OTTAWA — High cholesterol levels predict heart disease. High blood-sugar levels can predict diabetes. But no single test exists to predict who will develop Parkinson's disease, the second leading brain-wasting disorder behind Alzheimer's.
Now, a decade-long effort which started at Harvard University and continued in Ottawa, has yielded a method that, in principle, could identify people at risk of developing a disease that afflicts an estimated 150,000 Canadians.
The story behind this finding shows why progress toward preventing or curing Parkinson's has been so slow. It also highlights how recent advances in Alzheimer's research served as a model for what some researchers have already dubbed "the Ottawa test" for Parkinson's.
The disease is defined by the death of brain cells that produce dopamine, a chemical messenger between nerve cells. It's the loss of dopamine-producing nerve cells that lead to Parkinson's symptoms of rigidity, poor balance and uncontrollable shaking.
Currently, the lack of a definitive test means physicians only reach a diagnosis by testing for — and eliminating — other diseases that can cause the same symptoms. Patients are also assessed according to the severity of those physical symptoms. But the method is so imprecise that it can lead to diagnosis only when the disease is already well advanced.
An international team led by Dr. Michael Schlossmacher, a neuroscientist at the Ottawa Hospital Research Institute, believes it has identified signature proteins in the blood and spinal fluid that show the progression of Parkinson's in the brain.
The findings, presented last month at the World Parkinson's Congress in Scotland, require further testing. But if proven, the protein markers could form the basis of a test to screen people for early signs of the disease.
It might also allow scientists to study how the disease progresses and, perhaps, find drugs to slow or halt the process.
"We in (the) Parkinson's (field) are still stuck in the old days, where it's only the clinical impression and examination that determines whether this is Parkinson's or not," said Schlossmacher, who's also the Canada research chair in Parkinson's at the University of Ottawa.
"We have to move forward to laboratory-based measurements that are more objective than subjective."
His research has attracted $40 million from the Michael J. Fox Foundation, which is funding a five-year study of a spinal-fluid test to detect Parkinson's, developed by Schlossmacher and his collaborators in Germany and the United Arab Emirates.
Up to 700 patients with advanced Parkinson's are expected to be enrolled in Canada, the U.S. and Europe. The large-scale trial would allow physicians and scientists from around the world to verify the accuracy and effectiveness of the test independently.
Spinal taps, which involve inserting a needle into the lower back and withdrawing a small amount fluid, have drawbacks. Many doctors and patients are nervous about the procedure, which they fear will be painful and cause headaches, infection, or nerve damage.
For that reason, Schlossmacher's team is also at the early stages of developing a blood test for Parkinson's, a much less invasive procedure. The experimental blood test has so far been tried in nearly 600 patients in Canada and the United States.
Both tests aim to measure a telltale Parkinson's protein known as alpha-synuclein, which is found at abnormally low levels in the spinal fluid of seven out of 10 patients with the disease — because, researchers believe, once it's in a person's nervous system, it collects in the brain in deposits that damage neurons and lead to the debilitating symptoms of Parkinson's.
Some people have a genetic predisposition to high alpha-synuclein levels, and a blood test could look for high levels of the protein in the blood, where it would be detectable long before it began causing symptoms.
But because at least 15 per cent of patients with the disease don't appear to have elevated levels of alpha-synuclein, the protein is not necessarily a definitive test. Indeed, it remains to be seen how many people who have it actually end up with the disease. But that is part of the research project.
The idea for a Parkinson's diagnostic test emerged nearly 20 years ago, when Schlossmacher was a post-doctoral fellow at Harvard.
As a young researcher working with Dennis Selkoe, a leading Alzheimer's expert, Schlossmacher was assigned to look for the signature proteins that could be responsible for Alzheimer's.
In 1992, Schlossmacher was the lead author of a paper that, for the first time, identified a protein called beta-amyloid as a physical hallmark of Alzheimer's — a discovery that became the cornerstone of what is today a leading theory about how to treat the disease.
He recalled how Selkoe had urged him to branch out, saying: "You know, Parkinson's is 10 years behind Alzheimer's. Why don't you look into it?"
"It was my work there, in a very junior role, that inspired me to pursue Parkinson's and become a neurologist," Schlossmacher said.
In 2001, after completing his neurology training, Schlossmacher took his mentor's advice and began zeroing in on alpha-synuclein as one of the proteins that likely plays a key role in Parkinson's. In 2006, after leaving Harvard, Schlossmacher refined his research in Ottawa.
He said the next four years could decide whether real progress is made in Parkinson's diagnosis. "By then, we'll know whether it's really exciting and useful, or whether it was just a good idea."
BY PAULINE TAM, OTTAWA CITIZEN
Tuesday, October 19, 2010
Sunday, September 12, 2010
US to resume funding stem cell research
WASHINGTON — The U.S. government said Friday it’s back in the business of funding embryonic stem cell research — at least for now — after an appeals court temporarily lifted a judge’s ban.
The National Institutes of Health (NIH) said it is resuming its own research and will again evaluate applications from scientists who are seeking taxpayer money to do the work, a process that has been frozen since late last month.
An appeals court on Thursday temporarily stayed a judge’s preliminary order barring that funding until it could hear full arguments in the next few weeks.
In the meantime, the NIH said it is lifting its suspension of all grants and contracts involving use of the cells.
“We are pleased with the court’s interim ruling, which will allow promising stem cell research to continue” while the court battle is waged, said the NIH’s statement.
Scientists who already had received NIH grants had been told to continue working until their dollars ran out, but that 22 projects due to get yearly checks in September would have to find other money.
Now the question is whether the NIH will finish the reviews required for those projects during what could be only a temporary reprieve. No matter what, the case is certain to be bouncing around the court system for many months before there’s a final resolution.
“We believe it’s a shame that they would rush to push funding of embryonic stem cell research, and a waste of taxpayer money,” said Steven H. Aden, senior legal counsel for the Alliance Defense Fund, which is involved with the lawsuit that challenged the government funding.
Embryonic stem cells are master cells that can turn into any tissue of the body, and researchers hope one day to harness that power in ways that cure spinal cord injuries, Parkinson’s disease and other ailments.
Culling them from embryos left over after fertility treatment kills a days-old embryo. A 1996 law prohibits the use of taxpayer dollars in work that harms an embryo, so batches have been culled using private money. But those batches can reproduce in lab dishes indefinitely, and government policies say using taxpayer dollars to work with the already created batches is permissible.
Last month, U.S. District Court Judge Royce Lamberth disagreed, in a sharply worded preliminary injunction in which he argued that the research violated the intent of the 1996 law. Lamberth left little doubt that he is inclined to issue a final order barring funding, which will set off a new round of appeals.
Amid the back-and-forth, researchers are struggling to figure out how to secure long-running experiments.
“I take no solace in the ruling because so much uncertainty remains about the future of human stem cell research,” said Dr. George Daley, a leading stem cell researcher at Children’s Hospital Boston. “I won’t rest peacefully until there is a clear and unambiguous vote of support from the Congress for this vital research.”
Congress twice passed legislation specifically calling for tax-funded stem cell research, which President George W. Bush vetoed. Some Democrats are considering whether to try the legislation again.
The lawsuit was filed by two scientists who argued that President Barack Obama’s expansion of the number of stem cell lines available for government funding jeopardized their ability to win grants to research adult stem cells — ones that have already matured to create specific types of tissues — because of extra competition.
Many scientists believe the more flexible embryonic cells have more promise, but lots of work is under way with both kinds. The NIH’s estimated budget for next year would spend more than three times as much on research for adult stem cells as embryonic ones, said Patrick Clemins of the American Association for the Advancement of Science.
The National Institutes of Health (NIH) said it is resuming its own research and will again evaluate applications from scientists who are seeking taxpayer money to do the work, a process that has been frozen since late last month.
An appeals court on Thursday temporarily stayed a judge’s preliminary order barring that funding until it could hear full arguments in the next few weeks.
In the meantime, the NIH said it is lifting its suspension of all grants and contracts involving use of the cells.
“We are pleased with the court’s interim ruling, which will allow promising stem cell research to continue” while the court battle is waged, said the NIH’s statement.
Scientists who already had received NIH grants had been told to continue working until their dollars ran out, but that 22 projects due to get yearly checks in September would have to find other money.
Now the question is whether the NIH will finish the reviews required for those projects during what could be only a temporary reprieve. No matter what, the case is certain to be bouncing around the court system for many months before there’s a final resolution.
“We believe it’s a shame that they would rush to push funding of embryonic stem cell research, and a waste of taxpayer money,” said Steven H. Aden, senior legal counsel for the Alliance Defense Fund, which is involved with the lawsuit that challenged the government funding.
Embryonic stem cells are master cells that can turn into any tissue of the body, and researchers hope one day to harness that power in ways that cure spinal cord injuries, Parkinson’s disease and other ailments.
Culling them from embryos left over after fertility treatment kills a days-old embryo. A 1996 law prohibits the use of taxpayer dollars in work that harms an embryo, so batches have been culled using private money. But those batches can reproduce in lab dishes indefinitely, and government policies say using taxpayer dollars to work with the already created batches is permissible.
Last month, U.S. District Court Judge Royce Lamberth disagreed, in a sharply worded preliminary injunction in which he argued that the research violated the intent of the 1996 law. Lamberth left little doubt that he is inclined to issue a final order barring funding, which will set off a new round of appeals.
Amid the back-and-forth, researchers are struggling to figure out how to secure long-running experiments.
“I take no solace in the ruling because so much uncertainty remains about the future of human stem cell research,” said Dr. George Daley, a leading stem cell researcher at Children’s Hospital Boston. “I won’t rest peacefully until there is a clear and unambiguous vote of support from the Congress for this vital research.”
Congress twice passed legislation specifically calling for tax-funded stem cell research, which President George W. Bush vetoed. Some Democrats are considering whether to try the legislation again.
The lawsuit was filed by two scientists who argued that President Barack Obama’s expansion of the number of stem cell lines available for government funding jeopardized their ability to win grants to research adult stem cells — ones that have already matured to create specific types of tissues — because of extra competition.
Many scientists believe the more flexible embryonic cells have more promise, but lots of work is under way with both kinds. The NIH’s estimated budget for next year would spend more than three times as much on research for adult stem cells as embryonic ones, said Patrick Clemins of the American Association for the Advancement of Science.
Sunday, September 5, 2010
Parkinson’s patients good at automated tasks--study
Findings of a latest Queen’s research have proposed that individuals suffering from the Parkinson’s disease have better ability of performing programmed, automated errands than the normal people.
But Parkinson’s patients encountered difficulty when switching from simple to complex tasks, the researchers found.
A team of researchers from the Queen's Center for Neuroscience Studies initiated the present study that hoped to develop a better understanding of the ailment that affects the cognitive functioning of the brain.
"We often think of Parkinson's disease as being a disorder of motor function," Douglas Munoz, director of the Center and a Canada Research Chair in Neuroscience said. "But the issue is that the same circuit can affect more cognitive functions like planning and decision-making.”
Study details
For the study, the researchers conducted examination on people suffering from the Parkinson’s disease and a control group of normal people.
All the study subjects were asked to look at a light, and it was observed that Parkinson’s patients performed much better than the normal candidates. But, when the people were asked to look away from the light, the first group faced difficulty.
Ian Cameron, a PhD student at the Queen’s institute, is of the opinion that the findings of the study not only point out that the cognitive balance of the patients was affected due to the medications, but also showed the patient getting upset when asked to perform an alternate task.
The researchers are now further working to find out which part of the brain is affected by the currently available drugs that are prescribed to people suffering from Parkinson’s disease.
“Functional brain imaging in Parkinson’s patients will be used to help out in this study,” revealed Cameron.
The findings of the study have been published in an international interdisciplinary journal of cognitive and behavioural neuroscience, ‘Neuropsychologia’.
by Yashika kapoo
But Parkinson’s patients encountered difficulty when switching from simple to complex tasks, the researchers found.
A team of researchers from the Queen's Center for Neuroscience Studies initiated the present study that hoped to develop a better understanding of the ailment that affects the cognitive functioning of the brain.
"We often think of Parkinson's disease as being a disorder of motor function," Douglas Munoz, director of the Center and a Canada Research Chair in Neuroscience said. "But the issue is that the same circuit can affect more cognitive functions like planning and decision-making.”
Study details
For the study, the researchers conducted examination on people suffering from the Parkinson’s disease and a control group of normal people.
All the study subjects were asked to look at a light, and it was observed that Parkinson’s patients performed much better than the normal candidates. But, when the people were asked to look away from the light, the first group faced difficulty.
Ian Cameron, a PhD student at the Queen’s institute, is of the opinion that the findings of the study not only point out that the cognitive balance of the patients was affected due to the medications, but also showed the patient getting upset when asked to perform an alternate task.
The researchers are now further working to find out which part of the brain is affected by the currently available drugs that are prescribed to people suffering from Parkinson’s disease.
“Functional brain imaging in Parkinson’s patients will be used to help out in this study,” revealed Cameron.
The findings of the study have been published in an international interdisciplinary journal of cognitive and behavioural neuroscience, ‘Neuropsychologia’.
by Yashika kapoo
Thursday, August 12, 2010
Scientists Identify Molecular Mechanism Triggering Parkinson's Disease
Scientists have identified a molecular pathway responsible for the death of key nerve cells whose loss causes Parkinson's disease. This discovery not only may explain how a genetic mutation linked to Parkinson's causes the cells' death, but could also open the door to new therapeutic approaches for the malady.
In the study, investigators used an animal model, the common fruit fly, to show that the mutation results in impaired activity of recently discovered molecules called microRNAs, which fine-tune protein production in cells. This impairment, in turn, leads to the premature death of nerve cells specifically involved in the secretion of the brain chemical dopamine. The degeneration of these so-called dopaminergic nerve cells in the brain is a hallmark of Parkinson's.
"MicroRNA, whose role in the body has only recently begun to be figured out, has been implicated in cancer, cardiac dysfunction and faulty immune response," said Bingwei Lu, the study's senior author. "But this is the first time it has been identified as a key player in a neurodegenerative disease."
Parkinson's is a movement disorder characterized outwardly by tremor, difficulty in initiating movement, and postural imbalance and, in the brain, by a massive loss of the dopaminergic nerve cells in areas that fine-tune motor activity. It affects an estimated 1 million people in the United States. The incidence of Parkinson's, rare in younger people, increases dramatically with age, although nobody is sure why. Nor is it known why the most common mutation implicated in Parkinson's — LRRK2 G2019S, found in about one-third of all Parkinson's cases occurring among North African Arabs and North American Ashkenazi Jews — increases the likelihood of contracting the disease.
The new findings show that the LRRK2 mutation trips up the normal activity of microRNAs, resulting in the overproduction of at least two proteins that can cause certain cells, like brain cells, to die.
Understanding how microRNA can go wrong requires an understanding of its relationship to its much longer and better-known cousins, "messenger RNA" (or mRNA) molecules. The latter carry genetic recipes from a cell's DNA to specialized molecular machines that translate the instructions into the proteins that make up a cell. In contrast, a microRNA molecule is a very short string of RNA that doesn't contain instructions for making proteins but that can bind to parts of messenger RNA sequences that complement its own. As a result, the messenger RNA's sequence can no longer be read by the cell's protein-manufacturing apparatus, gumming up assembly of the protein it encodes.
It's only recently that scientists have started to understand microRNA's critical role.
The researchers in Lu's lab conducted their experiments in Drosophila, the fruit fly, which has previously proved itself a useful model for several neurodegenerative disorders, yielding substantial insights into Parkinson's, Alzheimer's and Huntington's diseases. They observed that certain proteins were being produced at higher-than-normal levels in the fly LRRK2 model of Parkinson's disease. What particularly drew their attention were two proteins that are important in regulating cell division. Mature nerve cells, which no longer divide, should not have high levels of these proteins; when they do, they are prone to premature cell death.
The researchers looked at the mRNAs containing the genetic recipes for the two overproduced proteins, and predicted that they would be bound by two specific microRNAs: let-7 and miR-184. When they then manipulated the activities of those two microRNA species in flies' brains, they had results consistent with the damage associated with Parkinson's. Diminishing the activity of let-7 in dopaminergic nerve cells, for example, caused both the increased production of one of the suspect proteins and degeneration of the cells.
The researchers showed that toning down the levels of these two proteins, in itself, prevented dopaminergic nerve cell death in the flies. "The flies no longer got symptoms of Parkinson's," said Lu. "This alone has immediate therapeutic implications. Many pharmaceutical companies are already making compounds that act on these two proteins, which in previous studies have been shown to be associated with cancer. It may be possible to take these compounds off the shelf or quickly adapt them for use in non-cancer indications such as Parkinson's."
The researchers then went a step further, showing how the genetic mutation of LRRK2 caused interference of microRNA molecules' ability to inhibit their target mRNAs. It leads to the disruption of a huge complex of molecular machinery that must operate smoothly in order for microRNA to do its job. This link between the common Parkinson's-producing mutation and consequent microRNA malfunction is a new finding.
"The clinical impact of our findings may be five to 10 years down the road," Lu said. "But their impact on our understanding of the disease process is immediate. We can now start testing compounds in mammals and cultured human dopaminergic cells to see if they can inhibit overproduction of these proteins and stave off dopaminergic cell death." Currently available drugs for Parkinson's disease temporarily alleviate its symptoms but can have undesirable side effects, and they don't prevent dopaminergic cells from dying.
References:
1. Gehrke et al. Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature, 2010; 466 (7306): 637 DOI:10.1038/nature09191
In the study, investigators used an animal model, the common fruit fly, to show that the mutation results in impaired activity of recently discovered molecules called microRNAs, which fine-tune protein production in cells. This impairment, in turn, leads to the premature death of nerve cells specifically involved in the secretion of the brain chemical dopamine. The degeneration of these so-called dopaminergic nerve cells in the brain is a hallmark of Parkinson's.
"MicroRNA, whose role in the body has only recently begun to be figured out, has been implicated in cancer, cardiac dysfunction and faulty immune response," said Bingwei Lu, the study's senior author. "But this is the first time it has been identified as a key player in a neurodegenerative disease."
Parkinson's is a movement disorder characterized outwardly by tremor, difficulty in initiating movement, and postural imbalance and, in the brain, by a massive loss of the dopaminergic nerve cells in areas that fine-tune motor activity. It affects an estimated 1 million people in the United States. The incidence of Parkinson's, rare in younger people, increases dramatically with age, although nobody is sure why. Nor is it known why the most common mutation implicated in Parkinson's — LRRK2 G2019S, found in about one-third of all Parkinson's cases occurring among North African Arabs and North American Ashkenazi Jews — increases the likelihood of contracting the disease.
The new findings show that the LRRK2 mutation trips up the normal activity of microRNAs, resulting in the overproduction of at least two proteins that can cause certain cells, like brain cells, to die.
Understanding how microRNA can go wrong requires an understanding of its relationship to its much longer and better-known cousins, "messenger RNA" (or mRNA) molecules. The latter carry genetic recipes from a cell's DNA to specialized molecular machines that translate the instructions into the proteins that make up a cell. In contrast, a microRNA molecule is a very short string of RNA that doesn't contain instructions for making proteins but that can bind to parts of messenger RNA sequences that complement its own. As a result, the messenger RNA's sequence can no longer be read by the cell's protein-manufacturing apparatus, gumming up assembly of the protein it encodes.
It's only recently that scientists have started to understand microRNA's critical role.
The researchers in Lu's lab conducted their experiments in Drosophila, the fruit fly, which has previously proved itself a useful model for several neurodegenerative disorders, yielding substantial insights into Parkinson's, Alzheimer's and Huntington's diseases. They observed that certain proteins were being produced at higher-than-normal levels in the fly LRRK2 model of Parkinson's disease. What particularly drew their attention were two proteins that are important in regulating cell division. Mature nerve cells, which no longer divide, should not have high levels of these proteins; when they do, they are prone to premature cell death.
The researchers looked at the mRNAs containing the genetic recipes for the two overproduced proteins, and predicted that they would be bound by two specific microRNAs: let-7 and miR-184. When they then manipulated the activities of those two microRNA species in flies' brains, they had results consistent with the damage associated with Parkinson's. Diminishing the activity of let-7 in dopaminergic nerve cells, for example, caused both the increased production of one of the suspect proteins and degeneration of the cells.
The researchers showed that toning down the levels of these two proteins, in itself, prevented dopaminergic nerve cell death in the flies. "The flies no longer got symptoms of Parkinson's," said Lu. "This alone has immediate therapeutic implications. Many pharmaceutical companies are already making compounds that act on these two proteins, which in previous studies have been shown to be associated with cancer. It may be possible to take these compounds off the shelf or quickly adapt them for use in non-cancer indications such as Parkinson's."
The researchers then went a step further, showing how the genetic mutation of LRRK2 caused interference of microRNA molecules' ability to inhibit their target mRNAs. It leads to the disruption of a huge complex of molecular machinery that must operate smoothly in order for microRNA to do its job. This link between the common Parkinson's-producing mutation and consequent microRNA malfunction is a new finding.
"The clinical impact of our findings may be five to 10 years down the road," Lu said. "But their impact on our understanding of the disease process is immediate. We can now start testing compounds in mammals and cultured human dopaminergic cells to see if they can inhibit overproduction of these proteins and stave off dopaminergic cell death." Currently available drugs for Parkinson's disease temporarily alleviate its symptoms but can have undesirable side effects, and they don't prevent dopaminergic cells from dying.
References:
1. Gehrke et al. Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature, 2010; 466 (7306): 637 DOI:10.1038/nature09191
Saturday, July 24, 2010
Lasers used to alleviate Parkinson's disease symptoms
Written and produced by Tim Didion
SAN FRANCISCO (KGO) -- A discovery by researchers at Stanford and the Gladstone Institutes in San Francisco could someday help alleviate the symptoms of Parkinson's disease.
They have mapped the pathways of the brain associated with the disease and the key to their breakthrough is laser light.
It may not look as dramatic as the light sabers in Star Wars, but Anatol Kreitzer believes this laser someday become a powerful weapon in the war against Parkinson's disease.
In his lab at San Francisco's Gladstone Institutes' Kreitzer's team is using lasers to manipulate neural pathways in the mice's brains whose cells have been genetically altered to respond to laser light.
A research assistant applies laser light to stimulate the neurons in a sample of living brain tissue, which is magnified on the screen.
The data collected has allowed Kreitzer's team to not only map specific neural pathways, but also identify their role in controlling movement. An interruption of that neuron function is believed to play a key role in diseases like Parkinson's.
"When we can identify the neural circuitry involved these diseases, then we can target it more specifically with drugs," Kreitzer said.
Researchers also believe the lasers could eventually have a more direct use. Not just as a research tool, but as an actual treatment for Parkinson's.
The current study builds on the work of Stanford University researcher Dr. Karl Deisseroth.
Last year, Deisseroth showed us how he was able to use laser light applied directly to a lab animal's brain to turn its dopamine receptors on and off first by addicting the animal to a substance and then reversing the craving and un-addicting it.
"And we use laser light to control, to tune and modify the behavior of brain cells," he said.
Collaborating with Deisseroth, the research team at Gladstone used that same technique, to turn neural pathways associated with Parkinson's on and off.
"We can do two things: We can actually simulate Parkinson's disease, we can cause mice to freeze. But we can also take mice that have Parkinson's disease and activate another pathway, and we can actually relieve the symptoms of that Parkinson's disease," Kreitzer said.
He envisions a day when the lasers might be used as an alternative form of deep brain stimulation. That's a therapy where electrodes which are surgically implanted to help control brain function in Parkinson's patients.
"Sometime in the future we can put things like diodes that are in an L.E.D. television, very small. You can imagine implanting those in the brain and using them to active neurons," Kreitzer said.
While implanting light sources in the human brain may be years or decades away, the technology is giving researcher their first chance to test out theories of how neural pathways interact.
The team believes other neural-based diseases like Huntington's and Tourette's syndrome may also be candidates for research using this laser light technique.
SAN FRANCISCO (KGO) -- A discovery by researchers at Stanford and the Gladstone Institutes in San Francisco could someday help alleviate the symptoms of Parkinson's disease.
They have mapped the pathways of the brain associated with the disease and the key to their breakthrough is laser light.
It may not look as dramatic as the light sabers in Star Wars, but Anatol Kreitzer believes this laser someday become a powerful weapon in the war against Parkinson's disease.
In his lab at San Francisco's Gladstone Institutes' Kreitzer's team is using lasers to manipulate neural pathways in the mice's brains whose cells have been genetically altered to respond to laser light.
A research assistant applies laser light to stimulate the neurons in a sample of living brain tissue, which is magnified on the screen.
The data collected has allowed Kreitzer's team to not only map specific neural pathways, but also identify their role in controlling movement. An interruption of that neuron function is believed to play a key role in diseases like Parkinson's.
"When we can identify the neural circuitry involved these diseases, then we can target it more specifically with drugs," Kreitzer said.
Researchers also believe the lasers could eventually have a more direct use. Not just as a research tool, but as an actual treatment for Parkinson's.
The current study builds on the work of Stanford University researcher Dr. Karl Deisseroth.
Last year, Deisseroth showed us how he was able to use laser light applied directly to a lab animal's brain to turn its dopamine receptors on and off first by addicting the animal to a substance and then reversing the craving and un-addicting it.
"And we use laser light to control, to tune and modify the behavior of brain cells," he said.
Collaborating with Deisseroth, the research team at Gladstone used that same technique, to turn neural pathways associated with Parkinson's on and off.
"We can do two things: We can actually simulate Parkinson's disease, we can cause mice to freeze. But we can also take mice that have Parkinson's disease and activate another pathway, and we can actually relieve the symptoms of that Parkinson's disease," Kreitzer said.
He envisions a day when the lasers might be used as an alternative form of deep brain stimulation. That's a therapy where electrodes which are surgically implanted to help control brain function in Parkinson's patients.
"Sometime in the future we can put things like diodes that are in an L.E.D. television, very small. You can imagine implanting those in the brain and using them to active neurons," Kreitzer said.
While implanting light sources in the human brain may be years or decades away, the technology is giving researcher their first chance to test out theories of how neural pathways interact.
The team believes other neural-based diseases like Huntington's and Tourette's syndrome may also be candidates for research using this laser light technique.
Saturday, July 17, 2010
Parkinson's Disease Research Uncovers Social Barrier
People with Parkinson's disease suffer social difficulties simply because of the way they talk, a McGill University researcher has discovered. Marc Pell, at McGill's School of Communication Sciences and Disorders, has learned that many people develop negative impressions about individuals with Parkinson's disease, based solely on how they communicate.
These perceptions limit opportunities for social interaction and full participation in society for those with the disease, reducing their quality of life. Pell's research offers the public a better understanding of the difficulties these patients face -- as well as an opportunity to promote greater inclusiveness.
The research was conducted in collaboration with Abhishek Jaywant, a research trainee in McGill's Neuropragmatics and Emotion Lab, and with financial support from the Canadian Institutes of Health Research and the Fonds de la recherche en santé du Québec. Aging adults both with and without Parkinson's were recorded as they described visual scenes. Their voices were then played to listeners who were unaware of the speaker's health status. Those with Parkinson's disease were perceived as less interested, less involved, less happy and less friendly than aging speakers without the disease. Negative impressions of their personality were specifically related to changes in the speaking voices caused by the disease, not the ability to describe the scenes.
The ability to communicate effectively is of paramount importance to the psychological well-being of all humans. This research emphasizes that problems with movement, which alter the speaking voice of Parkinsonian adults, create important social barriers and difficulties with interpersonal communication for those affected. These findings provide another avenue by which health professionals can address mental and emotional health issues in Parkinson's patients.
These perceptions limit opportunities for social interaction and full participation in society for those with the disease, reducing their quality of life. Pell's research offers the public a better understanding of the difficulties these patients face -- as well as an opportunity to promote greater inclusiveness.
The research was conducted in collaboration with Abhishek Jaywant, a research trainee in McGill's Neuropragmatics and Emotion Lab, and with financial support from the Canadian Institutes of Health Research and the Fonds de la recherche en santé du Québec. Aging adults both with and without Parkinson's were recorded as they described visual scenes. Their voices were then played to listeners who were unaware of the speaker's health status. Those with Parkinson's disease were perceived as less interested, less involved, less happy and less friendly than aging speakers without the disease. Negative impressions of their personality were specifically related to changes in the speaking voices caused by the disease, not the ability to describe the scenes.
The ability to communicate effectively is of paramount importance to the psychological well-being of all humans. This research emphasizes that problems with movement, which alter the speaking voice of Parkinsonian adults, create important social barriers and difficulties with interpersonal communication for those affected. These findings provide another avenue by which health professionals can address mental and emotional health issues in Parkinson's patients.
Saturday, July 10, 2010
How key circuits in the brain control movement
A new study that has identified how key circuits in the brain control movement could treat movement related disorders, such as Parkinson’s disease. Scientists Anatol Kreitzer, PhD and Karl Deisseroth, MD PhD at the Gladstone Institute of Neurological Disease (GIND) and Stanford University used genetic methods to allow mice to produce a light-sensitive protein in very select group of cells in the brain.
Researchers found that the mouse with the fibre optics implanted in the brain moved normally with the laser turned off and froze when the laser was turned on. With the laser off, and the mouse’s movement was restored. “It’s not something we can do for just a second,” Kreitzer said. “We can do this for as long as the laser is on.” “We generated mice that lacked dopamine, and these mice showed many of the same symptoms found in humans with Parkinson’s disease. But when we activated the ‘go’ pathway in these mice, they began to move around normally again. We restored all of their motor deficits with this treatment, even though the mice still lacked dopamine,” he added.
The research could be important for treating Parkinson’s and also other disorders involving these circuits, such as Huntington’s disease, Tourette’s syndrome, obsessive-compulsive disorder, and addiction.
The research is published in the journal Nature.
Researchers found that the mouse with the fibre optics implanted in the brain moved normally with the laser turned off and froze when the laser was turned on. With the laser off, and the mouse’s movement was restored. “It’s not something we can do for just a second,” Kreitzer said. “We can do this for as long as the laser is on.” “We generated mice that lacked dopamine, and these mice showed many of the same symptoms found in humans with Parkinson’s disease. But when we activated the ‘go’ pathway in these mice, they began to move around normally again. We restored all of their motor deficits with this treatment, even though the mice still lacked dopamine,” he added.
The research could be important for treating Parkinson’s and also other disorders involving these circuits, such as Huntington’s disease, Tourette’s syndrome, obsessive-compulsive disorder, and addiction.
The research is published in the journal Nature.
Tuesday, June 22, 2010
Neurologix Announces Successful Phase 2 Trial of Gene Therapy for Parkinson's Disease
Neurologix, Inc. (OTC Bulletin Board: NRGX),today announced positive results in a Phase 2 trial of its investigational gene therapy for advanced Parkinson's disease (PD), NLX-P101. Study participants who received NLX-P101 experienced statistically significant and clinically meaningful improvements in off-medication motor scores compared to control subjects who received sham surgery. In the trial, this benefit was seen at one month and continued virtually unchanged throughout the six month blinded study period. The results also demonstrated a positive safety profile for NLX-P101, with no serious adverse events related to the gene therapy or surgical procedure reported. Patients enrolled in the trial had moderate to advanced PD and were not adequately responsive to current therapies.
Neurologix, Inc., is a clinical-stage biotechnology company dedicated to the discovery, development and commercialization of gene therapies for serious disorders of the brain and central nervous system (CNS). Neurologix's investigational AAV (adeno-associated virus) vector gene therapy, NLX-P101, is a novel, non-dopaminergic approach that uses an inhibitory gene (glutamic acid decarboxylase or "GAD") to selectively alter the neural circuitry affected in PD and, thereby, normalize brain physiology. Neurologix's technology is the only gene therapy strategy currently in development which bypasses the dopamine system.
"We are extremely pleased that years of research by our group with AAV vector gene transfer technology has led to the unprecedented milestone of a statistically significant improvement in a double-blind, placebo-controlled trial of gene therapy for any neurological disorder," said Michael G. Kaplitt, MD, PhD, scientific co-founder of Neurologix, Inc., neurosurgeon, New York-Presbyterian Hospital/Weill Cornell Medical Center and Associate Professor and Vice Chairman for Research, Department of Neurological Surgery, Weill Cornell Medical College. "We now have solid scientific evidence to support NLX-P101 as an important, potential treatment for this devastating disease."
Matthew J. During, MD, DSc, Professor of Molecular Virology, Immunology and Medical Genetics, Neuroscience and Neurological Surgery, The Ohio State Medical School, and Professor of Molecular Medicine and Pathology, University of Auckland, New Zealand, and Michael G. Kaplitt, MD, PhD, are the scientific founders of Neurologix, Inc., and have been at the forefront of gene therapy research since 1989. This Phase 2 trial is the result of more than 15 years of progress with their work in AAV gene transfer technology. They were the first to demonstrate that AAV could be an effective gene therapy agent in the brain, which they reported in their landmark Nature Genetics paper in 1994. Drs. During, Kaplitt and colleagues subsequently published additional research demonstrating the beneficial effects of AAV-GAD gene therapy for Parkinson's disease in the journal Science in 2002. Today's findings build upon earlier positive results from the NLX-P101 Phase 1 trial, which was the first ever clinical gene therapy trial for Parkinson's disease. Results of that study appeared in 2007 as a cover article in The Lancet and in a second article in the Proceedings of the National Academy of Sciences.
Neurologix and Gene Therapy – A Novel Approach to Parkinson's Disease
In Parkinson's disease, patients lose dopamine-producing brain cells, resulting in substantial reductions in the activity and amount of GABA (gamma-aminobutyric acid), the major inhibitory neurotransmitter in the brain. This contributes to an abnormal increase in activity of the subthalamic nucleus (STN) of the brain, a key regulatory center for movement, and causes a dysfunction in brain circuitry responsible for coordinating movement. GABA is made by a gene called glutamic acid decarboxylase, or GAD.
Neurologix's gene therapy approach to PD aims to reset the overactive brain cells to inhibit electrical activity and return brain network activity to more normal levels. The strategy involves restoring GABA and thus improving the patient's motor control by using an AAV vector (a disabled, non-pathogenic virus) to deliver the GAD gene back into the STN. Increasing GAD causes more GABA to be synthesized, thus helping to calm the STN over-activity.
NLX-P101 is delivered to the brain through a standard, minimally-invasive surgical procedure that uses similar techniques to those currently employed in traditional surgery for PD. The Neurologix gene therapy procedure, however, does not require general anesthesia nor implantation of a permanent medical device in the brain.
"While dopamine clearly plays a role in Parkinson's disease, dopamine levels in the brain are inherently difficult to control, resulting in sub-optimal treatment outcomes for patients. We believe that by altering chemical targets further downstream in the brain's network that regulates movement, we have the potential to help improve outcomes and restore motor function for patients with advanced Parkinson's disease," added Matthew J. During, MD, DSc, scientific co-founder of Neurologix, Inc.
"Based on this data, we are confident that NLX-P101 has great potential to advance the treatment paradigm for Parkinson's patients, and to eventually offer an important, new therapy for patients with this debilitating disease. The study investigators continue to further evaluate the detailed data and we look forward to its publication or presentation," said Clark A. Johnson, President and Chief Executive Officer of the Company. "Today's news is also important validation for our ongoing development of other technologies for neurological and psychiatric diseases, including our advanced pre-clinical program in epilepsy. Given these results, we would look to pursue a strategic transaction which will maximize value for the Company."
Study Details
This double-blind, multi-center, randomized, sham-procedure-controlled Phase 2 study was designed to evaluate the safety and efficacy of NLX-P101 in patients with moderate to advanced PD who were not well-controlled on available medical therapy. Trial participants were randomized to receive either an infusion of NLX-P101 bilaterally into each subthalamic nucleus, or a sham infusion of a sterile saline solution. Each procedure was carried out under local anesthesia.
The primary measure of efficacy in the study was the difference in off-medication motor scores between the treated and sham groups on the Unified Parkinson's Disease Rating Scale (UPDRS) Part 3 (Motor section), which has long been the standard for clinical assessment in Parkinson's disease. All subjects were evaluated at baseline as well as one, three and six months after undergoing surgery.
The trial also showed that NLX-P101 was well-tolerated with no serious adverse events related to the drug or procedure reported. All treated subjects will continue to be monitored for safety for a 12-month period following their surgical procedure.
Neurologix, Inc., is a clinical-stage biotechnology company dedicated to the discovery, development and commercialization of gene therapies for serious disorders of the brain and central nervous system (CNS). Neurologix's investigational AAV (adeno-associated virus) vector gene therapy, NLX-P101, is a novel, non-dopaminergic approach that uses an inhibitory gene (glutamic acid decarboxylase or "GAD") to selectively alter the neural circuitry affected in PD and, thereby, normalize brain physiology. Neurologix's technology is the only gene therapy strategy currently in development which bypasses the dopamine system.
"We are extremely pleased that years of research by our group with AAV vector gene transfer technology has led to the unprecedented milestone of a statistically significant improvement in a double-blind, placebo-controlled trial of gene therapy for any neurological disorder," said Michael G. Kaplitt, MD, PhD, scientific co-founder of Neurologix, Inc., neurosurgeon, New York-Presbyterian Hospital/Weill Cornell Medical Center and Associate Professor and Vice Chairman for Research, Department of Neurological Surgery, Weill Cornell Medical College. "We now have solid scientific evidence to support NLX-P101 as an important, potential treatment for this devastating disease."
Matthew J. During, MD, DSc, Professor of Molecular Virology, Immunology and Medical Genetics, Neuroscience and Neurological Surgery, The Ohio State Medical School, and Professor of Molecular Medicine and Pathology, University of Auckland, New Zealand, and Michael G. Kaplitt, MD, PhD, are the scientific founders of Neurologix, Inc., and have been at the forefront of gene therapy research since 1989. This Phase 2 trial is the result of more than 15 years of progress with their work in AAV gene transfer technology. They were the first to demonstrate that AAV could be an effective gene therapy agent in the brain, which they reported in their landmark Nature Genetics paper in 1994. Drs. During, Kaplitt and colleagues subsequently published additional research demonstrating the beneficial effects of AAV-GAD gene therapy for Parkinson's disease in the journal Science in 2002. Today's findings build upon earlier positive results from the NLX-P101 Phase 1 trial, which was the first ever clinical gene therapy trial for Parkinson's disease. Results of that study appeared in 2007 as a cover article in The Lancet and in a second article in the Proceedings of the National Academy of Sciences.
Neurologix and Gene Therapy – A Novel Approach to Parkinson's Disease
In Parkinson's disease, patients lose dopamine-producing brain cells, resulting in substantial reductions in the activity and amount of GABA (gamma-aminobutyric acid), the major inhibitory neurotransmitter in the brain. This contributes to an abnormal increase in activity of the subthalamic nucleus (STN) of the brain, a key regulatory center for movement, and causes a dysfunction in brain circuitry responsible for coordinating movement. GABA is made by a gene called glutamic acid decarboxylase, or GAD.
Neurologix's gene therapy approach to PD aims to reset the overactive brain cells to inhibit electrical activity and return brain network activity to more normal levels. The strategy involves restoring GABA and thus improving the patient's motor control by using an AAV vector (a disabled, non-pathogenic virus) to deliver the GAD gene back into the STN. Increasing GAD causes more GABA to be synthesized, thus helping to calm the STN over-activity.
NLX-P101 is delivered to the brain through a standard, minimally-invasive surgical procedure that uses similar techniques to those currently employed in traditional surgery for PD. The Neurologix gene therapy procedure, however, does not require general anesthesia nor implantation of a permanent medical device in the brain.
"While dopamine clearly plays a role in Parkinson's disease, dopamine levels in the brain are inherently difficult to control, resulting in sub-optimal treatment outcomes for patients. We believe that by altering chemical targets further downstream in the brain's network that regulates movement, we have the potential to help improve outcomes and restore motor function for patients with advanced Parkinson's disease," added Matthew J. During, MD, DSc, scientific co-founder of Neurologix, Inc.
"Based on this data, we are confident that NLX-P101 has great potential to advance the treatment paradigm for Parkinson's patients, and to eventually offer an important, new therapy for patients with this debilitating disease. The study investigators continue to further evaluate the detailed data and we look forward to its publication or presentation," said Clark A. Johnson, President and Chief Executive Officer of the Company. "Today's news is also important validation for our ongoing development of other technologies for neurological and psychiatric diseases, including our advanced pre-clinical program in epilepsy. Given these results, we would look to pursue a strategic transaction which will maximize value for the Company."
Study Details
This double-blind, multi-center, randomized, sham-procedure-controlled Phase 2 study was designed to evaluate the safety and efficacy of NLX-P101 in patients with moderate to advanced PD who were not well-controlled on available medical therapy. Trial participants were randomized to receive either an infusion of NLX-P101 bilaterally into each subthalamic nucleus, or a sham infusion of a sterile saline solution. Each procedure was carried out under local anesthesia.
The primary measure of efficacy in the study was the difference in off-medication motor scores between the treated and sham groups on the Unified Parkinson's Disease Rating Scale (UPDRS) Part 3 (Motor section), which has long been the standard for clinical assessment in Parkinson's disease. All subjects were evaluated at baseline as well as one, three and six months after undergoing surgery.
The trial also showed that NLX-P101 was well-tolerated with no serious adverse events related to the drug or procedure reported. All treated subjects will continue to be monitored for safety for a 12-month period following their surgical procedure.
Thursday, June 10, 2010
Parallel brainstem circuit discovery suggests new path in Parkinson's research
By Paul Francuch
Chicago and Montreal researchers studying the lowly lamprey eel have identified an overlooked nervous system pathway running parallel to known brainstem locomotor command circuitry in vertebrates such as birds, fishes and mammals.
The finding is reported in Nature Neuroscience, online May 16, and highlighted in the magazine's "news and views" section.
Simon Alford, University of Illinois at Chicago professor of biological sciences and the article's corresponding author, said the role of a neurotransmitter associated with this parallel pathway may also suggest new research directions for treating Parkinson's disease.
Alford, along with his former graduate student and lead author Roy Smetana, now a University of Pittsburgh resident in psychiatry, worked with Université de Montréal and Université de Québec à Montréal neurobiologist Réjean Dubuc and his post-doctoral researcher Laurent Juvin in trying to sort out how the neurotransmitter analog muscarine modifies sensory information going to the brain.
Their work determined that muscarine stimulated neural activity, leading to locomotion in the laboratory lampreys.
The group focused its attention on a collection of brainstem neurons that tell the spinal cord to generate motor output that enables walking and other locomotion.
"We started looking at this group of neurons, which in the lamprey are conveniently very large, so they're easy to plant electrodes and record from," said Alford. "We discovered the muscarinic excitation was not working on these cells, but on a previously unknown group of cells within the brainstem."
What's more, these newly discovered brainstem neurons showed what Alford called a "very odd response" to the muscarine.
"Instead of just turning on -- like a synapse turns on a neuron and makes it fire -- when you put muscarine on these cells, they turn on and stay on" for a minute or longer which he said for a neurological reaction can be a very long time.
The researchers discovered the actual brain neurotransmitter that activates muscarine receptors -- another chemical, acetylcholine -- sends a signal to these newly discovered brainstem neurons, switching them on for the lengthy minute or so durations.
Alford said the finding opens up new insights into animal locomotion.
"It's a system for turning on your locomotor system and making you walk or run in a very coordinated, straight-line fashion sustaining locomotion for a considerable time," he said. "This simply was not known to exist before we discovered it."
The role of the neurotransmitter acetylcholine may ultimately suggest new Parkinson's disease treatments. While a key Parkinson's symptom is tremor, an advanced stage symptom is the inability to start a movement, such as walking. Symptoms associated with Parkinson's can be helped by reducing acetylcholine-mediated neurotransmission in the brain, but little work has focused on brainstem muscarine receptors in this disease.
"This may be a backdoor finding into a secondary effect of Parkinson's disease that's not well studied because most research emphasis has been on dopamine and the basal ganglia, a different neurotransmitter and region of the brain," Alford said.
Major funding for the research came from the National Institute of Neurological Disorders and Stroke, and the Canadian Institutes of Health Research.
Chicago and Montreal researchers studying the lowly lamprey eel have identified an overlooked nervous system pathway running parallel to known brainstem locomotor command circuitry in vertebrates such as birds, fishes and mammals.
The finding is reported in Nature Neuroscience, online May 16, and highlighted in the magazine's "news and views" section.
Simon Alford, University of Illinois at Chicago professor of biological sciences and the article's corresponding author, said the role of a neurotransmitter associated with this parallel pathway may also suggest new research directions for treating Parkinson's disease.
Alford, along with his former graduate student and lead author Roy Smetana, now a University of Pittsburgh resident in psychiatry, worked with Université de Montréal and Université de Québec à Montréal neurobiologist Réjean Dubuc and his post-doctoral researcher Laurent Juvin in trying to sort out how the neurotransmitter analog muscarine modifies sensory information going to the brain.
Their work determined that muscarine stimulated neural activity, leading to locomotion in the laboratory lampreys.
The group focused its attention on a collection of brainstem neurons that tell the spinal cord to generate motor output that enables walking and other locomotion.
"We started looking at this group of neurons, which in the lamprey are conveniently very large, so they're easy to plant electrodes and record from," said Alford. "We discovered the muscarinic excitation was not working on these cells, but on a previously unknown group of cells within the brainstem."
What's more, these newly discovered brainstem neurons showed what Alford called a "very odd response" to the muscarine.
"Instead of just turning on -- like a synapse turns on a neuron and makes it fire -- when you put muscarine on these cells, they turn on and stay on" for a minute or longer which he said for a neurological reaction can be a very long time.
The researchers discovered the actual brain neurotransmitter that activates muscarine receptors -- another chemical, acetylcholine -- sends a signal to these newly discovered brainstem neurons, switching them on for the lengthy minute or so durations.
Alford said the finding opens up new insights into animal locomotion.
"It's a system for turning on your locomotor system and making you walk or run in a very coordinated, straight-line fashion sustaining locomotion for a considerable time," he said. "This simply was not known to exist before we discovered it."
The role of the neurotransmitter acetylcholine may ultimately suggest new Parkinson's disease treatments. While a key Parkinson's symptom is tremor, an advanced stage symptom is the inability to start a movement, such as walking. Symptoms associated with Parkinson's can be helped by reducing acetylcholine-mediated neurotransmission in the brain, but little work has focused on brainstem muscarine receptors in this disease.
"This may be a backdoor finding into a secondary effect of Parkinson's disease that's not well studied because most research emphasis has been on dopamine and the basal ganglia, a different neurotransmitter and region of the brain," Alford said.
Major funding for the research came from the National Institute of Neurological Disorders and Stroke, and the Canadian Institutes of Health Research.
Wednesday, June 2, 2010
New 'brainstem circuitry' may aid Parkinson's treatment development
Healthcare News
A new brainstem circuitry in mammals may pave the way for an alternative way of looking at Parkinson's disease, according to new research.
Researchers are confident that a new brainstem circuit discovery could help with the treatment of Parkinson's disease in the future.
An overlooked nervous system pathway running parallel to the known brainstem has been discovered in mammals that may offer a new means of treating the condition, according to researchers from the universities of Pittsburgh, Illinois at Chicago, Montreal and Quebec.
The results, which are published in the journal Nature Neuroscience, show how a neurotransmitter associated with this alternative pathway modifies sensory information that is delivered to the brain.
Commenting on the findings, lead author Simon Alford suggested that the research opens up new avenues for general insights into animal and human locomotion.
He explained: "It's a system for turning on your locomotor system and making you walk or run in a very coordinated, straight-line fashion.
"This may be a backdoor finding into a secondary effect of Parkinson's disease that's not well studied because most research emphasis has been on dopamine and the basal ganglia, a different neurotransmitter and region of the brain."
Meanwhile, research published by scientists at the Rush University Medical Center in September suggested that high doses of over the counter vitamin supplements may slow the progression of Parkinson's disease.
A new brainstem circuitry in mammals may pave the way for an alternative way of looking at Parkinson's disease, according to new research.
Researchers are confident that a new brainstem circuit discovery could help with the treatment of Parkinson's disease in the future.
An overlooked nervous system pathway running parallel to the known brainstem has been discovered in mammals that may offer a new means of treating the condition, according to researchers from the universities of Pittsburgh, Illinois at Chicago, Montreal and Quebec.
The results, which are published in the journal Nature Neuroscience, show how a neurotransmitter associated with this alternative pathway modifies sensory information that is delivered to the brain.
Commenting on the findings, lead author Simon Alford suggested that the research opens up new avenues for general insights into animal and human locomotion.
He explained: "It's a system for turning on your locomotor system and making you walk or run in a very coordinated, straight-line fashion.
"This may be a backdoor finding into a secondary effect of Parkinson's disease that's not well studied because most research emphasis has been on dopamine and the basal ganglia, a different neurotransmitter and region of the brain."
Meanwhile, research published by scientists at the Rush University Medical Center in September suggested that high doses of over the counter vitamin supplements may slow the progression of Parkinson's disease.
Thursday, May 27, 2010
Deep Brain Stimulation Improves Quality of Life in Advanced Parkinson's
Megan Brooks
In a randomized, multicenter study of advanced Parkinson's disease (PD) patients, those treated with deep brain stimulation (DBS) of the subthalamic nucleus combined with best medical therapy had better self-reported quality of life at 1 year than those treated with best medical therapy alone.
The surgery group reported greater improvement in mobility and activities of daily living after 1 year and required a third less daily dopaminergic drugs than the control group, according to an article published online in the April 29 issue of The Lancet.
The differences noted were "clinically meaningful," the study team, with senior study author Keith Wheatley, DPhil, professor of medical statistics, Cancer Research UK Clinical Trials Unit, University of Birmingham, United Kingdom, concludes in the article, "but surgery is not without risk, and targeting of patients most likely to benefit might be warranted."
Self-Evaluation of Functional Status
The results are from the ongoing PD-SURG trial, a randomized, open-label trial.
The study involved 366 well-matched patients with advanced PD for whom current medical therapy was not providing adequate symptom control; 183 were randomly allocated to DBS plus best medical therapy (178 underwent DBS) and 183 to best medical therapy alone. In 174 of the surgery patients, the subthalamic nucleus was the surgical target and 176 procedures were bilateral.
Medical therapy could include apomorphine infusion according to local practice, other dopamine agonists, monoamine oxidase type B inhibitors, catechol-O-methyltransferase inhibitors, amantadine, or other drugs for PD symptoms.
The primary endpoint was the patients' self-evaluation of their functional status on the 39-item PD questionnaire (PDQ-39).
According to the investigators, the mean change from baseline to 1 year on the PDQ-39 summary index was −5.0 points in the surgery group and −0.3 point in the medical therapy group (difference, −4.7 points; 95% confidence interval [CI], −7.6 to −1.8; P = .01).
"The sample size for the trial was based on detecting a 10-point difference in the quality of life scale," Dr. Wheatley noted in an email to Medscape Neurology. "Of course, we would have liked a larger benefit, but the observed 5-point benefit is worthwhile for patients."
Significant differences favoring surgery were also seen in the mean change in the PDQ-39 score for mobility (−8.9; 95% CI, −13.8 to −4.0; P = .0004), activities of daily living (−12.4; 95% CI, −17.3 to −7.5; P < .0001), and bodily discomfort (−7.5; 95% CI, −12.6 to −2.4; P = .004). Between-group differences in all other domains of the PDQ-39 (eg, social support, cognition and communication) were not significant.
Verbal Fluency and Vocabulary
However, in an editorial published with the study, Maria C. Rodriguez-Oroz, MD, from University of Navarra in Pamplona, Spain, notes that a more detailed neuropsychological analysis of a subgroup of patients showed a decline in verbal fluency and vocabulary in the DBS group.
Still, at 1 year, patients who had the surgery were "better able to get about and perform their normal daily activities," Dr. Wheatley told Medscape Neurology, "and they needed a lot less medication than the patients in the medical therapy arm."
Patients in the surgery group were taking a mean levodopa equivalent dose of 894 mg/day (SD, 568 mg/day) at 1 year, whereas those in the medical group were on 1347 mg/day (SD, 585 mg/day; P < .0001), a difference of 453 mg/day (95% CI, 328 – 580), which represents a 34% reduction in mean daily dopaminergic drug requirement in the surgery group.
At baseline, 45 patients in each group were taking apomorphine. By 1 year, this had decreased to 13 in the surgery group and had increased to 63 in the medical therapy group.
The findings on the PDQ-39, the study team reports, "were mirrored by clinically meaningful differences on the United Parkinson's Disease Rating Scale (UPDRS), including the patient-rated UPDRS part IV, which showed substantial benefits of surgery in the time and severity of dyskinesia and off periods — the most common reasons for patients to be considered for surgery."
At 1 year, 75 patients in the surgery group vs 21 in the control group reported no waking day dyskinesia and 45 and 5, respectively, reported no off time (P < .0001 for both).
As expected, DBS was not without risk; 36 (19%) of 178 surgery patients had 43 surgery-related serious adverse events, most commonly infection. There was 1 unsuccessful suicide attempt after DBS in a patient who had a previous suicide attempt before the study. There was 1 surgery-related death due to hemorrhage.
Trial Differences, Advantages, Limitations
Dr. Rodriguez-Oroz says 3 aspects of this trial make it different from previous DBS trials in PD patients: "the trial includes a larger number of patients, has a longer follow-up, and permits treatment of patients in both groups with continuous infusion of apomorphine," which is increasingly being used for PD.
One major limitation of the trial, recognized by Dr. Rodriguez-Oroz and the study team, is that evaluators were not blinded to treatment allocation. Another, according to Dr. Rodriguez-Oroz, is that reports of improvements in dyskinesias and off periods were based on the UPDRS complications of therapy subsection rather than a "more reliable source," such as diaries, in which patients could note changes in motor abilities more immediately is another limitation.
A third limitation is that a standard definition of the on state was not specified; "instead, assessment of whether a patient was in the on state was left to the judgment of neurologists at each center."
"An excellent aspect of this trial is that follow-up will continue to 9 years," Dr. Rodriguez-Oroz notes. "This will provide invaluable information about the long-term benefit of surgery, especially in different subgroups of patients (eg, according to age, disease severity, disease duration, and reason for surgery)."
The study was supported by funding from the UK Medical Research Council and Parkinson's UK. One of the study investigators discloses having received travel grants from Medtronic, and another received reimbursement fees from Medtronic for time spent collecting and analyzing data as a member of the ad hoc adverse event committee for another DBS study. The other study authors have disclosed no relevant financial relationships. Dr. Rodriguez-Oroz discloses that she is on the advisory board of UCB Spain; receives payment for lectures and travel for scientific meetings from GlaxoSmithKline, UCB, Lundbeck, and Medtronic; and has received payment from Medtronic for teaching.
In a randomized, multicenter study of advanced Parkinson's disease (PD) patients, those treated with deep brain stimulation (DBS) of the subthalamic nucleus combined with best medical therapy had better self-reported quality of life at 1 year than those treated with best medical therapy alone.
The surgery group reported greater improvement in mobility and activities of daily living after 1 year and required a third less daily dopaminergic drugs than the control group, according to an article published online in the April 29 issue of The Lancet.
The differences noted were "clinically meaningful," the study team, with senior study author Keith Wheatley, DPhil, professor of medical statistics, Cancer Research UK Clinical Trials Unit, University of Birmingham, United Kingdom, concludes in the article, "but surgery is not without risk, and targeting of patients most likely to benefit might be warranted."
Self-Evaluation of Functional Status
The results are from the ongoing PD-SURG trial, a randomized, open-label trial.
The study involved 366 well-matched patients with advanced PD for whom current medical therapy was not providing adequate symptom control; 183 were randomly allocated to DBS plus best medical therapy (178 underwent DBS) and 183 to best medical therapy alone. In 174 of the surgery patients, the subthalamic nucleus was the surgical target and 176 procedures were bilateral.
Medical therapy could include apomorphine infusion according to local practice, other dopamine agonists, monoamine oxidase type B inhibitors, catechol-O-methyltransferase inhibitors, amantadine, or other drugs for PD symptoms.
The primary endpoint was the patients' self-evaluation of their functional status on the 39-item PD questionnaire (PDQ-39).
According to the investigators, the mean change from baseline to 1 year on the PDQ-39 summary index was −5.0 points in the surgery group and −0.3 point in the medical therapy group (difference, −4.7 points; 95% confidence interval [CI], −7.6 to −1.8; P = .01).
"The sample size for the trial was based on detecting a 10-point difference in the quality of life scale," Dr. Wheatley noted in an email to Medscape Neurology. "Of course, we would have liked a larger benefit, but the observed 5-point benefit is worthwhile for patients."
Significant differences favoring surgery were also seen in the mean change in the PDQ-39 score for mobility (−8.9; 95% CI, −13.8 to −4.0; P = .0004), activities of daily living (−12.4; 95% CI, −17.3 to −7.5; P < .0001), and bodily discomfort (−7.5; 95% CI, −12.6 to −2.4; P = .004). Between-group differences in all other domains of the PDQ-39 (eg, social support, cognition and communication) were not significant.
Verbal Fluency and Vocabulary
However, in an editorial published with the study, Maria C. Rodriguez-Oroz, MD, from University of Navarra in Pamplona, Spain, notes that a more detailed neuropsychological analysis of a subgroup of patients showed a decline in verbal fluency and vocabulary in the DBS group.
Still, at 1 year, patients who had the surgery were "better able to get about and perform their normal daily activities," Dr. Wheatley told Medscape Neurology, "and they needed a lot less medication than the patients in the medical therapy arm."
Patients in the surgery group were taking a mean levodopa equivalent dose of 894 mg/day (SD, 568 mg/day) at 1 year, whereas those in the medical group were on 1347 mg/day (SD, 585 mg/day; P < .0001), a difference of 453 mg/day (95% CI, 328 – 580), which represents a 34% reduction in mean daily dopaminergic drug requirement in the surgery group.
At baseline, 45 patients in each group were taking apomorphine. By 1 year, this had decreased to 13 in the surgery group and had increased to 63 in the medical therapy group.
The findings on the PDQ-39, the study team reports, "were mirrored by clinically meaningful differences on the United Parkinson's Disease Rating Scale (UPDRS), including the patient-rated UPDRS part IV, which showed substantial benefits of surgery in the time and severity of dyskinesia and off periods — the most common reasons for patients to be considered for surgery."
At 1 year, 75 patients in the surgery group vs 21 in the control group reported no waking day dyskinesia and 45 and 5, respectively, reported no off time (P < .0001 for both).
As expected, DBS was not without risk; 36 (19%) of 178 surgery patients had 43 surgery-related serious adverse events, most commonly infection. There was 1 unsuccessful suicide attempt after DBS in a patient who had a previous suicide attempt before the study. There was 1 surgery-related death due to hemorrhage.
Trial Differences, Advantages, Limitations
Dr. Rodriguez-Oroz says 3 aspects of this trial make it different from previous DBS trials in PD patients: "the trial includes a larger number of patients, has a longer follow-up, and permits treatment of patients in both groups with continuous infusion of apomorphine," which is increasingly being used for PD.
One major limitation of the trial, recognized by Dr. Rodriguez-Oroz and the study team, is that evaluators were not blinded to treatment allocation. Another, according to Dr. Rodriguez-Oroz, is that reports of improvements in dyskinesias and off periods were based on the UPDRS complications of therapy subsection rather than a "more reliable source," such as diaries, in which patients could note changes in motor abilities more immediately is another limitation.
A third limitation is that a standard definition of the on state was not specified; "instead, assessment of whether a patient was in the on state was left to the judgment of neurologists at each center."
"An excellent aspect of this trial is that follow-up will continue to 9 years," Dr. Rodriguez-Oroz notes. "This will provide invaluable information about the long-term benefit of surgery, especially in different subgroups of patients (eg, according to age, disease severity, disease duration, and reason for surgery)."
The study was supported by funding from the UK Medical Research Council and Parkinson's UK. One of the study investigators discloses having received travel grants from Medtronic, and another received reimbursement fees from Medtronic for time spent collecting and analyzing data as a member of the ad hoc adverse event committee for another DBS study. The other study authors have disclosed no relevant financial relationships. Dr. Rodriguez-Oroz discloses that she is on the advisory board of UCB Spain; receives payment for lectures and travel for scientific meetings from GlaxoSmithKline, UCB, Lundbeck, and Medtronic; and has received payment from Medtronic for teaching.
Tuesday, May 4, 2010
Voice Analysis May Allow Early Detection of Parkinson's
Changes in speech occur before other symptoms, could help speed diagnosis, findings show.
HealthDay News) -- A new voice analysis technique can identify changes in speech associated with the early stages of Parkinson's disease
, a new study has found.
"This is a noninvasive, reliable and accurate technique that only requires the patient to read out a few simple sentences," Shimon Sapir, of the department of communication sciences and disorders at the University of Haifa in Israel, who developed the new test, said in a university news release.
In many cases, Parkinson's disease is diagnosed based on muscle rigidity, tremors, slow movement and loss of balance. But by the time these symptoms are present, the disease is already well-advanced.
Since the muscles controlling voice and speech are affected in most people with Parkinson's disease, Sapir decided to develop an acoustic analysis method that identified differences between the speech of people with Parkinson's disease and healthy people. The method also tracks voice changes that occur in response to treatment or disease progression.
A series of tests showed that the new acoustic analysis technique is effective. The findings were published in a recent issue of the Journal of Speech, Language and Hearing Research.
"Doctors and scientists agree that early diagnosis of Parkinson's disease is important in order to slow down or even prevent the degenerative progress of this disease," Sapir said. "Today no treatment is available to this effect, but when treatment becomes feasible, early diagnosis is going to be crucial. There are various methods of brain imaging for detecting early signs of Parkinson's disease, but these methods are expensive -- particularly when attempting to screen a large population at risk. Hence the importance of developing techniques for early diagnosis that are valid, reliable, non-invasive, simple, readily available and inexpensive."
But Sapir added that "while our initial results are very encouraging, additional studies must be carried out in order to examine the new method. Also, given that the disease and its progression have different effects on individuals, speech analysis must be incorporated into a battery of tests that examine other signs and symptoms of the disease, such as changes in handwriting, cognitive functions, sense of smell, and more."
SOURCE U.S. News Health
HealthDay News) -- A new voice analysis technique can identify changes in speech associated with the early stages of Parkinson's disease
, a new study has found.
"This is a noninvasive, reliable and accurate technique that only requires the patient to read out a few simple sentences," Shimon Sapir, of the department of communication sciences and disorders at the University of Haifa in Israel, who developed the new test, said in a university news release.
In many cases, Parkinson's disease is diagnosed based on muscle rigidity, tremors, slow movement and loss of balance. But by the time these symptoms are present, the disease is already well-advanced.
Since the muscles controlling voice and speech are affected in most people with Parkinson's disease, Sapir decided to develop an acoustic analysis method that identified differences between the speech of people with Parkinson's disease and healthy people. The method also tracks voice changes that occur in response to treatment or disease progression.
A series of tests showed that the new acoustic analysis technique is effective. The findings were published in a recent issue of the Journal of Speech, Language and Hearing Research.
"Doctors and scientists agree that early diagnosis of Parkinson's disease is important in order to slow down or even prevent the degenerative progress of this disease," Sapir said. "Today no treatment is available to this effect, but when treatment becomes feasible, early diagnosis is going to be crucial. There are various methods of brain imaging for detecting early signs of Parkinson's disease, but these methods are expensive -- particularly when attempting to screen a large population at risk. Hence the importance of developing techniques for early diagnosis that are valid, reliable, non-invasive, simple, readily available and inexpensive."
But Sapir added that "while our initial results are very encouraging, additional studies must be carried out in order to examine the new method. Also, given that the disease and its progression have different effects on individuals, speech analysis must be incorporated into a battery of tests that examine other signs and symptoms of the disease, such as changes in handwriting, cognitive functions, sense of smell, and more."
SOURCE U.S. News Health
Wednesday, January 20, 2010
Dopamine replacement therapy causes brain dysfunction in patients with Parkinson disease, study says
Findings point to dopamine replacement therapy causing dysfunction in specific areas of the brain
People with Parkinson’s Disease are more likely to display abnormal social behaviour and make poor decisions in ambiguous circumstances if they are pathological gamblers, according to research in the January issue of the European Journal of Neurology.
A number of studies have already associated pathological gambling with Parkinson’s, suggesting that it is a frequent impulse control disorder associated mainly with dopamine replacement therapy.
Researchers from the Raul Carrea Institute for Neurological Research (FLENI) in Buenos Aires, Argentina, interviewed the immediate relatives of seven Parkinson’s patients who were pathological gamblers. They also interviewed the families of 13 patients – matched by age, sex, education and disease severity – who did not gamble.
They found that the gamblers were less co-operative with others, had difficulties making or keeping close relationships and often did what they wanted, without caring what other people thought.
The researchers also found that the patients in the pathological gambling group performed worse in the Iowa Gambling Task, which is used to assess decision-making abilities in ambiguous or risky situations.
“The object of this study was to assess decision-making processes in Parkinson’s Disease patients with and without pathological gambling by asking them and their relatives to take part in a series of tests” says Dr Ramon Leiguarda, an expert in cognitive neurology.
“We found that the patients in the pathological gambling group were more likely to make poor decisions and select disadvantageous alternatives more frequently than advantageous alternatives.”
The combination of poor decision-making and abnormal social behaviour has led the team to conclude that dopamine replacement therapy can induce dysfunction in the areas of the brain that control affective decision making – the ventromedial pre-frontal cortex and amygdala-ventral striatum system.
Six of the seven pathological gamblers who took part in the study were male. At the time of the study they had an average age of 61 and their average age at diagnosis was 52.
Six of the patients had no history of gambling before developing Parkinson’s Disease. One patient had played poker with friends for 30 years, but his gambling behaviour exacerbated after starting dopamine replacement therapy and now included roulette and horse racing.
The other six participants said that their preferred type of gambling was slot machines.
Four of the seven displayed other impulse control disorders – two were also compulsive shoppers and two displayed hypersexuality.
“We believe that the behaviour highlighted in our study, combined with previous research into the links between Parkinson’s Disease and pathological gambling, point to dopamine replacement therapy causing dysfunction in specific areas of the brain” says Dr Leiguarda.
“Further studies that assess Parkinson’s Disease patients recovering from pathological gambling are needed to better understand the physiopathology of this impulse control disorder.”
For more information go to www.parkinsonresearchfoundation.org
People with Parkinson’s Disease are more likely to display abnormal social behaviour and make poor decisions in ambiguous circumstances if they are pathological gamblers, according to research in the January issue of the European Journal of Neurology.
A number of studies have already associated pathological gambling with Parkinson’s, suggesting that it is a frequent impulse control disorder associated mainly with dopamine replacement therapy.
Researchers from the Raul Carrea Institute for Neurological Research (FLENI) in Buenos Aires, Argentina, interviewed the immediate relatives of seven Parkinson’s patients who were pathological gamblers. They also interviewed the families of 13 patients – matched by age, sex, education and disease severity – who did not gamble.
They found that the gamblers were less co-operative with others, had difficulties making or keeping close relationships and often did what they wanted, without caring what other people thought.
The researchers also found that the patients in the pathological gambling group performed worse in the Iowa Gambling Task, which is used to assess decision-making abilities in ambiguous or risky situations.
“The object of this study was to assess decision-making processes in Parkinson’s Disease patients with and without pathological gambling by asking them and their relatives to take part in a series of tests” says Dr Ramon Leiguarda, an expert in cognitive neurology.
“We found that the patients in the pathological gambling group were more likely to make poor decisions and select disadvantageous alternatives more frequently than advantageous alternatives.”
The combination of poor decision-making and abnormal social behaviour has led the team to conclude that dopamine replacement therapy can induce dysfunction in the areas of the brain that control affective decision making – the ventromedial pre-frontal cortex and amygdala-ventral striatum system.
Six of the seven pathological gamblers who took part in the study were male. At the time of the study they had an average age of 61 and their average age at diagnosis was 52.
Six of the patients had no history of gambling before developing Parkinson’s Disease. One patient had played poker with friends for 30 years, but his gambling behaviour exacerbated after starting dopamine replacement therapy and now included roulette and horse racing.
The other six participants said that their preferred type of gambling was slot machines.
Four of the seven displayed other impulse control disorders – two were also compulsive shoppers and two displayed hypersexuality.
“We believe that the behaviour highlighted in our study, combined with previous research into the links between Parkinson’s Disease and pathological gambling, point to dopamine replacement therapy causing dysfunction in specific areas of the brain” says Dr Leiguarda.
“Further studies that assess Parkinson’s Disease patients recovering from pathological gambling are needed to better understand the physiopathology of this impulse control disorder.”
For more information go to www.parkinsonresearchfoundation.org
Monday, January 11, 2010
Small molecules 'protect cells in Parkinson's disease models'
Parkinson's disease could be fought with small molecules, new research suggests.
A number of structurally-similar small molecules appear to be able to protect cells from alpha-synuclein toxicity in several instances of Parkinson's disease, new research has concluded.
Susan Lundquist and her team at the Whitehead Institute used a form of brewers' yeast injected with several compounds and found that it was able to fight off Parkinson's disease-like cells.
Daniel Tardiff, a post-doctoral researcher with Ms Lindquist, said that theoretically speaking, if a compound is having a beneficial effect on yeast cells, in a worm and in primary neurons, it might "actually be a potential therapeutic avenue or drug".
He continued: "Though we started in yeast, one of those compounds could actually have some potential for human health in Parkinson's disease. That's always a lofty goal."
The upcoming World Parkinson Congress will be held in Glasgow from September 28th to October 1st 2010 and will provide an international forum for the latest medical practices, scientific discoveries and carers' initiatives related to Parkinson's disease.
For more information go to www.parkinsonresearchfoundation.org
A number of structurally-similar small molecules appear to be able to protect cells from alpha-synuclein toxicity in several instances of Parkinson's disease, new research has concluded.
Susan Lundquist and her team at the Whitehead Institute used a form of brewers' yeast injected with several compounds and found that it was able to fight off Parkinson's disease-like cells.
Daniel Tardiff, a post-doctoral researcher with Ms Lindquist, said that theoretically speaking, if a compound is having a beneficial effect on yeast cells, in a worm and in primary neurons, it might "actually be a potential therapeutic avenue or drug".
He continued: "Though we started in yeast, one of those compounds could actually have some potential for human health in Parkinson's disease. That's always a lofty goal."
The upcoming World Parkinson Congress will be held in Glasgow from September 28th to October 1st 2010 and will provide an international forum for the latest medical practices, scientific discoveries and carers' initiatives related to Parkinson's disease.
For more information go to www.parkinsonresearchfoundation.org
Monday, January 4, 2010
Despite Earlier Doubts, Feinstein Study Shows Fetal Transplants May Benefit Parkinson’s Patients Over Age 60
Fetal transplant surgery for Parkinson’s disease went on experimentally for more than a decade before it was put to the ultimate test in a double-blind, randomized study. It turned out that only patients under 60-years-old showed any benefit, but some also developed uncontrolled jerking movements that washed away hope for the technique. The findings were the death knell for the promising procedure.
But scientists involved with brain imaging studies of the fetal transplant recipients did not put away their study tools. In fact, they kept bringing the Parkinson’s patients back into the laboratory to take snapshots of their brains over time. And what they have now found, and reported in the latest issue of The Journal of Nuclear Medicine (JNM), is that people over age 60 began to show improvements more than a year after fetal dopamine cells were infused into the brain region damaged by Parkinson’s.
“This was totally surprising,” said David Eidelberg, MD, director of the Center for Neurosciences at The Feinstein Institute for Medical Research in Manhasset, NY. “The use of fetal transplantation for Parkinson’s encountered a good deal of skepticism after five patients in the study (all under age 60) developed dyskinesias.”
Dr. Eidelberg said that the Parkinson’s community basically forgot about the research and turned their attention to other promising techniques.
There were 33 patients, 13 of whom were over age 60 when the cells were infused into their brains. It was a double-blinded study so that 19 patients received the fetal cells and 14 others had a sham surgery and were offered the fetal cell transplant a year later. But by that time, the word had come out about the devastating side effect (the dyskinesias) and some older people opted out of the second surgery.
The Feinstein researchers have now looked at the brains of the transplanted patients two years and four years after the initial infusion of fetal cells. And they learned a few things: Beyond the first five people who developed dyskinesia, none of the other 15 younger people in the study showed signs of the troubling side effect. In about 25 percent of the cases, clinical improvement was noted and the transplanted cells were still working to make the dopamine up to four years later.
They also discovered that the older people gradually got better after the first year and that their improvements continued over the long term. “The older the brain, the harder it is to integrate the graft,” said Dr. Eidelberg. “But the PET scans told us that the graft was viable. And it took awhile before the cells worked to improve symptoms.”
The Feinstein group has identified two different brain networks hard hit in the disease. One is obvious: the motor regions that, when damaged, lead to tremors, rigidity and difficulty initiating movement. The other piece relates to cognition and mood, and there are discrete brain regions that worsen over time. In this study, researchers found that people did better overall on motor functions if they entered the study with their putamen intact – putamen is an area of the brain that governs cognition and mood. Dopamine is the key brain chemical in both these networks and it is critical for motor planning. When dementia sets in, people may have improvements in the motor network, but it isn’t observable because their cognitive network is abnormal and their ability to make plans to move is impaired.
The good news, said Dr. Eidelberg, is that the grafts stayed where they were and delivered dopamine to the tissue. The finding is critical as the field moves to transplant other types of cells, including embryonic stem cells or their ultimate product.
For more information go to www.parkinsonresearchfoundation.org
But scientists involved with brain imaging studies of the fetal transplant recipients did not put away their study tools. In fact, they kept bringing the Parkinson’s patients back into the laboratory to take snapshots of their brains over time. And what they have now found, and reported in the latest issue of The Journal of Nuclear Medicine (JNM), is that people over age 60 began to show improvements more than a year after fetal dopamine cells were infused into the brain region damaged by Parkinson’s.
“This was totally surprising,” said David Eidelberg, MD, director of the Center for Neurosciences at The Feinstein Institute for Medical Research in Manhasset, NY. “The use of fetal transplantation for Parkinson’s encountered a good deal of skepticism after five patients in the study (all under age 60) developed dyskinesias.”
Dr. Eidelberg said that the Parkinson’s community basically forgot about the research and turned their attention to other promising techniques.
There were 33 patients, 13 of whom were over age 60 when the cells were infused into their brains. It was a double-blinded study so that 19 patients received the fetal cells and 14 others had a sham surgery and were offered the fetal cell transplant a year later. But by that time, the word had come out about the devastating side effect (the dyskinesias) and some older people opted out of the second surgery.
The Feinstein researchers have now looked at the brains of the transplanted patients two years and four years after the initial infusion of fetal cells. And they learned a few things: Beyond the first five people who developed dyskinesia, none of the other 15 younger people in the study showed signs of the troubling side effect. In about 25 percent of the cases, clinical improvement was noted and the transplanted cells were still working to make the dopamine up to four years later.
They also discovered that the older people gradually got better after the first year and that their improvements continued over the long term. “The older the brain, the harder it is to integrate the graft,” said Dr. Eidelberg. “But the PET scans told us that the graft was viable. And it took awhile before the cells worked to improve symptoms.”
The Feinstein group has identified two different brain networks hard hit in the disease. One is obvious: the motor regions that, when damaged, lead to tremors, rigidity and difficulty initiating movement. The other piece relates to cognition and mood, and there are discrete brain regions that worsen over time. In this study, researchers found that people did better overall on motor functions if they entered the study with their putamen intact – putamen is an area of the brain that governs cognition and mood. Dopamine is the key brain chemical in both these networks and it is critical for motor planning. When dementia sets in, people may have improvements in the motor network, but it isn’t observable because their cognitive network is abnormal and their ability to make plans to move is impaired.
The good news, said Dr. Eidelberg, is that the grafts stayed where they were and delivered dopamine to the tissue. The finding is critical as the field moves to transplant other types of cells, including embryonic stem cells or their ultimate product.
For more information go to www.parkinsonresearchfoundation.org
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