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1.
Mov Disord ; 39(4): 733-738, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38357797

RESUMEN

BACKGROUND: SAGE-324/BIIB124 is an investigational positive allosteric modulator of GABAA receptors. OBJECTIVE: KINETIC (NCT04305275), a double-blind, randomized, placebo-controlled, phase 2 study, evaluated SAGE-324/BIIB124 in individuals with essential tremor (ET). METHODS: Individuals aged 18 to 80 years were randomly assigned 1:1 to orally receive 60 mg of SAGE-324/BIIB124 or placebo once daily for 28 days. The primary endpoint was change from baseline in The Essential Tremor Rating Assessment Scale-Performance Subscale (TETRAS-PS) Item 4 (upper-limb tremor) at day 29 with SAGE-324/BIIB124 versus placebo. RESULTS: Between May 2020 and February 2021, 69 U.S. participants were randomly assigned to receive SAGE-324/BIIB124 (n = 34) or placebo (n = 35). There was a significant reduction from baseline in TETRAS-PS Item 4 at day 29 with SAGE-324/BIIB124 versus placebo (least squares mean [standard error]: -2.31 [0.401] vs. -1.24 [0.349], P = 0.0491). The most common treatment-emergent adverse events included somnolence, dizziness, fatigue, and balance disorder. CONCLUSION: These results support further development of SAGE-324/BIIB124 for potential ET treatment. © 2024 Sage Therapeutics, Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Temblor Esencial , Humanos , Temblor Esencial/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Femenino , Anciano , Método Doble Ciego , Adulto , Anciano de 80 o más Años , Adulto Joven , Adolescente , Resultado del Tratamiento
2.
J Clin Med ; 13(7)2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38610834

RESUMEN

Background: Depression is common in patients with Parkinson's disease (PD) and significantly impacts both the patients and their caregivers. The associations between depression and the responses from commonly used questionnaires for PD patients were assessed. New patients presenting to the Movement Disorder Center completed a number of questionnaires, including assessments of the motor and non-motor symptoms of PD, including depression. Methods: The PD patients were grouped according to severity of depression: none, mild, and moderate-severe, based on the Geriatric Depression Scale (GDS) scores. The mean scores of the Unified PD Rating Scale (UPDRS), Montreal Cognitive Assessment (MoCA), Epworth Sleepiness Scale (ESS), Non-motor Symptoms Scale (NMSS), PD Quality of life (PDQ-39), Hoehn and Yahr score (H&Y), levodopa equivalent daily dose (LEDD), and number of antidepressants used were collected. There were 1214 PD patients included. Results: Increasing depression scores were associated with worsening motor symptoms (according to the UPDRS and H&Y), non-motor symptoms (according to the NMSS), cognition (according to the MoCA), sleepiness (according to the ESS), and quality of life (according to the PDQ-39) (all p-values of p < 0.001). Only half of the patients with mild or moderate-severe depression were taking antidepressants, and the LEDD increased with depression severity. The risk of depression increased by 16% and 5% for every 1-point increase in the NMSS and PDQ-39 scores, respectively. Conclusions: Depression is often unrecognized and undertreated and should be assessed regularly in PD patients, especially in those who demonstrate changes in motor or non-motor symptoms.

3.
Parkinsonism Relat Disord ; 122: 106086, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38538475

RESUMEN

Essential tremor (ET) is one of the most common tremor disorders and can be disabling in its affect on daily activities. There have been major breakthroughs in the treatment of tremor and ET is the subject of important ongoing research. This review will present recent advancements in the epidemiology, genetics, pathophysiology, diagnosis, comorbidities, and imaging of ET. Current and future treatment options in the management of ET will also be reviewed. The need for continued innovation and scientific inquiry to address the unmet needs of persons of ET will be highlighted.


Asunto(s)
Temblor Esencial , Temblor Esencial/diagnóstico , Temblor Esencial/fisiopatología , Temblor Esencial/terapia , Temblor Esencial/epidemiología , Humanos
4.
Clin Park Relat Disord ; 10: 100256, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38770047

RESUMEN

Introduction: Parkinson's disease (PD) is associated with increased mortality risk (MR), reflecting progression of motor and nonmotor symptoms. PD psychosis (PDP), a common nonmotor symptom, increases with prolonged disease and elevates the MR of PD even further. Pimavanserin is the only FDA-approved treatment for PDP. This review summarizes real-world evidence around the MR of patients with PDP treated with pimavanserin versus off-label atypical antipsychotics. Methods: A PubMed search was conducted using the following search terms: pimavanserin AND antipsychotic AND mortality AND Parkinson's disease AND psychosis. Inclusion criteria specified the entry of retrospective, observational, and open-label studies comparing pimavanserin to atypical antipsychotics or untreated controls. Results: A total of 10 of the 32 articles met inclusion criteria. Among five comparisons of pimavanserin with atypical antipsychotics, two were large (n = 21,719; n = 21,975), representative, Medicare-database studies, which demonstrated comparable or lower all-cause pimavanserin MR. Among three pimavanserin versus control studies, two reported lower or comparable pimavanserin MR and one, long-term care study reported higher MR for pimavanserin versus non-pimavanserin treated patients with unknown PDP status. Two open-label extensions reported pimavanserin mortality rates of 6.45 and 18.8 deaths per 100 patient-years, which are comparable to, or lower than, mortality rates for PD, PDP, and other atypical antipsychotics. Most studies (70 %; 7 of 10) demonstrated pimavanserin's MR was lower than or similar to other atypical antipsychotics or untreated controls. Conclusions: Pimavanserin did not increase the MR in PDP. Pimavanserin's MR appears to be comparable to or lower than other atypical antipsychotics prescribed for PDP, including quetiapine.

5.
Gait Posture ; 113: 139-144, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38897002

RESUMEN

BACKGROUND: Gait impairment is an early marker of Parkinson's disease (PD) and is frequently monitored to evaluate disease progression. Wearable sensors are increasingly being used to quantify gait in the real-world setting among people with PD (pwPD). Particularly, embedding wearables on devices or clothing that are worn daily may represent a useful strategy to improve compliance and regular monitoring of gait. RESEARCH QUESTION: The current investigation examined the validity of innovative smart glasses to measure gait among pwPD. METHODS: Participants wore the smart glasses and 6 APDM gait sensors simultaneously, while performing two walking tasks: the 3-meters Timed Up and Go test (TUG) and the 7-meters Stand and Walk (SAW) test. The following spatiotemporal gait parameters were calculated from the data collected using the two different devices: step time, step length, swing percentage, TUG duration, turn duration, and turn velocity. RESULTS: A total of 31 pwPD (mean age=68.6±8.5 years; 35.48 % female(N=11), mean Unified Parkinson's Disease Rating Scale (UPDRS) total score=32.1±14.7) participated in the study. Smart glasses achieved high validity in measuring step time (ICC=0.92, p=0.01) and TUG duration (ICC=0.96, p=0.03) compared to APDM sensors. On the other hand, the smart glasses did not achieve adequate validity when measuring step length, swing percentage, turn duration or turn velocity. SIGNIFICANCE: The current study suggests that smart glasses has the potential to measure TUG and step time in individuals living with PD. However, further research is needed to improve algorithms for sensors worn on the head.

6.
medRxiv ; 2024 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-38352617

RESUMEN

Aims: Balance requires the cortical control of visual, somatosensory, and vestibular inputs. The aim of this cross-sectional study was to compare the contributions of each of these systems on postural control and cortical activity using a sensory reweighting approach between participants with Parkinson's disease (PD) and controls. Methods: Ten participants with PD (age: 72 ± 9; 3 women; Hoehn & Yahr: 2 [1.5 - 2.50]) and 11 controls (age: 70 ± 3; 4 women) completed a sensory organization test in virtual reality (VR-SOT) while cortical activity was being recorded using electroencephalography (EEG). Conditions 1 to 3 were completed on a stable platform; conditions 4 to 6 on a foam. Conditions 1 and 4 were done with eyes open; conditions 2 and 5 in a darkened VR environment; and conditions 3 and 6 in a moving VR environment. Linear mixed models were used to evaluate changes in center of pressure (COP) displacement and EEG alpha and theta/beta ratio power between the two groups across the postural control conditions. Condition 1 was used as reference in all analyses. Results: Participants with PD showed greater COP displacement than controls in the anteroposterior (AP) direction when relying on vestibular input (condition 5; p<0.0001). The mediolateral (ML) COP sway was greater in PD than in controls when relying on the somatosensory (condition 2; p = 0.03), visual (condition 4; p = 0.002), and vestibular (condition 5; p < 0.0001) systems. Participants with PD exhibited greater alpha power compared to controls when relying on visual input (condition 2; p = 0.003) and greater theta/beta ratio power when relying on somatosensory input (condition 4; p = 0.001). Conclusions: PD affects reweighting of postural control, exemplified by greater COP displacement and increased cortical activity. Further research is needed to establish the temporal dynamics between cortical activity and COP displacement.

7.
Clin Park Relat Disord ; 11: 100264, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39175580

RESUMEN

Introduction: In the United States (US), prophylactic treatment with the antiemetic trimethobenzamide has been used before initiating apomorphine therapy. However, US trimethobenzamide stores have been depleted, leaving uncertainty regarding whether antiemetic pretreatment is needed. Methods: This modified Delphi panel aimed to inform circumstances when apomorphine is initiated without antiemetic pretreatment. During Round 1, a panel of 9 US movement disorder specialists rated the appropriateness of prescribing apomorphine therapy with and without antiemetic pretreatment across 192 patient scenarios and were able to review their scores in relation to other scores. During the Round 2, consensus was defined for each scenario as either strong (>75 % agreement) or moderate (66 % agreement). Results: There was strong consensus on 118 of 192 scenario's (97 as appropriate and 21 as inappropriate), moderate consensus on 29 scenarios, some agreement on 32 scenarios, and lack of agreement on 13 scenarios. In the absence of an antiemetic, there was strong consensus that titration schedules should be flexible and based on dose response. However, the group only reached moderate consensus on the speed of titration, highlighting the need for more systematic information on this area. In the presence of an antiemetic, panelists considered usual initial dosing and flexible titration to be appropriate in most scenarios except for when the patient is already experiencing dopaminergic adverse events. Conclusions: Experts generally reached consensus that apomorphine can usually be prescribed without antiemetic pretreatment. Recommendations described here reflect the areas of greatest agreement among a panel of experts based on current available evidence.

8.
Mov Disord Clin Pract ; 11(7): 861-866, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38465885

RESUMEN

BACKGROUND: Foslevodopa/foscarbidopa is a subcutaneous infusion of levodopa/carbidopa prodrugs. OBJECTIVES: Assess correlations between sleep and efficacy from interim data of a phase 3 trial of foslevodopa/foscarbidopa (NCT03781167). METHODS: Pearson correlations between sleep (Parkinson's Disease Sleep Scale-2 [PDSS-2]) and quality of life (QoL; Parkinson's Disease Questionnaire-39), motor experiences of daily living (m-EDL; Movement Disorder Society-Unified Parkinson's Disease Scale Part II), and "Off"/"On" times were calculated for baseline and week 26 improvements. Regression analyses were adjusted for baseline PDSS-2 score. RESULTS: Baseline sleep correlated moderately with QoL (r = 0.44, P < 0.001) and weakly with m-EDL (r = 0.28; P < 0.001). Sleep improvement weakly correlated with improved "Off" time (r = 0.37; P < 0.001) and QoL (r = 0.36; P < 0.001). Regression analyses demonstrated significant positive associations for improved sleep, "Off" time, QoL, and m-EDL. CONCLUSIONS: Improved sleep with foslevodopa/foscarbidopa was associated with improved QoL and "Off" time.


Asunto(s)
Antiparkinsonianos , Carbidopa , Combinación de Medicamentos , Levodopa , Enfermedad de Parkinson , Calidad de Vida , Sueño , Humanos , Carbidopa/administración & dosificación , Carbidopa/uso terapéutico , Levodopa/administración & dosificación , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Masculino , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/uso terapéutico , Femenino , Persona de Mediana Edad , Sueño/efectos de los fármacos , Anciano , Resultado del Tratamiento , Método Doble Ciego , Actividades Cotidianas
9.
Clin Park Relat Disord ; 10: 100239, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38419617

RESUMEN

Background: As Parkinson's disease (PD) advances, management is challenged by an increasingly variable and inconsistent response to oral dopaminergic therapy, requiring special considerations by the provider. Continuous 24 h/day subcutaneous infusion of foslevodopa/foscarbidopa (LDp/CDp) provides steady dopaminergic stimulation that can reduce symptom fluctuation. Objective: Our aim is to review the initiation, optimization, and maintenance of LDp/CDp therapy, identify possible challenges, and share potential mitigations. Methods: Review available LDp/CDp clinical trial data for practical considerations regarding the management of patients during LDp/CDp therapy initiation, optimization, and maintenance based on investigator clinical trial experience. Results: LDp/CDp initiation, optimization, and maintenance can be done without hospitalization in the clinic setting. Continuous 24 h/day LDp/CDp infusion can offer more precise symptom control than oral medications, showing improvements in motor fluctuations during both daytime and nighttime hours. Challenges include infusion-site adverse events for which early detection and prompt management may be required, as well as systemic adverse events (eg, hallucinations) that may require adjustment of the infusion rate or other interventions. A learning curve should be anticipated with initiation of therapy, and expectation setting with patients and care partners is key to successful initiation and maintenance of therapy. Conclusion: Continuous subcutaneous infusion of LDp/CDp represents a promising therapeutic option for individuals with PD. Individualized dose optimization during both daytime and nighttime hours, coupled with patient education, and early recognition of certain adverse events (plus their appropriate management) are required for the success of this minimally invasive and highly efficacious therapy.

10.
Lancet Neurol ; 23(1): 37-45, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38101901

RESUMEN

BACKGROUND: Converging lines of evidence suggest that microglia are relevant to Parkinson's disease pathogenesis, justifying exploration of therapeutic agents thought to attenuate pathogenic microglial function. We sought to test the safety and efficacy of NLY01-a brain-penetrant, pegylated, longer-lasting version of exenatide (a glucagon-like peptide-1 receptor agonist) that is believed to be anti-inflammatory via reduction of microglia activation-in Parkinson's disease. METHODS: We report a 36-week, randomised, double-blind, placebo-controlled study of NLY01 in participants with early untreated Parkinson's disease conducted at 58 movement disorder clinics in the USA. Participants meeting UK Brain Bank or Movement Disorder Society research criteria for Parkinson's disease were randomly allocated (1:1:1) to one of two active treatment groups (2·5 mg or 5·0 mg NLY01) or matching placebo, based on a central computer-generated randomisation scheme using permuted block randomisation with varying block sizes. All participants, investigators, coordinators, study staff, and sponsor personnel were masked to treatment assignments throughout the study. The primary efficacy endpoint for the primary analysis population (defined as all randomly assigned participants who received at least one dose of study drug) was change from baseline to week 36 in the sum of Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III. Safety was assessed in the safety population (all randomly allocated participants who received at least one dose of the study drug) with documentation of adverse events, vital signs, electrocardiograms, clinical laboratory assessments, physical examination, and scales for suicidality, sleepiness, impulsivity, and depression. This trial is complete and registered at ClinicalTrials.gov, NCT04154072. FINDINGS: The study took place between Jan 28, 2020, and Feb 16, 2023. 447 individuals were screened, of whom 255 eligible participants were randomly assigned (85 to each study group). One patient assigned to placebo did not receive study treatment and was not included in the primary analysis. At 36 weeks, 2·5 mg and 5·0 mg NLY01 did not differ from placebo with respect to change in sum scores on MDS-UPDRS parts II and III: difference versus placebo -0·39 (95% CI -2·96 to 2·18; p=0·77) for 2·5 mg and 0·36 (-2·28 to 3·00; p=0·79) for 5·0 mg. Treatment-emergent adverse events were similar across groups (reported in 71 [84%] of 85 patients on 2·5 mg NLY01, 79 [93%] of 85 on 5·0 mg, and 73 [87%] of 84 on placebo), with gastrointestinal disorders the most commonly observed class in active groups (52 [61%] for 2·5 mg, 64 [75%] for 5·0 mg, and 30 [36%] for placebo) and nausea the most common event overall (33 [39%] for 2·5 mg, 49 [58%] for 5·0 mg, and 16 [19%] for placebo). No deaths occurred during the study. INTERPRETATION: NLY01 at 2·5 and 5·0 mg was not associated with any improvement in Parkinson's disease motor or non-motor features compared with placebo. A subgroup analysis raised the possibility of motor benefit in younger participants. Further study is needed to determine whether these exploratory observations are replicable. FUNDING: D&D Pharmatech-Neuraly.


Asunto(s)
Exenatida , Agonistas Receptor de Péptidos Similares al Glucagón , Enfermedad de Parkinson , Humanos , Método Doble Ciego , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/complicaciones , Resultado del Tratamiento , Exenatida/análogos & derivados , Exenatida/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Agonistas Receptor de Péptidos Similares al Glucagón/uso terapéutico
11.
Lancet Neurol ; 23(5): 465-476, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38499015

RESUMEN

BACKGROUND: Conventional oral levodopa therapy for the treatment of Parkinson's disease can be associated with variations in plasma concentrations. Levodopa infusion strategies might provide more consistent drug delivery and fewer motor fluctuations. We aimed to assess the safety and efficacy of a continuous 24 h/day subcutaneous infusion of ND0612 (a levodopa-carbidopa solution) compared with oral immediate-release levodopa-carbidopa for the treatment of motor fluctuations in people with Parkinson's disease. METHODS: We conducted a phase 3, randomised, double-blind, double-dummy, active-controlled, multicentre trial at 117 academic and community neurology sites in 16 countries, including in Europe, Israel, and the USA. Eligible participants were men and women aged 30 years or older with a diagnosis of Parkinson's disease (Hoehn and Yahr stage ≤3 in the on state) who experienced at least 2·5 h/day of off time. Participants underwent an open-label run-in phase (<12 weeks), during which time optimal regimens were established for both oral immediate-release levodopa-carbidopa and for 24 h/day subcutaneous ND0612 infusion (levodopa-carbidopa 60·0/7·5 mg/mL), with supplemental oral levodopa-carbidopa if needed. Participants were then randomly assigned (1:1) to 12 weeks of double-blind treatment with their optimised regimen of either subcutaneous ND0612 or oral levodopa-carbidopa, with matching oral or subcutaneous placebo given as required to maintain blinding. Randomisation was done via an interactive web response system, stratified by region, using a permuted block schedule. Participants, study partners, treating investigators, study site personnel, and the sponsor were masked to treatment group allocation. The primary efficacy endpoint was the change from baseline (ie, time of randomisation, when all patients were receiving an optimised open-label ND0612 regimen) to end of the double-blind phase in total daily on time without troublesome dyskinesia, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT04006210, and is complete. FINDINGS: Between Sept 30, 2019, and April 8, 2022, 381 participants were enrolled, of whom 259 (68%) were randomly assigned, 128 (49%) to subcutaneous ND0612 and 131 (51%) to oral levodopa-carbidopa. 243 (94%) participants completed the study. Treatment with subcutaneous ND0612 provided an additional 1·72 h (95% CI 1·08 to 2·36) of on time without troublesome dyskinesia compared with oral levodopa-carbidopa (change from baseline of -0·48 h [-0·94 to -0·02] with subcutaneous ND0612 vs -2·20 h [-2·65 to -1·74] with oral levodopa-carbidopa; p<0·0001). Significant treatment differences favouring subcutaneous ND0612 were also found in the first four of nine prespecified hierarchical outcomes of daily off time (-1·40 h [95% CI -1·99 to -0·80]), Movement Disorders Society-Unified Parkinson's Disease Rating Scale part II scores (-3·05 [-4·28 to -1·81]), Patients Global Impression of Change (odds ratio [OR] 5·31 [2·67 to 10·58]), and Clinical Global Impression of Improvement (OR 7·23 [3·57 to 14·64]). Hierarchical testing ended after the fourth secondary endpoint. Adverse events were reported by 287 (89%) of 322 participants during open-label ND0612 optimisation, and by 103 (80%) of 128 in the ND0612 group and 97 (74%) of 131 in the oral levodopa-carbidopa group during the double-blind phase. The most common adverse events were infusion-site reactions (266 [83%] participants during open-label ND0612, and 73 [57%] in the ND0612 group vs 56 [43%] in the oral levodopa-carbidopa group during the double-blind phase), most of which were mild. Serious adverse events in four participants in the ND0612 group were related to study treatment (infusion-site cellulitis [n=2], infusion-site abscess and infusion-site ulcer [n=1]; and paraesthesia and peripheral sensorimotor neuropathy [n=1]). One participant in the ND0612 group died during the double-blind phase, but the death was not related to study treatment (fall leading to traumatic brain injury). INTERPRETATION: Results of this phase 3 study showed that subcutaneous ND0612 used in combination with oral immediate-release levodopa-carbidopa increased on time without troublesome dyskinesia and reduced off time, with a favourable benefit-risk profile. ND0612 might offer a safe and efficacious subcutaneous levodopa infusion approach to managing motor fluctuations in people with Parkinson's disease. The ongoing open-label extension phase will provide further information on the long-term efficacy and safety of treatment. FUNDING: NeuroDerm.


Asunto(s)
Discinesias , Enfermedad de Parkinson , Masculino , Humanos , Femenino , Enfermedad de Parkinson/tratamiento farmacológico , Levodopa/uso terapéutico , Carbidopa/efectos adversos , Antiparkinsonianos/uso terapéutico , Infusiones Subcutáneas , Discinesias/tratamiento farmacológico , Método Doble Ciego , Resultado del Tratamiento
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