Journal of Parkinson's disease最新文献

Parkinson's disease (PD) carries substantial psychosocial burden. Using a database of responses by people with PD reporting up to five "most bothersome problems," we identified 225 fear-based verbatims, which were organized using the framework method into 26 categories. Commonly-reported fears included uncertainty of progression (n = 60, 26.7%), fear of future cognitive impairment (n = 24, 10.7%) and fear of becoming a burden on others (n = 23, 10.2%). Fears in PD are wide-ranging and can constitute the most bothersome aspect of the condition. These data can be used to design interventions to lessen the psychosocial burden of PD.

Background: Pre-clinical studies suggest that c-Abl activation may play an important role in the etiology of Parkinson's disease, making c-Abl an important target to evaluate for potential disease-modification.

Objective: To assess safety, tolerability, and pharmacokinetics of the c-Abl inhibitor risvodetinib (IkT-148009) in healthy subjects and participants with Parkinson's disease.

Methods: Part 1 (single ascending dose (SAD)) and Part 2 (7-day multiple ascending dose (MAD)) studies were in healthy volunteers. Participants were randomized 3 : 1 across 9 SAD doses and 3 MAD doses of risvodetinib (IkT-148009) or placebo. Part 3 was a MAD study conducted at two doses in 14 participants with mild-to-moderate PD (MAD-PD). Primary outcome measures were safety, tolerability and pharmacokinetics. Exploratory outcomes in PD participants included clinical measures of PD state, GI function, and cerebrospinal fluid (CSF) concentration.

Results: 108 patients were treated with no dropouts. The SAD tested doses ranging from 12.5 to 325 mg, while the MAD tested 25 to 200 mg and MAD-PD tested 50 to 100 mg in Parkinson's participants. All active doses had a favorable safety profile with no clinically meaningful adverse events. Single dose pharmacokinetics were approximately linear between 12.5 mg and 200 mg for both Cmax and AUC0 - inf without distinction between healthy volunteers and participants with PD. Exposures at each dose were high relative to other drugs in the same kinase inhibitor class.

Conclusions: Risvodetinib (IkT-148009) was well tolerated, had a favorable safety and pharmacology profile over 7-day dosing, did not induce serious adverse events and did not appear to induce deleterious side-effects in participants administered anti-PD medications.

Background: There is significant unmet need for effective and efficiently delivered care for people with Parkinson's disease (PwP). We undertook a service improvement initiative to co-develop and implement a new care pathway, Home Based Care (HBC), based on supported self-management, remote monitoring and the ability to trigger a healthcare contact when needed.

Objective: To evaluate feasibility, acceptability and safety of Home Based Care.

Methods: We evaluated data from the first 100 patients on HBC for 6 months. Patient monitoring, performed at baseline and 6-monthly, comprised motor (MDS-UPDRS II and accelerometer), non-motor (NMSQ, PDSS-2, HADS) and quality of life (PDQ) measures. Care quality was audited against Parkinson's UK national audit standards. Process measures captured feasibility. Acceptability was assessed using a mixed-methods approach comprising questionnaires and semi-structured interviews.

Results: Between October 2019 and January 2021, 108 PwP were enrolled onto HBC, with data from 100 being available at 6 months. Over 90% of all questionnaires were returned, 97% were complete or had < 3 missing items. Reporting and communications occurred within agreed timeframes. Compared with baseline, after 6m on HBC, PD symptoms were stable; more PwP felt listened to (90% vs. 79%) and able to seek help (79% vs. 68%). HBC met 93% of national audit criteria. Key themes from the interviews included autonomy and empowerment.

Conclusions: We have demonstrated acceptability, feasibility and safety of our novel remotely delivered Parkinson's care pathway. Ensuring scalability will widen its reach and realize its benefits for underserved communities, enabling formal comparisons with standard care and cost-effectiveness evaluation.

Patients with Parkinson's disease are highly vulnerable for cognitive decline. Thus, early intervention by means of working memory training (WMT) may be effective for the preservation of cognition. However, the influence of structural brain properties, i.e., cortical thickness and volume of white matter lesions on training responsiveness have not been studied. Here, behavioral and neuroimaging data of 46 patients with Parkinson's disease, 21 of whom engaged in home-based, computerized adaptive WMT, was analyzed. While cortical thickness and white matter lesions volume were associated with cognitive performance at baseline, these structural brain properties do not seem to determine WMT responsiveness.

Lewy bodies (LBs) are pathological hallmarks of Parkinson's disease and dementia with Lewy bodies, characterized by the accumulation of α-synuclein (αSyn) protein in the brain. While LBs were first described a century ago, their formation and morphogenesis mechanisms remain incompletely understood. Here, we present a historical overview of LB definitions and highlight the importance of semantic clarity and precise definitions when describing brain inclusions. Recent breakthroughs in imaging revealed shared features within LB subsets and the enrichment of membrane-bound organelles in these structures, challenging the conventional LB formation model. We discuss the involvement of emerging concepts of liquid-liquid phase separation, where biomolecules demix from a solution to form dense condensates, as a potential LB formation mechanism. Finally, we emphasize the need for the operational definitions of LBs based on morphological characteristics and detection protocols, particularly in studies investigating LB formation mechanisms. A better understanding of LB organization and ultrastructure can contribute to the development of targeted therapeutic strategies for synucleinopathies.

Aging is a major risk factor for Parkinson's disease (PD). Genetic mutations account for a small percentage of cases and the majority appears to be sporadic, with yet unclear causes. However, various environmental factors have been linked to an increased risk of developing PD and, therefore, understanding the complex interplay between genetic and environmental factors is crucial for developing effective disease-modifying therapies. Several studies identified a connection between type 2 diabetes (T2DM) and PD. T2DM is characterized by insulin resistance and failure of β-cells to compensate, leading to hyperglycemia and serious comorbidities. Both PD and T2DM share misregulated processes, including mitochondrial dysfunction, oxidative stress, chronic inflammation, altered proteostasis, protein aggregation, and misregulation of glucose metabolism. Chronic or recurring hyperglycemia is a T2DM hallmark and can lead to increased methylglyoxal (MGO) production, which is responsible for protein glycation. Glycation of alpha-synuclein (aSyn), a central player in PD pathogenesis, accelerates the deleterious aSyn effects. Interestingly, MGO blood plasma levels and aSyn glycation are significantly elevated in T2DM patients, suggesting a molecular mechanism underlying the T2DM - PD link. Compared to high constant glucose levels, glycemic variability (fluctuations in blood glucose levels), can be more detrimental for diabetic patients, causing oxidative stress, inflammation, and endothelial damage. Accordingly, it is imperative for future research to prioritize the exploration of glucose variability's influence on PD development and progression. This involves moving beyond the binary classification of patients as diabetic or non-diabetic, aiming to pave the way for the development of enhanced therapeutic interventions.

Background: Research indicates that people with Parkinson's disease (PwPs) may experience challenges in both peripheral and central auditory processing, although findings are inconsistent across studies. Due to the diversity of auditory measures used, there is a need for standardized, replicable hearing assessments to clarify which aspects of audition are impacted in PWPs and whether they are linked to motor and non-motor symptoms.

Objective: To characterize auditory processes and their possible alteration in PwPs. To address this, we collected a comprehensive set of standardized measures of audition using PART, a digital testing platform designed to facilitate replication. Additionally, we examined the relationship between auditory, cognitive, and clinical variables in PwPs.

Methods: We included 44 PwPs and 54 age and education matched healthy controls. Assessments included detection of diotic and dichotic frequency modulation, temporal gaps, spectro-temporal broad-band modulation, and speech-on-speech masking.

Results: We found no statistically significant differences in auditory processing measures between PwPs and the comparison group (ps > 0.07). In PwPs, an auditory processing composite score showed significant medium size correlations with cognitive measures (0.39 < r<0.41, ps < 0.02) and clinical variables of motor symptom severity, quality of life, depression, and caretaker burden (0.33 < r<0.52, ps < 0.03).

Conclusions: While larger datasets are needed to clarify whether PwPs experience more auditory difficulties than healthy controls, our results underscore the importance of considering auditory processing on the symptomatic spectrum of Parkinson's disease using standardized replicable methodologies.

Background: Exercise promotion interventions for people with Parkinson's disease (PD) are often offered on a face-to-face basis, follow a generic "one-size-fit-all" approach, and are not typically delivered at diagnosis. Considering PD's heterogenous nature, the existing evidence on the merits of exercise on symptom management and the expressed wishes of people living with PD for access to timely and tailored evidence-based information, there is a demand for interventions that are easily accessible, scalable and co-designed with people living with PD.

Objective: Evaluate the feasibility and acceptability of a co-designed digital intervention promoting exercise and physical activity, in people newly diagnosed with PD.

Methods: Thirty people living with PD for less than one year participated in an assessor-blinded randomized feasibility trial from June 2022 to April 2023. The intervention group received the 8-week Knowledge, Exercise Efficacy and Participation (KEEP) intervention comprising 6 interactive digital modules and 4 online live group discussions facilitated by a specialist physiotherapist. Assessments were performed at baseline, post intervention and at 6-month follow up.

Results: Thirty participants were recruited to target with a 64% recruitment rate (30/47). All but one participant completed the 6-month follow-up assessment. There was high retention (97%), module completion (91%), and online discussion attendance (88%). Outcome measure collection was feasible, including accelerometer data with a daily average wear time of 23.9 hours (SD:0.295).

Conclusions: The KEEP intervention was feasible and acceptable in people newly diagnosed with PD. A larger trial is needed to assess intervention efficacy and correlation between knowledge, self-efficacy, and activity levels.

Background: Noradrenergic signaling declines in Parkinson's disease (PD) following locus coeruleus neurodegeneration. Epidemiologic studies demonstrate that β-acting drugs slow PD progression.

Objective: The primary objective was to compare the safety and effects of 3 β-adrenoceptor (β-AR) acting drugs on central nervous system (CNS) function after a single dose in healthy volunteers (HVs) and evaluate the effects of multiple doses of β-AR acting drugs in HVs and PD-patients.

Methods: In Part A, HVs received single doses of 32 mg salbutamol, 160μg clenbuterol, 60 mg pindolol and placebo administered in a randomized, 4-way cross-over study. In Part B (randomized cross-over) and Part C (parallel, 2:1 randomized), placebo and/or clenbuterol (20μg on Day 1, 40μg on Day 2, 80μg on Days 3-7) were administered. CNS functions were assessed using the NeuroCart test battery, including pupillometry, adaptive tracking and recall tests.

Results: Twenty-seven HVs and 12 PD-patients completed the study. Clenbuterol improved and pindolol reduced the adaptive tracking and immediate verbal recall performance. Clenbuterol and salbutamol increased and pindolol decreased pupil-to-iris ratios. Clenbuterol was selected for Parts B and C. In Part B, clenbuterol significantly increased performance in adaptive tracking with a tendency toward improved performance in immediate and delayed verbal recall. In Part C trends toward improved performance in immediate and delayed verbal recall were observed in PD-patients. Typical cardiovascular peripheral β2-AR effects were observed with clenbuterol.

Conclusions: This study demonstrates the pro-cognitive effects of clenbuterol in HVs with similar trends in PD-patients. The mechanism of action is likely activation of β2-ARs in the CNS.