The 2006 Parkinson's Unity Walk Funds Research Grants
Through the generous support of its corporate sponsors, 100% of all donations made to the Parkinson's Unity Walk are distributed among the major U.S. Parkinson's disease foundations for Parkinson's disease research. The foundations include: (1) American Parkinson Disease Association; (2) the National Parkinson's Foundation; (3) the Parkinson's Action Network; (4) the Parkinson's Disease Foundation; (5) the Michael J. Fox Foundation for Parkinson's Research; (6) The Parkinson Alliance; and (7) the Parkinson's Institute.
We are excited to share with you information about the following grants —all of which are made possible from 2006 Parkinson's Unity Walk distributions. We will update the grants with progress reports as they are made available to us. In September 2007, updates to several grants were provided to us. Those updates are indicated below in red.
1. The American Parkinson Disease Association is using its distribution to fund:
Grant awarded to: Chad Rienstra, PhD
Project Title: Structural studies of membrane-bound a-synuclein by 3D solid-state NMR
Project Description: a-Synuclein (a-S) is the primary component of Lewy bodies, the pathological hallmark of Parkinson’s disease (PD). The mechanisms of a-S aggregation are not well understood at atomic resolution detail. A variety of evidence supports the hypothesis that the membrane-associated state of a-S is involved in PD progression; for example, specific types of lipids promote a-S aggregation, and lipids have been found in Lewy bodies. In addition, a-S is known to adopt a helical structure when in association with membranes. We hypothesize that this is the physiologically functional form of a-S, and the specific ways in which the structure change due to mutation are likely related to PD progression. In this study, vesicle-associated WT a-S and the PD-related mutant A30P will be studied by SSNMR. High-resolution structures obtained will improve theunderstanding of the relation of membrane-bound a-S to PD pathogenesis, potentially revealing new therapeutic targets and strategies.
September 2007 Project Update:
The goal of the project is to determine the atomic-resolution, 3D structure of vesicle-bound a-S using magic-angle spinning (MAS) solid-state NMR (SSNMR). Evidence supports the hypothesis that the membrane-associated state of a-synuclein is involved in PD progression. Specific types of lipids promote a-S aggregation and lipids have been found in Lewy Bodies. In addition, a-S is known to adopt a helical structure when association with membranes. The hypothesis is that the physiologically functional form of a-S and the specific ways in which the structure change due to mutation are likely related to PD progression. High resolution structures obtained will improve the understanding of the relation of membrane-bound a-S to PD pathogenesis, potentially revealing new therapeutic targets and strategies.
Grant Awarded to: Evan Snyder, MD, PhD
Project Title: Human Neural Stem Cells for Dopamine Reconstruction – Spontaneous vs. Directed Differentiation.
Project Description: The developmental stage of stem cells is most efficient for restoring dopaminergic function in vivo: human neural stem cells (hNSCs) or human embryonic stem cells (hESCs). The transplantation of (hNSCs) into MPTP-lesioned monkey model is a valid therapeutic strategy leading to functional recovery. The number of grafted animals will be increased and further systemic and comparative transplantations will be performed. The aim will be to further define the cellular mechanisms that led to stem cell based functional recovery in the MPTP lesioned monkeys. The hNSCs (undifferentiated vs predifferential) to hESCs. The additional mechanisms besides cell replacement that stem cells display while reciprocally interacting with the host tissue will be investigated. The conditions that influence stem cell migration and stem cell based neuroprotection that promote functional improvement will be defined. A powerful new organotypic slice co-culture model has been established to address the mechanics of the studies being performed. In the rodent model co-culturing of the ventral midbrain (containing the substantia nigra) together with striatal tissue will be able to maintain the whole ventral midbrain including the substantia nigra on both sides and allow the reconstruction of important aspects of the nigro-striatal pathway in vitro. Ultimately allowing a better understanding of cell replacement and neuroprotection of DA neurons under specific conditions (e.g. stem cell grafting, MPTP application ,neeuroprotection with FGF-20).
September 2007 Project Update:
Evidence was found that more plastic undifferentiated hNSC’s are in fact an effective and restorative strategy in the well-established MPTP-lesioned primate model of PD. In this study undifferentiated hNSC’s were transplanted into an adult male primate which received systemic MPTP injection before in order to cause selective permanent bilateral destruction on midbrain DA neurons and striatal projections, depletion od DA concentrations and signs of parkinsonism. After the severity of parkinsonism was confirmed with a behavioral scoring method, human NSC’s were injected stereotaxically bilaterally into the right substantia nigra (SN) and caudate nuclei. Five primates injected with hNSC were compared with three that received placebo injections and were observed for four months pre and post after surgery. The severely-affected hNSC-grafted primates improved progressively and were significantly different from controls for the entire post treatment period. These differences were highly significant functionally as well as statistically and included activities of daily living, such as the ability to walk, sit, and self-feed compared with the placebo subjects, who were unable to do so. None of the grafted primates developed dyskinesias. The data suggest that the primate CNS may benefit from human stem cell derived replacement of missing cell types (including neurons) and from supportive effects of other stem cell-derived progeny that may be necessary for promoting optimal recovery via the variety of mechanisms described.
2. The National Parkinson Foundation is using its distribution to fund the following:
Grant Awarded to: Katherine Sturm-Ramirez, Ph.D. – St. Jude Children’s Research Hospital
Project Title: “Is H5N1 influenza virus a novel etiological agent in the development of experimental parkinsonism?”
The etiology of Parkinson’s disease is multivariate, ranging from identified generic mutations to strict environmental causation and exposure to viruses. Most influenza infection in humans cause respiratory disease, but occasionally the brain can also be affected. The greatest influenza pandemic of the 20th century, the Spanish Flu, occurred in 1918. It is estimated that about 25-30% of the world population was infection and upward of 40 million people died in less than a year. About the same time, the world was hit by an unusual epidemic of neurological diseases. Circumstantial and epidemiological evidence links post-encephalitic Parkinsonism to the 1918 influenza pandemic, but a causal link was never formally proven as the pandemic occurred before the advent of modern virology. Interestingly, the virus that caused the Spanish Flu pandemic was recently resurrected in the laboratory and detailed analysis shows that it was most likely an avian influenza virus passed directly from a bird to a human, followed by mutations allowing this strain to efficiently transmit from human to human. In light of the recent events involving another avian influenza strain, the highly pathogenic H5N1, this finding is of great concern. With the current risk of a human influenza pandemic due to H5N1 that is currently spreading rapidly throughout the world, the potential for another outbreak of post-encephalitic parkinsonism is significant. In this application, we propose to investigate if infection with avian H5N1 influenza viruses can either directly or indirectly lead to the death of neurons in the substantia nigra pars compacta, a hallmark of Parkinson’s disease in a mammaliam species.
September 2007 Project Update:
The etiology of Parkinson’s disease (PD) is diverse. PD has been shown to be caused by genetic mutations, exposure to environmental toxins as well as following infection (postencephalic PD). One such infection is influenza. Although influenza infection generally causes respiratory disease, it can occasionally affect the brain. During the 1918 avian influenza pandemic, approximately 25% of the world’s population became infected. Shortly afterwards, around 1920, an unusual epidemic of neurological diseases was observed, including post-encephalitic Parkinsonism (PEP). A causal link with influenza has been suggested by epidemiological studies and is of great concern considering the current global spread of the highly pathogenic H5N1 (Bird Flu) virus. H5N1 viruses can infect the nervous system of mammals. Thus, if H5N1 were to become pandemic, another epidemic of PEP could ensue. This project examined if H5N1 can directly or indirectly lead to death of neurons in the brain, including those in the substantia nigra, the neuronal population most associated with PD. We studied mice in this project since they are an excellent models for influenza infection as well as PD. As has been observed in humans, we found that about 1/3 of the mice infected with H5N1 developed neurological symptoms such as loss of balance and other motor problems similar to those seen in PD. Examination of the brain from these mice showed widespread dissemination of the H5N1 virus at all levels of the nervous system, including the basal ganglia (one of the brain structures affected in PD). We also examined if the presence of H5N1 in the brain caused neurons to die. We used a marker of cell death called activated caspase-3. We found activated caspase-3 in the nervous system in regions where H5N1 was detected. At this time, we do not know if the cells expressing activated caspase-3 are the same cells that are H5N1 positive or if the presence of the H5N1 is toxic to cells in its immediate environs. Nevertheless, this work has shown that the H5N1 virus, which at this time has the greatest influenza pandemic potential, can both infect and cause cell death in the CNS including the structures affected in PD. This suggests that if H5N1 were to become pandemic, a post-influenza consequence could be a sharp increase in encephalitic parkinsonism.
Grant Awarded to: Michael S. Okun, M.D. – University of Florida College of Medicine
Project Title: “The MOST Study: Mood and STN DBS”
Unilateral and bilateral STN DBS have become a common treatment for medication refractory PD patients. Following STN DBS, practitioners have documented worrisome mood and behavioral side effects including depression, anxiety, mania, obsessive-compulsive behavior, and suicidality. The purposes of this study are: 1) to characterize the mood and behavioral changes following unilateral and bilateral STN DBS, 2) to determine if they are more common in unilateral or bilateral STN DBS, 3) to characterize the patient profile of those at greatest risk of acquiring these side effects, and 4) to improve and document the effective treatment strategies for patients experiencing these effects.
September 2007 Project Update:
The research is prospective and blinded between sites, thus there are no results that can be reported. The UF site has met enrollment criteria of ten patients per year during the first and second year of the study. The Mt. Sinai site has enrolled eight during year two for a total of eleven. Mt. Sinai has a plan for year three to recruit the requisite number of patients for the study.
The research is ongoing, but important for safety and targeting in PD surgery. The research will define the mood and behavioral effects of DBS in STN. There are few studies despite the widespread use of DBS. There are no studies available to patients and practitioners looking at the important use of staging procedures. The knowledge obtained in this study may provide information essential to patient selection, surgical target selection, and improved patient management. Such knowledge is significant as non-motor effects of DBS may have a larger impact than the motor effects when considering quality of life and overall function.
3. Parkinson's Action Network (PAN), founded in 1991, is the unified education and advocacy voice of the Parkinson's community, fighting for a cure. Through education and interaction with the Parkinson's community, scientists, lawmakers, opinion leaders, and the public at large, PAN works to increase awareness about Parkinson's disease and advocates for increased federal support for Parkinson's research.
PAN also provides the information and resources necessary to empower people with Parkinson's disease to act on their own behalf and gain a greater sense of control over their health and their future. For more information on PAN, please see its website at www.parkinsonsaction.org.
4. Parkinson’s Disease Foundation is using its distribution to fund the following:
Investigator: Katherine J. Franz, PhD Duke University, NC
Project Title: Design and Synthesis of ROS-Sensitive Iron Chelators
In Parkinson’s disease, dopamine-producing cells within the substantia nigra region of the brain experience increased levels of oxidative stress that result in cell malfunction and eventually cell death. Whereas iron is an essential and beneficial component of healthy cells, in diseased cells it can be a dangerous ingredient that causes oxidative stress by combining with oxygen to produce reactive oxygen species (ROS) and free radicals. We are designing chelating agents that will sequester and inactivate this detrimental iron. Unlike typical antioxidants that neutralize free radicals only after they are produced, effective iron chelators can potentially switch off production of harmful radicals altogether by disabling the source.
Our strategy to design targeted iron chelators as therapeutic agents for Parkinson’s disease is to develop “masked” chelators that will trigger only under conditions of oxidative stress. A common toxicity issue associated with currently available chelation therapies is their side reactions that alter healthy metal distribution. In the absence of oxidative stress, the masked chelators will be innocuous bystanders that will not interfere with beneficial metals. Disease conditions that elevate oxidative stress, however, will activate and unmask a potent chelator that can selectively sequester the destructive iron that is the source of ROS generation. In order to achieve this goal, our primary focus is to develop the chemistry required to assemble and characterize this new family of molecules designed to inhibit oxidative stress in Parkinson’s disease.
Investigator: Peter Teisman, PhD University of Aberdeen, Scotland
Project Title: S100B- the main culprit of RAGE (receptor for advanced glycation endproduts) mediated cell death?
Parkinson’s disease is a common neurodegenerative disorder of unknown origin. Major symptoms are tremor, muscle stiffness, paucity of voluntary movements, and postural instability affecting not only the patient, but also relatives and people involved in the care of these patients. The symptoms are due to the death of brain cells, called dopaminergic neurons.
These cells release dopamine, which is necessary to perform normal motor function. As of today it remains unknown (except for genetically inherited cases, making about 20% of all cases) why these neurons die and lead finally to Parkinson’s disease. The most potent treatment for Parkinson’s disease remains the administration of a precursor of dopamine, L-DOPA, which, by replenishing the brain with dopamine, alleviates almost all Parkinson symptoms. But treatment with L-DOPA leads to side-effects which are eventually as debilitating as Parkinson itself. Therefore it is an urgent need to acquire a deeper understanding how the disease develops to find treatments aimed at halting or slowing down the progression of the disease at an earlier stage.
We have recently shown a role for a receptor called RAGE in Parkinson's disease pathologic process. RAGE is a receptor that has also been identified to be involved in Alzheimer’s disease and its activation occurs by a protein family called S100. We investigated the role of RAGE in Parkinson’s disease by the use of a neurotoxin, called MPTP, in mice. Administration of this neurotoxin replicates most of the biochemical and pathological characteristic of Parkinson’s disease in mice. We found, that mice, which lack this receptor, are protected against the toxin, thereby indicating an important role for RAGE in the pathogenesis of Parkinson’s disease. We also found, that S100, as indicated a ligand for RAGE, is increased after MPTP. One protein seems to be of major importance: S100B.Mice, which lack S100B expression will be injected with MPTP and we will investigate, whether these mice are protected against the toxin. We will further investigate, whether S100B mediates its effect via RAGE, or if different pathways are involved in S100B mediated cell death. Not only will the proposed study help us to understand the pathogenesis of Parkinson’s disease in a better way, but it can also lead to the development of new therapeutic strategies in preventing the occurrence of Parkinson’s disease.
September 2007 Project Update:
This group looked at a neuronal receptor called RAGE that has already been shown to be pathogenic in Alzheimer’s disease. Thus their aim seems to be neurodegeneration and prevention of same. This receptor is activated by a mediator or ligand called S100B, one of a large known family. Transgenic mice injected with the neurotoxin MPTP were used to learn which might be protected against the toxin among the litter. I believe the receptor (RAGE) to be heterozygous, since they were able to use healthy littermates as their control animals. (If I am correct, then only one allele is transferred from the parent thus the animals are appropriate controls.)
Investigator: Xiaoxi Zhuang, PhD University of Chicago, IL
Project Title: A Transgenic Mouse Model to Test Dopamine Toxicity Induced Neurodegeneration
We have generated a transgenic mouse line with inducible expression of DAT in forebrain, especially striatal, neurons. We predict that uptake of dopamine by these cells will lead to dopamine toxicity and cell death due to the lack to protective machineries that pack cytosolic dopamine into vesicles. The proposed studies represent the first step in validating such a model.
September 2007 Project Update:
Dr. Xiaoxi Zhuang and his colleagues have made an extraordinary contribution to our present knowledge of the beneficial vs detrimental effects of levo-dihydroxyphenylalanine (levodopa). If their data prevail as experiments move up the chain, they explain why the drug, though it remains the gold standard for symptomatic therapy in patients with Parkinson’s disease, is used as late as possible in diagnosed patients by those neurologists with wide experience.
Though it is not the dopamine cycling throughout the brain, it seems that it is the dopamine captured in the cytosol that is the neurodegenerative culprit. Cytosolic dopamine is both oxidated and autoxidated, and, because PD causes a decrease in total glutathione, cannot be easily handled by the ubiquitin-proteasomal system. It thus sits there and causes cell death.
We do not yet know the cause(s) of the failure of the cellular regulatory mechanisms (that protect the healthy brain) in idiopathic disease. Such causes may prove to be genetic (other than the specific genetic forms of parkinsonism already identified), environmental or both/other. But this group’s research accomplishment will help future scientists to determine the pathways to the ultimate goal: neuroprotection
5. The Michael J. Fox Foundation for Parkinson's Research will use its grant toward the Community Fast Track initiative, Target Validation Initiative, and Clinical Discovery Program.
Under the Community Fast Track Initiative, researchers are invited to submit investigator-initiated grant application to conduct new, novel or innovative research relevant to the cure, cause, prevention, or improved treatment of PD and its complications. As soon the 2006 awards are made public they will be posted.
The projects being funded under the Target Validation Initiative are:
Mathias Baehr, MD, of University Hospital Göttingen (Germany) and colleagues will work to validate recent studies showing that G-CSF (granulocyte-colony stimulating factor) — a drug already approved for use in cancer patients — can protect dopamine neurons in mice exposed to the PD toxin MPTP.
Benjamin Wolozin, MD, PhD, of Boston University School of Medicine will screen for compounds that protect against oxidative stress in the forkhead transcription factor pathway, which regulates expression of antioxidant genes, potentially providing an umbrella of protection against oxidative stress in PD.
Two separate awardees — Valina Dawson, PhD, of Johns Hopkins School of Medicine and Richard Eglen, PhD, of DiscoverRx Corporation — will independently identify small molecules that can bind to and inhibit LRRK2 enzymatic activity. Overactivity of LRRK2 is associated with both familial and sporadic forms of Parkinson's.
Michael Schlossmacher, PhD, of Harvard Medical School will screen small molecule libraries for compounds that can either reduce expression of the protein alpha-synuclein or increase expression of the protein parkin. Reducing alpha-synuclein may block formation of toxic aggregates, while increasing parkin has been shown to be protective in PD models.
Mona Thiruchelvam, PhD, of Robert Wood Johnson Medical School will screen non-feminizing estrogen analogs (synthetic or natural chemical compounds that resemble naturally occurring estrogens, but eliminate some potentially adverse side effects) for their ability to protect dopamine neurons in culture. The evidence for estrogen’s neuroprotective potential is considerable: Epidemiological data demonstrate a lower risk of PD in women than in men; estrogen replacement therapy further reduces risk; and protective effects of estrogen have been seen in animal models of PD.
Other teams will investigate potential approaches to alleviate the symptoms of Parkinson's and/or reduce levodopa-induced dyskinesias:
Alan Kopin, MD, of Tufts-New England Medical Center, will screen small molecule compounds to detect chemical activators of GRP88, a novel receptor whose location and similarity to certain other receptors suggest that it may play a role in modulating motor function. GRP88 is expressed almost exclusively in the striatum, a region of the brain that becomes impaired with the dopamine loss characterizing PD.
Cecilia Lundberg, PhD, of Lund University (Sweden), will use a gene therapy approach to target the enzyme GAD67, which may be responsible for basal ganglia overactivity that potentially underlies the disease’s motor symptoms.
Erwin Bezard, PhD, of the University of Bordeaux (France) and colleagues will use gene therapy to deliver proteins called GRKs to the brains of dyskinetic animal models. GRKs limit the duration of dopamine signaling, and their levels are reduced in animal models of dyskinesia as well as in postmortem brain tissue from dyskinetic Parkinson's patients.
Gretchen Snyder, PhD, of Intra-Cellular Therapies, Inc., will investigate strategies to boost the strength of any remaining dopamine in the PD brain by targeting the enzyme phosphodiesterase 1B, which is normally involved in regulating dopamine signaling in the brain.
The projects being funded under the Clinical Discovery Program fall into three categories: improving existing therapies, addressing unmet needs of Parkinson's patients and understanding Parkinson's etiology and pathogenesis through studies in patient populations.
Improving Existing Therapies
Eliahu Heldman, PhD, chief scientific officer of NeuroDerm, Ltd., an Israeli biotech firm, will develop a transdermal skin patch for continuous delivery of levodopa and conduct initial testing in human subjects. Continuous dopamine delivery systems have generated a great deal of interest among Parkinson’s researchers, because it is hypothesized that dyskinesias — disruptive, jerky movements associated with long-term levodopa therapy — result from the sharp fluctuations in dopamine blood levels that characterize oral administration of levodopa. But to date, all attempts at achieving continuous delivery have proved impractical or infeasible, and attempts to deliver levodopa transdermally have failed because, among other reasons, the drug is unstable and cannot penetrate the skin. NeuroDerm has innovated a system involving stabilizers and skin penetration enhancers, and has demonstrated early success in animal models, maintaining steady therapeutic levodopa bloodlevels with no intolerable side effects.
Robert Chen, MA, MBBChir, MSc, FRCPC, of Toronto Western Research Institute, will focus on understanding the mechanism of action in deep brain stimulation (DBS) surgery and identifying ways to improve on current stimulation approaches. Dr. Chen's team will examine electrical activity recorded directly from the basal ganglia (an area of the brain whose abnormal functioning is related to Parkinson's) in patients undergoing DBS surgery. This will allow the researchers to determine the specific clinical effects of DBS in each individual. The results will lead to greater understanding of the functional organization of the basal ganglia, potentially improving current DBS approaches and expanding the population of patients who could benefit from stimulation-based treatment.
Addressing Patients' Unmet Needs
Three projects reflect the Foundation's commitment to drive research into “dopamine non-responsive” Parkinson's symptoms, an array of troubling, largely non-motor aspects of the disease that many patients call more distressing than the better-known motor symptoms — but that nonetheless remain under-researched and poorly understood.
Meg Morris, a physical therapist on the faculty of the University of Melbourne, Australia, will conduct a rigorous clinical study to test physical therapy approaches that could potentially prevent and treat falls in Parkinson’s patients. Results from this study could provide clinicians with a validated strength training and educational approach to limit falls and improve patients’ postural stability.
Jau-Shin Lou, MD, PhD, of Oregon Health and Sciences University, will investigate the physiological mechanisms responsible for fatigue, a common Parkinson's symptom that dramatically detracts from quality of life.
Emily Wang, PhD, of Rush University Medical Center, will test a device that provides patients with altered auditory feedback to improve speech problems, common in people with Parkinson’s. Patients wear the device in one ear and hear their own speech through it after a short time delay and with a shift in pitch while they speak. In preliminary testing, seven of eight patients who used the device made significant improvements in their speech, allowing them to express themselves more effectively with their families, caregivers and physicians. The researchers will next test the device for both short- and long-term gains in 20 patients over the course of one year.
Understanding Parkinson’s Etiology and Pathogenesis
Jonathan Haines, PhD, of Vanderbilt University has identified a population of Ohio Amish in which several individuals are affected with Parkinson’s. He has completed initial work in this population to identify what he believes to be three novel genetic alterations associated with Parkinson’s, and will next attempt to find a novel causal gene for the disease.
Brad Racette, MD, of Washington University in St. Louis, will conduct a detailed study on the purported relationship between exposure to welding chemicals and Parkinson’s risk. Specifically, working with a cohort of welders, Dr. Racette will correlate lifetime exposures to welding chemicals with risk for Parkinson’s. Additionally, he will conduct neuroimaging studies on asymptomatic welders to determine whether they demonstrate any damage to the nigrostriatal system.
6. The Parkinson Alliance is using its distribution to fund the following:
Investigator: The Laboratories of Michael Jakowec, PhD, and Giselle Petzinger, MD., Department of Neurology, University of Southern California.
The adult brain possesses a tremendous capacity to change in response to environmental cues including learning, memory, and injury. This phenomenon is termed neuroplasticity. One of the key areas of focus of research in our laboratories is to find ways by which we can guide neuroplasticity in the adult brain in order to overcome injuries to the basal ganglia, an area of the brain affected in Parkinson's disease. Our recent studies in an animal model of Parkinson's disease have shown that intensive treadmill exercise plays a critical role in overcoming many of the motor deficits seen in this model. In collaboration with a number of investigators at USC, we are studying the molecular mechanisms responsible for this observation. At this point we know that there are significant changes in how the brain handles dopamine including alterations in the pattern of expression of receptors that normally bind this important neurotransmitter. In addition, we have found that despite a severe depletion of dopamine, similar to that which may exist in Parkinson's disease, exercise is to change how the brain releases dopamine from remaining nigrostriatal terminals. This new way to handle dopamine may be one mechanism by which the brain is able to compensate for injury leading to improvement in motor function. We have also found significant alterations in other neurotransmitter systems in the injured brain with exercise, including changes in the expression of pathways that use both glutamate and serotonin, two systems that may lead to altered dopamine function in recovery.
An important need in our Parkinson's Disease Research Program is to improve our capacity to carryout critical electrophysiological studies of individual neurons within the injured basal ganglia of our models of Parkinson's disease. In close collaboration with Dr. John Walsh in the Andrus Center for Gerontology here at USC, we are carrying out such investigations. By studying single cells we are able to dissect their molecular profile and directly compare those whose recovery has been enhanced by exercise with those that have not. The addition of a new state-of-the-art camera to our existing equipment will allow us to improve the precision and impact of our studies. Under high magnification the new camera will assist us to probe deep within the basal ganglia, target individual neurons, gather their electrophysiological characteristics, and remove their sub-cellular contents for the molecular analysis of genes and proteins responsible for their altered function. Such information will reveal to us the important mechanisms responsible for exercise enhanced recovery of motor behavior within the injured brain and may help identify new therapeutic targets for the treatment of Parkinson's disease.
Project Title: FDDNP-PET as a Surrogate marker in Parkinson's disease
Investigator: Yvette M. Bordelon, MD, PhD, Department of Neurology, UCLA
I was recruited to the UCLA Department of Neurology as an Assistant Professor in November of 2004 after completing my fellowship in Movement Disorders with Dr. Stanley Fahn at Columbia University. I divide my time between clinical work in the Movement Disorders clinic and translational research (bringing the information gained from basic science laboratory investigation into the clinical practice and treatment of Parkinson disease and other neurologic disorders). I believe that we will see dramatic progress in clinical research in the next several years if we are allowed to pursue translational research projects now that will identify promising studies and techniques to expedite and refine the many impending clinical trials in the study of Parkinson disease. This translational research needs to keep pace with the basic science work in order to provide the scientific community and our patients with the meaningful results necessary to further identify the underlying causes of disease and guide disease-modifying treatments for disorders such as PD for which there are no known cures.
Surrogate markers are test results that can be used to measure a certain characteristic of a disease. Surrogate markers can be used to test effectiveness of particular treatments quickly and efficiently in clinical trials. Currently, there are no known surrogate markers for PD but the need to identify them cannot be overemphasized. Brain imaging holds the highest promise in this capacity as it is safe and non-invasive. A powerful imaging technique in the study of neurologic diseases is positron emission tomography (PET). UCLA has a long history in the field of PET imaging and is home to many researchers responsible for the development of novel imaging compounds and techniques. Recently, Dr. Jorge Barrio developed a new PET compound (FDDNP) that labels abnormal protein aggregates in brains of patients with Alzheimer disease. Altered protein processing and accumulation of protein aggregates is emerging as a common process in many neurologic diseases including Parkinson disease. Alpha-synuclein and other proteins aggregate into Lewy bodies in neurons in PD. A surrogate marker for this hallmark of PD would revolutionize the study of the disorder and expedite the identification of potentially curative therapies. We are now planning to conduct a pilot study using FDDNP-PET in patients with PD. If FDDNP-PET is able to identify abnormal protein accumulation in PD patients, the effects on the world of PD clinical trials would be far-reaching. We plan to use the funds contributed by Team Parkinson to obtain these FDDNP-PET scans in PD patients for the pilot study examining it as a possible surrogate marker in Parkinson disease. The data collected from this pilot study will then be used to apply for a federal grant to support a large project examining this technique further. The support from Team Parkinson is greatly appreciated and will have a significant impact on the conduction of this important line of research.
Project Title: Motor control studies at UCLA
Investigator: Dr. Allan Wu
The UCLA Motor Control Laboratory, under the direction of Dr. Allan Wu, within the Division of Movement Disorders, Department of Neurology, will research transcranial magnetic stimulation (TMS) studies in Parkinson's disease (PD) patients.
The goal of the UCLA Motor Control Laboratory is to apply motor control principles toward the assessment of movement problems in PD patients. Such principles have the potential to be objective markers of parkinsonian impairment which can then be used to characterize different stages of PD or to assess responses to therapy. The laboratory studies motor control by analyzing goal-directed actions (reaching, grasping, pointing) using a 3-dimensional motion capture system. Transcranial magnetic stimulation
(TMS) now adds the ability to investigate the neural basis for these motor control principles.
TMS uses a brief magnetic field to noninvasively and painlessly stimulate the human brain. When TMS is applied over a given brain region during the planning or execution of a goal-oriented action, the resulting effects on that action provide information about the role that brain region plays in generating that particular movement. When applied over the motor cortex, TMS can evoke a muscle twitch. By monitoring this muscle twitch, we can obtain direct information about the activity of the motor output circuit when planning or executing movements. By examining differences in TMS effects between PD patients and normal subjects, we increase our understanding of the neural basis of normal motor control of voluntary movements and how this neural system is altered in Parkinson's disease.
Project Title: Neuropsychiatric behaviors/compulsive behaviors in Parkinson's disease and the neuroimaging component of a large trial evaluating the effects of exercise in PD.
Principal Investigator: Dr. Jennifer S. Hui, MD with the division of Movement Disorders at the University of Southern California:
Non-motor symptoms of Parkinson's disease: Mood, Cognition, and Behavioral Changes:
Although non-motor symptoms are often not well-recognized in Parkinson's disease (PD), they can be even more disruptive and disabling than the motor manifestations of the disease in up to 30% of patients. These non-motor symptoms include changes in mood, memory, cognition, and behavioral changes such as obsessions and compulsions.
Recent increased awareness of certain compulsive behaviors in PD has highlighted the potential role of medication in the manifestation of these behavioral changes. In particular, dopamine agonists have been implicated in compulsive gambling, shopping, eating and hypersexuality. These behaviors have not been studied in detail, and the risk factors for developing these behaviors are unknown.
Dr. Hui has been studying these behaviors in PD, and is developing an easily administered confidential questionnaire for the screening and detection of compulsive behaviors in PD. It is important to recognize these behaviors early on, because they can be alleviated by simple medication changes. A questionnaire will allow for earlier and confidential reporting of these symptoms, on topics which may be of a personally sensitive nature to patients. Additionally, identifying risk factors for these behaviors will lead to more appropriate, therapeutic choices.
To many PD patients, the non-motor symptoms of their disease are under-recognized, yet significantly impact quality of life. Research in this area is often overlooked and under-funded, making support for these projects more important for the comprehensive treatment of PD.
Fallypride imaging in Parkinson's disease:
The adult brain at all stages of life possesses tremendous capacity for repair, which is called neuroplasticity. It is known that exercise after brain injury has a tremendous influence on guiding repair. Recent studies from our department strongly support that exercise, particularly intensive treadmill training, can influence symptoms of Parkinson's disease (PD). For example, studies utilizing intensive treadmill training exercise in both patients and animal models of PD show motor benefit. As a means to optimize the effect of treadmill training in humans, we have employed body weight supported treadmill training which allows a patient to practice normal walking parameters at a high velocity and over an extended period of time. The body weight supported treadmill training (BWSTT) is a motorized treadmill in which the subject wears a harness and then a percentage of the patient's body weight is supported or taken up.
We will be undertaking a trial evaluating the effects of BWSTT therapy in early PD and incorporating an imaging component to ascertain whether this intervention will lead to changes within brain regions known to be affected by PD. To test this hypothesis, individuals will be examined using Positron Emission Tomography (PET) imaging, a noninvasive radiological method for imaging brain function/metabolism. These PET imaging studies will utilize a unique, state of the art, labeled tracer called Fallypride. This state of the art approach to imaging has many advantages over traditional imaging for PD which is typically performed using the tracer fluorodopa. Fallypride scans allow for a higher resolution image that is more specific for the brain changes in PD.
The funding will assist in assessing the validity and reliability of this new imaging ligand as a potential tool for studying the brains of PD patients in an exercise paradigm.
7. The Parkinson’s Institute is using its distribution to fund the following:
Project Title: Mutation screening of genes for monogenic Parkinson’s disease in a large clinic-based cohort
Background and Significance: Since the discovery of mutations in the alpha-synuclein gene, at least four other genes, Parkin, PINK1, DJ-1, and LRRK2, have been reported to cause monogenetic forms parkinsonism. Changes in Parkin, PINK1, and DJ-1 result in early-onset parkinsonism with an autosomal recessive inheritance pattern, whereas LRRK2 and alpha-synuclein typically show a dominant pattern of inheritance. To date, clinical detection of mutations in these genes has not had direct medical or therapeutic consequences for a patients and the role for genetic counseling in most of these cases has yet to be clearly defined. However, if a targeted therapy for these genetic forms becomes available in the future, it will be of outmost importance to detect these patients and carriers. Furthermore, a specific mutation in the LRRK2 gene has now been reported to be present 1.5% of all sporadic causes of PD, making it the most common form of typical parkinsonism in which we know the cause.
The goal of this study is to answer critical questions regarding the overall contribution of mutations in the different genes in a movement disorders clinic. Given the increasing number of mutations that can contribute to the a parkinsonian phenotype, and the increasing complexity of their manifestations, the time has come where we urgently need to define their exact contribution to Parkinson’s disease and related movement disorders. Gaining such knowledge is of obvious importance to better understanding the cause or causes of movement disorders; the results of this work also has direct implications for affected individuals, both in terms of potential therapeutic outcomes of research on specific mutations, and in terms of implications for future generations who may be at risk for disease. In addition, the research proposed here will allow for careful clinical studies of the phenotype, which could ultimately make it possible to predict a certain gene to be involved in the disease process. To answer these crucial questions, we plan to collect clinical data as well as blood for DNA extraction from all patients followed in the outpatient clinic of the Parkinson’s Institute, as well as a substantial number of controls.
This study is novel in that previously reported studies have been subject to referral biase or were consortia with highly selective referral criteria, so that these numbers may not reflect the mutation rate in the general population. While the planned study will not be truly population based, it will come closer to obtaining a realistic view of the genetic contributions to Parkinson’s disease and related disorders, as we plan to screen all clinic patients. Furthermore, with this large clinical and genetic screen, we have a realistic possibility of developing guidelines for neurologists to make predictions regarding molecular testing and would help to prioritize what genes need to be tested.
In July 2005, we launched an initial screen to test several populations at the Parkinson’s Institute for 35 known mutations in the different genes for monogenic parkinsonism; in addition we sequenced the Parkin gene completely in these populations. We screened 299 patients from four different cohorts in our outpatient clinic, which were as follows: (i) 21 patients with early onset PD with age of onset < 40 year old, (ii) 38 probands with a positive family history for PD (defined as one or more 1st degree relatives with PD, (iii) 228 patients with typical, late-onset PD (> age 50). In addition, we screened 188 samples from our brain bank for the same sequence changes. Control subjects included 284 samples obtained from spouses/friends of patients. Genomic DNA was screened for previously reported mutations in SNCA, UCH-L1, PINK1, DJ-1, and LRRK2. As noted above, the entire coding region of the Parkin gene was sequenced. Similar to other studies, we that the found that the G2019S mutation in LRRK2 was the most common mutation, with approximately a 1-2% frequency. We also found a mutation in the PINK1 gene, which has probably a founder on the Philippines. A manuscript on this finding has been submitted to a scientific journal and is now “in press”.
Methodology and Study Design:
In this study we attempt to recruit every patient in our outpatient clinic. We estimate that approximately 1500 patients will participate, including 50-100 early-onset cases and 150-200 families. The patients will receive an initial package describing the study when they check-in for their appointment. If they are interested in participating, after giving informed consent, they will donate ~ 20ml blood for the genetic testing. For every patient we will also take a short video, which can be later reviewed by a consensus committee to confirm the diagnosis.
DNA will be extracted and an aliquot of the collected blood will be stored under special conditions to be transformed at a later time-point if needed for functional studies.
In this study, we will sequence Parkin, PINK1, and DJ-1 completely including intron-exon boundaries and the promoter region; we will also sequence certain exons of the LRRK2 gene, which have shown to be mutations hot-spots, and test for three known changes in the SNCA gene and gene dosage alterations in Parkin and SNCA. The equipment required for this will include an ABI 3100 capillary sequencer and ABI 7900 HT quantitative RT PCR machine.
When patients talk to geneticists, invariably their most pressing question is “What is the chance that my children will get Parkinson’s?” Neurologists want to know the frequency of the mutations in the different genes and the implications of these changes for their patients. ?” Unfortunately we are not yet to the point that we can definitively answer these questions. With the proposed screen we should ultimately be able to address all of these questions. To date there has yet to be a complete screening of known genes in a large and broad-based movement disorders clinical population. The study planned here has the potential to answer critical questions relate to the frequency and contributions of genetic forms of parkinsonism in a movement disorders practice, and therefore to some degree in the patient population in general. This type of information is very important for the neurological community if they are going to be able to clearly determine the impact of genetics in their practices. Furthermore, these studies are likely to teach us a great deal more about the clinical manifestations of these various forms of parkinsonism, and will likely lead to numerous new research leads in regard to both genetic parkinsonisms as well as the more common sporadic form of the disease. Ultimately this research could have significant therapeutic implications for all of these disorders as well.
September 2007 Project Update:
Progress to date: To date, we have enrolled a total of 736 subjects in our study and have identified 57 families with parkinsonism. All patients were seen at our Clinical Center at the Parkinson’s Institute.
LRRK 2 (PARK 8): In the first phase of this study, DNA samples were tested for the most common mutation for Parkinson’s disease, the LRRK2 G2019S mutation that is found in 1-2% of all sporadic cases. Five familial cases and one sporadic case with Parkinson’s diseases were detected. Three families have multigenerational pedigrees with five or more affected individuals. One is a family of Jewish descent, one family originates from Cuba, and one from Mexico. We are now in the process of carrying out a detailed evaluation of these families that includes administering a standardized set of clinical instruments, including tests for smell, color discrimination, memory, sleep behavior, and mood. Interestingly, the latter family shows a striking anticipation, meaning that there is an age at onset discrepancy for PD of 35+ years. By history, all affected family members with an early onset of symptoms for Parkinson’s disease worked as seasonal workers on farms and in the fields for 6 months per year. This represents the first example of a genetic form of parkinsonism that may have been triggered by environmental toxicants such as pesticide exposure in this family.
PARKIN (PARK 2): In addition to a previously identified family with PARK 2 parkinsonism, during the current study period we identified a new family with Parkin-positive parkinsonism. The age at onset in the proband was 14 years of age. She was found to be a compound heterozygote for a 2bp-deletion in exon 2 on one chromosome, and a complete exon 2 deletion on the other chromosome in the Parkin gene. The paternal grandfather has late-onset Parkinson’s disease and is presumably a carrier of one mutation. This family highlights a very important (and controversial issue regarding the genetics of PARK 2 parkinsonism, and that is the question of whether carriers of only one mutation in the PARKIN gene are more susceptible to PD. We are also investigating this family in more detail.
PINK 1 (PARK 6): We have also identified a known mutation in the PINK1 gene in a patient with a Filipino background (see last year’s report). We believe that this mutation has a founder effect on the Philippines, because it is also seen in a heterozygous state in unaffected controls. This case is notable because of its similarity to another movement disorder called dopa-responsive dystonia (DRD). During this project period, we published a report on this patient that described in detail the clinical characteristics and their differential diagnosis in this PINK 1-form of genetic parkinsonism.
We conclude that approximately 1% of our clinic population has parkinsonism and/or a related movement disorder due to an underlying genetic cause. Two cases were early-onset, both of which had PARKIN mutations. Five had a strong family history, all of whom LRRK2 mutations. In addition, another patient proved to be an apparently sporadic LRRK2 carrier. These results suggest that it is probably not yet warranted to carry out genetic testing in sporadic late-onset PD cases, but, as might be expected, familial cases have a much higher yield of mutations in the known genes for PD. While generalized clinical testing premature, there is no doubt that clinical and basic research on these rare genetic forms of parkinsonism can provide clues on underlying disease mechanisms in all forms of parkinsonism, and clues into factors determine severity, progression, and age at onset. Ultimately, all of the clues have a high probability of leading us to new strategies in therapy for both the genetic and non-genetic forms of the disease. For these reasons, we are plan to continue and expand this important with for a second year with the support of Unity Walk Funding.