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Erwan Bezard - One of the best experts on this subject based on the ideXlab platform.
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levodopa induced Dyskinesia in parkinson disease current and evolving concepts
Annals of Neurology, 2018Co-Authors: Alberto J Espay, Erwan Bezard, Susan H. Fox, Francesca Morgante, Aristide Merola, Alfonso Fasano, Luca Marsili, Barbara PicconiAbstract:Levodopa-Induced Dyskinesia is a common complication in Parkinson disease. Pathogenic mechanisms include phasic stimulation of dopamine receptors, nonphysiological levodopa-to-dopamine conversion in serotonergic neurons, hyperactivity of corticostriatal glutamatergic transmission, and overstimulation of nicotinic acetylcholine receptors on dopamine-releasing axons. Delay in initiating levodopa is no longer recommended, as Dyskinesia development is a function of disease duration rather than cumulative levodopa exposure. We review current and in-development treatments for peak-dose Dyskinesia but suggest that improvements in levodopa delivery alone may reduce its future prevalence. Ann Neurol 2018;84:797-811.
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a phase 2a trial of the novel mglur5 negative allosteric modulator dipraglurant for levodopa induced Dyskinesia in parkinson s disease
Movement Disorders, 2016Co-Authors: François Tison, Charlotte Keywood, Mark Wakefield, Franck Durif, Erwan Bezard, Jean-christophe Corvol, Karla Eggert, Stuart Isaacson, Mark F LewAbstract:Background The metabotropic glutamate receptor 5-negative allosteric modulator dipraglurant reduces Levodopa-Induced Dyskinesia in the MPTP-macaque model. The objective of this study was to assess the safety, tolerability (primary objective), and efficacy (secondary objective) of dipraglurant on Levodopa-Induced Dyskinesia in Parkinson's disease (PD). Methods The study was a phase 2A double-blind, placebo-controlled, randomized (2:1), 4-week, parallel-group, multicenter dose-escalation (from 50 mg once daily to 100 mg 3 times daily) clinical trial involving 76 PD subjects with moderate to severe Levodopa-Induced Dyskinesia. Safety and tolerability were assessed based on clinical and biological examination and adverse events recording. Secondary efficacy outcome measures included the modified Abnormal Involuntary Movement Scale, UPDRS, and diaries. Pharmacokinetics were measured at 3 visits following a single dose. Results Fifty-two patients were exposed to dipraglurant and 24 to placebo. There were no major safety concerns. Two subjects did not complete the study because of adverse events. Most frequent adverse events included Dyskinesia, dizziness, nausea, and fatigue. Dipraglurant significantly reduced peak dose Dyskinesia (modified Abnormal Involuntary Movement Scale) on day 1 (50 mg, 20%; P = 0.04) and on day 14 (100 mg, 32%; P =0 .04) and across a 3-hour postdose period on day 14 (P = 0.04). There was no evidence of worsening of parkinsonism. Dipraglurant was rapidly absorbed (tmax = 1 hour). The 100-mg dose led to a mean Cmax of 1844 ng/mL on day 28. Conclusions Dipraglurant proved to be safe and well tolerated in its first administration to PD patients. Its efficacy in reversing Levodopa-Induced Dyskinesia warrants further investigations in a larger number of patients. © 2016 International Parkinson and Movement Disorder Society
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A Phase 2A Trial of the Novel mGluR5-Negative Allosteric Modulator Dipraglurant for Levodopa-Induced Dyskinesia in Parkinson's Disease.
Movement Disorders, 2016Co-Authors: François Tison, Charlotte Keywood, Mark Wakefield, Franck Durif, Erwan Bezard, Jean-christophe Corvol, Karla Eggert, Mark Lew, Stuart Isaacson, Sonia-maria PoliAbstract:The metabotropic glutamate receptor 5-negative allosteric modulator dipraglurant reduces Levodopa-Induced Dyskinesia in the MPTP-macaque model. The objective of this study was to assess the safety, tolerability (primary objective), and efficacy (secondary objective) of dipraglurant on Levodopa-Induced Dyskinesia in Parkinson's disease (PD). The study was a phase 2A double-blind, placebo-controlled, randomized (2:1), 4-week, parallel-group, multicenter dose-escalation (from 50 mg once daily to 100 mg 3 times daily) clinical trial involving 76 PD subjects with moderate to severe Levodopa-Induced Dyskinesia. Safety and tolerability were assessed based on clinical and biological examination and adverse events recording. Secondary efficacy outcome measures included the modified Abnormal Involuntary Movement Scale, UPDRS, and diaries. Pharmacokinetics were measured at 3 visits following a single dose. Fifty-two patients were exposed to dipraglurant and 24 to placebo. There were no major safety concerns. Two subjects did not complete the study because of adverse events. Most frequent adverse events included Dyskinesia, dizziness, nausea, and fatigue. Dipraglurant significantly reduced peak dose Dyskinesia (modified Abnormal Involuntary Movement Scale) on day 1 (50 mg, 20%; P = 0.04) and on day 14 (100 mg, 32%; P =0 .04) and across a 3-hour postdose period on day 14 (P = 0.04). There was no evidence of worsening of parkinsonism. Dipraglurant was rapidly absorbed (tmax = 1 hour). The 100-mg dose led to a mean Cmax of 1844 ng/mL on day 28. Dipraglurant proved to be safe and well tolerated in its first administration to PD patients. Its efficacy in reversing Levodopa-Induced Dyskinesia warrants further investigations in a larger number of patients. © 2016 International Parkinson and Movement Disorder Society.
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A critique of available scales and presentation of the non-human primate Dyskinesia rating scale
Movement Disorders, 2012Co-Authors: Susan H. Fox, Tom H. Johnston, Jonathan Brotchie, Erwan BezardAbstract:Levodopa-Induced Dyskinesia (LID) is a major limitation of long-term management of Parkinson's disease. The roadblocks that have hindered the development of new treatments for Levodopa-Induced Dyskinesia were discussed at a meeting organized by the Michael J. Fox Foundation for Parkinson's research (New York, NY, March 2011). Among these, the lack of consensus methodology and clinical applicability for eliciting and rating LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys was highlighted as a particular concern. Here we present an update on the practical use of rating scales for evaluating LID in MPTP-lesioned primate models of PD, with a focus on macaques, and present specifics on the Non-Human Primate Dyskinesia Rating Scale.
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maladaptive plasticity of serotonin axon terminals in levodopa induced Dyskinesia
Annals of Neurology, 2010Co-Authors: Daniella Rylander, Erwan Bezard, Sandra Dovero, Martin Parent, Sean S Osullivan, Andrew J Lees, Laurent Descarries, Angela M CenciAbstract:OBJECTIVE:: Striatal serotonin projections have been implicated in Levodopa-Induced Dyskinesia by providing an unregulated source of dopamine release. We set out to determine whether these projections are affected by levodopa treatment in a way that would favor the occurrence of Dyskinesia. METHODS:: As an index of terminal serotonin innervation density, we measured radioligand binding to the plasma membrane serotonin transporter (SERT) in levodopa-treated dyskinetic and nondyskinetic subjects, using brain tissue from both rat and monkey models of Parkinson disease as well as parkinsonian patients. In addition, striatal tissue from dyskinetic rats was used for morphological and ultrastructural analyses of serotonin axon terminals, and for studies of stimulated [(3)H]dopamine release. RESULTS:: Across all conditions examined, striatal levels of SERT radioligand binding were significantly elevated in dyskinetic subjects compared to nondyskinetic cases. In the rat striatum, dyskinesiogenic levodopa treatment had induced sprouting of serotonin axon varicosities having a relatively high synaptic incidence. This response was associated with increased depolarization-induced [(3)H]dopamine release and with a stronger release potentiation by brain-derived neurotrophic factor. INTERPRETATION:: This study provides the first evidence that L-dopa treatment induces sprouting of serotonin axon terminals, with an increased incidence of synaptic contacts, and a larger activity-dependent potentiation of dopamine release in the dopamine-denervated striatum. Treatment-induced plasticity of the serotonin innervation may therefore represent a previously unappreciated cause of altered dopamine dynamics. These results are important for understanding the mechanisms by which L-dopa pharmacotherapy predisposes to Dyskinesia, and for defining biomarkers of motor complications in Parkinsons disease. Ann Neurol 2010. (Less)
Barbara Picconi - One of the best experts on this subject based on the ideXlab platform.
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levodopa induced Dyskinesia in parkinson disease current and evolving concepts
Annals of Neurology, 2018Co-Authors: Alberto J Espay, Erwan Bezard, Susan H. Fox, Francesca Morgante, Aristide Merola, Alfonso Fasano, Luca Marsili, Barbara PicconiAbstract:Levodopa-Induced Dyskinesia is a common complication in Parkinson disease. Pathogenic mechanisms include phasic stimulation of dopamine receptors, nonphysiological levodopa-to-dopamine conversion in serotonergic neurons, hyperactivity of corticostriatal glutamatergic transmission, and overstimulation of nicotinic acetylcholine receptors on dopamine-releasing axons. Delay in initiating levodopa is no longer recommended, as Dyskinesia development is a function of disease duration rather than cumulative levodopa exposure. We review current and in-development treatments for peak-dose Dyskinesia but suggest that improvements in levodopa delivery alone may reduce its future prevalence. Ann Neurol 2018;84:797-811.
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Glutamate Receptors and Levodopa-Induced Dyskinesia
Levodopa-Induced Dyskinesia in Parkinson's Disease, 2014Co-Authors: Barbara Picconi, Paolo CalabresiAbstract:Levodopa is considered the therapy of choice for Parkinson’s disease (PD) treatment. After the early phases of the disease, in which levodopa treatment is highly effective against parkinsonian symptoms, uncontrolled motor fluctuations and abnormal movements named Levodopa-Induced Dyskinesia (LID) appears. An efficient anti-parkinsonian/antidyskinetic therapy has not so far been developed. Altered glutamatergic transmission is one of the main pathophysiological features of LID within basal ganglia circuit. Experimental evidence shows that the trafficking and the localization of the glutamate ionotropic (NMDA and AMPA) and metabotropic receptors in the synaptic cleft appear to have a relevant role in the pathogenesis of LID. Glutamate receptors have therefore been considered as potential targets for a novel pharmacological intervention in PD and LID treatment. Here we report an overview from the main preclinical studies in experimental models of PD and LID to the most recent clinical trials in PD patients describing the pros and cons of the use of glutamate receptor agents.
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Inhibition of phosphodiesterases rescues striatal long-term depression and reduces Levodopa-Induced Dyskinesia.
Brain : a journal of neurology, 2010Co-Authors: Barbara Picconi, Massimiliano Di Filippo, Veronica Ghiglieri, Vincenza Bagetta, Vincent Paillè, Valentina Pendolino, Alessandro Tozzi, Carmela Giampà, Francesca R Fusco, Carmelo SgobioAbstract:The aim of the present study was to evaluate the role of the nitric oxide/cyclic guanosine monophosphate pathway in corticostriatal long-term depression induction in a model of Levodopa-Induced Dyskinesia in experimental parkinsonism. Moreover, we have also analysed the possibility of targeting striatal phosphodiesterases to reduce Levodopa-Induced Dyskinesia. To study synaptic plasticity in sham-operated rats and in 6-hydroxydopamine lesioned animals chronically treated with therapeutic doses of levodopa, recordings from striatal spiny neurons were taken using either intracellular recordings with sharp electrodes or whole-cell patch clamp techniques. Behavioural analysis of Levodopa-Induced abnormal involuntary movements was performed before and after the treatment with two different inhibitors of phosphodiesterases, zaprinast and UK-343664. Levodopa-Induced Dyskinesia was associated with the loss of long-term depression expression at glutamatergic striatal synapses onto spiny neurons. Both zaprinast and UK-343664 were able to rescue the induction of this form of synaptic plasticity via a mechanism requiring the modulation of intracellular cyclic guanosine monophosphate levels. This effect on synaptic plasticity was paralleled by a significant reduction of abnormal movements following intrastriatal injection of phosphodiesterase inhibitors. Our findings suggest that drugs selectively targeting phosphodiesterases can ameliorate Levodopa-Induced Dyskinesia, possibly by restoring physiological synaptic plasticity in the striatum. Future studies exploring the possible therapeutic effects of phosphodiesterase inhibitors in non-human primate models of Parkinson's disease and the involvement of striatal synaptic plasticity in these effects remain necessary to validate this hypothesis.
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Inhibition of phosphodiesterases rescues striatal long-term depression and reduces Levodopa-Induced Dyskinesia.
Brain, 2010Co-Authors: Barbara Picconi, Massimiliano Di Filippo, Veronica Ghiglieri, Vincenza Bagetta, Vincent Paillè, Valentina Pendolino, Alessandro Tozzi, Carmela Giampà, Francesca R Fusco, Carmelo SgobioAbstract:The aim of the present study was to evaluate the role of the nitric oxide/cyclic guanosine monophosphate pathway in corticostriatal long-term depression induction in a model of Levodopa-Induced Dyskinesia in experimental parkinsonism. Moreover, we have also analysed the possibility of targeting striatal phosphodiesterases to reduce Levodopa-Induced Dyskinesia. To study synaptic plasticity in sham-operated rats and in 6-hydroxydopamine lesioned animals chronically treated with therapeutic doses of levodopa, recordings from striatal spiny neurons were taken using either intracellular recordings with sharp electrodes or whole-cell patch clamp techniques. Behavioural analysis of Levodopa-Induced abnormal involuntary movements was performed before and after the treatment with two different inhibitors of phosphodiesterases, zaprinast and UK-343664. Levodopa-Induced Dyskinesia was associated with the loss of long-term depression expression at glutamatergic striatal synapses onto spiny neurons. Both zaprinast and UK-343664 were able to rescue the induction of this form of synaptic plasticity via a mechanism requiring the modulation of intracellular cyclic guanosine monophosphate levels. This effect on synaptic plasticity was paralleled by a significant reduction of abnormal movements following intrastriatal injection of phosphodiesterase inhibitors. Our findings suggest that drugs selectively targeting phosphodiesterases can ameliorate Levodopa-Induced Dyskinesia, possibly by restoring physiological synaptic plasticity in the striatum. Future studies exploring the possible therapeutic effects of phosphodiesterase inhibitors in non-human primate models of Parkinson’s disease and the involvement of striatal synaptic plasticity in these effects remain necessary to validate this hypothesis. * Abbreviations : 6-OHDA : 6-hydroxydopamine AP : anteroposterior cGMP : cyclic guanosine monophosphate DARPP-32 : dopamine and cyclic AMP-regulated phosphoprotein 32kDa DV : dorsoventral EPSC : excitatory postsynaptic current EPSP : excitatory postsynaptic potential L : lateral l-dopa : levodopa VEH : vehicle
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Molecular mechanisms underlying levodopa‐induced Dyskinesia
Movement Disorders, 2008Co-Authors: Paolo Calabresi, Massimiliano Di Filippo, Veronica Ghiglieri, Barbara PicconiAbstract:Although levodopa remains the most effective drug for the symptomatic treatment of Parkinson's disease, chronic therapy with this pharmacological compound initiates a complex cascade of cellular and molecular downstream effects resulting in the development of abnormal involuntary movements. The precise mechanisms underlying the development of levodopa induced Dyskinesia, however, are far from being completely elucidated. In the present review, we will describe changes in long-term synaptic excitability following dopamine (DA) denervation and long-term levodopa treatment leading to abnormal involuntary movements. In particular, we will address the role of both DA D1 receptors and NMDA glutamate receptors in the induction and maintenance of Dyskinesia and abnormal synaptic plasticity. We will also describe the possible interaction between these two receptors in the pathophysiology of Dyskinesia taking the advantage of the existing knowledge concerning the mechanisms underlying drug abuse. This latter pathophysiological condition, in fact, seems to share several biochemical transduction pathways with those implicated in Levodopa-Induced Dyskinesia. Finally, we will briefly discuss the possible implication of A2A adenosine receptors in long-term motor complications of levodopa therapy and focus on the interaction between A2A and D2 receptors. Future studies are required to understand how the interaction between these various biochemical steps converge to produce a long-term change in neuronal excitability within the basal ganglia leading to abnormal involuntary movements following levodopa treatment in the DA-denervated state.
Carmelo Sgobio - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of phosphodiesterases rescues striatal long-term depression and reduces Levodopa-Induced Dyskinesia.
Brain : a journal of neurology, 2010Co-Authors: Barbara Picconi, Massimiliano Di Filippo, Veronica Ghiglieri, Vincenza Bagetta, Vincent Paillè, Valentina Pendolino, Alessandro Tozzi, Carmela Giampà, Francesca R Fusco, Carmelo SgobioAbstract:The aim of the present study was to evaluate the role of the nitric oxide/cyclic guanosine monophosphate pathway in corticostriatal long-term depression induction in a model of Levodopa-Induced Dyskinesia in experimental parkinsonism. Moreover, we have also analysed the possibility of targeting striatal phosphodiesterases to reduce Levodopa-Induced Dyskinesia. To study synaptic plasticity in sham-operated rats and in 6-hydroxydopamine lesioned animals chronically treated with therapeutic doses of levodopa, recordings from striatal spiny neurons were taken using either intracellular recordings with sharp electrodes or whole-cell patch clamp techniques. Behavioural analysis of Levodopa-Induced abnormal involuntary movements was performed before and after the treatment with two different inhibitors of phosphodiesterases, zaprinast and UK-343664. Levodopa-Induced Dyskinesia was associated with the loss of long-term depression expression at glutamatergic striatal synapses onto spiny neurons. Both zaprinast and UK-343664 were able to rescue the induction of this form of synaptic plasticity via a mechanism requiring the modulation of intracellular cyclic guanosine monophosphate levels. This effect on synaptic plasticity was paralleled by a significant reduction of abnormal movements following intrastriatal injection of phosphodiesterase inhibitors. Our findings suggest that drugs selectively targeting phosphodiesterases can ameliorate Levodopa-Induced Dyskinesia, possibly by restoring physiological synaptic plasticity in the striatum. Future studies exploring the possible therapeutic effects of phosphodiesterase inhibitors in non-human primate models of Parkinson's disease and the involvement of striatal synaptic plasticity in these effects remain necessary to validate this hypothesis.
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Inhibition of phosphodiesterases rescues striatal long-term depression and reduces Levodopa-Induced Dyskinesia.
Brain, 2010Co-Authors: Barbara Picconi, Massimiliano Di Filippo, Veronica Ghiglieri, Vincenza Bagetta, Vincent Paillè, Valentina Pendolino, Alessandro Tozzi, Carmela Giampà, Francesca R Fusco, Carmelo SgobioAbstract:The aim of the present study was to evaluate the role of the nitric oxide/cyclic guanosine monophosphate pathway in corticostriatal long-term depression induction in a model of Levodopa-Induced Dyskinesia in experimental parkinsonism. Moreover, we have also analysed the possibility of targeting striatal phosphodiesterases to reduce Levodopa-Induced Dyskinesia. To study synaptic plasticity in sham-operated rats and in 6-hydroxydopamine lesioned animals chronically treated with therapeutic doses of levodopa, recordings from striatal spiny neurons were taken using either intracellular recordings with sharp electrodes or whole-cell patch clamp techniques. Behavioural analysis of Levodopa-Induced abnormal involuntary movements was performed before and after the treatment with two different inhibitors of phosphodiesterases, zaprinast and UK-343664. Levodopa-Induced Dyskinesia was associated with the loss of long-term depression expression at glutamatergic striatal synapses onto spiny neurons. Both zaprinast and UK-343664 were able to rescue the induction of this form of synaptic plasticity via a mechanism requiring the modulation of intracellular cyclic guanosine monophosphate levels. This effect on synaptic plasticity was paralleled by a significant reduction of abnormal movements following intrastriatal injection of phosphodiesterase inhibitors. Our findings suggest that drugs selectively targeting phosphodiesterases can ameliorate Levodopa-Induced Dyskinesia, possibly by restoring physiological synaptic plasticity in the striatum. Future studies exploring the possible therapeutic effects of phosphodiesterase inhibitors in non-human primate models of Parkinson’s disease and the involvement of striatal synaptic plasticity in these effects remain necessary to validate this hypothesis. * Abbreviations : 6-OHDA : 6-hydroxydopamine AP : anteroposterior cGMP : cyclic guanosine monophosphate DARPP-32 : dopamine and cyclic AMP-regulated phosphoprotein 32kDa DV : dorsoventral EPSC : excitatory postsynaptic current EPSP : excitatory postsynaptic potential L : lateral l-dopa : levodopa VEH : vehicle
Susan H. Fox - One of the best experts on this subject based on the ideXlab platform.
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Treatment of Levodopa-Induced Dyskinesia in Parkinson’s Disease
Current Clinical Neurology, 2019Co-Authors: Susan H. FoxAbstract:Levodopa-Induced Dyskinesia (LID) is a common consequence of effectively treating PD. Management depends on recognizing the pattern and timing, in response to levodopa doses. Thus LID can occur at the peak effect of levodopa (mainly chorea) or when the levels are lower or in-between doses (usually dystonia). In addition, evaluating the level of disability associated with the movements is important, as not all LID requires treatment. For peak-dose LID, reducing dopaminergic drugs is helpful. Specific treatment includes amantadine. Off period, or low-dose LID, often responds to increased dopamine levels by treating the OFF periods. Prevention of LID is key by keeping individual doses of levodopa as low as possible but with good motor control in the long term.
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levodopa induced Dyskinesia in parkinson disease current and evolving concepts
Annals of Neurology, 2018Co-Authors: Alberto J Espay, Erwan Bezard, Susan H. Fox, Francesca Morgante, Aristide Merola, Alfonso Fasano, Luca Marsili, Barbara PicconiAbstract:Levodopa-Induced Dyskinesia is a common complication in Parkinson disease. Pathogenic mechanisms include phasic stimulation of dopamine receptors, nonphysiological levodopa-to-dopamine conversion in serotonergic neurons, hyperactivity of corticostriatal glutamatergic transmission, and overstimulation of nicotinic acetylcholine receptors on dopamine-releasing axons. Delay in initiating levodopa is no longer recommended, as Dyskinesia development is a function of disease duration rather than cumulative levodopa exposure. We review current and in-development treatments for peak-dose Dyskinesia but suggest that improvements in levodopa delivery alone may reduce its future prevalence. Ann Neurol 2018;84:797-811.
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Vision-based assessment of parkinsonism and Levodopa-Induced Dyskinesia with pose estimation
BMC, 2018Co-Authors: Tiago A. Mestre, Susan H. Fox, Babak TaatiAbstract:Abstract Background Despite the effectiveness of levodopa for treatment of Parkinson’s disease (PD), prolonged usage leads to development of motor complications, most notably Levodopa-Induced Dyskinesia (LID). Persons with PD and their physicians must regularly modify treatment regimens and timing for optimal relief of symptoms. While standardized clinical rating scales exist for assessing the severity of PD symptoms, they must be administered by a trained medical professional and are inherently subjective. Computer vision is an attractive, non-contact, potential solution for automated assessment of PD, made possible by recent advances in computational power and deep learning algorithms. The objective of this paper was to evaluate the feasibility of vision-based assessment of parkinsonism and LID using pose estimation. Methods Nine participants with PD and LID completed a levodopa infusion protocol, where symptoms were assessed at regular intervals using the Unified Dyskinesia Rating Scale (UDysRS) and Unified Parkinson’s Disease Rating Scale (UPDRS). Movement trajectories of individual joints were extracted from videos of PD assessment using Convolutional Pose Machines, a pose estimation algorithm built with deep learning. Features of the movement trajectories (e.g. kinematic, frequency) were used to train random forests to detect and estimate the severity of parkinsonism and LID. Communication and drinking tasks were used to assess LID, while leg agility and toe tapping tasks were used to assess parkinsonism. Feature sets from tasks were also combined to predict total UDysRS and UPDRS Part III scores. Results For LID, the communication task yielded the best results (detection: AUC = 0.930, severity estimation: r = 0.661). For parkinsonism, leg agility had better results for severity estimation (r = 0.618), while toe tapping was better for detection (AUC = 0.773). UDysRS and UPDRS Part III scores were predicted with r = 0.741 and 0.530, respectively. Conclusion The proposed system provides insight into the potential of computer vision and deep learning for clinical application in PD and demonstrates promising performance for the future translation of deep learning to PD clinical practices. Convenient and objective assessment of PD symptoms will facilitate more frequent touchpoints between patients and clinicians, leading to better tailoring of treatment and quality of care
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trial of dextromethorphan quinidine to treat levodopa induced Dyskinesia in parkinson s disease
Movement Disorders, 2017Co-Authors: Susan H. Fox, Anthony E. Lang, John G. Nutt, Leonard Verhagen Metman, Matthew Brodsky, Stewart A Factor, Laura E Pope, Nadine Knowles, Joao SiffertAbstract:Background: Nondopaminergic pathways represent potential targets to treat Levodopa-Induced Dyskinesia in Parkinson's disease (PD). This pilot-study (NCT01767129) examined the safety/efficacy of the sigma-1 receptor-agonist and glutamatergic/monoaminergic modulator, dextromethorphan plus quinidine (to inhibit rapid dextromethorphan metabolism), for treating Levodopa-Induced Dyskinesia. Methods: PD patients were randomized to dextromethorphan/quinidine (45 mg/10 mg twice daily)/placebo in two 2-week double-blind, crossover treatment periods, with intervening 2-week washout. After 14 days, a 2-hour intravenous levodopa-infusion was administered. Patient examinations were videotaped before infusion (“off” state) and every 30 minutes during and afterwards until patients returned to “off.” The primary endpoint was Dyskinesia-severity during infusion measured by Unified Dyskinesia Rating Scale part 3 area-under-curve scores (blinded expert rated). Additional endpoints included other Dyskinesia/motor assessments, global measures of clinical-change, and adverse-events. Results: A total of 13 patients were randomized and completed the study (efficacy-evaluable population). Dyskinesia-severity was nonsignificantly lower with dextromethorphan/quinidine than placebo during infusion (area-under-curve 966.5 vs 1048.8; P = .191 [efficacy-evaluable patients]), and significantly lower in a post-hoc sensitivity analysis of the per-protocol-population (efficacy-evaluable patients with ≥ 80% study-drug-compliance, n = 12) when measured from infusion start to 4-hours post–infusion completion (area-under-curve 1585.0 vs 1911.3; P = .024). Mean peak Dyskinesia decreased significantly from infusion-start to return to “off” (13.3 vs 14.9; P = .018 [efficacy-evaluable patients]). A total of 9 patients rated Dyskinesia “much/very much improved” on dextromethorphan/quinidine versus 1-patient on placebo. Dextromethorphan/quinidine did not worsen PD-motor scores, was generally well tolerated, and was associated with more frequent adverse events. Conclusion: This study provides preliminary evidence of clinical benefit with dextromethorphan/quinidine for treating Levodopa-Induced Dyskinesia in PD. Larger studies with a longer treatment duration need to corroborate these early findings. © 2017 International Parkinson and Movement Disorder Society
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famotidine a histamine h2 receptor antagonist does not reduce levodopa induced Dyskinesia in parkinson s disease a proof of concept study
Movement Disorders Clinical Practice, 2014Co-Authors: Tiago A. Mestre, Binit B Shah, Barbara S Connolly, Camila De Aquino, Amaal Al Dhakeel, Richard A Walsh, Taneera Ghate, Jane P Lui, Susan H. FoxAbstract:The neural mechanisms underlying Levodopa-Induced Dyskinesia (LID) in Parkinson's disease (PD) may involve histamine (H2) receptors on striatopallidal pathways. We recently demonstrated that the clinically available oral histamine H2 receptor antagonist (H2 RA), famotidine, can reduce l-dopa-induced chorea in MPTP-lesioned macaques. We hypothesized that famotidine may be useful in the treatment of LID in PD patients. We performed a proof-of-concept, double-blind, randomized, multiple cross-over (4×) trial. Seven PD subjects with bothersome Dyskinesia were randomized to oral famotidine 80, 120, and 160 mg/day and placebo. Each subject was randomized to receive each of the four treatment phases for 14 days followed by a 7-day wash-out period between each treatment phase. The primary outcome measure was change in the Unified Dyskinesia Rating Scale (UDysRS; part III) between placebo and famotidine. Secondary outcomes were UDysRS (parts I and II), Global Impression of Change, Lang-Fahn Activities of Daily Living Dyskinesia Scale, Unified Parkinson's Disease Rating part III, and adverse events (AEs). Outcomes were evaluated pre- and post-treatment per dose and analyzed using a mixed-effects linear model. There was no significant effect of famotidine treatment on any of the primary or secondary outcome measures compared to placebo (each dose and all doses combined). There were no significant AEs. Even though the sample size of the current study is limited, famotidine seems to be safe in patients with PD and LID, but showed no potential as an antidyskinetic agent.
Celine Guigoni - One of the best experts on this subject based on the ideXlab platform.
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increased d1 dopamine receptor signaling in levodopa induced Dyskinesia
Annals of Neurology, 2005Co-Authors: Incarnation Aubert, Christian E Gross, Celine Guigoni, Kerstin Hakansson, Qin Li, Sandra Dovero, Nicole Barthe, Bernard Bioulac, Gilberto Fisone, Bertrand BlochAbstract:Involuntary movements, or Dyskinesia, represent a debilitating complication of levodopa therapy for Parkinson's disease. Although changes affecting D1 and D2 dopamine receptors have been studied in association with this condition, no causal relationship has yet been established. Taking advantage of a monkey brain bank constituted to study Levodopa-Induced Dyskinesia, we report changes affecting D1 and D2 dopamine receptors within the striatum of normal, parkinsonian, nondyskinetic levodopa-treated parkinsonian, and dyskinetic levodopa-treated parkinsonian animals. Whereas D1 receptor expression itself is not related to Dyskinesia, D1 sensitivity per D1 receptor measured by D1 agonist-induced [35S]GTPγS binding is linearly related to Dyskinesia. Moreover, the striata of dyskinetic animals show higher levels of cyclin-dependent kinase 5 (Cdk5) and of the dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32). Our data suggest that Levodopa-Induced Dyskinesia results from increased dopamine D1 receptor–mediated transmission at the level of the direct pathway. Ann Neurol 2004
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increased d1 dopamine receptor signaling in levodopa induced Dyskinesia
Annals of Neurology, 2005Co-Authors: Incarnation Aubert, Christian E Gross, Celine Guigoni, Kerstin Hakansson, Sandra Dovero, Nicole Barthe, Bernard Bioulac, Gilberto Fisone, Bertrand Bloch, Erwan BezardAbstract:Involuntary movements, or Dyskinesia, represent a debilitating complication of levodopa therapy for Parkinson's disease. Although changes affecting D(1) and D(2) dopamine receptors have been studied in association with this condition, no causal relationship has yet been established. Taking advantage of a monkey brain bank constituted to study Levodopa-Induced Dyskinesia, we report changes affecting D(1) and D(2) dopamine receptors within the striatum of normal, parkinsonian, nondyskinetic levodopa-treated parkinsonian, and dyskinetic levodopa-treated parkinsonian animals. Whereas D(1) receptor expression itself is not related to Dyskinesia, D(1) sensitivity per D(1) receptor measured by D(1) agonist-induced [(35)S]GTPgammaS binding is linearly related to Dyskinesia. Moreover, the striata of dyskinetic animals show higher levels of cyclin-dependent kinase 5 (Cdk5) and of the dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32). Our data suggest that Levodopa-Induced Dyskinesia results from increased dopamine D(1) receptor-mediated transmission at the level of the direct pathway.
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Pathogenesis of Levodopa-Induced Dyskinesia: focus on D1 and D3 dopamine receptors
Parkinsonism & Related Disorders, 2005Co-Authors: Celine Guigoni, Incarnation Aubert, Ulrich R Mach, Holger Stark, Ludovic Leriche, Vsevolod V. Gurevich, Jeffrey L. Benovic, S. Ferry, Kerstin HakanssonAbstract:Involuntary movements, or Dyskinesia, represent a debilitating complication of levodopa therapy for Parkinson's disease. Taking advantage of a monkey brain bank constituted to study the pathophysiology of Levodopa-Induced Dyskinesia, we here report the changes affecting D1, D2 and D3 dopamine receptors within the striatum of four experimental groups of non-human primates: normal, parkinsonian, parkinsonian treated with levodopa without or with Dyskinesia. We also report the possible role of arrestin and G protein-coupled receptor kinases.
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Levodopa‐induced Dyskinesia in MPTP‐treated macaques is not dependent on the extent and pattern of nigrostrial lesioning
The European journal of neuroscience, 2005Co-Authors: Celine Guigoni, Christian E Gross, Incarnation Aubert, Sandra Dovero, Bernard Bioulac, Bertrand Bloch, Eugenia V. Gurevich, Erwan BezardAbstract:The extent of nigrostriatal denervation is presumed to play a role in the genesis of Levodopa-Induced Dyskinesia. Yet some parkinsonian patients who have been treated over a long period do not develop Dyskinesia, raising the possibility that the pattern of denervation is as important as the extent of lesioning as a risk factor. Here we study the extent and pattern of nigrostriatal denervation in a homogeneous population of parkinsonian macaque monkeys chronically treated with levodopa. Based on the characteristics of the lesioning, non-dyskinetic animals could not be differentiated from those with Dyskinesia. Indeed, the number of tyrosine-hydroxylase (TH)-immunopositive neurons in the substantia nigra pars compacta, striatal dopamine transporter (DAT) binding and TH immunostaining, as well as the overall TH striatal content measured by Western blotting were identical. Moreover, the patterns of lesioning assessed by a detailed analysis of the TH- and DAT-immunopositive striatal fibers were comparable in all functional quadrants and at all rostro-caudal levels considered. These data indicate that neither the extent nor the pattern of nigrostriatal lesioning are sufficient to explain the occurrence of Levodopa-Induced Dyskinesia.