Freezing of gait (FOG) is a common and debilitating symptom in Parkinson’s disease (PD) that requires early detection for timely intervention. In this study, we developed an explainable SHAP-XGBoost model integrating clinical assessments and dopamine transporter (DAT) imaging to identify L-dopa responsive FOG. The internal cohort included 516 participants, with the model trained on a subset and validated on both internal and external test sets (Parkinson’s Progression Markers Initiative, PPMI). The model demonstrated strong predictive performance, achieving AUCs of 0.90, 0.89, and 0.75 on the internal training, internal test, and external PPMI sets, respectively. SHAP analysis revealed that Hoehn & Yahr (H&Y) staging and DAT availability in the contralateral anterior putamen were the most influential features. Threshold analyses identified key cutoffs: around 5 years for disease duration, 64 years for age, and 35.7 for MDS-UPDRS Part III score. Notably, among patients with milder motor symptoms (H&Y ≤ 2.5), a contralateral anterior putamen SBR below 1.25 was associated with a higher FOG risk compared to those with H&Y > 2.5. In summary, our explainable model effectively detects L-dopa responsive FOG by leveraging clinical and DAT imaging data, emphasizing the contralateral anterior putamen as a critical region in FOG pathophysiology.
{"title":"Explainable SHAP- XGBoost with DAT and clinical data for freezing of gait detection in Parkinson disease","authors":"Shuxian Jin, Yumeng Qi, Yayun Yan, Wenhua Ren, Xue Wang, Ying Chang","doi":"10.1038/s41531-025-01254-y","DOIUrl":"https://doi.org/10.1038/s41531-025-01254-y","url":null,"abstract":"Freezing of gait (FOG) is a common and debilitating symptom in Parkinson’s disease (PD) that requires early detection for timely intervention. In this study, we developed an explainable SHAP-XGBoost model integrating clinical assessments and dopamine transporter (DAT) imaging to identify L-dopa responsive FOG. The internal cohort included 516 participants, with the model trained on a subset and validated on both internal and external test sets (Parkinson’s Progression Markers Initiative, PPMI). The model demonstrated strong predictive performance, achieving AUCs of 0.90, 0.89, and 0.75 on the internal training, internal test, and external PPMI sets, respectively. SHAP analysis revealed that Hoehn & Yahr (H&Y) staging and DAT availability in the contralateral anterior putamen were the most influential features. Threshold analyses identified key cutoffs: around 5 years for disease duration, 64 years for age, and 35.7 for MDS-UPDRS Part III score. Notably, among patients with milder motor symptoms (H&Y ≤ 2.5), a contralateral anterior putamen SBR below 1.25 was associated with a higher FOG risk compared to those with H&Y > 2.5. In summary, our explainable model effectively detects L-dopa responsive FOG by leveraging clinical and DAT imaging data, emphasizing the contralateral anterior putamen as a critical region in FOG pathophysiology.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"20 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908421","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 : 2026-01-08DOI: 10.1038/s41531-025-01253-z
Seohee Choi, Ryul Kim, Soonwook Kwon, Jin-Sun Jun, Kyeongho Byun, Nyeonju Kang, Kiwon Park, Jee-Young Lee, Beomseok Jeon
Although muscle mass loss is an emerging public health concern, its prevalence, associated factors, and clinical significance in Parkinson’s disease (PD) remain unclear. This matched case-control study aimed to investigate the prevalence of low muscle mass (LMM) and to examine its association with orthostatic hypotension (OH) and orthostatic symptoms in 409 PD patients with Hoehn and Yahr stage ≤3, compared with 2045 age-, sex-, and height-matched controls from a nationwide database. OH was defined according to the international consensus. LMM was more prevalent in PD patients than in controls, particularly among men and those aged ≥70 years. Among PD patients, the prevalence of OH did not differ between those with and without LMM. Although LMM was linked to greater orthostatic blood pressure reductions at 30 s after standing, there were no differences in the frequency or severity of orthostatic symptoms according to LMM status. These findings suggest that although mild to moderate PD is associated with an increased risk of LMM, its impact on OH and related symptoms appears to be modest. Further longitudinal studies are needed to clarify the clinical implications of LMM in PD.
{"title":"Prevalence of low muscle mass and its association with orthostatic hypotension and related symptoms in Parkinson’s disease","authors":"Seohee Choi, Ryul Kim, Soonwook Kwon, Jin-Sun Jun, Kyeongho Byun, Nyeonju Kang, Kiwon Park, Jee-Young Lee, Beomseok Jeon","doi":"10.1038/s41531-025-01253-z","DOIUrl":"https://doi.org/10.1038/s41531-025-01253-z","url":null,"abstract":"Although muscle mass loss is an emerging public health concern, its prevalence, associated factors, and clinical significance in Parkinson’s disease (PD) remain unclear. This matched case-control study aimed to investigate the prevalence of low muscle mass (LMM) and to examine its association with orthostatic hypotension (OH) and orthostatic symptoms in 409 PD patients with Hoehn and Yahr stage ≤3, compared with 2045 age-, sex-, and height-matched controls from a nationwide database. OH was defined according to the international consensus. LMM was more prevalent in PD patients than in controls, particularly among men and those aged ≥70 years. Among PD patients, the prevalence of OH did not differ between those with and without LMM. Although LMM was linked to greater orthostatic blood pressure reductions at 30 s after standing, there were no differences in the frequency or severity of orthostatic symptoms according to LMM status. These findings suggest that although mild to moderate PD is associated with an increased risk of LMM, its impact on OH and related symptoms appears to be modest. Further longitudinal studies are needed to clarify the clinical implications of LMM in PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"29 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145919909","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 : 2026-01-07DOI: 10.1038/s41531-025-01248-w
Alexandros Vamvakas, Tim Van Balkom, Guido Van Wingen, Jan Booij, Daniel Weintraub, Henk W. Berendse, Odile A. van den Heuvel, Chris Vriend
{"title":"Prediction of impulse control disorders in Parkinson’s disease through a longitudinal machine learning study","authors":"Alexandros Vamvakas, Tim Van Balkom, Guido Van Wingen, Jan Booij, Daniel Weintraub, Henk W. Berendse, Odile A. van den Heuvel, Chris Vriend","doi":"10.1038/s41531-025-01248-w","DOIUrl":"https://doi.org/10.1038/s41531-025-01248-w","url":null,"abstract":"","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"21 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908212","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 : 2026-01-03DOI: 10.1038/s41531-025-01241-3
Delaram Safarpour,Meredith Spindler,Travis H Turner,Neepa Patel,Okeanis Vaou,Laura Y Cabrera,Christopher Tolleson,Philip W Tipton,Camila Aquino,Todd M Herrington,Christos Sidiropoulos,Nathan Hantke,Mitesh Lotia,Svjetlana Miocinovic,Vibhash D Sharma,Kelly A Mills,Kathryn Wyman-Chick,Camilla Kilbane,Corneliu Luca,Leonardo Almeida,Joshua Rosenow,Hwai Yin Ooi,Zoltan Mari,Lan Luo,Renato P Munhoz,Sol De Jesus,Harini Sarva,Monica Arena,Gonzalo Revuelta,Kelvin L Chou,Alfonso Fasano,Mustafa S Siddiqui,Joohi Jimenez-Shahed,
Deep brain Stimulation (DBS) surgery effectively alleviates troublesome motor symptoms of Parkinson's disease (PD) such as tremor, rigidity, bradykinesia, motor fluctuations and dyskinesia. It also improves some non-motor symptoms and quality of life. DBS should thus be considered when these symptoms interfere with quality of life despite optimal medical treatment. While DBS benefits are clear, access by eligible patients remains low. Patients and their caregivers should be educated regarding DBS surgery and referrals for surgical evaluation should occur alongside ongoing medication adjustments-particularly when those changes fail to adequately control motor symptoms-regardless of the stage of disease progression. This international panel of DBS experts developed consensus recommendations with the goals of promoting timely referrals and approvals, while reducing misconceptions and stigma associated with brain surgery. These recommendations provide a framework for referring providers, ensuring that appropriate candidates receive timely access to this beneficial treatment.
{"title":"Consensus expert recommendations for referral of Parkinson's disease patients for deep brain stimulation surgery.","authors":"Delaram Safarpour,Meredith Spindler,Travis H Turner,Neepa Patel,Okeanis Vaou,Laura Y Cabrera,Christopher Tolleson,Philip W Tipton,Camila Aquino,Todd M Herrington,Christos Sidiropoulos,Nathan Hantke,Mitesh Lotia,Svjetlana Miocinovic,Vibhash D Sharma,Kelly A Mills,Kathryn Wyman-Chick,Camilla Kilbane,Corneliu Luca,Leonardo Almeida,Joshua Rosenow,Hwai Yin Ooi,Zoltan Mari,Lan Luo,Renato P Munhoz,Sol De Jesus,Harini Sarva,Monica Arena,Gonzalo Revuelta,Kelvin L Chou,Alfonso Fasano,Mustafa S Siddiqui,Joohi Jimenez-Shahed, ","doi":"10.1038/s41531-025-01241-3","DOIUrl":"https://doi.org/10.1038/s41531-025-01241-3","url":null,"abstract":"Deep brain Stimulation (DBS) surgery effectively alleviates troublesome motor symptoms of Parkinson's disease (PD) such as tremor, rigidity, bradykinesia, motor fluctuations and dyskinesia. It also improves some non-motor symptoms and quality of life. DBS should thus be considered when these symptoms interfere with quality of life despite optimal medical treatment. While DBS benefits are clear, access by eligible patients remains low. Patients and their caregivers should be educated regarding DBS surgery and referrals for surgical evaluation should occur alongside ongoing medication adjustments-particularly when those changes fail to adequately control motor symptoms-regardless of the stage of disease progression. This international panel of DBS experts developed consensus recommendations with the goals of promoting timely referrals and approvals, while reducing misconceptions and stigma associated with brain surgery. These recommendations provide a framework for referring providers, ensuring that appropriate candidates receive timely access to this beneficial treatment.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"26 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893979","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 : 2025-12-26DOI: 10.1038/s41531-025-01227-1
Lydia Chougar, Christina Tremblay, Aline Delva, Marie Filiatrault, Andrew Vo, Justine Y Hansen, Asa Farahani, Bratislav Misic, Parsa Khalafi, Charles-Etienne Castonguay, Guy Rouleau, Jean-Christophe Corvol, Marie Vidailhet, Bertrand Degos, Nadya Pyatigorskaya, Christine Payan, David Grabli, Stéphane Lehéricy, Alain Dagher, Shady Rahayel
Oligodendroglial pathology is a hallmark of multiple system atrophy (MSA), yet it remains unclear whether MRI-detected atrophy reflects underlying biological mechanisms. This study investigated whether regional atrophy aligns with gene expression and neurotransmitter systems. We recruited 65 MSA patients and derived brain atrophy measures from T1-weighted MRIs. Using postmortem data from the Allen Human Brain Atlas, partial least squares (PLS) regression identified gene expression components associated with brain atrophy. Gene enrichment analyses explored biological processes, and annotation mapping identified neurotransmitter systems matching atrophy patterns. Specificity was tested against 57 patients with Parkinson's disease. Atrophy primarily affected the cerebellar white matter, pons, putamen, olive, and substantia nigra. PLS revealed two latent variables explaining 27.5% of the covariance. Atrophic regions overexpressed genes linked to mitochondrial function and oligodendrocytes, showing patterns distinct from Parkinson's disease. These regions also exhibited lower serotonin and GABA levels, and higher acetylcholine and noradrenaline receptor densities. MRI-derived atrophy in MSA is biologically grounded and may inform future therapeutic studies.
{"title":"MRI-derived atrophy in multiple system atrophy aligns with mitochondrial and glial gene expression patterns.","authors":"Lydia Chougar, Christina Tremblay, Aline Delva, Marie Filiatrault, Andrew Vo, Justine Y Hansen, Asa Farahani, Bratislav Misic, Parsa Khalafi, Charles-Etienne Castonguay, Guy Rouleau, Jean-Christophe Corvol, Marie Vidailhet, Bertrand Degos, Nadya Pyatigorskaya, Christine Payan, David Grabli, Stéphane Lehéricy, Alain Dagher, Shady Rahayel","doi":"10.1038/s41531-025-01227-1","DOIUrl":"10.1038/s41531-025-01227-1","url":null,"abstract":"<p><p>Oligodendroglial pathology is a hallmark of multiple system atrophy (MSA), yet it remains unclear whether MRI-detected atrophy reflects underlying biological mechanisms. This study investigated whether regional atrophy aligns with gene expression and neurotransmitter systems. We recruited 65 MSA patients and derived brain atrophy measures from T1-weighted MRIs. Using postmortem data from the Allen Human Brain Atlas, partial least squares (PLS) regression identified gene expression components associated with brain atrophy. Gene enrichment analyses explored biological processes, and annotation mapping identified neurotransmitter systems matching atrophy patterns. Specificity was tested against 57 patients with Parkinson's disease. Atrophy primarily affected the cerebellar white matter, pons, putamen, olive, and substantia nigra. PLS revealed two latent variables explaining 27.5% of the covariance. Atrophic regions overexpressed genes linked to mitochondrial function and oligodendrocytes, showing patterns distinct from Parkinson's disease. These regions also exhibited lower serotonin and GABA levels, and higher acetylcholine and noradrenaline receptor densities. MRI-derived atrophy in MSA is biologically grounded and may inform future therapeutic studies.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":" ","pages":"16"},"PeriodicalIF":8.2,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12800306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-26DOI: 10.1038/s41531-025-01235-1
Laura Pérez-Carasol, Saul Martinez-Horta, Andrea Horta-Barba, Helena Bejr-Kasem, Juan Marín-Lahoz, Jesús Perez-Perez, Ignacio Aracil-Bolaños, Javier Pagonabarraga, Jaime Kulisevsky
Minor hallucinations are frequent and clinically relevant in Parkinson's disease (PD), often preceding cognitive decline and more complex psychotic symptoms. These subtle perceptual anomalies are thought to result from an imbalance between degraded sensory input and dysregulated higher-order cognitive processes. Because visual categorization relies on the integration of perceptual, semantic, and evaluative operations, it provides a powerful framework to investigate the neural mechanisms underlying hallucination vulnerability. Ninety-three non-demented PD patients (mean age = 68.4 years, 41% female) performed a visual categorization task with faces, objects, and face-like stimuli during 19-channel electroencephalography. Patients were classified by hallucination (present/absent) and cognitive status (normal/MCI), yielding four subgroups. Hallucinating patients showed reduced accuracy for faces and objects despite preserved reaction times, with the greatest impairment in those with both hallucinations and cognitive deficits. Event-related potentials revealed reduced N170, enhanced N300, and diminished P600 amplitudes in hallucinating patients, particularly with MCI. Source estimation indicated reduced occipito-temporal activation (N170), premature engagement of default mode and hippocampal regions (N300), and impaired posterior control signals (P600). These findings delineate a progressive disruption of visual-semantic integration in PD hallucinations, reflecting the convergence of impaired sensory encoding, semantic overactivation, and weakened top-down cognitive control, a mechanistic signature of hallucination vulnerability in PD.
{"title":"Disrupted visual-to-semantic dynamics promote visual hallucinations in Parkinson's disease.","authors":"Laura Pérez-Carasol, Saul Martinez-Horta, Andrea Horta-Barba, Helena Bejr-Kasem, Juan Marín-Lahoz, Jesús Perez-Perez, Ignacio Aracil-Bolaños, Javier Pagonabarraga, Jaime Kulisevsky","doi":"10.1038/s41531-025-01235-1","DOIUrl":"10.1038/s41531-025-01235-1","url":null,"abstract":"<p><p>Minor hallucinations are frequent and clinically relevant in Parkinson's disease (PD), often preceding cognitive decline and more complex psychotic symptoms. These subtle perceptual anomalies are thought to result from an imbalance between degraded sensory input and dysregulated higher-order cognitive processes. Because visual categorization relies on the integration of perceptual, semantic, and evaluative operations, it provides a powerful framework to investigate the neural mechanisms underlying hallucination vulnerability. Ninety-three non-demented PD patients (mean age = 68.4 years, 41% female) performed a visual categorization task with faces, objects, and face-like stimuli during 19-channel electroencephalography. Patients were classified by hallucination (present/absent) and cognitive status (normal/MCI), yielding four subgroups. Hallucinating patients showed reduced accuracy for faces and objects despite preserved reaction times, with the greatest impairment in those with both hallucinations and cognitive deficits. Event-related potentials revealed reduced N170, enhanced N300, and diminished P600 amplitudes in hallucinating patients, particularly with MCI. Source estimation indicated reduced occipito-temporal activation (N170), premature engagement of default mode and hippocampal regions (N300), and impaired posterior control signals (P600). These findings delineate a progressive disruption of visual-semantic integration in PD hallucinations, reflecting the convergence of impaired sensory encoding, semantic overactivation, and weakened top-down cognitive control, a mechanistic signature of hallucination vulnerability in PD.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":" ","pages":"24"},"PeriodicalIF":8.2,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12827262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-26DOI: 10.1038/s41531-025-01220-8
Haneul Kim, Forouzan Rafie, Amir H Nekouei, Meghan E Kazanski, Madeleine E Hackney
The present study is an exploratory secondary analysis examining associations between Parkinson's disease (PD) characteristics and compliance and satisfaction with exercise programs as part of ongoing clinical trial research. 36 participants with PD engaged in either adapted tango (AT; n = 20) or supervised walking (WALK; n = 16) classes for 16 months. This trial was registered at ClinicalTrials.gov (NCT04122690) on October 10, 2019. PD-related metrics, dyskinesia frequency and duration, OFF-time, freezing of gait (FOG), disease duration, Hoehn-Yahr stage, and motor and cognitive function were collected. Linear regression models assessed associations with attendance and satisfaction. Attendance varied widely (range: 1-76; mean ± SD: 39.1 ± 26.0 sessions), with overall satisfaction favorable (4.0 ± 0.8 on a 5-point scale). Dyskinesia metrics showed negative correlations with compliance: percentage of dyskinesia (β = -0.381, R2 = 0.145, p = 0.055) and total dyskinesia duration (β = -0.377, R2 = 0.142, p = 0.058). Compliance positively predicted satisfaction (β = 0.378, R2 = 0.143, p = 0.063). Montreal Cognitive Assessment (MoCA) was the strongest satisfaction predictor (β = 0.396, R2 = 0.157, p = 0.050), followed by the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores (β = -0.343, R2 = 0.118, p = 0.093). FOG had no significant effect on attendance or satisfaction. Findings indicate dyskinesia limits compliance, while cognitive function enhances satisfaction, emphasizing the need for tailored exercise.
本研究是一项探索性的二次分析，旨在研究帕金森病（PD）特征与运动计划的依从性和满意度之间的关系，作为正在进行的临床试验研究的一部分。36名PD患者参加了16个月的改编探戈（AT, n = 20）或监督步行（WALK, n = 16）课程。该试验于2019年10月10日在ClinicalTrials.gov （NCT04122690）注册。收集pd相关指标、运动障碍频率和持续时间、off时间、步态冻结（FOG）、疾病持续时间、Hoehn-Yahr分期、运动和认知功能。线性回归模型评估出勤率和满意度之间的关系。出席率差异很大（范围：1-76；平均值±标准差：39.1±26.0次），总体满意度较好（5分制4.0±0.8）。运动障碍指标与依从性呈负相关：运动障碍百分比（β = -0.381, R2 = 0.145, p = 0.055）和运动障碍总持续时间（β = -0.377, R2 = 0.142, p = 0.058）。依从性正向预测满意度（β = 0.378, R2 = 0.143, p = 0.063）。蒙特利尔认知评估（MoCA）是最强的满意度预测因子（β = 0.396, R2 = 0.157, p = 0.050），其次是运动障碍学会赞助的统一帕金森病评定量表（MDS-UPDRS）评分（β = -0.343, R2 = 0.118, p = 0.093）。FOG对出勤率和满意度没有显著影响。研究结果表明，运动障碍限制了依从性，而认知功能增强了满意度，强调了量身定制运动的必要性。
{"title":"Compliance and Satisfaction for 16 months of Adapted Tango vs. Supervised Walking for People with Parkinson's.","authors":"Haneul Kim, Forouzan Rafie, Amir H Nekouei, Meghan E Kazanski, Madeleine E Hackney","doi":"10.1038/s41531-025-01220-8","DOIUrl":"10.1038/s41531-025-01220-8","url":null,"abstract":"<p><p>The present study is an exploratory secondary analysis examining associations between Parkinson's disease (PD) characteristics and compliance and satisfaction with exercise programs as part of ongoing clinical trial research. 36 participants with PD engaged in either adapted tango (AT; n = 20) or supervised walking (WALK; n = 16) classes for 16 months. This trial was registered at ClinicalTrials.gov (NCT04122690) on October 10, 2019. PD-related metrics, dyskinesia frequency and duration, OFF-time, freezing of gait (FOG), disease duration, Hoehn-Yahr stage, and motor and cognitive function were collected. Linear regression models assessed associations with attendance and satisfaction. Attendance varied widely (range: 1-76; mean ± SD: 39.1 ± 26.0 sessions), with overall satisfaction favorable (4.0 ± 0.8 on a 5-point scale). Dyskinesia metrics showed negative correlations with compliance: percentage of dyskinesia (β = -0.381, R<sup>2</sup> = 0.145, p = 0.055) and total dyskinesia duration (β = -0.377, R<sup>2</sup> = 0.142, p = 0.058). Compliance positively predicted satisfaction (β = 0.378, R<sup>2</sup> = 0.143, p = 0.063). Montreal Cognitive Assessment (MoCA) was the strongest satisfaction predictor (β = 0.396, R<sup>2</sup> = 0.157, p = 0.050), followed by the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores (β = -0.343, R<sup>2</sup> = 0.118, p = 0.093). FOG had no significant effect on attendance or satisfaction. Findings indicate dyskinesia limits compliance, while cognitive function enhances satisfaction, emphasizing the need for tailored exercise.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":" ","pages":"13"},"PeriodicalIF":8.2,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12796157/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-23DOI: 10.1038/s41531-025-01207-5
Aliya C M Warden,Craig J McAllister,Damian Cruse,Ben Wright,Hayley J MacDonald
Dopamine agonists in Parkinson's disease increase the risk of impulse control disorders, yet the underlying neural mechanisms remain unclear. This study aimed to identify objective neurophysiological markers of impaired impulse control in Parkinson's linking to impulsivity problems. Nineteen people with Parkinson's (PwPD) on ropinirole and 18 healthy older adults performed an impulse control task requiring response withholding and inhibition. Transcranial magnetic stimulation was delivered, with corticomotor excitability (CME) and muscle bursts measured via electromyography. During response withholding, PwPD showed early relative increases in CME and more frequent dysfunctional muscle bursts, leading to more variable responses. During response inhibition, PwPD exhibited reduced CME suppression and increased muscle bursting, leading to delayed inhibition which was associated with problematic impulsive behaviours. The neurophysiological measures were associated with more advanced disease and may serve as early, objective markers of impulse control dysfunction, with future work required to assess their utility in predicting impulsive disorders.
{"title":"Muscle bursting and corticomotor excitability mark impaired impulse control in Parkinson's disease.","authors":"Aliya C M Warden,Craig J McAllister,Damian Cruse,Ben Wright,Hayley J MacDonald","doi":"10.1038/s41531-025-01207-5","DOIUrl":"https://doi.org/10.1038/s41531-025-01207-5","url":null,"abstract":"Dopamine agonists in Parkinson's disease increase the risk of impulse control disorders, yet the underlying neural mechanisms remain unclear. This study aimed to identify objective neurophysiological markers of impaired impulse control in Parkinson's linking to impulsivity problems. Nineteen people with Parkinson's (PwPD) on ropinirole and 18 healthy older adults performed an impulse control task requiring response withholding and inhibition. Transcranial magnetic stimulation was delivered, with corticomotor excitability (CME) and muscle bursts measured via electromyography. During response withholding, PwPD showed early relative increases in CME and more frequent dysfunctional muscle bursts, leading to more variable responses. During response inhibition, PwPD exhibited reduced CME suppression and increased muscle bursting, leading to delayed inhibition which was associated with problematic impulsive behaviours. The neurophysiological measures were associated with more advanced disease and may serve as early, objective markers of impulse control dysfunction, with future work required to assess their utility in predicting impulsive disorders.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145807880","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 : 2025-12-22DOI: 10.1038/s41531-025-01209-3
Juliana I. Choza, Mahek Virani, Nathan C. Kuhn, Marie Adams, Joseph Kochmanski, Alison I. Bernstein
Epigenetic mechanisms mediate interactions between aging, genetics, and environmental factors in sporadic Parkinson’s disease (PD). While multiple studies have explored DNA modifications in PD, few focus on 5-hydroxymethylcytosine (5hmc), which is important in the central nervous system and sensitive to environmental exposures. Existing studies have not differentiated between 5-methylcytosine (5mc) and 5hmc or have analyzed them separately. In this study, we modeled 5mc and 5hmc data simultaneously. We identified 108 cytosines with significant PD-associated shifts between these marks in an enriched neuronal population from PD postmortem parietal cortex, within 83 genes and 34 enhancers associated with 67 genes. These data potentially link epigenetic regulation of genes related to LRRK2 and endolysosomal sorting (RAB32 and AGAP1), and genes involved in neuroinflammation, the inflammasome, and neurodevelopment with early changes in PD and suggest that there are significant shifts between 5mC and 5hmC associated with PD in genes not captured by standard methods.
{"title":"Parkinson’s disease-associated alterations in DNA methylation and hydroxymethylation in human brain","authors":"Juliana I. Choza, Mahek Virani, Nathan C. Kuhn, Marie Adams, Joseph Kochmanski, Alison I. Bernstein","doi":"10.1038/s41531-025-01209-3","DOIUrl":"https://doi.org/10.1038/s41531-025-01209-3","url":null,"abstract":"Epigenetic mechanisms mediate interactions between aging, genetics, and environmental factors in sporadic Parkinson’s disease (PD). While multiple studies have explored DNA modifications in PD, few focus on 5-hydroxymethylcytosine (5hmc), which is important in the central nervous system and sensitive to environmental exposures. Existing studies have not differentiated between 5-methylcytosine (5mc) and 5hmc or have analyzed them separately. In this study, we modeled 5mc and 5hmc data simultaneously. We identified 108 cytosines with significant PD-associated shifts between these marks in an enriched neuronal population from PD postmortem parietal cortex, within 83 genes and 34 enhancers associated with 67 genes. These data potentially link epigenetic regulation of genes related to LRRK2 and endolysosomal sorting (RAB32 and AGAP1), and genes involved in neuroinflammation, the inflammasome, and neurodevelopment with early changes in PD and suggest that there are significant shifts between 5mC and 5hmC associated with PD in genes not captured by standard methods.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"32 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801559","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}
Parkinson’s disease (PD) involves dopaminergic neuron loss and neuroinflammation, with leucine-rich repeat kinase 2 (LRRK2) mutations identified as major genetic risk factors. However, the pathogenic mechanism of the novel LRRK2-P1446L mutation remains unknown. Here, we designed LRRK2-P1446L mutant mice and demonstrated that the novel LRRK2-P1446L mutation drives neurodegeneration through death-associated protein kinase 1 (DAPK1) dysregulation. This mutation downregulates LRRK2 while upregulating DAPK1, which concurrently triggers microglial PI3K/Akt-dependent NF-κB activation (inducing IL-1β/IL-6/TNF-α expression) and neuronal mitochondrial apoptosis (via a Bax/Bcl-2 imbalance). Integrative multiomics revealed suppressed expression of the neuroprotective molecule tuftsin, which negatively correlated with DAPK1 expression and was linked to microbiota alterations. Our work establishes DAPK1 as a pivotal hub mediating neuroinflammation and apoptosis in LRRK2-related PD pathogenesis, and reveals novel associations with the gut-brain axis. These findings support DAPK1 inhibition as a promising therapeutic strategy, while the negative correlation with tuftsin suggests its restoration may be a potential future avenue for intervention.
{"title":"The LRRK2 P1446L mutation triggers dopaminergic neurodegeneration via DAPK1-mediated microglial neuroinflammation and neuronal apoptosis","authors":"Liuyan Ding, Hui Shu, Minshan Chen, Fengchu Liang, Tingting Gan, Xingting Huang, Xiaolei Liang, Kangting Luo, Linfeng Qiu, Weiqing Huang, Xiaoqin Zhu, Xiaoyun Huang, Wenlong Zhang, Pingyi Xu","doi":"10.1038/s41531-025-01234-2","DOIUrl":"https://doi.org/10.1038/s41531-025-01234-2","url":null,"abstract":"Parkinson’s disease (PD) involves dopaminergic neuron loss and neuroinflammation, with leucine-rich repeat kinase 2 (LRRK2) mutations identified as major genetic risk factors. However, the pathogenic mechanism of the novel LRRK2-P1446L mutation remains unknown. Here, we designed LRRK2-P1446L mutant mice and demonstrated that the novel LRRK2-P1446L mutation drives neurodegeneration through death-associated protein kinase 1 (DAPK1) dysregulation. This mutation downregulates LRRK2 while upregulating DAPK1, which concurrently triggers microglial PI3K/Akt-dependent NF-κB activation (inducing IL-1β/IL-6/TNF-α expression) and neuronal mitochondrial apoptosis (via a Bax/Bcl-2 imbalance). Integrative multiomics revealed suppressed expression of the neuroprotective molecule tuftsin, which negatively correlated with DAPK1 expression and was linked to microbiota alterations. Our work establishes DAPK1 as a pivotal hub mediating neuroinflammation and apoptosis in LRRK2-related PD pathogenesis, and reveals novel associations with the gut-brain axis. These findings support DAPK1 inhibition as a promising therapeutic strategy, while the negative correlation with tuftsin suggests its restoration may be a potential future avenue for intervention.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"248 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796447","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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