Does consuming low-fat dairy increase the risk of Parkinson’s disease?

Consuming at least three servings of low-fat dairy a day is associated with a greater risk of developing Parkinson’s disease compared to consuming less than one serving a day, according to a large study published in the June 7, 2017, online issue of Neurology®, the medical journal of the American Academy of Neurology. In addition, drinking more than one serving of low-fat or skim milk per day is associated with a greater risk of developing Parkinson’s disease compared to drinking less than one serving per week. The study results do not show that dairy products cause Parkinson’s disease — they just show an association.

“Our study is the largest analysis of dairy and Parkinson’s to date,” said Katherine C. Hughes, ScD, of the Harvard T.H. Chan School of Public Health in Boston. “The results provide evidence of a modest increased risk of Parkinson’s with greater consumption of low-fat dairy products. Such dairy products, which are widely consumed, could potentially be a modifiable risk factor for the disease.”

For the study, researchers analyzed approximately 25 years of data on 80,736 women enrolled in the Nurses’ Health Study and 48,610 men enrolled in the Health Professionals’ Follow-up Study. Participants in these studies completed health questionnaires every two years and diet questionnaires every four years. During that time, 1,036 people developed Parkinson’s.

Researchers examined what kinds of dairy each person consumed, including milk, cream, cheese, yogurt, ice cream, butter, margarine and sherbet. They then looked at whether full-fat dairy, as whole milk, was associated with a risk of Parkinson’s disease; there was no association. However, those who consumed at least three servings of low-fat dairy a day had a 34 percent greater chance of developing Parkinson’s than people who consumed less than one serving per day. The researchers also found that when looking specifically at skim and low-fat milk consumption, there was a 39 percent greater chance of developing Parkinson’s for people who consumed more than one serving per day compared to those who consumed less than one serving per week. Eating sherbet or frozen yogurt also was linked to a modest increased risk.

In a meta-analysis, looking at a group of studies, the researchers found that total dairy intake was associated with an increased risk of Parkinson’s disease.

The overall conclusions from these studies was that frequent consumption of dairy products was associated with a modest increased risk of Parkinson’s disease.

It is important to note that the risk of developing Parkinson’s was still very low. Of the 5,830 people who consumed at least three servings per day of low-fat dairy at the start of the study, only 60 people, or 1 percent, developed the disease over the study period. In comparison, of the 77,864 people who consumed less than one serving per day of low-fat dairy, 483 people, or 0.6 percent, developed Parkinson’s.

“Frequently consuming low-fat dairy products was associated with a modest increased risk of Parkinson’s disease,” said Hughes.

One limitation of the study was that early Parkinson’s symptoms may have affected the dietary behaviors and questionnaire responses of study participants.

More research is needed before recommendations can be made about dairy consumption.

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Infection with seasonal flu may increase risk of developing Parkinson’s disease

Most cases of Parkinson’s have no known cause, and researchers continue to debate and study possible factors that may contribute to the disease. Research reported in the journal npj Parkinson’s Disease suggests that a certain strain of influenza virus predisposes mice to developing pathologies that mimic those seen in Parkinson’s disease.

“This study has provided more evidence to support the idea that environmental factors, including influenza may be involved in Parkinson’s disease,” says Richard J. Smeyne, Ph.D., Professor of Neuroscience in the Sidney Kimmel Medical College at Thomas Jefferson University and Director of the Jefferson Parkinson’s Disease Center in the Vickie and Jack Farber Institute for Neuroscience. “Here we demonstrate that even mice who fully recover from the H1N1 influenza virus responsible for the previous pandemic (also called ‘swine flu’) are later more susceptible to chemical toxins known to trigger Parkinson’s in the lab.”

Previously, Dr. Smeyne and his collaborator Dr. Stacey Schultz-Cherry in the Department of Infectious Disease at St. Jude Children’s Research Hospital in Memphis, TN, showed that a deadly H5N1 strain of influenza (so-called Bird Flu) that has a high mortality rate (60 percent of those infected died from the disease) was able to infect nerve cells, travel to the brain, and cause inflammation that, the researchers showed, would later result in Parkinson’s-like symptoms in mice. Inflammation in the brain that does not resolve appropriately, such as after traumatic injury to head, has also been linked to Parkinson’s.

Building on that work, the current paper looked at a less lethal strain, the H1N1 “swine flu,” that does not infect neurons, but which, the researchers showed, still caused inflammation in the brain via inflammatory chemicals or cytokines released by immune cells involved in fighting the infection.

Using a model of Parkinson’s disease in which the toxin MPTP, made famous in book “The Case of the Frozen Addicts,” induces Parkinson’s-like symptoms in humans and mice, Dr. Smeyne showed that mice infected with H1N1, even long after the initial infection, had more severe Parkinson’s symptoms than those who had not been infected with the flu. Importantly, when mice were vaccinated against the H1N1, or were given antiviral medications such as Tamiflu at the time of flu infection, the increased sensitivity to MPTP was eliminated.

“The H1N1 virus that we studied belongs to the family of Type A influenzas, which we are exposed to on a yearly basis,” says Dr. Smeyne. “Although the work presented here has yet to be replicated in humans, we believe it provides good reason to investigate this relationship further in light of the simple and potentially powerful impact that seasonal flu vaccination could have on long-term brain health.”

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Mechanisms behind sensory deficits in Parkinson’s disease

Although Parkinson’s disease is often associated with motor symptoms such as stiffness, poor balance and trembling, the first symptoms are often sensory and include a reduced sense of touch and smell. In a study on mice, researchers at Karolinska Institutet have now been able to identify neural circuits and mechanisms behind this loss of sensory perception. The study, which is published in the scientific journal Neuron, may open avenues to methods of earlier diagnosis.

There are some 18,000 people with Parkinson’s disease in Sweden, and around 2,000 new diagnoses every year. The disease, which is one of our most common neurological conditions, is currently incurable, although its symptoms can be alleviated.

When we think of Parkinson’s disease, we often focus on its motor symptoms, such as stiffness and trembling, which are caused by a gradual decrease in the dopamine supply to a brain area called the striatum, the primary input nucleus of the basal ganglia.

Research on Parkinson’s disease has mainly focused on these motor impairments. However, patients are also affected by severe sensory problems, including an impaired sense of smell, touch and vision, and this area of research has remained relatively neglected.

“Our study highlights the sensory aspects of basal ganglia function and presents a new approach to the mechanisms behind the sensory impairments seen in Parkinson’s disease,” says Gilad Silberberg, associate professor at Karolinska Institutet’s Department of Neuroscience.

The researchers in the present study used a light puff of air to stimulate either the right or left whiskers of mice, some of which had an especially low number of dopamine cells, while using a new optogenetic tool called an optopatcher. Applying this technique, which enables the activity of neurons to be recorded during manipulation with light, they were able to see which neurons in the basal ganglia were active and when they transmitted signals.

“By studying neuronal activity in the striatum, we found that the neurons in dopamine-depleted mice did not properly signal if it was the right or left whiskers that were being stimulated,” says Dr Silberberg. “But when we treated the mice with L-DOPA, the most commonly used Parkinson’s drug, they recovered their ability to distinguish between left and right.”

It is hoped that the discovery will open the way for methods of earlier diagnosis.

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What is survival among patients with Parkinson, Dementia with lewy bodies?

A new article published by JAMA Neurology compares survival rates among patients with synucleinopathies, including Parkinson disease, dementia with Lewy bodies, Parkinson disease dementia and multiple system atrophy with parkinsonism, with individuals in the general population.

The population-based study by Rodolfo Savica, M.D., Ph.D., and coauthors of the Mayo Clinic, Rochester Minn., included all the residents of Minnesota’s Olmsted County and identified 461 patients with synucleinopathies and 452 patients without for comparison.

From 1991 through 2010, the 461 patients with a synucleinopathy diagnosis included 309 with Parkinson disease, 81 with dementia with Lewy bodies, 55 with Parkinson disease dementia and 16 with multiple system atrophy with parkinsonism. Parkinsonism was defined as the presence of at least 2 of 4 cardinal signs: rest tremor, bradykinesia, rigidity and impaired postural reflexes.

Of the 461 patients with synucleinopathies, 316 (68.6 percent) died during follow-up, while among the 452 participants used for comparison, 220 (48.7 percent) died during follow-up.

Overall, patients with synucleinopathies died about two years earlier than participants without in the comparison group. The highest risk of death was seen among patients with multiple system atrophy with parkinsonism, followed by patients with dementia with Lewy bodies, Parkinson disease dementia and Parkinson disease, according to the results.

The authors note some limitations of their study. “Our findings contribute important new evidence about the natural history and survival of people affected by synucleinopathies of various types. Our results may be helpful to guide clinicians counseling patients and caregivers,” according to the article.

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Could Parkinson’s disease start in the gut?

Parkinson’s disease may start in the gut and spread to the brain via the vagus nerve, according to a study published in the April 26, 2017, online issue of Neurology®, the medical journal of the American Academy of Neurology. The vagus nerve extends from the brainstem to the abdomen and controls unconscious body processes like heart rate and food digestion.

The preliminary study examined people who had resection surgery, removing the main trunk or branches of the vagus nerve. The surgery, called vagotomy, is used for people with ulcers. Researchers used national registers in Sweden to compare 9,430 people who had a vagotomy over a 40-year period to 377,200 people from the general population. During that time, 101 people who had a vagotomy developed Parkinson’s disease, or 1.07 percent, compared to 4,829 people in the control group, or 1.28 percent. This difference was not significant.

But when researchers analyzed the results for the two different types of vagotomy surgery, they found that people who had a truncal vagotomy at least five years earlier were less likely to develop Parkinson’s disease than those who had not had the surgery and had been followed for at least five years. In a truncal vagotomy, the nerve trunk is fully resected. In a selective vagotomy, only some branches of the nerve are resected.

A total of 19 people who had truncal vagotomy at least five years earlier developed the disease, or 0.78 percent, compared to 3,932 people who had no surgery and had been followed for at least five years, at 1.15 percent. By contrast, 60 people who had selective vagotomy five years earlier developed Parkinson’s disease, or 1.08 percent.

After adjusting for factors such as chronic obstructive pulmonary disease, diabetes, arthritis and other conditions, researchers found that people who had a truncal vagotomy at least five years before were 40 percent less likely to develop Parkinson’s disease than those who had not had the surgery and had been followed for at least five years.

“These results provide preliminary evidence that Parkinson’s disease may start in the gut,” said study author Bojing Liu, MSc, of the Karolinska Instituet in Stockholm, Sweden. “Other evidence for this hypothesis is that people with Parkinson’s disease often have gastrointestinal problems such as constipation, that can start decades before they develop the disease. In addition, other studies have shown that people who will later develop Parkinson’s disease have a protein believed to play a key role in Parkinson’s disease in their gut.”

The theory is that these proteins can fold in the wrong way and spread that mistake from cell to cell.

“Much more research is needed to test this theory and to help us understand the role this may play in the development of Parkinson’s,” Liu said. Additionally, since Parkinson’s is a syndrome, there may be multiple causes and pathways.

Even though the study was large, Liu said one limitation was small numbers in certain subgroups. Also, the researchers could not control for all potential factors that could affect the risk of Parkinson’s disease, such as smoking, coffee drinking or genetics.

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Milk study improves understanding of age-related diseases

A new study on UHT milk is helping scientists to better understand Alzheimer’s, Parkinson’s and type 2 diabetes, opening the door to improved treatments for these age-related diseases.

About 500 million people worldwide suffer from these diseases, which cause millions of deaths each year.

Co-lead researcher, ANU Professor John Carver, said that two unrelated proteins aggregate in UHT milk over a period of months to form clusters called amyloid fibrils, which cause the milk to transform from a liquid into a gel.

He said the same type of protein clusters are found in plaque deposits in cases of Alzheimer’s and Parkinson’s.

“Parkinson’s, dementia and type 2 diabetes are big problems for the ageing population in Australia and many other countries around the world,” said Professor Carver from the ANU Research School of Chemistry.

“Our interest in milk proteins led to a discovery of the reason for this gelling phenomenon occurring in aged UHT milk.”

“The research does not suggest UHT milk can cause these age-related diseases.”

Professor Carver said milk proteins changed structurally when heated briefly to around 140 degrees to produce UHT milk, causing the gelling phenomenon with long-term storage.

He said normal pasteurised milk did not form amyloid fibrils.

ANU worked with CSIRO, University of Wollongong and international researchers on the study, which is published in the journal Small.

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US burden of neurological disease is nearly $800 billion/year

The most common neurological diseases cost the United States $789 billion in 2014, and this figure is projected to grow as the elderly population doubles between 2011 and 2050, according to a new study published in the April issue of the Annals of Neurology. The research shows the price tag of this serious, annual financial burden for the nation, and comes at a time when the new administration has proposed significant budget cuts for federally-funded research.

Based on this demographic trend, the American Neurological Association (ANA) commissioned a study led by former ANA marketing committee and public advocacy committee chair Clifton L. Gooch, MD, currently professor and chair of the Department of Neurology at the University of South Florida’s Morsani College of Medicine in Tampa. The study, The Burden of Neurological Disease in the United States: A Summary Report and Call to Action, details the annual cost of nine key neurological diseases and disorders, including Alzheimer’s disease and other dementias; low back pain; stroke; traumatic brain injury; migraine; epilepsy; multiple sclerosis; spinal cord injury; and Parkinson’s disease. Neurological diseases impact an estimated 100 million Americans every year, with the costs of dementia and stroke alone projected to total more than $600 billion by 2030.

A “Moonshot” for Neurology:

The huge and sustained capital investments made in cardiovascular and cancer research starting in the 1970s have increased lifespan. Ironically, these gains have increased the number of elderly who are most susceptible to neurological disease, creating a growing epidemic.

“Neurological research, like cancer, needs its own ‘Moonshot’ to focus substantial research investment on the neurological diseases that are impacting the mortality and quality of life of more and more Americans every year,” said Gooch, referring to the $1.8 billion in funding for cancer research authorized by Congress in 2016. “We hope the findings of this report will serve as a wake-up call to

Congress to increase much needed basic and clinical research funding required to discover treatments which can mitigate, and ultimately cure, the major neurological diseases which have such profound effects in our patients and for the national economy.”

“The future of funding for neurological research was a concern in 2012 when the ANA voted to support this investigation,” said ANA President Barbara G. Vickrey, MD, MPH. “With the cuts currently proposed to the NIH budget by the President of the United States, it is of even greater concern today. As representatives of the scholars working to eradicate these diseases, we feel we must raise our collective voices, armed with the facts.”

Researchers compiled the report through a detailed review of the world literature of the most costly and most prevalent neurological diseases in the United States. To be conservative, researchers focused on the prevalence and cost estimates they considered most comprehensive and accurate, excluding disorders like depression and chronic pain, which often have mixed etiologies beyond primary nervous system injury.

A conservative estimate:

“A full accounting of all neurological disorders, would of course, push cost estimates substantially higher,” the authors wrote. Direct and indirect costs for each of the major diseases were estimated based on care norms for each disease and are detailed in the report.

Alzheimer’s and other dementias accounted for $243 billion of the $789 billion total, while chronic low back pain represented $177 billion; and stroke, $110 billion.

Dollar figures were converted to 2014 values using the all-items consumer price index for non-medical (indirect) costs. Direct costs were converted using the medical price index.

In addition to documenting the financial costs of neurological disease, Gooch and his USF colleagues recommend an action plan for reducing the burden through infrastructure investment in neurological research and enhanced clinical management of neurological disorders. Specifics include:

  • Acceleration of translational research in preventative and disease-modifying therapy;
  • Enhanced outcome and comparative effectiveness research;
  • Comprehensive databasing and tracking of neurological disease; and
  • Taking advocacy to the next level, coordinating efforts at the individual, neurology association, and local, state and federal government levels to make funding these initiatives a priority.

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Surprising culprit in nerve cell damage identified

In many neurodegenerative conditions — Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and peripheral neuropathy among them — an early defect is the loss of axons, the wiring of the nervous system. When axons are lost, nerve cells can’t communicate as they should, and nervous system function is impaired. In peripheral neuropathy in particular, and perhaps other diseases, sick axons trigger a self-destruct program.

In new research, scientists at Washington University School of Medicine in St. Louis have implicated a specific molecule in the self-destruction of axons. Understanding just how that damage occurs may help researchers find a way to halt it.

The study is published March 22 in the journal Neuron.

“Axons break down in a lot of neurodegenerative diseases,” said senior author Jeffrey D. Milbrandt, MD, PhD, the James S. McDonnell Professor and head of the Department of Genetics. “Despite the fact these diseases have different causes, they are all likely rooted in the same pathway that triggers axon degeneration. If we could find a way to block the pathway, it could be beneficial for many different kinds of patients.”

Since the molecular pathway that leads to loss of axons appears to do more harm than good, it’s not clear what role this self-destruct mechanism plays in normal life. But scientists suspect that if the pathway that destroys axons could be paused or halted, it would slow or prevent the gradual loss of nervous system function and the debilitating symptoms that result. One such condition, peripheral neuropathy, affects about 20 million people in the United States. It often develops following chemotherapy or from nerve damage associated with diabetes, and can cause persistent pain, burning, stinging, itching, numbness and muscle weakness.

“Peripheral neuropathy is by far the most common neurodegenerative disease,” said co-author Aaron DiAntonio, MD, PhD, the Alan A. and Edith L. Wolff Professor of Developmental Biology. “Patients don’t die from it, but it has a huge impact on quality of life.”

In previous studies, Stefanie Geisler, MD, an assistant professor of neurology, working with DiAntonio and Milbrandt, showed that blocking this axon self-destruction pathway prevented the development of peripheral neuropathy in mice treated with the chemotherapy agent vincristine. The hope is that if methods are developed to block this pathway in people, then it might be possible to slow or prevent the development of neuropathy in patients.

Toward that end, the Milbrandt and DiAntonio labs showed that a molecule called SARM1 is a central player in the self-destruct pathway of axons. In healthy neurons, SARM1 is present but inactive. For reasons that are unclear, injury or disease activate SARM1, which sets off a series of events that drains a key cellular fuel — called nicotinamide adenine dinucleotide (NAD) — and leads to destruction of the axon. Though the researchers previously had shown SARM1 was required for this chain of events to play out, the details of the process were unknown.

SARM1 and similar molecules — those containing what are called TIR domains — most often are studied in the context of immunity, where these domains serve as scaffolds. Essentially, TIR domains provide a haven for the assembly of molecules or proteins to perform their work.

The researchers had assumed that SARM1 acted as a scaffold to provide support for the work of destroying axons, beginning with the rapid loss of cellular fuel that occurs minutes after SARM1 becomes active. The scientists set about searching for the demolition crew — the active molecule or molecules that use the SARM1 scaffold to carry out the demolition. The study’s first author, Kow A. Essuman, a Howard Hughes Medical Institute Medical Research Fellow and an MD/PhD student in Milbrandt’s lab, performed a litany of cellular and biochemical experiments searching for the demolition crew and came up empty.

“We performed multiple experiments but could not identify molecules that are traditionally known to consume NAD,” Essuman said.

But as a last resort, the investigators tested SARM1 itself. To their great surprise, they found it was doing more than simply providing a passive platform. Specifically, the researchers showed SARM1’s TIR domain acts as an enzyme, a molecule that carries out biochemical reactions, in this case destroying axons by first burning all their NAD cellular fuel.

“There are more than 1,000 papers describing the function of proteins containing TIR domains,” DiAntonio said. “No one had ever shown that this type of molecule could be an enzyme. So we went into our experiments assuming SARM1 was only a scaffold and that there must be some other enzyme responsible for demolition of the axon. We essentially searched for a demolition crew, only to discover that the scaffold itself is destroying the structure. It’s the last thing you would expect.”

The findings suggest molecules similar to SARM1 — those with TIR domains and known to serve as scaffolds in the immune system — may prove to have additional functions that go beyond their structural roles. The research also invites a search for drugs that block the SARM1 enzyme from triggering axonal destruction.

 

Exercising 2.5 hours per week associated with slower declines in Parkinson’s disease patients

Parkinson’s disease (PD) is a progressive condition that often results in mobility impairments and can lead to decreased health-related quality of life (HRQL) and death. There is evidence that physical activity can delay decline in PD patients. In a study in the Journal of Parkinson’s Disease, researchers determined that that people who exercised regularly had significantly slower declines in HRQL and mobility over a two-year period.

Lead investigator Miriam R. Rafferty, PhD, of Northwestern University and Rehabilitation Institute of Chicago, describes the main findings of the study. “We found that people with Parkinson’s disease who maintained exercise 150 minutes per week had a smaller decline in quality of life and mobility over two years compared to people who did not exercise or exercised less. The smaller decline was significant for people who started the study as regular exercisers, as well as for people who started to exercise 150 minutes per week after their first study-related visit.”

The data came from the National Parkinson Foundation Quality Improvement Initiative (NPF-QII), an international, multicenter, prospective clinical study of care and outcomes that has recorded data from 21 sites in North America, the Netherlands, and Israel identified as Centers of Excellence by the National Parkinson Foundation. Over 3400 participants provided data over two years, with information collected during at least three clinic visits. The NPF-QII study collects demographics, disease duration, Hoehn and Yahr stage (HY), brief cognitive assessments, as well as data on pharmacologic and non-pharmacologic management of PD symptoms. These observational study visits are scheduled on a yearly basis. At each visit, exercise is measured by the self-reported number of hours per week of exercise.

The Parkinson Disease Questionnaire (PDQ-39) is used to measure patient-reported, PD-specific HRQL. Functional mobility was measured by the Timed Up and Go (TUG) test, in which performance is tested by timing participants as they rise from a chair, walk three meters, turn, and return to a sitting position.

Although this study did not determine which type of exercise is best, it suggests that any type of exercise done with a “dose” of at least 150 minutes per week is better than not exercising. “People with PD should feel empowered to find the type of exercise they enjoy, even those with more advanced symptoms,” remarked Dr. Rafferty.

An unanticipated finding from the study was that the HRQL benefit associated with 30-minute increases in exercise per week was greatest in people with advanced PD. These data have significant implications for making exercise and physical activity more accessible to people with more severe disability. People with more advanced PD may have poor access to regular exercise, as their mobility impairments would limit their independent participation in existing community and group exercise programs.

“The most important part of the study,” according to Dr. Rafferty, “is that it suggests that people who are not currently achieving recommended levels of exercise could start to exercise today to lessen the declines in quality of life and mobility that can occur with this progressive disease.”

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Researchers help map future of precision medicine in Parkinson’s disease

Two landmark publications with one or more co-authors from the University of Cincinnati Gardner Neuroscience Institute outline a transformative approach to defining, studying and treating Parkinson’s disease. Rather than approaching Parkinson’s disease as a single entity, the international cadre of researchers advocates targeting therapies to distinct “nodes or clusters” of patients based on specific symptoms or molecular features of their disease.

Alberto Espay, MD, associate professor of neurology at the UC College of Medicine and director of the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders, is lead author of the publications, which recently appeared online in the journals Nature Reviews Neurology and Movement Disorders.

“The time has come to ask what we should be doing differently,” Espay says. “Medical science has made a global investment of $23 billion in therapies with the promise to slow down the progression of Parkinson’s disease, and the 17 completed phase III clinical trials have yielded little more than disappointment. We need to ask whether the growing number of failed trials might be explained by our single-target and single-disease approach to drug development.”

Espay and his colleagues theorize that Parkinson’s is not one disease but rather several diseases when considered from genetic and molecular perspectives. They acknowledge that viewing Parkinson’s as a single disorder that predominantly involves dopamine-neuron degeneration has been useful in the development of treatments for symptoms, such as tremor and unstable walking, that touch the vast majority of patients. At the same time, this view has yet to deliver a therapy that is effective in slowing, modifying or curing Parkinson’s. One important reason, Espay says, could be that promising molecular therapies have been tested in large clinical trials of people who share the diagnosis of Parkinson’s, but not to the specific disease subtype most likely to benefit.

The researchers advocate a “precision medicine” approach that is rooted in systems biology, an inter-disciplinary study that focuses on the complex interactions of biological systems.

“Looking at the disease from a systems biology perspective allows us to recognize that our patients can be divided into subtypes based on genetic, biological and molecular abnormalities,” Espay says. “As a result, they will respond differently to different therapies.”

Neurologists have long observed the many faces of Parkinson’s in their patients. Some progress rapidly in their disease, some slowly. Some develop dementia relatively early, while others do not.

Tests have also revealed that patients develop deposits of alpha-synuclein, a protein, to varying degrees in the brain, colon, heart, skin, and olfactory bulb. But while these deposits have been thought to be common denominators in most individuals with Parkinson’s, they may represent byproducts of a range of biological abnormalities and may not be the best targets of therapy. “Chasing this tail could prove an elusive target,” Espay says.

Toward an Ideal Set of Biomarkers

Espay and his colleagues say the field must work to develop an ideal set of biomarkers. Their sobering conclusion comes after an investment of $45 million by the Michael J. Fox Foundation in the Parkinson’s Progression Markers Initiative (PPMI). Espay, the site leader for Cincinnati’s portion of the 33-site study, had hoped the effort would help researchers discover biomarkers that would pinpoint underlying disease processes.

The ideal approach, Espay and his co-authors write, would start with “an assessment of biological processes” in large populations of aging individuals. The assessments would capture brain scans, genetic profiles and other biological measurements of healthy and unhealthy individuals over time. Abnormal signals within each of these biological measurements would then be traced to the group of people from which they emerge. In so doing, the field would develop “unbiased biomarkers” that drive the creation of specific disease subtypes.

“This process is the reverse of what we have today, with biomarkers being validated by anchoring them to the patient’s observable clinical features, or phenotypes,” Espay says.

Espay has likened the situation to an earlier period in oncology, when researchers sought “the cure for cancer.” Over a period of decades, cancer researchers evolved away from that blanket focus to an understanding of cancer’s profound complexity. They learned to assess a cancer’s molecular profile and to target its unique mutation or vulnerability. In so doing they ushered in the age of precision medicine — the matching of drugs to disease subtypes.

“The neurologist of the future would look very much like the oncologist of the present,” Espay says. “The diagnosis of Parkinson’s disease will be complete only when a biomarker profiling is capable of identifying the molecular subtypes of disease and suggest a disease-modifying treatment to apply.”

Bowel cancer medication could help combat early-onset Parkinson’s disease

People with certain forms of early-onset Parkinson’s disease could potentially benefit from taking a medication used to treat certain forms of cancer, according to new research by University of Leicester scientists and funded by the Medical Research Council.

The study, which has been published in Science Matters, suggests that folinic acid, which is used in medications to treat bowel cancer, can also protect neurons associated with Parkinson’s disease in fruit flies.

Dr Miguel Martins from the MRC Toxicology Unit at the University of Leicester explained: “Parkinson’s disease is a disabling disorder for which no cure is yet available; further, after dopaminergic neurons are lost, only a few palliative treatment options for Parkinson’s symptoms are available. Therefore, treatments that either prevent or delay the onset of the disease at an early stage are needed.

“Folinic acid is already approved and used for applications in the clinic as an adjuvant during chemotherapy and can be administered orally, as a dietary supplement, or intravenously.

“Thus, the drug safety risk is low, and drug development for repurposing folinic acid as a treatment for Parkinson’s disease would be faster than for a novel drug.

“With this in mind, it seems worthwhile to further test the supplementation of folinic acid in clinical trials with human participants as a potential preventative or palliative therapeutic for PD and to expand the repertoire of treatment options.”

The researchers studied fruit flies with faulty mitochondria caused by a mutation that mimics Parkinson’s disease in humans. Lab experiments, like this, allow us to draw conclusions about the effect of folinic acid on neurons in fruit flies.

Previous research by the team has shown that folic acid protects neurons in models of Parkinson’s disease. Folinic acid is related to folic acid but is metabolically more active.

In contrast to folic acid, folinic acid taken orally can penetrate into the human brain.

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‘Red hair’ gene variant may underlie association between melanoma and Parkinson’s disease

A gene variant that produces red hair and fair skin in humans and in mice, which increases the risk of the dangerous skin cancer melanoma, may also contribute to the known association between melanoma and Parkinson’s disease. In their paper appearing in the March issue of Annals of Neurology and previously published online, Massachusetts General Hospital (MGH) investigators report that mice carrying the red hair variant of the melanocortin 1 receptor (MC1R) gene have reduced production of the neurotransmitter dopamine in the substantia nigra — the brain structure in which dopamine-producing neurons are destroyed in Parkinson’s disease (PD) — and are more susceptible to toxins known to damage those neurons.

“This study is the first to show direct influences of the melanoma-linked MC1R gene on dopaminergic neurons in the brain and may provide evidence for targeting MC1R as a novel therapeutic strategy for PD,” says Xiqun Chen, MD, PhD, of the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), lead and corresponding author of the report. “It also forms a foundation for further interdisciplinary investigations into the dual role of this gene in tumorigenesis within melanocytes — the pigment cells in which melanoma develops — and the degeneration of dopaminergic neurons, improving our understanding of why and how melanoma and Parkinson’s disease are linked.”

Inherited variants of the MC1R gene determine skin pigmentation, with the most common form leading to greater production of the darker pigment called eumelanin and the red-hair-associated variant, which inactivates the gene’s function, increasing production of the lighter pigment called pheomelanin. Not only does pheomelanin provide less protection from ultraviolet damage to the skin than does eumelanin, but a 2012 study led by David Fisher, MD, PhD — chief of the MGH Department of Dermatology, director of the Cutaneous Biology Research Center and a co-author of the current study — found it also may directly contribute to melanoma development.

While patients with Parkinson’s disease have a reduced risk of developing most types of cancer, their higher-than-expected risk of melanoma is well recognized, as is the increased risk of PD in patients with melanoma. Several recent studies also have found evidence suggesting increased PD risk in individuals with red-hair-associated variants of MC1R, so the current study was designed to explore that potential role of the gene in PD and specifically in dopamine-producing neurons of the substantia nigra.

The team’s experiments showed that, in mice with the common form of MC1R, the gene is expressed in dopamine-producing neurons in the substantia nigra. The red-haired mice in which the gene is inactivated because of a mutation were found to have fewer dopamine-producing neurons and as they aged developed a progressive decline in movement and a drop in dopamine levels. They also were more sensitive to toxic substances known to damage dopamine-producing neurons and had indications of increased oxidative stress — which the 2012 study implied was involved in pheomelanin-associated melanoma risk — in brain structures adjacent to the substantia nigra. Treatment with a substance that increases MC1R signaling reduced the susceptibility of mice with the common variant to a neurotoxin, further supporting a protective role for the gene’s activity.

“Since MC1R regulates pigmentation and red hair is a shared risk factor for both melanoma and Parkinson’s disease, it is possible that, in both conditions, MC1R’s role involves pigmentation and related oxidative stress,” says Chen, an assistant professor of Neurology at Harvard Medical School. “Our findings suggest further investigation into the potential of MC1R-activating agents as novel neuroprotective therapies for PD, and together with epidemiological evidence, may offer information that could guide those carrying MC1R variants to seek advice from dermatologists or neurologists about their personal risk for melanoma and Parkinson’s disease.” Chen’s team is continuing to pursue this line of research.

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Researchers suggest new theory for how Parkinson’s disease develops

The toxic protein behind Parkinson’s disease may not spread like an infection from nerve cell to nerve, according to a new theory by Technion and Harvard University scientists. Instead, the protein, called alpha-synuclein, may simultaneously affect all parts of the nervous system inside and outside of the brain. Their findings could change how Parkinson’s is treated, the researchers say.

Associate Professor Simone Engelender of the Technion-Israel Institute of Technology and her colleague Ole Isacson at Harvard Medical School describe this “threshold theory” of Parkinson’s for the first time in a report published in the January issue of Trends in Neuroscience.

“Instead of studying how proteins move from one neuron to another and searching for compounds that prevent the ‘spread’ of aggregated α-synuclein, we need to study why α-synuclein accumulates within neurons and how these neurons die in the disease, and search for compounds that prevent the general neuronal dysfunction,” said Professor Engelender.

Parkinson’s disease destroys nerve cells throughout the body, especially key neurons in the brain that produce a compound called dopamine that helps to control movement and posture. The disease grows worse over time, and there is no known cure. More than one million people in the United States have the disorder, according to the Parkinson’s Disease Foundation.

The disease is caused by accumulation of α-synuclein, which overwhelms and destroys nerve cells. The most commonly-held theory about the disease suggests that patients get progressively worse as clumps of α-synuclein spread between neurons, almost like an infection.

But Engelender and Isacson think the scientific evidence points to a different model of the disease. Instead of spreading from neuron to neuron, they say, aggregations of α-synuclein develop throughout the body at the same time. Different parts of the nervous system vary in how much of this toxic protein they can tolerate, depending on how well the cells in that part of the system work together to compensate for any destroyed cells.

The researchers say their theory fits better with patients’ symptoms than the infection-style theory. Engelender and Isacson’s theory may help explain, for example, why some of the earliest signs of the disease appear in places like the gastrointestinal tract that have no neurons to compensate for a dysfunction and therefore have a lower threshold of tolerance for α-synuclein toxicity.

The new theory may also affect how the disease is treated. For instance, some scientists have recommended a procedure that severs part of the vagus nerve, which runs outside the brain, to prevent the spread of α-synuclein from the body to the brain. The threshold theory, Engelender said, suggests that this operation would be unnecessary.

“The only specific treatment that is and will continue to be beneficial is the replenishment of dopamine in the brain, through the intake of the supplement L-Dopa, to improve the motor symptoms,” said Engelender. “This has been done for several decades and should be continued to be done since it can at least alleviate the motor symptoms for a few years, even if does not cure and does not prevent the progression of the disease.”

“Nevertheless, I believe that the search for compounds that specifically decrease α-synuclein levels are the only hope to provide a real and more effective treatment for the disease,” Engelender added.

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Materials provided by American Technion Society. Note: Content may be edited for style and length.

Discovery of genetic switch could help to prevent symptoms of Parkinson’s disease

A genetic ‘switch’ has been discovered by MRC researchers at the University of Leicester which could help to prevent or delay the symptoms of Parkinson’s disease.

In a paper published in the journal Cell Death and Differentiation, the team discovered that a gene called ATF4 plays a key role in Parkinson’s disease, acting as a ‘switch’ for genes that control mitochondrial metabolism for neuron health.

Dr Miguel Martins from the MRC Toxicology Unit at the University of Leicester, who led the research, explained: “When the expression of ATF4 is reduced in flies, expression of these mitochondrial genes drops. This drop results in dramatic locomotor defects, decreased lifespan, and dysfunctional mitochondria in the brain.

“Interestingly, when we overexpressed these mitochondrial genes in fly models of Parkinson’s, mitochondrial function was reestablished, and neuron loss was avoided.”

By discovering the gene networks that orchestrate this process, the researchers have singled out new therapeutic targets that could prevent neuron loss.

Some forms of Parkinson’s are caused by mutations in the genes PINK1 and PARKIN, which are instrumental in mitochondrial quality control.

Fruit flies with mutations in these genes accumulate defective mitochondria and exhibit Parkinson’s-like changes, including loss of neurons.

The researchers used PINK1 and PARKIN mutant flies to search for other critical Parkinson’s genes — and using a bioinformatics approach discovered that the ATF4 gene plays a key role.

Dr Martins added: “Studying the roles of these genes in human neurons could lead to tailored interventions that could one day prevent or delay the neuronal loss seen in Parkinson’s.”

The findings build upon recent research by the University of Leicester team, which recently discovered several genes that protect neurons in Parkinson’s disease, creating possibilities for new treatment options.

Two of the genes — PINK1 and PARKIN — affect how mitochondria break down amino acids to generate nucleotides — the metabolism of these molecules generates the energy that cells need to live.

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Neurotrophic factor GDNF is an important regulator of dopamine neurons in the brain

New research results are expanding our understanding of the physiological role of the glial cell line-derived neurotrophic factor GDNF in the function of the brain’s dopamine systems. In an article recently published in the Journal of Neuroscience, University of Helsinki researchers establish that GDNF is an important physiological regulator of the functioning of the brain’s dopamine neurons.

Dopamine neurons have an important role in cognitive control, learning and motor control. GDNF is best known for its ability to protect dopaminergic neurons from damage, which is why it is currently in clinical trials for treatment of Parkinson’s patients. Nevertheless, the significance of endogenous GDNF that is produced in our brains for the regulation of the dopamine systems is still poorly understood.

Dr Jaan-Olle Andressoo from the Institute of Biotechnology has developed new transgenic mice which have allowed researchers to gain much more reliable information on the physiological functions of GDNF. The studies were conducted in close cooperation with the research groups led by Professor Mart Saarma and Dr Petteri Piepponen, docent of pharmacology.

The new research results indicate that the GDNF produced in the brain regulates dopamine reuptake. Mice with no GDNF in their brains displayed significantly stronger reuptake of dopamine into nerve endings.

“The reuptake of dopamine is the most important factor regulating the brain’s dopamine balance and signalling. In practice this means that differences in GDNF levels might explain certain differences in people’s ability to learn or focus,” explains Jaakko Kopra, a researcher in Andressoo’s group.

In addition, the transgenic mice had an atypically low reaction to amphetamine, which specifically targets the dopamine transporter in the brain. These observations were associated with changes in the functionality, amount and localization of the dopamine transporter in the nerve endings.

“So we know that GDNF regulates the amount and localization of the dopamine transporter in the neurons, but we suspect that there may be additional mechanisms. It seems that the relationship between GDNF and dopamine transporter is surprisingly complex, which is of course interesting from a researcher viewpoint,” explains Kopra.

Mice with GDNF removed from their brain in adulthood displayed very similar changes. This indicates that the underlying cause for the changes is not the impact of GDNF on brain development. The group’s previously published studies on the same mouse models demonstrated that contrary to expectations, the removal of GDNF does not lead to the destruction of dopamine neurons. This means that these new results significantly expand our understanding of physiological GDNF, from a factor protecting dopamine neurons to a dynamic regulator of their function.

“This knowledge is crucial for developing new treatments for not just Parkinson’s disease, but also for addiction, ADHD and bipolar disorder, as all of these diseases are associated with some type of disorder in the function of the dopamine neurons, and specifically in the dopamine transporter,” states Kopra.

In their ongoing research, Andressoo’s group seeks to gain more information on the mechanisms through which endogenous GDNF regulates dopamine transporter function.

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Materials provided by Helsingin yliopisto (University of Helsinki). Note: Content may be edited for style and length.