Dyskinetic Parkinson's Disease Patients Research Articles

A video-atlas of levodopa-induced dyskinesia in Parkinson's disease: terminology matters.

Dyskinesia is a common complication of long-term levodopa therapy in patients with Parkinson's disease (PD), which often worsens the quality of life. It is usually dose-dependent and emerges possibly due to pulsatile stimulation of dopamine receptors. Delineating the pattern of dyskinesia is crucial for determining the most effective therapeutic approach, a task that often presents challenges for numerous neurologists. This article comprehensively describes various patterns of dyskinesia in PD patients and features video demonstration of some of the common forms of dyskinesia. We have used a real case scenario as an example to lead the discussion on the phenomenology, distinguishing features, and management of various types of dyskinesia. A comprehensive literature search was conducted in PubMed using "dyskinesia" as a keyword. The prototype case with videos highlights the differentiating features of dyskinesia along with the treatment strategies. A wide range of descriptive rubrics have been used for certain dyskinesia which are described in detail in this article. The newer types of dyskinesia associated with continuous dopaminergic stimulation in patients with advanced PD and their implications have been described. As there are distinct ways of managing various types of dyskinesia, understanding the phenomenology and chronology of dyskinesia is vital for the optimal management of dyskinetic PD patients. We suggest that dyskinesia should be classified broadly into peak-dose dyskinesia (PDD), biphasic dyskinesia (BD), and OFF-period dystonia. The occurrence of low-dose dyskinesia and complex dyskinesia of continuous dopaminergic treatments should be known to specialists and will require additional studies.

Lack of correlation between dyskinesia and pallidal serotonin transporter expression-induced by L-Dopa and Pramipexole in hemiparkinsonian rats

The role of pallidal serotonergic terminals in the development of L-Dopa-induced dyskinesias (LIDs) in Parkinson's disease (PD) has been recently highlighted correlating pallidal serotonin transporter (SERT) expression levels with dyskinesias severity. However, the role of external globus pallidus (GPe, GP in rodents) serotonergic function in LIDs is still controversial since several studies have shown no differences in GPe serotonin (SER) and SERT levels between dyskinetic and non-dyskinetic PD patients. In addition, the increase in pallidal SERT/dopamine transporter (DAT) binding ratio obtained in positron emission tomography studies has been shown similar in both subtypes of PD patients. Based on these controversial results, further studies are required to clarify the possible involvement of GPe serotonergic activity in LIDs expression.We investigated the pallidal SER and SERT expression changes and the abnormal involuntary movements (AIMs) induced by L-Dopa or the D3/D2 dopamine (DA) agonist, Pramipexole, in partial unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. L-Dopa treatment led to an increment of axial (p < 0.01), limb (p < 0.01), and orolingual (p < 0.01) AIMs. However, Pramipexole treatment did not induce AIMs. The number of GP SERT-positive axon varicosities was increased in L-Dopa (p < 0.05) and Pramipexole (p < 0.01) treated rats. No differences were observed in the number of GP SERT-positive varicosities between L-Dopa and Pramipexole treatments.Our results indicate a lack of correlation between GP SERT expression levels and the development of AIMs suggesting that pallidal serotonergic fibers are not responsible for LIDs. The possible involvement of the SER system in dyskinesia may include other mechanisms.

Altered brain structural topological properties in Parkinson's disease with levodopa-induced dyskinesias

ObjectivesIn this study, the alterations of structural topological properties in Parkinson's disease (PD) patients with levodopa-induced dyskinesias (LIDs) were explored using white matter structural network connectome derived from diffusion tensor imaging (DTI). Methods21 dyskinetic PD patients, 21 non-dyskinetic PD patients and 25 healthy controls were studied in global and nodal topological properties of structural networks after controlling age, gender and education. Afterwards, post hoc analyses were performed to explore further differences. Finally, multiple linear regression analysis was employed to test the associations between significant different properties and the severity of dyskinesias in PD. ResultsDyskinetic PD patients exhibited significant increased global efficiency, local efficiency, clustering coefficient, but decreased shortest path length compared with the non-dyskinetic. Additionally, increased nodal efficiency in bilateral inferior frontal gyrus (IFG), right putamen, right thalamus, and decreased nodal shortest path length in bilateral IFG and right thalamus, were discovered in dyskinetic PD in comparison with non-dyskinetic PD. Notably, a negative correlation between the Abnormal Involuntary Movement Scale (AIMS) scores and shortest path length of whole-brain network was found in PD with LIDs. ConclusionsOur results indicated excessively optimized topological organization of whole-brain structural connectome in PD patients with LIDs. These findings also illustrated that excessively strengthened basal ganglia-thalamocortical nodal structural connections played an important role in the presence of LIDs.

Animal models of L-DOPA-induced dyskinesia: the 6-OHDA-lesioned rat and mouse.

Appearance of L-DOPA-induced dyskinesia (LID) represents a major limitation in the pharmacological therapy with the dopamine precursor L-DOPA. Indeed, the vast majority of parkinsonian patients develop dyskinesia within 9-10years of L-DOPA oral administration. This makes the discovery of new therapeutic strategies an important need. In the last decades, several animal models of Parkinson's disease (PD) have been developed, to both study mechanisms underlying PD pathology and treatment-induced side effects (i.e., LID) and to screen for new potential anti-parkinsonian and anti-dyskinetic treatments. Among all the models developed, the 6-OHDA-lesioned rodents represent the models of choice to mimic PD motor symptoms and LID, thanks to their reproducibility and translational value. Under L-DOPA treatment, rodents sustaining 6-OHDA lesions develop abnormal involuntary movements with dystonic and hyperkinetic features, resembling what seen in dyskinetic PD patients. These models have been extensively validated by the evidence that dyskinetic behaviors are alleviated by compounds reducing dyskinesia in patients and non-human primate models of PD. This article will focus on the translational value of the 6-OHDA rodent models of LID, highlighting their main features, advantages and disadvantages in preclinical research.

Markers of impaired motor and cognitive volition in Parkinson's disease: Correlates of dopamine dysregulation syndrome, impulse control disorder, and dyskinesias

IntroductionDopaminergic therapy in Parkinson's disease (PD) can be associated with both motoric (e.g., dyskinesias) and neuropsychiatric adverse effects. Examples of the latter include Dopamine Dysregulation Syndrome (DDS) and impulse control disorder (ICD), which are separate but related behavioral/psychiatric complications of treatment in PD. Dysregulation of volition characterizes both dyskinesias and DDS/ICD; thus, we analyzed potential disease-related correlates in a large PD cohort. MethodsWe analyzed cross-sectional data from 654 participants collected through the NINDS Parkinson's Disease Biomarkers Program. DDS/ICD symptoms and dyskinesias were assessed using the Movement Disorders Society (revised) Unified Parkinson's Disease Rating Scale. Potential associated variables were selected from PD-validated or PD-specific scales of neuropsychiatric or motoric status. Multivariable models with DDS/ICD or dyskinesia presence outcomes were produced with backward stepwise regression to identify factors independently associated with DDS/ICD and/or dyskinesias. ResultsFifty-three (8.1%) participants endorsed DDS and/or ICD symptoms and 150 (22.9%) were dyskinetic. In multivariable analysis, psychosis was independently associated with both dyskinesias (p = 0.006) and DDS/ICD (p < 0.001). Unpredictable motor fluctuations (p = 0.026) and depression (p = 0.023) were also associated with DDS/ICD; female sex (p = 0.025), low tremor score (p = 0.001) and high akinesia-rigidity score (p < 0.001) were associated with dyskinesias. ConclusionsOur findings suggest that psychosis may be an important marker of impaired volition across motor and cognitive domains. Unpredictable motor fluctuations, psychosis, and depression may together comprise a phenotypic profile of patients at increased risk for DDS/ICD. Similarly, dyskinetic PD patients should be closely monitored for psychotic symptoms and treated appropriately.

Levodopa treatment and dendritic spine pathology.

ABSTRACTParkinson's disease (PD) is a neurodegenerative disorder associated with the progressive loss of nigrostriatal dopaminergic neurons. Levodopa is the most effective treatment for the motor symptoms of PD. However, chronic oral levodopa treatment can lead to various motor and nonmotor complications because of nonphysiological pulsatile dopaminergic stimulation in the brain. Examinations of autopsy cases with PD have revealed a decreased number of dendritic spines of striatal neurons. Animal models of PD have revealed altered density and morphology of dendritic spines of neurons in various brain regions after dopaminergic denervation or dopaminergic denervation plus levodopa treatment, indicating altered synaptic transmission. Recent studies using rodent models have reported dendritic spine head enlargement in the caudate‐putamen, nucleus accumbens, primary motor cortex, and prefrontal cortex in cases where chronic levodopa treatment following dopaminergic denervation induced dyskinesia‐like abnormal involuntary movement. Hypertrophy of spines results from insertion of alpha‐amino‐2,3‐dihydro‐5‐methyl‐3‐oxo‐4‐isoxazolepropanoic acid receptors into the postsynaptic membrane. Such spine enlargement indicates hypersensitivity of the synapse to excitatory inputs and is compatible with a lack of depotentiation, which is an electrophysiological hallmark of levodopa‐induced dyskinesia found in the corticostriatal synapses of dyskinetic animals and the motor cortex of dyskinetic PD patients. This synaptic plasticity may be one of the mechanisms underlying the priming of levodopa‐induced complications such as levodopa‐induced dyskinesia and dopamine dysregulation syndrome. Drugs that could potentially prevent spine enlargement, such as calcium channel blockers, N‐methyl‐D‐aspartate receptor antagonists, alpha‐amino‐2,3‐dihydro‐5‐methyl‐3‐oxo‐4‐isoxazolepropanoic acid receptor antagonists, and metabotropic glutamate receptor antagonists, are candidates for treatment of levodopa‐induced complications in PD. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Cortical plasticity and levodopa-induced dyskinesias in Parkinson's disease: Connecting the dots in a multicomponent network.

Levodopa-induced dyskinesias are motor complications following long term dopaminergic therapy in Parkinson's disease (PD). Impaired brain plasticity resulting in the creation of aberrant motor maps intended to encode normal voluntary movement is proposed to result in the development of dyskinesias. Traditionally, the various nodes in the motor network like the striato-cortical and the cerebello-thalamic loops were thought to function independent of each other with little communication among them. Anatomical evidence from primates revealed the existence of reciprocal loops between the basal ganglia and the cerebellum providing an anatomical basis for communication between the motor network loops. Dyskinetic PD patients reveal impaired brain plasticity within the motor cortex which may be modulated by cortico-cortical, cerebello-cortical or striato-cortical connections. In this article, we review the evidence for altered plasticity in the multicomponent motor network in the context of levodopa induced dyskinesias in PD. Current evidence suggests a pivotal role for the cerebellum in the larger motor network with the ability to integrate sensorimotor information and independently influence multiple nodes in this network. Targeting the cerebellum seems to be a justified approach for future interventions aimed at attenuating levodopa-induced dyskinesias.

Monoamine transporter contributions to l-DOPA effects in hemi-parkinsonian rats

l-DOPA is the standard treatment for Parkinson's disease (PD), but chronic treatment typically leads to abnormal involuntary movement or dyskinesia (LID) development. Although poorly understood, dyskinetic mechanisms involve a complex interaction between the remaining dopamine system and the semi-homologous serotonin and norepinephrine systems. Serotonin and norepinephrine transporters (SERT and NET, respectively) have affinity for dopamine uptake especially when dopamine transporters (DAT) are scant. Monoamine reuptake inhibitors have been reported to modulate l-DOPA's anti-parkinsonian effects, but DAT, SERT, and NET's contribution to dyskinesia has not been well delineated. The current investigation sought to uncover the differential expression and function of DAT, SERT, and NET in the l-DOPA-treated hemi-parkinsonian rat. Protein analysis of striatal monoamine transporters in unilateral sham or 6-hydroxydopamine-lesioned rats treated with l-DOPA (0 or 6 mg/kg) showed lesion-induced DAT loss and l-DOPA-induced gain in SERT:DAT and NET:DAT ratios in lesioned rats which positively correlated with dyskinesia expression, suggesting functional shifts among monoamine transporters in the dyskinetic state. SERT blockade with citalopram (3, 5 mg/kg) reduced LID while DAT and NET blockade with GBR-12909 (5, 10 mg/kg) and nisoxetine (5, 10 mg/kg), respectively, mildly exacerbated dyskinesia expression. Transporter inhibition did not significantly alter l-DOPA's ability to reverse motor deficit. Overall, DA and DAT loss with l-DOPA treatment appear to precipitate gain in SERT and NET function. Strong correlations with LID and direct behavioral comparisons of selective transporter blockade reveal novel implications for SERT, DAT, and NET as potential biomarkers and therapeutic targets in the hemi-parkinsonian model and dyskinetic PD patients.

NMDA receptor GluN2A/GluN2B subunit ratio as synaptic trait of levodopa-induced dyskinesias: from experimental models to patients.

Levodopa-induced dyskinesias (LIDs) are major complications in the pharmacological management of Parkinson’s disease (PD). Abnormal glutamatergic transmission in the striatum is considered a key factor in the development of LIDs. This work aims at: (i) characterizing N-methyl-D-aspartate (NMDA) receptor GluN2A/GluN2B subunit ratio as a common synaptic trait in rat and primate models of LIDs as well as in dyskinetic PD patients; and (ii) validating the potential therapeutic effect of a cell-permeable peptide (CPP) interfering with GluN2A synaptic localization on the dyskinetic behavior of these experimental models of LIDs. Here we demonstrate an altered ratio of synaptic GluN2A/GluN2B-containing NMDA receptors in the striatum of levodopa-treated dyskinetic rats and monkeys as well as in post-mortem tissue from dyskinetic PD patients. The modulation of synaptic NMDA receptor composition by a cell-permeable peptide interfering with GluN2A subunit interaction with the scaffolding protein postsynaptic density protein 95 (PSD-95) leads to a reduction in the dyskinetic motor behavior in the two animal models of LIDs. Our results indicate that targeting synaptic NMDA receptor subunit composition may represent an intriguing therapeutic approach aimed at ameliorating levodopa motor side effects.

Serotonin impairment in CSF of PD patients, without an apparent clinical counterpart.

In Parkinson's disease (PD), several studies have detected an impaired serotonin (5-HT) pathway, likely affecting both motor and non-motor domains. However, the precise impact of 5-HT impairment is far from established. Here, we have used a HPLC chromatographic method, in a homogenous cohort (n = 35) of non fluctuating, non dyskinetic PD patients, to assess the concentration of 5-HT and its metabolite 5-HIAA in peripheral cerebrospinal fluid (CSF) obtained from lumbar puncture (LP). LP was performed following three days of therapy withdrawal, in order to vanish the effects of prolonged released dopamine agonists (DA), and in absence of any serotonergic agent. The PD patient group showed a significantly reduced CSF level of both 5-HT and 5-HIAA compared to either age-matched control subjects (n = 18), or Alzheimer's disease patients (n = 20). However, no correlation emerged between 5-HT/5-HIAA concentrations and UPDRS-III (r = −0.12), disease duration (r = −0.1), age (r = −0.27) and MMSE (r = 0.11). Intriguingly, low CSF 5-HT levels did not differ for gender or for motor phenotype (in terms of non-tremor dominant subtype and tremor dominant subtype). Further, low CSF 5-HT levels did not correlate with the presence of depression, apathy or sleep disturbance. Our findings support the contention that 5-HT impairment is a cardinal feature of stable PD, probably representing a hallmark of diffuse Lewy bodies deposition in the brainstem. However, clinical relevance remains uncertain. Given these findings, an add-on therapy with serotonergic agents seems questionable in PD patients, or should be individually tailored, unless severe depression is present.

Prefrontal alterations in Parkinson's disease with levodopa‐induced dyskinesia during fMRI motor task

Levodopa-induced dyskinesia represents disabling complication of long-term therapy with dopaminergic drugs in treating Parkinson's disease (PD). Recently, our group demonstrated that PD patients with levodopa-induced dyskinesia were characterized by abnormal volumetric changes in the inferior prefrontal gyrus. In this study, the functional relevance of this structural abnormality was explored using functional magnetic resonance imaging. Ten dyskinetic PD patients and 10 nondyskinetic PD patients were studied in the OFF phase with functional magnetic resonance imaging while performing externally and internally triggered visuomotor tasks. Although neither group demonstrated behavioral differences during execution of motor tasks, magnetic resonance imaging analysis detected significant changes in target cortical regions. In particular, PD patients with levodopa-induced dyskinesia showed significant overactivity in the supplementary motor area and underactivity in the right inferior prefrontal gyrus during execution of both tasks when compared with PD patients without levodopa-induced dyskinesia. Moreover, these prefrontal functional alterations were significantly correlated with Abnormal Involuntary Movement Scale scores. This functional magnetic resonance imaging study together with our previous volumetric findings highlights the role of the prefrontal cortex in the neuronal mechanisms of dyskinesia.

Dyskinetic Parkinson’s disease patients demonstrate motor abnormalities off medication

The pathophysiology of L-dopa-induced dyskinesias (LIDs) in Parkinson's disease (PD) remains poorly understood. The presence of superimposed LIDs clearly differentiates motor performance of dyskinetic from non-dyskinetic PD subjects when they are on medication, but here, we investigated whether their respective motor performance differs while subjects are off L-dopa medication and LIDs are not apparent. We assessed the motor performance of nine dyskinetic and ten non-dyskinetic PD subjects off L-dopa, and of ten age-matched control subjects, during a visually guided tracking task. As previous studies have suggested that linear dynamical system (LDS) models are useful to assess motor performance in PD in addition to overall tracking error, we used LDS models to assess the damping ratio parameter of motor behavior while controlling for disease severity. While overall tracking error did not significantly differ across groups, dyskinetic PD subjects demonstrated a significantly decreased mean damping ratio compared with control and non-dyskinetic PD subjects. For both groups, greater disease severity significantly predicted a lower damping ratio, but even after controlling for disease severity, the damping ratio for dyskinetic subjects was significantly lower. Our results demonstrate, somewhat counter-intuitively, that motor performance of dyskinetic and non-dyskinetic PD subjects differ, even off L-dopa when no dyskinesias are seen. A decreased damping ratio is indicative of a tendency to overshoot a target during motor performance, similar to the dysmetria found in cerebellar patients. We discuss the possibility of motor abnormalities in dyskinetic PD patients off medication in relation to altered functional cerebellar changes described in PD.

Actigraphic Evaluation of Motor Fluctuations in Patients with Parkinson's Disease

ABSTRACTBackground: There is growing interest in developing inexpensive and objective motor fluctuation evaluation methods for Parkinson's disease (PD). Objectives: We aim to compare activity level in the off state, on state, and dyskinetic periods as evaluated either by a physician during a levodopa challenge or by a 72-hr on–off diary self-evaluation in the ambulatory setting. Finally, the effect of daily activities on motor activity in PD and healthy controls was further explored. Methods: The study was conducted in three consecutive phases. For phase I, in which the on state, off state, and dyskinesia were evaluated using actigraphy, recordings were made during standard acute levodopa challenge in nine dyskinetic PD patients. For phase II, a different set of 16 dyskinetic PD patients was monitored in the ambulatory setting for 72 consecutive hours by actigraphy and a standardized on–off diary. For phase III, 62 PD patients and 14 age- and sex-matched healthy controls wore an actigraph and completed a daily activities diary for 7 days. Results: No differences in activity level between on state and off state during the acute levodopa challenge (phase I) or the 72-hr ambulatory period (phase II) were found. Activity during dyskinesia periods was significantly higher than during on state periods without dyskinesia (p < .01). During the third phase, dyskinetic PD patients and healthy controls showed higher actigraphy-measured activity as compared to de novo, stable, or fluctuating PD (p < .0001), which remained unaltered by daily activities performed during the study period. Tremor UPDRS scores did not correlate with activity level. Conclusions: These results confirm the lack of specificity of simple wrist-worn actigraphy and further suggest it may be suitable for dyskinesia assessment but not for on state and off state evaluation.

RTMS effects on levodopa induced dyskinesias in Parkinson's disease patients: Searching for effective cortical targets

Long-term therapy with levodopa and dopamine agonists in Parkinson's disease (PD) patients is complicated by the development of fluctuations in motor response, such as levo-dopa induced dyskinesia (LID). Repetitive Transcranial Magnetic Stimulation (rTMS) has been recently put forward as a possible therapeutic tool able to LID in PD. Trains of 1 Hz rTMS applied either over the supplementary motor area (SMA) or the primary motor cortex (M1) were able to induce a transient reduction in the severity of LID, confirming that an over-activity of these areas plays a crucial role in the pathophysiology of LID. However, repeated sessions of rTMS were not effective in inducing persistent beneficial clinical effects. Functional or metabolic changes have been reported in the cerebellum in studies in PD patients treated with procedures known to alleviate LID, such as deep brain stimulation. Therefore, the effects of rTMS applied over the lateral cerebellum has been recently tested in patients with LID. A two-week course of bilateral cerebellar rTMS induced persistent clinical beneficial effects, reducing peak-dose LID for up to four weeks after the end of the daily stimulation period. These findings demonstrate that rTMS is a potential tool in individuating the best cortical targets and the optimal parameters of stimulation able to improve LID in dyskinetic PD patients.

Placebo influences on dyskinesia in Parkinson's disease

Clinical features that are prognostic indicators of placebo response among dyskinetic Parkinson's disease patients were determined. Placebo-associated improvements occur in Parkinsonism, but responses in dyskinesia have not been studied. Placebo data from two multicenter studies with identical design comparing sarizotan to placebo for treating dyskinesia were accessed. Sarizotan (2 mg/day) failed to improve dyskinesia compared with placebo, but both treatments improved dyskinesia compared with baseline. Stepwise regression identified baseline characteristics that influenced dyskinesia response to placebo, and these factors were entered into a logistic regression model to quantify their influence on placebo-related dyskinesia improvements and worsening. Because placebo-associated improvements in Parkinsonism have been attributed to heightened dopaminergic activity, we also examined the association between changes in Parkinsonism and dyskinesia. Four hundred eighty-four subjects received placebo treatment; 178 met criteria for placebo-associated dyskinesia improvement and 37 for dyskinesia worsening. Older age, lower baseline Parkinsonism score, and lower total daily levodopa doses were associated with placebo-associated improvement, whereas lower baseline dyskinesia score was associated with placebo-associated worsening. Placebo-associated dyskinesia changes were not correlated with Parkinsonism changes, and all effects in the sarizotan group were statistically explained by the placebo-effect regression model. Dyskinesias are affected by placebo treatment. The absence of correlation between placebo-induced changes in dyskinesia and Parkinsonism argues against a dopaminergic activation mechanism to explain placebo-associated improvements in dyskinesia. The magnitude and variance of placebo-related changes and the factors that influence them can be helpful in the design of future clinical trials of antidyskinetic agents.

Prevalence and treatment strategies of dyskinesia in patients with Parkinson’s disease

A study into the prevalence and treatment of dyskinesia in Parkinson's disease (PD) patients was performed with 380 PD specialists' completed interviews relating to PD and retrospectively completed 1900 patient record forms for patients with dyskinesia. Physicians reported, that 34% of their PD patients experience dyskinesia, 57% of dyskinetic PD patients were affected by moderately-to-completely disabling dyskinesia. Treatment of dyskinesia was looked upon as not satisfactory, fractionating of levodopa dose was used as first choice therapeutic option of dyskinesia.

Bradykinesia in patients with Parkinson's disease having levodopa-induced dyskinesias

We investigated the likelihood that bradykinesia coexisted with levodopa-induced dyskinesias (LID) in 10 dyskinetic Parkinson's disease patients (DPD). Their motor performance was compared to that of 10 age/gender-matched non-dyskinetic patients (NDPD) and 10 healthy controls. Whole-body movement (WBM) and rapid alternating movements (RAM) at the wrist were recorded simultaneously using 6-degree of freedom magnetic motion tracker and forearm rotational sensors, respectively. WBM was recorded prior to, and while subjects performed pronation–supination movements of their dominant hand with maximal rotational excursion, and as fast as possible for 10s. RANGE, VELOCITY and IRREGULARITY of pronation–supination cycles were quantified to assess motor performance. Results show that DPD patients had greater WBM than NDPD and controls during rest and RAM performance, as expected. There were no differences in motor performance between DPD and NDPD groups for RANGE and VELOCITY, despite significantly longer disease duration for the DPD group (15.5 ± 6.2 years versus 6.6 ± 2.6 years). However, both the NDPD and DPD groups showed significantly lower RANGE and reduced VELOCITY compared to controls, suggesting the presence of bradykinesia. For IRREGULARITY, DPD patients showed increased fluctuations in pronation–supination cycle amplitude compared to NDPD and controls. However, the lack of correlation between WBM magnitude and IRREGULARITY within the DPD group (Spearman's rank order, ρ = 0.31, p > 0.05), suggests that LID were not the primary cause of increased IRREGULARITY. In conclusion, our results demonstrated that bradykinesia can coexist with dyskinesias, suggestive of distinct neural circuits. Our results also demonstrated that the occurrence of LID is not inevitably accompanied with worsening of motor performance.

Increased adenosine A2A receptors in the brain of Parkinson's disease patients with dyskinesias.

Brain adenosine A2A receptors have recently attracted considerable attention because of their interaction with the dopaminergic system and as potential targets for Parkinson's disease pharmacotherapy. Post mortem adenosine A2A receptor mRNA and [3H]SCH 58261- specific binding to adenosine A2A receptor were studied in the brain of Parkinson's disease patients using in situ hybridization and receptor binding autoradiography, respectively. Fourteen levodopa-treated Parkinson's disease patients, of which seven developed dyskinesias and seven did not, were compared with nine controls. Nigrostriatal denervation was similar between dyskinetic and non-dyskinetic Parkinson's disease patients, as assessed with catecholamine concentrations and [125I]RTI-121-specific binding to dopamine transporters. A2A receptor mRNA levels (+129%; P < 0.01) and [3H]SCH 58261-specific binding (+32%, P < 0.01) were increased in the putamen (lateral and medial) of dyskinetic patients compared with controls. The increase of adenosine A2A receptor mRNA in dyskinetic Parkinson's disease patients was also significant compared with non-dyskinetic Parkinson's disease patients (+60%; P < 0.05) in the lateral putamen. Moreover, [3H]SCH 58261-specific binding to adenosine A2A receptors was increased in the external globus pallidus (+24%; P < 0.001) of Parkinson's disease patients compared with controls, regardless of the dyskinesigenic response to levodopa. No change of adenosine A2A receptors was observed in the caudate nucleus, whereas adenosine A2A receptor protein and mRNA levels in the internal globus pallidus were not different from background. These findings suggest that increased synthesis of adenosine A2A receptors in striatopallidal pathway neurons is associated with the development of dyskinesias following long-term levodopa therapy in Parkinson's disease.

Effects of dopamine metabolites on locomotor activities and on the binding of dopamine: Relevance to the side effects of L-dopa

L-dopa is the major treatment for Parkinson's disease (PD), but its efficacy is limited by the presence of dyskinesia. The dyskinesia develops over a period of exposure to L-dopa and is related to the dosage, therefore, the cause may involve inductive changes that produce toxic levels of metabolites, interfering with dopamine (DA) neurotransmission. Chronic L-dopa induces catechol-O-methyltransferase (COMT) and methionine adenosyl transferase (MAT), enzymes involved in the methylation of catecholamines (CA). In addition, high levels of 3-O-methyl-dopa have been reported in the plasma of dyskinetic PD patients, treated with L-dopa, as compared to non-dyskinetic patients, therefore, the methyl metabolites of CA may be increased during L-dopa therapy and may be involved in the dyskinesia. Since large amounts of DA are produced from L-dopa and DA is extensively methylated, the methyl metabolites of DA, 3-methoxytyramine (3-MT) and 3,4-dimethoxyphenylethylamine (DIMPEA), may be also involved. The first step in knowing this, is to assess the behavioral and DA-receptor activities of 3-MT and DIMPEA. In the rat, the intraventricular injection of 0.5 μM of DIMPEA increased the total distance traveled (TD) by over 100%, the number of movement (NM) made by 40% and the time spent moving (MT) by about 36%. Identical doses of 3-MT decreased the TD by 42%, NM by 22% and MT by 39%. DIMPEA (1 mM) increased the binding of DA with brain membranes by 44.7%, whereas 3-MT decreased it by 15.8%. The results show that 3-MT and DIMPEA are behaviorally active and in parallel, they interact with the binding sites for DA, consequently, they may contribute to the side effects of L-dopa. L-dopa produces high levels of DA and induces MAT and COMT. It is proposed, therefore, that DA will be methylated to 3-MT and 3-MT to DIMPEA. At threshold level each product will inhibit, allosterically, its enzyme of methylation, causing sequential and rhythmic up and down regulation of its concentration. At peak levels these hydrophobic metabolites will modulate the actions of DA on synaptic membranes, causing abnormal movements, at times, resembling the “on-off effects”.