Research file
Study: Freezing of gait (walking movement) in Parkinsons disease may be a problem of space perception.

Researcher:Chad A. Lebold, master of science graduate in Wilfrid LaurierUniversitys department of kinesiology and physical education.

Studyfocus: Lebold designed experiments to determine the underlying causesof motor freezing episodes experienced by some Parkinsons diseasepatients, along with the cues that could lead to an improved quality oflife.

His research project was called: Freezing of Gait in Parkinsons Disease: A Perceptual Cause for a Motor Impairment?

Ourgoal was to challenge current beliefs that freezing is a motorimpairment, instead suggesting that patients are having problems withspace perception because of sensory-perceptual issues that interferewith movement, Lebold said.

Lebold examined the gait of threedifferent groups of subjects those with Parkinsons disease andfreezing episodes, those with Parkinsons disease but no freezing, anda control group) as they walked toward doorways of varying widths. Thegoal was to determine how their behaviour was affected by doorway size.

Parkinsons patients who experience freezing episodes showedthe greatest change in gait as they approached the narrow doorway, withmore gait variability, shorter steps and widening their base ofsupport.

Combining visual feedback aids in perceptuallydemanding conditions gave us a greater understanding of the deficitsassociated with gait in Parkinsons disease, Lebold said.

Wewere surprised to find that even Parkinsons patients who do notexperience freezing were influenced by the perception of a narrowdoorway and exhibited behaviours similar to those with freezing.

Thestudy emphasized the importance of thinking outside the box andquestioning what the underlying mechanism for clinical motorimpairments might be, said Quincy Almeida, study co-author and anassociate professor of kinesiology and physical education, as well asdirector of the Sun Life Financial Movement Disorders Research andRehabilitation Centre.

The results of this research hopefullywill provide a greater understanding of one of the most debilitatingdisorders associated with Parkinsons disease, Lebold said.

Thefindings could also impact the direction of future research, hopefullyleading to successful intervention and prevention strategies for gaitdisorders.

Future research will determine the specific aspects of the doorways that affect subjects walking patterns.

A major discovery is challenging accepted thinking about amyloids thefibrous protein deposits associated with diseases such as Alzheimer'sand Parkinson's and may open up a potential new area for therapeutics.

Itwas believed that amyloid fibrils - rope-like structures made up ofproteins sometimes known as fibres - are inert, but that there may betoxic phases during their formation which can damage cells and causedisease.

But in a paper published today [04 December 2009] inthe Journal of Biological Chemistry, scientists at the University ofLeeds have shown that amyloid fibres are in fact toxic - and that theshorter the fibre, the more toxic it becomes.

"This is a majorstep forward in our understanding of amyloid fibrils which play a rolein such a large number of diseases," said Professor Sheena Radford ofthe Astbury Centre for Structural Molecular Biology and the Faculty ofBiological Sciences.

"We've revisited an old suspect with verysurprising results. Whilst we've only looked in detail at three of the30 or so proteins that form amyloid in human disease, our results showthat the fibres they produce are indeed toxic to cells especially whenthey are fragmented into shorter fibres. "

Amyloid deposits canaccumulate at many different sites in the body or can remain localisedto one particular organ or tissue, causing a range of differentdiseases. Amyloid deposits can be seen in the brain, in diseases suchas Parkinson's and Alzheimer's, whereas in otheramyloid diseases deposits can be found elsewhere in the body, in thejoints, liver and many other organs. Amyloid deposits are also closelylinked to the development of Type II diabetes.

Professor Radfordsaid: "Problems in the self-assembly process that results in theformation of amyloid are a natural consequence of longer life. In fact85 per cent of all cases of disease caused by amyloid deposits are seenin those over the age of sixty or so."

The study was funded bythe Wellcome Trust and the Biotechnology and Biological SciencesResearch Council (BBSRC), supporting a team that included both cellbiologists and biophysicists.

The next stage of this work isto look at a greater number of proteins that form amyloid fibres inorder to consolidate these findings, says co-author and cell biologistDr Eric Hewitt. "What we've discovered is fundamental and offers awhole new area for those working on therapeutics in this area. Weanticipate that when we look at amyloid fibres formed from otherproteins, they may well follow the same rules."

The team also hopes to discover why the shorter amyloid fibres are more toxic that their longer counterparts.

"Itmay be that because they're smaller it's easier for them to infiltratecells," says Dr Hewitt. "We've observed them killing cells, but we'renot sure yet exactly how they do it. Nor do we know whether these shortfibres form naturally when amyloid fibres assemble or whether somemolecular process makes them disassemble or fragment into shorterfibres.These are our next big challenges."

US researchers report finding that ghrelin, a hormone produced in thestomach that regulates appetite and how the body deposits fat, may beused to boost resistance to or slow the development of Parkinson'sdisease.

The study is the work of Dr Tamas Horvath, chair andprofessor of comparative medicine and professor of neurobiology andobstetrics and gynecology at the Yale University School of Medicine,New Haven, Connecticut, and colleagues and was published earlier thismonth in The Journal of Neuroscience.

Parkinson's disease is aneurodegenerative disorder where dopamine neurons in an area of themidbrain known as the substantia nigra, which is responsible fordopamine production, start to die off.

As less dopamine isproduced, the symptoms become more severe, so that eventually peoplewith the disease have difficulty walking, have restricted and delayedmovements, get tremors in their head and limbs, lose their appetite,can't eat properly, and have periods of immobility or "freezing".

Wealready know that ghrelin targets the hypothalamus and affectsappetite, food intake and how the body deposits fat. The authors wrotethat ghrelin receptors at sites outside of the hypothalamus also"promote circuit activity associated with learning and memory, andreward seeking behavior". And recent human studies have shown that bodymass index (BMI), stored fat and diabetes are linked to Parkinson'sdisease.

In this study, Horvath and colleagues discovered that ghrelin also protects the neurons that make dopamine.

"Wealso found that, in addition to its influence on appetite, ghrelin isresponsible for direct activation of the brain's dopamine cells," saidHorvath. He explained that because the hormone is made in the stomach,it circulates normally in the bloodstream, "so it could easily be usedto boost resistance to Parkinson's or it could be used to slow thedevelopment of the disease".

For the study, which was supportedby the Michael J Fox Foundation for Parkinson's Research, Horvath andcolleagues gave one group of mice extra ghrelin, and while anothergroup were genetically engineered to lack the hormone and its receptor.

When compared to a group of control mice, the mice that had impaired ghrelin action in the brain had more dopamine loss.

Theauthors explained that the mice that were given extra ghrelin lostfewer substantia nigra pars compacta dopamine cells and showed"restricted striatal dopamine loss", while the mice that weregenetically engineered to lack the hormone and its receptors lost moresubstantia nigra pars compacta dopamine cells and showed "loweredstriatal dopamine levels". The effect in the genetically engineeredmice was reversed when they switched the ghrelin receptor on.

Theyconcluded that their study supports the idea that ghrelin could be anew therapeutic strategy to fight neurodegeneration, loss of appetiteand body weight linked with Parkinson's disease.

Horvath saidthey could see these results being applicable to humans because theghrelin system is preserved through various species.

Theresearchers are now planning to find out how ghrelin levels differbetween healthy people and people with Parkinsons disease, and whetherchanges in ghrelin levels might serve as a biomarker of diseasesusceptibility and development.

Teheran Times

Gene mutations linked to inherited Parkinson'sdisease also appear to be connected to the more common form of thedisease that strikes people whose relatives don't have it, researchersnow say.

The findings come from the largest Parkinson's disease genetic study of its kind, published online Nov. 15 in Nature Genetics.

Inthe study, an international team of researchers confirmed thatmutations in the alpha-synuclein gene and microtubule associatedprotein tau boost the risk of developing Parkinson's disease.

Parkinson's, a neurological disorder, affects about 1.5 million Americans and disrupts the body's ability to move properly.

Withthis better understanding of the underlying genetic variants involvedin the progress of this disorder, we have more insight into the causesand underlying biology of this disease, Andrew B. Singleton, chief ofthe neurogenetics laboratory at the U.S. National Institute on Agingand co-leader of the study, said in a news release from the agency. Wehope this new understanding will one day provide us with strategies todelay, or even prevent, the development of Parkinson's disease.

Dr.Richard J. Hodes, director of the institute, said in the news releasethat the findings support the notion that the sporadic and rarefamilial forms of the disease are related and that common geneticvariability plays a role in developing the disorder.

Researchers at Iowa State University have found an essential key topossibly cure Parkinson's disease and are looking for others.

AnumanthaKanthasamy, a distinguished professor of biomedical sciences and W.Eugene and Linda R. Lloyd Endowed Chair in Neurotoxicology at the ISUCollege of Veterinary Medicine, has been working to understand thecomplex mechanisms of the disease for more than a decade and thinks hehas found hope for the cure.

Parkinson's disease sufferers lack a sufficient amount of a brain chemical called dopamine.

Kanthasamy'sresearch shows that there is specific protein that is naturally presentin human brains that -- for no known reason -- kills the brain cellsthat make dopamine.

The cells that are being killed are the ones that produce the needed dopamine.

"Wehave millions of cells in our brains," said Kanthasamy, "InParkinson's, about 10,000 of these brain cells die; no one knows why."

Kanthasamydiscovered that a novel protein -- known as protein kinase-C(specifically PKC) - is killing the dopamine-producing cells.

Kanthasamyand his research staff discovered a compound that neutralizes thecell-killing kinase-C and allows the dopamine-producing cells tosurvive and function.

"With a lot of hard work, and little bitof luck, we found something important," he said. "And when you findsomething like this you say, 'This is great because it can be a targetfor developing new drugs.'"

Now, Kanthasamy's group is lookingfor additional compounds that also can serve to neutralize proteinkinase-C. By identifying more compounds that perform the function ofneutralizing kinase-C, researchers are more likely to locate one thatworks well and has few side effects.

This discovery is expected to provide new treatment options to stop the progression of the disease or even cure it.

Thestudy is being funded by a Grow Iowa Values Fund grant. The goal of thegrant program is to support development of technologies with commercialpotential and to support the growth of companies using thosetechnologies. Kanthasamy is working on this research with PKBiosciences Corp., an Iowa-based startup company. Funding was alsoprovided by the National Institutes of Health.

"Once we findthe compound, we need to make sure it's safe. If everything goes well,it could take about 10 years, and then we might be able to seesomething that will truly make a difference in the lives of people withthis disorder," said Kanthasamy.

Parkinson's disease strikesaround 50,000 people each year, and there are approximately 1 millionpeople with the disease. Parkinson's sufferers include actor Michael J.Fox and former boxing champion Muhammad Ali.

As people growolder, the cells that produce dopamine naturally die, causing dopaminelevels to fall gradually over time. When the levels continue to dropbelow 60 to 70 percent, the person will start to have Parkinson'sdisease symptoms, according to Kanthasamy.

"Everybody has a little Parkinson's in theory," he said. "But you can't see it until the level of dopamine gets too low."

Eliminatingthe symptoms of Parkinson's disease doesn't require people to berestored to 100 percent of previous dopamine levels, but only to afraction of that.

"If you can bring dopamine up to the 40-50 percent level, you'll see a functioning, normal person," he said.

Currently, there is no cure for Parkinson's and available therapies only treat the symptoms.

Majorcontributing factors for getting Parkinson's disease include prolongedexposure to metals or pesticides and other environmental chemicals,according to Kanthasamy.

Symptoms of Parkinson's diseaseinclude trembling in hands, arms, legs, jaw, and face; rigidity orstiffness of the limbs and trunk; slowness of movement; and impairedbalance and coordination. As these symptoms become more pronounced,patients may have difficulty walking, talking, or completing othersimple tasks. Because the disease typically affects people over the ageof 50, the National Institutes of Health anticipates the incidence ofParkinson's will increase as the nation's population ages.

TUNISIAONLINENEWS
A Tunisian neurosurgeon has developed a new therapy for Parkinsons disease, which remains an incurable disease so far.

Thistherapy involves the regular and continuous stimulation of dopamine, asubstance whose deficiency causes motor dysfunction. It is injectedinto the brains of three genes required for synthesis of dopamine inorder to ensure a continuous secretion.

The standard treatmentfor this condition is limited to irregular stimulation of dopaminewhich leads later abnormal movements just as troublesome as the diseaseitself.

The medical and scientific achievement is the result offour years of research by the team Bashir Jarraya and Stphane Palfi,neurosurgeons at the hospital Henri Mendori in Paris. It has beentested on primates, which have subsequently been able to get 80 % oftheir motor skills. Clinical trials are underway in six patients.

Parkinsonsdisease is a disorder that affects nerve cells, or neurons, in a partof the brain that controls muscle movement. Parkinsons disease belongsto a group of conditions called movement disorders. In Parkinsons,neurons that make a chemical called dopamine die or do not workproperly. Dopamine normally sends signals that help coordinatemovements. It usually starts between the age of 55 and 65.

According to a study by an international research team, carriers of a rare, genetic condition called Gaucher disease have a 5 times greater risk of developing Parkinson's disease.

Previous studies have linked several genes to Parkinson's disease and this study conclusively shows that mutations in the gene responsible for Gaucher disease are among the most significant risk factors found to date for Parkinson's disease.

Parkinson's disease, a neurological condition that typically causes tremors and stiffness in movement, affects about 1 to 2 percent of people over the age of 60. The chance of developing Parkinson's disease increases with age and involves a combination of environmental risk factors and genetic susceptibility.

Gaucher disease occurs when an individual inherits two defective copies of the GBA gene, which codes for an enzyme called glucocerebrosidase. This enzyme breaks down a fatty substance called glucocerebroside, which, when not properly disposed of, can harm the spleen, liver, lungs, bone marrow and, in some cases, the brain. The enzyme functions in a part of the cell called the lysosome, where cellular components are broken down, or metabolized, for recycling.

In the past, it was thought that people who carry just one altered GBA gene were unaffected. However, in recent years, research groups at the National Human Genome Research Institute (NHGRI) and elsewhere have completed small studies suggesting that carriers of GBA alterations may have an increased risk of developing Parkinson's disease.

The research team examined the frequency of GBA alterations in 5,691 patients with Parkinson's disease, including 780 Ashkenazi Jews, a population in which a particular type of Gaucher disease is more prevalent. Those data were matched against 4,898 unaffected volunteers, called controls, which included 387 Ashkenazi Jews.

At least one of the two common GBA alterations was found in 3.2 percent of Parkinson's patients and 0.6 percent of controls. Among the Ashkenazi subjects, 15.3 percent of those with Parkinson's disease carried a GBA alteration compared to 3.4 percent of Ashkenazi controls.

In addition to screening for the two common alterations, five of the research centers sequenced the entire GBA gene in 1,642 non-Ashkenazi patients with Parkinson's disease and 609 non-Ashkenazi controls. Using this more thorough method, they found many additional alterations associated with Parkinson's disease, and showed that 7 percent of patients carried an alteration, indicating that it is important to look beyond the two common alterations to gain a true picture of risk in the general population.

Besides significantly increasing the risk of Parkinson's disease, GBA alterations also appear to increase the likelihood of early disease onset. According to the new study, Parkinson's patients with GBA alterations developed symptoms an average of four years earlier than other Parkinson's patients.

Overall, the researchers found that the association between GBA and Parkinson's disease is not confined to any single ethnicity or to specific GBA mutations, though they did find that some gene alterations are seen more frequently in certain populations. Compared with the general population, in which GBA alterations occur in fewer than one out of 100 people, GBA alterations occur in at least one out of 16 people of Ashkenazi descent. However, many GBA mutation carriers as well as patients with Gaucher disease never develop Parkinson's disease, so this appears to be only one of several risk factors involved.

Parkinson's disease is a neurodegenerative disorder of unknown cause that affects nearly five million individuals worldwide.

Under a research grant from MJFF, Sigma Advanced Genetic Engineering (Sage) Labs - an initiative of Sigma-Aldrich's Research Biotech business unit - will use novel CompoZr zinc finger nuclease (ZFN) technology in an effort to create superior preclinical research models critically needed for the development of transformative treatments for Parkinson's disease.

The models, which are expected to take as little as one year to develop, will be made broadly accessible to scientists throughout the Parkinson's research community in order to speed basic research and drug development efforts field-wide.

Although current mammalian models adequately recapitulate some outward symptoms of Parkinson's disease, no existing model has been able to accurately mimic the onset and progression of the underlying disease processes that characterise the disease in humans.

Research already conducted into the genetic causes of Parkinson's disease has identified a number of genes but indicates a strong connection to mutations in five particular genes: LRRRK2, alpha-synuclein, DJ-1, Parkin and Pink1.

MJFF funding will allow Sigma-Aldrich's efforts to create five novel rat models with each of these genes knocked out.

Adopting a new approach to developing more effective and targeted research models, Sage Labs will use the CompoZr ZFN technology in its efforts to design 'knockout' rat models in which the genes known to be directly implicated in Parkinson's disease are omitted.

This research is expected to facilitate the development of new models that scientists believe will provide a better understanding of Parkinson's disease at the molecular, biochemical, physiological and behavioural levels.

This knowledge may, in turn, result in new therapeutic targets and approaches for the treatment of Parkinson's disease.

Because rats are physiologically similar to humans, they are ideal subjects for modelling human diseases and have been an important species for research in a number of fields including physiology, endocrinology, neurology, toxicology and cancer.

Until recently it has been impossible to create rat models with particular genes de-activated, or 'knocked out'.

However, using CompoZr ZFN technology, scientists at Sage Labs are able to generate animal models with targeted genetic changes to better understand gene function and develop new therapeutic approaches.

A group of doctors training at Beth Israel Deaconess Medical Center started a unique program last week to learn about genetic tests marketed to consumers, placing them in the vanguard of preparations to guide patients through the dawning Wild West age of personalized medicine.

Part of the instruction will come from having the young physicians test their own DNA in search of genes linked to various illnesses.

Private companies have begun offering a flurry of tests that purport to tell patients their genetic risks, for everything from Parkinson’s disease to obesity. Tests that can be ordered over the Internet need only a simple cheek swab to hunt for gene variations associated with particular diseases.

Ultimately, genetic tests offer the promise of dramatically improving and personalizing health care - guiding doctors to therapies tailored to a person’s genetic idiosyncrasies, or allowing patients to take preventive steps based on risks that lurk in their genes.

But today, the results can be hard to interpret and can mislead patients - and scientific understanding of the genetics of common diseases is still evolving - so the tests have drawn concern and opposition from much of the medical establishment. As the science races forward, in the lab and into the marketplace, doctors are realizing they need to be ready to assess the information and assist their patients.

“We can bury our head in the sand and pretend it’s not happening, we can suppress the information and tell patients not to go near it, or we can figure out strategies to play a constructive role as this new era of genomic and personalized medicine rolls out,’’ said Dr. Mark Boguski, an associate professor of pathology at Harvard Medical School who will be one of the instructors of the class. “That’s what we’re trying to do: prepare our trainees - not because the technology is ready for prime time today, but people are using it, and it’s clear it’s going to play a role in the future.’’

Doctors in their second and final years of pathology residency training will take the class - attending lectures and researching the science behind the tests. If they choose, they can look at their own test results, submitting a sample to the genetic testing company Navigenics.

Boguski said the inspiration for the class came from his own experience, when he used tests from three companies to learn more about his DNA and see what information the companies provided about various diseases and conditions. Examining his own data, he said, helped make the experience more immediate.

“I’m curious to see what’s there,’’ said Dr. Thomas Gage, a resident who said he would participate in the testing. “A lot of this stuff can be interpreted too easily sometimes. . . . So I think that’s where you have to be a little bit skeptical. Still, it’s information.’

The program is being offered to pathologists because they are the specialists who perform and interpret lab tests.

“This has always been our role: blood tests, cultures, urine, those samples come to pathology, where the test is done,’’ said Dr. Jeffrey Saffitz, chairman of the pathology department at Beth Israel Deaconess. “We see this personalized genomic analysis as a modern extension of our traditional role.’’

But the program is just a starting point in what will have to be an all-out effort to give medical professionals a good grounding in the use of genetics.

Dr. W. Gregory Feero, special adviser to the director of the National Human Genome Research Institute, said efforts are being made to increase genetic competency among medical professionals, including nurses, physician assistants, and specialists.

Many medical schools include genetics in their curriculum, he said, but the subject tends to drop out of the discussion as students progress from the “book years’’ to clinical practice.

The American College of Medical Genetics, a professional organization, has issued a cautionary statement about direct-to-consumer genetic testing. Much of the concern stems from consumers’ expectations, which have been set by the notion that a particular gene is responsible for a trait or a disease - determining eye color, for example, or whether a person has cystic fibrosis. But for common diseases, it appears that any single variant of a gene elevates risk only slightly - and the likelihood of falling ill is influenced by other factors, such as environment, lifestyle, and other genes that have yet to be identified. There is no evidence yet that finding out such information results in better outcomes, and great worry among physicians is that consumers who seek such information without medical advice may misinterpret their results.

Still, the organization’s president, Dr. Bruce Korf, said efforts like the one at Beth Israel Deaconess are essential to give doctors the ability to evaluate genetics information, even though most of it is not useful now.

“My personal view is we have relied way too much on lectures and not enough on innovative models based on case teaching or other simulations that are much more real than . . . hearing someone talk about something,’’ he said.

Dr. Joel Hirschhorn, an associate professor of genetics at Harvard Medical School who co-teaches a three-week genetics curriculum, said science is moving so fast that fourth-year medical students wouldn’t have been taught what this year’s first-year students will learn, so efforts like the one at Beth Israel Deaconess are important.

San Francisco Business Times - by Steven E.F. Brown

Impax Laboratories Inc. said a drug it’s testing for use against Parkinson’s Disease did well in a mid-stage clinical trial.

The Hayward business (NASDAQ: IPXL), led by CEO Larry Hsu, makes generic drugs. It also has its own drug-making division, Impax Pharmaceuticals, led by President Michael Nestor, which is working on this drug.

This formulation of carbidopa-levdopa, IPX066, was tested against an existing carbidopa-levdopa drug called Sinemet, made by Merck & Co. (NYSE: MRK) and sold by Bristol-Myers Squibb Co. (NYSE: BMY). It performed better than Sinemet in this test, with the comparison being a measurement of “off” time reported by Parkinson’s patients during waking hours. IPX066 improved those symptoms for two hours longer in the test than Sinemet.

This Phase II trial enrolled 27 people with advanced Parkinson’s Disease. Impax is signing people up now for a Phase III test of the drug and plans another one early next year.

Transgenomic and Power3 Medical Products have announced the advance online publication of a clinical research paper in the Biochemical and Biophysical Research Communications scientific journal.

The study, entitled 'Abnormal Serum Concentrations of Proteins in Parkinson's Disease', demonstrates the usefulness of a protein biomarker panel to distinguish Parkinson's Disease (PD) patients from age-matched normal controls, independent of the severity of symptoms, using clinical blood serum samples.

The analytic technology forms the basis for the NuroproPD test for PD being commercialised by Transgenomic as per a licensing/collaboration agreement with Power3Medical signed in early 2009.

The publication of the peer-reviewed article is described as a validation milestone in the clinical development of the NuroproPD diagnostic assay.

The article describes the use of analytically validated quantitative 2D gel electrophoresis to identify protein biomarkers for diagnosing PD using serum from routinely collected blood samples.

Some 57 protein biomarkers, which had been discovered using retrospective blood serum samples from various neurodegenerative diseases, were then applied specifically to PD in a prospective clinical investigation using freshly collected blood serum from PD patients and age-matched normal controls.

A multi-variate statistical method, stepwise linear discriminant analysis, selected a combination of 21 of the biomarkers as optimal to distinguish PD patients from controls.

When applied to the PD samples, the 21-protein set had sensitivity of 93.3 per cent (52 of 56 PD correctly classified) and specificity of 92.9 per cent (28 of 30 controls correctly classified); 15 of 15 patients with mild and 28 of 30 with moderate-to-severe symptoms were correctly classified, as were all six PD samples from an independent site.

Craig Tuttle, chief executive officer of Transgenomic, said: 'We are enthusiastic about the acceptance of our paper in this established peer-reviewed scientific journal.

'It represents independent external validation of the clinical data and so increases the confidence that we have in NuroproPD to be a meaningful tool for the diagnosis of Parkinson's Disease, especially early in its course.

'We are completing the clinical validation of the assay in our CLIA-certified molecular testing laboratory and will be launching the assay in the very near future,' he added.

Dr Ira Goldknopf, president and chief scientific officer of Power3 Medical and lead author on the paper, said: 'In the US, there are an estimated 1.5 million individuals with Parkinson's Disease.

'Unfortunately, by the time patients are given a probable diagnosis, many have already suffered substantial and irreparable brain damage, rendering treatment less effective.

'The fact that these results were obtained using fresh blood serum, in the same way that the test will be performed in a clinical diagnostic setting, provides further support for their robustness and their commercial value.' Clinical investigators in the study were Dr Katerina Markopoulou of Thessaly University in Greece, Dr Marwan Sabbagh and Dr Holly Shill of Banner Sun Health Research Institute in Sun City, Arizona, and Dr Stanley Appel of the Texas Methodist Health System in Houston.

Although Parkinson’s disease is most commonly viewed as a “movement brouhaha,” scientists give birth to establish that the disease also causes widespread abnormalities in touch and idea - effects that give birth to second been verified using useful winning resonance imaging (fMRI) of the brain.

The new findings, by scientists at Emory University School of Medicine and Zhejiang University Medical School in Hangzhou China, were presented on Oct. 17 at the Society for Neuroscience meeting in Atlanta.

Scientists studying Parkinson’s disease (PD) previously have focused on the brain’s motor and premotor cortex, but not the somatosensory or the visual cortex. But Emory neurologist Krish Sathian, MD, PhD, and colleagues had earlier discovered, through tests of tactile ability, that PD patients have sensory problems with touch. They designed a study using fMRI to investigate the brain changes underlying these sensory abnormalities.

Dr. Sathian’s research group studied six patients with moderately advanced PD and six age-matched healthy controls. After documenting the typical movement problems of PD and ruling out dementia and nerve problems in the PD patients, they administered a common test of tactile ability to both groups, asking the participants to use their fingers to distinguish the orientation of ridges and grooves on plastic gratings. At the same time, they conducted a brain-scanning study using fMRI. This technology measures activations of neurons in different areas of the brain by means of variations in blood flow as an individual does a particular task.

The fMRI scans showed that the PD patients had much less activation of the somatosensory areas in the brain’s cortex than did the healthy controls. The scientists also were surprised to find similar widespread differences in the visual cortex, although the task involved touch, not vision.

“Our finding that the visual cortex is affected in Parkinson’s disease, while surprising, makes sense given that our laboratory and many others have shown previously that areas of the brain’s visual cortex are intimately involved in the sense of touch,” Dr. Sathian notes. “Although the reasons for this are uncertain, they may involve a process of mental visualization of the tactile stimuli and may also reflect a multisensory capability of the visual cortex.”

Dr. Sathian believes the study shows that the traditional boundaries between brain systems involved in touch and vision, and between those involved in sensation and movement, are artificial constructs that break down with more in-depth study. From a practical standpoint, it shows that patients with PD and other movement disorders have considerable problems in addition to movement control.

“These problems need to be appreciated in caring for these patients and in designing newer strategies for treatment and rehabilitation,” Dr. Sathian emphasizes.

The discovery in rats answers an important question — how can new, therapeutic genes that have been irrevocably delivered to the human brain to treat Parkinson's be controlled if the genes unexpectedly start causing problems?

Meanwhile, in a review of Parkinson treatments, the researchers say that prior experimental attempts using growth factors — naturally occurring substances that cause cells to grow and divide — to rescue dying brain cells may have failed because they occurred too late in the course of the disease.

Together, the findings suggest that gene therapy to enable the brain to retain its ability to produce dopamine, a neurotransmitter that falls in critically short supply in Parkinson's patients, could be safely attempted during earlier stages of the disease with an added likelihood of success.

Parkinson's disease affects more than 1 million Americans, causing patients to gradually develop movement problems, including tremors, stiffness and slowness. It is caused by degeneration and death of nerve connections that produce dopamine, a substance necessary for communication between cells that coordinate movement.

"We have worked every day for 10 years to design a construct to the gene delivery vector that enhances the safety profile of gene transfer for Parkinson's disease," said Ronald Mandel, a professor of neuroscience at UF's McKnight Brain Institute and the Powell Gene Therapy Center. "With that added measure of safety, we believe we can intervene with gene transfer in patients at earlier stages of the disease. We strongly believe that trials to save dopamine-producing connections in patients with Parkinson's disease have failed because the therapy went into patients who were in the late stages of the disease and who had too few remaining dopamine-producing connections."

Often patients are given prescriptions for levodopa, or L-dopa, which is converted into dopamine by enzymes in the brain. But the treatment loses its effectiveness over time and does nothing to slow the disease's progression.

Although the incidence of Parkinson's disease has remained relatively consistent in recent years, patients today often have access to more treatment options.Important areas of research include ongoing studies to learn more about genetic and environmental causes for the disease and clinical trials to develop new treatments for primary symptoms (e.g., slow movements, tremors, unsteady gait) and secondary symptoms (e.g., psychosocial issues, depression, anxiety, decreased mental function).

The National Institutes of Health (NIH) is working with other organizations, such as the Parkinson's Institute and Clinical Center, the American Parkinson Disease Association, and the Michael J. Fox Foundation for Parkinson's Research, to establish registries for patients who have Parkinson's disease. These regional and statewide registries may provide important information about potential triggers, risk factors, and causes for Parkinson's disease, and possibly lead to a cure.

According to the NIH, six genes and several substances that attack nerve cells (neurotoxins) that are associated with Parkinson's disease had been identified as of January 2008. A number of ongoing studies are focused on further examining the link between Parkinson's disease and environmental factors, such as exposure to pesticides (substances used to kill insects that damage plants and crops) and other chemicals.

Genetic testing may provide important information about hereditary risk factors for Parkinson's disease and help identify the cellular process that causes the condition. By studying the role of genes in Parkinson's disease, physicians may be able to determine who is at increased risk for developing Parkinson's and provide earlier treatment. Information from genetic studies also may lead to the development of new treatment plans.

Some of these studies involve ribonucleic acid (RNA), which is a substance in cells that controls protein synthesis (i.e., the combining of proteins within cells) and may play a role in the development of Parkinson's disease. Scientists are trying to determine if it is possible to interfere with gene expression and "silence" RNA by inserting a substance called silencing RNA (sRNA; also called interfering RNA) into the brain. RNA-targeted silencing technology may be used to treat Parkinson's disease and other neurological conditions (e.g., Huntington's disease, dystonia).


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Treatments that are currently being investigated include stem cell therapy, gene therapy, and new medications to protect nerve cells (neurons) from damage and slow progression of the disease. In stem cell research, undeveloped cells found in bone marrow and lymphatic tissues (called stem cells or hemocytoblasts) are used to reconstitute damaged brain cells (e.g., neurons).

Stem cell research is somewhat controversial. Stem cells may be obtained from discarded blood in a newborn's umbilical cord, from adult bone marrow, or from an aborted embryo. Recent research has shown that skin cells may be able to take on characteristics of embryonic stem cells (i.e., cells taken from human embryos), which may reduce the controversy surrounding this experimental treatment and help to advance stem cell research further.

Gene therapy involves loading safe viruses containing important genetic information and/or growth enzymes directly into targeted areas of the brain to rejuvenate damaged cells.

Clinical trials involve using substances that affect cell function (e.g., creatine, coenzyme Q10 [CoQ10], GM-1 ganglioside, minocycline) to help protect and restore nerve cells. Other trials involve targeting deep brain stimulation (DBS) to specific areas of the brain that thought to be involved in Parkinson's disease development (e.g., the paramedian nucleus [PPN] in the brainstem). Targeting this area may improve walking and balance in patients who have Parkinson's.

New deep brain stimulation (DBS) devices are also being developed. DBS targets the subthalamic nucleus, the globus pallidus, or the thalamus in the brain. In DBS, an implanted electrode is used to inactivate, not destroy, the targeted area. The electrode is connected to the brain via a wire that runs beneath the patient's skin to a stimulator and battery pack in the patient's chest. Deep brain stimulation is a reversible treatment that allows for precise control of symptoms.

In patients who have Parkinson's disease, oral medications (e.g., levodopa, carbidopa, dopamine agonists) often are absorbed slowly in the stomach, reducing the effectiveness of the drug. New drug delivery methods are being developed to prevent decreased absorption and improve the medications' effectiveness.

These delivery methods include transdermal patches (which are worn on the skin and allow medication to be continuously absorbed), subcutaneous (beneath the skin) injections, and intraduodenal infusions (which involve introducing medication directly into the upper portion of the small intestine [duodenum]). New combinations of medications and the use of medications already approved to treat other conditions also are being studied.

Additional Parkinson's disease research is focused on developing new types of treatments to reduce symptoms of the condition. These treatments include a device to help relieve the "masked face" associated with Parkinson's, exercise and weight training programs, and physical and occupational therapy.

Current studies show that patients who have Parkinson's disease often benefit from treatment provided by a health care team that includes a number of different medical providers (called multi-disciplinary care). This medical team may include geriatric specialists, neurologists, neurosurgeons, psychologists, and speech-language pathologists.

In recent years, Parkinson's research has advanced to the point that halting the progression of PD, restoring lost function, and even preventing the disease are all considered realistic goals. While the ultimate goal of preventing PD may take years to achieve, researchers are making great progress in understanding and treating PD.

One of the most exciting areas of PD research is genetics. Studying the genes responsible for inherited cases can help researchers understand both inherited and sporadic cases of the disease. Identifying gene defects can also help researchers understand how PD occurs, develop animal models that accurately mimic the neuronal death in human PD, identify new drug targets, and improve diagnosis.

As discussed in the “What Genes are Linked to Parkinson's Disease?" section, several genes have been definitively linked to PD in some people. Researchers also have identified a number of other genes that may play a role and are working to confirm these findings. In addition, several chromosomal regions have been linked to PD in some families. Researchers hope to identify the genes located in these chromosomal regions and to determine which of them may play roles in PD.

Researchers funded by NINDS are gathering information and DNA samples from hundreds of families with PD and are conducting large-scale gene expression studies to identify genes that are abnormally active or inactive in PD. They also are comparing gene activity in PD with gene activity in similar diseases such as progressive supranuclear palsy.

Some scientists have found evidence that specific variations in the DNA of mitochondria – structures in cells that provide the energy for cellular activity — can increase the risk of getting PD, while other variations are associated with a lowered risk of the disorder. They also have found that PD patients have more mitochondrial DNA (mtDNA) variations than patients with other movement disorders or Alzheimer's disease. Researchers are working to define how these mtDNA variations may lead to PD.

In addition to identifying new genes for PD, researchers are trying to learn how known PD genes function and how the gene mutations cause disease. For example, a 2005 study found that the normal alpha-synuclein protein may help other proteins that are important for nerve transmission to fold correctly. Other studies have suggested that the normal parkin protein protects neurons from a variety of threats, including alpha-synuclein toxicity and excitotoxicity.

Scientists continue to study environmental toxins such as pesticides and herbicides that can cause PD symptoms in animals. They have found that exposing rodents to the pesticide rotenone and several other agricultural chemicals can cause cellular and behavioral changes that mimic those seen in PD. Other studies have suggested that prenatal exposure to certain toxins can increase susceptibility to PD in adulthood. An NIH-sponsored program called the Collaborative Centers for Parkinson's Disease Environmental Research (CCPDER) focuses on how occupational exposure to toxins and use of caffeine and other substances may affect the risk of PD.

Another major area of PD research involves the cell's protein disposal system, called the ubiquitin-proteasome system. If this disposal system fails to work correctly, toxins and other substances may build up to harmful levels, leading to cell death. The ubiquitin-proteasome system requires interactions between several proteins, including parkin and UCH-L1. Therefore, disruption of the ubiquitin-proteasome system may partially explain how mutations in these genes cause PD.

Other studies focus on how Lewy bodies form and what role they play in PD. Some studies suggest that Lewy bodies are a byproduct of degenerative processes within neurons, while others indicate that Lewy bodies are a protective mechanism by which neurons lock away abnormal molecules that might otherwise be harmful. Additional studies have found that alpha-synuclein clumps alter gene expression and bind to vesicles within the cell in ways that could be harmful.

Another common topic of PD research is excitotoxicity – overstimulation of nerve cells that leads to cell damage or death. In excitotoxicity, the brain becomes oversensitized to the neurotransmitter glutamate, which increases activity in the brain. The dopamine deficiency in PD causes overactivity of neurons in the subthalamic nucleus, which may lead to excitotoxic damage there and in other parts of the brain. Researchers also have found that dysfunction of the cells' mitochondria can make dopamine-producing neurons vulnerable to glutamate.

Other researchers are focusing on how inflammation may affect PD. Inflammation is common to a variety of neurodegenerative diseases, including PD, Alzheimer's disease, HIV-1-associated dementia, and amyotrophic lateral sclerosis. Several studies have shown that inflammation-promoting molecules increase cell death after treatment with the toxin MPTP. Inhibiting the inflammation with drugs or by genetic engineering prevented some of the neuronal degeneration in these studies. Other research has shown that dopamine neurons in brains from patients with PD have higher levels of an inflammatory enzyme called COX-2 than those of people without PD. Inhibiting COX-2 doubled the number of neurons that survived in a mouse model for PD.

Since the discovery that MPTP causes parkinsonian symptoms in humans, scientists have found that by injecting MPTP and certain other toxins into laboratory animals, they can reproduce the brain lesions that cause these symptoms. This allows them to study the mechanisms of the disease and helps in the development of new treatments. They also have developed animal models with alterations of the alpha-synuclein and parkin genes. Other researchers have used genetic engineering to develop mice with disrupted mitochondrial function in dopamine neurons. These animals have many of the characteristics associated with PD.

Biomarkers for PD – measurable characteristics that can reveal whether the disease is developing or progressing – are another focus of research. Such biomarkers could help doctors detect the disease before symptoms appear and improve diagnosis of the disease. They also would show if medications and other types of therapy have a positive or negative effect on the course of the disease. Some of the most promising biomarkers for PD are brain imaging techniques. For example, some researchers are using positron emission tomography (PET) brain scans to try to identify metabolic changes in the brains of people with PD and to determine how these changes relate to disease symptoms. Other potential biomarkers for PD include alterations in gene expression.

Researchers also are conducting many studies of new or improved therapies for PD. While deep brain stimulation (DBS) is now FDA-approved and has been used in thousands of people with PD, researchers continue to try to improve the technology and surgical techniques in this therapy. For example, some studies are comparing DBS to the best medical therapy and trying to determine which part of the brain is the best location for stimulation. Another clinical trial is studying how DBS affects depression and quality of life.

Other clinical studies are testing whether transcranial electrical polarization (TEP) or transcranial magnetic stimulation (TMS) can reduce the symptoms of PD. In TEP, electrodes placed on the scalp are used to generate an electrical current that modifies signals in the brain's cortex. In TMS, an insulated coil of wire on the scalp is used to generate a brief electrical current.

One of the enduring questions in PD research has been how treatment with levodopa and other dopaminergic drugs affects progression of the disease. Researchers are continuing to try to clarify these effects. One study has suggested that PD patients with a low-activity variant of the gene for COMT (which breaks down dopamine) perform worse than others on tests of cognition, and that dopaminergic drugs may worsen cognition in these people, perhaps because the reduced COMT activity causes dopamine to build up to harmful levels in some parts of the brain. In the future, it may become possible to test for such individual gene differences in order to improve treatment of PD.

A variety of new drug treatments are in clinical trials for PD. These include a drug called GM1 ganglioside that increases dopamine levels in the brain. Researchers are testing whether this drug can reduce symptoms, delay disease progression, or partially restore damaged brain cells in PD patients. Other studies are testing whether a drug called istradefylline can improve motor function in PD, and whether a drug called ACP-103 that blocks receptors for the neurotransmitter serotonin will lessen the severity of parkinsonian symptoms and levodopa-associated complications in PD patients. Other topics of research include controlled-release formulas of PD drugs and implantable pumps that give a continuous supply of levodopa.

Some researchers are testing potential neuroprotective drugs to see if they can slow the progression of PD. One study, called NET-PD (Neuroexploratory Trials in Parkinson's Disease), is evaluating minocycline, creatine, coenzyme Q10, and GPI-1485 to determine if any of these agents should be considered for further testing. The NET-PD study may evaluate other possible neuroprotective agents in the future. Drugs found to be successful in the pilot phases may move to large phase III trials involving hundreds of patients. A separate group of researchers is investigating the effects of either 1200 or 2400 milligrams of coenzyme Q10 in 600 patients. Several MAO-B inhibitors, including selegiline, lazabemide, and rasagiline, also are in clinical trials to determine if they have neuroprotective effects in people with PD.

Nerve growth factors, or neurotrophic factors, which support survival, growth, and development of brain cells, are another type of potential therapy for PD. One such drug, glial cell line-derived neurotrophic factor (GDNF), has been shown to protect dopamine neurons and to promote their survival in animal models of PD. This drug has been tested in several clinical trials for people with PD, and the drug appeared to cause regrowth of dopamine nerve fibers in one person who received the drug. However, a phase II clinical study of GDNF was halted in 2004 because the treatment did not show any clinical benefit after 6 months, and some data suggested that it might even be harmful. Other neurotrophins that may be useful for treating PD include neurotrophin-4 (NT-4), brain-derived neurotrophic factor (BDNF), and fibroblast growth factor 2 (FGF-2).

While there is currently no proof that any dietary supplements can slow PD, several clinical studies are testing whether supplementation with vitamin B12 and other substances may be helpful. A 2005 study found that dietary restriction — reducing the number of calories normally consumed – helped to increase abnormally low levels of the neurotransmitter glutamate in a mouse model for early PD. The study also suggested that dietary restriction affected dopamine activity in the brain. Another study showed that dietary restriction before the onset of PD in a mouse model helped to protect dopamine-producing neurons.

Other studies are looking at treatments that might improve some of the secondary symptoms of PD, such as depression and swallowing disorders. One clinical trial is investigating whether a drug called quetiapine can reduce psychosis or agitation in PD patients with dementia and in dementia patients with parkinsonian symptoms. Some studies also are examining whether transcranial magnetic stimulation or a food supplement called s-adenosyl-methionine (SAM-e) can alleviate depression in people with PD, and whether levetiracetam, a drug approved to treat epilepsy, can reduce dyskinesias in Parkinson's patients without interfering with other PD drugs.

Another approach to treating PD is to implant cells to replace those lost in the disease. Researchers are conducting clinical trials of a cell therapy in which human retinal epithelial cells attached to microscopic gelatin beads are implanted into the brains of people with advanced PD. The retinal epithelial cells produce levodopa. The investigators hope that this therapy will enhance brain levels of dopamine.

Starting in the 1990s, researchers conducted a controlled clinical trial of fetal tissue implants in people with PD. They attempted to replace lost dopamine-producing neurons with healthy ones from fetal tissue in order to improve movement and the response to medications. While many of the implanted cells survived in the brain and produced dopamine, this therapy was associated with only modest functional improvements, mostly in patients under the age of 60. Unfortunately, some of the people who received the transplants developed disabling dyskinesias that could not be relieved by reducing antiparkinsonian medications.

Another type of cell therapy involves stem cells. Stem cells derived from embryos can develop into any kind of cell in the body, while others, called progenitor cells, are more restricted. One study transplanted neural progenitor cells derived from human embryonic stem cells into a rat model of PD. The cells appeared to trigger improvement on several behavioral tests, although relatively few of the transplanted cells became dopamine-producing neurons. Other researchers are developing methods to improve the number of dopamine-producing cells that can be grown from embryonic stem cells in culture.

Researchers also are exploring whether stem cells from adult brains might be useful in treating PD. They have shown that the brain's white matter contains multipotent progenitor cells that can multiply and form all the major cell types of the brain, including neurons.

Gene therapy is yet another approach to treating PD. A study of gene therapy in non-human primate models of PD is testing different genes and gene-delivery techniques in an effort to refine this kind of treatment. An early-phase clinical study is also testing whether using the adeno-associated virus type 2 (AAV2) to deliver the gene for a nerve growth factor called neurturin is safe for use in people with PD. Another study is testing the safety of gene therapy using AAV to deliver a gene for human aromatic L-amino acid decarboxylase, an enzyme that helps convert levodopa to dopamine in the brain. Other investigators are testing whether gene therapy to increase the amount of glutamic acid decarboxylase, which helps produce an inhibitory neurotransmitter called GABA, might reduce the overactivity of neurons in the brain that results from lack of dopamine.

Another potential approach to treating PD is to use a vaccine to modify the immune system in a way that can protect dopamine-producing neurons. One vaccine study in mice used a drug called copolymer-1 that increases the number of immune T cells that secrete anti-inflammatory cytokines and growth factors. The researchers injected copolymer-1-treated immune cells into a mouse model for PD. The vaccine modified the behavior of supporting (glial) cells in the brain so that their responses were beneficial rather than harmful. It also reduced the amount of neurodegeneration in the mice, reduced inflammation, and increased production of nerve growth factors. Another study delivered a vaccine containing alpha-synuclein in a mouse model of PD and showed that the mice developed antibodies that reduced the accumulation of abnormal alpha-synuclein. While these studies are preliminary, investigators hope that similar approaches might one day be tested in humans.

The nerve cell death that helps drive Parkinson's disease may be triggered by a harmful modification in a particular nerve cell protein, new research reveals.

The modification in question -- an apparently toxic mix of the protein alpha-synuclein and the critical neurotransmitter dopamine -- can be found in all Parkinson's patients, researchers say.

The change short-circuits a process that allows aging nerve cells to stay healthy by purging themselves of damaged molecules, researchers explain in the Jan. 2 online issue of The Journal of Clinical Investigation.

"The general idea is that, in Parkinson's, the neurons accumulate lots of garbage," explained study author Dr. Ana Maria Cuervo, an associate professor in the department of anatomy and structural biology at Yeshiva University's Albert Einstein College of Medicine, in New York City.

"Normally," she said, "this garbage is removed before it builds up, and is dumped into garbage containers called lysosomes, which make sure things can move about the neurons fast and freely."

Such a filtering process for disposing of damaged molecules is known as "autophagy," a term that literally means "self-eating."

"But sometimes, this mechanism fails," Cuervo noted. "And now we have found the reason why. It is because of the formation of this particular modified protein, which acts kind of like chewing gum in the middle of the nerve cell."

"It's not a normal protein," she stressed. "It's very sticky, and any other proteins passing by get stuck to it, so you get all these abnormal things, these stones in the middle of the cell's highways, that are not being removed, and eventually the [brain] cells can't move things around as they should, and they die."

In an earlier effort, the same research team had found that mutant forms of alpha-synuclein -- as opposed to modified forms -- also block the desired breakdown of damaged nerve cell molecules. Such mutant proteins are present in the 5 percent to 10 percent of Parkinson's patients struck with a relatively rare, familial form of the disease.

"But the novelty of our work today is that the modified protein mechanism we found this time will apply to all Parkinson's patients," noted Cuervo. "And so it becomes possible that in the future we can design drugs to improve the function of the garbage containers, the lysosomes, in all Parkinson's patients, and maybe overcome the problem that these nerve cells have handling the modified molecules."

Cuervo and her Einstein colleagues conducted the study, based on laboratory work with male rats, in collaboration with scientists from Columbia University in New York City, the University of Pennsylvania, and Harvard Medical School in Boston.

The National Parkinson Foundation estimates that 1.5 million Americans are affected with Parkinson's disease, the most common degenerative brain disorder affecting movement.

The nerve damage that's characteristic of this incurable disease brings about a dramatic loss of muscle control, typically manifesting as tremors, stiffness, and a loss of balance and agility.

Though optimistic about her work, Cuervo emphasized that translating the latest findings into new preventive and curative interventions will require a lot more research and time.

"I want to be very cautious," she said. "We are far from a final cure. It's not something we can do tomorrow. It's going to take some time. But now we know what the problem is. And we think that we have something, a target, to focus on."

Nonetheless, Dr. Robert Burke, director of the Morris K. Udall Parkinson's Disease Research Center of Excellence at Columbia University, called the new findings a "big step forward."

"Their first finding was only related to the mutant form of the protein which is very rare," he noted. "Whereas here they have shown that dopamine-modified neurons also block the system. This means they now have something that appears applicable to patients with the much more common sporadic form of Parkinson's. And that is very, very helpful."

While numerous hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of neurodegenerative diseases, the theory of oxidative stress has received considerable support. Although many correlations have been established and encouraging evidence has been obtained, conclusive proof of causation for the oxidative stress hypothesis is lacking and potential cures have not emerged.

Therefore it is likely that other factors, possibly in coordination with oxidative stress, contribute to neuron death. Using Parkinson's disease (PD) as the paradigm, this review explores the hypothesis that oxidative modifications, mitochondrial functional disruption, and impairment of protein degradation constitute three interrelated molecular pathways that execute neuron death.

These intertwined events are the consequence of environmental exposure, genetic factors, and endogenous risks and constitute a "Bermuda triangle"that may be considered the underlying cause of neurodegenerative pathogenesis.

Author: Kristen MalkusElpida TsikaHarry Ischiropoulos
Credits/Source: Molecular Neurodegeneration 2009, 4:24

A family of genetically modified monkeys with glowing green feet have been created by Japanese scientists in an experiment that could advance research into diseases such as Parkinson’s and Huntington’s.

Although GM monkeys have been born before, the marmosets are being regarded as a scientific milestone because they are the first to have passed a genetically engineered trait from one generation to the next.

The achievement raises the possibility of colonies of GM monkeys being bred for use in medical research. Scientists avoid experimenting on primates when possible, but they remain the best available animal models for studying many conditions, especially brain disorders and infectious viruses such as HIV.

It may now be possible to breed monkeys with mutations causing them to develop diseases such as Huntington’s and motor neuron disease, enabling scientists to study their progress and to develop treatments.
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The research has raised ethical concerns because it could lead to an increase in the number of experiments on primates. Some research groups said, however, that the use of GM monkeys could reduce the number of animals needed because they provided better models for human disease.

A team led by Erika Sasaki, of Keio University, inserted the green fluorescent protein (GFP) gene into 91 marmoset embryos using a modified virus, and 80 of these were transferred to surrogate mothers.

The experiment led to the birth of five offspring, named Hisui, Wakaba, Banko and twins Kei and Kou. Keikou means “fluorescent” in Japanese. Kou’s sperm was then used to fertilise eggs by IVF, resulting in the birth of two more GM marmosets with skin on the soles of their feet that glows green under ultraviolet light. One survived, but the other died after being bitten by its mother. The research is published in the journal Nature.

“The successful creation of transgenic marmosets provides a new animal model for human disease that has the great advantage of a close genetic relationship with humans,” the researchers wrote.

Gerald Schatten, of the University of Pittsburgh, who led the team that created Andi, the first GM primate, in 2000, and Shoukhrat Mitalipov, of the Oregon National Primate Research Centre, said: “The birth of this transgenic marmoset baby is undoubtedly a milestone. The cumbersome and often frustrating process of making a transgenic animal from scratch need now only occur with founder animals.” They pointed out, though, that marmosets were not as useful as rhesus macaques or baboons for modelling some human diseases.

Kieran Breen, director of research and development at the Parkinson’s Disease Society, said: “This is potentially very exciting for the future of research into the causes of Parkinson’s disease.” Simon Festing, the chief executive of Understanding Animal Research, said: “Ethical evaluation and public engagement are vital to maintain confidence in such research.”

Together, two common pesticides may increase the risk of Parkinson’s disease.
Apr 27, 2009

Costello, S, M Cockburn, J Bronstein, X Zhang and B Ritz. 2009. Parkinson's disease and residential exposure to maneb and paraquat from agricultural applications in the Central Valley of California. American Journal of Epidemiology 169: 919-926.
Synopsis by Jonathan Chevrier, Ph.D.

The risk of Parkinson's disease increases in people who live near farm fields sprayed with a combination of pesticides.

A recent study conducted in California’s Central Valley found that people who lived near fields sprayed with a combination of pesticides used on crops such as potatoes, dry beans and tomatoes had an increased risk of Parkinson’s disease.

This is the first study to evaluate associations between exposure to a combination of pesticides and the risk of Parkinson’s disease.

These results add to the growing literature suggesting that exposure to multiple chemicals may be more harmful than exposure to individual chemicals and contribute to the debate of evaluating chemical safety one at a time rather than in combination.

The cause of Parkinson’s disease is still a mystery to scientists but reports of higher risks of this ailment in farmers and in rural populations have lead some to hypothesize that exposure to pesticide mixtures may be a contributor.

The scientists found that people who live within 500 meters of a field sprayed with the pesticides maneb and paraquat in combination, but not individually, had a 75 percent higher risk of Parkinson’s disease relative to controls. Being exposed to the mixture at a younger age resulted in an even higher risk. Individuals potentially exposed to these pesticides when they were 60 years old or younger were 5 times more likely to be diagnosed with Parkinson’s disease.

These results are predicted by studies which showed that exposing rodents to maneb and paraquat together resulted in reduced motor activity, nerve cell loss and decreased levels the neurotransmitter dopamine in certain areas of the brain as observed in Parkinson's patients. Animal studies also predicted Costello's finding that effects of these pesticides would be more important when exposure occured at a younger age.

Researchers obtained these results after comparing potential exposure to pesticides in 368 people with Parkinson’s diseases and 341 people without living in an agricultural area. Exposure was estimated using land-use maps and data from the California Pesticide Use Report, a program which requires that the precise date, chemical and location of spraying be reported to the State.

However, biological markers, such as pesticide concentrations in urine and blood, were not measured. Other factors associated with living close to certain fields may explain the reported association.

UCLA researchers have provided strong new evidence linking at least some cases of Parkinson's disease to exposure to pesticides. Researchers have suspected for some time that pesticides may cause the neurodegenerative disorder, and experiments in animals have shown that the chemicals, particularly the fungicide maneb and the herbicide paraquat, can cause Parkinson-like symptoms in animals. But proving it in humans has been difficult because of problems in assessing exposure to the agents.

Parkinson's is a disorder of the central nervous system that often impairs the sufferer's motor skills, speech and other functions. It is not fatal of itself, but complications often are. The disease has been recognized since the Middle Ages but became more prevalent in the 20th century. As many as 180 of every 100,000 Americans develop it.

To explore a potential connection to pesticides, epidemiologist Beate Ritz of UCLA and her graduate student Sadie Costello, now at UC Berkeley, studied public records of pesticide applications in California's Central Valley from 1974 to 1999. Every application of pesticides to crops must be registered with the state. Working with Myles Cockburn of USC, they developed a tool to estimate pesticide exposure in areas immediately adjacent to the fields.

They then identified 368 longtime residents who lived within 500 yards of fields where the chemicals had been sprayed and compared them to 341 carefully matched controls who did not live near the fields.

They reported in the current issue of the American Journal of Epidemiology that people who lived next to fields where maneb or paraquat had been sprayed were, on average, about 75% more likely to develop the disease. But those who developed the early-onset form of the disease -- contracting it before the age of 60 -- had double the risk of contracting it if they were exposed to either maneb or paraquat alone and four times the risk if they were exposed to both. In most cases, the exposure occurred years before the onset of the disease. Exposure to other pesticides did not appreciably alter the risk.

"The results confirmed two previous observations from animal studies," Ritz said. "One, that exposure to multiple chemicals may increase the effect of each chemical. That's important, since humans are often exposed to more than one pesticide in the environment. And second, that the timing of the exposure is also important."

-- Thomas H. Maugh II

Board recommends 8 new conditions for medical-marijuana use

Sue Vorenberg |

4/13/2009 - 4/14/09
The Department of Health's Medical Advisory Board wants to let more people with chronic conditions into the approved group of patients that can use marijuana for medical purposes.

The board will ask Health Secretary Alfredo Vigil to add eight new conditions to 14 that have so far been included in the state Medical Cannabis Program.

The program provides protection from state prosecution for approved users of medical marijuana. Patients must apply to the state to be eligible.

The proposed new conditions are: chronic muscle inflammation accompanied by muscle weakness; severe osteoarthritis; rheumatoid arthritis; reactive arthritis; post-polio syndrome; Parkinson's disease; Alzheimer's; and severe chronic pain.

Each condition must meet specific requirements to be eligible, and the board is planning to provide data to back up the suggestions in its final proposal, said Deborah Busemeyer, a spokeswoman for the department.

"The secretary will be looking for scientific evidence that the conditions meet legal requirements," Busemeyer said. "That is, that they are chronic, debilitating conditions where the patient can find no relief elsewhere."

Once the board finishes the proposal, Vigil will have 10 days to decide if he will approve some or all of the list.

"It depends on what's in the recommendations," Busemeyer said. "Last time, though, he approved the majority of them, but not all of them."

So far, the approved conditions are: cancer; glaucoma; multiple sclerosis; epilepsy; spinal-cord damage with intractable spasticity; HIV/AIDS; painful peripheral neuropathy; intractable nausea/vomiting; severe anorexia/cachexia; hepatitis-C infection currently receiving antiviral treatment; Crohn's disease; post-traumatic stress disorder; and Lou Gehrig's disease. Hospice patients are also eligible.

There are 284 patients in the program so far.

The state also recently approved a license for the first nonprofit group to produce and distribute marijuana to patients in the program. The group hasn't yet started distribution.

Mirapex, Other Parkinson’s Disease Drugs Linked to Compulsive Gambling, Hypersexuality
Date Published: Tuesday, April 14th, 2009

Mirapex and other dopamine agonists used to treat Parkinson’s Disease have been linked to the development of extreme behaviors by yet another study. According to researchers at the Mayo Clinic, one in five patients taking such drugs in a recent study developed behavior disorders, such as compulsive gambling or hypersexuality.

Dopamine agonists like Mirapex have long been suspected of causing compulsive behavior. The suspicion was bolstered last June, when researchers investigating the link between dopamine agonists and compulsive behavior presented their findings at International Congress of Parkinson’s Disease and Movement Disorders conference in Chicago. The study, which looked at more than 3,000 patients from 46 medical centers in the United States and Canada, found that Parkinson’s patients on dopamine agonists are nearly three times more likely to have at least one impulse-control disorder - including gambling addiction - compared with patients receiving other treatments.

Parkinson’s Disease occurs because of a lack of the neurotransmitter dopamine in certain areas of the brain. A dopamine agonist works by mimicking the effects of this chemical. However, dopamine is also known to produce a “rush” in the brain of people who are anticipating a reward or excitement. Many experts believe that such a biochemical reaction is behind the reports of compulsive behavior linked to dopamine agonists like Mirapex.

The Mayo Clinic study involved 267 patients treated between 2004 and 2006 in a seven-county area around the Mayo clinic. Sixty-six were taking a dopamine agonist at a therapeutic level, but only 38 were using doses in the therapeutic range, 178 were taking carbidopa/levodopa without a dopamine agonist, and 23 were untreated.

Six of the patients taking dopamine agonists developed a behavioral disorder (an occurrence rate of 18.4 percent for this group). Five developed a gambling addiction and five became hypersexual (both disorders developed in three of the patients). Other compulsive behaviors were noted as well. Though in some cases the behaviors continued for years, the Mayo Clinic researchers found that they abated when the patients stopped dopamine agonist therapy.

None of these behaviors were seen in untreated patients, those taking less than a therapeutic dose of a dopamine agonist, or patients receiving treatment with carbidopa/levodopa alone, the researchers said.

The researchers advised that the severity of the problems seen indicated that patients and doctors needed to be more aware of the behavioral side effects associated with dopamine agonists. In at least 2 cases, patients were subjected to intense psychiatric treatment before dopamine agonists were recognized as a likely cause of their disorder.

“Physicians treating Parkinson’s Disease with dopamine agonists should obviously warn the patients, spouses, and families of such risks because they may not recognize the relationship to the drug until disastrous consequences have occurred,” the study authors said.

Study identifies gene that contributes to Parkinson's disease
April 4, 3:01 PM ·

MJFF has funded over $142 million in research to date

A new study helps to explain why people who carry mutations in a gene known as Nurr1 develop a rare, inherited form of Parkinson's disease (PD), the most prevalent movement disorder in people over the age of 65. A research team from the University of California, San Diego School of Medicine and the Salk Institute for Biological Studies in La Jolla has identified a protein in the brain of mice that protects neurons from excessive inflammation, which can lead to neurodegenerative disorders such as Parkinson's disease.

Their study, which identifies the protective function of a protein called Nurr1 and defines the pathway by which it works, was published in the April 3rd edition of the medical journal Cell.

Parkinson's disease belongs to a group of conditions called motor system disorders, which are the result of the loss of dopamine-producing brain cells. The four primary symptoms of PD are trembling in hands, arms, legs, jaw, and face; rigidity, or stiffness of the limbs and trunk; slowness of movement; and impaired balance and coordination. As these symptoms become more pronounced, patients may have difficulty walking, talking, or completing other simple tasks.

Contact: Cathleen Genova

A new study in the April 3rd issue of the journal Cell, a Cell Press publication, helps to explain why people who carry mutations in a gene known as Nurr1 develop a rare, inherited form of Parkinson's disease, the most prevalent movement disorder in people over the age of 65.

They have found evidence that the gene normally acts to suppress an inflammatory response and, in turn, the production of neurotoxins in the brain. Those neurotoxins can otherwise spawn the damage to dopaminergic neurons that is characteristic of Parkinson's disease. The findings not only offer new insight into the causes of the disease, but also may point to new avenues for therapy, according to the researchers.

In its normal form, "the gene protects against Parkinson's," said Christopher Glass of the University of California, San Diego. "This system functions in the brain, and probably in other parts of the body, to protect from the deleterious effects of excessive inflammation." When the Nurr1 gene is disabled, as it is in those with the rare familial form of Parkinson's disease, it leads to a pattern of inflammation that is exaggerated in both magnitude and duration, he added.

The causes of most common forms of Parkinson's remain poorly understood, but the disease is generally associated with an inflammatory component involving cells known as microglia, the researchers explained. Those microglia act as sentinel cells, keeping a lookout for potential infection or tissue injury in the central nervous system.

As for Nurr1, studies had found it plays an important role in dopaminergic neurons and that people with a rare mutant form of the gene produce too little of the protein it encodes, leading them to develop Parkinson's disease late in life. Earlier reports also showed that Nurr1 operates in cells other than neurons, where its activity is increased by inflammatory factors.

Glass and his colleague Kaoru Saijo, also of UCSD, suspected that Nurr1's roles outside of neurons might also be involved in Parkinson's disease. Indeed, they've now shown that Nurr1 limits the activity of pro-inflammatory neurotoxic mediators in microglia and in cells known as astrocytes, which serve as support cells to neurons. When Nurr1's activity is reduced, microglia launch an exaggerated inflammatory response that is amplified further by astrocytes. It is this overreaction that leads to the production of factors that ultimately kill dopaminergic neurons.

The findings suggest that inflammation may be an important general contributor to Parkinson's disease, which in the vast majority of cases has not been traced to any genetic cause, Saijo said. The researchers noted that while experts have grown to appreciate that Parkinson's disease has an inflammatory component, questions still remain about its role as a cause or consequence of the disease.

"We think if inflammation is not an initiating event, it is definitely a part of the process that could amplify the disease," Glass said. That's a key point moving forward, he said, because it suggests there should be further efforts to evaluate and test anti-inflammatory therapies in the treatment of Parkinson's. Treatments designed to interrupt the signals between microglia and astrocytes might hold additional promise for fighting the disease.

The new results may also have implications for the ultimate success or failure of stem cell therapies, Glass said. If the progression of Parkinson's disease is significantly influenced by inflammation as the researchers suggest, then any cell-based therapies designed to replace the dopaminergic neurons that are lost with new ones will also "have to deal with this process."

###

The researchers include Kaoru Saijo, University of California, San Diego, La Jolla, California, CA; Beate Winner, The Salk Institute for Biological Studies, La Jolla, CA; Christian T. Carson, The Salk Institute for Biological Studies, La Jolla, CA; Jana G. Collier, University of California, San Diego, La Jolla, California, CA; Leah Boyer, University of California, San Diego, La Jolla, California, CA, The Salk Institute for Biological Studies, La Jolla, CA; Michael G. Rosenfeld, University of California, San Diego, La Jolla, California, CA, Howard Hughes Medical Institute; Fred H. Gage, The Salk Institute for Biological Studies, La Jolla, CA; and Christopher K. Glass, University of California, San Diego, La Jolla, California, CA.

Careful Site Selection Required for Deep-Brain Stimulation Treatment in Patients With Parkinson's Disease: Presented at AD/PD

By Chris Berrie

PRAGUE, Czech Republic -- March 14, 2009 -- Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is as effective as DBS of the globus pallidus (GPi) for improvements of fine motor function in patients with idiopathic Parkinson's disease (PD) when they were on medication, researchers noted here at the 9th International Conference on Alzheimer's and Parkinson's Diseases (AD/PD). When off medication, however, these patients can experience greater long-term adverse events with STN stimulation, despite the fact that it reduces the levodopa dosing needed for symptom management.

DBS is an alternative therapy for patients with PD, and involves surgical implantation of an electronic device into the STN or the GPi, with stimulation at both sites being effective in reducing motor symptoms.

"Deep brain stimulation is typically done when pharmacologic remedies fail, and it is currently done at more of an advanced stage of disease," noted principal investigator Tracie Caller, MD, Dartmouth Hitchcock Medical Centre, Lebanon, New Hampshire, presenting a systematic review here on March 14.

With little known about which stimulation site produces better outcomes, Dr. Caller's analysis was designed to compare the efficacy and safety of DBS of the STN and the GPi for reducing fine-motor symptoms in patients with PD.

Dr. Caller and colleagues searched the MEDLINE database, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov Web site, and bibliographies and meeting abstracts for relevant studies for direct comparisons of STN and GPi stimulation. They needed to report Unified PD Rating Scale (UPDRS) scores at preoperative baseline levels and at a minimum follow-up of 6 weeks. An assessment of the data quality was carried out by 2 blinded, independent reviewers.

Thirteen reviewed studies were found to be eligible according to inclusion criteria. The combined patient numbers saw DBS in the STN for 282 patients and in the GPi for 140 patients. Mean baseline characteristics were as follows: age 50 to 64 years; disease duration 8 to 17 years; and UPDRS motor scores off medication of 40 to 64.

Mean reductions in off-medicine UPDRS motor scores for the STN and GPi subjects at trial follow-up were 47% and 36%, respectively. On medication, these benefits were lower, at 14% and 20%, with 36% and 5% of subjects, respectively, showing reductions in levodopa treatments during follow-up.

The mean difference in the UPDRS motor scores across these trials thus demonstrated a significant benefit when off medication in favour of DBS in the STN over the GPi (-8.75; 95% confidence interval [CI], -13.46 to -4.04; P < .0001), although this benefit was lost when patients were on medication (1.73; -2.71 to 6.17; P = .09).

The adverse effects related to these stimulation sites were significantly higher for stimulation in the STN (risk ratio, 4.27; 95% CI, 1.17-15.52; P = .03). As the severities of these adverse effects were reported differently across the studies, however, this significant difference might not provide an accurate reflection overall of which adverse events were truly clinically significant, the researchers concluded.

"We tend to prefer subthalamic nuclear stimulation right now, clinically, but I think that with the rate of adverse effects of stimulation we need to be a little more careful in selecting who we are applying this technique to," Dr. Caller indicated.

[Presentation title: Deep Brain Stimulation of the Subthalamic Nucleus Versus Globus Pallidus for Parkinson's Disease: A Systematic Review. Abstract P2-135]

Meg Farris / Eyewitness News

NEW ORLEANS – The tremors caused by Parkinson's Disease can be life changing. But in a recent study, doctors found that deep-brain stimulation works better than the best medicine at improving quality of life.

A local man told Eyewitness News how the treatment is working for him, and a local doctor talked all about the breakthrough treatments that are on the horizon.

Gene Falgoust's family and co-workers at the refinery noticed at times his finger or leg would shake. Then years ago, when he was 47 years old, came the medical diagnosis.

"Well I said it can't be happening to me, but in the long run, I just accepted it," he said.

For a while, the part of his brain that was dying from Parkinson's Disease was helped with medication, but then he needed something more.

So what happened when he had deep brain stimulation?

"I stopped shaking. I wasn't shaking as much. I still shake now and then but not as much as I used too," said Gene.

Ochsner Neurologist and Parkinson's specialist Dr. J. Rao brought Falgoust into surgery. And while Falgoust was completely awake, the doctor opened up his skull to expose a part of his brain. Then they found the area that was causing the shaking problems and implanted a wire into it.

"When we are in the operating room, we check it with the hand-held battery operated gizmo and make sure it stops. We don't get out of the operating room until we are absolutely sure we found the spot (in the brain) that will make it stop," Rao said.

The wire is connected to a device about the size of a pacemaker and is programmed to give Falgoust the exact stimulation that he needs.

You can see the impression of the wire running up Gene's neck, and the stimulators in his body. He had one side done the old way using a painful halo to keep his head still during surgery, but just recently he had the other side of the brain done in a newer, more comfortable way, with a tower-like device.

"The procedure was different the first time I had it done. I had to wear a halo and it was piercing my skull. It was really painful, but this time nothing, and you have to be awake for the surgery and I could hear the doctors talking," Gene explains.

And Dr. Rao can turn the device on and off from the outside of Gene's body. You can see what happens when Gene's deep brain stimulator is off: he shakes continuously. When it is on, his hands are still.

"I'd always be embarrassed when I'd go out in public. You know everybody in Vacherie, it's a little town, but everybody in Vacherie prayed for me.”

But now his life has changed.

"I can write my name, I can do almost anything I want to now, he says.

Even dress himself.

"Yeah, well my wife had to help me at times. Now I do it all on my own," he adds.

The makers of the stimulator say not everyone is a candidate for it, but for people who are, you can instantly see the difference it makes in their lives. And while this is not brand new technology, Rao said in the next 10 years this will lead to major new changes.

"This is an enormously exciting time to be doing that," Rao said.

A nanochip alone will be implanted in the brain to fix the symptoms. It's already been done in animals. A gene will be introduced into the body to make the dopamine that the dying part of the brain can no longer make.

Growth factors, a protein that allows the dying cells to survive, could be available.

And your own stem cells could be made to go repair the damaged ones in the brain.

Rao says with the aging baby boomers, this technology could not come at a better time.

"The incidence in Parkinson's Disease is going to increase by 40-70 percent in Louisiana in the next 10 years," Dr. Rao cautions.

So for people such as Gene, the hope is as his disease gets worse, scientists will give him the opportunity to live even better.

One and a half million American's have Parkinson's, with 60,000 new cases diagnosed each year.

Women who count more years between their first period and menopause have a lower risk of developing Parkinson's disease, new research indicates.

The findings, which will be presented at the American Academy of Neurology's 61st annual meeting in Seattle in April, suggest that longer exposure to the body's own hormones may help protect brain cells affected by Parkinson's disease, says study author Rachel Saunders-Pullman, of Albert Einstein College of Medicine in the Bronx and Beth Israel Medical Center in New York and a member of the American Academy of Neurology.

Parkinson's is a nervous system disorder that occurs when special brain cells that make dopamine, a chemical messenger in the brain, die or become impaired. It leads to trembling and movement problems.

In the study, the researchers analyzed the medical records of 74,000 women who experienced natural menopause and about 7,800 women who went through surgical menopause. Among women with natural menopause, those who had a fertile lifespan of more than 39 years had about a 25-percent lower risk of developing Parkinson's than women with a fertile lifespan of less than 33 years.

Women who had menopause from surgery had almost twice the risk of developing the disease if they had previously taken hormone therapy and stopped than if they had never taken hormone therapy. Taking hormones did not have any effect on natural menopause women.

Author Saunders-Pullman says more research is required to understand why women with four or more pregnancies are at increased risk.

"This study does not support a role for treatment with hormone therapy in preventing Parkinson's, but there are still many unanswered questions," she says.

--By Mary Brophy Marcus, USA TODAY

At the 38th annual meeting of the Society for Neuroscience, researchers have identified an ideal time to collect human embryonic stem cells to treat Parkinson’s disease.

Lorraine Iacovitti, Ph.D., professor and interim director of the Farber Institute for Neurosciences of Thomas Jefferson University have found that a stage during dopamine neuron differentiation can be the ideal time for that. The researcher team found that neural progenitor cells that express the gene Lmx1a are committed to the midbrain dopamine neuron lineage, but still retain proliferative capacity. Because of these characteristics, the stage at which Lmx1a is expressed may be ideal for transplantation.

The Lmx1a-positive cells cannot be identified solely by this transcription factor. However, Dr. Iacovitti and her team also found that a large percentage of the Lmx1a-positive cells express a cell surface protein called TrkB. This protein was not expressed on any of the other cell types identified in the cell culture. With TrkB as a cell surface marker, dopamine neuron progenitor cells derived from human embryonic stem cells can be selected from a heterogenous population using magnetic-activated cell sorting (MACS) or fluorescence-activated cell sorting (FACS).

Source: Science Daily

by Steven Ertelt
LifeNews.com Editor
February 16, 2009

Los Angeles, CA (LifeNews.com) -- Scientists have published a paper in a medical journal describing the results of the world's first clinical trial using autologous neural stem cells for the treatment of Parkinson's disease. A leading bioethics watchdog says the results show more money should be put behind adult stem cells.

UCLA researchers published their results in February issue of the Bentham Open Stem Cell Journal which outlines the long term results of the trial.

"We have documented the first successful adult neural stem cell transplantation to reverse the effects of Parkinson's disease and demonstrated the long term safety and therapeutic effects of this approach," says lead author Dr. Michel Levesque.

The paper describes how Levesque's team was able to isolate patient-derived neural stem cells, multiply them in vitro and ultimately differentiate them to produce mature neurons before they are reintroduced into the brain.

The team was able to inject the adult stem cells without the need for immunosuppressants. Unlike embryonic stem cells, adult stem cell injections don't cause a patient's immune system to reject the cells.

The adult stem cells were highly beneficial for the patient involved in the study.

"Of particular note are the striking results this study yielded -- for the five years following the procedure the patient's motor scales improved by over 80% for at least 36 months," Levesque wrote.

He said he hoped a larger clinical trial would replicate the findings.

Dr. David Prentice, a former biology professor at Indiana State University who is now a fellow with the Family Research Council, tells LifeNews.com that the results of the study are wonderful news for patients.

"This evidence had been presented previously, but we now have the peer-reviewed scientific evidence for the effectiveness of adult stem cells in alleviating Parkinson's symptoms," he said. "While the data show that the technique needs refinement, this patient went for several years with little to no symptoms of his disease, even with only half of the brain treated with his own adult stem cells."

Prentice says the results continue to prove that adult stem cells outpace their embryonic counterparts.

"People need to take notice that it is not embryonic stem cells that provide promise of treatments in the future, but rather it is adult stem cells that are already providing safe and effective therapies for patients now, without the problems of rejection or tumors," Prentice explains.

"We need to pour our resources, especially taxpayer dollars, into adult stem cell research to foster more and better treatments and put the patients first," he told LifeNews.com.

Levesque is a principal investigator for NeuroGeneration, a biotechnology company, and is affiliated with the UCLA School of Medicine and the Brain Research Institute.

ScienceDaily (Feb. 10, 2009) — By shifting a normal protective mechanism into overdrive, a University of Wisconsin-Madison scientist has completely shielded mice from a toxic chemical that would otherwise cause Parkinson's disease.

Parkinson's disease is a disabling and sometimes fatal disease that afflicts 1.5 million Americans, with about 60,000 new cases annually. Its major symptoms, including tremors and sluggish movement, have been traced to death of small numbers of nerve cells in the substantia nigra, a brain region that helps regulate movement.

Adding extra copies of a gene that makes a normal, protective protein neutralized a toxic chemical that would normally devastate the substantia nigra. "This complete abolition of toxicity was far greater than we expected," says Jeffrey Johnson, a UW-Madison professor of pharmacy. "It was striking. We thought we would see a 20 or 30 or 40 percent reduction in cell death."

The protective mechanism is initiated by a protein called Nrf-2, which is present in people and in mice, says Johnson. Nrf-2 (transcription factor NF-E2-related factor) is made by astrocytes, brain cells that play a supportive role to the neurons, which are the cells that actually carry nerve signals.

In recent years, researchers looking at a range of neurodegenerative diseases, including Alzheimer's and Lou Gehrig's diseases as well as Parkinson's, have focused on the astrocytes in their quest to help the brain protect itself from stressful conditions that are deadly to neurons. "Astrocytes way outnumber neurons and are found throughout the central nervous system," says Johnson. "Neurons have always gotten the Academy Awards, but astrocyte dysfunction is becoming a central theme in neurodegenerative disease. If we can figure out how to fix a sick astrocyte, or even prevent it from getting sick, that could offer profound protection against almost all neurodegenerative diseases."

Because neurons are impossible to replace, the present research focus in neurodegenerative disease is on preventing their death in the first place. Parkinson's disease can be treated for a time by replacing dopamine, the brain chemical made by the substantia nigra, but the treatment loses its efficacy over time.

In a study funded by the National Institute of Environmental Health Sciences and published in today's Proceedings of the National Academy of Sciences, Johnson and UW-Madison colleagues Pei-Chun Chen, Marcelo Vargas and Delinda Johnson studied mice with extra Nrf-2 genes. The astrocytes in these mice produced about twice the normal level of Nrf-2 protein.

The researchers then dosed the mice with MPTP, a chemical that kills neurons in the substantia nigra and has become the major mechanism for studying Parkinson's disease in mice. The toxicity of MPTP was discovered in 1982, when young drug users in California developed the classic symptoms of Parkinson's disease, a disease that usually strikes those over age 60. Researchers found that the synthetic heroin these people had used was contaminated with MPTP, and further studies showed that MPTP is highly toxic to nerve cells in the substantia nigra.

When astrocytes make Nrf-2, the protein attaches to their DNA, kick-starting activity in hundreds of genes that release chemicals that can protect nearby neurons from oxidation – a series of chemical reactions that can injure or kill cells. "The astrocytes are also probably sucking up the bad stuff, thereby reducing the oxidative environment and stress on the neurons," says Johnson, adding that his laboratory is trying to identify those specific protective chemicals.

Nobody can predict when a manipulation of Nrf-2 could reach clinical trials, which Johnson says are at the very least two years in the future. While these experiments altered the mouse cells with genetic engineering, human trials would probably use drugs to boost Nrf-2 production in astrocytes. Several labs, including Johnson's, are already searching for candidate drugs.

The stakes are high, Johnson says, because Nrf-2 also protects brain cells in models of such fatal brain diseases as Alzheimer's, ALS, and Huntington's disease.

Normally, neurons die in these neurodegenerative diseases to "commit suicide" through a process called programmed cell death. "Nrf-2 seems to rebalance the system," Johnson says, "in favor of what we call programmed cell life."

---

(Ivanhoe Newswire) -- If results of a new study conducted in mice can be applied to people, Parkinson's disease and other neurological conditions may have met their match.

Researchers from the University of Wisconsin-Madison have found boosting levels of the naturally occurring protein Nrf-2 completely shields mice from a chemical known to induce Parkinson's disease. The protein is made by brain cells called astrocytes, which researchers believe help support neurons, the cells that actually carry nerve signals. When neurons die, they cannot be replaced, which leads to the devastating effects of neurological conditions.

"Neurons have always gotten the Academy Awards, but astrocyte dysfunction is becoming a central theme in neurodegenerative disease," study author Jeffrey Johnson was quoted as saying. "If we can figure out how to fix a sick astrocyte, or even prevent it from getting sick, which could offer profound protection against almost all neurodegenerative diseases."

In this study, mice who were genetically engineering to have extra Nrf-2 genes produced about twice the normal level of Nrf-2. When researchers injected them with a chemical called MPTP, which is known to kill neurons and cause Parkinson's, the extra Nrf-2 was 100 percent effective in warding off the chemical.

Johnson says he and his colleagues expected to see some reduction in cell death due to the treatment, but were surprised at the totality of the results. "This complete abolition of toxicity was far greater than we expected. It was striking."

Tests in humans are still at least a couple of years away, but the researchers are already looking for candidate drugs that could boost Nrf-2 production in human astrocytes. If suitable drugs are found, it could mean effective treatments not only for Parkinson's disease, but also Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and other conditions involving the brain.

SOURCE: Proceedings of the National Academy of Sciences, published online February 2, 2009

GENEVA, SWITZERLAND, Jan 28, 2009 (MARKET WIRE via COMTEX) ----Addex Pharmaceuticals (SWISS: ADXN: 0.925, 0.015, 1.65%) announced today the successful completion of two Phase I studies of a newly developed modified release formulation of ADX48621. The studies showed that ADX48621, a metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator (NAM) in development for Parkinson's disease levodopa induced dyskinesia (PD-LID), is safe and well-tolerated in healthy volunteers, including those over 50 years old.

Study ADX48621-102 consisted of two parts. Part One was a randomized, two-way crossover comparison in 12 healthy subjects of the pharmacokinetics, safety and tolerability of the original active pharmaceutical ingredient (API) in capsule with the modified release capsule. Part Two was a double-blind, placebo-controlled, multiple ascending, repeat dose study in 24 healthy subjects using three different doses of the modified release formulation. The study showed that the new formulation achieved satisfactory pharmacokinetics, safety and tolerability with single and repeat dose administration across the dose range planned to be used for the Phase IIa proof of concept study in PD-LID, which is expected to start later this year.

Study ADX48621-103 was a two-period crossover study that evaluated the safety, tolerability and pharmacokinetics of ADX48621 following single oral dosing in older healthy subjects (aged over 50 years) both fasting and following a high fat meal. ADX48621 was well tolerated by this group of older subjects and gave satisfactory drug exposure both in the fasted and fed states.

Chief Medical Officer Charlotte Keywood said: "The good safety and tolerability results for ADX48621 in older subjects are of particular interest because we plan to start Phase IIa proof of concept studies with the compound in Parkinson's disease dyskinesia later in the year."

mGluR5 inhibition has achieved clinical proof of concept in humans with PD-LID and separately in a primate model of PD-LID in studies with another company's mGluR5 inhibitor. Inhibition of mGluR5 has therapeutic potential in multiple indications because mGluR5 is involved in a variety of functions in the central and peripheral nervous systems*. In addition to PD-LID, mGluR5 inhibitors have achieved clinical proof of concept in separate studies in patients with gastroesophageal reflux disease (GERD), migraine and generalized anxiety disorder (GAD). Inhibition of mGluR5 also has potential in Fragile X syndrome. Our lead product, the mGluR5 inhibitor ADX10059, has been shown to have a superior effect to placebo in acute treatment of GERD and migraine headache in Phase IIa testing.

*mGluR5 antagonists: Discovery, characterization and drug development, Current Opinion in Drug Discovery & Development 2008 11(5):655-665

About Addex

Addex Pharmaceuticals (www.addexpharma.com) discovers and develops allosteric modulators for human health. Allosteric modulators are a different kind of orally available small molecule therapeutic agent, which we believe will offer patients better results than classical drugs. Our lead allosteric modulator product, ADX10059, has achieved clinical proof of concept and is in Phase IIb testing for the treatment of GERD and, separately, migraine headache. Both are important diseases for which existing products with limited efficacy have established multi-billion dollar markets despite sub-optimal efficacy. ADX10059 is a first-in-class mGluR5 inhibitor, a therapeutic strategy that also is being pursued in multiple indications by large pharma competitors.

Our products and technology already have proven their value through our relationships with four of the top 10 pharmaceutical companies in the world. Specifically, in two separate agreements with Merck & Co., Inc., we are developing allosteric modulators as drugs to treat Parkinson's disease and schizophrenia. A third agreement, with Johnson & Johnson, is focused on development of allosteric modulators to treat anxiety and schizophrenia. Separately, the investment funds of Roche and GlaxoSmithKline have extended their validation of our technology, products and management by making significant investments in Addex.

 Contacts Chris Maggos Head of IR & Communications Addex
  Pharmaceuticals +41 22 884 15 11 chris.maggos@addexpharma.com 

Disclaimer

The foregoing release may contain forward-looking statements that can be identified by terminology such as "not approvable", "continue", "believes", "believe", "will", "remained open to exploring", "would", "could", or similar expressions, or by express or implied discussions regarding Addex Pharmaceuticals Ltd, its business, the potential approval of its products by regulatory authorities, or regarding potential future revenues from such products. Such forward-looking statements reflect the current views of Addex Pharmaceuticals Ltd regarding future events, future economic performance or prospects, and, by their very nature, involve inherent risks and uncertainties, both general and specific, whether known or unknown, and/or any other factor that may materially differ from the plans, objectives, expectations, estimates and intentions expressed or implied in such forward-looking statements. Such may in particular cause actual results with allosteric modulators of mGluR2, mGluR4, mGluR5, mGluR7 or other therapeutic targets to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that allosteric modulators of mGluR2, mGluR4, mGluR5, mGluR7 will be approved for sale in any market or by any regulatory authority. Nor can there be any guarantee that allosteric modulators of mGluR2, mGluR4, mGluR5, mGluR7 or other therapeutic targets will achieve any particular levels of revenue (if any) in the future. In particular, management's expectations regarding allosteric modulators of mGluR2, mGluR4, mGluR5, mGluR7 or other therapeutic targets could be affected by, among other things, unexpected actions by our partners, unexpected regulatory actions or delays or government regulation generally; unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; competition in general; government, industry and general public pricing pressures; the company's ability to obtain or maintain patent or other proprietary intellectual property protection. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Addex Pharmaceuticals Ltd is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise, except as may be required by applicable laws.

"I strongly support expanding research on stem cells. I believe that the restrictions that President Bush has placed on funding of human embryonic stem cell research have handcuffed our scientists and hindered our ability to compete with other nations. As president, I will lift the current administration's ban on federal funding of research on embryonic stem cell lines created after Aug. 9, 2001 through executive order, and I will ensure that all research on stem cells is conducted ethically and with rigorous oversight."

Nearly three-quarters of Americans want President Barack Obama to fulfil his campaign commitment to lift the restrictions on embryonic stem cell research according to a recent poll conducted for the Coalition for the Advancement of Medical Research (CAMR) by Opinion Research Corp. This can be accomplished either by Obama issuing an executive order or by Congress passing the bipartisan Stem Cell Research Enhancement Act H.R.3/S.5.

Both Obama and Congress have cited stem cell research as a top priority but some think it is too divisive an issue to be handled early in the new administration, remembering how President Clinton loss ground over the issue of gays in the military.

"I myself would favor legislation, so it is the law" said Speaker Nancy Pelosi.

Though the odds are good that the bill will pass in Congress, some Democrats worry about the off-year elections coming in 2010 when 70 of their seats will be in competitive races.

In Obama's inaugural speech he urged all of us to make "the hard decisions." By signing an executive order or prodding congress to pass the Stem Cell bill he would show the world that the last eight years of grinding science under the wheels of right wing religious fanaticism are definitely over. It will also show that the government has some compassion for the ever increasing numbers of chronically ill.

The Obama campaign published the following statement about advanced stem cell research:

"Despite recent advances pointing to alternatives like adult stem cell and cord blood, embryonic stem cells remain unmatched in their potential for treatment of a wide variety of diseases and health conditions. Barack Obama has been a long-term supporter of increased stem cell research. He introduced legislation while a member of the Illinois Senate that would allow embryonic stem cell research in Illinois. Obama has cosponsored legislation to allow greater federal government funding on a wider array of stem cell lines. Obama believes we need high ethical standards that allow for research on stem cells derived from embryos produced for in vitro fertilization, embryos that would otherwise be needlessly destroyed"

By employing science, technology and innovation to work to solve an urgent health care issue, more campaign and administrative goals could be reached. Finding solutions through private companies and university-based research would promote American business abroad ultimately. Grants to university research and tax credits to private company R & D would meet some of those goals.

Allowing research to proceed on embryonic stem cells which would otherwise be destroyed might pave the way for reducing health care costs. This in turn would reduce the long term need for that health care. There is a significant list of diseases which could benefit from advanced stem cell research and development. There are millions of people who could be affected in a positive way by the results of such research. And they and their families are still waiting.

It makes more sense to have healthier people who can live long and productive lives than to have sick people who can survive to old age but have huge medical costs and diminished quality of life.

Sources:
The Raw Story, Dems consider overturning stem cell ban
Nature Sept, 2008, Obama interview
Scientific American Congresswoman Slams Religious Right's Assult on Science, August 2008

CLEVELAND - (Business Wire) Copernicus Therapeutics, Inc., announced today a collaborative effort with the University of Kentucky (UK) to develop a DNA nanoparticle therapy for Parkinson’s disease. Based on positive initial treatments in a rat model of Parkinson’s disease, conducted by Dr. David Yurek at UK, a second phase of studies will now work to optimize the nanoparticle payload, a DNA expression system that is capable of expressing candidate therapeutic genes for months, if not years, in the affected brain regions of Parkinson’s disease patients.

“Copernicus’ unique, non-viral nanoparticle formulation is designed to safely and effectively deliver and express therapeutic genes and siRNAs to sites of human disease, including the brain, eye, and lung,” said Mark J. Cooper, senior VP of Science and Medical Affairs at Copernicus. “We are most encouraged by the positive treatment results of Parkinson’s disease rats treated with DNA nanoparticles containing the GDNF gene. Copernicus has developed proprietary expression elements that achieve long term gene expression in various tissues, and sustained expression of GDNF in the rat brain will lead to further IND-track studies for a phase I human clinical trial in Parkinson’s disease subjects.”

“I have long maintained that it is important for UK researchers to reach out and partner with industry leaders,” said UK President Lee T. Todd, Jr. “Dr. Yurek’s research collaboration with Copernicus Therapeutics is a perfect example of how we can leverage the innovation and discovery in our labs to add value to private sector companies. And I hope the partnership will lead to some important breakthroughs in our on-going battle against Parkinson’s disease.”

Funding for this project has been provided by The Michael J. Fox Foundation for Parkinson’s Research.

About Copernicus

Copernicus Therapeutics, Inc., a privately held biotechnology company, is dedicated to delivering the promise of nucleic acid therapeutics. The same technology that delivers the GDNF gene to Parkinson’s disease patients can be applied to treating other brain disorders, retinitis pigmentosa and other ocular diseases, and the lung manifestations of cystic fibrosis. The Copernicus multi-component delivery platform and expression systems can be used to develop nucleic acid therapies for numerous human diseases. Additional information about Copernicus is available at 

Copernicus Therapeutics, Inc.
Mark J. Cooper, M.D., 216-231-0227 x 23
Sr. V.P. of Science and Medical Affairs
or
Robert C. Moen, M.D., Ph.D., 216-231-0227 x26
President & CEO

People with Parkinson's disease who have a pacemaker-like device implanted in the brain spend an extra four-plus hours a day free of tremors and involuntary movements than they do on medication, according to the largest study of the treatment, which is known as deep brain stimulation.

However, deep brain stimulation also has a correspondingly greater risk of problems, such as infection, because of the complicated surgery, according to the study published Tuesday in the Journal of the American Medical Association.

"It definitely is brain surgery and that should give anyone pause," says David Charles, M.D., of Vanderbilt University, in Nashville, Tennessee, who was not involved in the new study. Nevertheless, he adds, most of the problems seen in the study were related to the surgery itself, and many had resolved themselves within six months.

The findings are "encouraging," he says, given that previous research has suggested that patients might develop much more serious problems, such as major depression and suicidal thoughts, than were seen in the current study. Health.com: My life with Parkinson's

In deep brain stimulation, electrodes are used to deliver electrical impulses to the substantia nigra, a crescent-shaped region in the center of the brain that controls and coordinates movement. In patients with Parkinson's disease, dopamine-producing nerve cells in this region degenerate, causing tremors, stiffness, slowed movement, and loss of coordination.

Drugs such as levodopa can help reduce tremors and involuntary movements. But for many people, this medication loses its effectiveness over time, while the side effects -- such as sudden jerky movements, chewing motions, and hand tremors -- get worse.

Introduced in the late 1990s, deep brain stimulation is becoming more widely accepted to treat such patients. But most studies have not been conducted in a way to clearly demonstrate the risks and benefits compared with medication alone.

In the new study, a team led by Frances Weaver, Ph.D., director of the Center for Management of Complex Chronic Care at the Hines VA Hospital, in Hines, Illinois, randomly assigned 255 Parkinson's patients to deep brain stimulation or medical therapy, which could include physical therapy, medication, and other appropriate treatment. A quarter of the patients were older than 70.

Six months after treatment, the deep brain stimulation patients reported about 4.6 more hours a day of "on" time, meaning time without movement problems; those in the control group showed no "on" time improvement. In all, 71 percent of the deep brain stimulation patients had improvements in their motor function, compared to 32 percent of the medical therapy patients.

When Parkinson's patients start a new drug, Weaver notes, they will see at best an hour or two more of "on" time a day.

"It's huge, and more than that, it's consistent with what other studies are finding too," says Charles. "It's a large study at multiple centers with lots of patients and it's done in a very rigorous manner."

Charles is conducting a clinical trial of deep brain stimulation in patients with very early Parkinson's disease, which, like Weaver's research, is partially funded by the company that makes the stimulation device -- Medtronic. Charles has served as faculty for Medtronic educational programs and consulted with the company, as did one researcher on the JAMA study.

Overall, deep brain stimulation patients were nearly four times as likely to have serious post-surgery problems, such as infections, disorders of the nervous system, or psychiatric problems. Ten percent of surgery patients developed infections in the surgical site, and one person died. Serious falls also were more common among deep brain stimulation patients during the six months after surgery.

People who had deep brain stimulation were also more likely to develop depression, confusion, and anxiety, although these changes were minor, according to Weaver and her colleagues, and it's not yet clear how much of an effect they had on patients. Health.com: Natural cures for depression

The surgery is extremely complex, Weaver notes; first, patients must have the electrodes implanted in the brain, which has to happen while they are awake so the surgeon can test the effects of touching various brain regions in order to make sure they are putting the device in the right place. Then patients undergo surgery to implant the pacing device, usually in the chest, which must be done under general anesthesia. If a patient develops an infection, it may be necessary to remove the device and replace it with a new one.

The fact that the study included a relatively high number of people over 70 may have contributed to the high rate of adverse events, Weaver explains. But the benefits seen for patients -- including the older people, who fared as well as the younger patients -- are "great news," Charles says.

Anyone considering deep brain stimulation should keep these risks in mind and work with his or her physician to determine if the benefits will outweigh these relatively rare -- but significant -- dangers, Weaver advises.

More than 1 million people in the United States have Parkinson's disease, and 50,000 new cases are diagnosed each year. Actor Michael J. Fox is arguably the most famous person with the disease; his was diagnosed in 1991. Health.com: Michael J. Fox keeps up the fight

In 1998, Fox underwent a type of brain surgery called a thalamotomy, in which a tiny portion of brain tissue is destroyed. This type of surgery gives a similar result to deep brain stimulation, but is not reversible. With deep brain stimulation, doctors can halt the electrical impulses if necessary. More than 35,000 deep brain stimulation procedures have been performed around the world, according to the American Association of Neurological Surgeons, and the procedure is being studied as a treatment for depression and other conditions as well.

EPG Online News

A new study could lead to a better understanding of how Parkinson's patients can improve their chances of survival.

Researchers at Emory University School of Medicine in Atlanta, USA, looked how clumps of aggregated proteins inside cells, known as Lewy bodies, can appear in the brains of patients with neurodegenerative diseases.

It was discovered that MEF2D, a genetic survival circuit, can be sensitive to alpha-synuclein – a major component in Lewy bodies – which could help scientists understand how Parkinson's sufferers become susceptible to brain cell death.

Dr Zixu Mao, associate professor of pharmacology at the university and one of the experts behind the study, said: "We've identified what could be an important pathway for controlling cell loss and survival in Parkinson's disease."

The report is due to be published in the January 2nd issue of medical publication Science and could lead to further research into how drugs can regulate MEF2D to allow brain cells to survive longer in those with Parkinson's disease.

MEF2D is a human gene that is also known as MADS box transcription enhancer factor 2, polypeptide D or myocyte enhancer factor 2D.