Emergence Of Dyskinesia Research Articles

Glutamate modulation for the treatment of levodopa induced dyskinesia: abrief review of the drugs tested in the clinic.

Levodopa is the standard treatment for Parkinson's disease, but its use is marred by the emergence of dyskinesia, for which treatment options remain limited. Here, we review the glutamatergic modulators that were assessed for their antidyskinetic potential in clinical trials, including N-methyl-D-aspartate (NMDA) antagonists, agonists at the glycine-binding site on NMDA receptors, metabotropic glutamate (mGlu) 4 agonists, mGlu5 antagonists, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonists and glutamate release inhibitors. Several agents that were investigated are not selective for their targets, raising uncertainty about the extent to which glutamatergic modulation contributed to their effects. Except for amantadine, the use of glutamatergic modulators for the treatment of dyskinesia in Parkinson's disease remains largely investigational, with promising results obtained with mGlu5 negative allosteric modulation.

Altered interhemispheric synchrony in Parkinson\u2019s disease patients with levodopa-induced dyskinesias

Levodopa-induced dyskinesias are common motor complication of Parkinson’s disease after 4–6 years of treatment. The hallmarks of dyskinesias include unilateral onset and the tendency to appear on the more affected body sides. There is a growing literature documenting the lateralization abnormalities are associated with the emergence of dyskinesias. Our investigation aimed to explore interhemispheric functional and its corresponding morphological asymmetry. A total of 22 dyskinetic patients, 23 nondyskinetic patients, and 26 controls were enrolled. Resting-state functional magnetic resonance imaging scans were performed twice before and after dopaminergic medication. Voxel-mirrored Homotopic Connectivity (VMHC) and Freesurfer were employed to assess the synchronicity of functional connectivity and structural alternations between hemispheres. During OFF state, dyskinetic patients showed desynchronization of inferior frontal cortex (IFC) when compared to nondyskinetic patients. And during ON state, dyskinetic patients showed desynchronization of IFC and pre-supplementary motor area (pre-SMA) when compared to nondyskinetic patients. However, there was no corresponding significant asymmetries in cortical thickness. Moreover, the degree of desynchronization of IFC and pre-SMA in dyskinetic pateients during ON state were negatively correlated with the Abnormal Involuntary Movement Scale (AIMS) scores. Notably, among patients who showed asymmetrical dyskinesias, there was a significant negative correlation between VMHC values of IFC and dyskinesias symptom asymmetry. Our findings suggested that uncoordinated inhibitory control over motor circuits may underlie the neural mechanisms of dyskinesias in Parkinson’s disease and be related to its severity and lateralization.

Factors Associated With Dyskinesia in Parkinson's Disease in Mainland China.

Background and Objectives: Studies examining the risk factors for dyskinesia in Parkinson's disease (PD) have been inconsistent, and racial differences exist. Since there have been no systematic studies of the characteristics of dyskinesia in the Mainland Chinese population, we sought to elucidate the risk factors for dyskinesia.Methods: A total of 1974 PD patients from Mainland China were systematically investigated by univariable and multivariable analyses. PD patients with and without dyskinesia were stratified into 4 groups according to levodopa equivalent daily dose (LEDD) and analyzed by a Cox proportional hazards model. A longitudinal study of 87 patients with dyskinesia was classified into 3 groups according to the duration from onset of PD to the initiation of levodopa, and comparisons among groups were analyzed by the Mann-Whitney test.Results: Early age of onset, long disease duration, being female, high LEDD, low UPDRS III scores (ON-state) and high Hoehn-Yahr stage (ON-state) were predictors of dyskinesia. Dyskinesia was levodopa dosage-dependent, and the incidence increased remarkably when LEDD exceeded 300 mg/d (p < 0.05). The emergence of dyskinesia had no association with the initiation time of levodopa, and if the latter was more than 4 years, the duration of time on chronic levodopa free of motor complications was significantly shortened.Conclusions: We found risk factors for the prediction of dyskinesia. Our data shows that physicians should be cautious if the LEDD exceeds 300 mg/d. The development of dyskinesia was not correlated with the time of levodopa initiation.

Dopamine Reuptake Inhibitors in Parkinson's Disease: A Review of Nonhuman Primate Studies and Clinical Trials.

Striatal dopamine deficiency is the core feature of the pathology of Parkinson's disease (PD), and dopamine replacement with l-3,4-dihydroxyphenylalanine (l-DOPA) is the mainstay of PD treatment. Unfortunately, chronic l-DOPA administration is marred by the emergence of dyskinesia and wearing-off. Alternatives to l-DOPA for alleviation of parkinsonism are of interest, although none can match the efficacy of l-DOPA to date. Catechol-O-methyltransferase and monoamine oxidase inhibitors are currently used to alleviate wearing-off, but they do not increase "on-time" without exacerbating dyskinesia. Alternate approaches to dopamine replacement in parkinsonism generally (and to wearing-off and dyskinesia, specifically) are therefore urgently needed. Inasmuch as they increase synaptic dopamine levels, dopamine transporter (DAT) inhibitors, whether they are selective or have actions on noradrenaline or serotonin transporters, theoretically represent an attractive way to alleviate parkinsonism per se and potentially enhance l-DOPA antiparkinsonian action (provided that sufficient dopamine terminals remain within the striatum). Several nonhuman primate studies and clinical trials have been performed to evaluate the potential of DAT inhibitors for PD. In this article, we review nonhuman primate studies and clinical trials, we summarize the current knowledge of DAT inhibitors in PD, and we propose a hypothesis as to how tailoring the selectivity of DAT inhibitors might maximize the benefits of DAT inhibition in PD.

Dyskinesia in Parkinson's Disease Therapy

L-DOPA is still regarded as the standard pharmacotherapy for the treatment of the motor symptoms of Parkinson's disease (PD). However, the efficacy of this drug is limited by the emergence of dystonic and choreic involuntary movements, generally referred to as dyskinesia. Current interventions to treat dyskinesia are mainly based on continuous delivery of L-DOPA, administration of glutamatergic drugs (i.e., amantadine), replacement or combined administration of L-DOPA with less dyskinetic, albeit less effective, dopaminergic agonists, and deep-brain stimulation of discrete regions of the basal ganglia. Preclinical research, on the other hand, is searching for novel approaches to the treatment of L-DOPA-induced dyskinesia, targeting alternative neurotransmitter systems, such as the serotonin, adenosine, and opioid systems, or identifying abnormalities in intracellular signal transduction and synaptic plasticity associated to this condition. This Special Issue discusses recent breakthroughs in this direction and, at the same time, provides an update of the clinical features and management of L-DOPA-induced dyskinesia. The article by J. Guridi et al. describes the mechanisms underlying the various forms of dyskinesia produced by prolonged administration of L-DOPA. Basic pathophysiological mechanisms and current treatments are presented in detail and critically discussed. I. Aviles-Olmos et al. focus on the comparison between L-DOPA-induced dyskinesia and graft-induced dyskinesia, an analogous condition observed in response to transplantation of fetal dopaminergic cells in PD patients. This article also provides a timely discussion of the use of gene therapy in PD and of its effects on dyskinesia. The article by N. Tambasco et al. presents the clinical and epidemiological characteristics of dyskinesia and describes the management of this condition, based on the use of various types of dopaminergic agonists. On the same line, J. C. P. Piedad and A. E. Cavanna discuss more in detail the use of pramipexole, an agonist at dopamine D2-type receptors, in the treatment of dyskinesia. A number of signaling components potentially implicated in dyskinesia have been discovered during the last decade. In this regard, V. Ghiglieri et al. provide a comprehensive overview of the mechanisms and the possible pathological consequences of abnormalities affecting various forms of corticostriatal plasticity associated to L-DOPA-induced dyskinesia. Recently, studies have pointed to the serotonergic system as a key player in the aberrant effects produced by L-DOPA and linked to the emergence of dyskinesia. The article by S. Navailles and P. De Deurwaerdere describes the evidence at the basis of this hypothesis and discusses the use of therapeutic approaches designed to prevent this phenomenon. On the same subject, E. Shin et al. discuss the experimental and clinical evidence implicating the serotonin system in L-DOPA- and graft-induced dyskinesia. Drugs acting as antagonists at adenosine A2A receptors have attracted considerable interest as antiparkinsonian and antidyskinetic agents. The article by M. Morelli et al. provides a critical appraisal of the potential therapeutic properties of these compounds, as determined in experimental models of PD and L-DOPA-induced dyskinesia. Finally, G. Frazzitta et al. present an interesting study showing the beneficial effects produced on dyskinesia by intensive physiotherapeutic rehabilitation. These results are discussed with regard to similar studies performed in animal models of PD.

Striatal inhibition of calpains prevents levodopa-induced neurochemical changes and abnormal involuntary movements in the hemiparkinsonian rat model

Pharmacological dopamine replacement with l-3,4-dihydroxyphenylalanine (l-DOPA) remains the most effective approach to treat the motor symptoms of Parkinson's disease (PD). However, as the disease progresses, the therapeutic response to l-DOPA gradually becomes erratic and is associated with the emergence of dyskinesia in the majority of patients. The pathogenesis of l-DOPA-induced dyskinesia (LID) is still unknown. In the current study, using the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD, we demonstrated that the calcium-dependent proteins calpains and cdk5 of the striatum play a critical role in the behavioral and molecular changes evoked by l-DOPA therapy. We first confirmed that l-DOPA reversed PD symptoms, assessed by the cylinder, stepping and vibrissae-elicited reaching tests in this animal model, and elicited robust abnormal involuntary movements (AIMs) reminiscent of LID. Interestingly, intrastriatal infusion of the calpains inhibitor MDL28170, and to a lower extent the cdk5 inhibitor roscovitine, reduced the severity and amplitude of AIMs without affecting l-DOPA's antiparkinsonian effects. Notably, the calpains and cdk5 inhibitors totally reversed the striatal molecular changes attributed to l-DOPA therapy, such as ERK1/2 and dynamin phosphorylation. Another fascinating observation was that l-DOPA therapy, in combination with intrastriatal infusion of MDL28170, augmented tyrosine hydroxylase levels in the striatum of lesioned rats without affecting the number of dopaminergic cells in the substantia nigra. These findings disclose a novel mechanism underlying the maladaptive alterations induced by l-DOPA therapy in the 6-OHDA rat model of PD.

Contribution of pre-synaptic mechanisms to l-DOPA-induced dyskinesia

Positron emission tomography (PET) imaging studies have shown that peak-dose dyskinesia is associated to abnormally high levels of synaptic dopamine (DA) in the caudate-putamen of dyskinetic L-DOPA-treated patients. High striatal extracellular DA levels have also been found in dyskinetic 6-OHDA-lesioned rats as compared to non-dyskinetic ones, suggesting that extracellular DA levels may play a key role in the induction of dyskinesia. In this article we review the evidences pointing to the serotonin system as the primary cause for the abnormally high levels of L-DOPA-derived extracellular DA in Parkinson's disease, and we discuss the feasibility of a therapeutic approach targeting this system.

Anatomic Localization of Dyskinesia in Children with “Profound” Perinatal Hypoxic-Ischemic Injury

CP is a common feature of perinatal HIBD in the context of "acute profound" injury, and in this article, we have studied the possible anatomic substrates of dyskinesia. We have reviewed the extent of brain injury in children with dyskinetic and spastic CP due to acute profound hypoxia to identify sites of injury that explain why only some children develop movement disorders. It is known that the STN has a role in the development of movement disorders; therefore, we have specifically studied it. We retrospectively reviewed MR imaging of 40 consecutive children referred to our center with CP confirmed to be due to acute profound hypoxic-ischemic injury. All children received the same high-resolution MR imaging protocol with the same 1.5T scanner. Two pediatric neuroradiologists reviewed the imaging. Logistic regression was applied to identify multivariable predictors that differentiate dyskinetic and spastic CP. Twenty children had dyskinetic CP and 20 had spastic CP. Children with dyskinetic CP had more frequent injury to the STN, as manifest by increased T2 signal intensity. Children with spastic CP had more severe damage to white matter in the vicinity of the paracentral lobule. Injuries to the putamen, caudate, and globus pallidus were not significant predictors of dyskinesia. We have shown an association between hypoxic-ischemic injury to the STN at birth and the emergence of dyskinesia later in life.

Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson's disease: implications for dyskinesias.

Peak-dose dyskinesias are abnormal movements that usually occur 1 h after oral administration of levodopa, and often complicate chronic treatment of Parkinson's disease. We investigated by PET with [11C]raclopride whether Parkinson's disease progression modifies the striatal changes in synaptic dopamine levels induced by levodopa administration, and whether this modification, if present, could have an impact on the emergence of dyskinesias. We found that, 1 h after oral administration of standard-release 250/25 mg of levodopa/carbidopa, levodopa-induced increases in synaptic dopamine levels (as estimated by striatal changes in [11C]raclopride binding potential) correlated positively with duration of Parkinson's disease symptoms (for the caudate nucleus, r = 0.79, P < 0.001; for the putamen, r = 0.88, P < 0.0001). Patients with peak-dose dyskinesias had larger 1-h increases in synaptic dopamine levels than stable responders, but there were no between-group differences in [11C]raclopride binding 4 h post-levodopa. The corresponding (time x group) interaction term in the repeated measures analysis of covariance was significant, even after adjusting for between-group differences in duration of Parkinson's disease symptoms (for the caudate nucleus, P = 0.030; for the putamen, P = 0.021). Our results indicate that, at the synaptic level, an identical dose of levodopa induces increasingly larger 1-h changes in dopamine levels as Parkinson's disease progresses. Large levodopa-induced increases in synaptic dopamine concentration can lead to dramatic changes in receptor occupancy, which may be responsible for the emergence of peak-dose dyskinesias in Parkinson's disease.

Effects of riluzole on the electrophysiological activity of pallidal neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkey

The effect of riluzole administration, an antiglutamatergic compound, on the electrophysiological activity of the pallidal complex of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys is compared with those induced by two dosages of levodopa ( l-DOPA), the first affording the best clinical alleviation, the second sufficient to induce dyskinesias. Both dosages of l-DOPA reduced sharply the firing frequency of globus pallidus pars internalis (GPi) neurons (respectively, 43.8±23.0 and 27.4±20.2 vs. 111.2±31.4 Hz), decreased the percentage of bursting cells (respectively, 60.7 and 50.0 vs. 80.3%) and augmented the number of regular cells (respectively, 6.5 and 33.0 vs. 4.8%). Riluzole restored the firing frequency (75.0±26.9 Hz) and the firing pattern of the GPi (39.7% bursting, 9.5% regular and 50.8% irregular). These results suggest that the emergence of dyskinesia may well be due to a modification of the neuronal messages transmitted from the GPi to the motor nuclei of the thalamus. Riluzole would represent an interesting alternative to dopamine therapy in Parkinson's disease since it regularizes firing but does not cause dyskinesia.

The primate subthalamic nucleus. III. Changes in motor behavior and neuronal activity in the internal pallidum induced by subthalamic inactivation in the MPTP model of parkinsonism.

1. The effects of reversible and irreversible pharmacological manipulations of the neuronal activity in the subthalamic nucleus (STN) on parkinsonian motor signs and neuronal activity in the internal segment of the globus pallidus (GPi) were studied in African green monkeys rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 2. Muscimol injections (< or = 1 microliter, 1 microgram/microliter) into STN reduced neuronal activity recorded at the injection site within minutes. This was immediately followed by reduced akinesia, tremor, and rigidity, as well as the emergence of dyskinesias in contralateral limbs. The motor effects were accompanied by generalized behavioral activation, lasted between 10 and 60 min, and were strongly dependent on the site of injection, with injections into the lateral "arm area" of STN first affecting contralateral arm movements and injections into the "leg" area affecting leg movements first. 3. Bicuculline injections (< or = 1 microliter, 1 microgram/microliter) into STN marginally increased the neuronal activity and induced neuronal discharge in bursts. Rigidity, akinesia, and tremor in the contralateral limbs were not changed. 4. Injections of ibotenic acid in two animals (2 and 7 microliters, 10 micrograms/microliters) resulted in 70 and 51% destruction of STN, respectively. Similarly to the muscimol injections, this resulted in a reduction of the neuronal activity, a reversal of parkinsonian motor signs, and the development of dyskinesias in the contralateral limbs. 5. Although tremor was significantly reduced after STN lesions, periodic oscillatory neuronal activity in GPi persisted. The strength of modulation of the neuronal oscillation was not significantly changed after STN lesion. 6. The percentage of cells in GPi exhibiting increases in discharge in response to torque application was significantly reduced after STN lesion. The magnitude and duration of the responses with increase in firing rate were reduced after STN lesioning. 7. These results support the hypothesis that abnormally increased tonic and phasic activity in STN leads to abnormal GPi activity and is a major factor in the development of parkinsonian motor signs. Furthermore they imply that cells in the basal ganglia have the intrinsic property of discharging in periodic bursts, which is unmasked under parkinsonian conditions.

A quantitative study of levodopa-induced dyskinesia in Parkinson's disease.

The present study addressed the question of whether the emergence and severity of levodopa-induced dyskinesia was related to the therapeutic benefits derived from levodopa. Eight PD patients with clinically observed levodopa-induced dyskinesia were studied prior to and for two hours following a single dose of Sinemet (carbidopa/levodopa). Quantitative instrumental procedures were used to assess upper extremity dyskinesia, rigidity and bradykinesia. Results indicated that all patients exhibited significant reduction in their parkinsonism within 45 minutes following treatment. Reduction in bradykinesia, but not rigidity appeared to coincide with the emergence of dyskinesia. There was a significant relationship between severity of dyskinesia and the degree of improvement in movement velocity but not rigidity. Further analyses revealed that this relationship depended largely on the age of the patient. These findings are discussed as they pertain to a unified model of basal ganglia movement disorders which places dyskinesia and bradykinesia at opposite extremes along a continuum.