Parkinsonism & related disorders最新文献_第2页

Aggregated α-synuclein in erythrocytes as a potential biomarker for idiopathic Parkinson's Disease

IF 3.1 3区医学 Q2 CLINICAL NEUROLOGY

Parkinsonism & related disorders

Pub Date : 2025-02-06 DOI: 10.1016/j.parkreldis.2025.107321

Konstantina Dimoula , Nikolaos Papagiannakis , Matina Maniati , Leonidas Stefanis , Evangelia Emmanouilidou

Background

Mostly known for its implication in synucleinopathies, including Parkinson's disease (PD), α-synuclein is predominantly expressed in the nervous system. Most of the peripheral α-synuclein is found in erythrocytes, and several studies have examined a possible association between erythrocytic α-synuclein and PD.

Methods

We have used a recently developed ELISA that selectively detects fibrillar and oligomeric α-synuclein to measure aggregated α-synuclein in red blood cells (RBCs) collected from PD patients and age/sex-matched control individuals (n = 35). The PD group included patients without any common mutation (genetically undetermined group, GU-PD, n = 56) as well as mutation carriers in the α-synuclein gene (A53T-PD, n = 28) and glucocerebrosidase gene (GBA-PD, n = 24).

Results

We found that the concentration of aggregated α-synuclein in erythrocytes was significantly increased in GU-PD patients compared to controls. A53T-PD and GBA-PD patients exhibited similar levels of erythrocytic aggregated α-synuclein as the control group. The levels of fibrillar/oligomeric α-synuclein in RBCs were reduced in respect to the age of control individuals suggesting that the observed increase in the GU-PD cohort was not due to normal aging. Parallel assessment of monomeric α-synuclein revealed that aggregated, but not total, α-synuclein could discriminate PD patients from control individuals.

Conclusions

The elevation of aggregated α-synuclein in GU-PD erythrocytes, which is not related to aging, suggests that these forms may be indicative of PD pathology and possibly accumulate upon disease establishment. As such, aggregated α-synuclein in RBCs could be a potential biomarker for PD diagnosis.

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引用次数: 0

Variable expressivity of KMT2B variants at codon 2565 in patients with dystonia and developmental disorders

IF 3.1 3区医学 Q2 CLINICAL NEUROLOGY

Parkinsonism & related disorders

Pub Date : 2025-02-05 DOI: 10.1016/j.parkreldis.2025.107319

Antonia M. Stehr , Jan Fischer , Nazanin Mirza-Schreiber , Katerina Bernardi , Joseph Porrmann , Philip Harrer , Frank Kaiser , Rami Abou Jamra , Juliane Winkelmann , Robert Jech , Anne Koy , Konrad Oexle , Michael Zech

Introduction

Variable expressivity is an emerging characteristic of KMT2B-related dystonia. However, it remains poorly understood whether variants reoccurring at specific sites of lysine-specific methlytransferase-2B (KMT2B) can drive intra- and interfamilial clinical heterogeneity. Our goal was to ascertain independent families with variants affecting residue Arg2565 of KMT2B.

Methods

Whole-exome/genome sequencing, multi-site recruitment, genotype-phenotype correlations, and DNA methylation episignature analysis were performed.

Results

We report four individuals from two families harboring the variant c.7693C > G, p.Arg2565Gly. In an additional patient, a de-novo c.7693C > T, p.Arg2565Cys variant was identified. The observed phenotypic spectrum ranged from childhood-onset dystonia (N = 2) over unspecific intellectual disability syndromes (N = 2) to undiagnosed behavioral symptoms in adulthood (N = 1). Samples bearing p.Arg2565Gly had a KMT2B-typical episignature, although the effect on methylation was less pronounced than in carriers of loss-of-function KMT2B variants.

Conclusions

We established the existence of a KMT2B missense-mutation hotspot associated with varying degrees of disease severity and expression, providing information for patient counseling and elucidation of pathomechanisms.

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引用次数: 0

Non-pharmacological rehabilitation for people living with advanced Parkinson's disease: A scoping review of interventions.

IF 3.1 3区医学 Q2 CLINICAL NEUROLOGY

Parkinsonism & related disorders

Pub Date : 2025-02-04 DOI: 10.1016/j.parkreldis.2025.107317

Johanne Andersen Elbek, Birgitte Nørgaard, Tina Pedersen, Jette Thuesen

Background: Rehabilitation becomes increasingly important in the more advanced stages of Parkinson's Disease. As the disease reaches its more debilitating stages and pharmacological or surgical treatment becomes less relevant, non-pharmacological interventions including rehabilitation become key. Existing systematic interventions typically focus on individuals in the early to mid-stages of the disease. The objective of this scoping review was to identify and map the available evidence on non-pharmacological rehabilitation interventions for people living with advanced Parkinson's disease.

Methods: This scoping review was conducted following the methodology for scoping reviews developed by the Joanna Briggs Institute. A systematic search was conducted in PubMed, EMBASE, CINAHL, and Cochrane. Studies published in English from 2000 to May 2024 were considered eligible and screened for relevance.

Results: Thirteen studies were included. The majority of the interventions were experimental; one had a focus on feasibility and one had a mixed focus on effect and feasibility. Most interventions were referred to as either rehabilitation, training, or therapy, with the two feasibility interventions focusing on comprehensive assessment and referrals. The majority used modalities concerned with levels of functioning. Studies focusing on stage 4 (H&Y) Parkinson's disease were prominent.

Conclusions: This scoping review provides a foundational overview of existing non-pharmacological rehabilitation interventions for advanced Parkinson's disease, revealing a small yet diverse range of approaches, from single-disciplinary to multidisciplinary interventions. It offers initial insights that can point to areas where further research can solidify and expand effective, targeted care strategies for people living with advanced Parkinson's disease.

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引用次数: 0

Machine Learning-based World Health Organization Disability Assessment Schedule for persons with Parkinson's disease

IF 3.1 3区医学 Q2 CLINICAL NEUROLOGY

Parkinsonism & related disorders

Pub Date : 2025-02-04 DOI: 10.1016/j.parkreldis.2025.107316

Meng-Lin Lee , Gong-Hong Lin , Yi-Ching Wang , Shih-Chieh Lee , Ching-Lin Hsieh

Introduction

The World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) is a well-known measure to assess disability in persons with Parkinson's disease (PD). The purpose of this study was to develop a short form of the WHODAS 2.0 for persons with PD using a machine learning-based methodology (ML-WHODAS) and to examine the efficiency (i.e., number of items needed to be administered) and validity of the ML-WHODAS.

Methods

A secondary data analysis was performed. Data were randomly assigned to training datasets (80 %) and validation datasets (20 %). For developing the ML-WHODAS, the eXtreme Gradient Boosting (XGBoost) regressor was used to select the most informative items from the training datasets, and then the final XGBoost model was generated. The efficiency, concurrent validity, and convergent validity of the ML-WHODAS were then examined using the validation dataset.

Results

Data from 1633 patients were randomly assigned into the training dataset (1306) and the validation dataset (327). Eighteen items were selected for the ML-WHODAS to reproduce 6 domain scores and one global score of the original WHODAS 2.0. In the validation dataset, the Pearson's coefficients r between the scores of the ML-WHODAS and WHODAS 2.0 were 0.97–0.99, indicating very high concurrent validity. Significant correlations were found regarding convergent validity of the domain and global scores.

Conclusions

The ML-WHODAS showed good efficiency and validity compared to the WHODAS 2.0 in persons with PD. The ML-WHODAS demonstrates its potential as an alternative to the WHODAS 2.0, though further validations (e.g., test-retest reliability and responsiveness) are warranted.

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引用次数: 0

Big data and transformative bioinformatics in genomic diagnostics and beyond.

IF 3.1 3区医学 Q2 CLINICAL NEUROLOGY

Parkinsonism & related disorders

Pub Date : 2025-02-03 DOI: 10.1016/j.parkreldis.2025.107311

Alice Saparov, Michael Zech

The current era of high-throughput analysis-driven research offers invaluable insights into disease etiologies, accurate diagnostics, pathogenesis, and personalized therapy. In the field of movement disorders, investigators are facing an increasing growth in the volume of produced patient-derived datasets, providing substantial opportunities for precision medicine approaches based on extensive information accessibility and advanced annotation practices. Integrating data from multiple sources, including phenomics, genomics, and multi-omics, is crucial for comprehensively understanding different types of movement disorders. Here, we explore formats and analytics of big data generated for patients with movement disorders, including strategies to meaningfully share the data for optimized patient benefit. We review computational methods that are essential to accelerate the process of evaluating the increasing amounts of specialized data collected. Based on concrete examples, we highlight how bioinformatic approaches facilitate the translation of multidimensional biological information into clinically relevant knowledge. Moreover, we outline the feasibility of computer-aided therapeutic target evaluation, and we discuss the importance of expanding the focus of big data research to understudied phenotypes such as dystonia.

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引用次数: 0

Beyond the cerebello-thalamo-cortical tract: Remote structural changes after VIM-MRgFUS in essential tremor

IF 3.1 3区医学 Q2 CLINICAL NEUROLOGY

Parkinsonism & related disorders

Pub Date : 2025-02-03 DOI: 10.1016/j.parkreldis.2025.107318

Jonas Krauss , Neeraj Upadhyay , Veronika Purrer , Valeri Borger , Marcel Daamen , Angelika Maurer , Carsten Schmeel , Alexander Radbruch , Ullrich Wüllner , Henning Boecker

Introduction

Essential tremor (ET) is a progressive disorder characterized by altered network connectivity between the cerebellum, thalamus, and cortical regions. Magnetic Resonance-guided Focused Ultrasound (MRgFUS) of the ventral intermediate nucleus (VIM) is an effective, minimally invasive treatment for ET. The impact of MRgFUS interventions on regional Gray Matter Volume (GMV) are as yet not well understood.

Methods

Forty-six patients with medication-resistant ET underwent unilateral VIM-MRgFUS. Voxel-based morphometry was applied to investigate GMV changes over a time span of 6 months in the whole brain and the thalamus in particular to investigate local and distant effects.

Results

Clinically, contralateral tremor significantly decreased by 68 % at 6 months following MRgFUS. In addition to local GMV decreases in thalamic nuclei (VIM, ventral lateral posterior, centromedian thalamus and pulvinar), VBM revealed remote GMV decreases in the ipsilesional insula and the anterior cingulate cortex as well as the contralesional middle occipital gyrus. Increased GMV was found in the right superior and middle temporal gyrus, as well as in the left inferior temporal gyrus. There was no significant correlation between regional GMV declines and tremor improvement. However, temporal volume increases were associated with improved motor-related functional abilities and quality of life outcomes.

Conclusion

Our findings implicate distributed structural changes following unilateral VIM-MRgFUS. Structural losses could reflect Wallerian degeneration of VIM output neurons or plasticity due to decreased sensory input following tremor improvement.

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引用次数: 0

Duration of “Good On” time per dose: Immediate-release carbidopa-levodopa vs. extended-release carbidopa-levodopa (IPX203, CREXONT®) 每次给药的“有效”时间：卡比多巴-左旋多巴速释与卡比多巴-左旋多巴缓释（IPX203, CREXONT®）

IF 3.1 3区医学 Q2 CLINICAL NEUROLOGY

Parkinsonism & related disorders

Pub Date : 2025-02-01 DOI: 10.1016/j.parkreldis.2024.107239

R.A. Hauser , H.H. Fernandez , J. Jimenez-Shahed , S. Allard , G. Banisadr , S. Fisher , R. D'Souza

Background

For Parkinson's disease patients with motor fluctuations, the duration of benefit per levodopa dose is a key metric that reflects a patient's clinical response.

Objective

Determine the difference in mean durations of “Good On” time per dose of subjects randomized to extended-release carbidopa-levodopa (ER CD-LD; IPX203; CREXONT®) vs. immediate-release (IR) CD-LD in the RISE-PD trial.

Methods

“Good On” time per dose was assessed at the end of the IR CD-LD dose adjustment phase (Visit 2/Week 3) and compared to End of Study (Visit 7/EOS) between IPX203 and IR CD-LD groups. In addition, to understand if “Good On” time per dose for IR CD-LD before conversion to IPX203 could impact the magnitude of change in “Good On” time per dose of IPX203 vs. IR CD-LD after conversion, subjects were rank-ordered and divided into quartiles based on their initial “Good On” time per dose optimized IR CD-LD values. Changes in “Good On” time per dose between IPX203 and IR CD-LD groups were then compared for each quartile from Visit 2 to EOS.

Results

IPX203 increased “Good On” time per dose compared to IR CD-LD by a mean of 1.6 h (p < 0.0001). The mean differences in “Good On” time per dose between IPX203 and IR CD-LD were 1.53h for quartile one, 1.39h for quartile two, 1.83h for quartile three, and 1.56h for quartile four (p < 0.0001 for all quartiles).

Conclusion

IPX203 significantly increased “Good On” time per dose regardless of the duration of “Good On” time per dose observed with IR CD-LD.

背景：对于运动波动的帕金森病患者，每次左旋多巴剂量的获益持续时间是反映患者临床反应的关键指标。目的：确定随机分配给卡比多巴-左旋多巴缓释片（ER CD-LD）的受试者每次剂量的平均“开启”时间的差异；IPX203;CREXONT®)与即刻释放（IR） CD-LD在RISE-PD试验中的对比。方法：在IR CD-LD剂量调整阶段（第2次访问/第3周）结束时评估每次剂量的“良好开启”时间，并与IPX203组和IR CD-LD组的研究结束（第7次访问/EOS）进行比较。此外，为了了解转换为IPX203前IR CD-LD的每剂量“良好开启”时间是否会影响转换后IPX203与IR CD-LD的每剂量“良好开启”时间的变化程度，根据受试者初始的每剂量优化IR CD-LD值的“良好开启”时间对受试者进行排序并分为四分位数。然后比较IPX203组和IR CD-LD组从第2次访问到EOS的每个四分位数之间的每次剂量“良好启动”时间的变化。结果：与IR CD-LD相比，IPX203使每次剂量的“良好启动”时间平均增加1.6 h (p)。结论：IPX203显著增加了每次剂量的“良好启动”时间，与IR CD-LD观察到的每次剂量“良好启动”时间的持续时间无关。

{"title":"Duration of “Good On” time per dose: Immediate-release carbidopa-levodopa vs. extended-release carbidopa-levodopa (IPX203, CREXONT®)","authors":"R.A. Hauser , H.H. Fernandez , J. Jimenez-Shahed , S. Allard , G. Banisadr , S. Fisher , R. D'Souza","doi":"10.1016/j.parkreldis.2024.107239","DOIUrl":"10.1016/j.parkreldis.2024.107239","url":null,"abstract":"<div><h3>Background</h3><div>For Parkinson's disease patients with motor fluctuations, the duration of benefit per levodopa dose is a key metric that reflects a patient's clinical response.</div></div><div><h3>Objective</h3><div>Determine the difference in mean durations of “Good On” time per dose of subjects randomized to extended-release carbidopa-levodopa (ER CD-LD; IPX203; CREXONT®) vs. immediate-release (IR) CD-LD in the RISE-PD trial.</div></div><div><h3>Methods</h3><div>“Good On” time per dose was assessed at the end of the IR CD-LD dose adjustment phase (Visit 2/Week 3) and compared to End of Study (Visit 7/EOS) between IPX203 and IR CD-LD groups. In addition, to understand if “Good On” time per dose for IR CD-LD before conversion to IPX203 could impact the magnitude of change in “Good On” time per dose of IPX203 vs. IR CD-LD after conversion, subjects were rank-ordered and divided into quartiles based on their initial “Good On” time per dose optimized IR CD-LD values. Changes in “Good On” time per dose between IPX203 and IR CD-LD groups were then compared for each quartile from Visit 2 to EOS.</div></div><div><h3>Results</h3><div>IPX203 increased “Good On” time per dose compared to IR CD-LD by a mean of 1.6 h (p < 0.0001). The mean differences in “Good On” time per dose between IPX203 and IR CD-LD were 1.53h for quartile one, 1.39h for quartile two, 1.83h for quartile three, and 1.56h for quartile four (p < 0.0001 for all quartiles).</div></div><div><h3>Conclusion</h3><div>IPX203 significantly increased “Good On” time per dose regardless of the duration of “Good On” time per dose observed with IR CD-LD.</div></div>","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"131 ","pages":"Article 107239"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A rare variant in the UQCRC1 gene, p.(Gly405Val) in three Austrian Parkinson's patients 在三名奥地利帕金森患者中发现了罕见的UQCRC1基因变异p.（Gly405Val）。

IF 3.1 3区医学 Q2 CLINICAL NEUROLOGY

Parkinsonism & related disorders

Pub Date : 2025-02-01 DOI: 10.1016/j.parkreldis.2024.107250

Christof Brücke , Thomas Brücke , Walter Pirker , Alexander Zimprich

Background

Variants in the UQCRC1 gene have been proposed to cause autosomal dominant Parkinson's disease with neuropathy. However, definitive confirmation of UQCRC1 as an authentic Parkinson's gene remains elusive, as follow-up studies have not yet provided conclusive evidence.

Methods

382 Austrian Parkinson's patients, particularly selected for familial and/or early onset cases, were Exome sequenced.

Results

We found three unrelated patients with a positive family history of the disease who shared the same rare missense variant in the UQCRC1 gene: c.1214G > T; p.(Gly405Val). The variant is very rare in the control population, with an allele frequency of 2 × 10⁻⁶ in the gnomAD database. None of the three patients carries a rare variant in a monogenic Parkinson's disease gene.

Conclusion

We suggest that UQCRC1 p.(Gly405Val) probably contributes to the development of the disease in these three patients. Our findings provide further evidence that UQCRC1 is a ‘bona fide’ Parkinson's disease gene.

背景：已提出UQCRC1基因变异可导致常染色体显性帕金森病伴神经病变。然而，由于后续研究尚未提供确凿的证据，UQCRC1作为帕金森病基因的确切确认仍然难以捉摸。方法：对382例奥地利帕金森病患者，特别是家族性和/或早发病例进行外显子组测序。结果：我们发现了3例不相关且有阳性家族史的患者，他们在UQCRC1基因中具有相同的罕见错义变异：c.1214G > T；(Gly405Val页)。该变异在对照人群中非常罕见，在gnomAD数据库中等位基因频率为2 × 10-6。这三名患者都没有携带罕见的单基因帕金森病基因变异。结论：我们认为UQCRC1 p.（Gly405Val）可能参与了这3例患者的疾病发展。我们的发现进一步证明了UQCRC1是一个‘真正的’帕金森病基因。

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引用次数: 0

Commentary on “The use of hypoglycemic drugs in Parkinson's disease: An updated meta-analysis of randomized controlled trials” 对“帕金森病降糖药物的使用：随机对照试验的最新荟萃分析”的评论。

IF 3.1 3区医学 Q2 CLINICAL NEUROLOGY

Parkinsonism & related disorders

Pub Date : 2025-02-01 DOI: 10.1016/j.parkreldis.2024.107247

Shubham Kumar , Ahmad Neyazi , Rachana Mehta , Ranjana Sah

引用次数: 0

Flattened red nucleus in progressive supranuclear palsy detected by quantitative susceptibility mapping 定量敏感性图检测进行性核上性麻痹的扁平红核。

IF 3.1 3区医学 Q2 CLINICAL NEUROLOGY

Parkinsonism & related disorders

Pub Date : 2025-02-01 DOI: 10.1016/j.parkreldis.2024.107251

Kazuya Kawabata , Fumihiko Banno , Yasuaki Mizutani , Toshiki Maeda , Ryunosuke Nagao , Sayuri Shima , Kazuhiro Murayama , Yoshiharu Ohno , Tetsuya Maeda , Makoto Sasaki , Akihiro Ueda , Mizuki Ito , Hirohisa Watanabe

Introduction

Progressive supranuclear palsy (PSP) involves midbrain structures, including the red nucleus (RN), an iron-rich region that appears as a high-contrast area on quantitative susceptibility mapping (QSM). RN may serve as a promising biomarker for differentiating parkinsonism. However, RN deformation in PSP remains elusive. This study aimed to evaluate RN deformation in PSP using coronal QSM images and compare them with those of Parkinson's disease (PD) and healthy controls (HC).

Methods

We evaluated the QSM images of 22 patients with PSP, 37 patients with PD, and 43 HC. We developed a grading system to assess RN deformation on coronal QSM images and classified them into three grades. The midbrain and RN volumes were extracted using distinct approaches, and their relationship with grading was investigated. For validation, coronal QSM images of 16 PSP patients from a different institution were assessed.

Results

In PSP, 59 % of the patients displayed a flattened RN of grade 3, which we termed a Rice-Grain Appearance. The volume reductions in midbrain and RN were associated with deformation. Differentiation based on the presence of this appearance yielded a specificity of 1.000 (CI: 1.000–1.000) and sensitivity of 0.591 (0.385–0.796) for distinguishing PSP from others. Secondary dataset also showed that 56 % of patients with PSP were classified as grade 3.

Conclusion

In coronal QSM images, the flattened RN shape appears to be specific to PSP compared to PD and HC and may serve as a marker to help differentiate PSP in future clinical settings.

进行性核上性麻痹（PSP）涉及中脑结构，包括红核（RN），这是一个富含铁的区域，在定量易感性制图（QSM）上显示为高对比度区域。RN可能作为一种有前景的帕金森病鉴别生物标志物。然而，PSP的RN变形仍然难以捉摸。本研究旨在利用冠状面QSM图像评估PSP的RN变形，并将其与帕金森病（PD）和健康对照（HC）进行比较。方法：对22例PSP、37例PD、43例HC的QSM图像进行评价。我们开发了一个分级系统来评估冠状QSM图像的RN变形，并将其分为三个等级。使用不同的方法提取中脑和RN体积，并研究它们与分级的关系。为了验证，我们评估了来自不同机构的16名PSP患者的冠状QSM图像。结果：在PSP中，59%的患者表现为3级扁平RN，我们称之为米粒外观。中脑和RN的体积减少与变形有关。基于这种外观的区分产生了1.000的特异性（CI: 1.000-1.000）和0.591（0.385-0.796）的敏感性。次级数据集也显示56%的PSP患者被分类为3级。结论：与PD和HC相比，冠状QSM图像中扁平的RN形状似乎是PSP的特异性特征，可以作为未来临床环境中帮助区分PSP的标志。

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引用次数: 0