Dyskinesia and Pain in Advanced Parkinson's Disease: Post Hoc Analysis from the Phase 3b, Open-Label, Randomized DYSCOVER Study.

INTRODUCTION: The DYSCOVER study was a phase 3b, open-label, randomized trial (NCT02799381) that evaluated levodopa-carbidopa intestinal gel (LCIG) versus optimized medical treatment (OMT) in patients with Parkinson's disease (PD) and a high burden of dyskinesia at baseline (defined as Unified Dyskinesia Rating Scale [UDysRS] total score ≥ 30). At week 12, patients receiving LCIG versus OMT experienced significant improvements in dyskinesia, pain, and health-related outcomes. The objective of this analysis was to examine correlations between dyskinesia, pain, and health-related outcomes in PD. METHODS: This post hoc analysis assessed correlations between UDysRS, King's Parkinson's Disease Pain Scale (KPPS), 8-item Parkinson's Disease Questionnaire (PDQ-8), Unified Parkinson's Disease Rating Scale part II, Clinical Global Impression of Severity (CGI-S) or Change (CGI-C), and "On" time without troublesome dyskinesia at baseline and after 12 weeks of LCIG or OMT. Correlations were assessed by Pearson correlation coefficients (categorization: weak, r = 0.20-0.39; moderate, r = 0.40-0.59; strong, r ≥ 0.60). RESULTS: Among 61 patients, moderate-to-strong positive and significant correlations were observed between UDysRS and KPPS scores (baseline, r = 0.47; week 12 change from baseline [CFB], r = 0.63; all p < 0.001). UDysRS and KPPS scores had moderate-to-strong positive and highly significant correlations with PDQ-8 scores (baseline, r = 0.45 and 0.46, respectively; CFB, r = 0.54 and 0.64, respectively; all p < 0.001). Moderate positive and significant correlations were observed between UDysRS and CGI-S/CGI-C scores (baseline, r = 0.41; CFB, r = 0.47; all p < 0.001). CONCLUSIONS: In patients with high dyskinesia burden, positive correlations were observed between dyskinesia, pain, and health-related quality of life (HRQoL) at baseline. Improvements in dyskinesia and pain were associated with improvements in HRQoL, demonstrating the clinical burden of troublesome dyskinesia. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov identifier NCT02799381.

Sodium nitroprusside enhances stepping test performance and increases medium spiny neurons responsiveness to cortical inputs in a rat model of Levodopa-induced dyskinesias.

Levodopa (L-DOPA) is the classical gold standard treatment for Parkinson's disease. However, its chronic administration can lead to the development of L-DOPA-induced dyskinesias (LIDs). Dysregulation of the nitric oxide-cyclic guanosine monophosphate pathway in striatal networks has been linked to deficits in corticostriatal transmission in LIDs. This study investigated the effects of the nitric oxide (NO) donor sodium nitroprusside (SNP) on behavioural and electrophysiological outcomes in sham-operated and 6-hydroxydopamine-lesioned rats chronically treated with vehicle or L-DOPA, respectively. In sham-operated animals, systemic administration of SNP increased the spike probability of putative striatal medium spiny neurons (MSNs) in response to electrical stimulation of the primary motor cortex. In 6-hydroxydopamine-lesioned animals, SNP improved the stepping test performance without exacerbating abnormal involuntary movements. Additionally, SNP significantly increased the responsiveness of putative striatal MSNs in the dyskinetic striatum. These findings highlight the critical role of the NO signalling pathway in facilitating the responsiveness of striatal MSNs in both the intact and dyskinetic striata. The study suggests that SNP has the potential to enhance L-DOPA's effects in the stepping test without exacerbating abnormal involuntary movements, thereby offering new possibilities for optimizing Parkinson's disease therapy. In conclusion, this study highlights the involvement of the NO signalling pathway in the pathophysiology of LIDs.

BK Channelopathies and KCNMA1-Linked Disease Models.

Novel KCNMA1 variants, encoding the BK K+ channel, are associated with a debilitating dyskinesia and epilepsy syndrome. Neurodevelopmental delay, cognitive disability, and brain and structural malformations are also diagnosed at lower incidence. More than half of affected individuals present with a rare negative episodic motor disorder, paroxysmal nonkinesigenic dyskinesia (PNKD3). The mechanistic relationship of PNKD3 to epilepsy and the broader spectrum of KCNMA1-associated symptomology is unknown. This review summarizes patient-associated KCNMA1 variants within the BK channel structure, functional classifications, genotype-phenotype associations, disease models, and treatment. Patient and transgenic animal data suggest delineation of gain-of-function (GOF) and loss-of-function KCNMA1 neurogenetic disease, validating two heterozygous alleles encoding GOF BK channels (D434G and N999S) as causing seizure and PNKD3. This discovery led to a variant-defined therapeutic approach for PNKD3, providing initial insight into the neurological basis. A comprehensive clinical definition of monogenic KCNMA1-linked disease and the neuronal mechanisms currently remain priorities for continued investigation.

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.

Which side are they on? Diagnosing primary ciliary dyskinesias in low- or middle-income countries: A review and case series.

Background: Primary ciliary dyskinesia (PCD) is a rare genetic condition with a variable clinical presentation, making its diagnosis a challenge. We describe two unrelated sibling pairs with PCD: adult siblings in the first and perinatal/neonatal in the second. Both families highlight the more common and rarer clinical manifestations of PCD. We use these cases to highlight: (i) current understanding of the underlying genetic and pathophysiological mechanisms of PCD; (ii) the diversity of cardiac and respiratory features of PCD across a wide age range; (iii) aspects of the history and clinical examination that should raise suspicion of PCD; and (iv) the role of next-generation sequencing gene panel testing in confirmation of the diagnosis. We note genomic evidence predicting that PCD is relatively common in black African populations. Study synopsis: What the study adds. This review of two sibling pairs illustrates the variable histories, presentations, diagnostic processes and clinical courses of primary ciliary dyskinesia (PCD) in low- or middle-income countries (LMICs), highlighting the diagnostic challenges faced when encountering such patients in settings where there may not be access to specialised resources. Possible diagnostic tools that can be used are discussed, weighing up their pros and cons in an LMIC setting, and a potential diagnostic approach that can be adapted to the treating clinician's own context is provided.Implications of the findings. Confirmation of the diagnosis of primary ciliary dyskinesia is no longer limited to well-resourced institutions, but can be done in less specialised environments using novel, highly accurate next-generation sequencing gene panel testing, reducing the need to transport patients as well as the overall cost to the healthcare system. Well-resourced institutions that see high volumes of patients with PCD can invest in new highly sensitive diagnostic tools such as high-speed video microscopy. There is a need for research investigating the validity of tools such as ciliary immunofluorescence in the South African population.

SYNAPSES. Estudio observacional europeo para evaluar la seguridad y la efectividad de la safinamida en la práctica clínica habitual: análisis post hoc de la población española del estudio / SYNAPSES. A European observational study to evaluate the safety and the effectiveness of safinamide in routine clinical practice: post-hoc analysis of the Spanish study population

Introducción La enfermedad de Parkinson (EP) es una afección neurodegenerativa progresiva relacionada con la edad que requiere nuevas alternativas terapéuticas. La safinamida, un nuevo tratamiento complementario de la levodopa, afecta positivamente a las fluctuaciones de esta enfermedad al modular los sistemas dopaminérgico y glutamatérgico. Para investigar más a fondo el uso de la safinamida en la práctica clínica rutinaria europea, el presente análisis post hoc tiene como objetivo comprender el perfil de seguridad de la safinamida dentro de la población española del estudio. Pacientes y métodos Se evaluó a 511 pacientes españoles con EP al inicio, cuatro (±1), ocho (±1) y 12 (±1) meses después de iniciar el tratamiento con safinamida. Se utilizaron la puntuación total de la escala unificada de puntuación de la enfermedad de Parkinson (UPDRS) y la puntuación de la UPDRS III, durante el tiempo en on para medir la gravedad general de la EP y las complicaciones motoras, respectivamente, mientras que la gravedad de los acontecimientos adversos se evaluó siguiendo los criterios de los investigadores. Resultados La safinamida mostró un perfil de seguridad favorable en la población española del estudio, aunque la prescripción a pacientes con enfermedades psiquiátricas y el uso para indicaciones no autorizadas fueron más frecuentes que en la población europea del estudio. En España se observaron mejoras clínicamente significativas en las puntuaciones de la UPDRS cuando se utilizó la safinamida como único tratamiento complementario a la levodopa (el 57,4 y el 53,7% de los pacientes) y cuando se venía de administrar rasagilina (el 55,1% de los pacientes). Las complicaciones motoras se redujeron del 83,2 al 63,3% tras el período de estudio. No se detectaron mayores problemas de seguridad en ningún subgrupo de pacientes, aunque los pacientes con deterioro cognitivo mostraron una frecuencia algo superior de acontecimientos adversos. Conclusiones ... (AU)

Introduction. Parkinson’s Disease (PD) is a progressive age-related neurodegenerative condition requiring new therapeutic alternatives. Safinamide, a novel levodopa add-on therapy, positively affects disease fluctuations by modulating both dopaminergic and glutamatergic systems. To further investigate the use of safinamide in European routine clinical practice, the present post-hoc analysis aimed to understand safinamide’s safety profile within the Spanish study population. Patients and methods. Five hundred eleven Spanish patients with PD were evaluated at baseline, four (±1), eight (±1), and 12 (±1) months after initiating safinamide treatment. Unified Parkinson’s Disease Rating Scale (UPDRS) total score and UPDRS part III score during on time were used to measure the overall severity of PD and motor complications, respectively, while the severity of adverse events was evaluated following the investigators’ criteria. Results. Safinamide showed a favourable safety profile within the Spanish study population, although prescription to patients with psychiatric conditions and off-label use were more frequent than in the European study population. In Spain, clinically meaningful improvements were observed in UPDRS scores when safinamide was used as the only add-on therapy to levodopa (57.4% and 53.7% of patients) and when switching from rasagiline (55.1% of patients). Motor complications were reduced from 83.2% to 63.3% after the study period. Increased safety concerns were undetected in any patient subgroup, although patients with cognitive impairment showed a slightly higher frequency of adverse events. Conclusions. This subanalysis further supports safinamide use as a safe and efficacious option for the management of motor fluctuations in different subgroups of levodopa-treated patients. However, safinamide should be used with caution in patients with cognitive impairment. (AU)

Radiomics and Hybrid Models Based on Machine Learning to Predict Levodopa-Induced Dyskinesia of Parkinson's Disease in the First 6 Years of Levodopa Treatment.

BACKGROUND: Current research on the prediction of movement complications associated with levodopa therapy in Parkinson's disease (PD) is limited. levodopa-induced dyskinesia (LID) is a movement complication that seriously affects the life quality of PD patients. One-third of PD patients develop LID within 1 to 6 years of levodopa treatment. This study aimed to construct models based on radiomics and machine learning to predict early LID in PD. METHODS: We extracted radiomics features from the T1-weighted MRI obtained in the baseline of 49 PD control and 54 PD with LID in the first 6 years of levodopa therapy. Six brain regions related to the onset of PD were segmented as regions of interest (ROIs). The least absolute shrinkage and selection operator (LASSO) was used for feature selection. Using the machine learning methods of support vector machine (SVM), random forest (RF), and AdaBoost, we constructed radiomics models and hybrid models. The hybrid models combined the radiomics features and the Unified Parkinson's Disease Rating Scale part III (UPDRS III) total score. The five-fold cross-validation was performed and repeated 20 times to validate the stability of the classifiers. We used sensitivity, specificity, accuracy, receiver operating characteristic (ROC) curves, and area under the ROC curve (AUC) for model validation. RESULTS: We selected 33 out of 6138 radiomics features. In the testing set of the radiomics model, the AUC values of the SVM, RF, and AdaBoost classifiers were 0.905, 0.808, and 0.778, respectively, and the accuracies were 0.839, 0.742, and 0.710. The hybrid models had better prediction performance. In the testing set, the AUC values of SVM, RF, and AdaBoost classifiers were 0.958, 0.861, and 0.832, respectively, and the accuracies were 0.903, 0.806, and 0.774. CONCLUSIONS: Our results indicate that T1-weighted MRI is valuable in predicting early LID in PD. This work demonstrates that the combination of radiomics features and clinical features has good potential and value for identifying early LID in PD.

Non-Psychosis Symptoms of Clozapine Withdrawal: a Systematic Review.

OBJECTIVE: Clozapine is a potent antipsychotic medication with a complex receptor profile. It is reserved for treatment-resistant schizophrenia. We systematically reviewed studies of non-psychosis symptoms of clozapine withdrawal. METHODS: CINAHL, Medline, PsycINFO, PubMed, and the Cochrane Database of Systematic Reviews were searched using the keywords 'clozapine,' and 'withdrawal,' or 'supersensitivity,' 'cessation,' 'rebound,' or 'discontinuation'. Studies related to non-psychosis symptoms after clozapine withdrawal were included. RESULTS: Five original studies and 63 case reports / series were included in analysis. In 195 patients included in the five original studies, approximately 20% experienced non-psychosis symptoms following discontinuation of clozapine. In 89 patients in four of the studies, 27 experienced cholinergic rebound, 13 exhibited extrapyramidal symptoms (including tardive dyskinesia), and three had catatonia. In 63 case reports / series included, 72 patients with non-psychosis symptoms were reported, which were catatonia (n=30), dystonia or dyskinesia (n=17), cholinergic rebound (n=11), serotonin syndrome (n=4), mania (n=3), insomnia (n=3), neuroleptic malignant syndrome (NMS) [n=3, one of them had both catatonia and NMS], and de novo obsessive compulsive symptoms (n=2). Restarting clozapine appeared to be the most effective treatment. CONCLUSIONS: Non-psychosis symptoms following clozapine withdrawal have important clinical implications. Clinicians should be aware of the possible presentations of symptoms to ensure early recognition and management. Further research is warranted to better characterise the prevalence, risk factors, prognosis, and optimal drug dosing for each withdrawal symptom.

Levodopa-Induced Dyskinesias in Parkinson's Disease: An Overview on Pathophysiology, Clinical Manifestations, Therapy Management Strategies and Future Directions.

Since its first introduction, levodopa has become the cornerstone for the treatment of Parkinson's disease and remains the leading therapeutic choice for motor control therapy so far. Unfortunately, the subsequent appearance of abnormal involuntary movements, known as dyskinesias, is a frequent drawback. Despite the deep knowledge of this complication, in terms of clinical phenomenology and the temporal relationship during a levodopa regimen, less is clear about the pathophysiological mechanisms underpinning it. As the disease progresses, specific oscillatory activities of both motor cortical and basal ganglia neurons and variation in levodopa metabolism, in terms of the dopamine receptor stimulation pattern and turnover rate, underlie dyskinesia onset. This review aims to provide a global overview on levodopa-induced dyskinesias, focusing on pathophysiology, clinical manifestations, therapy management strategies and future directions.

[Tardive dyskinesia]. / Tardivnaya diskineziya.

Tardive dyskinesia (TD) is a delayed, often irreversible iatrogenic movement disorder caused by long-term use of that dopamine receptors blocking drugs. Prevention of TD is paramount, and clinicians should follow best practice recommendations for prescribing antipsychotics, as well as reduction the using of dopamine receptor blocking drugs for non-psychiatric prescriptions. Replacement of antipsychotics with lower affinity for D2 receptors drugs, addition of VMAT2 (tetrabenazine), botulinum therapy, amantadine may be effective. In detection and incurable cases, the possibility of neuromodulation of brain structures should be considered. Most methods for testing TD currently have an insufficient level of evidence, although they include recommendations from professional communities. There is a great need for new clinical trials.

Gradient boosting DD-MLP Net: An ensemble learning model using near-infrared spectroscopy to classify after-stroke dyskinesia degree during exercise.

This study aims to develop an automatic assessment of after-stroke dyskinesias degree by combining machine learning and near-infrared spectroscopy (NIRS). Thirty-five subjects were divided into five stages (healthy, patient: Brunnstrom stages 3, 4, 5, 6). NIRS was used to record the muscular hemodynamic responses from bilateral femoris (biceps brachii) muscles during passive and active upper (lower) limbs circular exercise. We used the D-S evidence theory to conduct feature information fusion and established a Gradient Boosting DD-MLP Net model, combining the dendrite network and multilayer perceptron, to realize automatic dyskinesias degree evaluation. Our model classified the upper limb dyskinesias with high accuracy: 98.91% under the passive mode and 98.69% under the active mode, and classified the lower limb dyskinesias with high accuracy: 99.45% and 99.63% under the passive and active modes, respectively. Our model combined with NIRS has great potential in monitoring the after-stroke dyskinesias degree and guiding rehabilitation training.

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.

Effect of Tiaoshen Changzhi acupuncture on behavior and striatum ΔFosB in rats with levodopa-induced dyskinesias.

This study aims to study the effffects of Tiaoshen Changzhi acupuncture on behavior and striatum ΔFosB in rats with Levodopa-induced Dyskinesias (LIDs). In this experimental study, Levodopa-induced Dyskinesia (LID) rat models were established by 6-OHDA double-target injection and randomly assigned to six groups, with ten rats in each group. The rats were subjected to difffferent interventions for 28 days, and their behavior was observed. Additionally, the content of ΔFosB, a marker of neuronal activation, in the rat striatum was detected by immunohistochemistry and qRT-PCR. In contrallateral rotation behavior experiment and AIM experiment, the score of the model group was significantly increased, compared with the model group, the score of the Western medicine group, the ordinary acupuncture group and the Tiaoshen Changzhi group was significantly decreased (P < 0.01), the score of the Western medicine group and the Tiaoshen Changzhi group was significantly lower than the ordinary acupuncture group (P < 0.01), there was no statistical significance between the Western medicine group and the Tiaoshen Changzhi group (P>0.05). In the left forelimb function test, the score of the model group was significantly decreased, and compared with the model group, the left forelimb function score of the Western medicine group, the ordinary acupuncture group and the Tiaoshen Changzhi group were significantly increased (P < 0.01). The left forelimb function score of the Western medicine group and the Tiaoshen Changzhi group was higher than the ordinary acupuncture group (P < 0.05, P < 0.01). There was no statistical significance between Western medicine group and Tiaoshen Changzhi group (P > 0.05). After treatment, the content of ΔFosB in the striatum of the Western medicine group, the ordinary acupuncture group and the Tiaoshen Changzhi acupuncture group all decreased, the Western medicine group was better than the ordinary acupuncture group (P < 0.01), and the Tiaoshen Changzhi acupuncture group was better than the ordinary acupuncture group (P < 0.05). Tiaoshen Changzhi acupuncture can improve the behavioral performance of LID rats, reduce abnormal involuntary movement and contralateral rotation behavior and enhance the motor function of the left forelimb of rats. One of its therapeutic mechanisms for LID may be to reduce the expression level of ΔFosB in the striatum of LID rats, thereby reducing the symptoms of LID rats.

Doxycycline to treat levodopa-induced dyskinesias in Parkinson's disease: a preliminary study / Doxiciclina no tratamento das discinesias induzidas pela doença de Parkinson: um estudo preliminar

Abstract 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, week4, 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

Resumo 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.

Chronic H3R activation reduces L-Dopa-induced dyskinesia, normalizes cortical GABA and glutamate levels, and increases striatal dopamine D1R mRNA expression in 6-hydroxydopamine-lesioned male rats.

RATIONALE: Dyskinesias induced by L-3,4-dihydroxyphenylalanine, L-Dopa (LIDs), are the major complication in the pharmacological treatment of Parkinson's disease. LIDs induce overactivity of the glutamatergic cortico-striatal projections, and drugs that reduce glutamatergic overactivity exert antidyskinetic actions. Chronic administration of immepip, agonist at histamine H3 receptors (H3R), reduces LIDs and diminishes GABA and glutamate content in striatal dialysates (Avila-Luna et al., Psychopharmacology 236: 1937-1948, 2019). OBJECTIVES AND METHODS: In rats unilaterally lesioned with 6-hydroxydopamine in the substantia nigra pars compacta (SNc), we examined whether the chronic administration of immepip and their withdrawal modify LIDs, the effect of L-Dopa on glutamate and GABA content, and mRNA levels of dopamine D1 receptors (D1Rs) and H3Rs in the cerebral cortex and striatum. RESULTS: The administration of L-Dopa for 21 days induced LIDs. This effect was accompanied by increased GABA and glutamate levels in the cerebral cortex ipsi and contralateral to the lesioned SNc, and immepip administration prevented (GABA) or reduced (glutamate) these actions. In the striatum, GABA content increased in the ipsilateral nucleus, an effect prevented by immepip. L-Dopa administration had no significant effects on striatal glutamate levels. In lesioned and L-Dopa-treated animals, D1R mRNA decreased in the ipsilateral striatum, an effect prevented by immepip administration. CONCLUSIONS: Our results indicate that chronic H3R activation reduces LIDs and the overactivity of glutamatergic cortico-striatal projections, providing further evidence for an interaction between D1Rs and H3Rs in the cortex and striatum under normal and pathological conditions.

Effective Management of "OFF" Episodes in Parkinson's Disease: Emerging Treatment Strategies and Unmet Clinical Needs.

Motor complications related to the chronic administration of levodopa and failure to prevent the neurodegenerative disease process counterbalance the pivotal discovery of levodopa as the cornerstone of PD treatment. Excellent motor control is offered early during the course of treatment, but this diminishes as pathological changes in the striatum lead to synaptic dopamine levels becoming completely dependent on exogenous dopamine. This non-physiologic stimulation of dopamine receptors eventually manifests as OFF episodes. As no disease modifying therapy exists for PD that can disrupt these pathological changes, most research and treatment focuses on optimization of dopaminergic stimulation of striatal receptors so that they mimic tonic, physiologic stimulation as closely as possible. Strategies focusing on these challenges have included non-pharmacologic approaches, optimizing levodopa pharmacokinetics, using adjunctive treatments including those with non-dopaminergic mechanisms, and implementing rescue therapies. Device aided therapies, including surgery, are also available. In this review, we will focus on effective management of motor symptoms related to OFF periods, including emerging strategies. Unmet clinical needs will be discussed, including non-motor symptoms, targeted molecular therapies and disease modifying therapy.

Deficiencia del transportador de glucosa tipo 1: aspectos clínicos, diagnóstico y terapéutica / Glucose transporter type 1 deficiency syndrome: clinical aspects, diagnosis, and treatment

El síndrome de deficiencia del transportador de glucosa tipo 1 es una enfermedad de causa genética, que involucra el gen SLC2A1. En general, se presenta durante los primeros años de vida con retraso en la adquisición de pautas madurativas, epilepsia farmacorresistente y desórdenes del movimiento. La clínica y la disminución de glucosa en líquido cefalorraquídeo permiten sospechar el diagnóstico, el cual debe ser confirmado mediante el estudio molecular del gen SLC2A1. Debido a que se trata de una enfermedad poco frecuente y de expresión clínica variable, el diagnóstico precoz suele representar un desafío para los equipos de salud. Este es importante, ya que la implementación de la terapia cetogénica logra controlar las manifestaciones clínicas y mejora el pronóstico a largo plazo. Presentamos una revisión sobre el déficit del transportador de glucosa tipo 1, que abarca sus características clínicas, bioquímicas, moleculares y terapéuticas.

Glucose transporter type 1 deficiency with a typical onset is a genetic disorder associated with the SLC2A1 gene. Usually appears during the first years of life with severe developmental delay, drugresistant epilepsy, and movement disorders. Diagnosis is suspected based on clinical manifestations and a low glucose level in cerebrospinal fluid, and should be confirmed by the molecular genetic study of the SLC2A1 gene. As it is a rare disease with variable clinical expression, early diagnosis is often challenging for the healthcare team. Nevertheless, this is important because early implementation of ketogenic therapy will lead to control of the clinical manifestations and a better long-term prognosis. Here we review the glucose transporter type 1 deficiency syndrome focusing on its clinical, biochemical, molecular, and therapeutic characteristics.

The Role of Striatal Cav1.3 Calcium Channels in Therapeutics for Parkinson's Disease.

Parkinson's disease (PD) is a relentlessly progressive neurodegenerative disorder with typical motor symptoms that include rigidity, tremor, and akinesia/bradykinesia, in addition to a host of non-motor symptoms. Motor symptoms are caused by progressive and selective degeneration of dopamine (DA) neurons in the SN pars compacta (SNpc) and the accompanying loss of striatal DA innervation from these neurons. With the exception of monogenic forms of PD, the etiology of idiopathic PD remains unknown. While there are a number of symptomatic treatment options available to individuals with PD, these therapies do not work uniformly well in all patients, and eventually most are plagued with waning efficacy and significant side-effect liability with disease progression. The incidence of PD increases with aging, and as such the expected burden of this disease will continue to escalate as our aging population increases (Dorsey et al. Neurology 68:384-386, 2007). The daunting personal and socioeconomic burden has pressed scientists and clinicians to find improved symptomatic treatment options devoid side-effect liability and meaningful disease-modifying therapies. Federal and private sources have supported clinical investigations over the past two-plus decades; however, no trial has yet been successful in finding an effective therapy to slow progression of PD, and there is currently just one FDA approved drug to treat the antiparkinsonian side-effect known as levodopa-induced dyskinesia (LID) that impacts approximately 90% of all individuals with PD. In this review, we present biological rationale and experimental evidence on the potential therapeutic role of the L-type voltage-gated Cav1.3 calcium (Ca2+) channels in two distinct brain regions, with two distinct mechanisms of action, in impacting the lives of individuals with PD. Our primary emphasis will be on the role of Cav1.3 channels in the striatum and the compelling evidence of their involvement in LID side-effect liability. We also briefly discuss the role of these same Ca2+ channels in the SNpc and the longstanding interest in Cav1.3 in this brain region in halting or delaying progression of PD.

Low serum uric acid levels and levodopa-induced dyskinesia in Parkinson's disease / Níveis séricos baixos de ácido úrico e discinesia induzida por levodopa na doença de Parkinson

Abstract Background Levodopa is the most used and effective medication for motor symptoms of Parkinson disease (PD), its long-term use is associated with the appearance of levodopa-induced dyskinesia (LID). Uric acid (UA) is believed to play an important neuroprotective role in PD. Objective To investigate if serum UA levels are related with the presence of LIDs in PD patients. Also, we investigated the associations among UA levels and clinical features of PD. Methods We enrolled 81 PD patients (dyskinesia = 48; no dyskinesia = 33) in the present study. A blood sample was collected to evaluate serum UA levels, clinical evaluation included the following instruments: Montreal Cognitive Assessment (MoCA), Beck Depression Inventory II (BDI-II), MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Hoehn and Yahr (HY), and the sub-item 4.1 of MDS-UPDRS IV (score ≥ 1). Additional relevant clinical information was obtained by a clinical questionnaire. Results Serum UA levels were lower in the dyskinesia group when compared with the no dyskinesia group. The same result was found in the UA levels of both men and women. The multivariate analysis showed lower uric acid levels were significantly associated with having dyskinesia (odds ratio [OR] = 0.424; 95% confidence interval [CI]: 0.221-0.746; p= 0.005). Additional analysis verified that serum UA levels are inversely correlated with depressive symptoms, disease duration, MDS-UPDRS IV and time spent with dyskinesia. A positive correlation was found with age at onset of PD symptoms. Conclusions The present study provides a possible role of serum UA levels in LID present in PD patients.

Resumo Antecedentes A levodopa é a medicação mais utilizada e eficaz para os sintomas motores da doença de Parkinson (DP); seu uso a longo prazo está associado ao aparecimento de discinesia induzida por levodopa (LID). Acredita-se que o ácido úrico desempenhe um importante papel neuroprotetor na DP. Objetivo Investigar se os níveis séricos de AU estão relacionados com a presença de LID em pacientes com DP. Além disso, investigamos as associações entre os níveis de AU e as características clínicas da DP. Métodos Foram incluídos 81 pacientes com DP (discinesia = 48; sem discinesia = 33) no presente estudo. Uma amostra de sangue foi coletada para avaliar os níveis séricos de AU, a avaliação clínica incluiu os seguintes instrumentos: Avaliação Cognitiva de Montreal (MoCA), Inventário de Depressão de Beck (BDI-II), MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Hoehn and Yahr (HY) e o subitem 4.1 da MDS-UPDRS IV (escore ≥ 1). Informações clínicas relevantes adicionais foram obtidas por meio de um questionário clínico. Resultados Os níveis séricos de AU foram menores no grupo com discinesia quando comparados ao grupo sem discinesia. O mesmo resultado foi encontrado nos níveis de AU de homens e mulheres. A análise multivariada mostrou que níveis mais baixos de ácido úrico foram significativamente associados a ter discinesia (odds ratio [OR] = 0,424; intervalo de confiança (IC) de 95%: 0,221-0,746; p= 0,005). Análises adicionais verificaram que os níveis séricos de AU estão inversamente correlacionados com sintomas depressivos, duração da doença, MDS-UPDRS IV e tempo gasto com discinesia. Uma correlação positiva foi encontrada com a idade de início dos sintomas da DP. Conclusões O presente estudo fornece um possível papel dos níveis séricos de AU na LID presente em pacientes com DP.

Use of virtual reality for targeted physical rehabilitation: Case report on managing functional motor disorder.

Virtual reality (VR) technology has seen increasing use in physical rehabilitation and in the management of acute and chronic pain. Functional movement disorders (FMDs) are a source of disability with no known association to neurologic pathology, and patients are generally offered multidisciplinary treatment approaches to improve functional movement. However, patients who are not compliant with rehabilitation may have persistent FMD and long-term disability. Given VR's use in physical rehabilitation, it may serve as a useful adjunct for the management of FMD. Utilizing an application called MovementTM to create a playlist of targeted applications for the restoration of motor function and balance, this case study presents the application of VR as a tool to engage patients in physical therapy for the management of FMD. The VR games were selected to encourage movement while customization of levels within the games facilitated achievement of physical therapy goals. Physical rehabilitation aided by VR, when used in collaboration with a multidisciplinary care team, may be used to facilitate recovery from FMD.