Dyskinesia In PD Research Articles

Activation of mGlu 2/3 receptors with the orthosteric agonist LY-404,039 alleviates dyskinesia in experimental parkinsonism.

LY-404,039 is an orthosteric agonist at metabotropic glutamate 2 and 3 (mGlu 2/3 ) receptors, with a possible additional agonist effect at dopamine D 2 receptors. LY-404,039 and its pro-drug, LY-2140023, have previously been tested in clinical trials for psychiatric indications and could therefore be repurposed if they were shown to be efficacious in other conditions. We have recently demonstrated that the mGlu 2/3 orthosteric agonist LY-354,740 alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat without hampering the anti-parkinsonian action of L-DOPA. Here, we seek to take advantage of a possible additional D 2 -agonist effect of LY-404,039 and see if an anti-parkinsonian benefit might be achieved in addition to the antidyskinetic effect of mGlu 2/3 activation. To this end, we have administered LY-404,039 (vehicle, 0.1, 1 and 10 mg/kg) to 6-OHDA-lesioned rats, after which the severity of axial, limbs and oro-lingual (ALO) AIMs was assessed. The addition of LY-404,039 10 mg/kg to L-DOPA resulted in a significant reduction of ALO AIMs over 60-100 min (54%, P < 0.05). In addition, LY-404,039 significantly enhanced the antiparkinsonian effect of L-DOPA, assessed through the cylinder test (76%, P < 0.01). These results provide further evidence that mGlu 2/3 orthosteric stimulation may alleviate dyskinesia in PD and, in the specific case of LY-404,039, a possible D 2 -agonist effect might also make it attractive to address motor fluctuations. Because LY-404,039 and its pro-drug have been administered to humans, they could possibly be advanced to Phase IIa trials rapidly for the treatment of motor complications in PD.

Subthalamic deep brain stimulation improves vascular endothelial function in Parkinson's disease

ObjectivesVascular health (white matter change, vascular risk factor, angiogenesis, microvascular alteration) is associated with clinical progression or levodopa-induced dyskinesia in PD. Vascular endothelial function is known to reflect the earliest vascular change. While DBS can improve motor and non-motor symptoms, the effect of DBS on vascular endothelial function is unknown. Thus, we aimed to investigate whether DBS surgery could impact vascular endothelial function in PD. MethodA total of 20 PD patients were recruited. Vascular endothelial function was evaluated with flow-mediated dilation (FMD). FMD was investigated before and after one year of DBS surgery. ResultsFMD improved (6.01 ± 1.58 to 6.84 ± 1.57, p = 0.027). While the level of homocysteine slightly decreased (13.8 ± 4.1 to 13.0 ± 3.2, p = 0.05), there was no significant correlation between FMD changes and homocysteine levels (r = 0.42, p = 0.065). FMD change was associated with baseline age (r = −0.59, p = 0.006) but not with disease duration (p = 0.73), baseline UPDRS III (p = 0.81), change of UPDRS III and dyskinesia, and LEDD change (p = 0.94). Multivariate linear regression analysis revealed that only age (B = −0.139; p = 0.024) was significantly and inversely correlated with the change of FMD. ConclusionsWe found that STN-DBS improves vascular endothelial function in PD. Further studies are needed to clarify the exact pathogenesis and clinical implication of beneficial effects on vascular endothelial dysfunction in PD.

The effect of levodopa treatment on vascular endothelial function in Parkinson's disease.

There has been increasing awareness that micro-vascular alteration or vascular inflammation has been associated with levodopa-induced dyskinesia in PD. Vascular endothelial function assessed by flow mediated dilation (FMD) is known to reflect early microvascular change. We compare the impact of levodopa or dopamine agonist treatment on the change of FMD in de novo PD patients. This retrospective study used a selected sample from registry. We identified de-novo PD patients who underwent FMD at baseline, and follow-up FMD after 1year (± 2month) of levodopa (n = 18) or dopamine agonist (n = 18) treatment. FMD decreased after levodopa (8.60 ± 0.46 to 7.21 ± 0.4, p = 0.002) but there were no significant changes after DA treatment (8.33 ± 0.38 to 8.22 ± 0.33, p = 0.26). Homocysteine rose (11.52 ± 0.45 to 14.33 ± 0.68, p < 0.05) during levodopa treatment, but dopamine agonist had no effect (10.59 ± 0.38 to 11.38 ± 0.67, p = 0.184). Correlation analysis revealed that the changes in homocysteine level had non-significant correlation with FMD change (r = - 0.30, p = 0.06). FMD change was not associated with age (p = 0.47), disease duration (p = 0.81), baseline motor UPDRS (p = 0.43), motor UPDRS change (p = 0.64), levodopa equivalent dose change (p = 0.65). We found that 1-year levodopa treatment may adversely affect vascular endothelial function in de novo PD. Further studies are needed to clarify the exact pathogenesis and clinical implication of levodopa-induced endothelial dysfunction in PD.

Evaluation of the effects of the mGlu2/3 antagonist LY341495 on dyskinesia and psychosis-like behaviours in the MPTP-lesioned marmoset.

We have previously demonstrated that the metabotropic glutamate 2 and 3 (mGlu2/3) antagonist LY341495 reverses the anti-dyskinetic and anti-psychotic benefits conferred by mGlu2 activation and serotonin 2A (5-HT2A) antagonism. Here, we hypothesised that a higher dose of LY341495, associated with a higher antagonistic effect at mGlu3 receptors, would result in a reduction of the reversal of mGlu2 activation and 5-HT2A blockade on dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. After induction of parkinsonism with MPTP, marmosets entered 3 streams of experiments, in which the following treatments were administered, in combination with l-3,4-dihydroxyphenylalanine (L-DOPA), after which dyskinesia, psychosis-like behaviours (PLBs) and parkinsonism were rated: 1. vehicle/vehicle, LY354740 (mGlu2/3 orthosteric agonist)/vehicle, LY354740/LY341495 1mg/kg and LY354740/LY341495 3mg/kg; 2. vehicle/vehicle, LY487379 (mGlu2 positive allosteric modulator)/vehicle, LY487379/LY341495 1mg/kg and LY487379/LY341495 3mg/kg; 3. vehicle/vehicle, EMD-281,014 (5-HT2A antagonist)/vehicle, EMD-281,014/LY341495 1mg/kg and EMD-281,014/LY341495 3mg/kg. Each of LY354740, LY487379 and EMD-281,014 reduced the severity of L-DOPA-induced dyskinesia, by 55%, 39% and 40%, respectively (all p < 0.001), as well as the severity of PLBs, by 48%, 36% and 41%, respectively (all p < 0.001). Adding LY341495 1 and 3mg/kg to each of LY354740, LY487379 and EMD-281,014 resulted in a dose-dependent reversal of their anti-dyskinetic and anti-psychotic actions. No effect on the anti-parkinsonian action of L-DOPA was noted with any treatment combination. These results suggest that an antagonistic effect at mGlu3 receptors may not be sufficient to overcome the deleterious effect of mGlu2 blockade on dyskinesia in PD. It remains to be seen whether similar effects would have been obtained with a selective mGlu3 antagonist.

Resting-state connectivity predicts levodopa-induced dyskinesias in Parkinson's disease.

ABSTRACTBackgroundLevodopa‐induced dyskinesias are a common side effect of dopaminergic therapy in PD, but their neural correlates remain poorly understood.ObjectivesThis study examines whether dyskinesias are associated with abnormal dopaminergic modulation of resting‐state cortico‐striatal connectivity.MethodsTwelve PD patients with peak‐of‐dose dyskinesias and 12 patients without dyskinesias were withdrawn from dopaminergic medication. All patients received a single dose of fast‐acting soluble levodopa and then underwent resting‐state functional magnetic resonance imaging before any dyskinesias emerged. Levodopa‐induced modulation of cortico‐striatal resting‐state connectivity was assessed between the putamen and the following 3 cortical regions of interest: supplementary motor area, primary sensorimotor cortex, and right inferior frontal gyrus. These functional connectivity measures were entered into a linear support vector classifier to predict whether an individual patient would develop dyskinesias after levodopa intake. Linear regression analysis was applied to test which connectivity measures would predict dyskinesia severity.ResultsDopaminergic modulation of resting‐state connectivity between the putamen and primary sensorimotor cortex in the most affected hemisphere predicted whether patients would develop dyskinesias with a specificity of 100% and a sensitivity of 91% (P < .0001). Modulation of resting‐state connectivity between the supplementary motor area and putamen predicted interindividual differences in dyskinesia severity (R 2 = 0.627, P = .004). Resting‐state connectivity between the right inferior frontal gyrus and putamen neither predicted dyskinesia status nor dyskinesia severity.ConclusionsThe results corroborate the notion that altered dopaminergic modulation of cortico‐striatal connectivity plays a key role in the pathophysiology of dyskinesias in PD. © 2016 International Parkinson and Movement Disorder Society

N03 Efficacy, Safety, And Tolerability Of Afq056 For The Treatment Of Chorea In Patients With Huntington's Disease

<h3>Background</h3> Treatments of chorea in patients with HD have limited efficacy and side-effects. AFQ056, a selective metabotropic glutamate receptor-5 antagonist shown to reduce levodopa-induced dyskinesia in PD, was hypothesised to reduce chorea in HD. <h3>Objective</h3> To assess anti-choreatic efficacy, safety, and tolerability of AFQ056 (Mavoglurant) in HD. <h3>Methods</h3> This was a 32-day randomised, double-blind, parallel-group, placebo (pbo)-controlled, proof-of-concept study. Patients were 30–85 years old, with HD (CAG ≥36) in clinical stage I–III, and maximal chorea sum score &gt;10 in the UHDRS-TMS. Patients were randomised (1:1) to AFQ056 (Days 1–12, titration 25–150mg bid; Days 13–28, 150mg bid; Days 29–32, 50mg bid) or pbo. Primary objectives were to assess efficacy of AFQ056 vs pbo at Day 28 on UHDRS-TMS maximal chorea sum score and orientation index (non-dominant hand) from quantitative-motor (Q-Motor) grasping task and to assess safety and tolerability of AFQ056. Key secondary efficacy assessments included total UHDRS-TMS, UHDRS-TMS Luria score, UHDRS-TMS finger taps, and additional Q-Motor measures. <h3>Results</h3> Overall 42 patients (mean age 55.2 years, HD duration 6.6 years) were randomised. At Day 28, there were no significant improvements on UHDRS-TMS maximal chorea sum score (p = 0.155) or orientation index (non-dominant hand, p = 0.626) in AFQ056-treated patients vs pbo. A significant reduction in Q-Motor speeded-tapping variability was observed favouring AFQ056 vs pbo (p = 0.011) and reverting at study end; this was accompanied by UHDRS-TMS finger-tapping scores showing a trend towards improvement. No significant treatment effects were observed at Day 28 on other key secondary endpoints. Adverse events were reported by 14 and 12 AFQ056- and pbo-treated patients, respectively. <h3>Conclusions</h3> AFQ056 did not reduce involuntary choreatic movements in HD. The Q-Motor findings in speeded-tapping may reflect an improvement in fine motor coordination, but their clinical relevance is unknown. Overall, AFQ056 was well tolerated. Study supported by Novartis Pharma AG.

The H3 receptor agonist immepip does not affect l-dopa-induced abnormal involuntary movements in 6-OHDA-lesioned rats

The treatment of dyskinesia in Parkinson׳s disease remains poor but H3 receptor agonists have been suggested as a novel pharmacological approach. We examined the effects of the H3 agonist, immepip, in 6-OHDA-lesioned rats exhibiting AIMs (abnormal involuntary movements), a rat analogue of dyskinesia, in response to l-dopa compared to the known anti-dyskinetic agents amantadine, MK-801 and 8-OHDPAT. We then attempted to extend these studies in to dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated common marmosets.Amantadine, MK-801 and 8-OHDPAT all dose-dependently reduced l-dopa-induced axial, lingual and oral (ALO) AIMs in 6-OHDA-lesioned animals accompanied by a reduction in contralateral rotation with higher doses of amantadine and MK-801. By contrast, immepip had no effect on AIMs expression or contralateral rotation. In the MPTP-treated common marmoset exhibiting dyskinesia to l-dopa, immepip alone induced retching and in combination with l-dopa administered subcutaneously or orally induced the rapid onset of retching and vomiting which was not controlled by pretreatment with domperidone. Administration of the unrelated H3 agonist, imetit had the same effect. Despite causing negative side-effects, it appears that both agonists reduced the antiparkinsonian response to l-dopa resulting in reduced dyskinesia.H3 agonists appear unlikely candidates for the treatment of dyskinesia in PD based on lack of evidence of efficacy and potential adverse effects.

Catechol‐O‐methyltransferase Val158Met and the risk of dyskinesias in Parkinson's disease

The A-allele of the catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with decreased enzymatic activity and higher dopamine availability. We studied 219 patients with PD who were free of dyskinesias at baseline and underwent thorough annual examinations. The A-allele of the COMT Val158Met polymorphism was related to an increased risk of developing dyskinesias during follow-up, in a dose-dependent manner (adjusted hazard ratios for the AG and AA genotypes [compared to GG]: 2.09 [95% confidence interval (CI), 1.07-4.06] and 2.81 [CI, 1.43-5.54], respectively). This finding suggests that genetic factors may affect susceptibility to dyskinesias in PD.

Preventing and controlling dyskinesia in Parkinson's disease-A view of current knowledge and future opportunities

Dyskinesia affects ∼30 to 40% of patients with Parkinson's disease but treatment options for the prevention of dyskinesia induction and for the suppression of established dyskinesia are limited. This situation is made more difficult by a poor understanding of the pathphysiology of the processes underlying both the priming for dyskinesia and the manifestations of involuntary movements. Loss of tonic stimulation of striatal dopamine receptors in PD and its replacement by pulsatile dopaminergic stimulation using short acting drugs has been proposed as leading to the abnormalities that cause dyskinesia induction. As a consequence, the concept of continuous dopaminergic stimulation (CDS) was introduced to explain why longer acting dopamine agonists do not produce the same intensity of dyskinesia. Key to these ideas has been the use of both 6-OHDA lesioned rodent models of PD and, in particular MPTP-treated primates. Comparison of the ability to induce dyskinesia of the same dopamine agonists given by pulsatile or continuous administration or more constant administration of Levodopa (L-dopa) has shown that constant drug delivery (CDD) dramatically reduces dyskinesia induction. Similar conclusions have been reached from clinical investigations in PD. Recent studies in MPTP-treated primates have also suggested that switching from pulsatile drug delivery to CDD can be utilized to inhibit dyskinesia expression. However, CDS does explain some important features of dyskinesia induction in PD but it may not apply to early PD when remaining dopaminergic neurones buffer against pulsatile stimulation. In addition, CDS may not apply when comparing between drug classes and it appears that it is CDD which is more important in regulating therapeutic efficacy. Recently, studies in MPTP-treated primates have suggested that a range of nondopaminerigic drugs might be useful in suppressing dyskinesia. These have included 5-HT-1A agonists and α-2 adrenergic antagonists and a variety of other molecular entities. Unfortunately, these findings are not always reproducible in the same models and do not translate into clinically useful effects. Preclinical studies have suggested a number of directions that might be utilized to prevent dyskinesia in PD. However, much of what is proposed is empirically-based and we still do not have a good understanding of why dyskinesia appears, why it persists or how to bring the movements under control. Certainly, the use of CDD can reduce dyskinesia intensity but other factors also influence its appearance and it is these that we need to study at the preclinical level if effective therapies are to be developed. © 2008 Movement Disorder Society

1.503 Genetics, plasticity and dyskinesia in PD

1.503 Genetics, plasticity and dyskinesia in PD

Genetic polymorphism affects timing of levodopa-induced dyskinesias in PD

Genetic polymorphism affects timing of levodopa-induced dyskinesias in PD

Clozapine attenuates levodopa-induced dyskinesias in PD

Clozapine attenuates levodopa-induced dyskinesias in PD

Clozapine attenuates levodopa-induced dyskinesias in PD

Clozapine attenuates levodopa-induced dyskinesias in PD

Which factors influence therapeutic decisions in Parkinson's disease?

Development of dyskinesia is a common phenomenon during the long-term course of Parkinson's disease. During the last few years, some but not all pathogenetic mechanisms causing dyskinesias in PD have become better understood. Severity of Parkinson's disease and levodopa dosing are the main clinical risk factors. Most concepts underline the significance of pulsatile D1-receptor stimulation for the development of dyskinesias. The interactions between D1- and D2-mediated STR-Gpi pathways and colocalized neuropeptides are important but not fully understood. Glutamatergic overactivity might also be a significant pathogenetic factor. According to these pathophysiological concepts, therapeutic strategies focus mainly on continuous postsynaptic DA-receptor stimulation by long-acting DA-agonists or highly selective D2-agonists. Another strategy is the use of NMDA antagonists.

Interactions between deep brain stimulation and levodopa in Parkinson's disease.

To quantify the effects of deep brain stimulation (DBS) of globus pallidus interna (GPi) and subthalamic nucleus (STN) on motor fluctuations and dyskinesia in PD and to determine how the response to levodopa was modified by DBS. Patients report that DBS reduces levodopa-induced motor fluctuations and dyskinesia throughout the day, but this has not been objectively measured. Further, the means by which DBS alters the response to levodopa to improve motor fluctuations is unknown. Twelve subjects, six with bilateral GPi electrodes and six with bilateral STN electrodes, were studied 12 to 33 months after surgery. To quantify motor fluctuations and dyskinesia, subjects were monitored hourly throughout 2 waking days with their usual oral medications, 1 day with DBS on and 1 day with DBS off, with subjects and nurse raters blinded to DBS status. To examine the effects of DBS on levodopa pharmacodynamics, the effects of a 2-hour levodopa infusion were examined, 1 day with DBS on and 1 day with DBS off, again under double-blind conditions. Time course of variations in parkinsonism was evaluated by tapping speed, arising and walking speed, tremor scores, and dyskinesia scores. DBS raised the mean tapping speed and reduced the coefficient of variation during the waking day. This was achieved by increasing the lowest or trough tapping speed between doses of antiparkinson medications. Mean walking speed was modestly increased and mean tremor scores were reduced. DBS increased the drug-off tapping speed, but neither the peak response nor the duration of response to levodopa was affected by DBS. The study was not powered to detect differences between GPi and STN stimulation and the only difference that approached significance was that GPi reduced peak dyskinesia and STN tended to increase peak dyskinesia. DBS objectively reduces motor fluctuations. This is achieved by reduction of drug-off disability and not by alterations in levodopa pharmacodynamics. This finding suggests alleviation of interdose trough disability as an alternative strategy to prolonging the effects of each dose of levodopa as a means to reduce motor fluctuations.

Dyskinesia in Parkinson's disease. Pathophysiology and clinical risk factors.

Development of dyskinesia is a common phenomenon during the long-term course of Parkinson's disease. During the last few years some but not all pathogenetic mechanisms causing dyskinesias in PD have been better understood. Severity of Parkinson's disease and levodopa dosing are the main clinical risk factors. Most concepts underline the significance of pulsatile D1-receptor stimulation for the development of dyskinesias. The interactions between D1- and D2-mediated STR-Gpi pathways and co-localized neuropeptides are important but not fully understood. Glutamatergic overactivity might also be a significant pathogenetic factor. According to these pathophysiological concepts, therapeutic strategies focus mainly on continuous postsynaptic DA-receptor stimulation by long acting DA agonists or highly selective D2 agonists. Another strategy is the use of NMDA antagonists.

Dopamine D2 receptor gene polymorphism and the risk of levodopa-induced dyskinesias in PD.

To investigate whether polymorphisms in the genes for dopamine receptors D1 and D2 are associated with the risk of developing peak-dose dyskinesias in PD. Peak-dose dyskinesias are the most common side effects of levodopa therapy for PD. The identified predictors may only partially account for the risk of developing peak-dose dyskinesias because a substantial proportion of patients never develop peak-dose dyskinesias. Genetic factors could play a role in determining the occurrence of peak-dose dyskinesias. A case-control study of 136 subjects with sporadic PD and 224 population control subjects. We studied three polymorphisms involving the dopamine receptor D1 gene and one intronic short tandem repeat polymorphism of the dopamine receptor D2 gene. The polymorphisms of the dopamine receptor D1 gene were not associated with the risk of developing PD or peak-dose dyskinesias. The 15 allele of the polymorphism of the dopamine receptor D2 gene was more frequent in parkinsonian subjects than in control subjects. More important, the frequency of both the 13 allele and the 14 allele of the dopamine receptor D2 gene polymorphism was higher in nondyskinetic than in the dyskinetic PD subjects. The risk reduction of developing peak-dose dyskinesias for PD subjects carrying at least 1 of the 13 or 14 alleles was 72% with respect to the PD subjects who did not carry these alleles. Certain alleles of the short tandem repeat polymorphism of the dopamine receptor D2 gene reduce the risk of developing peak-dose dyskinesias and could contribute to varying susceptibility to develop peak-dose dyskinesias during levodopa therapy.