Pub Date : 2025-12-02DOI: 10.1016/j.parkreldis.2025.108139
Vikram V. Holla , Debjyoti Dhar , Riyanka Kumari , Nitish Kamble , Ravi Yadav , Babylakshmi Muthusamy , Pramod Kumar Pal
Pathogenic variants in TSPOAP1, encoding RIMBP1, cause ultra-rare autosomal recessive dystonia (DYT-TSPOAP1/DYT-22), with only two reports worldwide. Clinical features include upper-segment–predominant dystonia, intellectual disability, eye movement abnormalities, and cerebellar atrophy. We describe two unrelated patients with adolescent-onset generalized dystonia showing cranio-caudal progression due to novel truncating variants in the TSPOAP1 gene.
{"title":"Expanding the genotypic and phenotypic spectrum of DYT-TSPOAP1: First report from India","authors":"Vikram V. Holla , Debjyoti Dhar , Riyanka Kumari , Nitish Kamble , Ravi Yadav , Babylakshmi Muthusamy , Pramod Kumar Pal","doi":"10.1016/j.parkreldis.2025.108139","DOIUrl":"10.1016/j.parkreldis.2025.108139","url":null,"abstract":"<div><div>Pathogenic variants in <em>TSPOAP1</em>, encoding RIMBP1, cause ultra-rare autosomal recessive dystonia (DYT-TSPOAP1/DYT-22), with only two reports worldwide. Clinical features include upper-segment–predominant dystonia, intellectual disability, eye movement abnormalities, and cerebellar atrophy. We describe two unrelated patients with adolescent-onset generalized dystonia showing cranio-caudal progression due to novel truncating variants in the <em>TSPOAP1</em> gene.</div></div>","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"142 ","pages":"Article 108139"},"PeriodicalIF":3.4,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145725159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.parkreldis.2025.108138
Halil Onder, Dilek Iscan, Helin Tunc, Zehra Yavuz, Selcuk Comoglu
Background
Fear-of-falling (FOF) in Parkinson's disease (PD) reflects both motor and non-motor determinants and is associated with reduced quality of life (QoL). However, its dominant clinical drivers in highly concerned patients remain unclear.
Objective
To identify and characterize distinct clinical phenotypes underlying high fall-related concern in PD.
Methods
In this cross-sectional study of 460 PD patients, FOF was assessed with the Falls Efficacy Scale–International (FES-I). Independent correlates were identified via stepwise regression. Patients with high FES-I (≥28; n = 199) were classified into phenotypes according to their predominant predictor: motor daily-living disability (MDS-UPDRS II), anxiety (HAM-A), or OFF-state gait impairment.
Results
In the full cohort, FES-I was most strongly associated with MDS-II, anxiety, freezing severity, body bradykinesia, and constipation (R2 = 0.334). In the high-FES-I subgroup, MDS-II and anxiety remained significant, while gait-OFF emerged as a significant predictor (R2 = 0.319). Phenotypic analysis identified three subgroups: motor-disability–driven (n = 58; marked functional limitations, higher postural/gait impairment, and despite expectations, greater freezing severity than the gait-impairment group), anxiety-driven (n = 63; mild motor deficits but high affective burden), and gait-impairment–driven (n = 37; severe axial gait deficits with relatively preserved non-axial motor function and low affective symptoms). These groups differed in disease duration, axial scores, non-motor burden, and depression, but not in age, sex, or PD subtype.
Conclusions
High FOF in PD can arise from distinct, relatively “pure” phenotypes—motor-disability, anxiety, or gait impairment. Recognizing these drivers may guide phenotype-specific rehabilitation, such as targeted physiotherapy for gait-dominant cases or psychological interventions for anxiety-driven profiles, potentially improving functional outcomes and QoL.
{"title":"High fear-of-falling in Parkinson's disease: Distinct clinical phenotypes with motor and non-motor dominance","authors":"Halil Onder, Dilek Iscan, Helin Tunc, Zehra Yavuz, Selcuk Comoglu","doi":"10.1016/j.parkreldis.2025.108138","DOIUrl":"10.1016/j.parkreldis.2025.108138","url":null,"abstract":"<div><h3>Background</h3><div>Fear-of-falling (FOF) in Parkinson's disease (PD) reflects both motor and non-motor determinants and is associated with reduced quality of life (QoL). However, its dominant clinical drivers in highly concerned patients remain unclear.</div></div><div><h3>Objective</h3><div>To identify and characterize distinct clinical phenotypes underlying high fall-related concern in PD.</div></div><div><h3>Methods</h3><div>In this cross-sectional study of 460 PD patients, FOF was assessed with the Falls Efficacy Scale–International (FES-I). Independent correlates were identified via stepwise regression. Patients with high FES-I (≥28; n = 199) were classified into phenotypes according to their predominant predictor: motor daily-living disability (MDS-UPDRS II), anxiety (HAM-A), or OFF-state gait impairment.</div></div><div><h3>Results</h3><div>In the full cohort, FES-I was most strongly associated with MDS-II, anxiety, freezing severity, body bradykinesia, and constipation (R<sup>2</sup> = 0.334). In the high-FES-I subgroup, MDS-II and anxiety remained significant, while gait-OFF emerged as a significant predictor (R<sup>2</sup> = 0.319). Phenotypic analysis identified three subgroups: motor-disability–driven (n = 58; marked functional limitations, higher postural/gait impairment, and despite expectations, greater freezing severity than the gait-impairment group), anxiety-driven (n = 63; mild motor deficits but high affective burden), and gait-impairment–driven (n = 37; severe axial gait deficits with relatively preserved non-axial motor function and low affective symptoms). These groups differed in disease duration, axial scores, non-motor burden, and depression, but not in age, sex, or PD subtype.</div></div><div><h3>Conclusions</h3><div>High FOF in PD can arise from distinct, relatively “pure” phenotypes—motor-disability, anxiety, or gait impairment. Recognizing these drivers may guide phenotype-specific rehabilitation, such as targeted physiotherapy for gait-dominant cases or psychological interventions for anxiety-driven profiles, potentially improving functional outcomes and QoL.</div></div>","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"142 ","pages":"Article 108138"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.parkreldis.2025.108136
Su Hyeon Ha , Seoyeon Kim , Seungmin Lee , Bora Jin , Kyung Ah Woo , Jung Hwan Shin , Han-Joon Kim
Introduction
Approximately one-third of patients with Parkinson's disease (PD) develop dementia, and anticholinergic use has been implicated as a risk factor, particularly with prolonged exposure. This study examined whether short-term anticholinergic use was associated with differing dementia incidence between cognitive and non-cognitive adverse effects groups.
Methods
We retrospectively reviewed records of 209 PD patients prescribed anticholinergics (trihexyphenidyl, benztropine, or amantadine) for the first time at Seoul National University Hospital between 2011 and 2020. Patients were classified into three groups: those who discontinued due to cognitive or non-cognitive adverse effects, and those who continued long-term use without adverse effects. Dementia incidence was compared across groups using Kaplan–Meier analysis, and multivariable logistic regression adjusted for age, sex, and disease duration.
Results
Of the 155 patients analyzed, 62 continued long-term use, whereas 12 and 81 discontinued due to cognitive and non-cognitive adverse effects, respectively. Baseline characteristics and anticholinergic dosages were comparable among groups. After covariate adjustment, dementia incidence did not differ between cognitive and non-cognitive adverse effects groups (adjusted OR = 1.17, 95 % CI 0.13–10.22, p = 0.890). Excluding those who discontinued due to lack of effect yielded similar results (adjusted OR = 0.68, 95 % CI 0.10–4.59, p = 0.690). No significant difference was observed between the long-term use and cognitive adverse effects group (adjusted OR = 1.57, 95 % CI 0.23–10.89, p = 0.646).
Conclusions
The cognitive adverse effects of anticholinergics were not associated with increased dementia risk. Prospective studies assessing individual variability in anticholinergic sensitivity and cognitive outcomes in PD are warranted.
大约三分之一的帕金森病（PD）患者发展为痴呆，抗胆碱能药物的使用被认为是一个危险因素，特别是长期使用。这项研究调查了短期抗胆碱能药物的使用是否与认知和非认知不良反应组之间痴呆发病率的差异有关。方法回顾性分析2011年至2020年首尔大学医院首次使用抗胆碱能药物（三苯基、苯妥品或金刚烷胺）的209例PD患者的记录。患者被分为三组：因认知或非认知不良反应而停用的患者，以及继续长期使用无不良反应的患者。采用Kaplan-Meier分析比较各组痴呆发病率，并对年龄、性别和病程进行多变量logistic回归校正。结果在155例患者中，62例继续长期使用，而12例和81例分别因认知和非认知不良反应而停止使用。各组间基线特征和抗胆碱能剂量具有可比性。协变量调整后，认知不良反应组和非认知不良反应组痴呆发病率无差异（调整后OR = 1.17, 95% CI 0.13-10.22, p = 0.890）。排除那些因缺乏疗效而停止治疗的患者也得到了类似的结果（调整后OR = 0.68, 95% CI 0.10-4.59, p = 0.690）。长期用药组与认知不良反应组比较，差异无统计学意义（校正OR = 1.57, 95% CI 0.23-10.89, p = 0.646）。结论抗胆碱能药物的认知不良反应与痴呆风险增加无关。评估PD患者抗胆碱能敏感性和认知结果的个体差异的前瞻性研究是有必要的。
{"title":"Association between cognitive adverse effects of anticholinergic medication and development of dementia in Parkinson's disease","authors":"Su Hyeon Ha , Seoyeon Kim , Seungmin Lee , Bora Jin , Kyung Ah Woo , Jung Hwan Shin , Han-Joon Kim","doi":"10.1016/j.parkreldis.2025.108136","DOIUrl":"10.1016/j.parkreldis.2025.108136","url":null,"abstract":"<div><h3>Introduction</h3><div>Approximately one-third of patients with Parkinson's disease (PD) develop dementia, and anticholinergic use has been implicated as a risk factor, particularly with prolonged exposure. This study examined whether short-term anticholinergic use was associated with differing dementia incidence between cognitive and non-cognitive adverse effects groups.</div></div><div><h3>Methods</h3><div>We retrospectively reviewed records of 209 PD patients prescribed anticholinergics (trihexyphenidyl, benztropine, or amantadine) for the first time at Seoul National University Hospital between 2011 and 2020. Patients were classified into three groups: those who discontinued due to cognitive or non-cognitive adverse effects, and those who continued long-term use without adverse effects. Dementia incidence was compared across groups using Kaplan–Meier analysis, and multivariable logistic regression adjusted for age, sex, and disease duration.</div></div><div><h3>Results</h3><div>Of the 155 patients analyzed, 62 continued long-term use, whereas 12 and 81 discontinued due to cognitive and non-cognitive adverse effects, respectively. Baseline characteristics and anticholinergic dosages were comparable among groups. After covariate adjustment, dementia incidence did not differ between cognitive and non-cognitive adverse effects groups (adjusted OR = 1.17, 95 % CI 0.13–10.22, <em>p</em> = 0.890). Excluding those who discontinued due to lack of effect yielded similar results (adjusted OR = 0.68, 95 % CI 0.10–4.59, <em>p</em> = 0.690). No significant difference was observed between the long-term use and cognitive adverse effects group (adjusted OR = 1.57, 95 % CI 0.23–10.89, <em>p</em> = 0.646).</div></div><div><h3>Conclusions</h3><div>The cognitive adverse effects of anticholinergics were not associated with increased dementia risk. Prospective studies assessing individual variability in anticholinergic sensitivity and cognitive outcomes in PD are warranted.</div></div>","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"142 ","pages":"Article 108136"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Family caregivers of people with advanced Parkinson's disease (PD) experience substantial psychological, physical, and economic strain. The optimal intensity (“dose”) of structured caregiver training to lessen this burden is unknown and rarely quantified.
Methods
We prospectively followed 1757 family caregivers (April 2021–February 2025) at a single tertiary PD center. Caregivers received a predefined seven-module (∼30-h) curriculum (PD management, mobility/fall prevention, behavior/communication, caregiver self-care, system navigation, emergency response). Training exposure was summarized on a 0–100 index (dose, timing, engagement, boosters) and analyzed in tertiles. Mixed-effects models related exposure to Zarit Burden Interview (ZBI) change over 18 months (24-month extension) and to depressive symptoms, healthcare use, and quality of life.
Results
Among 1757 caregivers supporting 1757 patients with advanced PD, higher training exposure was associated with greater 18-month ZBI improvement (−4.4 vs −2.5 points for high vs low exposure; p < 0.001). Spline analyses indicated the steepest associated benefit at ∼40–55 exposure units and minimal added gain beyond ∼75 units; within this range a ≥7-point ZBI reduction yielded an NNT-equivalent of 2.4 under a causal assumption. Higher exposure was also associated with fewer emergency visits, lower depressive symptoms, and better quality of life. Gains were smaller in older, less educated, and multiply disadvantaged caregivers, and were largely maintained at 24 months (92.4 % retention).
Conclusion
Higher caregiver training exposure was associated with lower burden, better mood, and less healthcare use in advanced PD. These single-center observational data do not prove causality or generalizability; multi-site randomized or stepped-wedge trials are needed.
{"title":"Reducing caregiver burden in advanced Parkinson's disease through targeted training: A longitudinal study with dose-response modeling","authors":"Yunli Ge, Qiya Tong, Xiaolin Song, Chun Liu, Mengli Yang, Yingpu Feng","doi":"10.1016/j.parkreldis.2025.108137","DOIUrl":"10.1016/j.parkreldis.2025.108137","url":null,"abstract":"<div><h3>Background</h3><div>Family caregivers of people with advanced Parkinson's disease (PD) experience substantial psychological, physical, and economic strain. The optimal intensity (“dose”) of structured caregiver training to lessen this burden is unknown and rarely quantified.</div></div><div><h3>Methods</h3><div>We prospectively followed 1757 family caregivers (April 2021–February 2025) at a single tertiary PD center. Caregivers received a predefined seven-module (∼30-h) curriculum (PD management, mobility/fall prevention, behavior/communication, caregiver self-care, system navigation, emergency response). Training exposure was summarized on a 0–100 index (dose, timing, engagement, boosters) and analyzed in tertiles. Mixed-effects models related exposure to Zarit Burden Interview (ZBI) change over 18 months (24-month extension) and to depressive symptoms, healthcare use, and quality of life.</div></div><div><h3>Results</h3><div>Among 1757 caregivers supporting 1757 patients with advanced PD, higher training exposure was associated with greater 18-month ZBI improvement (−4.4 vs −2.5 points for high vs low exposure; p < 0.001). Spline analyses indicated the steepest associated benefit at ∼40–55 exposure units and minimal added gain beyond ∼75 units; within this range a ≥7-point ZBI reduction yielded an NNT-equivalent of 2.4 under a causal assumption. Higher exposure was also associated with fewer emergency visits, lower depressive symptoms, and better quality of life. Gains were smaller in older, less educated, and multiply disadvantaged caregivers, and were largely maintained at 24 months (92.4 % retention).</div></div><div><h3>Conclusion</h3><div>Higher caregiver training exposure was associated with lower burden, better mood, and less healthcare use in advanced PD. These single-center observational data do not prove causality or generalizability; multi-site randomized or stepped-wedge trials are needed.</div></div>","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"142 ","pages":"Article 108137"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145715406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Infection-related movement disorders (IRMD) constitute nearly one-fifth of secondary movement disorders, with higher prevalence in endemic regions. Timely recognition is critical, as many are treatable or preventable yet they often mimic primary movement disorders, leading to diagnostic delays.
Methods
We conducted an observational prospective cohort study at the Movement Disorders Clinic of a tertiary-care centre in India (May 2024–July 2025). All consecutive patients fulfilling the 2024 International Parkinson and Movement Disorder Society consensus criteria for IRMD were included. Clinical, radiological, laboratory, therapeutic, and outcome data were systematically analysed and classified using the MDS six-axis framework.
Results
Of 1102 patients screened, 100 (9.1 %) fulfilled criteria for IRMD (median age 22 years; male: female = 7:3). A preceding infection was identifiable in 80 %, most often viral (64 %) or mycobacterial (18 %). The most frequent etiologies were SSPE (40 %), TB-related (18 %), and JCV-related (12 %). Hyperkinetic disorders predominated (51 %), particularly myoclonus and dystonia, followed by ataxia (22 %). Associated features included cognitive/behavioral symptoms (34 %) and seizures (22 %). Infection-directed therapy was administered in 91 %, with symptomatic management in 59 %. Outcomes were monophasic with improvement in 35 %, static in 15 %, progressive in 17 %, and relapsing in 5 %; mortality was 16 %, largely among SSPE.
Discussion
IRMD constitute a substantial proportion of movement disorders in India, with a predilection for younger patients. SSPE and tuberculosis emerged as leading etiologies. Strengthening vaccination programs and early recognition are pivotal to improving outcomes. Collaborative multicentric studies are essential to refine diagnostic and therapeutic strategies in this understudied domain.
{"title":"Phenotypic spectrum, etiology and outcomes of infection-related movement disorders: An observational cohort study","authors":"Divyani Garg , Archita Makharia , Ayush Agarwal, Farsana Mustafa, Divya M. Radhakrishnan, Roopa Rajan, Achal Kumar Srivastava","doi":"10.1016/j.parkreldis.2025.108135","DOIUrl":"10.1016/j.parkreldis.2025.108135","url":null,"abstract":"<div><h3>Background</h3><div>Infection-related movement disorders (IRMD) constitute nearly one-fifth of secondary movement disorders, with higher prevalence in endemic regions. Timely recognition is critical, as many are treatable or preventable yet they often mimic primary movement disorders, leading to diagnostic delays.</div></div><div><h3>Methods</h3><div>We conducted an observational prospective cohort study at the Movement Disorders Clinic of a tertiary-care centre in India (May 2024–July 2025). All consecutive patients fulfilling the 2024 International Parkinson and Movement Disorder Society consensus criteria for IRMD were included. Clinical, radiological, laboratory, therapeutic, and outcome data were systematically analysed and classified using the MDS six-axis framework.</div></div><div><h3>Results</h3><div>Of 1102 patients screened, 100 (9.1 %) fulfilled criteria for IRMD (median age 22 years; male: female = 7:3). A preceding infection was identifiable in 80 %, most often viral (64 %) or mycobacterial (18 %). The most frequent etiologies were SSPE (40 %), TB-related (18 %), and JCV-related (12 %). Hyperkinetic disorders predominated (51 %), particularly myoclonus and dystonia, followed by ataxia (22 %). Associated features included cognitive/behavioral symptoms (34 %) and seizures (22 %). Infection-directed therapy was administered in 91 %, with symptomatic management in 59 %. Outcomes were monophasic with improvement in 35 %, static in 15 %, progressive in 17 %, and relapsing in 5 %; mortality was 16 %, largely among SSPE.</div></div><div><h3>Discussion</h3><div>IRMD constitute a substantial proportion of movement disorders in India, with a predilection for younger patients. SSPE and tuberculosis emerged as leading etiologies. Strengthening vaccination programs and early recognition are pivotal to improving outcomes. Collaborative multicentric studies are essential to refine diagnostic and therapeutic strategies in this understudied domain.</div></div>","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"142 ","pages":"Article 108135"},"PeriodicalIF":3.4,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-27DOI: 10.1016/j.parkreldis.2025.108092
Zachary Schneider , Hui Liu , Mohammad Dehestani , Mary B. Makarious , Peter Wild Crea , Sara Bandres-Ciga , Thomas Gasser , Jonggeol J. Kim , Global Parkinson's Genetics Program (GP2)
Rare damaging variants in the SLC25A46 gene were recently reported to be associated with optic atrophy and parkinsonism in compound heterozygous state. Here, we comprehensively investigated the role of SLC25A46 variation in idiopathic Parkinson's disease (PD) by leveraging whole genome sequencing (WGS) and genotyping imputed data from the Global Parkinson's Genetics Program (GP2) and the Accelerating Medicines Partnership for Parkinson's disease initiative (AMP-PD). Our analyses included genotyping imputed data from 19,573 PD cases and 11,748 neurologically healthy controls of European, African Admixed, African, East Asian, Ashkenazi Jewish, Middle Eastern, Central Asian, and Latino and Indigenous people of the Americas ancestries from GP2. Additionally, we mined WGS data from 924 PD patients and 229 healthy controls, as well as 3359 PD cases and 4153 neurologically healthy controls of European ancestry from GP2 and AMP-PD, respectively. Burden analysis of rare non-synonymous variants across case-control individuals from WGS data did not find evidence of SLC25A46 association with PD. Of the four SLC25A46 variants observed, the p.K256R variant previously reported by Bitetto et al. was found in 1/3359 controls and 1/4153 cases of European ancestry but its association was not significant. In addition, we identified p.E79K/p.V211M in 1/3359 controls and 1/4153 cases, without confirmation of a putative compound heterozygosity effect due to the lack of phasing data. This variant was also identified in Admixed American/Latin American, African Admixed, Ashkenazi Jewish, and Central Asian ancestries. However, no significant enrichment in cases versus controls was observed. Our results do not support a major role for SLC25A46 in idiopathic PD in the European population or other ancestries, though our imputation results require cautious interpretation for ultra-rare variants.
{"title":"Assessment of SLC25A46 variants in idiopathic Parkinson's disease","authors":"Zachary Schneider , Hui Liu , Mohammad Dehestani , Mary B. Makarious , Peter Wild Crea , Sara Bandres-Ciga , Thomas Gasser , Jonggeol J. Kim , Global Parkinson's Genetics Program (GP2)","doi":"10.1016/j.parkreldis.2025.108092","DOIUrl":"10.1016/j.parkreldis.2025.108092","url":null,"abstract":"<div><div>Rare damaging variants in the <em>SLC25A46</em> gene were recently reported to be associated with optic atrophy and parkinsonism in compound heterozygous state. Here, we comprehensively investigated the role of <em>SLC25A46</em> variation in idiopathic Parkinson's disease (PD) by leveraging whole genome sequencing (WGS) and genotyping imputed data from the Global Parkinson's Genetics Program (GP2) and the Accelerating Medicines Partnership for Parkinson's disease initiative (AMP-PD). Our analyses included genotyping imputed data from 19,573 PD cases and 11,748 neurologically healthy controls of European, African Admixed, African, East Asian, Ashkenazi Jewish, Middle Eastern, Central Asian, and Latino and Indigenous people of the Americas ancestries from GP2. Additionally, we mined WGS data from 924 PD patients and 229 healthy controls, as well as 3359 PD cases and 4153 neurologically healthy controls of European ancestry from GP2 and AMP-PD, respectively. Burden analysis of rare non-synonymous variants across case-control individuals from WGS data did not find evidence of <em>SLC25A46</em> association with PD. Of the four <em>SLC25A46</em> variants observed, the p.K256R variant previously reported by Bitetto et al. was found in 1/3359 controls and 1/4153 cases of European ancestry but its association was not significant. In addition, we identified p.E79K/p.V211M in 1/3359 controls and 1/4153 cases, without confirmation of a putative compound heterozygosity effect due to the lack of phasing data. This variant was also identified in Admixed American/Latin American, African Admixed, Ashkenazi Jewish, and Central Asian ancestries. However, no significant enrichment in cases versus controls was observed. Our results do not support a major role for <em>SLC25A46</em> in idiopathic PD in the European population or other ancestries, though our imputation results require cautious interpretation for ultra-rare variants.</div></div>","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"143 ","pages":"Article 108092"},"PeriodicalIF":3.4,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1016/j.parkreldis.2025.108134
Giacomo Portaro , Michelangelo Giacomelli , Sara Grisanti , Lisa Taruffi , Giulia Di Rauso , Valentina Fioravanti , Gaetano Salomone , Giacomo Argenziano , Rossella Sabadini , Giulia Toschi , Ottavia Iotti , Isabella Campanini , Andrea Merlo , Lorenzo Cavazzuti , Benedetta Damiano , Sara Scaltriti , Augusto Scaglioni , Jefri J. Paul , Peter Bauer , Giuseppe Biagini , Francesco Cavallieri
Introduction
In recent years, retinal structural changes have attracted considerable attention as a potential biomarker of neurodegeneration in Parkinson's disease (PD). Several studies have reported a reduced Retinal Nerve Fiber Layer (pRNFL) thickness in patients with PD compared with age-matched controls. However, potential retinal differences between “idiopathic” PD and GBA1-associated PD (GBA-PD) remain largely unexplored.
Methods
In this single-center observational study, we enrolled 59 PD patients: 32 GBA-PD and 27 non-mutated (NM-PD). A comprehensive clinical assessment included MoCA, MDS-UPDRS and Hoehn-Yahr. Spectral-domain OCT measured pRNFL thickness at 3.5, 4.1 and 4.7 mm diameters across six sectors. Statistical analysis assessed intergroup differences and associations with clinical variables.
Results
NM-PD exhibited significantly thinner temporal sectors compared to GBA-PD (p < .05, Mann-Whitney U test). In NM-PD, positive correlations emerged between temporal-superior pRNFL and MoCA scores, in line with previous studies, and, more surprisingly, between nasal-inferior sector and MDS-UPDRS part-IV. No robust associations with clinical variables were found in GBA-PD.
Conclusions
This study demonstrates differences in retinal thickness between GBA-PD and NM-PD. In particular, a lower pRNFL in NM-PD may be the product of a different pathophysiological mechanism. Moreover, sector-specific retinal thickness showed correlations to cognitive impairment and motor complications in NM-PD. These observations provide novel insights into genotype-specific mechanisms of neurodegeneration in PD and suggest that retinal imaging may offer a window into both cognitive and motor complications. Further longitudinal studies, including healthy controls and expanded retinal layer analyses, are needed to confirm and expand these findings.
{"title":"Retinal structural changes in Parkinson's disease: differences in pRNFL thickness between GBA1-associated and idiopathic cases","authors":"Giacomo Portaro , Michelangelo Giacomelli , Sara Grisanti , Lisa Taruffi , Giulia Di Rauso , Valentina Fioravanti , Gaetano Salomone , Giacomo Argenziano , Rossella Sabadini , Giulia Toschi , Ottavia Iotti , Isabella Campanini , Andrea Merlo , Lorenzo Cavazzuti , Benedetta Damiano , Sara Scaltriti , Augusto Scaglioni , Jefri J. Paul , Peter Bauer , Giuseppe Biagini , Francesco Cavallieri","doi":"10.1016/j.parkreldis.2025.108134","DOIUrl":"10.1016/j.parkreldis.2025.108134","url":null,"abstract":"<div><h3>Introduction</h3><div>In recent years, retinal structural changes have attracted considerable attention as a potential biomarker of neurodegeneration in Parkinson's disease (PD). Several studies have reported a reduced Retinal Nerve Fiber Layer (pRNFL) thickness in patients with PD compared with age-matched controls. However, potential retinal differences between “idiopathic” PD and GBA1-associated PD (GBA-PD) remain largely unexplored.</div></div><div><h3>Methods</h3><div>In this single-center observational study, we enrolled 59 PD patients: 32 GBA-PD and 27 non-mutated (NM-PD). A comprehensive clinical assessment included MoCA, MDS-UPDRS and Hoehn-Yahr. Spectral-domain OCT measured pRNFL thickness at 3.5, 4.1 and 4.7 mm diameters across six sectors. Statistical analysis assessed intergroup differences and associations with clinical variables.</div></div><div><h3>Results</h3><div>NM-PD exhibited significantly thinner temporal sectors compared to GBA-PD (p < .05, Mann-Whitney <em>U</em> test). In NM-PD, positive correlations emerged between temporal-superior pRNFL and MoCA scores, in line with previous studies, and, more surprisingly, between nasal-inferior sector and MDS-UPDRS part-IV. No robust associations with clinical variables were found in GBA-PD.</div></div><div><h3>Conclusions</h3><div>This study demonstrates differences in retinal thickness between GBA-PD and NM-PD. In particular, a lower pRNFL in NM-PD may be the product of a different pathophysiological mechanism. Moreover, sector-specific retinal thickness showed correlations to cognitive impairment and motor complications in NM-PD. These observations provide novel insights into genotype-specific mechanisms of neurodegeneration in PD and suggest that retinal imaging may offer a window into both cognitive and motor complications. Further longitudinal studies, including healthy controls and expanded retinal layer analyses, are needed to confirm and expand these findings.</div></div>","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"142 ","pages":"Article 108134"},"PeriodicalIF":3.4,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25DOI: 10.1016/j.parkreldis.2025.108129
Zhimin Xu , Andy Jiang , Nishitha Bujala , Ariel Sackonvitz , Colleen Bond , Carolin Dohle , Katherine Amodeo
Background
Patients with Parkinson's disease (PD) face heightened risks during hospitalization, including prolonged hospital stay and discharge to higher levels of care. Possible contributing factors include non-adherence to home medication regimens and administration of contraindicated medications.
Objective
To evaluate the impact of Best Practice Advisory (BPA), integration into Electronic Medical Records (EMRs) aimed at minimizing the prescription of contraindicated dopamine blocking agents (DBA) in hospitalized PD patients.
Methods
This is a single center, retrospective, cohort study comparing frequency of administration of contraindicated medications before and after implementation of a BPA at Westchester Medical Center (WMC) between January 2023 and July 2024. The primary outcome is the prescription of DBA. Secondary outcomes included discharge level of care, and hospital length of stay.
Results
Two-hundred and eleven charts were reviewed, and patients with confirmed diagnosis of PD or related Parkinsonism, who were prescribed dopaminergic medications at the time of admission were included. After BPA implementation, there was a statistically significant drop in rates of contraindicated prescriptions for psychosis and antiemetics, 33.33 %–2.86 % (p < 0.001) and 11.11 %–0 % (p < 0.001), respectively. There were no significant changes in LOS or discharge to higher levels of care between periods.
Conclusion
Implementing a BPA effectively reduced the prescription of contraindicated medications for PD patients. This highlights the value of targeted BPAs in improving PD patient safety and lays the groundwork for further medication quality improvement initiatives aimed at optimizing inpatient care for this vulnerable population.
背景：帕金森病（PD）患者在住院期间面临更高的风险，包括延长住院时间和出院时接受更高水平的护理。可能的影响因素包括不遵守家庭用药方案和服用禁忌症药物。目的：评估最佳实践咨询（BPA）的影响，并将其整合到电子病历（EMRs）中，以最大限度地减少住院PD患者禁忌多巴胺阻断剂（DBA）的处方。方法：这是一项单中心、回顾性、队列研究，比较了2023年1月至2024年7月在Westchester Medical center （WMC）实施BPA前后禁忌症药物的使用频率。主要结果是DBA的处方。次要结局包括出院护理水平和住院时间。结果：我们回顾了211张图表，纳入了确诊为PD或相关帕金森病的患者，并在入院时服用了多巴胺能药物。实施双酚a后，精神病和止吐药的禁忌症处方率下降了33.33% - 2.86% (p)。结论：实施双酚a有效减少了PD患者的禁忌症药物处方。这突出了靶向双酚a在改善PD患者安全方面的价值，并为进一步提高药物质量的举措奠定了基础，旨在优化这一弱势群体的住院护理。
{"title":"Impact of best practice advisory on reducing contraindicated medications in hospitalized patients with Parkinson's disease","authors":"Zhimin Xu , Andy Jiang , Nishitha Bujala , Ariel Sackonvitz , Colleen Bond , Carolin Dohle , Katherine Amodeo","doi":"10.1016/j.parkreldis.2025.108129","DOIUrl":"10.1016/j.parkreldis.2025.108129","url":null,"abstract":"<div><h3>Background</h3><div>Patients with Parkinson's disease (PD) face heightened risks during hospitalization, including prolonged hospital stay and discharge to higher levels of care. Possible contributing factors include non-adherence to home medication regimens and administration of contraindicated medications.</div></div><div><h3>Objective</h3><div>To evaluate the impact of Best Practice Advisory (BPA), integration into Electronic Medical Records (EMRs) aimed at minimizing the prescription of contraindicated dopamine blocking agents (DBA) in hospitalized PD patients.</div></div><div><h3>Methods</h3><div>This is a single center, retrospective, cohort study comparing frequency of administration of contraindicated medications before and after implementation of a BPA at Westchester Medical Center (WMC) between January 2023 and July 2024. The primary outcome is the prescription of DBA. Secondary outcomes included discharge level of care, and hospital length of stay.</div></div><div><h3>Results</h3><div>Two-hundred and eleven charts were reviewed, and patients with confirmed diagnosis of PD or related Parkinsonism, who were prescribed dopaminergic medications at the time of admission were included. After BPA implementation, there was a statistically significant drop in rates of contraindicated prescriptions for psychosis and antiemetics, 33.33 %–2.86 % (p < 0.001) and 11.11 %–0 % (p < 0.001), respectively. There were no significant changes in LOS or discharge to higher levels of care between periods.</div></div><div><h3>Conclusion</h3><div>Implementing a BPA effectively reduced the prescription of contraindicated medications for PD patients. This highlights the value of targeted BPAs in improving PD patient safety and lays the groundwork for further medication quality improvement initiatives aimed at optimizing inpatient care for this vulnerable population.</div></div>","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"142 ","pages":"Article 108129"},"PeriodicalIF":3.4,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145669167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cervical dystonia (CD) may affect not only head posture but also gait and balance. The relationship between quantitative gait abnormalities and perceived disability, the contribution of head tremor (HT) and the impact of botulinum toxin (BoNT) on these disturbances remain unclear.
Methods
We analyzed gait and balance in twenty-one CD patients (nine with HT) and twenty-two healthy controls (HC) by wearable sensors. Validated scales for CD severity, pain and quality of life (Tsui; TWSTRS-2; CDQ24; CDIP58) were used and CD patients re-evaluated one month after BoNT. Functional impact of gait impairment was assessed by multivariate analyses.
Results
Compared with HC, CD patients showed reduced gait speed, cadence, and stride length, longer double-support time, greater stride-length variability (SLV), and increased postural sway (all p < 0.05). SLV was the only gait parameter associated with the CDIP58-Walking subscale (p = 0.003) and remained an independent predictor after age, sex, CD-duration and CD-severity adjustment (p = 0.035). Patients with HT had greater sway than those without tremor after adjusting for disease severity (p = 0.038). All gait and balance parameters were similar after BoNT, except for reduced gait asymmetry. In the HT subgroup, sway improved significantly (p = 0.011).
Conclusions
This study confirms subtle gait and balance abnormalities in CD, with SLV emerging as a potential biomarker of functional impairment. HT appears to exacerbate balance dysfunction, while BoNT may partly improve sway in this subgroup. These findings suggest that sensor-based gait analysis may complement clinical evaluation and guide management in CD.
{"title":"Unraveling gait and balance impairment in cervical dystonia: associated features, functional implications, and the effect of botulinum toxin","authors":"Silvia Galli , Claudia Ledda , Silvia Gallo , Maurizio Zibetti , Francesco Marenco , Marcello Campagnoli , Domiziana Rinaldi , Morena Giovannelli , Carlo Alberto Artusi , Gabriele Imbalzano , Leonardo Lopiano","doi":"10.1016/j.parkreldis.2025.108130","DOIUrl":"10.1016/j.parkreldis.2025.108130","url":null,"abstract":"<div><h3>Background</h3><div>Cervical dystonia (CD) may affect not only head posture but also gait and balance. The relationship between quantitative gait abnormalities and perceived disability, the contribution of head tremor (HT) and the impact of botulinum toxin (BoNT) on these disturbances remain unclear.</div></div><div><h3>Methods</h3><div>We analyzed gait and balance in twenty-one CD patients (nine with HT) and twenty-two healthy controls (HC) by wearable sensors. Validated scales for CD severity, pain and quality of life (Tsui; TWSTRS-2; CDQ24; CDIP58) were used and CD patients re-evaluated one month after BoNT. Functional impact of gait impairment was assessed by multivariate analyses.</div></div><div><h3>Results</h3><div>Compared with HC, CD patients showed reduced gait speed, cadence, and stride length, longer double-support time, greater stride-length variability (SLV), and increased postural sway (all p < 0.05). SLV was the only gait parameter associated with the CDIP58-Walking subscale (p = 0.003) and remained an independent predictor after age, sex, CD-duration and CD-severity adjustment (p = 0.035). Patients with HT had greater sway than those without tremor after adjusting for disease severity (p = 0.038). All gait and balance parameters were similar after BoNT, except for reduced gait asymmetry. In the HT subgroup, sway improved significantly (p = 0.011).</div></div><div><h3>Conclusions</h3><div>This study confirms subtle gait and balance abnormalities in CD, with SLV emerging as a potential biomarker of functional impairment. HT appears to exacerbate balance dysfunction, while BoNT may partly improve sway in this subgroup. These findings suggest that sensor-based gait analysis may complement clinical evaluation and guide management in CD.</div></div>","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"142 ","pages":"Article 108130"},"PeriodicalIF":3.4,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25DOI: 10.1016/j.parkreldis.2025.108131
Karla Salinas-Barboza, Juan Manuel Altamirano
{"title":"Phenotypic heterogeneity in P102L Gerstmann-Sträussler-Scheinker disease: A case of spastic paraparesis with ataxia.","authors":"Karla Salinas-Barboza, Juan Manuel Altamirano","doi":"10.1016/j.parkreldis.2025.108131","DOIUrl":"https://doi.org/10.1016/j.parkreldis.2025.108131","url":null,"abstract":"","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":" ","pages":"108131"},"PeriodicalIF":3.4,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145637714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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