BACKGROUND: Levodopa-induced dyskinesias (LID) are frequent in Parkinson\'s disease (PD).
OBJECTIVE: To analyze the change in the frequency of LID over time, identify LID related factors, and characterize how LID impact on patients\' quality of life (QoL).
METHODS: PD patients from the 5-year follow-up COPPADIS cohort were included. LID were defined as a non-zero score in the item \"Time spent with dyskinesia\" of the Unified Parkinson\'s Disease Rating Scale-part IV (UPDRS-IV). The UPDRS-IV was applied at baseline (V0) and annually for 5 years. The 39-item Parkinson\'s disease Questionnaire Summary Index (PQ-39SI) was used to asses QoL.
RESULTS: The frequency of LID at V0 in 672 PD patients (62.4 ± 8.9 years old; 60.1% males) with a mean disease duration of 5.5 ± 4.3 years was 18.9% (127/672) and increased progressively to 42.6% (185/434) at 5-year follow-up (V5). The frequency of disabling LID, painful LID, and morning dystonia increased from 6.9%, 3.3%, and 10.6% at V0 to 17.3%, 5.5%, and 24% at V5, respectively. Significant independent factors associated with LID (P < 0.05) were a longer disease duration and time under levodopa treatment, a higher dose of levodopa, a lower weight and dose of dopamine agonist, pain severity and the presence of motor fluctuations. LID at V0 (β = 0.073; P = 0.027; R2 = 0.62) and to develop disabling LID at V5 (β = 0.088; P = 0.009; R2 = 0.73) were independently associated with a higher score on the PDQ-39SI.
CONCLUSIONS: LID are frequent in PD patients. A higher dose of levodopa and lower weight were factors associated to LID. LID significantly impact QoL.

BACKGROUND: Levodopa-induced dyskinesia (LID) is a debilitating motor feature in a subset of patients with Parkinson\'s disease (PD) after prolonged therapeutic administration of levodopa. Preliminary animal and human studies are suggestive of a key role of dopamine type 3 (D3) receptor polymorphism (Ser9Gly; rs6280) in LID. Its contribution to development of LID among Indian PD patients has remained relatively unexplored and merits further investigation.
METHODS: 200 well-characterised PD patients (100 without LID and 100 with LID) and 100 age-matched healthy controls were recruited from the outpatient department of Institute of Neurosciences Kolkata. MDS-UPDRS (Unified Parkinson\'s Disease Rating Scale from International Movement Disorder Society) Part III and AIMS (abnormal involuntary movement scale) were performed for estimation of severity of motor features and LID respectively in the ON state of the disease. Participants were analysed for the presence of Ser9Gly single nucleotide variant (SNV) (rs6280) by polymerase chain reaction followed by restriction fragment length polymorphism techniques.
RESULTS: The frequency of AA genotype (serine type) was more frequently present in PD patients with LID compared to PD patients without LID (50 % vs 28 %; P = 0.002; OR = 2.57, 95 % CI: 1.43 - 4.62). The abnormal involuntary movement scale score was significantly higher in PD patients with AA genotype compared to carriers of glycine allele (AG + GG) (4.08 ± 3.35; P = 0.002).
CONCLUSIONS: We observed a significant association of serine type SNV (rs6280) in D3 receptor gene in a cohort of PD patients with LID from India. More severe motor severity was found in patients with glycine substitution of the same SNV. The current study emphasised the role of D3 receptor in the pathogenesis of LID.

BACKGROUND: Preclinical evidence suggests that co-administration of the 5-HT1A agonist buspirone and the 5-HT1B/1D agonist zolmitriptan act synergistically to reduce dyskinesia to a greater extent than that achieved by either drug alone.
OBJECTIVE: Assess the therapeutic potential of a fixed-dose buspirone and zolmitriptan combination in Parkinson\'s disease (PD) patients with levodopa-induced dyskinesia.
METHODS: Single-center, randomized, placebo-controlled, two-way crossover study (NCT02439203) of a fixed-dose buspirone/zolmitriptan regimen (10/1.25 mg three times a day) in 30 patients with PD experiencing at least moderately disabling peak-effect dyskinesia.
RESULTS: Seven days of treatment with buspirone/zolmitriptan added to levodopa significantly reduced dyskinesia as assessed by Abnormal Involuntary Movement Scale scores versus placebo (mean treatment effect vs. placebo: -4.2 [-6.1, -2.3]) without significantly worsening Unified Parkinson\'s Disease Rating Scale (UPDRS) Part III (ON) scores (mean treatment effect vs. placebo: 0.6 [-0.1, 1.3]). No serious adverse events were reported.
CONCLUSIONS: In this proof-of-concept study, addition of buspirone/zolmitriptan to the patients\' PD medication regimen significantly reduced dyskinesia severity without worsening motor function. © 2024 International Parkinson and Movement Disorder Society.

Levodopa-induced dyskinesia (LID) is a common motor complication of levodopa therapy in patients with Parkinson\'s disease (PD). Doxycycline is a widely used and inexpensive tetracycline with anti-inflammatory properties.
To evaluate the efficacy and safety of doxycycline in patients with PD and LID.
This was an open-label, uncontrolled, single-arm, single-center, phase 2 proof-of-concept study in patients with PD with functional impact of dyskinesia, which used levodopa three times daily, in a movement disorders clinic in Brazil. Participants were treated with doxycycline 200 mg/day for 12 weeks, with evaluations at baseline, week 4, and week 12 of treatment. The primary outcome measure was the change from baseline in the Unified Dyskinesia Rating Scale (UDysRS) total score at week 12, evaluated by two blinded raters. Key secondary outcomes measures were OFF time and ON time with troublesome dyskinesia in the PD home diary.
Eight patients with PD were treated and evaluated. Doxycycline 200 mg/day reduced the UDysRS total score at week 12, compared with baseline (Friedman χ2 = 9.6; p = 0.008). Further, doxycycline reduced the ON time with troublesome dyskinesia (Friedman χ2 = 10.8; p = 0.004) without worsening parkinsonism. There were no severe adverse events, and dyspepsia was the commonest event.
In this preliminary, open-label and uncontrolled trial, doxycycline was effective in reducing LID and safe after a 12-week treatment. Further well-designed placebo-controlled clinical trials with a longer duration and a larger number of participants are needed.
https://ensaiosclinicos.gov.br, identifier: RBR-1047fwbf.
A discinesia induzida por levodopa (DIL) é uma complicação motora comum da terapia com levodopa em pacientes com doença de Parkinson (DP). A doxiciclina é uma tetraciclina amplamente usada e barata, com propriedade anti-inflamatória.
Avaliar a eficácia e segurança da doxiciclina em pacientes com DP e DIL. MéTODOS:  Este foi um estudo aberto, não-controlado, de braço único, monocêntrico, fase 2 e de prova de conceito, em pacientes com DP e impacto funcional das discinesias, que usavam levodopa três vezes ao dia, em um ambulatório de distúrbios de movimento no Brasil. Os participantes foram tratados com doxiciclina 200 mg/dia por 12 semanas, com avaliações na base, na semana 4 e na semana 12 do tratamento. A medida de desfecho primário foi a mudança no escore total da Unified Dyskinesia Rating Scale (UDysRS) da base à semana 12, avaliada por dois avaliadores cegos. As medidas-chave de desfecho secundário fora o tempo em OFF e tempo em ON com discinesia problemática.
Oito pacientes com DP foram tratados e avaliados. A doxiciclina 200 mg/dia reduziu o escore total da UDysRS na semana 12, comparado com a avaliação inicial (χ2 de Friedman = 9.6; p = 0.008). Além disso, a doxiciclina reduziu o tempo em ON com discinesia problemática (χ2 de Friedman = 10.8; p = 0.004) sem piorar o parkinsonismo. Não houve eventos adversos graves, e dispepsia foi o evento mais comum. CONCLUSãO:  No presente estudo preliminar, aberto e não-controlado, a doxiciclina foi eficaz em reduzir as DIL e segura após tratamento por 12 semanas. Estudos clínicos bem-desenhados e placebo-controlados adicionais, com duração mais longa e maior número de participantes, são necessários.

暂无摘要。

There is a substantial gap in life expectancy between patients with severe mental illness (SMI) and the general population and it is important to understand which factors contribute to this difference. Research suggests an association between tardive dyskinesia (TD) and mortality; however, results are inconclusive. In addition, studies investigating associations between parkinsonism or akathisia and mortality are rare. We hypothesized that TD would be a risk factor for mortality in patients with SMI.
We studied a cohort of 157 patients diagnosed predominantly with schizophrenia on the former Netherlands Antilles. TD, parkinsonism, and akathisia were assessed with rating scales on eight occasions over a period of 18 years. Twenty-four years after baseline, survival status and if applicable date of death were determined. Associations between movement disorders and survival were analyzed using Cox regression. Sex, age, antipsychotics, antidepressants and benzodiazepines at each measurement occasion were tested as covariates.
Parkinsonism was a significant risk factor with an HR of 1.02 per point on the motor subscale of the Unified Parkinson\'s Disease Rating Scale (range 0-56). TD and akathisia were not significantly associated with mortality.
Parkinsonism may be an important risk factor for mortality in SMI patients. This finding calls for more follow-up and intervention studies to confirm this finding and to explore whether treatment or prevention of parkinsonism can reduce excess mortality.

Aim of the study was to evaluate possible associations between cognitive dysfunctions and development of Levodopa Induced Dyskinesia (LID). PD patients from the Parkinson\'s disease Cognitive impairment Study cohort who underwent a baseline and follow-up neuropsychological evaluations were enrolled. Mild Cognitive Impairment (PD-MCI) was diagnosed according to MDS level II criteria. The following cognitive domains were evaluated: episodic memory, attention, executive function, visuo-spatial function and language. A domain was considered as impaired when the subject scored 2 standard deviation below normality cut-off values in at least one test for each domain. Levodopa equivalent dose, UPDRS-ME and LID were recorded at baseline and follow-up. To identify possible neuropsychological predictors associated with the probability of LID development at follow-up, Cox proportional-hazards regression model was used. Out of 139 PD patients enrolled (87 men, mean age 65.7 ± 9.4), 18 (12.9%) were dyskinetic at baseline. Out of 121 patients non-dyskinetic at baseline, 22 (18.1%) developed LID at follow-up. The impairment of the attention and executive domains strongly predicted the development of LID (HR 4.45;95%CI 1.49-13.23 and HR 3.46; 95%CI 1.26-9.48 respectively). Impairment of the attention and executive domains increased the risk of dyskinesia reflecting the alteration of common cortical network.

Drug-induced movement disorders (DIMDs) are commonly encountered, but an often-under-reported subgroup of movement disorders.
We aimed to highlight the spectrum of DIMDs in patients taking different groups of drugs at our movement disorder center.
It is a cross-sectional descriptive study including 97 consecutive DIMDs patients diagnosed over the past two years (2017-2019).
The mean ± standard deviation (SD) age of our study population was 35.89 ± 17.8 years (Range-2-80 years). There were 51 males and 46 females. Different DIMDs observed included tardive dystonia (n = 41; 42.2%), postural tremor (n = 38; 39.2%), parkinsonism (n = 32; 33%), tardive dyskinesia (n = 21; 21.6%), acute dystonia (n = 10; 10.3%), neuroleptic malignant syndrome (NMS) (n = 2; 2.1%), and others [(n = 10; 10.30%) including chorea and stereotypy each in 3; acute dyskinesia in 2; and myoclonic jerks and acute akathisia each in 1 patient]. Of these 97 patients, 49 had more than one type of DIMDs while 48 had a single type of DIMDs. In our study 37 (38%) patients had received non-dopamine receptor blocking agents (non-DRBA), 30 (31%) patients had received dopamine receptor blocking agents (DRBA), and 30 (31%) patients had received both DRBA and non-DRBA.
Tardive dystonia was the most common DIMDs observed in our study. Our DIMDs patients were younger than other reported studies. We observed a significant number of non-DRBA drugs causing DIMD in our study as compared to previous studies. Drug-induced parkinsonism (DIP) was the most common DIMDs in the DRBA group. Tardive dystonia was the most common DIMDs seen in DRBA + non-DRBA group and the second most common in the DRBA and non-DRBA group. The postural tremor was the most common DIMDs in the non-DRBA group.

ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system in development for patients with Parkinson\'s disease (PD) experiencing motor fluctuationsObjective:Evaluate the efficacy and safety of two ND0612 dosing regimens in patients with PD.
This was a 28-day open-label study (NCT02577523) in PD patients with ≥2.5 hours/day of OFF time despite optimized treatment. Patients were randomized to treatment with either a 24-hour infusion (levodopa/carbidopa dose of 720/90 mg) or a 14-hour \'waking-day\' infusion (levodopa/carbidopa dose of 538/68 mg plus a morning oral dose of 150/15 mg). Supplemental oral doses of levodopa were permitted for patients in both groups if required. In-clinic assessments of OFF time (primary endpoint) and ON time with or without dyskinesia were determined by a blinded rater over 8 hours (normalized to 16 hours).
A total of 38 patients were randomized and 33 (87%) completed the study. Compared to baseline, OFF time for the overall population was reduced by a least squares (LS) mean[95% CI] of 2.0[- 3.3, - 0.7] hours (p = 0.003). ON time with no/mild dyskinesia (no troublesome dyskinesia) was increased from baseline by a LS mean of 3.3[2.0, 4.6] hours (p < 0.0001), and ON time with moderate/severe dyskinesia was reduced by a LS mean of 1.2[- 1.8, - 0.5] hours (p≤0.001). Reduction in OFF time was larger in the 24-hour group (- 2.8[- 4.6, - 0.9] hours; p = 0.004) than in the 14-hour group (- 1.3[- 3.1, 0.5] hours; p = 0.16). Complete resolution of OFF time was observed in 42% (n = 8) of patients in the 24-hour group. Infusion site reactions were the most common adverse event.
This study demonstrates the feasibility and safety of continuous subcutaneous delivery of levodopa as a treatment for PD and provides preliminary evidence of efficacy.

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset has been used extensively to model Parkinson\'s disease, L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and, more recently, dopaminergic psychosis. Whereas several experimental drugs have been tested in this primate, many of which subsequently underwent clinical trials, efficacy thresholds in the marmoset that would predict efficacy in the clinic are lacking. Here, we aimed to determine such efficacy end points that would be indicative of likely efficacy in clinical studies. To do so, we used the evidence-based medicine reviews published by the International Parkinson and Movement Disorder Society (IPMDS) to select drugs that were rated as clinically efficacious, likely efficacious or not efficacious for the treatment of parkinsonism, dyskinesia and psychosis. We then reviewed the literature in the MPTP-lesioned marmoset and identified articles reporting the effects of drugs that were included in the IPMDS recommendations, following which we estimated efficacy thresholds in the marmoset that would predict efficacy at the clinical level. We propose that, when drugs are administered as monotherapy, ≥ 50% reduction of global parkinsonism may be necessary to predict the possibility of clinical efficacy. As adjunct to a low dose of L-DOPA, we propose that an additional reduction of global parkinsonism ≥ 25% might predict clinical efficacy. As adjunct to an optimal dose of L-DOPA, we propose that additional anti-parkinsonian benefit ≥ 20%, with global parkinsonism as the end point, might predict clinical efficacy. For the treatment of dyskinesia, we suggest that the predictability threshold be set at ≥ 25% reduction of peak dose dyskinesia, while we believe that this threshold should be > 50% reduction of peak dose psychosis-like behaviours for psychosis-related end points. This article represents the first step in determining what efficacy might be necessary to achieve in pre-clinical studies in the MPTP-lesioned marmoset prior to confidently advancing drugs to clinical trials. We hope that it will help in the drug discovery and development process, notably by avoiding exposing patients to drugs that have little probability of clinical efficacy based upon pre-clinical experiments.