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Parkinson's Disease Research Web: International Research

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International Research

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One of the most significant developments in the history of Parkinson's disease (PD) research resulted from a fortuitous international collaboration in the mid-1990s. Researchers had believed for some time that PD was attributed to environmental exposures; however, clinicians had also noticed PD occurring in families. Roger Duvoisin, M.D., of UMDNJ-Robert Wood Johnson Medical School, was one such researcher, who along with an international research team, had identified a large PD kindred in the town of Contursi, Italy. They followed the family carefully for many years. In August of 1995, NIH sponsored a workshop on PD to which Duvoisin attended, along with intramural scientists from NHGRI and NINDS. As the group examined the pedigree, the genetic ramifications were evident. Soon after, the NIH scientists, led by Mihael Polymeropoulos, M.D., of NHGRI, carried out a genetic analysis of the Contursi kindred DNA. They discovered the first familial PD mutation, localized to the α-synuclein gene, and thus transformed the field of PD research in many critical ways. Perhaps most importantly, the community began to appreciate the genetic contribution to the disease; to date there are now four additional genes known to be implicated in PD in addition to α-synuclein, and there are still more loci for which genes have yet to be identified. As the function of these genes has been explored, researchers have also discovered important links between individuals with hereditary PD and those with the sporadic form of the disease, that have yielded a wealth of information on the general pathology of the disorder. For example, the mutant α-synuclein protein is known to be the primary component of Lewy bodies - the intracellular neuronal inclusions that are a pathological hallmark of parkinsonian neurodegeneration - in individuals with familial PD and in those without a family history. A second gene mutation linked to early-onset PD - in the parkin gene - appears to interfere with the normal operation of the ubiquitin system, which breaks down damaged or misfolded proteins inside neurons. Although individuals with parkin mutations do not exhibit precisely the same pathological changes as those with sporadic PD (e.g., Lewy bodies), abnormalities in protein processing may be a common link between the various types of PD. It is important to note that the parkin finding was discovered by a Japanese group studying several Japanese PD kindreds.

It is clear that profound research discoveries can be made when groups of scientists from around the world can interact and collaborate. This is particularly true for the genetics research described above, but also important for all different areas of PD research. Following is a summary of research activities in PD currently underway around the world. This information was provided to NINDS in response to inquiries made prior to the 2002 Parkinson's Disease Coordination Summit, organized by the NIH Director. We hope to have information on other countries as it is made available.

Initial α-synuclein publication:

Polymeropoulos MH, Higgins JJ, Golbe LI, Johnson WG, Ide SE, Di Iorio G, Sanges G, Stenroos ES, Pho LT, Schaffer AA, Lazzarini AM, Nussbaum RL, Duvoisin RC. (1996). Mapping of a gene for Parkinson's disease to chromosome 4q21-q23. Science, Nov 15; 274(5290):1197-9 [abstract]

Initial parkin publication:

Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998). Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature, Apr 9; 392(6676):605-8 [abstract]

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Argentina

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Australia

The Chief Executive Officer of the National Health and Medical Research Council reports a total of 26 new and continuing grants on PD funded between 2000 and 2002. Areas of interest identified in these awards include the cellular basis of dyskinesias, cell death in PD, circuitry of the basal ganglia, genetic influences in Lewy body disease, PET imaging, regenerative capacity of the substantia nigra, Australian models of palliative care in neurodegenerative disorders, assessment of dementia subtypes in PD, the role of mitochondrial DNA in PD, and the involvement of hippocampal atrophy in PD.

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Brazil

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Canada

The Minister of Health reports over 80 projects related to PD that are currently being funded by the Canadian Institutes of Health Research, the major federal funding agency for health research in Canada. Topics of these studies include: the mechanism of action of deep brain stimulation (DBS), the effects of neural transplantation on basal ganglia activity, dyskinesias, the etiology of sporadic PD, dopamine receptor desensitization, PET and functional MRI imaging in PD, neurophysiological studies of the human subthalamic nucleus, posture and locomotion in PD, vesicular amine transport in neurodegenerative disease, neurotrophic factor effects on cultured SN neurons, predictive features of PD, cell transplantation approaches for PD, and occupational risk factors for PD.

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Chile

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China

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Czech Republic

The Ministry of Health reports past and present studies on PD in a number of research areas, including: changes in brain connectivity during deep brain stimulation, pharmacological studies of glutamate antagonists and gabaergic therapy, a clinical study of deep brain stimulation, and studies of walking disturbances in PD. Czech researchers are also working towards the development of standard treatment procedures for PD, standards of monitoring of PD, an international database of PD, and have completed the establishment of two specialized movement disorders centers in Praha and Brno.

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Denmark

A representative of Bispebjerg Hospital reports the presence of PD clinics in at least two cities, and research projects ongoing at both Bispebjerg as well as the Aarhus University Hospital. These projects include: the epidemiology of PD in the Faroe Islands and the Island of Als, imaging studies (including PET, SPECT, and functional MRI), clinical studies of deep brain stimulation (including effects on sleep and quality of life), genetic studies both in young onset and typical PD, modeling of PD in the pig using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; for use in DBS and anatomical/histopathological research), analysis of urological problems that accompany PD (and effects of DBS on these problems), and the differential diagnosis of PD.

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Egypt

The Minister of Health and Population of Cairo, Egypt indicates that researchers in his country are exploring several areas of PD research, including surgical treatment of movement disorders, the use of magnetic stimulation to treat PD, and the possible involvement of mitochondrial abnormalities in several movement disorders including ataxia, dystonia, and Parkinson "plus" syndromes.

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France

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Germany

Germany's primary research program in PD is called the Parkinson Competence Network. This national research project, supported by the BMBF (Federal Ministry of Education and Research), was developed to optimize the research into and care of patients with PD. Its main objectives are to: 1) improve patient care; 2) optimize and coordinate research; 3) link research and care including a quick knowledge transfer from research to practice and vice versa; 4) promote education and training; 5) develop central databases for patient data, and cost and care research using uniform, standardized documentation; and 6) develop tissue-collections to undertake research at a cellular and genetic basis to research the causes of PD.

The Federal Ministry of Education and Research also sponsors a "Brain-Net," an association of ten "central university-based brain banks where neurological and psychiatric diseases are defined according to pathological and genetic[al] criteria." The materials in the banks are made available for neuroscience researchers in the Federal Republic of Germany.

German researchers are also working with their Israeli counterparts on a number of projects in the field of molecular neuroscience. Currently, this collaboration includes a project designed to characterize neural dynamics in PD (comparing rodent and non-human primate models of the disorder). Lastly, several German laboratories are investigating cell replacement strategies for PD.

Research Highlight

Staging of brain pathology related to sporadic Parkinson's disease. Braak et al., Neurobiol Aging. 2003 Mar-Apr;24(2):197-211. Sporadic Parkinson's disease involves multiple neuronal systems and results from changes developing in a few susceptible types of nerve cells. Essential for neuropathological diagnosis are alpha-synuclein-immunopositive Lewy neurites and Lewy bodies. The pathological process targets specific induction sites: lesions initially occur in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus. Thereafter, less vulnerable nuclear grays and cortical areas gradually become affected. The disease process in the brain stem pursues an ascending course with little interindividual variation. The pathology in the anterior olfactory nucleus makes fewer incursions into related areas than that developing in the brain stem. Cortical involvement ensues, beginning with the anteromedial temporal mesocortex. From there, the neocortex succumbs, commencing with high order sensory association and prefrontal areas. First order sensory association/premotor areas and primary sensory/motor fields then follow suit. This study traces the course of the pathology in incidental and symptomatic Parkinson cases proposing a staging procedure based upon the readily recognizable topographical extent of the lesions.

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Hungary

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Iceland

Research Highlight

A susceptibility gene for late-onset idiopathic Parkinson's disease. Hicks et al., Ann Neurol 2002 Nov;52(5):549-55. Eight regions of the genome (PARK1-8) have been implicated in autosomal dominant and autosomal recessive forms of early-onset Parkinson's disease. These forms constitute a few of all cases. However, except for a haplotype in six families (PARK3), no study has successfully mapped a gene or described mutations that contribute to the common late-onset Parkinson's disease. Some have even suggested that a genetic component does not exist. We cross-matched our nationwide genealogy database with a population-based list of Icelandic Parkinson's disease patients to search for families with more than one patient. We performed a genomewide scan on 117 patients and 168 of their unaffected relatives within 51 families using 781 microsatellite markers. Allele-sharing, model-independent analysis of the results showed linkage to a region on chromosome 1p32 with a logarithm of odds score of 3.9 (Z(lr) = 4.2). By increasing the information content with additional microsatellite markers in this region, we found that the logarithm of odds score increased to 4.9 (Z(lr) = 4.8). This result corresponds to an unadjusted p value of 1.0 x 10(-6) and p < 0.005 after adjusting for a genomewide search. We designate this region PARK10. We therefore have successfully mapped, to genomewide significance, a susceptibility gene for late-onset Parkinson's disease using multiple families drawn across a whole population. Identification of the susceptibility gene in this region may pave the way for a better understanding of the disease process, which, in turn, may lead to improved diagnostics and therapeutics.

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India

Research Highlight

Depression leading to attempted suicide after bilateral subthalamic nucleus stimulation for Parkinson's disease. Doshi et al, Mov Disord. 2002 Sep;17(5):1084-5. Subthalamic nucleus stimulation is emerging as an effective surgical therapy for PD. It is considered to be a safe procedure with little morbidity, the most common complications being intracranial haemorrhage and hardware failure. We report on three cases of depression, one of whom attempted suicide after bilateral subthalamic nucleus stimulation.

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Israel

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Italy

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Japan

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Korea

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Mexico

The General Coordinator for the Mexican Nacional Institutes of Health reports that their research community has explored several areas of PD over the past decade, including the toxicity of the neurotoxin MPTP - used to generate a very useful model of parkinsonism in rodents and non-human primates. Many of these studies have explored compounds that may be able to intervene in the pathway of this toxin to protect neurons. Researchers in Mexico have also been involved in clinical studies of PD, including a clinical trial of cultured adrenal chromaffin cell transplants into the striatum to treat PD, an examination of iron metabolism in individuals with PD, and a longitudinal study of the effects of taking a break from L-Dopa therapy on the long-term course of the disease.

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Netherlands

Research Highlight

Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism.

Bonifati et al., Science. 2003 Jan 10;299(5604):256-9. Epub 2002 Nov 21. The DJ-1 gene encodes a ubiquitous, highly conserved protein. Here, we show that DJ-1 mutations are associated with PARK7, a monogenic form of human parkinsonism. The function of the DJ-1 protein remains unknown, but evidence suggests its involvement in the oxidative stress response. Our findings indicate that loss of DJ-1 function leads to neurodegeneration. Elucidating the physiological role of DJ-1 protein may promote understanding of the mechanisms of brain neuronal maintenance and pathogenesis of Parkinson's disease.

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New Zealand

The Minister of Health reports a major research program in New Zealand on "Neurodegenerative Diseases of the Brain," carried out in the Department of Anatomy at the University of Auckland. In addition to this program, the Health Research Council is supporting two other projects on characterization of vectors for gene therapy in PD, and studies of the adult neuron in neurodegeneration.

Weblinks:
www.neurological.org.nz
www.parkinsons.org.nz

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Norway

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Poland

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Russia

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South Africa

As reported by the Health Attaché and Department of Health and Human Services Regional Representative, several investigators in South Africa are engaged in PD research. These researchers, located at six universities, are exploring the epidemiology of PD, the cell biology of the disorder, studies of dopaminergic cells in culture, gene expression in PD, the role of support groups for individuals with PD, and several groups are using non-human primates to explore the fundamental basis of PD and possible treatments.

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Spain

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Sweden

Research Highlight

Evidence for neurogenesis in the adult mammalian substantia nigra. Zhao et al., Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7925-30. Epub 2003 Jun 05. New neurons are generated from stem cells in a few regions of the adult mammalian brain. Here we provide evidence for the generation of dopaminergic projection neurons of the type that are lost in Parkinson's disease from stem cells in the adult rodent brain and show that the rate of neurogenesis is increased after a lesion. The number of new neurons generated under physiological conditions in substantia nigra pars compacta was found to be several orders of magnitude smaller than in the granular cell layer of the dentate gyrus of the hippocampus. However, if the rate of neuronal turnover is constant, the entire population of dopaminergic neurons in substantia nigra could be replaced during the lifespan of a mouse. These data indicate that neurogenesis in the adult brain is more widespread than previously thought and may have implications for our understanding of the pathogenesis and treatment of neurodegenerative disorders such as Parkinson's disease.

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Taiwan

The Section Chief of the Science and Technology Development branch of the Department of Health reports a small number of PD projects currently ongoing in Taiwan, including studies of imaging approaches that can be used to diagnose and evaluate PD, changes in the spinocerebellar atrophy genes in individuals with familial PD, dopamine transporters and familial PD, and neural stem cell research.

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Thailand

The Director of the Prasat Neurological Institute in Bangkok reports that PD research interests in Thailand include: epidemiology data from Thai PD patients, the genetics of young-onset PD, neuropathology in PD, and the surgical treatment of PD.

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Ukraine

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United Kingdom

The Parkinson's Disease Society (PDS), with over 300 branches throughout the UK, is active in five key areas of Parkinson's research, including: causes, progression, prevention, cure, and patient care. As well as having an extensive program of basic and applied science, the PDS funds many research projects on health and social care issues. The PDS is currently funding projects in stem cell research, gene therapy, current drug therapy, surgery, complementary therapies, and diagnosis and symptom management, including non-motor symptoms such as depression, sleep, and pain.

Research Highlight

Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease.

Gill et al. Nat Med. 2003 May;9(5):589-95. Epub 2003 Mar 31. Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor with restorative effects in a wide variety of rodent and primate models of Parkinson disease, but penetration into brain tissue from either the blood or the cerebro-spinal fluid is limited. Here we delivered GDNF directly into the putamen of five Parkinson patients in a phase 1 safety trial. One catheter needed to be repositioned and there were changes in the magnetic resonance images that disappeared after lowering the concentration of GDNF. After one year, there were no serious clinical side effects, a 39% improvement in the off-medication motor sub-score of the Unified Parkinson's Disease Rating Scale (UPDRS) and a 61% improvement in the activities of daily living sub-score. Medication-induced dyskinesias were reduced by 64% and were not observed off medication during chronic GDNF delivery. Positron emission tomography (PET) scans of [(18)F]dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, suggesting a direct effect of GDNF on dopamine function. This study warrants careful examination of GDNF as a treatment for Parkinson disease.

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Last updated February 09, 2005