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ABSTRACT: Mutations in Leucine-rich repeat kinase 2 (LRRK2) are linked to the most common familial forms and some sporadic forms of Parkinson's disease (PD). The LRRK2 protein contains two well-known functional domains, MAPKKK-like kinase and Rab-like GTPase domains. Emerging evidence shows that LRRK2 contains kinase activity which is enhanced in several PD-associated mutants of LRRK2. However, the GTPase activity of LRRK2 has yet to be formally demonstrated. Here, we produced and purified the epitope-tagged LRRK2 protein from transgenic mouse brain, and showed that purified brain LRRK2 possesses both kinase and GTPase activity as assayed by GTP binding and hydrolysis. The brain LRRK2 is associated with elevated kinase activity in comparison to that from transgenic lung or transfected cultured cells. In transfected cell cultures, we detected GTP hydrolysis activity in full-length as well as in GTPase domain of LRRK2. This result indicates that LRRK2 GTPase can be active independent of LRRK2 kinase activity (while LRRK2 kinase activity requires the presence of LRRK2 GTPase as previously shown). We further found that PD mutation R1441C/G in the GTPase domain causes reduced GTP hydrolysis activity, consistent with the altered enzymatic activity in the mutant LRRK2 carrying PD familial mutations. Therefore, our study shows the biochemical characteristics of brain-specific LRRK2 which is associated with robust kinase and GTPase activity. The distinctive levels of kinase/GTPase activity in brain LRRK2 may help explain LRRK2-associated neuronal functions or dysfunctions in the pathogenesis of PD.
Journal of Neurochemistry 11/2007; 103(1):238-47. · 4.06 Impact Factor
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C Warren Olanow
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ABSTRACT: A number of factors have been implicated in the pathogenesis of cell death in Parkinson's disease (PD). These include oxidative stress, mitochondrial dysfunction, inflammation, excitotoxicity, and apoptosis. While the precise pathogenic mechanism leading to neurodegeneration in PD is not known, there is considerable evidence suggesting that cell death occurs by way of a signal-mediated apoptotic process. PD is also characterized by intracellular proteinaceous inclusions or Lewy bodies. Proteolytic stress arises as a consequence of the excessive production of misfolded proteins, which exceed the capacity of the ubiquitin-proteasome system to degrade them. Recent genetic and laboratory studies support the possible relevance of proteolytic stress to both familial and sporadic forms of PD. Postmortem studies have shown that in the SNc of sporadic PD patients there are reduced levels of the alpha subunit of the 20S proteasome and reduced proteolytic enzyme activities. A determination as to the precise cause of cell death in PD, and the identification of specific targets for the development of drugs that might modify disease progression is one of the most critical goals in PD research. It is anticipated that over the next few years there will be a flurry of scientific activity examining the mechanism of cell death and putative neuroprotective interventions.
Movement Disorders 10/2007; 22 Suppl 17:S335-42. · 4.51 Impact Factor
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ABSTRACT: Manganese is an essential trace metal that is widely used in industry, particularly in the manufacture of steel. Exposure to high levels of manganese can cause neurotoxicity with the development of a form of parkinsonism known as manganism. It has recently been hypothesized that manganese exposure might also cause or accelerate the development of Parkinson disease (PD). This article is a review of the pathologic studies that have been reported in patients with manganism and in primates experimentally intoxicated with manganese. They demonstrate a consistent pattern characterized by damage to the globus pallidus (particularly the internal segment) with sparing of the substantia nigra pars compacta and the absence of Lewy bodies. This finding contrasts with what is seen in PD, in which there is preferential degeneration of dopamine neurons in the substantia nigra pars compacta coupled with Lewy bodies and preservation of the pallidum. These pathologic findings do not support the notion that manganese causes PD but rather argues that manganese-induced parkinsonism and PD are distinct and separate disease entities.
Journal of Neuropathology and Experimental Neurology 09/2007; 66(8):675-82. · 4.26 Impact Factor
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Pablo Martinez-Martin,
Anthony H V Schapira,
Fabrizio Stocchi,
Kapil Sethi,
Per Odin,
Graeme MacPhee,
Richard G Brown,
Yogini Naidu,
Lisa Clayton,
Kazuo Abe, [......],
Alison Forbes,
Kieran Breen,
Susanne Tluk, C Warren Olanow,
Sue Thomas,
David Rye,
Annette Hand,
Adrian J Williams,
William Ondo,
K Ray Chaudhuri
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ABSTRACT: 2006, there was, no single instrument (questionnaire or scale) for attempting a comprehensive assessment of the wide range of nonmotor symptoms (NMS) of Parkinson's disease (PD). The PD nonmotor group, a multidisciplinary group of experts including patient group representatives developed and validated the NMS screening questionnaire (NMSQuest) comprising 30 items. The NMSQuest is a self completed screening tool designed to draw attention to the presence of NMS. In this paper, we present the results gathered from 545 patients using the definitive version of the NMSQuest highlighting the prevalence of the wide range of NMS flagged in the NMSQuest from consecutive PD patients in an international setting.
Movement Disorders 09/2007; 22(11):1623-9. · 4.51 Impact Factor
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ABSTRACT: In the past decade, there has been an increasing emphasis on laboratory-based translational research. This has led to significant scientific advances in our understanding of disease mechanisms and in the development of novel approaches to therapy such as gene therapy, RNA interference, and stem cells. However, the translation of these remarkable scientific achievements into new and effective disease-modifying therapies has lagged behind these scientific accomplishments. We use the term "translational experimental therapeutics" to describe the pathway between the discovery of a basic disease mechanism or novel therapeutic approach and its translation into an effective treatment for patients with a specific disease. In this article, we review the components of this pathway, and discuss issues that might impede this process. Only by optimizing this pathway can we realize the full therapeutic potential of current scientific discoveries and translate the astounding advances that have been accomplished in the laboratory into effective treatments for our patients.
Mount Sinai Journal of Medicine A Journal of Translational and Personalized Medicine 05/2007; 74(1):7-14. · 2.00 Impact Factor
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Christopher G Goetz,
Stanley Fahn,
Pablo Martinez-Martin,
Werner Poewe,
Cristina Sampaio,
Glenn T Stebbins,
Matthew B Stern,
Barbara C Tilley,
Richard Dodel,
Bruno Dubois, [......],
Andrew Lees,
Sue Leurgans,
Peter A LeWitt,
David Nyenhuis, C Warren Olanow,
Olivier Rascol,
Anette Schrag,
Jeanne A Teresi,
Jacobus J Van Hilten,
Nancy LaPelle
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ABSTRACT: This article presents the revision process, major innovations, and clinimetric testing program for the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (UPDRS), known as the MDS-UPDRS. The UPDRS is the most widely used scale for the clinical study of Parkinson's disease (PD). The MDS previously organized a critique of the UPDRS, which cited many strengths, but recommended revision of the scale to accommodate new advances and to resolve problematic areas. An MDS-UPDRS committee prepared the revision using the recommendations of the published critique of the scale. Subcommittees developed new material that was reviewed by the entire committee. A 1-day face-to-face committee meeting was organized to resolve areas of debate and to arrive at a working draft ready for clinimetric testing. The MDS-UPDRS retains the UPDRS structure of four parts with a total summed score, but the parts have been modified to provide a section that integrates nonmotor elements of PD: I, Nonmotor Experiences of Daily Living; II, Motor Experiences of Daily Living; III, Motor Examination; and IV, Motor Complications. All items have five response options with uniform anchors of 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Several questions in Part I and all of Part II are written as a patient/caregiver questionnaire, so that the total rater time should remain approximately 30 minutes. Detailed instructions for testing and data acquisition accompany the MDS-UPDRS in order to increase uniform usage. Multiple language editions are planned. A three-part clinimetric program will provide testing of reliability, validity, and responsiveness to interventions. Although the MDS-UPDRS will not be published until it has successfully passed clinimetric testing, explanation of the process, key changes, and clinimetric programs allow clinicians and researchers to understand and participate in the revision process.
Movement Disorders 02/2007; 22(1):41-7. · 4.51 Impact Factor
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ABSTRACT: The objective of this study is to conduct a dose-finding study of sarizotan in Parkinson's disease (PD) patients with dyskinesia to identify a safe dose and to identify a sensitive dyskinesia rating measure. Sarizotan is a novel compound with full 5-HT(1A) agonist properties and additional high affinity for D(3) and D(4) receptors. An open label study documented improvements in PD patients with levodopa-induced dyskinesia. There is no precedent for study designs or outcome measures in pivotal trials of antidyskinesia therapies. The approach used here was a multicenter, randomized, placebo-controlled, double-blind, parallel study. Included were PD patients optimized to levodopa and dopaminergic drugs with moderately disabling dyskinesias present greater than or equal to 25% of the waking day. Interventions included sarizotan 2, 4, or 10 mg/day or matching placebo, given in two doses. There were two outcome measures: the primary measure was change from baseline in diary-based on time without dyskinesia; the secondary measures were change from baseline in scores on the Abnormal Involuntary Movement Scale (AIMS), the composite score of Unified Parkinson's Disease Rating Scale (UPDRS) Items 32+33 (dyskinesia duration and disability) and total UPDRS. A total of 398 subjects were randomized, with 381 included in the intention-to-treat population. No significant changes occurred on sarizotan compared to placebo on any diary-based measure of dyskinesia or the AIMS score. The composite score of UPDRS Items 32+33 was significantly improved with 2 mg/day sarizotan, with a trend at 10 mg/day. Adverse events were not significantly different in sarizotan- and placebo-treated patients, but off time significantly increased with sarizotan 10 mg/day. Sarizotan 2 mg/day is a safe agent in PD patients with dyskinesia. To test its role in abating dyskinesia, future studies should focus on this dose and will use the composite score of UPDRS Items 32+33 as the primary outcome.
Movement Disorders 02/2007; 22(2):179-86. · 4.51 Impact Factor
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ABSTRACT: There is an important unmet medical need in Parkinson's disease for a neuroprotective treatment that slows or stops disease progression. TCH346 is a potent anti-apoptotic drug that protects against loss of dopaminergic neurons in laboratory models. Our aim was to assess TCH346 as a neuroprotective drug in patients with Parkinson's disease.
Patients presenting at 45 international movement disorder clinics with early untreated Parkinson's disease were assessed as part of this parallel-group, double-blind, randomised controlled trial. 301 eligible patients were randomly assigned 12-18 months' treatment with TCH346 at a daily dose of 0.5 mg (n=78), 2.5 mg (n=79), or 10 mg (n=73), or placebo (n=71), followed by a 4 week washout period. The primary outcome measure was time to development of a disability requiring dopaminergic treatment. Secondary outcome measures were the annual rate of change in the unified Parkinson's disease rating scale (UPDRS) and the PDQ-39, a measure of quality of life. Analyses were by intention-to-treat. This study is pending registration with .
255 patients completed the study. TCH346 did not differ from placebo for any of the study outcomes. Treatment was needed in 26 (34%) patients in the TCH346 0.5 mg group, 30 (38%) in the TCH346 2.5 mg group, 24 (33%) in the TCH346 10 mg group, and 23 (32%) in the placebo group. There were no significant differences between groups. There were no differences between groups in the annual change in the UPDRS or PDQ-39 either. Few patients withdrew because of adverse events and none was judged to be related to the study intervention.
TCH346 did not show evidence of a neuroprotective effect. The discrepancy between the preclinical promise of TCH346 and the clinical outcome could have arisen because of the use of laboratory models that do not accurately reflect the pathogenesis of Parkinson's disease, the doses of study drug used, insensitive clinical endpoints, and the patient population selected for study.
The Lancet Neurology 01/2007; 5(12):1013-20. · 23.46 Impact Factor
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ABSTRACT: Proteasome dysfunction has been demonstrated in Parkinson disease (PD), and proteasome inhibitors have been shown to induce degeneration of dopaminergic neurons in vitro and in vivo. The mechanism whereby proteasome dysfunction leads to dopaminergic cell death, however, is unknown. In this study, we show that proteasome inhibition in both PC12 cells and dopaminergic neurons derived from embryonic stem cells is associated with mitochondrial membrane permeabilization, activation of caspase-3, and nuclear changes consistent with apoptosis. Prior to the emergence of apoptotic features, we found that proteasome inhibition induced increased levels of phosphorylated p53. Inhibition of p53 by pifithrin-alpha or by RNA interference prevented mitochondrial membrane permeabilization and cytotoxicity. There was no increase in p53 mRNA in proteasome-inhibited cells, suggesting that p53 was increased in a transcription-independent manner. Further, there was no increase in Puma or Bax mRNA and p53 co-immunoprecipitated with Bcl-xL and Mdm2. These findings suggest that p53 mediates cell death by way of a direct mitochondrial effect in this model. We also observed increased levels of phosphorylated p53 in dopamine neurons of the substantia nigra pars compacta of mice following systemic administration of a proteasome inhibitor. These changes preceded degeneration of dopaminergic neurons. Increased phosphorylated p53 was also demonstrated in the substantia nigra pars compacta of post-mortem PD brains. These results suggest that abnormalities in p53 signaling play a role in dopaminergic cell death induced by proteasome inhibition and may be relevant to neurodegeneration in PD.
Journal of Biological Chemistry 01/2007; 281(51):39550-60. · 4.77 Impact Factor
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ABSTRACT: Increasing genetic, pathological, and experimental evidence suggest that neurodegeneration in both familial and sporadic forms of Parkinson's disease (PD) may be related to a defect in the capacity of the ubiquitin-proteasome system (UPS) to clear unwanted proteins, resulting in protein accumulation, aggregation, and cytotoxicity. This concept is supported by in vitro and in vivo laboratory experiments which show that inhibition of UPS function can cause neurodegeneration coupled with the formation of Lewy body-like inclusions. This hypothesis could account for the presence of protein aggregates and Lewy bodies in PD, the other biochemical features seen in the disorder, and the age-related vulnerability of the substantia nigra pars compacta. It also suggests novel targets for putative neuroprotective therapies for PD.
Movement Disorders 12/2006; 21(11):1806-23. · 4.51 Impact Factor
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ABSTRACT: We recently reported that systemic administration of a proteasome inhibitor induced a progressive levodopa-responsive, bradykinetic syndrome in rats with imaging, pathological, and biochemical features that strikingly resemble what is found in PD. This model has the potential to be a useful tool for studying the mechanism of cell death in Parkinson's disease and for testing putative neuroprotective agents. Since publication of these findings, several laboratories have sought to reproduce the model; some have been successful in replicating our findings, but others have not. The reason for this variability is not known, but resolution is critically important given the potential utility of this model. We have begun to examine various factors that alone or in combination might explain these differences, and we present in this article preliminary results from these studies.
Annals of Neurology 09/2006; 60(2):243-7. · 11.09 Impact Factor
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ABSTRACT: Levodopa-induced motor complications are a common source of disability for patients with Parkinson's disease. Evidence suggests that motor complications are associated with non-physiological, pulsatile stimulation of dopamine receptors. In healthy brains, dopamine neurons fire continuously, striatal dopamine concentrations are relatively constant, and there is continuous activation of dopamine receptors. In the dopamine-depleted state, standard levodopa therapy does not normalise the basal ganglia. Rather, levodopa or other short-acting dopaminergic drugs induce molecular changes and altered neuronal firing patterns in basal ganglia neurons leading to motor complications. The concept of continuous dopaminergic stimulation proposes that continuous delivery of a dopaminergic drug will prevent pulsatile stimulation and avoid motor complications. In monkeys treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and patients with Parkinson's disease, long-acting or continuous infusion of a dopaminergic drug reduces the risk of motor complications. The current challenge is to develop a long-acting oral formulation of levodopa that provides clinical benefits but avoids motor complications.
The Lancet Neurology 09/2006; 5(8):677-87. · 23.46 Impact Factor
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ABSTRACT: Continuous dopaminergic stimulation is a therapeutic strategy for the management of Parkinson's disease, which proposes that dopaminergic agents that provide continuous stimulation of striatal dopamine receptors will delay or prevent the onset of levodopa-related motor complications. Dopaminergic neurons in the basal ganglia normally fire in a random but continuous manner, so that striatal dopamine concentrations are maintained at a relatively constant level. In the dopamine-depleted state, however, intermittent oral doses of levodopa induce discontinuous stimulation of striatal dopamine receptors. This pulsatile stimulation leads to molecular and physiologic changes in basal ganglia neurons and the development of motor complications. These effects are reduced or avoided when dopaminergic therapies are delivered in a more continuous and physiologic manner. Studies in primate models and patients with Parkinson's disease have shown that continuous or long-acting dopaminergic agents are associated with a decreased risk of motor complications compared with short-acting dopamine agonists or levodopa formulations. Continuous dopaminergic stimulation can be achieved with a continuous infusion, but infusion therapies are cumbersome and not likely to be acceptable to patients with early disease. The current challenge is to develop a long-acting oral formulation of levodopa that provides comparable anti-parkinsonian benefits without motor complications.
Nature Clinical Practice Neurology 08/2006; 2(7):382-92. · 7.64 Impact Factor
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ABSTRACT: Concepts of pathogenesis in Parkinson's disease (PD) have been based on attempts to understand the mechanisms responsible for nigral dopaminergic cell death. Pathogenesis has been proposed to involve oxidative and nitrative stress, excitotoxicity, inflammation, mitochondrial dysfunction, and altered proteolysis. These processes are considered to form a complex cascade of interrelated events that lead to neuron death by way of apoptosis. However, current views on pathogenic mechanisms in PD may not be as exact as commonly proposed. Future concepts of pathogenesis in PD need to incorporate events leading to the destruction of non-dopaminergic nuclei and to distinguish between primary factors that are responsible for disease initiation and secondary factors that contribute to disease progression. Importantly, there is a need to determine whether PD is a single illness with a common pathogenesis or a group of related illnesses with different pathogenic mechanisms. This is an essential step to understanding pathogenesis and is critical to the development of comprehensive neuroprotective approaches to treatment.
Neurology 06/2006; 66(10 Suppl 4):S24-36. · 8.31 Impact Factor
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ABSTRACT: The cause and mechanism of neuronal death in sporadic Parkinson's disease (PD) continue to elude investigators. Recently, alterations in proteasomal function have been detected in the brain of patients with the illness. The biochemical basis of the defect and its relevance to the disease process are now being studied. The available results suggest that proteasomal dysfunction could underlie protein accumulation, Lewy body formation, and neuron death in PD. The cause of proteasomal dysfunction is unknown at present, but this could relate to gene mutations, oxidative damage, ATP depletion, or the actions of environmental toxins. It remains to be established if proteasomal dysfunction plays a primary or a secondary role in the initiation or progression of the neurodegenerative process in PD.
Neurology 06/2006; 66(10 Suppl 4):S37-49. · 8.31 Impact Factor
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C Warren Olanow
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ABSTRACT: A neuroprotective therapy that slows or stops disease progression is the major unmet medical need in Parkinson's disease (PD). Current evidence indicates that cell death in PD occurs, at least in part, by way of a signal-mediated apoptotic process. This raises the possibility that anti-apoptotic agents might be neuroprotective in PD. Propargylamines have been demonstrated to be potent anti-apoptotic agents in both in vitro and in vivo studies, presumably by maintaining glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a dimer and thereby preventing its nuclear translocation where it blocks upregulation of anti-apoptotic proteins. Selegiline is a monamine oxidase type B (MAO-B) inhibitor that incorporates a propargyl ring within its molecular structure. It was shown to delay the need for symptomatic therapy in untreated PD patients in the DATATOP study, but interpretation is confounded by its symptomatic effects. Rasagiline is another MAO-B inhibitor that contains a propargyl ring and has protective effects in laboratory models. A clinical trial utilizing a delayed start design demonstrated that patients initiated on rasagiline at baseline are improved at one year in comparison to patients initiated on placebo and switched to rasagiline at 6 months even though both groups were on the same treatment for the last 6 months of the study. These results argue against the benefit being due to a symptomatic effect and are consistent with rasagiline having a protective effect.
Neurology 06/2006; 66(10 Suppl 4):S69-79. · 8.31 Impact Factor
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ABSTRACT: Current therapies for Parkinson's disease (PD) are limited in their ability to control PD symptomatology, are associated with motor and psychiatric side effects, and do not prevent disease progression. Considerable scientific and media interest has focused on the potential value of gene and stem cell therapies to overcome these problems and to enhance the quality of life for PD patients. Gene therapies utilize a viral vector to deliver a protein of interest to specific brain region. Clinical trials of gene therapy are currently underway using adeno-associated virus to deliver AADC to the striatum, the trophic factor nurturin to the striatum, and GAD to the STN. To date, no serious adverse effects have been noted, but only a small number of patients have been studied. Stem cells are pluripotential cells that offer the potential of generating unlimited numbers of optimized dopamine cells for transplantation. Stem cells can be grown and expanded in tissue culture and then induced to differentiate into dopamine neuronal phenotypes. Transplantation of these cells into the striatum is associated with behavioral improvement in 6-OHDA rodents and MPTP monkeys. Still, only small numbers of transplanted dopaminergic cells survive, and benefits are modest. Clinical trials in PD have not yet been performed. There is considerable enthusiasm for the potential of these procedures, but there remains much to learn in the laboratory and neither has been established to be effective as a treatment for PD. Long term safety and efficacy trials have not been performed in PD patients and the potential of unanticipated side effects must be addressed. Further, neither treatment is expected to improve the non-dopaminergic features of PD.
Neurology 06/2006; 66(10 Suppl 4):S89-103. · 8.31 Impact Factor
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ABSTRACT: Parkinson's disease (PD) is a slowly progressive, age-related, neurodegenerative disorder. The cause and mechanism of neuronal death have been elusive. However, recent genetic, postmortem and experimental evidence show that protein accumulation and aggregation are prominent occurrences in both sporadic and familial PD. The relevance of these events to other cellular and biochemical changes, and to the neurodegenerative process, is being unraveled. It is increasingly evident that one or a combination of defects, including mutations, oxidative stress, mitochondrial impairment and dysfunction of the ubiquitin-proteasome system, lead to an excess production and aggregation of abnormal proteins in PD. In this respect, altered protein handling appears to be a central factor in the pathogenic process occurring in the various hereditary and sporadic forms of PD. This suggests that manipulation of proteolytic systems is a rational approach in the development of neuroprotective therapies that could modify the pathological course of PD.
Neurobiology of Aging 05/2006; 27(4):530-45. · 6.19 Impact Factor
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C Warren Olanow
The Lancet Neurology 02/2006; 5(1):3-5. · 23.46 Impact Factor
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ABSTRACT: Gait and balance disturbances are amongst the most disabling features of Parkinson's disease (PD), and are not adequately controlled with currently available medical and surgical therapies. Development of objective quantitative measures of these abnormalities would greatly help in the assessment and the development of therapeutic interventions. Recently, we developed a methodology, using dynamical system theory, for testing gait with a state-of-the-art motion-detection system (OPTOTRAK 3020, Northern Digital, Inc.). We also developed a model of the dynamics of the foot that predicts the stance and swing phase dynamics of normal walking. In the present study, we determined whether model parameters were altered in subjects with PD when they were tested on/off levodopa (LD) and on/off deep brain stimulation (DBS) in a 2 x 2 matrix.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 02/2006; 1:1228-31.
