Onset Of Levodopa-induced Dyskinesia Research Articles

AMPK-mediated autophagy pathway activation promotes ΔFosB degradation to improve levodopa-induced dyskinesia

BackgroundParkinson's disease patients on chronic levodopa often suffer from motor complications, which tend to reduce their quality of life. Levodopa-induced dyskinesia (LID) is one of the most prevalent motor complications, often characterized by abnormal involuntary movements, and the pathogenesis of LID is still unclear but recent studies have suggested the involvement of autophagy. MethodsThe onset of LID was mimicked by chronic levodopa treatment in a unilateral 6-hydroxydopamine (6-OHDA) -lesion rat model. Overexpression of ΔFosB in HEK293 cells to mimic the state of ΔFosB accumulation. The modulation of the AMP-activated protein kinase (AMPK)-mediated autophagy pathway using by metformin, AICAR (an AMPK activator), Compound C (an AMPK inhibitor) and chloroquine (an autophagy pathway inhibitor). The severity of LID was assessed by axial, limb, and orofacial (ALO) abnormal involuntary movements (AIMs) score and in vivo electrophysiology. The activity of AMPK pathway as well as autophagy markers and FosB-ΔFosB levels were detected by western blotting. RT-qPCR was performed to detect the transcription level of FosB-ΔFosB. The mechanism of autophagy dysfunction was further explored by immunofluorescence and transmission electron microscopy. ResultsIn vivo experiments demonstrated that chronic levodopa treatment reduced AMPK phosphorylation, impaired autophagosome-lysosomal fusion and caused FosB-ΔFosB accumulation in the striatum of PD rats. Long-term metformin intervention improved ALO AIMs scores as well as reduced the mean power of high gamma (hγ) oscillations and the proportion of striatal projection neurons unstable in response to dopamine for LID rats. Moreover, the intervention of metformin promoted AMPK phosphorylation, ameliorated the impairment of autophagosome-lysosomal fusion, thus, promoting FosB-ΔFosB degradation to attenuate its accumulation in the striatum of LID rats. However, the aforementioned roles of metformin were reversed by Compound C and chloroquine. The results of in vitro studies demonstrated the ability of metformin and AICAR to attenuate ΔFosB levels by promoting its degradation, while Compound C and chloroquine could block this effect. ConclusionsIn conclusion, our results suggest that long-term metformin treatment could promote ΔFosB degradation and thus attenuate the development of LID through activating the AMPK-mediated autophagy pathway. Overall, our results support the AMPK-mediated autophagy pathway as a novel therapeutic target for LID and also indicate that metformin is a promising therapeutic candidate for LID.

Continuous long-range measurement of tonic dopamine with advanced FSCV for pharmacodynamic analysis of levodopa-induced dyskinesia in Parkinson's disease.

Levodopa, a dopamine prodrug, alleviates the motor symptoms of Parkinson's disease (PD), but its chronic use gives rise to levodopa-induced dyskinesia (LID). However, it remains unclear whether levodopa pharmacodynamics is altered during the progressive onset of LID. Using in vivo fast-scan cyclic voltammetry and second-derivative-based background drift removal, we continuously measured tonic dopamine levels using high temporal resolution recording over 1-h. Increases to tonic dopamine levels following acute levodopa administration were slow and marginal within the naïve PD model. However, these levels increased faster and higher in the LID model. Furthermore, we identified a strong positive correlation of dyskinetic behavior with the rate of dopamine increase, but much less with its cumulative level, at each time point. Here, we identified the altered signature of striatal DA dynamics underlying LID in PD using an advanced FSCV technique that demonstrates the long-range dynamics of tonic dopamine following drug administration.

Contracted thalamic shape is associated with early development of levodopa-induced dyskinesia in Parkinson’s disease

Levodopa-induced dyskinesia (LID), a long-term motor complication in Parkinson’s disease (PD), is attributable to both presynaptic and postsynaptic mechanisms. However, no studies have evaluated the baseline structural changes associated with LID at a subcortical level in PD. A total of 116 right-handed PD patients were recruited and based on the LID latency of 5 years, we classified patients into those vulnerable to LID (PD-vLID, n = 49) and those resistant to LID (PD-rLID, n = 67). After adjusting for covariates including dopamine transporter (DAT) availability of the posterior putamen, we compared the subcortical shape between the groups and investigated its association with the onset of LID. The PD-vLID group had lower DAT availability in the posterior putamen, higher parkinsonian motor deficits, and faster increment in levodopa equivalent dose than the PD-rLID group. The PD-vLID group had significant inward deformation in the right thalamus compared to the PD-rLID group. Inward deformation in the thalamus was associated with an earlier onset of LID at baseline. This study suggests that independent of presynaptic dopamine depletion, the thalamus is a major neural substrate for LID and that a contracted thalamic shape at baseline is closely associated with an early development of LID.

Rapid drug increase and early onset of levodopa-induced dyskinesia in Parkinson's disease.

A higher levodopa dose is a strong risk factor for levodopa-induced dyskinesia (LID) in patients with Parkinson's disease (PD). However, levodopa dose can change during long-term medication. We explored the relationship between levodopa dose and time to onset of LID using longitudinal multicenter data. Medical records of 150 patients who were diagnosed with de novo PD and treated with levodopa until onset of LID were collected. Levodopa dose were assessed as the dose at 6 months from levodopa initiation and rate of dose increase between 6 months and onset of LID. The groups with earlier LID onset had higher levodopa and levodopa-equivalent dose at the first 6 months of treatment and rapid increase in both levodopa and levodopa-equivalent dose. Multivariable linear regression models revealed that female sex, severe motor symptom at levodopa initiation, and higher rate of increase in both levodopa and levodopa-equivalent dose were significantly associated with early onset of LID. The present results demonstrated that rapid increase in levodopa dose or levodopa-equivalent dose is associated with early onset of LID.

Brain-Region Specific Metabolic Abnormalities in Parkinson's Disease and Levodopa-Induced Dyskinesia.

Several lines of evidence point to alteration in brain metabolic homeostasis in Parkinson’s disease (PD) and levodopa-induced dyskinesia (LID), yet the metabolic mechanism in different brain regions underlying PD and LID remains largely unknown. The present study aimed to uncover the metabolic pathways across anatomical regions in the brain of PD and LID. Using an NMR-based metabolomic approach, we generated the metabolomics profiling data from six different brain regions of PD rats and following the onset of LIDs. The diversity of metabolite patterns across the brain and its relation to PD and LID were further investigated through principal component analysis (PCA) and multivariate general linear model. Compared with control rats, dopamine loss in PD rats produced a marked and persistent metabolic disturbance in neurotransmitter metabolism and energy pathway, resulting in a metabolic imbalance among different brain regions. In LID rats, levodopa replacement did not restore the midbrain-striatum metabolic crosstalk and metabolic disturbance throughout the brain was involved in levodopa related involuntary movements. Most notably, the midbrain and right cortex were identified as the primary regions of metabolic abnormalities in PD and LID rats. Neurochemical differences in metabolic phenotypes were mainly defined by various neurotransmitters including glutamate, glutamine and aspartate. Accordingly, we found that the PD and LID rats exhibited lower levels of synaptophysin (SYP), a marker for synaptic plasticity, compared with control rats. These findings provide key insights into the metabolic mechanism underlying PD and LID by defining brain-region specific metabolic phenotype, with implications for developing targeted therapies.

Effects of blackberry (<em>Morus nigra</em>) fruit juice on levodopa-induced dyskinesia in a mice model of Parkinson's disease

Background and objectiveLevodopa-induced dyskinesia (LID) is a movement disorder that occurs due to levodopa consumption for a long period to attenuate Parkinsonism. Plants have been the basis for medical treatments in human history and still widely practiced. Blackberry (Morus nigra) is one of the fruits rich in anthocyanin. The present study examined the effect of blackberry fruit juice on LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease in mice.Materials and methodsIn this study, 42 male mice were used, which were divided into six groups equally: one control group and five groups receiving MPTP injection. After confirmation of Parkinsonism in MPTP groups, one group was preserved without treatment and four other groups were treated with levodopa (50 mg/kg ip). After the onset of LID (2 weeks), one group was kept without additional treatment and three other groups were treated with three different doses of blackberry fruit juice (5, 10, and 15 mL/kg) with levodopa orally for 7 days. Abnormal involuntary movement scale (AIMS) and cylinder behavioral test were carried out according to the schedule. The collected data were analyzed using the SPSS software with the significant level of P<0.05.ResultsParkinson’s disease was confirmed with AIMS test on the fourth day after MPTP injection. The onset of LID was observed after 2 weeks of levodopa treatment using both behavioral tests. The result of administration of M. nigra fruit juice for 1 week showed that this addition is useful in hindering LID. These effects were more pronounced at doses 10 and 15 mL/kg with nearly the same results on attenuating AIMS. Low dose of the fruit juice does not seem to affect LID significantly.ConclusionM. nigra fruit juice is effective to attenuate LID in an MPTP-induced Parkinson mice model.

The association between early treatment with amantadine and delayed onset of levodopa-induced dyskinesia in patients with Parkinson’s disease

The association between early treatment with amantadine and delayed onset of levodopa-induced dyskinesia in patients with Parkinson’s disease

Presynaptic dopamine depletion determines the timing of levodopa-induced dyskinesia onset in Parkinson's disease.

Reduced presynaptic dopaminergic activity plays an important role in the development of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD). In this study, we investigated whether dopaminergic function in the nigrostriatal system is associated with the timing of LID onset. From among 412 drug-naive PD patients who underwent a dopamine transporter (DAT) PET scan during their baseline evaluation, we enrolled 65 patients who developed LID during a follow-up period of >2years. Based on the time from PD onset, LID was classified as early, intermediate or late onset. We then compared DAT availability in the striatal subregions of the patients in the three groups. The demographic characteristics did not differ among the three patient groups except for earlier intervention of levodopa therapy in the early LID onset group (p=0.001). After adjusting for age at PD onset, gender, timing of levodopa therapy from PD onset, and the severity of PD motor symptoms, DAT activity in the posterior putamen was found to be significantly lower in the early LID onset group than in the late LID onset group (p=0.017). Multivariate linear regression analysis showed that low DAT activity in the posterior putamen was significantly associated with the early appearance of LID in the early LID onset group (β=16.039, p=0.033). This study demonstrated that low DAT activity in the posterior putamen at baseline is a major risk factor for the early onset of LID in patients with PD, suggesting that the degree of presynaptic dopaminergic denervation plays an important role in determining the timing of LID onset.

Altered mGluR5 binding potential and glutamine concentration in the 6-OHDA rat model of acute Parkinson's disease and levodopa-induced dyskinesia

Several lines of evidence point to alterations in glutamatergic signaling in Parkinson's disease (PD) and levodopa-induced dyskinesia (LID), involving the metabotropic glutamate receptor type 5 (mGluR5). Using small-animal positron emission tomography (PET) with [18F]FPEB and proton magnetic resonance spectroscopy, we investigated cerebral changes in the mGluR5 and glutamate/glutamine availability in vivo in PD rats and following onset of LIDs. In parallel, behavioral tests were performed. Comparing PD to control rats, mGluR5 binding potential was decreased in a cluster comprising the bilateral caudate-putamen (CP), ipsilateral motor cortex and somatosensory cortex, and the contralateral somatosensory cortex and parietal association cortex, with the most pronounced reduction in the ipsilateral CP. mGluR5 binding potentials were not significantly altered upon levodopa (L-DOPA) treatment. However, following L-DOPA, an increase in relative mGluR5 uptake was present in the contralateral motor cortex and somatosensory cortex. Glutamate and glutamine concentrations did not differ between control and untreated PD rats or between hemispheres. Though, glutamine levels were higher in the contralateral CP of saline- and L-DOPA-treated rats as compared to the ipsilateral side. Relative mGluR5 uptake in the CP of levodopa-treated rats was also found positively correlated with abnormal involuntary movement scores. Conclusively, mGluR5 availability and glutamine concentrations in the CP are involved in PD, whereas mGluR5 availability in cortical regions may be involved in LID pathology.

The role of apolipoprotein E polymorphisms in levodopa-induced dyskinesia

To determine the relationship between apolipoprotein E (APOE) polymorphisms to the time to appearance of levodopa-induced dyskinesia (LID) in patients with Parkinson's disease. The APOE genotype of 155 consecutive patients treated with levodopa was determined and its effect on the time of onset of LID was examined using Cox regression model, controlling for gender, age of disease onset, time to initiation of levodopa treatment and history of smoking. Two patients were homozygous for the APOE ε2 allele, 7 had ε2/ε3, 1 had ε2/ε4, 130 had ε3/ε3, 12 had ε3/ε4 and 3 had ε4/ε4; LID appeared in 57.4% of the patients, appearing 4.1 ± 3.5 years after the initiation of levodopa treatment. The survival curve for LID was not affected by the APOE genotype (P = 0.34). APOE polymorphisms were found not to be associated with either the occurrence or the time to development of LID.

Cost Effectiveness of Rasagiline and Pramipexole as Treatment Strategies in Early Parkinsonʼs Disease in the UK Setting

Levodopa is the most effective treatment for the symptoms of Parkinson's disease (PD). However, after an initial period of benefit, several limitations become apparent, including motor complications such as dyskinesia. Dyskinesia can severely affect patients' quality of life and increases healthcare resource use. Thus, delaying the need for levodopa, and therefore the onset of levodopa-induced dyskinesia, is important. The aim of this study was to compare the cost effectiveness, from a UK healthcare payer perspective, of two antiparkinsonian treatment strategies in early PD: first-line monotherapy with rasagiline, a novel monoamine oxidase B inhibitor; and the non-ergoline dopamine receptor agonist pramipexole. An economic Markov model was developed as a pragmatic tool to derive comparative information on the effectiveness, utility and costs of these two strategies over a 5-year period. Model input data were obtained from the TEMPO study for rasagiline and from a study by the Parkinson Study Group for pramipexole. Effectiveness outcomes were time to levodopa and time to levodopa-induced dyskinesia. Cost and quality-adjusted life-year (QALY) data were derived from published sources. Rasagiline was the dominant strategy. Compared with pramipexole, use of the rasagiline strategy was estimated to reduce costs by 18% per patient over 5 years and was associated with an additional 10% delay in dyskinesia onset (0.41 years; 95% CI 0.27, 0.55). This strategy was also found to prolong the time to levodopa initiation by 25% through a gain of 0.83 levodopa-free years (95% CI 0.56, 1.1). In addition, use of the rasagiline strategy was found to generate a 5% gain in QALYs over 5 years compared with the pramipexole strategy (3.7 +/- 0.02 vs 3.51 +/- 0.03). Sensitivity analyses confirmed that the model was robust. Rasagiline represents a cost-effective alternative to pramipexole in the treatment of early PD in the UK.

The role of anxiety in the development of levodopa-induced dyskinesias in an animal model of Parkinson’s disease, and the effect of chronic treatment with the selective serotonin reuptake inhibitor citalopram

Levodopa-induced dyskinesia (LID) is an inevitable complication of the long-term treatment of Parkinson's disease (PD) with levodopa. In a rat model of LID, we observed that animals of almost identical genetic but slightly different environmental backgrounds displayed a very different profile in terms of their development and severity of LID. We hypothesised that this heterogeneity can be attributed to different levels of anxiety in individual animals. We evaluated the basal anxiety level of rats in this study using the elevated plus maze (EPM), open field (OF) test, and plasma corticosterone level. These animals then received unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway after which they were primed to develop LID. Finally, we manipulated the anxiety level of these animals by citalopram treatment over a 9-week period before they were killed. Although we could not establish an association between the anxiety level of rats with either the onset or severity of LID, our results showed that citalopram was able to mediate a partial alleviation in LID after chronic treatment, and the extent of recovery was negatively correlated to the anxiety measures of individual animals. Furthermore, this citalopram-mediated LID recovery appeared to be independent of any changes in striatal cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) and cyclin-dependent kinase 5 (Cdk5) system, in contrast to our previous studies with fetal ventral mesencephalon transplants. However, chronic citalopram treatment almost completely abolished the expression of serotonin receptor 1B (5HT1B) in the striatum in animals exhibiting LID recovery. These results indicate a novel association of serotonin receptors in the development of LID and contributes to the evidence that the serotonergic system may play an important role in such movements.

Clinical Features and Gene Analysis in Korean Patients With Early-Onset Parkinson Disease

Systematic analysis of clinical features and gene mutations has not been performed in Korean patients with early-onset Parkinson disease (PD). To investigate the clinical characteristics and genetic background of Korean patients with early-onset PD. Clinical and genetic study. University hospital. Ninety-four patients with early-onset PD (mean +/- SD age at onset, 39.8 +/- 7.3 years) of 1100 patients with PD. Analysis of clinical characteristics and mutation analysis of the parkin and PTEN-induced kinase (PINK1) genes by direct sequencing and gene-dosage analysis using the multiplex ligation-dependent probe amplification technique. The correlation between age at onset and clinical characteristics and the clinical features of patients with onset before age 30 years vs patients with onset after age 30 years. Because age at onset was younger, levodopa-induced dyskinesia and off-dystonia were more frequently observed (P=.008). Patients affected before age 30 years showed more frequent levodopa-induced dyskinesia and off-dystonia (P=.002). We identified 3 patients (5%) with parkin gene mutations but none with the PINK1 mutation. Earlier onset of levodopa-induced dyskinesia and off-dystonia were characteristic features of early-onset PD, especially before an onset age of 30 years. However, parkin gene mutations were less frequent in these patients than in Japanese groups reported elsewhere.