Read about patient concerns, family dilemmas, and the clinical dynamics of a weekly movement disorder clinic. Observe ways a movement disorder neurologist manages patient symptoms with medications, surgical referrals, physical therapy, and caregiver options. Find out more in my Weekly Journal.
Parkinson’s Progression Marker Initiative Reports Reduced Tau found in CSF of Parkinson’s subjects
The search for biological biomarkers to predict the risk or onset of Parkinson’s disease is important for the development of neuroprotective strategies that will benefit people who are at-risk, even before symptoms emerge. Through the search for biomarkers, there is potential for a permanent cure, instead of temporary symptomatic treatments. The Parkinson’s Progression Markers Initiative (PPMI) has over 800 research subjects at 32 research sites in 13 countries of the world, a large observational study that is producing some fascinating results.
Ken Marek, M.D. is the president and senior scientist at the Institute for Neurodegenerative Disorders in New Haven, Connecticut and also clinical professor of Neurology at Yale University. He is also the principal investigator for the PPMI study. In the past he said, “The entire goal of this study is to help us to accelerate therapies. The general way in which we can do that is by simply having tools that can be used to objectively measure disease, but the more specific way is that many of these biomarkers will hopefully identify subsets of individuals who may be affected in different ways. For example, some individuals with Parkinson disease might have more of a synuclein problem, whereas others have more of a LRRK2 problem. Using these biomarkers to direct therapy will also be extremely valuable in making those therapeutic trials more likely to be effective.”
Dr. Marek presented the most recent data from this study at the 18th International Congress of Parkinson’s Disease and Movement Disorders in Stockholm, Sweden.
He reported that one recent, significant observation has been that in the cerebrospinal fluid (CSF) samples from people with PARKINSON’S so far examined, there has been a reduction of tau. Tau is a protein abundantly found in neurons, but when it malfunctions and clumps together it contributes to neurodegeneration and is indicative of Alzheimer’s disease. Because PARKINSON’S is also a neurodegenerative disease, there was an expectation to find tau elevated in the CSF of PARKINSON’S patients. . So it was surprising to find that it was reduced. Similar results were reported in two smaller studies. “But our data is the biggest sample, it does seem to be a real finding” he said. Then he added: “We can’t explain it at the moment. It is leading to much discussion and additional research is needed to understand what we are seeing.”
The PPMI study has divided its research into four different categories. They are looking at clinical measures, such as can be measured by the Unified Parkinson’s Disease Rating Scale; imaging, including Magnetic Resonance Imaging (MRI) single photon emission computed tomography (PET scan) and photoacoustic computed tomography. The genetics category includes people with LRRK2 and synuclein mutations and there is a category for bio specimen samples of CSF, blood or plasma.
International Parkinson and Movement Disorder Society (MDS) 18th International Congress of Parkinson’s Disease and Movement Disorders Abstract 729
Medscape Medical News , Topic Alert June 20, 2014
Review by Marcia McCall
Three Dimensional Structure Revealed of an Important Neuronal Receptor
Two new studies, from two different research institutions have reported very similar findings less than a month apart. Both groups of researchers are very excited about the results of their research and its potential to lead to new therapeutic treatments for neurodegenerative diseases such as PARKINSON’S DISEASE, Huntington’s Disease and Alzheimer’s Disease as well as depression and schizophrenia. Their excitement comes from their newly visualized structure of the NMDA receptor giving insights into its complex function that plays such a vital role in neurological processes in the brain.
The first group of investigators published their data in the journal Science on May 29, 2014. Dr. Hiro Furukawa, an associate professor of biology, and his graduate student, Dr. Erkan Karakas, lead the team of researchers from Cold Spring Harbor Laboratory, a private, non-profit research institution in Cold Spring Harbor, New York. According to Dr. Furukawa, “Previously, our group and others have crystallized individual subunits of the receptor – just fragments – but that simply was not enough. To understand how this complex functions you need to see it all together, fully assembled.”
The second group of researchers are part of the Vollum Institute at Oregon Health and Science University in Portland, Oregon. They published their data on June 27th in the journal Nature. Dr. Eric Gouaux led a team of six investigators. He is a senior scientist and also an investigator with the Howard Hughes Medical Institute. An excited Dr. Gouaux said: “The NMDA receptor is one of the most essential, and still sometimes mysterious, receptors in our brain. Now, with this work, we can see it in fascinating detail.”
Both groups worked with the same innovative molecular photography called x-ray crystallography. X-ray crystallography is not a new imaging technique but a way to examine the structure of a molecule using x-rays deflected from the surface of a collection of those molecules that form a crystal structure. In this case, the researchers were examining the NMDA receptor, one of the most important for facilitating communication between neurons. This receptor is important in facilitating learning and memory. Malfunctions in this receptor are responsible for a wide range of neurological diseases, including PARKINSON’S DISEASE.
This receptor is called NMDA, which stands for N-methyl, d-aspartate. Its functional importance has been long understood, however its molecular structure and how it is controlled has been eluding researchers. The receptor is a complex composition of subunits, whose individual actions have been extensively documented in over three decades of research. Each unit has unique properties and operates in a distinct manner. Disturbances in these subunits causing either over or under activity are responsible for various neurological disorders. Until now understanding the interactions between the subunits and their total integration into the complex receptor has been limited.
Revealing the three dimensional structure of this receptor molecule has been an exhausting, tedious and time consuming labor. The image of the receptor that emerged from this research has been compared to a bouquet of flowers, a mushroom or a hot air balloon. It is this “balloon” part of the receptor that enables the cell to communicate through neurotransmitters, such as dopamine. Through visualization of the entire structure it is possible to see how the actions of one sub-unit regulates the response of a different sub-unit on the other side of the receptor and how each of the sub-units contribute to the activity of the NMDA receptor.
With this knowledge, scientists will be better able to develop specific treatments to control the NMDA receptor and affect their role in neurodegenerative diseases. Dr. Furukawa said, “Our structure defines the interfaces where multiple subunits and domains contact one another. In the future, these will guide the design of therapeutic compounds to treat a wide range of devastating neurological diseases.”
E. Karakas, H. Furukawa. Crystal structure of a heterotetrameric NMDA receptor ion channel. Science, 2014; 344 (6187): 992 DOI:10.1126/science.1251915
Chia-Hsueh Lee, Wei Lü, Jennifer Carlisle Michel, April Goehring, Juan Du, Xianqiang Song, Eric Gouaux. NMDA receptor structures reveal subunit arrangement and pore architecture. Nature, 2014; DOI: 10.1038/nature13548
Review by Marcia McCall
Clinical Trial Shows Levodopa is Still Best Treatment for Parkinson’s Disease
The results of a long term, open label clinical trial took place in the United Kingdom has shown that people with PARKINSON’S DISEASE had a better long-term benefit from levodopa than from other forms of treatment. Principal investigator for this seven-year study was Dr. Richard Gray, who was the director of the University of Birmingham Clinical Trials Unit but is now a professor at University of Oxford.
The trial was designed to allow doctors treating people newly diagnosed with PARKINSON’S DISEASE freedom to begin treatment with which ever drug they preferred, based on the patient’s own symptoms and medical status. Medications used included dopamine replacement with levodopa, dopamine agonists such as ropinerole or pramipexole or a monoamine oxidase type B inhibitor like selegiline or rasagiline. If symptom management was not achieved with initial treatment, doses could be increased or levodopa used as an adjunct or medication could be changed from agonist to levodopa.
There have always been questions in the minds of both patients and their doctors about which is the best way to begin treatment for PARKINSON’S DISEASE. Some thought that using levodopa early in the treatment process would limit its effectiveness later in the disease process or even lead to faster progression of the symptoms. Initial treatment with levodopa has often been found in other studies to induce dyskinesias making early treatment of PARKINSON’S symptoms with dopamine agonists of MAO-B inhibitors the first choice. But dopamine agonists also have a high incidence of troublesome side effects such as sleep disturbance or compulsive behaviors and lack of impulse control. This study followed 1620 patients for seven years to study the benefits and risks as well as the improvement in quality of life of the patients for both short term and long term treatment options.
An early discovery in this study was that treatment that began with monoamine oxidase type B Inhibitor was as effective as treatment that began with dopamine agonists. They also found that patients were more likely to discontinue their treatment with MAO-B inhibitors or dopamine agonists than patients taking levodopa. These treatments were discontinued usually due to quality of life issues or side effects that interfered with other aspects of the patients’ lives. Researchers used a quality of life scale (the PDQ- 39) to evaluate patient responses that were not measured by clinical evaluation scales.
After seven years of treatment, patients that had been started with levodopa therapy were doing only slightly better on scales of mobility. They were also more likely to develop dyskinesias. Patients on levodopa also rated their satisfaction with activities of daily living, cognitive abilities, communication skills and pain levels as being slightly better than the patients on agonists.
Study researchers believe this study dispels the thought that early treatment with levodopa limits its effectiveness later in the disease process. While the improvement and benefit was very small in the levodopa group, the difference in outcomes may have been dependent on the adverse effects of the dopamine agonists. Levodopa appears to maintain its effectiveness over time, however the risk of motor complications such as dyskinesias still remains. The results of this study may also be somewhat hampered because the research studied subjects over age 70. Younger onset subjects may have different responses leading to other outcomes.
For PARKINSON’S patients and their treating physicians, this study should help to relieve the anxiety that early treatment with levodopa will not induce a more rapid progression of the disease and may even improve the quality of life in the earliest stages.
PD MED Collaborative Group. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): a large, open-label, pragmatic randomized trial. The Lancet, 2014; DOI: 10.1016/S0140-6736(14)60683-8
Review by Marcia McCall
Practical Help for PARKINSON’S Patients from Wearable Computer Technology
A team of young computer researchers at Newcastle University in the U.K. have undertaken a study to help people with PARKINSON’S DISEASE. They want to use the newest interactive technology to help people with PARKINSON’S maintain their independence and preserve their dignity. Much to the delight and enthusiasm of the first PARKINSON’S volunteers, the new Google Glass improves not only their physical symptoms but helps their self esteem as well.
The Internet technology firm Google donated five pair of their new Google Glass to these innovative researchers. The Google Glass is Google’s first application of wearable computer technology. It is a headset, worn like a pair of regular, albeit designer-like, glasses that can connect to both the Internet and the wearer’s cellular phone. Google introduced it in 2012. These clever, technology savvy investigators, headed by Dr. John Vines at Newcastle University saw the potential for wearable computing technology to improve the lives of people with progressive diseases, such as PARKINSON’S DISEASE. But, of course, developing this potential had to be done in partnership with people who would use it: only they could tell if it really would be helpful.
Voice activation connects the Glass to the Internet so that tremulous or stiffened hands do not have to be used. Information appears unobtrusively on a small screen in the upper corner of one lens, and does not interfere with normal sight. Corrective lenses can also be used in the Glass. Like any mobile device, applications can be programmed into it that will provide the wearer with various types of information or reminders. It could be programmed to be a useful reminder to the wearer to take their medication on time or prompt them to speak more loudly, to remember to swallow to prevent drooling. Motion sensors in the Glass may also be able to help them get moving again if they experience freezing episodes. Best of all, it is discreet, giving cues to the wearer that no one else can see, saving them embarrassment in social situations
The interactive ability of the Glass can allow wearers to alert their caregivers their whereabouts, simply by looking through the lens. Wearers can also verbally request the device to make a phone call to any number of pre programmed specific persons or numbers, making communication much easier and faster for people whose motor skills are challenged. Each device can be programmed to the specific individual needs or requirements of the person using it and technology researchers like the ones at Newcastle are helping to develop the programs that will be particularly useful to the PARKINSON’S population.
Two of the volunteers who have been part of the Google Glass trial have had some very enthusiastic comments. “The difference is incredible. It hasn’t stopped the episodes completely and I still have to take the medication but it’s helping to control the symptoms so I can live my life.” And “They are just fantastic. The potential for someone with PARKINSON’S is endless.” While praise for help with the motor problems has been high, appreciation is also high for the discreet help that relieves embarrassment and improves confidence in social situations. Google Glass can help maintain independence and improve the quality of life.
Google Glass is still a prototypical computer technology. For one, it is very expensive at the present, $1,500 each. There are still developmental issues, and concerns that wearers could be using the device’s ability to take photos or videos to invade the privacy of unsuspecting people in public situation. At present, Google is giving users orientation and training sessions on the polite etiquette for use in public. As with all the newest technological devices, there will be future improvements and it will take some time for the public to become accustomed to the new device. But how wonderful that this new technology offers the potential to improve the lives of people with PARKINSON’S DISEASE.
“Exploring the acceptability of Google Glass as an everyday assistive device for people with Parkinson’s” Roisin McNaney, John Vines, Daniel ROggen, Madeline Batlaam, Penfei Zhang, Ivan Poliakov and Patrick Olivier. CHI2014. April 26-May 01. http://chi2014.acm.org/
“Everything you need to know about Google Glass” Haley Tsukayama, Washington Post, February 27, 2014
Review by Marcia McCall
Smoking, the Sense of Smell and PARKINSON’S DISEASE
Advice to the general population is that smoking is bad for your health…. very bad, indeed. But there has been information to the contrary for people with PARKINSON’S DISEASE…some 60 studies report that smokers have a lower risk of developing PARKINSON’S DISEASE. So, then, what are people with PARKINSON’S supposed to believe?
Smoking, for the general population, is known to lead to lung cancer, Chronic Obstructive Pulmonary Disease (COPD) and ultimately death. Smoking goes straight through the olfactory system, bypassing any intermediate functions that could serve as a filter, carrying any and all environmental toxins from tobacco or smoke straight to the lungs and the brain. It is well known that one of the early pre-motor symptoms of PARKINSON’S DISEASE is the loss of sense of smell. Could smoking possibly be implicated in this? Could smoking also be an environmental factor implicated in reducing the loss of dopamine producing neurons in the brain? Can the effects of smoking and early non-motor symptoms help explain the relationship between genetics and environmental factors leading to either neuroprotection or the development and progression of PARKINSON’S DISEASE?
A group of researchers at Pennsylvania State University, Milton S. Hershey Medical Center headed by Xuemei Huang, M.D., Ph.D. developed a study to improve understanding of whether or how smoking affects olfaction in PARKINSON’S DISEASE and how the involvement with olfaction contributes to the development of PD. They planned their study to. “test the hypothesis that smoking is associated with better olfaction in PARKINSON’S DISEASE.”
Seventy-six people with PARKINSON’S and seventy non- PARKINSON’S control subjects were recruited. Of the PARKINSON’S subjects, there were 22 with a history of smoking and 54 who had never smoked. In the control group, 17 were smokers and 53 were non-smokers. The histories of the smoking habits of all subjects were carefully noted. Only one PARKINSON subject and three of the control subjects were current, active smokers. While all the smokers had begun smoking in their mid to late teens, by their mid thirties they had stopped smoking. All subjects were assessed by the mini-mental state examination (MMSE) and the University of Pennsylvania Smell Identification Test (UPSIT). Non-motor symptoms were also carefully evaluated.
In the PARKINSON’S subject, age of onset was found to be at least 4 years later among the smokers than the nonsmokers. Control subjects had better results overall for UPSIT smell tests than the PARKINSON’S subjects, however the smoker PARKINSON’S subjects scored better than the nonsmokers. Smell scores among the PARKINSON’S subjects declined in relationship to age, but decline among the control subjects were not significant. Women tended to have much better sense of smell than male subjects in the control group, but this was not seen in the PARKINSON’S group. There was no correlation between the number of cigarettes smoked, the number of years smoked, or the years since the cessation of smoking and the scores of the UPSIT in the PARKINSON’S group, nor was there a correlation between the UPSIT scores and the age of onset or duration of the disease. This study also did not find a relationship between smoking and other non-motor symptoms, such as constipation, etc.
This research has shown some interesting results…that sense of smell in smokers is usually considered to be impaired was not found among the controls, and interestingly, the sense of smell among smokers in the PARKINSON’S group was better than that of the non-smokers. More interesting, that a history of smoking appears to confer a neuroprotective effect and delays the onset of the disease but that smoking after diagnosis or the use of nicotine patches does not offer the same protection. The results of this study suggest that the protection offered from smoking or nicotine may be a gradual process that occurs over many years before the onset of the motor symptoms.
The authors of this study do show a protective correlation between smoking and the onset of PARKINSON’S DISEASE; however they are aware that there may be other factors, such as personality traits, head trauma, or the use of other medications that may play a role in these results. Other studies will be needed to verify these results, but this study has made a genuine contribution to understanding the relationship between smoking and PARKINSON’S DISEASE.
Lucasson, E>B>; Sterling, N.W.;Lee, E-Y; Chen, H; Lewis, M.M.; Kong, L; Huang, X.; History of Smoking and Olfaction in Parkinson’s disease. Early View. Mov. Disord. doi 10.1002/mds.25912
Review by Marcia McCall
Two New Therapies for PARKINSON’S DISEASE Are Being Tested
Inhaled Therapy for PARKINSON’S DISEASE
A small pharmaceutical company, Civitas Therapeutics, has announce successful results of a Phase 2b clinical trial for a novel approach to delivery of levodopa that will alleviate “off” time in as little as 10 minutes. The novel technique is called Arcus inhalation technology and uses a proprietary combination of a powdered form of levodopa and an inhaler. 86 subjects took part in the clinical trial and the company is now negotiating with the Food and Drug Administration to introduce a Phase 3 clinical trial. The inhalation method that is the basis for the work of this company can speed up the availability of the medication and give patients more control over periods when oral medications take much longer to become effective. The company is small, only 30 employees at present, but stressed that there is a manufacturing facility near by that will speed the process of bringing the product to patients who need it.
ProSavin Tested for Efficacy and Safety
A report in the English medical journal Lancet gave the results of a trial of a lentiviral vector-based gene therapy. Researchers injected ProSavin bi-laterally directly into the putamens of 15 patients with motor fluctuations and at least a 5-year history of PARKINSON’S DISEASE. Three cohorts were given different doses, low, medium or high and the patients were followed for a year to assess safety, tolerability and efficacy. All subjects resumed their normal drug regimen after the surgery. Researchers were looking for the number and severity of adverse reactions, but also at the improvement in motor scores. There were many adverse reactions, most in the mild to moderate range and usually involved dyskinesias. There were no serious adverse events. However, motor response was significantly improved, tested off medication at 6 months and one year. ProSavin is a lentiviral vector-based gene therapy injected surgically into the striatum and putamen. The therapy is designed to restore dopamine production in patients with PARKINSON’S DISEASE.
Lancet, 2014 Mar 29; 383(9923): 1138-46. doi: 10.1016/S140-6736(13)61939-X. Epub 2014 Jan 10.
Review by Marcia McCall
The Search for Biomarkers in PARKINSON’S DISEASE – Part II
The search for a biological marker (biomarker) for the presence of PARKINSON’S DISEASE has been an ongoing and elusive process. Because of the variety of symptoms and their presentations and courses in different times in the disease process, finding one specific and unique identifier of any single symptom is exceedingly difficult. Adding to the difficulty, PARKINSON’S may not be a single disease, marked by a single disease process, but multiple disorders with similar pathologies that have unique differences. But the ability to diagnose accurately early, even before symptoms appear, would enable interventions to improve the quality of life or even to interrupt the progression of the disease. It would also lead to better targets for drug development and then be able to test the efficacy of the new drugs to provide effective treatments for specific symptoms.
The newly developed molecular research tools, proteomics, transcriptomics, metabolomics and genomics are making it possible to develop clinically applicable tests for susceptibility to disease and for diagnosing and following the progression of the disease. These molecular research tools examine biological fluids, such as blood, urine, saliva or cerebral spinal fluid, which for the most part are readily available, easy to obtain and can be processed economically. In the previous article, proteomic research highlighted the study of proteins and peptides and their application to diagnosing and establishing the disease state of the patient with PARKINSON’S DISEASE. Metabolomics is a research process that examines the metabolites, or chemical fingerprints, of various biological cellular processes. It can provide immediate information about the physical state of health on a cellular level. Combined with the information provided by the other “omics” and analyzed with biostatistics and bio information systems, a much more complete picture can be obtained of the state of the organism being observed.
Recent metabolomic studies have looked at the metabolites found in serum in healthy controls and people with PARKINSON’S DISEASE and found subtle distinctions. Such metabolic distinctions could be the result of dietary or personal metabolism processes, but overall, these studies revealed a statistically significant elevation of a metabolite called N-8-acetylspermidine, which appeared to be more prevalent in subjects with more advanced PARKINSON’S symptoms.
A research lab from the Division of Pulmonary, Allergy and Critical Care Medicine at Emory University in Atlanta, proposed to measure the metabolic signatures of slow versus rapidly progressing motor symptoms in PARKINSON’S DISEASE. They used serum samples that were collected from subjects within 3 years of diagnosis as well as from healthy controls. Using dual chromatography-high resolution mass spectromety to analyze the specimens, they found that elevated levels of N8-acetylspermidine were significantly higher in PARKINSON’S subjects that had the more rapidly progressing motor symptoms. Also, the presence of elevated N8-acetylspermidine was present early in the diagnosis and before the symptoms began to progress.
N8-acetylspermidine is a product that is excreted by cells and is found incases of traumatic brain injury or neuroinflamation and neuronal cell death. It is also involved in increasing the production of dopamine. The authors speculate that the increase in N8-acetylspermidine in rapidly progressing form of PARKINSON’S DISEASE, may be an attempt to increase dopamine production in remaining neurons or due to the effects of neuroinflamation.
Because N8-acetylspermidine can be detected early in the course of the disease and before symptoms rapidly escalate, it can serve a biomarker for the progression of the disease, but also may also signal a potential target for a pharmaceutical drug intervention.
Research using the molecular “omics” is still in the early stages, and much more technically complex than this article makes it appear. Knowledge gained from these technologies is progressing rapidly and other labs will be called upon to duplicate and validate these early studies. These are exciting times. Hope for people with PARKINSON’S has never been stronger.
James R Roede, Karan Uppal, Youngja Park, Kichun Lee, Vilinh Tran, Douglas Walker, Frederick H Strobel, Shannon L Rhodes, Beate Ritz, Dean P Jones; Serum metabolomics of slow vs. rapid motor progression Parkinson’s disease: a pilot study.PLoS One 2013 22;8(10):e77629. Epub 2013 Oct 22.
Review by Marcia McCall
The Search for Biomarkers in PARKINSON’S DISEASE – Part I
PARKINSON’S DISEASE is very complex. Making an accurate diagnosis depends on the observational skill of the physician doing a neurological exam and the types of symptoms exhibited by the patient. By the time symptoms have appeared, the disease is well established, the symptoms merely a marker of the progression of the disease. . Physicians and researchers have long sought some type of diagnostic test to define unique biomarkers that can accurately determine the presence or absence of this disease. The search for a biomarker is complicated by the fact that the motor and non-motor symptoms of PARKINSON’S DISEASE present at different times and affect different regions in the brain and therefore involve different biological processes. A disease with so many aspects as PARKINSON’S makes finding a unique, specific biomarker a bit like the proverbial search for the needle in a haystack. And additionally, the ideal test should also be able to measure the progression of the disease or predict development of certain symptoms.
Research has made tremendous progress in analyzing and understanding the biological processes involved in PARKINSON’S DISEASE, but usually, the analyses involve animal models of the disease, not actual humans. Research on humans can only be accomplished in individual brains after the patient has died. Some recent research has shown good results for biomarkers in cerebral spinal fluid (CSF), however that requires a lumbar puncture, a potentially painful procedure for a patient that may not have developed symptoms and also expensive to perform. Finding a reliable test using bodily fluids obtained less invasively, such as by a simple blood sample, has been the goal of some researchers using the newest “omics” research methods (proteomics, metabolomics, transcriptomics, genomics).
Proteomics is a study of proteins, and involves understanding the functions and structures as well as the complexities of the interactions of proteins involved in biological, pathological or pharmacological processes. Proteins are composed of peptides, strings of basic amino acid building blocks, and it is the combination of peptides that determine the nature of the protein. A collaboration of research institutions based at Washington State University in Seattle had done previous research in identifying proteins and peptides. A vast array of proteins can be found in human blood, proteins that come from all the organ systems in the human body found specifically in neurological diseases such as PARKINSON’S. Bringing their prior knowledge to a new proteomic research study, they narrowed the search down to the specific proteins found to be associated with functions of the central nervous system (CNS). These proteins are found in significantly smaller numbers, compared to proteins from other organs. From those CNS proteins, the research team then compared samples obtained from healthy controls to people previously diagnosed with PARKINSON’S DISEASE, and found the PARKINSON samples to have a distinctly altered profile.
Focusing on glycoproteins that have a previously explored relationship to PARKINSON’S, they then examined the peptides that compose the proteins. From an initial pool of 50 peptides, they found that 12 of them were consistently found in the plasma of people with PARKINSON’S, and further, that three of them correlated to specific diagnostic differences. A combination of two specific peptides showed a strong association with the severity of symptoms as diagnosed using the Unified Parkinson’s Disease Rating Scale (UPDRS). A combination of four specific peptides appears to be possible significant markers of PARKINSON’S DISEASE.
The researchers used a laboratory analysis method called selected reaction monitoring (SRM), which has a benefit of being fast, cost effective and is reproducible in different laboratories using different instruments. It is highly sensitive and can identify and quantify multiple proteins with high accuracy. They also used a particular technique that does not require the use of expensive antibodies, which again, would increase the efficiency for screening samples in clinical situations.
This research drew from a relatively large pool of subjects, 282, to be precise. It was successful in using easily obtained blood samples and a sensitive and cost efficient method for screening those samples for proteins and specific peptides. This research project brings the search for a unique diagnostic test for biomarkers to diagnose PARKINSON’S DISEASE many steps closer to reality. The results will need to be replicated and validated in many other independent studies and other researchers will add insights and refinement. This study does show the way to the development of diagnostic tests which can be done economically early and often to assist in diagnosis, follow disease progression and even track the effectiveness of treatments for PARKINSON’S DISEASE.
The principal investigator for this study was Jing Zhang, M.D., Ph.D. He is the Director and Shaw Professor of Neuropathology at the University of Washington, School of Medicine in Seattle, Washington. He received research assistance from The Veteran’s Affairs Puget Sound Health Care System, Department of Neurology, Oregon Health and Science University in Portland, OR and also from Department of Neurosciences, University of California at San Diego, La Jolla, CA. A total of 12 research assistants helped with this study.
Pan C, Zhou Y, Dator R, Ginghina C, ZhaoY, Movius J, Peskind, E, Zabetian C.P, Quinn J, Galasko D, Stewart T, Shi M, Zhang J. Targeted Discovery and Validation of Plasma Biomarkers of Parkinson’s Diseas J. Proteome Res., DOI: 10.1021/pr500421v pub. date May 22, 2014
Review by Marcia McCall
Transplanted Dopamine Cells Show Promise for Treating PARKINSON’S DISEASE
The big news this week was the story in Cell Reports; they transplanted dopamine cells that remained healthy and survived for 14 years. The research team, headed by Ole Isacson, M.D., from McLean Hospital and Harvard University in Boston, MA, found that they also improved the function of dopamine transporters (DAT) and mitochondria. Dopamine transporters are specialized proteins that carry the neurotransmitter dopamine. The researchers examined the brains of five subjects, all of whom had received injections of fetal cells when they were already in late stages of PARKINSON’S DISEASE. These subjects had died from causes other than PARKINSON’S and had given permission for their brains to be examined post mortem.
Fetal cell transplantation into the brains of people with PARKINSON’S DISEASE has a controversial history. Transplanted cells have previously been shown to follow the same path of deterioration that occurs in the subjects’ own cells. Transplanted cells also have been shown to develop Lewy bodies, the abnormal small inclusions of alpha-synuclein associated with the dementia sometimes seen in PARKINSON’S DISEASE. For these reasons, cell transplant therapy for PARKINSON’S DISEASE has been rather controversial. Additionally, the cells utilized in this currently reported study were derived from aborted fetuses, albeit with maternal approval for their use in research, but still a significant ethical issue in the United States, This study was performed 14 years ago in Canada. According to Dr. Isacson, only about 25 people have received this particular method of cell transplantation in the last two decades.
In this study, the researchers sought to understand the long-term interactions on the transplanted cells including the aging process. They specifically examined the dopamine transport (DAT) system and mitochondrial function as a means of neuronal expression. They examined both the transplanted cells and the dopamine producing cells of the patient’s own brain. The transplanted cells had remained healthy and free of the disease process, while the patient’s own cells showed the marked progression of the disease. Previous studies by other investigators have not shown the same results. Dr. Isacson suggests that perhaps it is the method of transplantation that improves the outcome.
Cell replacement therapy for PARKINSON’S DISEASE has the potential to provide better therapeutic treatment by replacing diseased and damaged neurons with healthy and functioning new ones. But there is as yet much that is not known about either the disease process itself or how transplanted cells can successfully graft into diseased tissue and restore function. Some studies using fetal cells have shown the transplanted cells do provide limited therapeutic benefit, alleviating some of the symptoms, however, the disease continues to progress, the cells were not a cure. Obtaining sufficient cells from aborted fetuses is also an ethical dilemma. Dopamine producing cells laboratory grown from embryonic stem cells also have a less than perfect record, while some recipients have benefited, others have seen the cells multiply to form tumors. Other attempts to grow stem cells from fibroblasts found in skin or from bone marrow have shown only limited success. More basic research is needed to understand both the genetics and biological processes involved for cell replacement.
Hallett et al., Long-Term Health of Dopaminergic Neuron Transplants in Parkinson’s Disease Patients, Cell Reports (2014), http://dx.doi.org/10.1016/j.celrep.2014.05.027 (article in press)
Review by Marcia McCall
Exenatide Trial Shows Promise to Help Motor and Cognitive Function in PD
Exenatide is a medication that has been around for quite some time; originally it was used as a treatment for Type 2 diabetes. The method of action of this drug appeared to be neuroprotective, even possibly stimulating the growth of new nerves, which drew the attention of researchers working on PARKINSON’S DISEASE.
Early studies in animal (mouse) models of PARKINSON’S DISEASE showed that exenatide enhanced the effects of levodopa and slowed the development of dyskinesias, the uncontrolled movements that are often caused by levodopa.
Since exenatide had already received Food and Drug Administration as a safe and tolerable medicine, the way to human trials was shorter. A small trial was conducted by a team lead by Thomas Foltynie, M.D. PhD. at University College of London where he is a Senior Lecturer in the Unit of Functional Neurosurgery. He has specialized in Parkinson’s research since 2003. This trial consisted of 44 subjects, 20 who given exenatide to take in addition to their regular Parkinson’s medications and 24 individuals who also had Parkinson’s, but did not receive exenatide and served as controls. The subjects who received exenatide took 20 micro grams twice a day for 12 months.
At the end of the 12 months, the subjects who had taken exenatide showed significant improvement in both motor and cognitive performance over those who did not using the Unified Parkinson’s Disease Rating Scale (UPDRS). At 14 months, two months after discontinuation of the drug, the subjects were again tested and the exenatide treatment group was still maintaining their improvement. One year after the end of the treatment time both groups were again re-evaluated and the exenatide treatment group continued to show significant benefit in both motor and cognitive function tests. The control group continued to show a slow deterioration, as would be expected with PARKINSON’S DISEASE.
Dr. Foltynie commented, “We found that patients on exenatide appeared essentially unchanged throughout and beyond the trial period, while the control group had the expected rate of gradual decline in movement and cognitive ability.” He believes that the promising results of this small trial need to be repeated in future, larger double blind trials
This project was funded by The Cure Parkinson’s Trust, a United Kingdom foundation founded in 2005 with the goal to raise money to fund PARKINSON’S DISEASE research. Their funded projects have included research on GDNF, alpha-synuclein and the role of calcium channels in PARKINSON’S, among other prospects for treatment. Tom Isaacs, the foundation president says, “Although we have to remain cautious on the estimation of these results, we are encouraged by the findings. This is the first time that I have come across a program that has the potential to make an enduring change in PARKINSON’S patients and we are excited by the potential of this scientific research.”
ciar Aviles-Olmos, MD, PhD; John Dickson, PhD, Zinovia Kefalopoulou, MD, PhD; Atbin Djamshidian, MD, PhD; Joshua Kahan, BSc; Peter Ell, FmedSci; Peter Whitton PhD; Richard Wyse; Tom Isaacs; Andrew Lees, MD, FRCP; Patricia Limousin, MD, PhD; and Thomas Foltynie, MRCP, PhD. Motor and Cognitive Advantages Persist 12 Months After Exenatide Exposure in Parkinson’s Disease. Journal of Parkinson’s Disease, May 2014 DOI: 10.3233/JPD-140364
Peter Whitton, Ph.D.; Stimulating the brain’s natural defences to stop nerve cell death – research project summary (PDF, 115KB)) – See more at: http://www.parkinsons.org.uk/content/diabetes-drug-potential-parkinsons#sthash.TNfWR3xr.dpuf
Review by Marcia McCall