Metabotropic Glutamate Receptor 4 (mGlu4) Positive Allosteric Modulators Lack Efficacy in Rat and Marmoset Models of L-DOPA-Induced Dyskinesia.

Background: Increased activity across corticostriatal glutamatergic synapses may contribute to L-DOPA-induced dyskinesia in Parkinson's disease. Given the weak efficacy and side-effect profile of amantadine, alternative strategies to reduce glutamate transmission are being investigated. Metabotropic glutamate receptor 4 (mGlu4) is a promising target since its activation would reduce glutamate release. Objective: We hypothesized that two mGlu4 positive allosteric modulators, Lu AF21934 ((1 S,2 R)-N1-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide) and ADX88178 (5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine), would provide relief in rat and primate models of L-DOPA-induced dyskinesia. Methods: The ability of Lu AF21934 or ADX88178 to reverse pre-established dyskinesia was examined in L-DOPA-primed 6-hydroxydopamine-lesioned rats expressing abnormal involuntary movements (AIMs) or in 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets expressing L-DOPA-induced dyskinesia. Additionally, the ability of Lu AF21934 to prevent the development of de novo L-DOPA-induced AIMs was explored in the 6-hydroxydopamine-lesioned rats. Results: Neither Lu AF21934 (10 or 30 mg/kg p.o.) nor ADX88178 (10 or 30 mg/kg p.o.) reduced pre-established AIMs in 6-hydroxydopamine-lesioned rats. Similarly, in L-DOPA-primed common marmosets, no reduction in established dyskinesia was observed with Lu AF21934 (3 or 10 mg/kg p.o.). Conversely, amantadine significantly reduced (>40%) the expression of dyskinesia in both models. Lu AF21934 also failed to suppress the development of AIMs in 6-hydroxydopamine-lesioned rats. Conclusions: This study found no benefit of mGlu4 positive allosteric modulators in tackling L-DOPA-induced dyskinesia. These findings are concordant with the recent failure of foliglurax in phase II clinical trials supporting the predictive validity of these pre-clinical dyskinesia models, while raising further doubt on the anti-dyskinetic potential of mGlu4 positive allosteric modulators.

Serotonin as a biomarker of toxin-induced Parkinsonism.

BACKGROUND: Loss of dopaminergic neurons underlies the motor symptoms of Parkinson's disease (PD). However stereotypical PD symptoms only manifest after approximately 80% of dopamine neurons have died making dopamine-related motor phenotypes unreliable markers of the earlier stages of the disease. There are other non-motor symptoms, such as depression, that may present decades before motor symptoms. METHODS: Because serotonin is implicated in depression, here we use niche, fast electrochemistry paired with mathematical modelling and machine learning to, for the first time, robustly evaluate serotonin neurochemistry in vivo in real time in a toxicological model of Parkinsonism, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). RESULTS: Mice treated with acute MPTP had lower concentrations of in vivo, evoked and ambient serotonin in the hippocampus, consistent with the clinical comorbidity of depression with PD. These mice did not chemically respond to SSRI, as strongly as control animals did, following the clinical literature showing that antidepressant success during PD is highly variable. Following L-DOPA administration, using a novel machine learning analysis tool, we observed a dynamic shift from evoked serotonin release in the hippocampus to dopamine release. We hypothesize that this finding shows, in real time, that serotonergic neurons uptake L-DOPA and produce dopamine at the expense of serotonin, supporting the significant clinical correlation between L-DOPA and depression. Finally, we found that this post L-DOPA dopamine release was less regulated, staying in the synapse for longer. This finding is perhaps due to lack of autoreceptor control and may provide a ground from which to study L-DOPA induced dyskinesia. CONCLUSIONS: These results validate key prior hypotheses about the roles of serotonin during PD and open an avenue to study to potentially improve therapeutics for levodopa-induced dyskinesia and depression.

Striatal Serotonin 4 Receptor is Increased in Experimental Parkinsonism and Dyskinesia.

Alterations of serotonin type 4 receptor levels are linked to mood disorders and cognitive deficits in several conditions. However, few studies have investigated 5-HT4R alterations in movement disorders. We wondered whether striatal 5-HT4R expression is altered in experimental parkinsonism. We used a brain bank tissue from a rat and a macaque model of Parkinson's disease (PD). We then investigated its in vivo PET imaging regulation in a cohort of macaques. Dopaminergic depletion increases striatal 5-HT4R in the two models, further augmented after dyskinesia-inducing L-Dopa. Pending confirmation in PD patients, the 5-HT4R might offer a therapeutic target for dampening PD's symptoms.

Levodopa-induced Dyskinesia in Parkinson's Disease: Plausible Inflammatory and Oxidative Stress Biomarkers.

BACKGROUND: Pathophysiology of levodopa-induced dyskinesia (LID) remains obscure. Increased dopamine metabolism due to prolonged levodopa treatment can exacerbate oxidative damage and neuroinflammatory pathology in Parkinson's disease (PD). Association of novel peripheral markers with LID severity might provide insight into LID pathomechanisms. OBJECTIVE: We aimed to study specific peripheral blood inflammatory-oxidative markers in LID patients and investigate their association with clinical severity of LID. METHOD: Motor, non-motor and cognitive changes in PD with and without LID compared to healthy-matched controls were identified. Within the same cohort, inflammatory marker (sLAG3, TOLLIP, NLRP3 and IL-1ß) levels and antioxidant enzyme activities were determined by ELISA and spectrophotometric methods. RESULTS: LID patients showed distinctly upregulated TOLLIP, IL-1ß levels with significant diminution of antioxidant activity compared to controls. Significant negative association of cognitive markers with oxidative changes was also observed. CONCLUSION: To our understanding, this is the first study that indicates the involvement of toll-like receptor-mediated distinct and low-grade inflammatory activation in LID pathophysiology.

Neuroplasticity in levodopa-induced dyskinesias: An overview on pathophysiology and therapeutic targets.

Levodopa-induced dyskinesias (LIDs) are a common complication in patients with Parkinson's disease (PD). A complex cascade of electrophysiological and molecular events that induce aberrant plasticity in the cortico-basal ganglia system plays a key role in the pathophysiology of LIDs. In the striatum, multiple neurotransmitters regulate the different forms of physiological synaptic plasticity to provide it in a bidirectional and Hebbian manner. In PD, impairment of both long-term potentiation (LTP) and long-term depression (LTD) progresses with disease and dopaminergic denervation of striatum. The altered balance between LTP and LTD processes leads to unidirectional changes in plasticity that cause network dysregulation and the development of involuntary movements. These alterations have been documented, in both experimental models and PD patients, not only in deep brain structures but also at motor cortex. Invasive and non-invasive neuromodulation treatments, as deep brain stimulation, transcranial magnetic stimulation, or transcranial direct current stimulation, may provide strategies to modulate the aberrant plasticity in the cortico-basal ganglia network of patients affected by LIDs, thus restoring normal neurophysiological functioning and treating dyskinesias. In this review, we discuss the evidence for neuroplasticity impairment in experimental PD models and in patients affected by LIDs, and potential neuromodulation strategies that may modulate aberrant plasticity.

Levodopa-induced dyskinesia: interplay between the N-methyl-D-aspartic acid receptor and neuroinflammation.

Parkinson's disease (PD) is a common neurodegenerative disorder of middle-aged and elderly people, clinically characterized by resting tremor, myotonia, reduced movement, and impaired postural balance. Clinically, patients with PD are often administered levodopa (L-DOPA) to improve their symptoms. However, after years of L-DOPA treatment, most patients experience complications of varying severity, including the "on-off phenomenon", decreased efficacy, and levodopa-induced dyskinesia (LID). The development of LID can seriously affect the quality of life of patients, but its pathogenesis is unclear and effective treatments are lacking. Glutamic acid (Glu)-mediated changes in synaptic plasticity play a major role in LID. The N-methyl-D-aspartic acid receptor (NMDAR), an ionotropic glutamate receptor, is closely associated with synaptic plasticity, and neuroinflammation can modulate NMDAR activation or expression; in addition, neuroinflammation may be involved in the development of LID. However, it is not clear whether NMDA receptors are co-regulated with neuroinflammation during LID formation. Here we review how neuroinflammation mediates the development of LID through the regulation of NMDA receptors, and assess whether common anti-inflammatory drugs and NMDA receptor antagonists may be able to mitigate the development of LID through the regulation of central neuroinflammation, thereby providing a new theoretical basis for finding new therapeutic targets for LID.

Shared GABA transmission pathology in dopamine agonist- and antagonist-induced dyskinesia.

Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist 3,4-dihydroxy-L-phenylalanine (L-DOPA) to treat Parkinson's disease (L-DOPA-induced dyskinesia [LID]) or dopamine antagonists to treat schizophrenia (tardive dyskinesia [TD]). However, it remains unknown why distinct types of medications for distinct neuropsychiatric disorders induce similar involuntary movements. Here, we search for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identify the enlarged axon terminals of striatal medium spiny neurons in LID and TD model mice. Striatal overexpression of the vesicular gamma-aminobutyric acid transporter (VGAT) is necessary and sufficient for modeling these structural changes; VGAT levels gate the functional and behavioral alterations in dyskinesia models. Our findings indicate that lowered type 2 dopamine receptor signaling with repetitive dopamine fluctuations is a common cause of VGAT overexpression and late-onset dyskinesia formation and that reducing dopamine fluctuation rescues dyskinesia pathology via VGAT downregulation.

The mGluR2/3 orthosteric agonist LY-404,039 reduces dyskinesia, psychosis-like behaviours and parkinsonism in the MPTP-lesioned marmoset.

LY-404,039 is an orthosteric agonist of metabotropic glutamate 2 and 3 receptors (mGluR2/3) that may harbour additional agonist effect at dopamine D2 receptors. LY-404,039 and its pro-drug, LY-2140023, have previously entered clinical trials as treatment options for schizophrenia. They could therefore be repurposed, if proven efficacious, for other conditions, notably Parkinson's disease (PD). We have previously shown that the mGluR2/3 orthosteric agonist LY-354,740 alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Unlike LY-404,039, LY-354,740 does not stimulate dopamine D2 receptors, suggesting that LY-404,039 may elicit broader therapeutic effects in PD. Here, we sought to investigate the effect of this possible additional dopamine D2-agonist action of LY-404,039 by assessing its efficacy on dyskinesia, PLBs and parkinsonism in the MPTP-lesioned marmoset. We first determined the pharmacokinetic profile of LY-404,039 in the marmoset, in order to select doses resulting in plasma concentrations known to be well tolerated in the clinic. Marmosets were then injected L-DOPA with either vehicle or LY-404,039 (0.1, 0.3, 1 and 10 mg/kg). The addition of LY-404,039 10 mg/kg to L-DOPA resulted in a significant reduction of global dyskinesia (by 55%, P < 0.01) and PLBs (by 50%, P < 0.05), as well as reduction of global parkinsonism (by 47%, P < 0.05). Our results provide additional support of the efficacy of mGluR2/3 orthosteric stimulation at alleviating dyskinesia, PLBs and parkinsonism. Because LY-404,039 has already been tested in clinical trials, it could be repurposed for indications related to PD.

Phenytoin-induced dyskinesia: a case report.

BACKGROUND: Dyskinesia is a movement disorder categorized by involuntary movement of muscle. Although dyskinesia can be brought on by taking medications, it can also be a symptom of a variety of diseases. Antiepileptic drug-induced involuntary movements have been well researched. Rare reports have been made for dyskinesia, a type of dystonia caused by phenytoin. The mechanism of its occurrence must be succinctly studied. CASE PRESENTATION: A 53-year-old Asian patient taking phenytoin (100 mg twice daily) experienced symptoms of perioral muscle involuntary movement, impaired speech, and generalized tremors and was admitted to the hospital. Brain magnetic resonance imaging showed significant development of encephalomalacia and porencephaly. The serum phenytoin levels were in the toxic range (33 g/ml). These were suggestive of phenytoin-induced dyskinesia. Levetiracetam and clonazepam were initiated, and the patient showed significant improvement in the symptoms. CONCLUSION: This case presented a substantial reference value for the differential diagnosis and treatment prognosis of phenytoin-induced dyskinesia. The phenytoin-induced dyskinesia in this patient was successfully reversed with prompt identification and treatment. According to the case study's findings, such people may benefit from periodic therapeutic drug monitoring.

Comparison of dyskinesia profiles after L-DOPA dose challenges with or without dopamine agonist coadministration.

Many patients with Parkinson's disease (PD) experiencing l-DOPA-induced dyskinesia (LID) receive adjunct treatment with dopamine agonists, whose functional impact on LID is unknown. We set out to compare temporal and topographic profiles of abnormal involuntary movements (AIMs) after l-DOPA dose challenges including or not the dopamine agonist ropinirole. Twenty-five patients with PD and a history of dyskinesias were sequentially administered either l-DOPA alone (150% of usual morning dose) or an equipotent combination of l-DOPA and ropinirole in random order. Involuntary movements were assessed by two blinded raters prior and every 30 min after drug dosing using the Clinical Dyskinesia Rating Scale (CDRS). A sensor-recording smartphone was secured to the patients' abdomen during the test sessions. The two raters' CDRS scores were highly reliable and concordant with models of hyperkinesia presence and severity trained on accelerometer data. The dyskinesia time curves differed between treatments as the l-DOPA-ropinirole combination resulted in lower peak severity but longer duration of the AIMs compared with l-DOPA alone. At the peak of the AIMs curve (60-120 min), l-DOPA induced a significantly higher total hyperkinesia score, whereas in the end phase (240-270 min), both hyperkinesia and dystonia tended to be more severe after the l-DOPA-ropinirole combination (though reaching statistical significance only for the item, arm dystonia). Our results pave the way for the introduction of a combined l-DOPA-ropinirole challenge test in the early clinical evaluation of antidyskinetic treatments. Furthermore, we propose a machine-learning method to predict CDRS hyperkinesia severity using accelerometer data.

5-HT1A agonists for levodopa-induced dyskinesia in Parkinson's disease.

Levodopa is the most effective agent for treating the symptoms of Parkinson's disease (PD). However, levodopa-induced dyskinesia remains a significant complication that manifests after few years of treatment, for which therapeutic options remain limited. Several agonists of the serotonin type 1A (5-HT1A) receptor with varying levels of efficacy and interaction at other sites, have been tested in the clinic. Clinical trials testing 5-HT1A agonists have yielded inconsistent results in alleviating dyskinesia, especially that the antidyskinetic benefit observed was often accompanied by an adverse effect on motor function. In this article, we summarize and analyze the various clinical trials performed with 5-HT1A agonists in PD patients with dyskinesia and offer perspectives on the future of this class of agents in PD.

After prolonged treatment with levodopa, patients with Parkinson's disease might start to experience abnormal involuntary movements, called 'dyskinesias'. These abnormal movements may be difficult to cope with since they can occur for several hours during the day and can hamper the quality of life. A potential approach to reduce the severity of dyskinesia, which has been the focus of extensive research, consists of stimulating a target inside the brain called the 5-HT_1A receptor. Several drugs harbouring this mechanism of action have been tested in clinical studies. Here, we provide an overview of these clinical studies and discuss their results.

Withdrawal-Emergent Dyskinesia Related to Benztropine: A Case Report.

INTRODUCTION: Benztropine is an anticholinergic drug used as a therapy for Parkinson's disease and treatment for extrapyramidal side effects. While tardive dyskinesia is an involuntary movement disorder that often occurs gradually after long-term use of medications, it does not commonly present acutely. CASE PRESENTATION: A 31-year-old White woman experiencing psychosis presented with spontaneous, acute-onset dyskinesia induced with the withdrawal of benztropine. She had been followed in our academic outpatient clinic for medication management and intermittent psychotherapy. DISCUSSION: The pathophysiology of tardive dyskinesia is not fully understood, but several hypotheses exist, including the involvement of changes in basal ganglia neuronal systems. To our knowledge, this is the first case report to document acute-onset dyskinesia associated with the withdrawal of benztropine. CONCLUSION: his case report, which describes an atypical response to discontinuing benztropine, might offer the scientific community potential clues to better understand the pathophysiology of tardive dyskinesia.

Doxycycline to treat levodopa-induced dyskinesias in Parkinson's disease: a preliminary study.

BACKGROUND: 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. OBJECTIVE: To evaluate the efficacy and safety of doxycycline in patients with PD and LID. METHODS: 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. RESULTS: 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. CONCLUSION: 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. CLINICAL TRIAL REGISTRATION: https://ensaiosclinicos.gov.br, identifier: RBR-1047fwbf.

ANTECEDENTES: 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. OBJETIVO: 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. RESULTADOS: 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.

7-Nitroindazole reduces L-DOPA-induced dyskinesias in non-human Parkinsonian primate.

Nitric oxide (NO) plays a pivotal role in integrating dopamine transmission in the basal ganglia and has been implicated in the pathogenesis of Parkinson disease (PD). The objective of this study was to ascertain whether the NO synthase inhibitor, 7-nitroindazole (7-NI), is able to reduce L-DOPA-induced dyskinesias (LIDs) in a non-human primate model of PD chronically intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Six Parkinsonian macaques were treated daily with L-DOPA for 3-4 months until they developed LIDs. Three animals were then co-treated with a single dose of 7-NI administered 45 min before each L-DOPA treatment. Dyskinetic MPTP-treated monkeys showed a significant decrease in LIDs compared with their scores without 7-NI treatment (p < 0.05). The anti-Parkinsonian effect of L-DOPA was similar in all three monkeys with and without 7-NI co-treatment. This improvement was significant with respect to the intensity and duration of LIDs while the beneficial effect of L-DOPA treatment was maintained and could represent a promising therapy to improve the quality of life of PD patients.

Scales for Antipsychotic-Associated Movement Disorders: Systematic Review, Critique, and Recommendations.

BACKGROUND: Antipsychotic-associated movement disorders remain common and disabling. Their screening and assessment are challenging due to clinical heterogeneity and different use of nomenclature between psychiatrists and neurologists. OBJECTIVE: An International Parkinson and Movement Disorder Society subcommittee aimed to rate psychometric quality of severity and screening instruments for antipsychotic-associated movement disorders. METHODS: Following the methodology adopted by previous International Parkinson and Movement Disorders Society subcommittee papers, instruments for antipsychotic-associated movement disorders were reviewed, applying a classification as "recommended," "recommended with caveats," "suggested," or "listed." RESULTS: Our review identified 23 instruments. The highest grade of recommendation reached is "recommended with caveats," assigned to seven severity rating instruments (Extrapyramidal Symptoms Rating Scale, Barnes Akathisia Rating Scale, Abnormal Involuntary Movements Scale, Drug-Induced Extra-Pyramidal Symptoms Scale, Maryland Psychiatric Research Centre involuntary movements scale, Simpson Angus Scale, and Matson Evaluation of Drug Side effects). Only three of these seven (Drug-Induced Extra-Pyramidal Symptoms Scale, Maryland Psychiatric Research Centre, Matson Evaluation of Drug Side effects) were also screening instruments. Their main caveats are insufficient demonstration of psychometric properties (internal consistency, skewing, responsiveness to change) and long duration of administration. Eight "suggested" instruments did not meet requirements for the "recommended" grade also because of insufficient psychometric validation. Other limitations shared by several instruments are lack of comprehensiveness in assessing the spectrum of antipsychotic-associated movement disorders and ambiguous nomenclature. CONCLUSIONS: The high number of instruments "recommended with caveats" does not support the need for developing new instruments for antipsychotic-associated movement disorders. However, addressing the caveats with new psychometric studies and revising existing instruments to improve the clarity of their nomenclature are recommended next steps. © 2023 International Parkinson and Movement Disorder Society.

Incidence and characteristics of post-COVID-19 parkinsonism and dyskinesia related to COVID-19 vaccines.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an infectious disease mainly affecting the respiratory system; however, a significant prevalence of neurological symptoms has been noted. OBJECTIVES: To investigate the incidence and characteristics of post-COVID-19 parkinsonism and to study dyskinesia related to COVID-19 vaccines. MATERIAL AND METHODS: The MEDLINE, PubMed, Scopus, and Web of Science databases were searched for all manuscripts relevant to post-COVID-19 parkinsonism and dyskinesia related to COVID-19 vaccines. Subsequently, we extracted and analysed data from the manuscripts in a structured manner. RESULTS: We found 24 patients with post-COVID-19 parkinsonism, with a mean onset age of 58 years after a mean of 30 days from the COVID-19 onset. Akinetic-rigid (n = 11) and mixed (n = 6) subtypes were the most common. Asymmetry was present in 13/15 patients. Brain MRI was unremarkable in 11/19, whereas dopaminergic system imaging was abnormal in 8/8 patients. Responsiveness to dopaminergic treatment was observed in 12/15 patients. Four patients improved after immunomodulatory therapy. Comorbidities were present in 9/24, encephalopathy symptoms in 11/24, and loss of smell in 9/13 patients. Most patients (n = 14) suffered serious COVID-19- related complications and three were treated with haloperidol. Parkinsonism improved (n = 5) or resolved (n = 4) during the follow-up. Five patients, with a mean age of 52, developed dyskinesia at a mean of 25 hours after receiving the COVID-19 mRNA vaccines. One patient had a history of neuropsychiatric symptoms and developed functional dyskinesia of the tongue. Four patients had a previous history of Parkinson's Disease (PD) with a mean duration of 10 years and developed dyskinesia and dystonia, which resolved (n = 2) or improved (n = 2) during the follow-up. CONCLUSIONS: Post-COVID-19 parkinsonism is a very rare complication, and it is likely that this is an umbrella syndrome that includes many different etiologies. Dyskinesia due to COVID-19 vaccines is exceedingly rare and probably has the same pathophysiological basis as in other conditions with exacerbation of PD symptoms.

Cross-Cultural Differences in Patient Perceptions of Dyskinesia in Parkinson's Disease.

BACKGROUND: The prevalence of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD) varies among geographical regions. Cultural differences in patient-based perceptions of LID have not been studied. OBJECTIVE: We compared patient and clinician evaluations of LID severity across multiple cultures in patients with PD. METHODS: The data set included the Unified Dyskinesia Rating (UDysRS) scores from 16 language translation programs (3566 patients). We defined the Perception Severity Index (PSI) as the ratio between normalized patient-based subjective ratings (UDysRS Part 1B) and normalized clinician examination (Parts 3 and 4) scores (Part 1B/Parts 3 + 4) and compared the PSI across languages. RESULTS: The mean PSI for the Chinese language (2.16) was higher than those of all other languages, whereas the ratio for the Korean language (0.73) was lower than those for Japanese, German, Turkish, Greek, Polish, and Finnish languages (corrected P values <0.05). CONCLUSIONS: Culture, as represented by language, affects the subjective perception of LID and needs to be considered in multinational clinical PD trials on dyskinesia. © 2023 International Parkinson and Movement Disorder Society.

Why Does Tardive Dyskinesia Have Oro-facial Predominance? A Network Analysis.

Tardive dyskinesia is a involuntary hyperkinetic disorder which usually occurs in older patients after long-term treatment with antipsychotic drugs. These dyskinesias are mostly irreversible and are frequently expressed in the tongue, cheeks, mandible, perioral area and other regions of the face. In this theoretical study we asked the question, why does tardive dyskinesia often have orofacial predominance? What might be the underlying neural network structure which contributes to this propensity? Graph analysis of high-level cortico-striato-thalamo-cortical network structure suggests a connectivity bottleneck. The number of walks of different lengths from the substantia nigra pars reticulata (SNr) to other vertices, as well as the returning cycles are the lowest in the network, which may indicate a higher damage susceptibility of this node. Analysis was also performed on published data from a recent high resolution histological study on cortico-striato-thalamo-cortical networks in rodents. Finer network partitioning and adjacency matrices demonstrated that the SNr has a heterogeneous connectivity structure and the number of local walks from nodes neighboring orofacial neural representation is higher, indicating possible early compensatory escape routes. However, with more extensive SNr damage the larger circuit compensation might be limited. This area of inquiry is important for future research, because identifying key vulnerable structures may provide more targeted therapeutical interventions.

Levodopa-induced dyskinesia is preceded by increased levels of anxiety and motor impairment in Parkinson's disease patients.

Introduction: Dopamine replacement therapy with levodopa is the gold standard treatment of Parkinson's disease (PD); however long-term levodopa use is associated with abnormal involuntary movements known as levodopa-induced dyskinesia (LID) in most patients. LID is not preventable and represents the major limitation of PD treatment.Objective: This study was aimed to find clinical and behavioral features that could be used to identify, years in advance, PD patients that are at high risk of developing LID in the future. Method: Data from PD patients enrolled in The Parkinson's progression markers initiative (PPMI, Michael J. Fox Foundation) that developed dyskinesia during their participation in the study were compared with those who did not, and with healthy controls.Result: LID was preceded byhigher levels of trait anxiety and increased motor impairment in PD patients. Additionally, younger age at PD diagnosis, earlier need for dopaminergic therapy and higher initial levodopa dose, were associated with future development of dyskinesia.Conclusion: These findings suggest that easily detectable clinical and behavioral alterations may help to identify PD patients that are more susceptible to develop LID.

Dyskinesia and Parkinson's disease: animal model, drug targets, and agents in preclinical testing.

INTRODUCTION: Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. PD patients exhibit a classic spectrum of motor symptoms, arising when dopamine neurons in the substantia nigra pars compacta are reduced by 60%. The dopamine precursor L-DOPA represents the most effective therapy for improving PD motor dysfunctions, thus far available. Unfortunately, long-term treatment with L-DOPA is associated with the development of severe side effects, resulting in abnormal involuntary movements termed levodopa-induced dyskinesia (LID). Amantadine is the only drug currently approved for the treatment of LID indicating that LID management is still an unmet need in PD and encouraging the search for novel anti-dyskinetic drugs or the assessment of combined therapies with different molecular targets. AREAS COVERED: This review provides an overview of the main preclinical models used to study LID and of the latest preclinical evidence on experimental and clinically available pharmacological approaches targeting non-dopaminergic systems. EXPERT OPINION: LIDs are supported by complex molecular and neurobiological mechanisms that are still being studied today. This complexity suggests the need of developing personalized pharmacological approach to obtain an effective amelioration of LID condition and improve the quality of life of PD patients.