Pub Date : 2026-03-25DOI: 10.1038/s41531-026-01326-7
Rebecca Cardini, Elisa Gervasoni, Stefano Giannoni-Luza, Anna Cavalca, Alessia Piva, Davide Cattaneo, Elisa Pelosin, Tommaso Bocci, Sara Marceglia, Alberto Priori, Matteo Guidetti
Balance impairments are among the most disabling symptoms of Parkinson and are often poorly responsive to pharmacological therapy. Physiotherapy (PT) is a key non-pharmacological intervention to improve postural control, though optimal exercise characteristics and dose remain unclear. We conducted a systematic review and dose–response meta-analysis to evaluate PT’s effectiveness on balance in people with Parkinson’s disease (PwPD) and define a dose–response relationship. A systematic search of PubMed/MEDLINE, EMBASE, and Web of Science was done from March-April 2024 and updated in February 2025. Eligibility criteria comprised RCTs or cross-over studies included adults with idiopathic PD receiving exercise targeting balance. Two reviewers independently assessed risk of bias using the Cochrane Risk of Bias tool for randomized trials (RoB 2.0). Thirty studies (n participants = 2,932; mean ± SD age = 69.3 ± 4.0 years; mean ± SD disease duration = 6.7 ± 1.6 years; mean ± SD Hoehn & Yahr = 2.3 ± 0.5) were included. Balance outcomes were Mini-Balance Evaluation Systems Test (Mini-BESTest), Timed Up and Go (TUG), Berg Balance Scale (BBS), Unified PD Rating Scale (UPDRS-III), and Sensory Organization Test (SOT). Physiotherapy led to moderate balance improvements (SMD = 0.56, 95%CI 0.38-0.74), with balance-specific training showing the greatest effect (SMD = 0.64, 95%CI 0.35-0.93). No clear linear dose–response was found between training volume and effect size. Subgroup analyses confirmed consistent benefits across Mini-BESTest, BBS, and TUG. These findings support personalized, balance-focused rehabilitation in PD and highlight the need for clearer intervention protocols.
平衡障碍是帕金森最严重的致残症状之一，通常对药物治疗反应不佳。物理治疗（PT）是改善体位控制的关键非药物干预，尽管最佳运动特性和剂量尚不清楚。我们进行了一项系统综述和剂量-反应荟萃分析，以评估PT对帕金森病（PwPD）患者平衡的有效性，并确定剂量-反应关系。系统检索PubMed/MEDLINE、EMBASE和Web of Science于2024年3 - 4月完成，并于2025年2月更新。入选标准包括随机对照试验或交叉研究，包括成人特发性PD患者接受以平衡为目标的运动。两位审稿人使用Cochrane随机试验偏倚风险工具（RoB 2.0）独立评估偏倚风险。纳入30项研究（n名受试者= 2932名；平均±SD年龄= 69.3±4.0岁；平均±SD病程= 6.7±1.6年；平均±SD Hoehn & Yahr = 2.3±0.5）。平衡结果包括mini - best评估系统测试（mini - best）、Timed Up and Go （TUG）、Berg平衡量表（BBS）、统一PD评定量表（UPDRS-III）和感觉组织测试（SOT）。物理治疗导致适度的平衡改善（SMD = 0.56, 95%CI 0.38-0.74），平衡训练显示出最大的效果（SMD = 0.64, 95%CI 0.35-0.93）。在训练量和效应量之间没有发现明显的线性剂量反应。亚组分析证实了mini - best、BBS和TUG的一致疗效。这些发现支持PD的个性化、以平衡为中心的康复，并强调需要更明确的干预方案。
{"title":"Physiotherapy interventions for balance impairments in Parkinson’s disease: evidence from a systematic review and dose-response meta-analysis","authors":"Rebecca Cardini, Elisa Gervasoni, Stefano Giannoni-Luza, Anna Cavalca, Alessia Piva, Davide Cattaneo, Elisa Pelosin, Tommaso Bocci, Sara Marceglia, Alberto Priori, Matteo Guidetti","doi":"10.1038/s41531-026-01326-7","DOIUrl":"https://doi.org/10.1038/s41531-026-01326-7","url":null,"abstract":"Balance impairments are among the most disabling symptoms of Parkinson and are often poorly responsive to pharmacological therapy. Physiotherapy (PT) is a key non-pharmacological intervention to improve postural control, though optimal exercise characteristics and dose remain unclear. We conducted a systematic review and dose–response meta-analysis to evaluate PT’s effectiveness on balance in people with Parkinson’s disease (PwPD) and define a dose–response relationship. A systematic search of PubMed/MEDLINE, EMBASE, and Web of Science was done from March-April 2024 and updated in February 2025. Eligibility criteria comprised RCTs or cross-over studies included adults with idiopathic PD receiving exercise targeting balance. Two reviewers independently assessed risk of bias using the Cochrane Risk of Bias tool for randomized trials (RoB 2.0). Thirty studies (n participants = 2,932; mean ± SD age = 69.3 ± 4.0 years; mean ± SD disease duration = 6.7 ± 1.6 years; mean ± SD Hoehn & Yahr = 2.3 ± 0.5) were included. Balance outcomes were Mini-Balance Evaluation Systems Test (Mini-BESTest), Timed Up and Go (TUG), Berg Balance Scale (BBS), Unified PD Rating Scale (UPDRS-III), and Sensory Organization Test (SOT). Physiotherapy led to moderate balance improvements (SMD = 0.56, 95%CI 0.38-0.74), with balance-specific training showing the greatest effect (SMD = 0.64, 95%CI 0.35-0.93). No clear linear dose–response was found between training volume and effect size. Subgroup analyses confirmed consistent benefits across Mini-BESTest, BBS, and TUG. These findings support personalized, balance-focused rehabilitation in PD and highlight the need for clearer intervention protocols.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-23DOI: 10.1038/s41531-026-01324-9
You Hyun Park, Yong Wook Kim, Dae Ryong Kang, Sang Chul Lee, Seo Yeon Yoon
{"title":"Publisher Correction: Prediction of all-cause mortality in Parkinson's disease with explainable artificial intelligence using administrative healthcare data.","authors":"You Hyun Park, Yong Wook Kim, Dae Ryong Kang, Sang Chul Lee, Seo Yeon Yoon","doi":"10.1038/s41531-026-01324-9","DOIUrl":"https://doi.org/10.1038/s41531-026-01324-9","url":null,"abstract":"","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"12 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147504503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-20DOI: 10.1038/s41531-026-01322-x
Philipp Antczak,Peter Brandt,Lav Radosavljević,Per Svenningsson,Joëlle Rüegg,Kristina Bečanović
5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic modifications increasingly recognized for their roles in Parkinson's disease (PD). In this study, we profiled 5mC and 5hmC in blood samples from individuals with PD to explore their relevance to disease status and progression. We observed significantly reduced global 5hmC levels in peripheral blood mononuclear cells (PBMCs) from PD cases compared to controls. Using the Illumina EPIC BeadArray, we conducted genome-wide analyses of 5mC and 5hmC in a subset of PD cases and controls to explore methylation and hydroxymethylation patterns. We identified differentially methylated and hydroxymethylated positions and regions enriched within introns, with both types of regions showing a marked concentration near exon-intron junctions. Positional analysis relative to exon-intron junctions revealed that proximal and distal regions mapped to partially different functional themes, suggesting that genomic context provides additional biological insight. Functional enrichment analyses also highlighted distinct biological roles for 5mC and 5hmC, with associated genes implicated in neurodevelopment, vascular remodeling, and neuroimmune signaling. Additionally, we demonstrate that global 5hmC levels, in combination with age and sex, are predictive of disease status, highlighting the potential of 5hmC as a blood-based biomarker for PD.
{"title":"Profiling of 5-hydroxymethylcytosine in blood reveals preferential enrichment at exon-intron junctions and predictive value for Parkinson's disease.","authors":"Philipp Antczak,Peter Brandt,Lav Radosavljević,Per Svenningsson,Joëlle Rüegg,Kristina Bečanović","doi":"10.1038/s41531-026-01322-x","DOIUrl":"https://doi.org/10.1038/s41531-026-01322-x","url":null,"abstract":"5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic modifications increasingly recognized for their roles in Parkinson's disease (PD). In this study, we profiled 5mC and 5hmC in blood samples from individuals with PD to explore their relevance to disease status and progression. We observed significantly reduced global 5hmC levels in peripheral blood mononuclear cells (PBMCs) from PD cases compared to controls. Using the Illumina EPIC BeadArray, we conducted genome-wide analyses of 5mC and 5hmC in a subset of PD cases and controls to explore methylation and hydroxymethylation patterns. We identified differentially methylated and hydroxymethylated positions and regions enriched within introns, with both types of regions showing a marked concentration near exon-intron junctions. Positional analysis relative to exon-intron junctions revealed that proximal and distal regions mapped to partially different functional themes, suggesting that genomic context provides additional biological insight. Functional enrichment analyses also highlighted distinct biological roles for 5mC and 5hmC, with associated genes implicated in neurodevelopment, vascular remodeling, and neuroimmune signaling. Additionally, we demonstrate that global 5hmC levels, in combination with age and sex, are predictive of disease status, highlighting the potential of 5hmC as a blood-based biomarker for PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"11 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147490008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To investigate whether age of onset (AAO) affects cerebrospinal fluid (CSF) C16 glucosylceramide (C16 GlcCer) and striatal dopamine transporter-specific binding ratios (DAT-SBRs) in Parkinson's disease (PD), and their associations with longitudinal autonomic and cognitive outcomes, we conducted a large-scale, multicenter, prospective observational cohort study. Late-onset PD (LOPD, AAO > 50 years) patients showed higher baseline CSF C16 GlcCer and lower DAT‑SBR in some striatal regions compared to early‑onset PD (EOPD, AAO ≤ 50 years). Higher DAT-SBR was associated with a lower risk of autonomic dysfunction (AutD) in both groups and with better longitudinal cognitive performance in LOPD. Importantly, only in LOPD did the interaction between C16 GlcCer and DAT‑SBR predict more favorable autonomic progression, independent of CSF α‑synuclein. In EOPD, AutD risk was primarily related to regional DAT loss. These findings suggest that AAO modulates sphingolipid‑dopaminergic crosstalk and supports the combined use of these biomarkers for risk stratification.
{"title":"Age at onset of Parkinson's disease modulates the sphingolipid-dopaminergic interplay in autonomic progression.","authors":"Zhinan Ye,Shishu Zhang,Zijia Liu,Junchao Wang,Junjie Li,Xicheng Yu,Xinyi Yuan,Zhuoyu Chen,Zihan Yuan,Ziyu Yang,Suwen Huang,Yiyun Weng,Dehao Yang","doi":"10.1038/s41531-026-01308-9","DOIUrl":"https://doi.org/10.1038/s41531-026-01308-9","url":null,"abstract":"To investigate whether age of onset (AAO) affects cerebrospinal fluid (CSF) C16 glucosylceramide (C16 GlcCer) and striatal dopamine transporter-specific binding ratios (DAT-SBRs) in Parkinson's disease (PD), and their associations with longitudinal autonomic and cognitive outcomes, we conducted a large-scale, multicenter, prospective observational cohort study. Late-onset PD (LOPD, AAO > 50 years) patients showed higher baseline CSF C16 GlcCer and lower DAT‑SBR in some striatal regions compared to early‑onset PD (EOPD, AAO ≤ 50 years). Higher DAT-SBR was associated with a lower risk of autonomic dysfunction (AutD) in both groups and with better longitudinal cognitive performance in LOPD. Importantly, only in LOPD did the interaction between C16 GlcCer and DAT‑SBR predict more favorable autonomic progression, independent of CSF α‑synuclein. In EOPD, AutD risk was primarily related to regional DAT loss. These findings suggest that AAO modulates sphingolipid‑dopaminergic crosstalk and supports the combined use of these biomarkers for risk stratification.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"6 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-19DOI: 10.1038/s41531-026-01304-z
Laura Kondrataviciute,Minesh Kapadia,Ivan Skelin,Srdjan Sumarac,Luka Zivkovic,Luis Antonio Franco Vergara,Sabika Jafri,Cherisse Tan,Hien Chau,Yuhan Hou,Savanna Blade,Xilin Liu,Clement Hamani,Taufik Valiante,William D Hutchison,Luka Milosevic,Lorraine V Kalia,Suneil K Kalia
Parkinson's disease (PD) is a movement disorder characterized by alpha-synuclein (a-Syn) aggregation, dopaminergic degeneration, and pathological beta oscillations (13-30 Hz) in the basal ganglia circuit. Deep brain stimulation (DBS) is an effective neurosurgical treatment for the motor symptoms of PD. However, the extent to which mitigation of beta oscillations mediates DBS therapeutic effects remains uncertain. Using an adeno-associated virus-mediated nigral A53T a-Syn overexpression rat model, we examined basal ganglia-thalamo-cortical electrophysiology and the model's responsiveness to DBS. In vivo recordings revealed early beta emergence in the motor cortex (MCx), spreading to the subthalamic nucleus (STN) and entopeduncular nucleus (EP) with neurodegeneration. This was accompanied by alterations in STN and EP single-unit activity. Awake-state beta oscillations manifested as transient bursts. Low- and high-frequency DBS differentially modulated beta bursts and motor performance. Our results demonstrate that the A53T a-Syn model replicates key PD-like electrophysiological features, providing a platform to investigate DBS mechanisms and optimize therapies targeting aberrant beta activity.
{"title":"Cortical and basal ganglia beta oscillations and frequency-dependent DBS effects in the A53T Parkinson's disease rat model.","authors":"Laura Kondrataviciute,Minesh Kapadia,Ivan Skelin,Srdjan Sumarac,Luka Zivkovic,Luis Antonio Franco Vergara,Sabika Jafri,Cherisse Tan,Hien Chau,Yuhan Hou,Savanna Blade,Xilin Liu,Clement Hamani,Taufik Valiante,William D Hutchison,Luka Milosevic,Lorraine V Kalia,Suneil K Kalia","doi":"10.1038/s41531-026-01304-z","DOIUrl":"https://doi.org/10.1038/s41531-026-01304-z","url":null,"abstract":"Parkinson's disease (PD) is a movement disorder characterized by alpha-synuclein (a-Syn) aggregation, dopaminergic degeneration, and pathological beta oscillations (13-30 Hz) in the basal ganglia circuit. Deep brain stimulation (DBS) is an effective neurosurgical treatment for the motor symptoms of PD. However, the extent to which mitigation of beta oscillations mediates DBS therapeutic effects remains uncertain. Using an adeno-associated virus-mediated nigral A53T a-Syn overexpression rat model, we examined basal ganglia-thalamo-cortical electrophysiology and the model's responsiveness to DBS. In vivo recordings revealed early beta emergence in the motor cortex (MCx), spreading to the subthalamic nucleus (STN) and entopeduncular nucleus (EP) with neurodegeneration. This was accompanied by alterations in STN and EP single-unit activity. Awake-state beta oscillations manifested as transient bursts. Low- and high-frequency DBS differentially modulated beta bursts and motor performance. Our results demonstrate that the A53T a-Syn model replicates key PD-like electrophysiological features, providing a platform to investigate DBS mechanisms and optimize therapies targeting aberrant beta activity.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"12 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-19DOI: 10.1038/s41531-026-01320-z
Luigi Fiorillo,Giovanni Lombardi,Nicolo La Porta,Lisa Arnaud,Marco Veneruso,Anna Castelnovo,Ilaria Bertaina,Claudio Staedler,Alain Kaelin-Lang,Salvatore Galati
Slow-wave activity during sleep facilitates synaptic downscaling, while theta activity during wakefulness reflects synaptic upscaling, and both processes may be altered in levodopa-induced dyskinesia (LID) in Parkinson's disease (PD). We compared actigraphy and high-density EEG in 12 healthy volunteers and three PD cohorts: early stage (EPD, n = 12), advanced non-dyskinetic (ADV, n = 13), and advanced dyskinetic (DYS, n = 11). Participants completed one week of actigraphy monitoring, followed by two resting-state EEG recordings conducted separately in the morning and evening. Wake-theta activity was analyzed using both linear and linear mixed-effects models, adjusted for age/sex, plus cluster-based non-parametric statistics, then related to clinical variables, and actigraphy-derived sleep metrics via partial correlations. Dyskinetic patients showed marked sleep disruption, elevated morning theta compared with controls (p = 0.006, d = 1.54) and EPD (p = 0.03, d = 0.85), along with a significantly reduced diurnal theta build-up compared with controls (p = 0.009, d = 1.57). EPD and ADV groups showed preserved diurnal increases. In dyskinetic patients, a higher levodopa equivalent daily dose (LEDD) was correlated with higher morning theta (ρ = 0.70, p = 0.023, pFDR=0.046) and smaller diurnal theta increases (ρ = -0.77, p = 0.009, pFDR=0.046). Relationships between theta and actigraphy-derived sleep metrics were weaker and inconsistent across groups. These findings suggest a dyskinesia-specific profile of impaired wake-related theta homeostasis, motivating longitudinal studies combining polysomnography and waking EEG.
睡眠时的慢波活动促进突触降阶，而清醒时的θ波活动反映突触升阶，这两个过程可能在左旋多巴诱导的帕金森病（PD）运动障碍（LID）中发生改变。我们比较了12名健康志愿者和三个PD队列的活动图和高密度脑电图：早期（EPD, n = 12）、晚期非运动障碍（ADV, n = 13）和晚期运动障碍（DYS, n = 11）。参与者完成了一周的活动记录仪监测，随后分别在早上和晚上进行两次静息状态脑电图记录。使用线性和线性混合效应模型分析Wake-theta活动，调整年龄/性别，加上基于簇的非参数统计，然后与临床变量相关，并通过部分相关性分析活动图衍生的睡眠指标。与对照组相比，运动障碍患者表现出明显的睡眠中断，早晨θ波升高（p = 0.006, d = 1.54）和EPD升高（p = 0.03, d = 0.85），与对照组相比，每日θ波积累显著减少（p = 0.009, d = 1.57）。EPD组和ADV组保持了日增。在运动障碍患者中，较高的左旋多巴当量日剂量（LEDD）与较高的早晨θ (ρ = 0.70, p = 0.023, pFDR=0.046)和较小的日θ升高（ρ = -0.77, p = 0.009, pFDR=0.046）相关。θ波和活动图衍生的睡眠指标之间的关系较弱，各组之间也不一致。这些发现表明，运动障碍是与清醒相关的θ波稳态受损的特定特征，这激发了结合多导睡眠图和清醒脑电图的纵向研究。
{"title":"Altered wakeful theta activity characterizes levodopa-induced dyskinesia in Parkinson's disease.","authors":"Luigi Fiorillo,Giovanni Lombardi,Nicolo La Porta,Lisa Arnaud,Marco Veneruso,Anna Castelnovo,Ilaria Bertaina,Claudio Staedler,Alain Kaelin-Lang,Salvatore Galati","doi":"10.1038/s41531-026-01320-z","DOIUrl":"https://doi.org/10.1038/s41531-026-01320-z","url":null,"abstract":"Slow-wave activity during sleep facilitates synaptic downscaling, while theta activity during wakefulness reflects synaptic upscaling, and both processes may be altered in levodopa-induced dyskinesia (LID) in Parkinson's disease (PD). We compared actigraphy and high-density EEG in 12 healthy volunteers and three PD cohorts: early stage (EPD, n = 12), advanced non-dyskinetic (ADV, n = 13), and advanced dyskinetic (DYS, n = 11). Participants completed one week of actigraphy monitoring, followed by two resting-state EEG recordings conducted separately in the morning and evening. Wake-theta activity was analyzed using both linear and linear mixed-effects models, adjusted for age/sex, plus cluster-based non-parametric statistics, then related to clinical variables, and actigraphy-derived sleep metrics via partial correlations. Dyskinetic patients showed marked sleep disruption, elevated morning theta compared with controls (p = 0.006, d = 1.54) and EPD (p = 0.03, d = 0.85), along with a significantly reduced diurnal theta build-up compared with controls (p = 0.009, d = 1.57). EPD and ADV groups showed preserved diurnal increases. In dyskinetic patients, a higher levodopa equivalent daily dose (LEDD) was correlated with higher morning theta (ρ = 0.70, p = 0.023, pFDR=0.046) and smaller diurnal theta increases (ρ = -0.77, p = 0.009, pFDR=0.046). Relationships between theta and actigraphy-derived sleep metrics were weaker and inconsistent across groups. These findings suggest a dyskinesia-specific profile of impaired wake-related theta homeostasis, motivating longitudinal studies combining polysomnography and waking EEG.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"13 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Non-motor symptoms (NMS) in Parkinson's Disease (PD) encompass a variety of symptoms which may differ in terms of presentation and severity according to gender. However, literature evidences are often conflicting due to the use of different instruments. The Non-Motor Symptoms Scale (NMSS) is a validated tool widely used to holistically assess NMSs in PD. We aimed to summarize available data on gender differences in NMS severity in PD using the NMSS. A literature review has been performed in the PubMed and Scopus databases up to 1st February 2025. A random effect model was used to report pooled effects. Nine full text articles have been included in the analysis, pooling the data of 4352 PD patients [N = 2453 (58%) men]. Women showed higher symptoms severity in mood/cognition whereas higher severity in the sexual domain was found in men. These findings highlight the need for a specific gender-related approach in PD.
{"title":"Sex differences in the severity of non-motor symptoms in Parkinson's disease: a systematic review and meta-analysis.","authors":"Calogero Edoardo Cicero,Claudio Terravecchia,Lavinia Lucia Pettinato,Silvia Tabbì,Giulia Donzuso,Donatella Contrafatto,Giovanni Mostile,Mario Zappia,Alessandra Nicoletti","doi":"10.1038/s41531-026-01323-w","DOIUrl":"https://doi.org/10.1038/s41531-026-01323-w","url":null,"abstract":"Non-motor symptoms (NMS) in Parkinson's Disease (PD) encompass a variety of symptoms which may differ in terms of presentation and severity according to gender. However, literature evidences are often conflicting due to the use of different instruments. The Non-Motor Symptoms Scale (NMSS) is a validated tool widely used to holistically assess NMSs in PD. We aimed to summarize available data on gender differences in NMS severity in PD using the NMSS. A literature review has been performed in the PubMed and Scopus databases up to 1st February 2025. A random effect model was used to report pooled effects. Nine full text articles have been included in the analysis, pooling the data of 4352 PD patients [N = 2453 (58%) men]. Women showed higher symptoms severity in mood/cognition whereas higher severity in the sexual domain was found in men. These findings highlight the need for a specific gender-related approach in PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"31 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-18DOI: 10.1038/s41531-026-01325-8
Xingzhi Guo,Peiyao Wei,Wenzhi Shi,Rong Zhou,Rui Li
Osteokines, primarily secreted by bone, have been implicated in brain function and Parkinson's disease (PD) pathogenesis, yet their circulating levels in PD and potential role in the relationship between bone mineral density (BMD) and PD remain unclear. 80 participants (40 PD patients and 40 controls) were enrolled to measure plasma levels of eight osteokines (GPNMB, OPN, SOST, DKK1, RANKL, FGF23, BMP2, and BMP4) and assess their associations with clinical scales. Mendelian randomization (MR), SMR, and colocalization analyses were performed to evaluate causal relationships between osteokines and PD. Restricted cubic spline (RCS) models were applied to explore nonlinear associations between BMD, osteokines, and PD. GPNMB levels were significantly elevated in PD patients and showed a linear association with PD risk. Higher GPNMB levels were associated with worse cognitive performance and clinical severity, while higher SOST levels correlated with milder symptoms. Genetic analyses consistently supported a causal and colocalized relationship between GPNMB and PD. Total coxa BMD and T-score were lower in PD, but not statistically significant. RCS analysis revealed an "n-shaped" association between total coxa T-score and both PD and GPNMB levels. Overall, GPNMB appears causally linked to PD risk and may mediate the bone-brain axis connecting BMD with PD susceptibility.
{"title":"Integrative clinical and genomic analyses reveal a causal role of GPNMB in the bone-brain axis of Parkinson's disease.","authors":"Xingzhi Guo,Peiyao Wei,Wenzhi Shi,Rong Zhou,Rui Li","doi":"10.1038/s41531-026-01325-8","DOIUrl":"https://doi.org/10.1038/s41531-026-01325-8","url":null,"abstract":"Osteokines, primarily secreted by bone, have been implicated in brain function and Parkinson's disease (PD) pathogenesis, yet their circulating levels in PD and potential role in the relationship between bone mineral density (BMD) and PD remain unclear. 80 participants (40 PD patients and 40 controls) were enrolled to measure plasma levels of eight osteokines (GPNMB, OPN, SOST, DKK1, RANKL, FGF23, BMP2, and BMP4) and assess their associations with clinical scales. Mendelian randomization (MR), SMR, and colocalization analyses were performed to evaluate causal relationships between osteokines and PD. Restricted cubic spline (RCS) models were applied to explore nonlinear associations between BMD, osteokines, and PD. GPNMB levels were significantly elevated in PD patients and showed a linear association with PD risk. Higher GPNMB levels were associated with worse cognitive performance and clinical severity, while higher SOST levels correlated with milder symptoms. Genetic analyses consistently supported a causal and colocalized relationship between GPNMB and PD. Total coxa BMD and T-score were lower in PD, but not statistically significant. RCS analysis revealed an \"n-shaped\" association between total coxa T-score and both PD and GPNMB levels. Overall, GPNMB appears causally linked to PD risk and may mediate the bone-brain axis connecting BMD with PD susceptibility.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"231 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-17DOI: 10.1038/s41531-026-01318-7
Yan Teng, Zhihao Liu, Fan Wei, Qin Tang, Manjun Li, Xingmin Chen, Jin Yi, Shu He, Jianli Xu, Yuqing Hang, Kaifang Wang, Yanzhuo Liu, Haisong Jiang, Weidong Le, Lu Yang
Dopaminergic (DA) neurons are highly susceptible to endoplasmic reticulum (ER) burden and redox imbalance, which drive their degeneration and contribute to Parkinson’s disease (PD) pathogenesis. Previous work established METTL14-mediated N6-methyladenosine (m6A) modification as critical for dopaminergic (DA) neuron survival. Here, we delineate the underlying mechanism by which m6A dysregulation triggers neurodegeneration through the post-transcriptional modulation of key target genes. Using Mettl14 conditional knockout mice, we identified the ER calcium channel ATP2A3—a key calcium homeostasis regulator and known PD biomarker—as a major target of METTL14. METTL14 deficiency significantly reduced ATP2A3 expression, thereby exacerbating ER homeostasis and oxidative stress, ultimately leading to DA neuronal death. Restoring METTL14 in vivo alleviates motor deficits and neurodegeneration. Our findings reveal that m6A-mediated regulation of ATP2A3 bridges RNA epigenetic dysregulation to PD pathogenesis, highlighting this axis as a potential therapeutic target in this disease.
{"title":"Loss of METTL14 in dopaminergic neurons disrupts ER homeostasis via m6A-dependent regulation of Atp2a3 mRNA: Implications for Parkinson’s Disease","authors":"Yan Teng, Zhihao Liu, Fan Wei, Qin Tang, Manjun Li, Xingmin Chen, Jin Yi, Shu He, Jianli Xu, Yuqing Hang, Kaifang Wang, Yanzhuo Liu, Haisong Jiang, Weidong Le, Lu Yang","doi":"10.1038/s41531-026-01318-7","DOIUrl":"https://doi.org/10.1038/s41531-026-01318-7","url":null,"abstract":"Dopaminergic (DA) neurons are highly susceptible to endoplasmic reticulum (ER) burden and redox imbalance, which drive their degeneration and contribute to Parkinson’s disease (PD) pathogenesis. Previous work established METTL14-mediated N6-methyladenosine (m6A) modification as critical for dopaminergic (DA) neuron survival. Here, we delineate the underlying mechanism by which m6A dysregulation triggers neurodegeneration through the post-transcriptional modulation of key target genes. Using Mettl14 conditional knockout mice, we identified the ER calcium channel ATP2A3—a key calcium homeostasis regulator and known PD biomarker—as a major target of METTL14. METTL14 deficiency significantly reduced ATP2A3 expression, thereby exacerbating ER homeostasis and oxidative stress, ultimately leading to DA neuronal death. Restoring METTL14 in vivo alleviates motor deficits and neurodegeneration. Our findings reveal that m6A-mediated regulation of ATP2A3 bridges RNA epigenetic dysregulation to PD pathogenesis, highlighting this axis as a potential therapeutic target in this disease.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"52 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-15DOI: 10.1038/s41531-026-01312-z
Shawn D'Souza,Aashish Batheja,Jeffrey Chen,Harsh P Shah,Vikram Seshadri,Nina Opem,Omar Al-Dulaimi,Jamie Toms,Pierre D'Haese,Benoit M Dawant,Rui Li,Paul Koch,Paul Larson,Kathryn L Holloway
Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is an effective treatment for medication‑refractory Parkinson's disease (PD), though outcomes vary widely. The influence of lead location relative to the GPi therapeutic sweetspot has not previously been examined within a multivariable regression framework. This study evaluated the predictive utility of volume-of-tissue-activated (VTA)-sweetspot overlap on postoperative UPDRS‑III outcomes in the CSP #468 cohort receiving bilateral GPi‑DBS, alongside demographic/clinical predictors, using two independently derived sweetspot models. CSP #468 was a multicenter randomized clinical trial with blinded 6‑month outcomes and robust collection of associated features of PD. A prior publication generated a cross validated 6‑month GPi-sweetspot from this dataset. An independent single‑surgeon cohort was used to construct a separate sweetspot uninfluenced by CSP outcomes. Multivariable modeling was completed using backward‑selection linear regression with Bonferroni correction. Models were checked for assumptions, data leakage, and overfitting. Each sweetspot-multivariable model's ability to predict outcomes in the opposite cohort was assessed. Both sweetspots localized to the primary motor GPi. The independent sweetspot multivariable model included VTA‑sweetspot overlap and levodopa response (R²Adj = 0.19) and remained robust under leave-one-out cross validation. The CSP sweetspot multivariable model also predicted outcomes in the independent cohort (p = 0.004), demonstrating meaningful external validity.
{"title":"Predictors of motor outcome with pallidal stimulation for Parkinson's disease from the CSP468 cohort.","authors":"Shawn D'Souza,Aashish Batheja,Jeffrey Chen,Harsh P Shah,Vikram Seshadri,Nina Opem,Omar Al-Dulaimi,Jamie Toms,Pierre D'Haese,Benoit M Dawant,Rui Li,Paul Koch,Paul Larson,Kathryn L Holloway","doi":"10.1038/s41531-026-01312-z","DOIUrl":"https://doi.org/10.1038/s41531-026-01312-z","url":null,"abstract":"Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is an effective treatment for medication‑refractory Parkinson's disease (PD), though outcomes vary widely. The influence of lead location relative to the GPi therapeutic sweetspot has not previously been examined within a multivariable regression framework. This study evaluated the predictive utility of volume-of-tissue-activated (VTA)-sweetspot overlap on postoperative UPDRS‑III outcomes in the CSP #468 cohort receiving bilateral GPi‑DBS, alongside demographic/clinical predictors, using two independently derived sweetspot models. CSP #468 was a multicenter randomized clinical trial with blinded 6‑month outcomes and robust collection of associated features of PD. A prior publication generated a cross validated 6‑month GPi-sweetspot from this dataset. An independent single‑surgeon cohort was used to construct a separate sweetspot uninfluenced by CSP outcomes. Multivariable modeling was completed using backward‑selection linear regression with Bonferroni correction. Models were checked for assumptions, data leakage, and overfitting. Each sweetspot-multivariable model's ability to predict outcomes in the opposite cohort was assessed. Both sweetspots localized to the primary motor GPi. The independent sweetspot multivariable model included VTA‑sweetspot overlap and levodopa response (R²Adj = 0.19) and remained robust under leave-one-out cross validation. The CSP sweetspot multivariable model also predicted outcomes in the independent cohort (p = 0.004), demonstrating meaningful external validity.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"308 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147454594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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