Journal of Parkinson's disease最新文献

Background: Freezing of gait (FoG) is a debilitating symptom of Parkinson's disease (PD) with limited response to dopaminergic medication and subthalamic deep brain stimulation (STN-DBS). Substantia nigra pars reticulata (SNr) stimulation could improve FoG.

Objective: To analyze the effect of combined STN-SNr stimulation at different frequencies on FoG.

Methods: We performed a double-blind, cross-over, randomized pilot trial involving STN-DBS treated PD patients with FoG. Participants received: high-frequency (HF) STN-DBS (S), combined HF-STN and SNr stimulation (C1), and combined HF-STN and low-frequency (LF) SNr stimulation (C2), for one month each. The primary endpoint was the score change in the New-Freezing-of-Gait-Questionnaire (NFOG-Q). Secondary analyses were performed on motor complications, axial symptoms, daily living activities, psychiatric symptoms, sleep, and patient preference.

Results: Fifteen patients received at least one combined stimulation. No significant difference in NFOG-Q scores was found between S, C1, and C2; one-third of patients showed a clinically significant improvement (≥8 points) with combined stimulations. Motor complications improved significantly with C1 and C2 (C1-S: 3.6 ± 3.8 vs. 4.9 ± 3.8, p = 0.046; C2-S: 2.7 ± 3.1 vs. 4.9 ± 3.8, p = 0.005). 80% of patients preferred the combined STN-SNr stimulation while blinded. All adverse events were manageable.

Conclusions: Our study did not prove a statistically significant improvement in NFOG-Q with STN-SNr stimulation; however, one-third of patients experienced a clinically meaningful FoG improvement, and the majority preferred to maintain STN-SNr stimulation. STN-SNr stimulation was both safe and effective in addressing motor complications and improving sleep quality, highlighting the importance of further exploration into the effects of combined STN-SNr stimulation.

Background: In pediatric age, the PRKN mutation is reported as one of the most common genetic causes of Parkinson's disease. However, detailed clinical data on PRKN patients with pediatric onset are scarce.

Objective: To describe clinical characteristics, disease progression, and management of PRKN patients with pediatric onset.

Methods: PRKN patients with onset of clinical signs before the age of 18 years were included in this retrospective multicenter study. Collected data included detailed clinical characteristics, progression, and disease management. Data presentation is descriptive due to the sample size.

Results: Nine patients (five females) were included from five French movement disorders centers. The mean age at symptom onset was 10.78 ± 2.22 years (median, 11; range, 7-14). Dystonia was the first most common motor symptom (six patients). The mean time from symptom onset to genetic diagnosis was 13.33 ± 9.21 years (median, 11; range, 3-32). The most commonly reported non-motor symptoms were sleep disorders (seven patients), anxiety (six patients), and depression (five patients). The first treatment was L-dopa in four patients, dopamine agonist in two, carbamazepine in two, and rasagiline in one. Dyskinesia and impulse control disorders were the most common treatment-related side effects (nine and six patients, respectively). Four patients underwent deep brain stimulation surgery. The last available follow-up was at 27.22 ± 14.05 years (median, 28; range, 6-56) after the diagnosis.

Conclusions: This is the first study reporting detailed clinical features and long-term management of PRKN patients with pediatric onset. Prompt diagnosis and appropriate treatment strategies are important to optimize disease management.

Background: The adaptive immune response has a role in Parkinson's disease (PD). Patients with LRRK2 or GBA1 mutations often exhibit distinct clinical characteristics.

Objective: To evaluate the involvement of adaptive immune response genes in three PD groups: GBA1-PD, LRRK2-PD, and non-carrier (NC)-PD.

Methods: Differentially expressed genes (DEGs) associated with PD were identified using four datasets. Of them, adaptive immune response genes were evaluated using whole-genome-sequencing of 201 unrelated Ashkenazi-Jewish (AJ) PD patients. Potential pathogenic variants were identified, and P2RX7 variants were assessed in 1200 AJ-PD patients. Burden analysis of rare variants (allele frequencies (AF) < 0.01) on disease risk, and association analyses of common variants (AF ≥ 0.01) with disease risk and age-at-onset (AAO) were conducted. AFs were compared to AJ-non-neuro cases reported in gnomAD. Variants associated with PD were further examined in an independent AJ cohort from AMP-PD.

Results: Of the four adaptive immune DEGs identified, CD8B2, P2RX7, IL27RA, and ZC3H12A, three common variants in P2RX7 were statistically significant: Tyr155His was associated with NC-PD (allelic OR = 1.15, p = 0.015) ; Arg276His was associated with LRRK2-PD (allelic OR = 2.10, p = 0.037), while Glu496Ala was associated with earlier AAO in LRRK2-PD (p = 0.014). Burden analysis showed no significant effect on PD-risk. In the AMP-PD cohort, odds ratios of the two risk variants were similar to the primary cohort, but did not reach significance, probably due to small control sample size (n = 263).

Conclusions: Common variants within P2RX7 are likely associated with PD-risk and earlier AAO. These findings further suggest P2RX7's involvement in PD and its potential interplay with LRRK2.

Background: Deep brain stimulation (DBS) is effective in managing motor symptoms in select cases of Parkinson's disease (PD). Nonetheless, the ideal timing for surgery and the comparative outcomes of unilateral versus bilateral DBS procedures remain under-researched areas.

Objective: We aimed to compare the impact of unilateral and bilateral DBS on the motor manifestations of PD using standardized Unified Parkinson's Disease Rating Scale Part-III (UPDRS-III).

Methods: We conducted a retrospective analysis of PD patients who underwent multidisciplinary DBS screening which made a formal recommendation for surgical approach. We compared unilateral, bilateral "rapid" (less than 2 months apart), and bilateral "staged" (5-11 months apart) implantation approaches. The study included 90 patients, 48 patients, and 42 patients from the 3 groups, respectively. The primary outcome was the percentage improvement in baseline off UPDRS-III scores compared to medication-off/DBS-on conditions at 3-6 months and 10-14 months post-surgery. Mann-Whitney U tests were used to compare scores within groups and across follow-up periods. The Kruskal-Wallis test assessed differences among groups. Furthermore, multiple regression analyses were performed to adjust for confounding variables.

Results: UPDRS-III scores improved significantly from baseline at both follow-up intervals regardless of the type of DBS staging approach. The Kruskal-Wallis test revealed no significant differences in UPDRS-III percentage improvement among groups at 3-6 months (p = 0.125) and 10-14 months (p = 0.298) post-DBS.

Conclusions: Our study revealed that in a single experienced DBS center which employed multidisciplinary screening, assignment to unilateral and bilateral DBS, both rapid and staged, targeting the STN or GPi, effectively improved motor symptoms for up to 14 months.

Background: Multiple system atrophy (MSA) and Parkinson's disease (PD) are caused by misfolded α-synuclein spreading throughout the central nervous system. While familial PD is linked to several α-synuclein mutations, no mutations are associated with MSA. We previously showed that the familial PD mutation E46K inhibits replication of MSA prions both in vitro and in vivo, providing key evidence to support the hypothesis that α-synuclein adopts unique strains in patients.

Objective: Here we sought to further interrogate α-synuclein misfolding to identify the structural determinants that contribute to MSA strain biology.

Methods: We engineered a panel of cell lines harbouring both PD-linked and novel mutations designed to identify key residues that facilitate α-synuclein misfolding in MSA. We also used Maestro in silico analyses to predict the effect of each mutation on α-synuclein misfolding into one of the reported MSA cryo-electron microscopy conformations.

Results: In many cases, our modelling accurately identified mutations that facilitated or inhibited MSA replication. However, Maestro was occasionally unable to predict the effect of a mutation, demonstrating the challenge of using computational tools to investigate intrinsically disordered proteins. Finally, we used our cellular models to determine the mechanism underlying the E46K-driven inhibition of MSA replication, finding that the E46/K80 salt bridge is necessary to support α-synuclein misfolding.

Conclusions: Our studies used a structure-based approach to investigate α-synuclein misfolding, resulting in the creation of a powerful panel of cell lines that can be used to interrogate MSA strain biology.

Abstract

Background:

Parkinson’s disease is a progressive neurodegenerative disorder mainly distinguished by sporadic etiology, although a genetic component is also well established. Variants in the LRRK2 gene are associated with both familiar and sporadic disease. We have previously shown that PAK6 and 14-3-3γ protein interact with and regulate the activity of LRRK2.

Objective:

The aim of this study is to quantify PAK6 and 14-3-3γ in plasma as reliable biomarkers for the diagnosis of both sporadic and LRRK2-linked Parkinson’s disease.

Methods:

After an initial quantification of PAK6 and 14-3-3γ expression by means of Western blot in post-mortem human brains, we verified the presence of the two proteins in plasma by using quantitative ELISA tests. We analyzed samples obtained from 39 healthy subjects, 40 patients with sporadic Parkinson’s disease, 50 LRRK2-G2019S non-manifesting carriers and 31 patients with LRRK2-G2019S Parkinson’s disease.

Results:

The amount of PAK6 and 14-3-3γ is significantly different in patients with Parkinson’s disease compared to healthy subjects. Moreover, the amount of PAK6 also varies with the presence of the G2019S mutation in the LRRK2 gene. Although the generalized linear models show a low association between the presence of Parkinson’s disease and PAK6, the kinase could be added in a broader panel of biomarkers for the diagnosis of Parkinson’s disease.

Conclusions:

Changes of PAK6 and 14-3-3γ amount in plasma represent a shared readout for patients affected by sporadic and LRRK2-linked Parkinson’s disease. Overall, they can contribute to the establishment of an extended panel of biomarkers for the diagnosis of Parkinson’s disease.

Abstract

Background:

Task prioritization involves allocating brain resources in a dual-task scenario, but the mechanistic details of how prioritization strategies affect dual-task walking performance for Parkinson’s disease (PD) are little understood.

Objective:

We investigated the performance benefits and corresponding neural signatures for people with PD during dual-task walking, using gait-prioritization (GP) and manual-prioritization (MP) strategies.

Methods:

Participants (N = 34) were asked to hold two inter-locking rings while walking and to prioritize either taking big steps (GP strategy) or separating the two rings (MP strategy). Gait parameters and ring-touch time were measured, and scalp electroencephalograph was performed.

Results:

Compared with the MP strategy, the GP strategy yielded faster walking speed and longer step length, whereas ring-touch time did not significantly differ between the two strategies. The MP strategy led to higher alpha (8–12 Hz) power in the posterior cortex and beta (13–35 Hz) power in the left frontal-temporal area, but the GP strategy was associated with stronger network connectivity in the beta band. Changes in walking speed and step length because of prioritization negatively correlated with changes in alpha power. Prioritization-related changes in ring-touch time correlated negatively with changes in beta power but positively with changes in beta network connectivity.

Conclusions:

A GP strategy in dual-task walking for PD can enhance walking speed and step length without compromising performance in a secondary manual task. This strategy augments attentional focus and facilitates compensatory reinforcement of inter-regional information exchange.