Continuous Levodopa Delivery with an Intraoral Micropump System: An Open-Label Pharmacokinetics and Clinical Study.

BACKGROUND: Double-blind studies have demonstrated that motor complications in Parkinson's disease (PD) can be reduced with continuous delivery of levodopa. The DopaFuse system is a novel, intraoral micropump that attaches to a retainer and uses a propellant to deliver levodopa/carbidopa (LD/CD) continuously into the mouth. OBJECTIVES: Evaluate the safety, pharmacokinetics, and efficacy of LD/CD delivered via the DopaFuse system compared to treatment with intermittent doses of standard oral LD/CD in PD patients with motor fluctuations. METHODS: This was a 2-week, open-label study (NCT04778176) in 16 PD patients treated with ≥4 levodopa doses/day and experiencing motor fluctuations. On Day 1 (clinic setting) patients received their usual dose of standard LD/CD; DopaFuse therapy was initiated on Day 2, and on Day 3 patients received DopaFuse plus a morning oral LD/CD dose. Patients returned home on Days 4-14 and returned for in-clinic assessment on Day 15. RESULTS: Continuous DopaFuse delivery of LD/CD was associated with reduced variability in plasma levodopa levels compared to oral LD/CD (mean ± SD levodopa Fluctuation Index reduced from 2.15 ± 0.59 on Day1 to 1.50 ± 0.55 on Day 2 (P = 0.0129) and to 1.03 ± 0.53 on Day 3 (P < 0.0001)). This pharmacokinetic improvement translated into significantly reduced OFF time with DopaFuse therapy (reduction of -1.72 ± 0.37 h at Day 15; P = 0.0004) and increased ON time without severe dyskinesias (increase of 1.72 ± 0.37 h at Day 15; P = 0.0004) versus oral LD/CD administration. DopaFuse therapy was not associated with any clinically significant adverse events. CONCLUSIONS: Continuous delivery of LD/CD using the DopaFuse system was associated with significantly less variability in plasma levodopa concentrations and reductions in OFF time compared to treatment with standard oral LD/CD therapy and was well tolerated. © 2024 International Parkinson and Movement Disorder Society.

Programme Dementia Prevention (pdp): A Nationwide Program for Personalized Prevention in Luxembourg.

BACKGROUND: With continuously aging societies, an increase in the number of people with cognitive decline is to be expected. Aside from the development of causative treatments, the successful implementation of prevention strategies is of utmost importance to reduce the high societal burden caused by neurodegenerative diseases leading to dementia among which the most common cause is Alzheimer's disease. OBJECTIVE: The aim of the Luxembourgish "programme dementia prevention (pdp)" is to prevent or at least delay dementia in an at-risk population through personalized multi-domain lifestyle interventions. The current work aims to provide a detailed overview of the methodology and presents initial results regarding the cohort characteristics and the implementation process. METHODS: In the frame of the pdp, an extensive neuropsychological evaluation and risk factor assessment are conducted for each participant. Based on the results, individualized multi-domain lifestyle interventions are suggested. RESULTS: A total number of 450 participants (Mean age = 69.5 years; SD = 10.8) have been screened at different recruitment sites throughout the country, among whom 425 participants (94.4%) met the selection criteria. CONCLUSIONS: We provide evidence supporting the feasibility of implementing a nationwide dementia prevention program and achieving successful recruitment of the target population by establishing a network of different healthcare providers.

Propagative α-synuclein seeds as serum biomarkers for synucleinopathies.

Abnormal α-synuclein aggregation is a key pathological feature of a group of neurodegenerative diseases known as synucleinopathies, which include Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy (MSA). The pathogenic ß-sheet seed conformation of α-synuclein is found in various tissues, suggesting potential as a biomarker, but few studies have been able to reliably detect these seeds in serum samples. In this study, we developed a modified assay system, called immunoprecipitation-based real-time quaking-induced conversion (IP/RT-QuIC), which enables the detection of pathogenic α-synuclein seeds in the serum of individuals with synucleinopathies. In our internal first and second cohorts, IP/RT-QuIC showed high diagnostic performance for differentiating PD versus controls (area under the curve (AUC): 0.96 (95% confidence interval (CI) 0.95-0.99)/AUC: 0.93 (95% CI 0.84-1.00)) and MSA versus controls (AUC: 0.64 (95% CI 0.49-0.79)/AUC: 0.73 (95% CI 0.49-0.98)). IP/RT-QuIC also showed high diagnostic performance in differentiating individuals with PD (AUC: 0.86 (95% CI 0.74-0.99)) and MSA (AUC: 0.80 (95% CI 0.65-0.97)) from controls in a blinded external cohort. Notably, amplified seeds maintained disease-specific properties, allowing the differentiation of samples from individuals with PD versus MSA. In summary, here we present a novel platform that may allow the detection of individuals with synucleinopathies using serum samples.

Luxembourg Parkinson's study -comprehensive baseline analysis of Parkinson's disease and atypical parkinsonism.

Background: Deep phenotyping of Parkinson's disease (PD) is essential to investigate this fastest-growing neurodegenerative disorder. Since 2015, over 800 individuals with PD and atypical parkinsonism along with more than 800 control subjects have been recruited in the frame of the observational, monocentric, nation-wide, longitudinal-prospective Luxembourg Parkinson's study. Objective: To profile the baseline dataset and to explore risk factors, comorbidities and clinical profiles associated with PD, atypical parkinsonism and controls. Methods: Epidemiological and clinical characteristics of all 1,648 participants divided in disease and control groups were investigated. Then, a cross-sectional group comparison was performed between the three largest groups: PD, progressive supranuclear palsy (PSP) and controls. Subsequently, multiple linear and logistic regression models were fitted adjusting for confounders. Results: The mean (SD) age at onset (AAO) of PD was 62.3 (11.8) years with 15% early onset (AAO < 50 years), mean disease duration 4.90 (5.16) years, male sex 66.5% and mean MDS-UPDRS III 35.2 (16.3). For PSP, the respective values were: 67.6 (8.2) years, all PSP with AAO > 50 years, 2.80 (2.62) years, 62.7% and 53.3 (19.5). The highest frequency of hyposmia was detected in PD followed by PSP and controls (72.9%; 53.2%; 14.7%), challenging the use of hyposmia as discriminating feature in PD vs. PSP. Alcohol abstinence was significantly higher in PD than controls (17.6 vs. 12.9%, p = 0.003). Conclusion: Luxembourg Parkinson's study constitutes a valuable resource to strengthen the understanding of complex traits in the aforementioned neurodegenerative disorders. It corroborated several previously observed clinical profiles, and provided insight on frequency of hyposmia in PSP and dietary habits, such as alcohol abstinence in PD.Clinical trial registration: clinicaltrials.gov, NCT05266872.

Experiences of adults with high-care needs and their family members with housing and support pathways in Australia.

PURPOSE: Many adults aged less than 65 years with high-care needs resulting from acquired disabilities are unable to access age-appropriate housing and support, and reside in residential aged care or live with family members who may struggle to navigate the disability support system. This qualitative study aimed to investigate the experiences of adults with high-care needs and their family members regarding pathways related to housing and support. METHOD: Two in-depth semi-structured interviews were conducted six months apart with 21 people aged 18 to 65 with high-care needs of varying etiology and living in different housing settings. Nineteen family members involved in decision-making about housing and supports were also interviewed. RESULTS: Thematic data analysis yielded five themes: (1) Traveling in different directions; (2) "the fight, the battle and the war"; (3) willing but wanting; (4) uncertainty and vulnerability; and (5) redefining social roles and relationships. CONCLUSIONS: Current disability policy is not satisfying the housing and support requirements of adults with high-care needs and their families. The findings provide rigorous, empirical evidence which indicate the urgent need to improve access to affordable, individualized housing and support packages, including financial, practical and informational support for family members involved in caring roles. Implications for Rehabilitation Individual preferences are an important consideration in housing and support arrangements for younger people with high-care needs alongside needs-based solutions. Individualized funding approaches may provide flexibility of care and choice in housing and support for people with disability. Family members willingly provide substantial informal care, support and advocacy for younger people with high needs but perceive their role as a constant "battle". Payment of family members in recognition of caring work was perceived as a solution to relieve family hardship and ensure optimal care.

Sleep disorders in Parkinson's disease: many causes, few therapeutic options.

Sleep symptoms in Parkinson's disease (PD) are frequent and have multifactorial and multilayered causes. Primary involvement of sleep/wake regulating centers in the brainstem, sleep problems caused by the nocturnal manifestation of motor and dysautonomic signs and medication-induced sleep problems are often impossible to disentangle in the individual patient. Two syndromes, hypersomnia and REM sleep behavior disorder (RBD), are increasingly recognized as harbingers of the core PD motor syndrome. RBD, associated with a panoply of other nonmotor symptoms, may predispose to a specific PD phenotype. Long-acting dopaminergic stimulation, when abating nocturnal akinesia, also improves subjective sleep quantity. While this strategy is backed up by several randomized controlled trials (RCT), other treatment recommendations are mostly based on case series or expert opinion. Thus we identified only two other RCT, one treating insomnia with eszopiclone, the other nocturnal behavioral abnormalities in demented PD patients with memantine. While the causal complexity of sleep problems in PD certainly hampers the design of therapeutic studies, multiple general treatment strategies against sleep disorders can however be applied efficiently in PD patients as well.

ISO 17025: practical benefits of implementing a quality system.

As a laboratory certified to ISO 9001:2000 and accredited to ISO 17025, rtech laboratories has incorporated an overall system for technical and quality management, which results in benefits observed in daily laboratory practices. Technical requirements were updated to include the addition of formal personnel training plans and detailed records, method development and validation procedures, measurement of method uncertainty, and a defined equipment calibration and maintenance program. In addition, a stronger definition of the sample preparation process was documented to maintain consistency in sampling, and a more rigorous quality control monitoring program was implemented for chemistry and microbiology. Management quality improvements focused on document control to maintain consistent analytical processes, improved monitoring of supplier performance, a contract review process for documenting customer requirements, and a system for handling customer comments and complaints, with continuous improvement through corrective and preventive action procedures and audits. Quarterly management review of corrective actions, nonconforming testing, and proficiency testing aid in determining long-term trending. The practical benefits of these technical and management quality improvements are seen on a daily basis in the laboratory. Faster identification and resolution of issues regarding methods, personnel or equipment, improved customer satisfaction, meeting quality requirements of specialized customers, and overall increased laboratory business are all the result of implementing an effective quality system.