Severe Levodopa-induced Dyskinesias Research Articles

Downregulation of striatal CaV1.3 inhibits the escalation of levodopa-induced dyskinesia in male and female parkinsonian rats of advanced age

In the past 25 years, the prevalence of Parkinson's disease (PD) has nearly doubled. Age remains the primary risk factor for PD and as the global aging population increases this trend is predicted to continue. Even when treated with levodopa, the gold standard dopamine (DA) replacement therapy, individuals with PD frequently develop therapeutic side effects. Levodopa-induced dyskinesia (LID), a common side effect of long-term levodopa use, represents a significant unmet clinical need in the treatment of PD. Previously, in young adult (3-month-old) male parkinsonian rats, we demonstrated that the silencing of CaV1.3 (Cacan1d) L-type voltage-gated calcium channels via striatal delivery of rAAV-CaV1.3-shRNA provides uniform protection against the induction of LID, and significant reduction of established severe LID. With the goal of more closely replicating a clinical demographic, the current study examined the effects of CaV1.3-targeted gene therapy on LID escalation in male and female parkinsonian rats of advanced age (18-month-old at study completion). We tested the hypothesis that silencing aberrant CaV1.3 channel activity in the parkinsonian striatum would prevent moderate to severe dyskinesia with levodopa dose escalation. To test this hypothesis, 15-month-old male and female F344 rats were rendered unilaterally parkinsonian and primed with low-dose (3–4 mg/kg) levodopa. Following the establishment of stable, mild dyskinesias, rats received an intrastriatal injection of either the Cacna1d-specific rAAV-CaV1.3-shRNA vector (CAV-shRNA), or the scramble control rAAV-SCR-shRNA vector (SCR-shRNA). Daily (M-Fr) low-dose levodopa was maintained for 4 weeks during the vector transduction and gene silencing window followed by escalation to 6 mg/kg, then to 12 mg/kg levodopa. SCR-shRNA-shRNA rats showed stable LID expression with low-dose levodopa and the predicted escalation of LID severity with increased levodopa doses. Conversely, complex behavioral responses were observed in aged rats receiving CAV-shRNA, with approximately half of the male and female subjects—therapeutic ‘Responders’—demonstrating protection against LID escalation, while the remaining half—therapeutic ‘Non-Responders’—showed LID escalation similar to SCR-shRNA rats. Post-mortem histological analyses revealed individual variability in the detection of Cacna1d regulation in the DA-depleted striatum of aged rats. However, taken together, male and female therapeutic ‘Responder’ rats receiving CAV-shRNA had significantly less striatal Cacna1d in their vector-injected striatum relative to contralateral striatum than those with SCR-shRNA. The current data suggest that mRNA-level silencing of striatal CaV1.3 channels maintains potency in a clinically relevant in vivo scenario by preventing dose-dependent dyskinesia escalation in rats of advanced age. As compared to the uniform response previously reported in young male rats, there was notable variability between individual aged rats, particularly females, in the current study. Future investigations are needed to derive the sex-specific and age-related mechanisms which underlie variable responses to gene therapy and to elucidate factors which determine the therapeutic efficacy of treatment for PD.

Dyskinesia matters.

Levodopa-induced dyskinesia (LID) represents a significant source of discomfort for people with Parkinson's disease (PD). It negatively affects quality of life, it is associated with both motor and nonmotor fluctuations, and it brings an increased risk of disability, balance problems, and falls. Although the prevalence of severe LID appears to be lower than in previous eras (likely owing to a more conservative use of oral levodopa), we have not yet found a way to prevent the development of this complication. Advanced surgical therapies, such as deep brain stimulation, ameliorate LID, but only a minority of PD patients qualify for these interventions. Although some have argued that PD patients would rather be ON with dyskinesia than OFF, the deeper truth is that patients would very much prefer to be ON without dyskinesia. As researchers and clinicians, we should aspire to make that goal a reality. To this end, translational research on LID is to be encouraged and persistently pursued. © 2019 International Parkinson and Movement Disorder Society.

Genetic silencing of striatal CaV1.3 prevents and ameliorates levodopa dyskinesia.

BackgroundLevodopa‐induced dyskinesias are an often debilitating side effect of levodopa therapy in Parkinson's disease. Although up to 90% of individuals with PD develop this side effect, uniformly effective and well‐tolerated antidyskinetic treatment remains a significant unmet need. The pathognomonic loss of striatal dopamine in PD results in dysregulation and disinhibition of striatal CaV1.3 calcium channels, leading to synaptopathology that appears to be involved in levodopa‐induced dyskinesias. Although there are clinically available drugs that can inhibit CaV1.3 channels, they are not adequately potent and have only partial and transient impact on levodopa‐induced dyskinesias.MethodsTo provide unequivocal target validation, free of pharmacological limitations, we developed a CaV1.3 shRNA to provide high‐potency, target‐selective, mRNA‐level silencing of striatal CaV1.3 channels and examined its ability to impact levodopa‐induced dyskinesias in severely parkinsonian rats.ResultsWe demonstrate that vector‐mediated silencing of striatal CaV1.3 expression in severely parkinsonian rats prior to the introduction of levodopa can uniformly and completely prevent induction of levodopa‐induced dyskinesias, and this antidyskinetic benefit persists long term and with high‐dose levodopa. In addition, this approach is capable of ameliorating preexisting severe levodopa‐induced dyskinesias. Importantly, motoric responses to low‐dose levodopa remained intact in the presence of striatal CaV1.3 silencing, indicating preservation of levodopa benefit without dyskinesia liability.DiscussionThe current data provide some of the most profound antidyskinetic benefit reported to date and suggest that genetic silencing of striatal CaV1.3 channels has the potential to transform treatment of individuals with PD by allowing maintenance of motor benefit of levodopa in the absence of the debilitating levodopa‐induced dyskinesia side effect. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Чи є місце палідотомії у сучасному лікуванні хвороби Паркінсона?

Objective – to determine the clinical significance of unilateral stereotactic radiofrequency pallidotomy (USRP) in patients with Parkinson's disease (PD) complicated by levodopa-induced dyskinesias (LID) and motor fluctuations (MF) one week and then one year after surgery. Materials and methods. From 2008 to 2016 USRP was performed in 16 patients (7 men and 9 women from 48 to 73 years old, average – 56 years) with PD complicated by LID and MF. The dynamics of the disease symptoms was interpreted on the basis of separate sections and points of the UPDRS. Results. The overall severity of contralateral LIDs decreased by 87.8 % one week after USRP, and after 1 year the difference compared with preoperative status was 85.4 %. According the assessment of axial dyskinesia, the values of the relevant indicators were 65.3 % and 42.0 %. Ipsilateral LIDs after USRP decreased by 25.0 %, but at the time of the control over the year, their severity even increased by 10.0 % compared to the preoperative level. A week after pallidotomy, a decrease in the expression of motor fluctuations was noted at 32.2 %, however, after a year this figure was 12.0 %. In assessing the effect of USRP on the separate symptoms of the OFF period of the PD, the contralateral rest tremor decreased by 70.0 % after week, and 60 % after a year of follow up. The decrease in the severity of contralateral rigidity the week after operation was noted at 71.4 %, and after a year of observation, this figure did not change significantly. The severity of contralateral hypokinesia decreased by 28.6 % in one week and 14.3 % in one year after pallidotomy. Ipsilateral tremor, rigidity and hypokinesia did not respond to intervention in any way, and, based on the results of the control, progressed insignificantly, which can be explained by the general progression of the disease. There was no positive or negative effect of USRP on postural instability. Transient speech disorders were found in 2 (12.5 %) cases. In 2 (12.5 %) patients contralateral paresis of facial muscle was observed. Conclusions. The control of contralateral LID, which has been observed for at least one year after surgery is the most prominent effect of USRP for PD. Positive effects on axial dyskinesias are partly depleted one year after the operation, while the effects on the ipsilateral LID are negligible and impermanent. The effects on motor fluctuations are moderately expiring during the year. The perceptible and persistent effects of USRP on contralateral tremor, rigidity and hypokinesia was observed. The symptoms of neurological deficitis after USRP are transient.

Altered Neuronal Firing Pattern of the Basal Ganglia Nucleus Plays a Role in Levodopa-Induced Dyskinesia in Patients with Parkinson’s Disease

Background: Levodopa therapy alleviates the symptoms of Parkinson’s disease (PD), but long-term treatment often leads to motor complications such as levodopa-induced dyskinesia (LID).Aim: To explore the neuronal activity in the basal ganglia nuclei in patients with PD and LID.Methods: Thirty patients with idiopathic PD (age, 55.1 ± 11.0 years; disease duration, 8.7 ± 5.6 years) were enrolled between August 2006 and August 2013 at the Xuanwu Hospital, Capital Medical University, China. Their Hoehn and Yahr (1967) scores ranged from 2–4 and their UPDRS III scores were 28.5 ± 5.2. Fifteen of them had severe LID (UPDRS IV scores of 6.7 ± 1.6). Microelectrode recording was performed in the globus pallidus internus (GPi) and subthalamic nucleus (STN) during pallidotomy (n = 12) or STN deep brain stimulation (DBS; bilateral, n = 12; unilateral, n = 6). The firing patterns and frequencies of various cell types were analyzed by assessing single cell interspike intervals (ISIs) and the corresponding coefficient of variation (CV).Results: A total of 295 neurons were identified from the GPi (n = 12) and STN (n = 18). These included 26 (8.8%) highly grouped discharge, 30 (10.2%) low frequency firing, 78 (26.4%) rapid tonic discharge, 103 (34.9%) irregular activity, and 58 (19.7%) tremor-related activity. There were significant differences between the two groups (p < 0.05) for neurons with irregular firing, highly irregular cluster-like firing, and low-frequency firing.Conclusion: Altered neuronal activity was observed in the basal ganglia nucleus of GPi and STN, and may play important roles in the pathophysiology of PD and LID.

709. rAAV-Mediated Regulation of Striatal Nurr1 Expression Alters Development and Severity of Levodopa-Induced Dyskinesias in the 6-OHDA Rat Model of Parkinson's Disease

Primary motor symptoms in Parkinson's disease arise due to a loss of dopaminergic innervation in the striatum. Treatment with levodopa (L-DOPA) is the current gold standard treatment for the motor symptoms that arise in PD due to dopamine (DA) depletion. However, a large portion of patients receiving L-DOPA treatment develop a series of debilitating hyperkinetic and dystonic movements known as L-DOPA-induced dyskinesias (LIDs). The molecular mechanisms behind LID development are unclear, as well as why some patients are resistant to LIDs and never acquire these symptoms. In an attempt to identify transcriptional differences between LID responders and LID non-responders in the rat parkinsonian 6-hydroxydopamine (6-OHDA) model, we performed a full genome array to identify differential transcript expression between these two groups. The orphan nuclear receptor Nurr1 was one transcript that was expressed at significantly higher levels—greater than 30 fold—in LID+ animals when compared to LID- animals. In the current study we sought to determine whether Nurr1 expression both promotes, and is required for, LID formation. Adult male Sprague-Dawley rats were rendered parkinsonian using6-OHDA. Animals that did not show a difference in paw use compared to a pre-lesion state were removed from the study one month later. At this time, remaining animals received a striatal injection of recombinant adeno-associated virus (rAAV) type 2/5 overexpressing either: 1) Nurr1 (or GFP as a control)(5×1013 vector genomes (vg)/ml) in order to test whether Nurr1 overexpression causes LIDs or 2) A shRNA targeting Nurr1 (or a titer-matched scrambled shRNA control)(2×1013 vg/ml) in order to test whether Nurr1 is required for LIDs. Four weeks following the vector injection, animals received escalating doses (0mg/kg – 24mg.kg) of L-DOPA every other day (M-Fr), and were evaluated for LIDs at 25 min intervals for 2-4 hours using the abnormal involuntary movement (AIM) rating scale. At doses equal to or exceeding 12mg/kg, Nurr1 overexpressing animals exhibited both more severe and longer lasting LIDs than their rAAV-GFP control counterparts. Conversely, dyskinesias were attenuated in animals receiving Nurr1-shRNA up to 18mg/kg of L-DOPA. In addition, postmortem analysis of striatal tissue revealed that the overexpression of the Nurr1 shRNA effectively inhibited the induction of L-DOPA induced Nurr1. These results demonstrate that overexpression of Nurr1 in the DA-depleted striatum of parkinsonian rats has a causative role in the expression of LIDs. Further, our data show that Nurr1 silencing in the striatum effectively inhibits the LID development. These data suggest that the maladaptive upregulation of Nurr1 in striatal neurons is a core event in the formation of LIDs. Consequently, targeting striatal Nurr1 activity may represent a novel therapeutic modality in the treatment of LIDs.

Quantitative motor assessment of dyskinesias in Parkinson's disease.

Although Levodopa-induced dyskinesias (LID) are one of the most compromising complications of dopaminergic treatment in Parkinson's disease (PD), there is no widely accepted assessment tool available that evaluates LID quantitatively. This is of relevance as objective assessment may help to facilitate proof-of-concept studies with novel treatments and thus eventually contribute to better patient care. PD patients were asked to perform a grip-lift task as well as tapping tasks assessed with the "Q-Motor" system. PD patients were separated into three groups according to their modified abnormal involuntary movement scale (M-AIMS)-score: PD patients without dyskinesias (PD(LID-) n = 17), with slight dyskinesias (PD(LID+) n = 15) and with severe dyskinesias (PD(LID++) n = 15). An explorative analysis to identify measures detecting LID was performed with 5 PD(LID-) and 5 PD(LID++) patients; these measures were then used in the remaining patients to assess the accuracy of the system to differentiate LID. The measures "Orientation-Index" and "Position-Index" of the grip-lift task differed significantly between the explorative cohorts. Using these two parameters for the differentiation of the remaining cohorts, the area under the ROC curve (AUC) yielded 0.809 for the differentiation of PD(LID-) vs. PD(LID++), 0.852 for the differentiation of PD(LID-) vs. PD(LID+) patients, and 0.830 for the differentiation of PD(LID+) and PD(LID++). The "Orientation-Index" and "Position-Index" of the Q-Motor assessment are sensitive, easy to apply and non-invasive measures for the objective assessment of manifestation and severity of LID.

Sustained Increase of PKA Activity in the Postcommissural Putamen of Dyskinetic Monkeys

Levodopa-induced dyskinesias (LID) are a frequent complication of Parkinson's disease pharmacotherapy that causes significant disability and narrows the therapeutic window. Pharmacological management of LID is challenging partly because the precise molecular mechanisms are not completely understood. Here, our aim was to determine molecular changes that could unveil targetable mechanisms underlying this drug complication. We examined the expression and downstream activity of dopamine receptors (DR) in the striatum of 1-methyl-4-phenyl-1,2,3,6 tetrahydropiridine (MPTP)-lesioned monkeys with and without L-DOPA treatment. Four monkeys were made dyskinetic and other four received a shorter course of L-DOPA and did not develop LID. Our results show that L-DOPA treatment induces an increase in DRD2 and DRD3 expression in the postcommissural putamen, but only DRD3 is correlated with the severity of LID. Dyskinetic monkeys show a hyperactivation of the canonical DRD1-signaling pathway, measured by an increased phosphorylation of protein kinase A (PKA) and its substrates, particularly DARPP32. In contrast, activation of the DRD2-signaling pathway, visible in the levels of Akt phosphorylated on Thr308 and GSK3β on Ser9, is associated with L-DOPA treatment, independently of the presence of dyskinesias. Our data clearly demonstrate that dyskinetic monkeys present a dysregulation of the DRD3 receptor and the DRD1 pathway with a sustained increase of PKA activity in the postcommissural putamen. Importantly, we found that all signaling changes related to long-term L-DOPA administration are exquisitely restricted to the postcommissural putamen, which may be related to the recurrent failure of pharmacological approaches.

Parkinsonian Patients and Poor Awareness of Dyskinesias

The question of whether the awareness of levodopa-induced dyskinesias (LID) is reduced, or altogether missing, in patients with Parkinson’s disease (PD) has been attracting growing interest. Why is this topic important? Firstly, as studies addressing the efficacy of drugs on LID employ patients’ motor diaries as an outcome measure, poor LID self-awareness might interfere with data collection in clinical trials; secondly, poor LID self-awareness may result in increased doses of dopaminergic drugs, which could in turn be associated with an enhanced risk of side effects such as LID. Lastly, understanding this phenomenon may shed light on some pathophysiological aspects of LID in PD. The few studies conducted so far concluded that at least a proportion of PD patients are either partially or totally unaware of the presence of LID. These studies used different methods to ascertain LID awareness as well as different patient populations. Consequently, several hypotheses have been postulated to explain poor self-awareness of LID, which suggest that several possible mechanisms may be implicated. An impairment in the experience of moving abnormally was suggested by Vitale et al. (1) in a pilot study conducted on PD patients (and on patients with Huntington disease). The authors found that poor LID self-awareness was more marked in PD patients with mild LID, and therefore suggested that poor LID self-awareness merely reflects the fact that when LID are mild, their interference with normal activities is limited and patients tend to underestimate them. These results, however, were not confirmed in the study conducted by Sitek et al. (2), who instead observed, by means of a video protocol, that poor selfawareness of LID was more pronounced in patients with longer symptom duration (and therefore with possibly more severe LID). This finding reported by Sitek et al. (2) thus suggests that other mechanisms are likely to play a role in the phenomenon of poor self-awareness of LID. Amanzio et al. (3) believed that factors linked to the cognitive domain might be involved. In a well planned study, they investigated whether awareness of different movement disorders in cognitively intact PD patients differs in the on and off states. The results of their study revealed a significant difference between awareness of LID measured in the on state and awareness of hypo-bradykinesia assessed in the off state. In particular, while 22 of the 25 patients enrolled in their study displayed a reduced awareness of LID, a reduced awareness of hypo-bradykinetic movement disorders was found in only 6 of the 25 patients. On the basis on these findings, the authors suggested that dopaminergic therapy may, by stimulating mesocortical–limbic pathways, exert a detrimental effect on the function of the orbitofrontal and cingulated frontal–subcortical loops, thereby contributing to a poor self-awareness of LID. Supporting this view, recent papers indeed showed that frontal cortex studied by advanced neuroimaging techniques differ between patients with or without LID. In one study, PD patients with LID had significant overactivity in the supplementary motor area and underactivity in the right inferior prefrontal gyrus during execution of motor tasks when compared with PD patients without LID (4). In addition, in another study cortical thickness analysis revealed a pronounced increase of thickness in the right inferior frontal sulcus in PD patients with LID with respect to PD patients without LID (5). The hypothesis of Amanzio et al. is not, however, supported by the observations of other authors, who found that poor self-awareness is not only associated with LID, but also with motor symptoms assessed in the off state, and that awareness of off motor symptoms improved, at least in part, during the on state following dopaminergic stimulation (1, 6, 7). Maier et al. (7) also found that the severity of impairment of motor self-awareness was unrelated to dopaminedependent executive functioning. These authors also reported that impaired awareness of abnormal movements (and therefore of LID) was significantly associated with the postural instability gait disorder phenotype of PD to a greater extent than with the hyperkinetic phenotype. Although the postural instability gait disorder phenotype is frequently associated with cognitive decline, it is noteworthy that the severity of the impaired awareness of movement in the study by Maier et al. (7) was not correlated with either disease duration or cognitive outcome. Other authors have proposed alternative or complementary hypotheses. For example, one noteworthy finding comes from the work by Jenkinson et al. (8), who highlighted the fact that normal motor awareness entails a correct comparison of intended vs. actual movement, and predicted in their work that anosognosia of LID in PD arises from a failure to detect discrepancies between intended movement and visual feedback. To test their hypothesis, they used a mirror to reverse the expected visual consequence of an executed movement. PD patients with poor self-awareness of LID did not

Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients

Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson's disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11C-DASB PET to evaluate serotonin terminal function and 11C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD.

Rhabdomyolysis induced by severe levodopa induced dyskinesia in a patient with Parkinson’s disease

A 74-year-old man with Parkinson’s disease (PD) who had been regularly taking levodopa for 17 years developed severe generalized dyskinesia of choreiform movement. He began to show bradykinesia and rigidity in right limbs at age 57 years. Levodopa treatment dramatically improved his parkinsonian symptoms. Three years after levodopa treatment, he began to feel wearing-off. At age 72 years, he suffered from levodopa-induced dyskinesia (LID) during levodopa on period and was immobile during the off period. Seven days before his first visit to emergency room, he began to feel deterioration of his symptoms with levodopa/ carbidopa 250/25 mg q.i.d. and controlled-release form of levodopa/benserazide 100/25 mg q.i.d. Although peak dose dyskinesia gradually worsened, he gradually increased the dosage until he was taking 12 tablets of levodopa/carbidopa 250/25 mg and four tablets of levodopa/benserazide 100/25 mg per day. The dyskinesia violently affected all four of his limbs and the trunk, and he could not stand or sit in a chair without support. His body temperature was 36.1 C, and serum creatine kinase (CK) level was 215 IU/L. The Unified Parkinson’s Disease Rating Scale (UPDRS) motor score was 64. Although the dosage of levodopa was lowered to levodopa/carbidopa 250/25 mg t.i.d. and controlled-release form of levodopa/benserazide 100/25 mg t.i.d., the violent dyskinesia persisted. We intermittently gave him 2 mg of midazolam intravenously, but failed to stop the dyskinesia when he was awake. After 2 days, he still showed dyskinesia with the same severity, but his mentality was clear. In contrast to his violent dyskinesia and immobility, he showed very mild rigidity in his arms and neck. His body temperature and serum CK level rose up to 38.2 C and 24,651 IU/L, respectively. Urine myoglobulin was markedly increased to 48.1 nmol/L. Leukocyte count in peripheral blood was 18,680/mm. Serum creatinine level was 176.8 lmol/L and serum potassium level 6.9 mmol/L. Rhabdomyolysis with acute renal failure was suspected. All dopaminergic medications were stopped and midazolam was continuously infused intravenously at a rate of 0.4–0.8 lg/min/kg. Five hours after the infusion, body temperature rapidly decreased to normal range. After 21 h of infusion, dyskinesia completely disappeared even without midazolam. Serum CK level decreased to 7,961 IU/L and normalized after following 5 days (Fig. 1). Because dyskinesia reappeared even with the trial of a levodopa/carbidopa 100/25 mg, he had to be maintained with selegiline, amantadine and pergolide. UPDRS motor score measured 1 month after this acute exacerbation of dyskinesia was 55. He was stabilized afterwards without recurrence of dyskinesia. In movement disorders, various causes of rhabdomyolysis have been reported, including status dystonicus, myoclonus, generalized chorea and parkinsonism-hyperpyrexia syndrome (PHS) in patients with parkinsonian diseases [1–4]. In PD, LID leading to rhabdomyolysis is a very rare phenomenon [5]. Two previously reported patients developed rhabdomyolysis by severe LID and C. H. Lyoo Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, 712 Eonjuro, Gangnam-gu, Seoul, South Korea e-mail: lyoochel@yuhs.ac

AFQ056 treatment of levodopa‐induced dyskinesias: Results of 2 randomized controlled trials

Study objectives were to assess the efficacy, safety, and tolerability of AFQ056 in Parkinson's disease patients with levodopa-induced dyskinesia. Two randomized, double-blind, placebo-controlled, parallel-group, in-patient studies for Parkinson's disease patients with moderate to severe levodopa-induced dyskinesia (study 1) and severe levodopa-induced dyskinesia (study 2) on stable dopaminergic therapy were performed. Patients received 25-150 mg AFQ056 or placebo twice daily for 16 days (both studies). Study 2 included a 4-day down-titration. Primary outcomes were the Lang-Fahn Activities of Daily Living Dyskinesia Scale (study 1), the modified Abnormal Involuntary Movement Scale (study 2), and the Unified Parkinson's Disease Rating Scale-part III (both studies). Secondary outcomes included the Unified Parkinson's Disease Rating Scale-part IV items 32-33. The primary analysis was change from baseline to day 16 on all outcomes. Treatment differences were assessed. Fifteen patients were randomized to AFQ056 and 16 to placebo in study 1; 14 patients were randomized to each group in study 2. AFQ056-treated patients showed significant improvements in dyskinesias on day 16 versus placebo (eg, Lang-Fahn Activities of Daily Living Dyskinesia Scale, P = .021 [study 1]; modified Abnormal Involuntary Movement Scale, P = .032 [study 2]). No significant changes were seen from baseline on day 16 on the Unified Parkinson's Disease Rating Scale-part III in either study. Adverse events were reported in both studies, including dizziness. Serious adverse events (most commonly worsening of dyskinesias, apparently associated with stopping treatment) were reported by 4 AFQ056-treated patients in study 1, and 3 patients (2 AFQ056-treated patient and 1 in the placebo group) in study 2. AFQ056 showed a clinically relevant and significant antidyskinetic effect without changing the antiparkinsonian effects of dopaminergic therapy. © 2011 Movement Disorder Society.

Levodopa-Induced Dyskinesias in Parkinson Disease Are Independent of the Extent of Striatal Dopaminergic Denervation

The physiopathology of levodopa-induced dyskinesias (LIDs) is unclear. Presynaptic pharmacokinetic and postsynaptic pharmacodynamic mechanisms may be involved. We have analyzed several clinical and pharmacological parameters, as well as the status of the presynaptic dopamine nigrostriatal pathway by using DaTSCAN, in 14 patients with Parkinson disease who developed early and severe LID despite using low doses of levodopa and 10 patients without this complication despite the use of high levodopa doses. Patients were matched for age at onset, duration, and severity of Parkinson disease. Statistically significant differences were observed only in the duration of LID during the levodopa challenge. However, clear differences were also observed in weight and sex distribution (women with low weight predominate in the group with dyskinesia), severity and duration of LID, and total levodopa dosage. The pattern of response to levodopa and the uptake of (123I)N-w-fluoropropyl-2[beta]-carbomethoxy-3[beta]-(4-iodophenyl)nortropane were similar in both groups. These results indicate that the development of LID needs additional contributions beyond nigrostriatal denervation. Factors related to sex and body weight could play an important role. However, these findings should be considered cautiously because of the limited statistical power of the study.

Patterns of neuronal activity in the basal ganglia nucleus in parkinsonian patients with levodopa-induced dyskinesia

To explore the patterns of neuronal activity in the basal ganglia nucleus in parkinsonian patients with levodopa-induced dyskinesia (LID). Sixteen idiopathic parkinsonian patients, 11 males and 5 female: 5; aged 56.1 +/- 11.9, with the mean disease duration of (10.1 +/- 6.6). years and Hoehn & Yahr score ranging 2 -4, all with the symptoms of tremor, rigidity, and bradykinesia, 8 with severe LID [with the mean unified Parkinson's disease rating scale (UPDRS) IV score of 6.8 +/- 1.5] underwent pallidotomy (n = 8) or subthalamic nucleus (STN) deep brain stimulation (DBS) implantation (6 bilaterally and 2 unilaterally). Microrecording was performed in the globus pallidus internus (GPi) and STN. Electromyogram (EMG) on the contralateral limbs to surgery was simultaneously recorded. Single unit analysis was performed. The interspike interval (ISI) and coefficient of variation (CV) of ISI were calculated. One-way ANOVA and rank test were employed to compare the ISI and CV among the patients. Two hundred and thirty-eight neurons were identified from the GPi (n = 8) and STN (n = 14). 22.6% of them were tremor-related neurons, 33.8% were rapid tonic neuronal activity[ related, and 29.0% were irregular neuronal activity-related. It was discovered that 8. 0% of the neurons from GPi and STN were with grouped discharge following long period pause with the CV of 87 +/- 0.55, and 7.5% of the neurons were with low frequency firing with the mean frequency of (17.7 +/- 5.9) Hz. ANOVA revealed that in the STN the CV of the neurons with irregular with grouped discharge was significantly higher than those of the neurons with irregular neuronal activity and with low frequency firing (both P < 0.05), the ISI of the neurons with irregular grouped discharge was significantly higher than that of the neurons with low frequency firing and significantly higher than that of the neurons irregular neuronal activity (both P < 0.05); and in the GPi the CV of the neurons with irregular grouped discharge was significantly lower than those of the neurons with irregular neuronal activity and those with low frequency firing and the ISI of the neurons with irregular grouped discharge was significantly higher than those of the other groups (all P < 0.05). Chi square test showed that majority of the neurons with grouped discharge and neurons with low frequency firing mainly existed in the GPi and STN of the PD patients with LID (all P < 0.05). The altered neuronal activity in the basal ganglia nucleus of GPi and STN plays an important role in the pathophysiology of PD and LID.

The course of dyskinesia induction by different treatment schedules of levodopa in Parkinsonian rats: Is continuous dopaminergic stimulation necessary?

The aim of the present study was to investigate the course of levodopa induced dyskinesia (LID) development in parkinsonian rats treated with several different levodopa dosing regiments. Administration of 6.25 mg/kg levodopa once daily did not induce any dyskinesia for the first 12.5 +/- 2.5 days. Then, LID gradually increased in intensity reaching an AIMs score on day 40 of 6.3 +/- 0.9. Treatment with 6.25 mg/kg of levodopa qid resulted in the rapid appearance of LID with a mean latency of 2 days and an AIMs score of 19.9 +/- 2.9 on day 10. Levodopa (25 mg/kg) once daily induced severe LID from the second day of treatment reaching an AIMs score of 35 +/- 3.2. In summary, the worst way for delivering levodopa was through intermittent administration of high doses. The daily cumulative dose of levodopa was found more important for LID induction than the total amount of levodopa received. In contrast, the best way to administer levodopa in respect to prevention/delay of LID was "low dopaminergic stimulation" with one low daily dose, instead of trying to achieve "continuous dopaminergic stimulation" using several levodopa doses throughout the day. The benefits of this strategy offered protection against severe dyskinesia even if subsequently subjects were switched to high dose levodopa.

A common leucine‐rich repeat kinase 2 gene mutation in familial and sporadic Parkinson's disease in Russia

A PARK8 form of Parkinson's disease (PD) is caused by a novel gene, leucine-rich repeat kinase 2 (LRRK2), and a single mutation G2019S was found in a proportion of LRRK2-associated cases of diverse ethnic origins. We performed the LRRK2 G2019S mutation analysis in 304 Russian patients with PD, including 291 sporadic and 13 autosomal dominant cases. The frequency of the LRRK2 G2019S was 0.7% amongst the sporadic patients (2/291) and 7.7% amongst familial PD (1/13). The mutation was also found in three unaffected relatives and absent in 700 control chromosomes. One patient carrying the LRRK2 G2019S was found earlier to have an additional mutation, a heterozygous duplication of exon 5 of the parkin gene. All patients carrying the LRRK2 G2019S exhibited typical levodopa-responsive parkinsonism, and severe levodopa-induced dyskinesia was observed in the patient carrying the LRRK2 and parkin mutations. There was notable variability in ages of the disease onset in G2019S carriers not explained by APOE genotypes. Two subsets of G2019S-positive patients had different PARK8 haplotypes suggesting that the LRRK2 G2019S in Russian patients had arisen independently on different chromosomes. Identification of common LRRK2 mutations in some PD patients without an overt family history has notable implications for genetic counseling.

Globus pallidus stimulation in advanced Parkinson’s disease

Deep brain stimulation (DBS) of the globus pallidus internus (GPi) has become an accepted therapeutic modality in selected Parkinson’s disease (PD) patients with severe levodopa-induced dyskinesias (LID) and on-off motor fluctuations. In comparison to subthalamic nucleus DBS there is a paucity of data on GPi DBS outcomes. We present our experience with a group of 20 PD patients (9 unilateral, 11 bilateral) who underwent GPi stimulation. PD motor symptoms were assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) part III scores and subscores, and dyskinesia using the Abnormal Involuntary Movement Scale (AIMS), UPDRS part IVa, and clinical global impression (CGI). At mean follow-up time of 7 months, bilateral stimulation reduced off-period motor scores by a mean of 46% and on-period motor scores by 18%. Unilateral stimulation reduced off-period motor scores by 18%. Dyskinesia severity was reduced by 76%, which was maintained after a mean follow-up time of 35 months. Antiparkinsonian medication dosage was unchanged. No major adverse effects were seen. Unilateral and bilateral GPi DBS provides lasting benefit in PD patients with severe LID. Beneficial effects on off-period motor symptoms are greater with bilateral stimulation; however, with maintenance of dopaminergic medication, unilateral procedures can also provide important and sustained benefits.

Efficacy and Safety of Simultaneous Bilateral Pallidotomy in Advanced Parkinson’s Disease

Background: Although unilateral pallidotomy is generally considered a safe and effective neurosurgical treatment for advanced Parkinson’s disease (PD), controversies concerning efficacy and adverse effects of bilateral posteroventral pallidotomy (PVP) exist and need to be resolved. Methods: We studied 8 patients with advanced PD who underwent simultaneous bilateral PVP. The patients were assessed preoperatively, immediately after surgery, and 6 and 12 months later. Results: Dyskinesia was almost entirely abolished immediately after surgery, as well as being significantly lower 1 year later (p < 0.05). The ‘off’ medication score of the Unified Parkinson’s Disease Rating Scale motor part (UPDRS III) was significantly improved after surgery (p < 0.05) but increased gradually after 6 months. The off medication score of activities of daily living tended to improve immediately after surgery, but it returned to preoperative levels at 12 months. There were no major complications of surgery. Conclusions: Simultaneous bilateral PVP may be a safe and highly effective method of reducing levodopa-induced dyskinesia. Our results suggest that simultaneous bilateral PVP may be a reasonable therapeutic option for advanced PD with severe levodopa-induced dyskinesia.

Pallidal stimulation reduces treatment‐induced dyskinesias in “minimal‐change” multiple system atrophy

Deep brain stimulation therapy is increasingly gaining acceptance in the management of levodopa-induced dyskinesia and fluctuations in idiopathic Parkinson's disease. It is generally not recommended for the other forms of parkinsonism such as progressive supranuclear palsy or multiple system atrophy where the response to levodopa is usually poor and disease progression more rapid, making any benefit short-lived. Here, we present an autopsy-confirmed case of "minimal-change" multiple system atrophy in whom pallidal stimulation surgery was effective in abolishing severe levodopa-induced dyskinesia.

The beneficial effects of subthalamic nucleus stimulation on manipulative finger force control in Parkinson's disease

We investigated the differential effects of levodopa medication and STN stimulation on finger force control in Parkinson subjects grasping to lift an object and performing vertical point-to-point movements of a hand-held object. The experiments were conducted in four treatment conditions: off-drug/off-stimulation, off-drug/on-stimulation, on-drug/off-stimulation and on-drug/on-stimulation. We found that the bradykinesia in Parkinsonian subjects improved by both levodopa medication and STN stimulation. As compared to healthy subjects, excessive grip force was observed in all Parkinson subjects, regardless of the treatment condition. This force excess was most pronounced in the on-drug condition and ameliorated by STN stimulation. We observed reliable correlations between the amount of force overflow and the severity of levodopa-induced dyskinesias in the on-drug condition. Despite some similarities regarding therapeutic effects on bradykinesia, our findings contrast with earlier observations with respect to the differential effects of levodopa and STN stimulation on the scaling of fingertip forces in Parkinson's disease. While levodopa causes an overshoot of fingertip forces, STN stimulation appears to be sufficient to alleviate, but not normalise the force excess. STN stimulation enables Parkinson subjects to scale grip force more accurately to the loads arising from voluntary manipulation of hand-held objects.