Parkinson's disease is a slowly progressive disorder that affects movement, muscle control, and balance. Part of the disease process develops as cells are destroyed in certain parts of the brain stem, particularly the substantia nigra. Nerve cells in the substantia nigra send out fibers to tissue located in both sides of the brain. There the cells release essential neurotransmitters that help control movement and coordination.
The field of movement disorders refers to conditions such as Parkinson's disease (PD), tremor, dystonia, tics, and other involuntary movements. These are complex disorders with genetic and environmental factors contributing to their cause. Movement disorders can be divided into two groups: those that result in too much movement and those that result in slowness or too little movement. One of the most common movement disorders is essential tremor, which is commonly familial and results in shaking of the hands, head, and voice. Another very common disorder is Parkinson’s disease, which is characterized by tremor, slowness of movement, and trouble walking. There are many other neurological disorders that resemble Parkinson's disease and are grouped under the term parkinsonism. While there are some clinical differences, often the only way to make a definitive diagnosis is by autopsy of the brain. Examples of other types of parkinsonism include Progressive Supranuclear Palsy, Multiple System Atrophy, and Cortical Basal Ganglionic Degeneration. Treatment of these syndromes generally consists of the same medications used for Parkinson's disease, although the response is often less satisfactory.
Mayo Clinic neurologists in Arizona, Jacksonville, and Rochester are conducting research investigating many movement disorders. Research is aimed at determining the cause for these disorders as well as finding new treatments that will improve symptoms and eventually slow or stop the progression of these disorders.
Mayo Clinic neurologists are pursuing complex, multiple, and interconnecting investigations with an overall goal of understanding the natural history of Parkinson's disease (as well as other movement disorders), finding its cause(s), and developing better treatments. The continual interaction of individuals and research teams and labs reflects the rapid and constant evolution of research in the field of neuroscience and constitutes an extraordinary strength that we believe is a model for medical research on any disease. Our research is a reflection of the unique collaboration and multidisciplinary work done at Mayo Clinic.
Below is a sampling of some of the current projects and achievements.
Epidemiology and Genetics of Parkinson's Disease
Walter A. Rocca, M.D., is working to clarify the etiology of Parkinson’s disease and to identify means to prevent it in independent but related studies based on different sampling and measurement strategies. The studies will use current work and preliminary findings, along with a control group of 800 cases of PD referred to the Mayo Clinic from a 120-mile radius or from a five-state region and 800 controls free of PD and parkinsonism.
The first is a historical cohort study to test the association between unilateral and bilateral oophorectomy before menopause and PD in an established population-based cohort. The study will include over 2,000 women who underwent oophorectomy and a corresponding group of women of the same age and residence who did not undergo oophorectomy.
A second historical cohort study will test the association between personality traits measured by the Minnesota Multiphasic Personality Inventory (MMPI) and PD in an established research cohort. The study will include nearly 9,000 persons who underwent MMPI testing while residing in Minnesota. The proposed case-control study is strong because it has adequate statistical power to confirm preliminary findings on the role of estrogen in PD and to explore the link between substance use and novelty seeking behaviors in PD. These studies will contribute greatly to understanding the causes and possible prevention of PD by exploring novel hypotheses and by using innovative methods.
E2007 as Adjunct Treatment to Levodopa in Patients with Parkinson’s Disease
Charles Adler, M.D., Ph.D., Virgilio Evidente, M.D., and Erika Driver-Dunckley, M.D., will conduct a randomized, double-blind, placebo-controlled, parallel group study of the efficacy and safety of 2 of E2007 (an investigational drug) and placebo in levodopa treated Parkinson’s Disease (PD) patients with motor fluctuations. Treatment will be given orally for twenty weeks with follow-up lasting up to twenty-four weeks (there is a two- to three-week screening period before treatment begins). Safety and efficacy will be monitored at multiple scheduled visits. This is a phase 3 study sponsored by Eisai Medical Research, Inc. The primary objective of this study is to compare the efficacy of certain doses of E2007 and a placebo in patients with PD who experience end-of-dose “wearing off” fluctuations in their motor function. Patient diaries will serve as the primary efficacy measure.
Fluorodopa Positron Emission Tomography in the Early Detection of Parkinson's Disease
Demetrius Maraganore, M.D., is working toward demonstrating that early PD can be discriminated from normal aging. This feasibility study is an indispensable step toward the development of fluorodopa positron emission tomography (PET) as a screening tool for preclinical detection in at risk family members.
The Molecular Epidemiology of Parkinson’s Disease
The Molecular Epidemiology of Parkinson’s Disease (MEPD) study is funded by the National Institutes of Health. Demetrius Maraganore, M.D., Ph.D., is leading this effort to study the pathogenesis of Parkinson’s disease. The study will have three major goals:
The Global Genetics Consortium
The Genetic Epidemiology of Parkinson's Disease Consortium (GEO-PD) was created with funding from the Michael J. Fox Foundation (Edmond J. Safra Global Genetics Consortia Program). The Consortium originally included twenty-four investigators from eighteen sites, eleven countries, and four continents who agreed to share biospecimens and available data for a collaborative-pooled analysis of alpha-synuclein gene promoter variability and Parkinson's disease. The consortium has since increased in size to represent multiple investigators from thirty-one sites, twenty countries, and six continents. By October 31, 2010, it is projected that the sites will have data and DNA available for more than 20,000 cases and 20,000 controls.
New members are actively sought for these and future projects, which will focus on genetic association studies of PD. Investigators are required to have data and DNA available for a minimum of 100 PD cases and 100 unrelated controls, and to be willing to share small aliquots of DNA from a small sub-sample for genotyping reliability studies.
The Arizona Parkinson’s Disease Consortium
The Arizona Parkinson’s Disease Consortium (APDC) includes investigators from multiple institutions throughout Arizona: Mayo Clinic Scottsdale, Sun Health Research Institute, Barrow Neurologic Institute, Banner Good Samaritan Medical Center, Arizona State University, and the Translational Genomics Research Institute. The APDC focuses on investigation into the causes and diagnosis of PD and dementia in PD, as well as formulation of cures and new treatments, including drug discovery and development that may ultimately lead to prevention, better treatments, and a cure for the disease.
Prescott Family Initiative with the Arizona Parkinson's Disease Consortium
Parkinson's disease is currently diagnosed clinically by finding slowness of movement along with either rest tremor or rigidity. However, the only way to definitively diagnose PD is by autopsy. In addition to being a disorder of movement, thirty to seventy-five percent of patients with PD develop dementia which can be very disabling. While there are treatments (medications and surgical procedures) that improve the motor symptoms, there are no treatments that slow or halt disease progression or prevent dementia in PD patients. Unfortunately, the underlying cause of PD and of dementia in PD is unknown. Charles H. Adler, M.D., Ph.D., of Mayo Clinic Arizona, and Thomas G. Beach, M.D., Ph.D., of Sun Health Research Institute, jointly lead the Arizona Parkinson Disease Consortium. This group of clinicians and scientists from five institutions in Arizona are working with the Brain and Body Donation Program at Sun Health Research Institute to enroll healthy elderly individuals and people with Parkinson’s disease, Alzheimer’s disease, and other neurologic disorders who are willing to donate their brain and other organs for research purposes. Currently there are 800 living subjects enrolled, and over 950 brains have been collected. Participants are evaluated annually by a movement disorders specialist, a behavioral neurologist, and a neuropsychologist looking for signs of PD and dementia. The major goal is to find the earliest clinical markers for the onset of PD and for the onset of dementia in people with PD so that studies of treatments to slow or stop these disorders can be started earlier. One of the critical features of the program is the confirmation of the clinical diagnosis by autopsy.
The Udall Center
As a Udall Center for Parkinson's Disease Center of Excellence, Mayo Clinic is one of only a handful of centers across the country that receive this special status, and with it, funding. These centers were created in 1997, through the Morris K. Udall Parkinson's Disease Research Act. The Udall Act establishes funding for eight additional grants. Research at the Udall Centers focus on improving the diagnosis and treatment of patients with Parkinson’s Disease and related neurodegenerative disorders and on gaining a better understanding of the fundamental cause(s) of the disease.
The Clinical Core is an international effort to identify and characterize multiplex families with PD for genetic studies. Large kindreds with PD are collected and characterized in an effort to discover new genes for PD. Functional imaging studies are used to detect preclinical cases in these kindreds in order to increase the statistical power of the kindreds. Other initiatives are studies of the genetics of restless legs syndrome (RLS) and familial dystonia. In addition to familial PD, the Clinical Core also recruits and follows sporadic PD patients and arranges for postmortem studies.
The Genetic Core provides genetic screening on families and also performs genome-wide linkage studies in the most informative kindreds. This effort includes screening for known PD genes, such as genes for parkin, a-synuclein, and LRRK2.
The Neuropathology Core performs postmortem evaluations of PD and related disorders, including a large (>400) and growing collection of progressive supranuclear palsy (PSP) brains. The PSP collection is the largest in the world, and DNA from this collection has contributed to identification of genetic risk factors for PSP. The Neuropathology Core also provides histologic support to the projects as well as DNA or brain tissue to researchers at Mayo Clinic and other institutions. One of the major outcomes from this collaboration was the discovery of new genes for frontotemporal dementia with parkinsonism on chromosome 17, namely tau (MAPT) and progranulin (PGRN). Clinicopathologic studies of these cases reveal parkinsonism in over seventy percent of the cases. The pathology in PGRN-related FTDP is characterized by TDP-43 immunoreactive neuronal inclusions. Further work by the Neuropathology Core has identified TDP-43 immunoreactive inclusions in disorders other than frontotemporal dementia, including some cases of familial PD.
Ongoing Research Projects at the Udall Center
One project builds upon the discovery, based upon research performed in the Udall Center, that there is multiplication of the a-synuclein gene (SNCA) in some cases of autosomal dominant, early-onset PD. This project focuses on population genetics of SNCA, characterization of SNCA multiplications (including the size and genes within the multiplication regions), and measurement of temporal and regional a-synuclein expression in normals and a-synucleinopathies. A recently published collaborative study with Global Genetics Consortium of Parkinson's disease, reported the first meta-analysis on over 2,500 PD cases and over 2,400 controls, which provided conclusive evidence that a polymorphism in SNCA is associated with risk of PD even in sporadic PD.
A second project is a clinicopathologic study that determines the frequency and clinical expression of Lewy bodies in normal individuals using the Mayo Medical Records Linkage System, with studies on the role of neuronal loss, inflammation, and tau on clinical features. The goal is to identify preclinical PD and to evaluate epidemiologic risk factors in this cohort compared to controls that do not have Lewy bodies. A recent observation from this study provides evidence to suggest that spinal cord involvement occurs early in the preclinical phase of PD. Analyses of striatal dopaminergic innervation indicates that striatal dopamine is decreased in preclinical PD compared to normals; however, the decrease is less than in PD.
A third project uses cell lines that inducibly express a-synuclein or tau in conjunction with oxidative stress or mitochondrial toxins, such as rotenone, to study truncated and aggregated a-synuclein, with the goal of determining the role of interacting proteins in aggregate formation and the effects of aggregates on proteasome function and gene expression. Experimental evidence from these studies suggests that casein kinase 2 and G protein receptor kinase 2 are involved in a-synuclein phosphorylation and that a-synuclein proteolysis involves calpain and lysosomal enzymes, such as cathepsin D. Both phosphorylation and proteolysis play a role in a-synuclein aggregation and may prove to be key targets for disease-modifying drug therapies for PD.
Discovery of a New Gene for Parkinson's Disease
The major discovery of the Udall Center, in collaboration with scientists in Germany and Austria, was finding the gene for autosomal dominant, late-onset PD linked to chromosome 12. The gene is called LRRK2 and is a large gene with fifty-one exons. The predicted 280-kDa protein has several functional domains, including a Roc domain that belongs to the Ras/GTPase superfamily, a COR domain, a leucine-rich repeat domain, a WD40 domain, and a tyrosine kinase catalytic domain. The function of LRRK2 and how disturbance in this function leads to PD remains to be determined, but preliminary results implicate its kinase function since several mutations have been found in this domain.
The discovery of LRRK2 was made possible through the efforts of the Clinical and Genetic Cores in identifying and characterizing large PD kindreds with autosomal dominant inheritance. In particular, two families (Family A and Family D) that were extensively characterized by the Clinical Core were found to carry different mutations in LRRK2. Screening of other familial PD cases by the Genetic Core identified several other families with distinct mutations. Given the results of studies in our Center and from others, it has become clear that mutations in LRRK2 are the most common genetic cause of autosomal dominant PD. The Genetic Core has assessed LRRK2 frequency, prevalence, and penetrance estimates in incident, community-based and post-mortem samples from many ethnicities. Common but distinct mutations in LRRK2 have been discovered in Caucasian and Asian populations that account for a sizable component to genetically-determined PD in both populations.
Pathologic characterization of six individuals from Families A and D who came to autopsy by the Neuropathology Core has shown mixed pathology. Three individuals had "nonspecific" neuronal loss and gliosis in the substantia nigra; two individuals had Lewy bodies (including one with diffuse Lewy body disease); and one had tau pathology, with neuronal and glial lesions that resembled those seen in 4R tauopathies, such as progressive supranuclear palsy. The Genetic Core has screened DNA samples of PD and other disorders from our brain bank and found additional cases with LRRK2 mutations. While most have had Lewy bodies, several have had either nonspecific pathology or tau pathology, as in the original studies of Families A and D. These studies have raised the possibility that disturbance in LRRK2 may be "upstream" of a number of different pathologic processes that lead to neurodegeneration and suggest that treatments targeting LRRK2 may have relevance not only to PD but to other neurodegenerative disorders such as PSP and FTDP.
A Developing Database
Ryan Uitti, M.D., is conducting research on the delineation of the longitudinal progression of all movement disorders. A comprehensive longitudinal database has been established employing validated examination ratings in more that 4,000 patient visits over ten years. In particular, work with Parkinson's disease focuses on asymmetry of motor findings and identifying factors predictive for specific long-term outcomes. He and his research team are actively comparing phenotypes between genetic and sporadic forms of parkinsonism. Research topics also include surgical treatment and outcome measures for Parkinson's disease, essential tremor, and dystonia. Clinical therapeutic trials are also being carried out for PD in conjunction with multi-center trials of the Parkinson Study Group (PSG), NIH (NET-PD), and industry.
Additional areas of research focus
Charles Adler, M.D., Ph.D., also is leading investigations of normal and abnormal movement in various disorders. This includes studying handwriting and other movements in patients with Parkinson's disease and the effect of medication and deep brain stimulation on the movements. Another area of research is Dr. Adler's investigations of new treatments for multiple movement disorders, including pharmaceutical trials as well as single site studies performed only at Mayo Clinic.
Yips: A Focal Task-Specific Dystonia
Dr. Adler and John N. Caviness, M.D., are conducting a study investigating joint position of the fingers and wrist and muscle contractions in the forearm and upper arm while putting. This study is in collaboration with researchers at Arizona State University. Some golfers complain of an involuntary movement while making a putt, and this is known as the yips. The research is comparing golfers who complain of the yips with golfers that do not complain of this. The goal of the research is to determine if some of the subjects with the yips have an involuntary movement disorder such as tremor or dystonia. This research may have implications to not only golf but other task-specific movement disorders such as writer’s cramp and musician’s cramp.
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