Enfermedad de Parkinson: actualización de estudios preclínicos con el uso de células troncales pluripotentes inducidas / Parkinson's disease: An update on preclinical studies of induced pluripotent stem cells

La enfermedad de Parkinson (EP) es la segunda enfermedad neurodegenerativa más común a nivel mundial en adultos mayores. Se caracteriza por la pérdida de neuronas dopaminérgicas (nDAs) en la sustancia nigra pars compacta del mesencéfalo y en algunos casos acompañada de la aparición de cuerpos intracitoplasmáticos de Lewy de -sinucleína, signo patognomónico de la enfermedad. La EP se diagnostica clínicamente por la presencia de alteraciones motoras principalmente, y en la actualidad los tratamientos presentan nula actividad neuroprotectora. Aún no se han establecido las causas exactas de la EP, por lo que en los últimos años se ha buscado el desarrollo de modelos preclínicos más precisos, utilizando células troncales pluripotentes inducidas, permitiendo el estudio de la enfermedad de manera in vitro para generar conocimiento novedoso sobre su patogénesis y el descubrimiento de nuevos posibles blancos terapéuticos o el desarrollo de nuevos fármacos.(AU)

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease among adults worldwide. It is characterised by the death of dopaminergic neurons in the substantia nigra pars compacta and, in some cases, presence of intracytoplasmic inclusions of α-synuclein, called Lewy bodies, a pathognomonic sign of the disease. Clinical diagnosis of PD is based on the presence of motor alterations. The treatments currently available have no neuroprotective effect. The exact causes of PD are poorly understood. Therefore, more precise preclinical models have been developed in recent years that use induced pluripotent stem cells. In vitro studies can provide new information on PD pathogenesis and may help to identify new therapeutic targets or to develop new drugs.(AU)

Temporal dynamics of cortical activity and postural control in response to the first levodopa dose of the day in people with Parkinson's disease.

BACKGROUND: Our understanding of how balance control responds to levodopa over the course of a single day in people with Parkinson's disease (PD) is limited with the majority of studies focused on isolated comparisons of ON vs. OFF levodopa medication. OBJECTIVE: To evaluate the temporal dynamics of postural control following the first levodopa dose of the day during a challenging standing task in a group of people with PD. METHODS: Changes in postural control were evaluated by monitoring cortical activity (covering frontal, motor, parietal and occipital areas), body sway parameters (force platform), and lower limb muscle activity (tibialis anterior and gastrocnemius medialis) in 15 individuals with PD during a semi-tandem standing task. Participants were assessed during two 60 second trials every 30 minutes (ON-30 ON-60 etc.) for 3 hours after the first matinal dose (ON-180). RESULTS: Compared to when tested OFF-medication, cortical activity was increased across all four regions from ON-60 to ON-120 with early increases in alpha and beta band activity observed at ON-30. Levodopa was associated with increased gastrocnemius medialis activity (ON-30 to ON-120) and ankle co-contraction (ON-60 to ON-120). Changes in body sway outcomes (particularly in the anterior-posterior direction) were evident from ON-60 to ON-120. CONCLUSIONS: Our results reveal a 60-minute window within which postural control outcomes may be obtained that are different compared to OFF-state and remain stable (from 60-minutes to 120-minutes after levodopa intake). Identifying a window of opportunity for measurement when individuals are optimally medicated is important for observations in a clinical and research setting.

New dopaminergic therapies for PD motor complications.

BACKGROUND: Motor complications, characterized by "off" periods - when anti-parkinsonian medications are ineffective - and dyskinesia, are the hallmark of advanced Parkinson's disease (PD). While levodopa is the gold standard PD medication in terms of efficacy, its short duration of effect coupled with progressive loss of dopaminergic neurons leads to motor complications and fails to treat off periods. PURPOSE OF REVIEW: This review focuses on novel dopaminergic therapies that were recently made clinically available or are currently in development for the treatment of motor complications. First, it will discuss rescue therapies for the treatment of off episodes, including novel apomorphine and levodopa formulations. Second, it will highlight adjunctive dopaminergic medications approved to reduce total daily off time. Third, it will discuss longer-acting levodopa formulations in development and introduce a novel selective dopamine agonist under study. Finally, it will cover novel dopaminergic delivery mechanisms, with specific focus on continuous subcutaneous infusions in development. SUMMARY: The breadth of dopaminergic therapies recently approved or in development for motor complications, and specifically off time reduction, evokes cautious optimism. Gains in reducing off time with rescue therapies, adjunctive medications or longer-acting levodopa formulations are modest, and underscore the need for more continuous dopaminergic delivery to address the underlying pathophysiology and translate to clinically meaningful improvement in motor complications.

Efficacy and safety evaluation of safinamide as an add-on treatment to levodopa for parkinson's disease.

INTRODUCTION: While levodopa is still the most effective treatment for Parkinson's disease, concerns about long-term complications such as wearing-off and dyskinesia with levodopa usage remain. AREAS COVERED: Safinamide is a highly selective and reversible monoamine oxidase B inhibitor introduced in the European Union, Japan, and the United States as an adjunctive agent to levodopa in PD patients with motor fluctuation. This review outlines the pharmacological properties, therapeutic effects, and tolerability of safinamide as an adjunct to levodopa in patients with advanced PD. Efficacy and safety findings from double-blind and placebo-controlled clinical trials for safinamide as an adjunct therapy to levodopa for PD are summarized. EXPERT OPINION: Safinamide was well tolerated as a treatment for PD, and there was no significant difference in the frequency and severity of adverse events between the safinamide and placebo groups. It was also suggested that safinamide had a beneficial effect on the accompanying non-motor symptoms such as PD-related pain. Safinamide may exhibit neuroprotective effects through antioxidant and anti-glutamate effects, and research on the disease-modifying effect of PD is desired in the future.

[Opicapone for the treatment of Parkinson's disease: real-life data in Spain]. / Opicapona para el tratamiento de la enfermedad de Parkinson: datos de vida real en España.

Opicapone is a catechol-O-methyl-transferase (iCOMT) inhibitor authorized in Europe in 2016 and indicated as adjunctive therapy to preparations of levodopa/ DOPA decarboxylase inhibitors in adult patients with Parkinson's disease and end-of-dose motor fluctuations who cannot be stabilised on those combinations. The efficacy of opicapone in these patients has been demonstrated in two pivotal randomized clinical trials, BIPARK I and BIPARK II, in which it has demonstrated its superiority versus placebo and non-inferiority versus entacapone. Although they constitute the gold standard for the evaluation of interventions, randomized clinical trials present limitations of external validity due to the use of strict eligibility criteria. Therefore, it is considered necessary to have a more comprehensive evaluation of the efficacy of the drug, complementing the information obtained from randomized clinical trials with that of "real world or real clinical practice" studies. The objective of this review has been to collect and put into perspective the information available on opicapone coming from real clinical practice studies in Spain. The data from Spain with opicapone in 18 series with more than 1,000 patients in total, confirm the safety and efficacy previously reported with this iCOMT. Furthermore, they show that opicapone is especially useful in patients with a less advanced stage of the disease and mild motor fluctuations, which would suggest that the earlier its introduction in the therapeutic scheme for the management of motor fluctuations, the better is the benefit-risk ratio for the drug.

TITLE: Opicapona para el tratamiento de la enfermedad de Parkinson: datos de vida real en España.Resumen. La opicapona es un inhibidor de la catecol-O-metiltransferasa (iCOMT) autorizado en Europa en 2016 como terapia adyuvante a las preparaciones de levodopa/inhibidores de la dopa descarboxilasa en pacientes adultos con enfermedad de Parkinson y fluctuaciones motoras de final de dosis que no puedan ser estabilizados con esas combinaciones. La eficacia de la opicapona en estos pacientes ha sido demostrada en dos ensayos clínicos pivotales, BIPARK I y BIPARK II, en los que se ha demostrado la superioridad frente al placebo y la no inferioridad frente a la entacapona. A pesar de que constituyen el estándar para la evaluación de intervenciones, los ensayos clínicos aleatorizados presentan limitaciones de validez externa debidas a la utilización de criterios estrictos de elegibilidad. Por tanto, se considera necesario disponer de una evaluación más amplia de la eficacia general del fármaco, complementando la información de los ensayos clínicos aleatorizados con estudios de 'vida real o práctica clínica real'. El objetivo de esta revisión ha sido recopilar y poner en perspectiva la información disponible sobre los resultados de la opicapona en estudios de práctica clínica real en España. Los datos acumulados en España con opicapona en 18 series con más de 1.000 pacientes confirman la seguridad y la eficacia de este iCOMT comunicadas previamente. Además, muestran que la opicapona es especialmente útil en pacientes en un estadio de la enfermedad menos avanzado y fluctuaciones motores leves, lo que sugeriría una mejor relación beneficio-riesgo cuanto más temprana sea su introducción en el esquema terapéutico para el tratamiento de las fluctuaciones motoras.

Clinical long-term nocturnal sleeping disturbances and excessive daytime sleepiness in Parkinson's disease.

OBJECTIVE: To prospectively evaluate nocturnal sleep problems and excessive daytime sleepiness (EDS) in Parkinson's disease (PD) patients, and analyze the influence of motor symptoms, treatment, and sex differences on sleep problems in PD. METHODS: Sleep disturbances of 103 PD patients were assessed with Parkinson's Disease Sleep Scale (PDSS) and the Epworth Sleepiness Scale (ESS). Student's t-test for related samples, one-way ANOVA with Tukey's HSD post hoc test were used to assess group differences. Bivariate correlations and mixed-effects linear regression models were used to analyze the association between clinical aspects and sleep disturbances over time. RESULTS: At baseline, 48.5% of PD patients presented nocturnal problems and 40% of patients presented EDS. The PDSS and ESS total score slightly improve over time. Nocturnal problems were associated with age and motor impartment, explaining the 51% of the variance of the PDSS model. Males presented less nocturnal disturbances and more EDS than females. Higher motor impairment and combined treatment (L-dopa and agonist) were related to more EDS, while disease duration and L-dopa in monotherapy were related to lower scores, explaining the 59% of the model. CONCLUSIONS: Sleep disturbances changed over time and age, diseases duration, motor impairment, treatment and sex were associated with nocturnal sleep problems and EDS. Agonist treatment alone or in combination with L-dopa might predict worse daytime sleepiness, while L-dopa in monotherapy is related to lower EDS, which significantly affects the quality of life of PD patients.

Opicapona para el tratamiento de la enfermedad de Parkinson: datos de vida real en España / Opicapone for the treatment of Parkinson's disease: real-life data in Spain

La opicapona es un inhibidor de la catecol-O-metiltransferasa (iCOMT) autorizado en Europa en 2016 como terapia adyuvante a las preparaciones de levodopa/inhibidores de la dopa descarboxilasa en pacientes adultos con enfermedad de Parkinson y fluctuaciones motoras de final de dosis que no puedan ser estabilizados con esas combinaciones. La eficacia de la opicapona en estos pacientes ha sido demostrada en dos ensayos clínicos pivotales, BIPARK I y BIPARK II, en los que se ha demostrado la superioridad frente al placebo y la no inferioridad frente a la entacapona. A pesar de que constituyen el estándar para la evaluación de intervenciones, los ensayos clínicos aleatorizados presentan limitaciones de validez externa debidas a la utilización de criterios estrictos de elegibilidad. Por tanto, se considera necesario disponer de una evaluación más amplia de la eficacia general del fármaco, complementando la información de los ensayos clínicos aleatorizados con estudios de ‘vida real o práctica clínica real’. El objetivo de esta revisión ha sido recopilar y poner en perspectiva la información disponible sobre los resultados de la opicapona en estudios de práctica clínica real en España. Los datos acumulados en España con opicapona en 18 series con más de 1.000 pacientes confirman la seguridad y la eficacia de este iCOMT comunicadas previamente. Además, muestran que la opicapona es especialmente útil en pacientes en un estadio de la enfermedad menos avanzado y fluctuaciones motores leves, lo que sugeriría una mejor relación beneficio-riesgo cuanto más temprana sea su introducción en el esquema terapéutico para el tratamiento de las fluctuaciones motoras.(AU)

Opicapone is a catechol-O-methyl-transferase (iCOMT) inhibitor authorized in Europe in 2016 and indicated as adjunctive therapy to preparations of levodopa/ DOPA decarboxylase inhibitors in adult patients with Parkinson’s disease and end-of-dose motor fluctuations who cannot be stabilised on those combinations. The efficacy of opicapone in these patients has been demonstrated in two pivotal randomized clinical trials, BIPARK I and BIPARK II, in which it has demonstrated its superiority versus placebo and non-inferiority versus entacapone. Although they constitute the gold standard for the evaluation of interventions, randomized clinical trials present limitations of external validity due to the use of strict eligibility criteria. Therefore, it is considered necessary to have a more comprehensive evaluation of the efficacy of the drug, complementing the information obtained from randomized clinical trials with that of “real world or real clinical practice” studies. The objective of this review has been to collect and put into perspective the information available on opicapone coming from real clinical practice studies in Spain. The data from Spain with opicapone in 18 series with more than 1,000 patients in total, confirm the safety and efficacy previously reported with this iCOMT. Furthermore, they show that opicapone is especially useful in patients with a less advanced stage of the disease and mild motor fluctuations, which would suggest that the earlier its introduction in the therapeutic scheme for the management of motor fluctuations, the better is the benefit-risk ratio for the drug.(AU)

Levodopa Challenge Test Predicts STN-DBS Outcomes in Various Parkinson's Disease Motor Subtypes: A More Accurate Judgment.

Background: The relationship between the levodopa challenge test (LDCT) and postoperative subthalamic nucleus-deep brain stimulation (STN-DBS) benefits is controversial in patients with Parkinson's disease (PD). We aim to evaluate the value of total levodopa response (TLR) and symptom levodopa response (SLR) in predicting postoperative improvement in different PD motor subtypes. Methods: Studies were split into a training set (147 patients) and a validation set (304 patients). We retrospectively collected data from 147 patients who received the Unified Parkinson's Disease Rating Scale- (UPDRS-) III and the Parkinson's Disease Questionnaire- (PDQ-) 39 evaluation. Patients were classified into tremor-dominant (TD), akinetic-rigid-dominant (AR), and mixed (MX) groups. Clinically important difference (CID) was employed to dichotomize DBS effects. For patients in each subtype group from the training set, we used the correlation and receiver operator characteristic (ROC) curve analyses to explore the strength of their relations. Areas under the curve (AUCs) were calculated and compared through the DeLong test. Results developed from the training set were applied into the validation set to predict postoperative improvement in different PD motor subtypes. Results: In the validation cohort, TLR significantly correlated with postoperative motor (p < 0.001) and quality of life (QOL) (p < 0.001) improvement in the MX group. The AUC between TLR and UPDRS-III (TU) is 0.800. The AUC between TLR and PDQ-39 (TP) is 0.770. An associated criterion in both TU and TP is around 50%. In the AR group, strong correlation was only found in SLR and PDQ-39 (SP) (p < 0.001). And the AUC of SP is significantly larger than that in TLR and PDQ-39 (TP) (p = 0.034). An associated criterion in SP is around 37%. No significant correlation was found in the TD group. Conclusions: We provide a more accurate judgment for LDCT. TLR strongly correlated with postoperative UPDRS-III and PDQ-39 improvement in MX patients. A TLR > 50% may indicate a higher possibility of clinically meaningful benefits from STN-DBS comparing to medication only. SLR can well predict QOL improvement in AR patients. Similarly, a SLR > 37% may indicate a higher possibility of clinically significant benefits from STN-DBS. LDCT provides limited information for TD patients.

Correlation between Serum Zinc Levels and Levodopa in Parkinson's Disease.

Long-term intake of potential zinc-chelating drugs may cause zinc deficiency. We postulated that zinc deficiency in Parkinson's disease (PD) patients was related to the intake of drugs such as levodopa. We investigated the relationship between zinc levels and levodopa administration period, dosage, and symptoms of zinc deficiency in PD patients. We measured serum zinc levels and analyzed correlations between serum zinc levels, the levodopa oral administration period, dosage, dosing frequency, and zinc deficiency symptoms including taste disorders. Data analyses were performed using Spearman's rank correlation coefficient. The mean serum zinc level was 60.5 ± 11.6 µg/dL. The mean administration period for levodopa was 8.0 ± 5.5 years, mean administration frequency 3.4 ± 0.9 times/d, and mean administration dose 420.6 ± 237.1 mg/d. Negative correlations between zinc levels and levodopa dosage and dosing frequency were found. Multiple regression analysis showed a significant correlation with the frequency of levodopa (ß = -0.360, p = 0.007). No significant change in clinical symptoms was observed after zinc administration, but anxiety tended to improve. Our results indicated that frequent levodopa administration strongly influenced serum zinc levels which may have alleviating effects on psychiatric symptoms; therefore, preventing zinc deficiency can be important during PD treatment.

Role of 5-HT1A Receptor in Vilazodone-Mediated Suppression of L-DOPA-Induced Dyskinesia and Increased Responsiveness to Cortical Input in Striatal Medium Spiny Neurons in an Animal Model of Parkinson's Disease.

L-DOPA therapy in Parkinson's disease (PD) is limited due to emerging L-DOPA-induced dyskinesia. Research has identified abnormal dopamine release from serotonergic (5-HT) terminals contributing to this dyskinesia. Selective serotonin reuptake inhibitors (SSRIs) or 5-HT receptor (5-HTr) agonists can regulate 5-HT activity and attenuate dyskinesia, but they often also produce a loss of the antiparkinsonian efficacy of L-DOPA. We investigated vilazodone, a novel multimodal 5-HT agent with SSRI and 5-HTr1A partial agonist properties, for its potential to reduce dyskinesia without interfering with the prokinetic effects of L-DOPA, and underlying mechanisms. We assessed vilazodone effects on L-DOPA-induced dyskinesia (abnormal involuntary movements, AIMs) and aberrant responsiveness to corticostriatal drive in striatal medium spiny neurons (MSNs) measured with in vivo single-unit extracellular recordings, in the 6-OHDA rat model of PD. Vilazodone (10 mg/kg) suppressed all subtypes (axial, limb, orolingual) of AIMs induced by L-DOPA (5 mg/kg) and the increase in MSN responsiveness to cortical stimulation (shorter spike onset latency). Both the antidyskinetic effects and reversal in MSN excitability by vilazodone were inhibited by the 5-HTr1A antagonist WAY-100635, demonstrating a critical role for 5-HTr1A in these vilazodone actions. Our results indicate that vilazodone may serve as an adjunct therapeutic for reducing dyskinesia in patients with PD.

Early factors for predicting discontinuation to subcutaneous Apomorphine infusion in Parkinson's disease: A prospective analysis of the Thai Apomorphine Registry.

INTRODUCTION: Although continuous subcutaneous apomorphine infusion (CSAI) is an effective therapy for Parkinson's disease (PD) with motor fluctuations, data from Asian cohorts is limited. The therapy is often discontinued due to the complexity of its delivery. METHODS: Fifty-one PD patients undergoing CSAI as an add-on therapy were enrolled in the Thai Apomorphine Registry, an electronic database that recorded clinical characteristics and parameters during the 14-consecutive-day titration and long-term follow-up. Factors at the time of titration were documented in order to identify predictors of long-term discontinuation. RESULTS: Following initiation, PD patients were administered a mean CSAI dose of 5.89 mg/h (SD 1.36) over a mean time of 12.28 h (SD 1.90) each day. The mean follow-up period was 626.2 days (SD 619.17). Significant reductions in UPDRS-I, II, III, and IV scores, total NMSQ score, PDQ-8 score, daily off and dyskinesia hours, Timed Up and Go test, walking step test, levodopa-equivalent daily dose, number of times a day the levodopa was taken versus pre-CSAI values were observed (p < 0.05, each). Thirty-five (68.6%) patients discontinued during the follow-up period. Relative risks of variables recorded at the time of titration that determined discontinuation of CSAI therapy were an absence of full-time caregivers, achieving a daily off hours reduction <3.5 h, and NMSQ scores at the time of CSAI titration ≥9.5 points. CONCLUSION: Identifying factors that predict discontinuation of CSAI at the time of its initiation may help physicians to better understand the patient's drug response and how to manage them long-term.

ND0612 (levodopa/carbidopa for subcutaneous infusion) in patients with Parkinson's disease and motor response fluctuations: A randomized, placebo-controlled phase 2 study.

INTRODUCTION: ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system under development for patients with Parkinson's disease (PD) and motor fluctuations. METHODS: This was a randomized, placebo-controlled, double-blind, 2-period study evaluating the safety and pharmacokinetics of ND0612 in PD patients on an optimized oral levodopa regimen and experiencing ≥2 h/day of OFF time. During Period-1, patients received their current standard of care (SoC) levodopa/carbidopa and were randomized (2:1) to 14 days treatment with adjunct ND0612 (daily levodopa/carbidopa dose of 270/63 mg) or placebo infusion +SoC. During Period-2, 16 patients were randomized to receive 7 days treatment with ND0612 or ND0612 plus oral entacapone. Reduction in OFF time was analyzed as an exploratory measure using a futility design with a predefined margin of 1.6 h. RESULTS: ND0612 was well-tolerated; most patients experienced infusion site nodules (95% vs. 56% with placebo), which all resolved without sequelae. Patients treated with adjunct ND0612 during Period-1 avoided deep troughs in levodopa plasma levels and had a decreased fluctuation index versus placebo (1.6 ± 0.5 vs 3.1 ± 1.6 at end of Period-1, respectively). In Period-2, the coadministration of entacapone with continuous ND0612 SC infusion translated to an increase in mean levodopa AUC0-10h compared to baseline. Exploratory efficacy analysis of Period 1 showed mean ± SD OFF time reductions of -2.13 ± 2.24 [90%CI: -2.8, ∞] hours (p = 0.84 using H0 of µ0 ≤-1.6). CONCLUSION: Levodopa/carbidopa infusion with ND0612 was generally well-tolerated and resulted in reduced fluctuations in plasma levodopa concentrations when given with SoC oral levodopa. ND0612 met the efficacy endpoint for the futility design.

Induction of Ticlike Involuntary Movements in Rats by Striatotomy and Subsequent Neurochemical Sensitization.

OBJECTIVE: It has been proposed that Tourette syndrome is associated with dysfunction in widespread cortical areas and globus pallidus externus hyperactivity secondary to dopaminergic hyperactivity and serotonergic/dynorphinergic hypoactivity. The main objective of this study was to test this hypothesis by developing an animal model of Tourette syndrome via striatotomy, followed by administration of drugs that mimic the neurotransmitter environment, so as to induce globus pallidus externus hyperactivity. METHODS: Rats were assigned to 3 groups: stereotactic striatotomy (STT) and striatal sham -lesion (SHAM) groups, treated with anterior and posterior striatum procedures in both hemispheres, and a group of nonoperated animals (NAIVE). Postoperatively, all rodents were blindly administered 3 drug protocols: levodopa/benserazide; levodopa/benserazide/ergotamine/naloxone (MIX); and saline. The animals were filmed at the peak action of these drugs. The videos were evaluated by a single blinded researcher. RESULTS: Six types of involuntary movements (IMs) were observed: cephalic, trunk jerks, oromandibular, forepaw jerks, dystonic, and locomotive. The number of animals with IM and the mean number of IM after both levodopa/benserazide and MIX was significantly higher in the STT compared with the SHAM and NAIVE groups. In the SHAM and NAIVE, MIX was superior to levodopa/benserazide in the induction of IM. In the STT, MIX was superior to levodopa/benserazide in the induction of trunk jerks. Appendicular IM were more common after posterior than after anterior striatotomy. CONCLUSIONS: These results show that striatotomy, followed by administration of levodopa/benserazide alone or associated with ergotamine and naloxone, is efficacious in inducing IM, supporting the hypothesis that led to this study.

Additive effects of mGluR2 positive allosteric modulation, mGluR2 orthosteric stimulation and 5-HT2AR antagonism on dyskinesia and psychosis-like behaviours in the MPTP-lesioned marmoset.

PURPOSE: Antagonising serotonin (5-HT) type 2A receptors (5-HT2AR) is an effective strategy to alleviate both dyskinesia and psychosis in Parkinson's disease (PD). We have recently shown that activation of metabotropic glutamate 2 receptors (mGluR2), via either orthosteric stimulation or positive allosteric modulation, enhances the anti-dyskinetic and anti-psychotic effects of 5-HT2AR antagonism. Here, we investigated if greater therapeutic efficacy would be achieved by combining 5-HT2AR antagonism with concurrent mGluR2 orthosteric stimulation and mGluR2 positive allosteric modulation. METHODS: Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets exhibiting dyskinesia and psychosis-like behaviours (PLBs) were administered L-3,4-dihydroxyphenylalanine (L-DOPA) in combination with vehicle or the 5-HT2AR antagonist EMD-281,014. EMD-281,014 was itself administered alone or with the mGluR2 orthosteric agonist (OA) LY-354,740, the mGluR2 positive allosteric modulator (PAM) LY-487,379 and combination thereof, after which the severity of dyskinesia, PLBs and parkinsonism was rated. RESULTS: EMD-281,014 reduced dyskinesia and PLBs by up to 47% and 40%, respectively (both P < 0.001). The addition of LY-354,740, LY-487,379 and LY-354,740/LY-487,379 decreased dyskinesia by 56%, 65% and 77%, while PLBs were diminished by 55%, 63% and 71% (all P < 0.001). All treatment combinations provided anti-dyskinetic and anti-psychotic benefits significantly greater than those conferred by EMD-281,014 alone (all P < 0.05). The combination of EMD-281,014/LY-354,740/LY-487,379 resulted in anti-dyskinetic and anti-psychotic effects significantly greater than those conferred by EMD-281,014 with either LY-354,740 or LY-487,379 (both P < 0.05). No deleterious effects on L-DOPA anti-parkinsonian action were observed. CONCLUSION: Our results suggest that combining 5-HT2AR antagonism with mGluR2 activation results in greater reduction of L-DOPA-induced dyskinesia and PD psychosis. They also indicate that further additive effect can be achieved when a mGluR2 OA and a mGluR2 PAM are combined with a 5-HT2AR antagonist than when a mGluR2 OA or a mGluR2 PAM are added to a 5-HT2AR antagonist.

Evaluation of microglia in a rodent model of Parkinson's disease primed with L-DOPA after sub-anesthetic ketamine treatment.

Parkinson's disease (PD) is a neurodegenerative disease caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc), characterized by motor dysfunction. While PD symptoms are well treated with L-DOPA, continuous use can cause L-DOPA-induced dyskinesia (LID). We have previously demonstrated that sub-anesthetic ketamine attenuated LID development in rodents, measured by abnormal involuntary movements (AIMs), and reduced the density of maladaptive striatal dendritic mushroom spines. Microglia may play a role by phagocytosing maladaptive neuronal spines. In this exploratory study, we hypothesized that ketamine would prevent AIMs and change microglia ramified morphology - an indicator of a microglia response. Unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats were primed with daily injections of L-DOPA for 14 days, treated on days 0 and 7 for 10-hours with sub-anesthetic ketamine (i.p.), and we replicated that this attenuated LID development. We further extended our prior work by showing that while ketamine treatment did lead to an increase of striatal interleukin-6 in dyskinetic rats, indicating a modulation of an inflammatory response, it did not change microglia number or morphology in the dyskinetic striatum. Yet an increase of CD68 in the SNpc of 6-OHDA-lesioned hemispheres post-ketamine indicates increased microglia phagocytosis suggestive of a lingering microglial response to 6-OHDA injury in the SNpc pointing to possible anti-inflammatory action in the PD model in addition to anti-dyskinetic action. In conclusion, we provide further support for sub-anesthetic ketamine treatment of LID. The mechanisms of action for ketamine, specifically related to inflammation and microglia phagocytic functions, are emerging, and require further examination.

Eight-year follow-up outcome of subthalamic deep brain stimulation for Parkinson's disease: Maintenance of therapeutic efficacy with a relatively low levodopa dosage and stimulation intensity.

AIMS: This follow-up study aimed to examine the 8-year efficacy and safety of subthalamic nucleus (STN) deep brain stimulation (DBS) for patients with Parkinson's disease (PD) in southern China. METHODS: The follow-up data of 10 patients with PD undergoing STN-DBS were analyzed. Motor symptoms were assessed before and 1, 3, 5, and 8 years after the surgery with stimulation-on in both off-medication (off-med) and on-medication (on-med) status using the Unified Parkinson's disease Rating Scale Part III. The quality of life was assessed using the 39-item Parkinson's Disease Questionnaire. The sleep, cognition, and emotion were evaluated using a series of nonmotor scales. Levodopa equivalent daily dose (LEDD) and stimulation parameters were recorded at each follow-up. RESULTS: The motor symptoms were improved by 50.9%, 37.7%, 36.7%, and 37.3% in 1, 3, 5, and 8 years, respectively, in the off-med / stimulation-on status compared with the baseline. The quality of life improved by 39.7% and 56.1% in 1 and 3 years, respectively, but declined to the preoperative level thereafter. The sleep, cognition, and emotion were mostly unchanged. LEDD reduced from 708.1 ± 172.5 mg to 330 ± 207.8 mg in 8 years. The stimulation parameters, including amplitude, pulse width, and frequency, were 2.77 ± 0.49 V, 71.3 ± 12.8 µs, and 121.5 ± 21 Hz, respectively, in 8 years. CONCLUSION: Long-term therapeutic efficacy of STN-DBS could be achieved even with relatively low stimulation intensity and medication dosage for PD patients in southern China. Motor improvement and medication reduction were maintained through the 8-year follow-up, but improvement in quality of life lasted for only 3 years. No definite changes was found in nonmotor symptoms after STN-DBS.

Insulin-like growth factor-1 level is a poor diagnostic indicator of growth hormone deficiency.

We evaluated the diagnostic accuracy of insulin-like growth factor-1 (IGF-1) for screening growth hormone deficiency (GHD) to determine the usefulness of IGF-1 as a screening test. Among 298 consecutive children who had short stature or decreased height velocity, we measured IGF-1 levels and performed growth hormone (GH) secretion test using clonidine, arginine, and, in cases with different results of the two tests, L-dopa. Patients with congenital abnormalities were excluded. GHD was defined as peak GH ≤ 6.0 ng/mL in the two tests. We identified 60 and 238 patients with and without GHD, respectively. The mean IGF-1 standard deviation (SD) was not significantly different between the GHD and non-GHD groups (p = 0.23). Receiver operating characteristic curve analysis demonstrated the best diagnostic accuracy at an IGF-1 cutoff of - 1.493 SD, with 0.685 sensitivity, 0.417 specificity, 0.25 positive and 0.823 negative predictive values, and 0.517 area under the curve. Correlation analysis revealed that none of the items of patients' characteristics increased the diagnostic power of IGF-1. IGF-1 level had poor diagnostic accuracy as a screening test for GHD. Therefore, IGF-1 should not be used alone for GHD screening. A predictive biomarker for GHD should be developed in the future.

A Microstirring Pill Enhances Bioavailability of Orally Administered Drugs.

Majority of drugs are administered orally, yet their efficient absorption is often difficult to achieve, with a low dose fraction reaching the blood compartment. Here, a microstirring pill technology is reported with built-in mixing capability for oral drug delivery that greatly enhances bioavailability of its therapeutic payload. Embedding microscopic stirrers into a pill matrix enables faster disintegration and dissolution, leading to improved release profiles of three widely used model drugs, aspirin, levodopa, and acetaminophen, without compromising their loading. Unlike recently developed drug-carrying nanomotors, drug molecules are not associated with the microstirrers, and hence there is no limitation on the loading capacity. These embedded microstirrers are fabricated through the asymmetric coating of titanium dioxide thin film onto magnesium microparticles. In vitro tests illustrate that the embedded microstirrers lead to substantial enhancement of local fluid transport. In vivo studies using murine and porcine models demonstrate that the localized stirring capability of microstirrers leads to enhanced bioavailability of drug payloads. Such improvements are of considerable importance in clinical scenarios where fast absorption and high bioavailability of therapeutics are critical. The encouraging results obtained in porcine model suggest that the microstirring pill technology has translational potential and can be developed toward practical biomedical applications.

Per-oral image guided gastrojejunostomy insertion for levodopa-carbidopa intestinal gel in Parkinson's disease is safe and may be advantageous.

BACKGROUND: Procedural aspects and complications of gastrojejunostomy insertion are important considerations in the use of levodopa-carbidopa intestinal gel therapy (LCIG) and may limit uptake. We describe our experience of using per-oral image guided gastrojejunostomy (PIG-J) which avoids the need for endoscopy and routine sedation in percutaneous endoscopic gastrojejunostomy (PEG-J) and allows more secure tube placement than radiologically inserted gastrojejunostomy techniques. METHODS: We describe a case series of 32 patients undergoing PIG-J insertion for LCIG therapy in a single centre. Under local anaesthetic, a fluoroscopy-guided gastric puncture allows access for the guidewire which is then used to pull through the gastrostomy tube allowing for secure fixation, followed by placement of the gastrojejunal extension. RESULTS: Between December 2015 to April 2020, 32/34 patients referred for PIG-J underwent this procedure successfully, 2 cases unsuccessful due to technical considerations. One patient developed delirium following successful implantation. Ten patients (31%) required a replacement tube due to blockage or displacement within the first 12 months of placement, including 2 patients who needed more than one replacement. Minor complications occurred in 10 other patients (31%), including infection (9 patients); a small haematoma not requiring intervention who later developed an infection (1 patient); and peri-stomal acid leakage (1 patient). CONCLUSION: In summary, PIG-J insertion is safe with a similar complication rate to traditional PEG-J, well tolerated and effective for use in LCIG administration. This may widen access to LCIG for PD patients who may not be suitable or unable to tolerate PEG-J.

Normal-sized basal ganglia perivascular space related to motor phenotype in Parkinson freezers.

Changes in basal ganglia (BG) perivascular spaces (PVSs) are related to motor and cognitive behaviors in Parkinson's disease (PD). However, the correlation between the initial motor phenotype and PVSs distribution/burden in PD freezing of gait (FOG) remains unclear. In addition, the normal-sized PVSs (nPVSs) have not been well-studied. With high-resolution 7T-MRI, we studied nPVSs burden in BG, thalamus, midbrain and centrum semiovale. The numbers and volume of nPVSs were assessed in 10 healthy controls, 10 PD patients without FOG, 20 with FOG [10 tremor dominant (TD), 10 non-TD subtype]. Correlation analyses were further performed in relation to clinical parameters. In this proof of concept study, we found that the nPVS burden of bilateral and right BG were significantly higher in freezers. A negative correlation existed between the tremor score and BG-nPVSs count. A positive correlation existed between the levodopa equivalent daily dose and BG-nPVSs count. The nPVS burden correlated with the progression to FOG in PD, but the distribution and burden of nPVS differ in TD vs. non-TD subtypes. High resolution 7T-MRI is a sensitive and reliable tool to evaluate BG-nPVS, and may be a useful imaging marker for predicting gait impairment that may evolve into FOG in PD.