a suitable dance partner that rapid motion sets in. Atoms on iron-oxide surfaces behave in a similar way: Only with the right molecular partner do they dance across the surface. Scientists at the Vienna University of Technology have now filmed the atoms, proving that carbon monoxide is the partner responsible for the quick motion. Their movies show that the motion leads directly to clustering — an effect that can do great harm in catalysts.The findings have now been published in the journal Nature Materials.Clusters — What a Waste of Atoms!”Metals such as gold or palladium are often used as catalysts to speed up certain chemical reactions,” says Professor Ulrike Diebold (Institute of Applied Physics, Vienna University of Technology). When the atoms ball together, most of them do not get into contact with the surrounding gas any more and the catalytic effect diminishes drastically. For this reason, Ulrike Diebold’s team investigates how clusters form from single atoms on a surface, and search for ways to inhibit the process.Theories about this effect have been discussed for years, but the researchers at the Vienna University of Technology have now directly observed the clustering of the atoms. “We are using palladium atoms on an extremely clean iron-oxide surfaces in an ultra high vacuum chamber. For several hours, we take pictures of the surface with a scanning tunneling microscope,” says Gareth Parkinson (Vienna University of Technology). These pictures were then made into a movie, in which the paths of the individual atoms could be tracked.The Skyhook EffectUsing this technique, the research team discovered that the rapid atomic dance on the surface is initiated by carbon monoxide molecules, which bind to individual palladium atoms. …

Read more

New technique for deep brain stimulation surgery proves accurate and safe

June 5, 2013 — The surgeon who more than two decades ago pioneered deep brain stimulation surgery in the United States to treat people with Parkinson’s disease and other movement disorders has now developed a new way to perform the surgery — which allows for more accurate placement of the brain electrodes and likely is safer for patients.The success and safety of the new surgical technique could have broad implications for deep brain stimulation, or DBS, surgery into the future, as it may increasingly be used to help with a wide range of medical issues beyond Parkinson’s disease and familial tremors.The new surgery also offers another distinct advantage: patients are asleep during the surgery, rather than being awake under local anesthesia to help surgeons determine placement of the electrodes as happens with the traditional DBS surgery.A study detailing the new surgical technique is being published in the June 2013 edition of the Journal of Neurosurgery, and has been published online at the journal’s website.”I think this will be how DBS surgery will be done in most cases going forward,” said Kim Burchiel, M.D., F.A.C.S., chair of neurological surgery at Oregon Health & Science University and the lead author of the Journal of Neurosurgery article. “This surgery allows for extremely accurate placement of the electrodes and it’s safer. Plus patients don’t need to be awake during this surgery — which will mean many more patients who can be helped by this surgery will now be willing to consider it.”DBS surgery was first developed in France in 1987. Burchiel was the first surgeon in North America to perform the surgery, as part of a Food and Drug Administration-approved clinical trial in 1991.The FDA approved the surgery for “essential tremor” in 1997 and for tremors associated with Parkinson’s disease in 2002. The surgery has been performed tens of thousands of times over the last decade or so in the United States, most often for familial tremor and Parkinson’s disease. Burchiel and his team at OHSU have performed the surgery more than 750 times.The surgery involves implanting very thin wire electrodes in the brain, connected to something like a pacemaker implanted in the chest. The system then stimulates the brain to often significantly reduce the tremors.For most of the last two decades, the DBS patient was required to be awake during surgery, to allow surgeons to determine through monitoring the patient’s symptoms and getting other conscious patient feedback whether the electrodes were placed in the right spots in the brain.But the traditional form of the surgery had drawbacks. Many patients who might have benefitted weren’t willing to undergo the sometimes 4 to 6 hour surgery while awake. There also is a small chance of hemorrhaging in the brain as the surgeon places or moves the electrodes to the right spot in the brain.The new technique uses advances in brain imaging in recent years to place the electrodes more safely, and more accurately, than in traditional DBS surgery. The surgical team uses CT scanning during the surgery itself, along with an MRI of the patient’s brain before the surgery, to precisely place the electrodes in the brain, while better ensuring no hemorrhaging or complications from the insertion of the electrode.The Journal of Neurosurgery article reported on 60 patients who had the surgery at OHSU over an 18-month period beginning in early 2011.”What our results say is that it’s safe, that we had no hemorrhaging or complications at all — and the accuracy of the electrode placement is the best ever reported,” Burchiel said.Burchiel and his team have done another 140 or so surgeries with the new procedure since enrollment in the study ended. …

Read more

Utilizzando il sito, accetti l'utilizzo dei cookie da parte nostra. maggiori informazioni

The cookie settings on this website are set to "allow cookies" to give you the best browsing experience possible. If you continue to use this website without changing your cookie settings or you click "Accept" below then you are consenting to this.

Close