Posts tagged parkinson's disease
Articles and news from the latest research reports.
Parkinson’s Disease Protein Causes Disease Spread and Neuron Death in Healthy Animals
Understanding how any disease progresses is one of the first and most important steps towards finding treatments to stop it. This has been the case for such brain-degenerating conditions as Alzheimer’s disease. Now, after several years of incremental study, researchers at the Perelman School of Medicine, University of Pennsylvania have been able to piece together important steps in how Parkinson’s disease (PD) spreads from cell to cell and leads to nerve cell death.
Their line of research also informs the general concept that this type of disease progression is a common pathway for such other neurodegenerative diseases as Alzheimer’s, Huntington’s, progressive supranuclear palsy, and possibly amyotrophic lateral sclerosis (ALS).
The Penn team found that injecting synthetic, misfolded and fibrillar α-Synuclein (α-Syn) – the PD disease protein — into the brains of normal, “wild-type” mice recapitulates the cascade of cellular demise seen in human PD patients.
Parkinson’s disease is characterized by abundant α-Syn clumps in neurons and the massive loss of midbrain dopamine-producing neurons. However, a cause-and-effect relationship between the formation of α-Syn clumps and neurodegeneration has been unclear.
In short, the Penn researchers found that, in healthy mice, a single injection of synthetic, misfolded α-Syn fibrils led to a cell-to-cell transmission of pathologic α-Syn proteins and the formation of Parkinson’s α-Syn clumps known as Lewy bodies in interconnected regions of the brain. Their findings appear in this week’s issue of Science. The team was led by senior author Virginia M.-Y Lee, PhD, director of the Center for Neurodegenerative Disease Research (CNDR) and professor of Pathology and Laboratory Medicine, and first author Kelvin C. Luk, PhD, research assistant professor in the CNDR.
Parkinson’s breakthough could slow disease progression
In an early-stage breakthrough, a team of Northwestern University scientists has developed a new family of compounds that could slow the progression of Parkinson’s disease.
Parkinson’s, the second most common neurodegenerative disease, is caused by the death of dopamine neurons, resulting in tremors, rigidity and difficulty moving. Current treatments target the symptoms but do not slow the progression of the disease.
The new compounds were developed by Richard B. Silverman, the John Evans Professor of Chemistry at the Weinberg College of Arts and Sciences and inventor of the molecule that became the well-known drug Lyrica, and D. James Surmeier, chair of physiology at Northwestern University Feinberg School of Medicine. Their research was published Oct. 23 in the journal Nature Communications.
The compounds work by slamming the door on an unwelcome and destructive guest — calcium. The compounds target and shut a relatively rare membrane protein that allows calcium to flood into dopamine neurons. Surmeier’s previously published research showed that calcium entry through this protein stresses dopamine neurons, potentially leading to premature aging and death. He also identified the precise protein involved — the Cav1.3 channel.
"These are the first compounds to selectively target this channel," Surmeier said. "By shutting down the channel, we should be able to slow the progression of the disease or significantly reduce the risk that anyone would get Parkinson’s disease if they take this drug early enough."
"We’ve developed a molecule that could be an entirely new mechanism for arresting Parkinson’s disease, rather than just treating the symptoms," Silverman said.
The compounds work in a similar way to the drug isradipine, for which a Phase 2 national clinical trial with Parkinson’s patients –- led by Northwestern Medicine neurologist Tanya Simuni, M.D. — was recently completed. But because isradipine interacts with other channels found in the walls of blood vessels, it can’t be used in a high enough concentration to be highly effective for Parkinson’s disease. (Simuni is the Arthur C. Nielsen Professor of Neurology at the Feinberg School and a physician at Northwestern Memorial Hospital.)
The challenge for Silverman was to design new compounds that specifically target this rare Cav1.3 channel, not those that are abundant in blood vessels. He and colleagues first used high-throughput screening to test 60,000 existing compounds, but none did the trick.
"We didn’t want to give up," Silverman said. He then tested some compounds he had developed in his lab for other neurodegenerative diseases. After Silverman identified one that had promise, Soosung Kang, a postdoctoral associate in Silverman’s lab, spent nine months refining the molecules until they were effective at shutting only the Cav1.3 channel.
In Surmeier’s lab, the drug developed by Silverman and Kang was tested by graduate student Gary Cooper in regions of a mouse brain that contained dopamine neurons. The drug did precisely what it was designed to do, without any obvious side effects.
"The drug relieved the stress on the cells," Surmeier said.
For the next step, the Northwestern team has to improve the pharmacology of the compounds to make them suitable for human use, test them on animals and move to a Phase 1 clinical trial.
"We have a long way to go before we are ready to give this drug, or a reasonable facsimile, to humans, but we are very encouraged," Surmeier said.
(Source: eurekalert.org)
Challenging Parkinson’s Dogma: Dopamine may not be the only key player in this tragic neurodegenerative disease
Scientists may have discovered why the standard treatment for Parkinson’s disease is often effective for only a limited period of time. Their research could lead to a better understanding of many brain disorders, from drug addiction to depression, that share certain signaling molecules involved in modulating brain activity.
A team led by Bernardo Sabatini, Takeda Professor of Neurobiology at Harvard Medical School, used mouse models to study dopamine neurons in the striatum, a region of the brain involved in both movement and learning. In people, these neurons release dopamine, a neurotransmitter that allows us to walk, speak and even type on a keyboard. When those cells die, as they do in Parkinson’s patients, so does the ability to easily initiate movement. Current Parkinson’s drugs are precursors of dopamine that are then converted into dopamine by cells in the brain.
The flip side of dopamine dearth is dopamine hyperactivity. Heroin, cocaine and amphetamines rev up or mimic dopamine neurons, ultimately reinforcing the learned reward of drug-taking. Other conditions such as obsessive-compulsive disorder, Tourette syndrome and even schizophrenia may also be related to the misregulation of dopamine.
In the October 11 issue of Nature, Sabatini and co-authors Nicolas Tritsch and Jun Ding reported that midbrain dopamine neurons release not only dopamine but also another neurotransmitter called GABA, which lowers neuronal activity. The previously unsuspected presence of GABA could explain why restoring only dopamine could cause initial improvements in Parkinson’s patients to eventually wane. And if GABA is made by the same cells that produce other neurotransmitters, such as depression-linked serotonin, similar single-focus treatments could be less successful for the same reason.
“If what we found in the mouse applies to the human, then dopamine’s only half the story,” said Sabatini.
Researchers use stem cells to show connection between neural cell disruption and Parkinson’s disease
A diverse team of biologists has shown using induced pluripotent stem cells (iPSCs) that a gene mutation that causes malformations in the structure of the nuclear envelope of neural cells, is associated with Parkinson’s disease. In their paper published in the journal Nature, they describe how they found iPSC cells taken from Parkinson’s patients over time demonstrated the same cell disruption found in neural cells taken from other deceased patient’s with the disease. They also found that by introducing a compound known to disrupt the gene mutation, that they could reverse the cell malformation.
Parkinson’s disease is a degenerative disorder of the nervous system characterized by shaking, slowness of movement and difficulty walking. Over time most patients succumb to dementia and eventually die. Much research has centered on the disruption and death of dopamine-generating cells as the root cause of the disorder despite evidence that such a disruption would not result in all of the symptoms Parkinson’s patient’s exhibit. For that reason, researchers have looked to other causes.
In this new effort, the researchers looked at possible reasons for disruption to the nuclear envelope, the thin film that separates the nucleus from the cytoplasm in neural cells. Such disruptions have been associated with Parkinson’s but no definitive correlation has been found, until now.
To gain a better understanding of what might be causing such disruptions, the research team obtained samples of induced iPSCs from Parkinson’s patients and allowed them to grow in an external environment. They noted that the same disruptions occurred as the iPSCs grew into neural cells, suggesting a genetic cause. Prior research had indicated that a mutation of the LRRK2 gene was connected to Parkinson’s disease but no clear indication of the mechanism involved had been found. Testing the cells derived from the iPSCs showed the same mutation, implicating it as a possible cause of the disorder. The researchers also induced the mutation in human embryo stem cells and found that they too developed the same disruption as they grew into neural cells as was found with the iPSCs.
Next the researchers generated a line of iPSCs minus the mutation and found that the cells did not develop the disruptions. They followed that up by adding a chemical compound known to disrupt the mutation to already affected cells and discovered that it prevented them from being disrupted as well.
The researchers don’t know why the mutation occurs but believe a new therapy for treating Parkinson’s patients might be on the horizon as a result of their research.
(Source: medicalxpress.com)
Parkinson’s could be detected by telephone call
A simple telephone call could help spot the early signs of Parkinson’s disease by tracking subtle changes in patients’ voices years before more severe symptoms emerge, researchers claim.
New technology being developed in America analyses tremors, breathiness and other weaknesses in people’s voices which are believed to be one of the condition’s earliest symptoms.
Experts at the Massachusetts Institute of Technology claim that their computer programme can pick out Parkinson’s sufferers with 99 per cent accuracy simply by analysing their speech.
Dr Max Little, a British researcher who is leading the initiative at MIT, now hopes to determine whether the same results could be produced from a patient speaking over the telephone.
By recruiting Parkinson’s patients and health volunteers to take part in a three-minute telephone call where they will say “ah”, speak some sentences and answer a few questions, he said the system could be programmed to diagnose people remotely, allowing earlier treatment.
He said: “Science tells us voice impairment might be an early sign of Parkinson’s. It sounds counterintuitive as Parkinson’s is a movement disorder but the voice is a form of movement.
"Neurologists look at changes in the ability to move, which is done with the limbs, but we are looking in the vocal organs – the sounds that come out of the mouth. We are fairly confident we can detect the disease over the telephone."
How does electrical stimulation affect the brain? A project by Aalto University and the University of Helsinki, launched in early 2012, studies the impact mechanism of deep brain stimulation and develops electrochemical sensors for more effective measuring of neurotransmitters in the brain. The long-term goals of the research are more specific treatment for Parkinson’s disease and many other diseases of the nervous system.
Deep Brain Stimulation Changes Rhythms to Treat Parkinson’s Disease and Tremor
ScienceDaily (Aug. 28, 2012) — Deep-brain stimulation (DBS) may stop uncontrollable shaking in patients with Parkinson’s disease and essential tremor by imposing its own rhythm on the brain, according to two studies published recently by University of Alabama at Birmingham researchers in the journal Movement Disorders. An article addressing brain stimulation for essential tremor was published online August 28; a related article on Parkinson’s disease was released May 30.
DBS uses an electrode implanted beneath the skin to deliver electrical pulses into the brain more than 100 times per second. Although this technology was approved by the Food and Drug Administration more than 15 years ago, it remains unclear how it reduces tremor and other symptoms of movement disorders.
With the help of electroencephalography or EEG — electrodes placed on the scalp — study authors used new techniques to suppress the electrical signal associated with the DBS electrode. That enabled the first clear, non-invasive EEG measurements of the underlying brain response during clinically effective, high-frequency brain stimulation in humans.
The results show that nerves in the cerebral cortex, the outer layer of the brain, fire with rapid and precise timing in response to individual stimulus pulses. This suggests that DBS may synchronize the firing of nerve cells and break the abnormal rhythms associated with involuntary movements in Parkinson’s disease and essential tremor.
The newly identified rhythm was captured during effective DBS treatment, so it could represent a new physiological measure of the stimulation dose, say the authors. If validated, such a yardstick could help to guide the fine-tuning of DBS stimulator settings in patients for more lasting relief, fewer side effects and less-frequent battery-replacement surgeries.
"Though it’s clear that more work is needed to better understand these initial observations, we’re very excited by our findings because they may provide a biological marker for improvement in the symptoms of these patients," says Harrison Walker, M.D., assistant professor in the UAB Department of Neurology’s Division of Movement Disorders and lead author of the study.
In current clinical practice, stimulator settings are adjusted by trial and error, requiring careful observation of changes in symptoms over multiple clinic visits. But such immediate, visual feedback may not be available as DBS is applied to neurological or psychiatric conditions such as epilepsy, severe depression or obsessive compulsive disorder. In these diseases, an effective dose measurement could be especially useful in optimizing DBS therapy.
Therapeutic Avenues for Parkinson’s Investigated
ScienceDaily (Aug. 23, 2012) — Scientists at the University of Houston (UH) have discovered what may possibly be a key ingredient in the fight against Parkinson’s disease.
Affecting more than 500,000 people in the U.S., Parkinson’s disease is a degenerative disorder of the central nervous system marked by a loss of certain nerve cells in the brain, causing a lack of dopamine. These dopamine-producing neurons are in a section of the midbrain that regulates body control and movement. In a study recently published in the Proceedings of the National Academy of Sciences (PNAS), researchers from the UH Center for Nuclear Receptors and Cell Signaling (CNRCS) demonstrated that the nuclear receptor liver X receptor beta (LXRbeta) may play a role in the prevention and treatment of this progressive neurodegenerative disease.
"LXRbeta performs an important function in the development of the central nervous system, and our work indicates that the presence of LXRbeta promotes the survival of dopaminergic neurons, which are the main source of dopamine in the central nervous system," said CNRCS director and professor Jan-Åke Gustafsson, whose lab discovered LXRbeta in 1995. "The receptor continues to show promise as a potential therapeutic target for this disease, as well as other neurological disorders."
To better understand the relationship between LXRbeta and Parkinson’s disease, the team worked with a potent neurotoxin, called MPTP, a contaminant found in street drugs that caused Parkinson’s in people who consumed these drugs. In lab settings, MPTP is used in murine models to simulate the disease and to study its pathology and possible treatments.
The researchers found that the absence of LXRbeta increased the harmful effects of MPTP on dopamine-producing neurons. Additionally, they found that using a drug that activates LXRbeta receptors prevented the destructive effects of MPTP and, therefore, may offer protection against the neurodegeneration of the midbrain.
"LXRbeta is not expressed in the dopamine-producing neurons, but instead in the microglia surrounding the neurons," Gustafsson said. "Microglia are the police of the brain, keeping things in order. In Parkinson’s disease the microglia are overactive and begin to destroy the healthy neurons in the neighborhood of those neurons damaged by MPTP. LXRbeta calms down the microglia and prevents collateral damage. Thus, we have discovered a novel therapeutic target for treatment of Parkinson’s disease."
Source: Science Daily
Sleep improves memory in people with Parkinson’s disease
Aug. 20, 2012 by Quinn Eastman
People with Parkinson’s disease performed markedly better on a test of working memory after a night’s sleep, and sleep disorders can interfere with that benefit, researchers have shown.
The ability of sleep to improve scores on a test of working memory specifically depends on how much slow wave sleep Parkinson’s patients obtain, researchers have found.
While the classic symptoms of Parkinson’s disease include tremors and slow movements, Parkinson’s can also affect someone’s memory, including “working memory.” Working memory is defined as the ability to temporarily store and manipulate information, rather than simply repeat it. The use of working memory is important in planning, problem solving and independent living.
The findings underline the importance of addressing sleep disorders in the care of patients with Parkinson’s, and indicate that working memory capacity in patients with Parkinson’s potentially can be improved with training. The results also have implications for the biology of sleep and memory.
The results were published this week in the journal Brain.
"It was known already that sleep is beneficial for memory, but here, we’ve been able to analyze what aspects of sleep are required for the improvements in working memory performance," says postdoctoral fellow Michael Scullin, who is the first author of the paper. The senior author is Donald Bliwise, professor of neurology at Emory University School of Medicine.
The performance boost from sleep was linked with the amount of slow wave sleep, or the deepest stage of sleep. Several research groups have reported that slow wave sleep is important for synaptic plasticity, the ability of brain cells to reorganize and make new connections.
Sleep apnea, the disruption of sleep caused by obstruction of the airway, interfered with sleep’s effects on memory. Study participants who showed signs of sleep apnea, if it was severe enough to lower their blood oxygen levels for more than five minutes, did not see a working memory test boost.
In this study, participants took a “digit span test,” in which they had to repeat a list of numbers forward and backward. The test was conducted in an escalating fashion: the list grows incrementally until someone makes a mistake. Participants took the digit span test eight times during a 48-hour period, four during the first day and four during the second. In between, they slept.
Repeating numbers in the original order is a test of short-term memory, while repeating the numbers in reverse order is a test of working memory.
"Repeating the list in reverse order requires some effort to manipulate the numbers, not just spit them back out again," Scullin says. "It’s also a purely verbal test, which is important when working with a population that may have motor impairments."
54 study participants had Parkinson’s disease, and 10 had dementia with Lewy bodies: a more advanced condition, where patients may have hallucinations or fluctuating cognition as well as motor symptoms. Those who had dementia with Lewy bodies saw no working memory boost from the night’s rest. As expected, their baseline level of performance was lower than the Parkinson’s group.
Participants with Parkinson’s who were taking dopamine-enhancing medications saw their performance on the digit span test jump up between the fourth and fifth test. On average, they could remember one more number backwards. The ability to repeat numbers backward improved, even though the ability to repeat numbers forward did not.
Patients needed to be taking dopamine-enhancing medications to see the most performance benefit from sleep. Patients not taking dopamine medications, even though they had generally had Parkinson’s for less time, did not experience as much of a performance benefit. This may reflect a role for dopamine, an important neurotransmitter, in memory.
Scullin and Bliwise are planning an expanded study of sleep and working memory, in healthy elderly people as well as patients with neurodegenerative diseases.
"Many elderly people go through a decline in how much slow wave sleep they experience, and this may be a significant contributor to working memory difficulties," Scullin says.
Source: Emory
Coffee May Help Some Parkinson’s Disease Movement Symptoms, Research Suggests
"Studies have shown that people who use caffeine are less likely to develop Parkinson’s disease, but this is one of the first studies in humans to show that caffeine can help with movement symptoms for people who already have the disease," said study author Ronald Postuma, MD, MSc, with McGill University in Montreal and the Research Institute of the McGill University Health Center. Postuma is also a member of the American Academy of Neurology.