Cognitive impairment (CI) is a common and early non-motor manifestation of Parkinson's disease (PD), yet its biochemical basis remains poorly understood. Given the emerging link between bile acids (BAs) and neurodegeneration, we investigated whether serum BA profiles differ by cognitive status in PD and whether they can classify CI. A total of 363 participants were enrolled, including 63 healthy controls, 154 PD patients with normal cognition, and 146 with CI. Serum BA concentrations were quantified by ultra-performance liquid chromatography-tandem mass spectrometry, and multivariate as well as machine learning analyses were applied. Compared with cognitively normal PD patients, those with CI exhibited distinct BA alterations, characterized by elevated deoxycholic and cholic acids and reduced glyco- and tauro-conjugated species. Deoxycholic acid showed the strongest negative correlations with cognitive scores. Machine learning models based on combined BA profiles, particularly the random forest classifier, achieved robust discrimination between PD-CI and PD-NC groups (AUC up to 0.90). These findings indicate that BA dysregulation is closely linked to cognitive impairment in PD and may serve as a promising metabolic biomarker for early detection. Clinical trial number. Not applicable.
{"title":"Classifying the risk of cognitive impairment in Parkinson's disease using serum bile acid profiles and machine learning.","authors":"Tong Shen,Can Cui,Ruiqi Liu,Xin Yin,Jie Zu,Wei Zhang,Liguo Dong,Chuanying Xu,Hailong Lu,Guiyun Cui,Xuebin Qu,Chu Zhang","doi":"10.1038/s41531-025-01229-z","DOIUrl":"https://doi.org/10.1038/s41531-025-01229-z","url":null,"abstract":"Cognitive impairment (CI) is a common and early non-motor manifestation of Parkinson's disease (PD), yet its biochemical basis remains poorly understood. Given the emerging link between bile acids (BAs) and neurodegeneration, we investigated whether serum BA profiles differ by cognitive status in PD and whether they can classify CI. A total of 363 participants were enrolled, including 63 healthy controls, 154 PD patients with normal cognition, and 146 with CI. Serum BA concentrations were quantified by ultra-performance liquid chromatography-tandem mass spectrometry, and multivariate as well as machine learning analyses were applied. Compared with cognitively normal PD patients, those with CI exhibited distinct BA alterations, characterized by elevated deoxycholic and cholic acids and reduced glyco- and tauro-conjugated species. Deoxycholic acid showed the strongest negative correlations with cognitive scores. Machine learning models based on combined BA profiles, particularly the random forest classifier, achieved robust discrimination between PD-CI and PD-NC groups (AUC up to 0.90). These findings indicate that BA dysregulation is closely linked to cognitive impairment in PD and may serve as a promising metabolic biomarker for early detection. Clinical trial number. Not applicable.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"29 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704413","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}
Deep Brain Stimulation (DBS) programming in Parkinson's disease relies on clinical evaluation, yet beta-band activity in local field potentials (LFPs) may offer objective guidance. We evaluated LFP-guided contact selection against clinical programming (CP) at initial monopolar review and long-term follow-up. Bipolar LFPs were recorded in patients with sensing-enabled DBS systems, where central levels were clinically chosen. Three methods based on beta peak amplitude were tested: Broad-Bipolar (non-adjacent rings), Narrow-Bipolar (contiguous rings), and Segment-Bipolar (horizontal segments). Performance was assessed using correlation, agreement, and selection similarity with CP and compared to random selection. Narrow-Bipolar showed the strongest correlation and agreement with CP at both timepoints, outperforming other methods and random selection. It showed the greatest selection stability over time and the highest prediction. Its performance was comparable to imaging-guided programming and did not differ between STN and GPi. These results support Narrow-Bipolar as a valid, easy-to-perform beta-based method for guiding DBS programming.
{"title":"Local field potentials survey to guide DBS programming in Parkinson's disease: a clinical-neurophysiological longitudinal study.","authors":"Valentina D'Onofrio,Luca Weis,Leonardo Rigon,Dario Ciprietti,Laura Ludovica Grassi,Andrea Landi,Camillo Porcaro,Gerd Tinkhauser,Angelo Antonini,Andrea Guerra","doi":"10.1038/s41531-025-01208-4","DOIUrl":"https://doi.org/10.1038/s41531-025-01208-4","url":null,"abstract":"Deep Brain Stimulation (DBS) programming in Parkinson's disease relies on clinical evaluation, yet beta-band activity in local field potentials (LFPs) may offer objective guidance. We evaluated LFP-guided contact selection against clinical programming (CP) at initial monopolar review and long-term follow-up. Bipolar LFPs were recorded in patients with sensing-enabled DBS systems, where central levels were clinically chosen. Three methods based on beta peak amplitude were tested: Broad-Bipolar (non-adjacent rings), Narrow-Bipolar (contiguous rings), and Segment-Bipolar (horizontal segments). Performance was assessed using correlation, agreement, and selection similarity with CP and compared to random selection. Narrow-Bipolar showed the strongest correlation and agreement with CP at both timepoints, outperforming other methods and random selection. It showed the greatest selection stability over time and the highest prediction. Its performance was comparable to imaging-guided programming and did not differ between STN and GPi. These results support Narrow-Bipolar as a valid, easy-to-perform beta-based method for guiding DBS programming.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"242 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696779","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 : 2025-12-06DOI: 10.1038/s41531-025-01223-5
Sijia Huang, Liche Zhou, Zhenghao Li, Tian Zeng, Yuchao Yang, Ningyuan Wang, Qianyi Yin, Xiaojin Wang, Hongjiang Wei, Jun Liu
{"title":"Longitudinal insights from iron accumulation in motor system of prodromal and clinical Parkinson’s disease","authors":"Sijia Huang, Liche Zhou, Zhenghao Li, Tian Zeng, Yuchao Yang, Ningyuan Wang, Qianyi Yin, Xiaojin Wang, Hongjiang Wei, Jun Liu","doi":"10.1038/s41531-025-01223-5","DOIUrl":"https://doi.org/10.1038/s41531-025-01223-5","url":null,"abstract":"","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"29 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680159","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 : 2025-12-05DOI: 10.1038/s41531-025-01194-7
Danish Anwer, Nicola Pietro Montaldo, Elva Maria Novoa-del-Toro, Diana Domanska, Hilde Loge Nilsen, Annikka Polster
Parkinson’s disease (PD) is a progressive neurodegenerative disorder. DNA repair dysfunction and integrated stress response (ISR) dysregulation have been implicated in PD pathophysiology, however, their role during the prodromal phase remains unclear. We analyzed longitudinal blood transcriptomic data from the Parkinson’s Progression Markers Initiative to assess DNA repair and ISR genes in healthy individuals, prodromal PD, and those with established PD. Logistic regression classifiers showed that DNA repair and ISR expression distinguished prodromal PD from healthy individuals, with accuracy peaking in later prodromal stages. In contrast, these pathways did not separate established PD from controls, suggesting a more prominent role early in progression. Gene expression variability in prodromal PD was high at baseline but decreased over time, indicating convergence as disease advances. Notably, 50% of DNA repair genes and 74% of ISR genes showed non-linear patterns, suggesting a transient adaptive response fading with progression. Feature importance analysis highlighted several predictors of prodromal PD, including ERCC6, PRIMPOL, NEIL2, and NTHL1. These findings indicate that DNA repair and ISR dysregulation are relevant in prodromal PD and may be biomarkers for early detection and intervention. Future research should validate these results in larger cohorts and evaluate diagnostic and therapeutic potential.
{"title":"Longitudinal assessment of DNA repair signature trajectory in prodromal versus established Parkinson’s disease","authors":"Danish Anwer, Nicola Pietro Montaldo, Elva Maria Novoa-del-Toro, Diana Domanska, Hilde Loge Nilsen, Annikka Polster","doi":"10.1038/s41531-025-01194-7","DOIUrl":"https://doi.org/10.1038/s41531-025-01194-7","url":null,"abstract":"Parkinson’s disease (PD) is a progressive neurodegenerative disorder. DNA repair dysfunction and integrated stress response (ISR) dysregulation have been implicated in PD pathophysiology, however, their role during the prodromal phase remains unclear. We analyzed longitudinal blood transcriptomic data from the Parkinson’s Progression Markers Initiative to assess DNA repair and ISR genes in healthy individuals, prodromal PD, and those with established PD. Logistic regression classifiers showed that DNA repair and ISR expression distinguished prodromal PD from healthy individuals, with accuracy peaking in later prodromal stages. In contrast, these pathways did not separate established PD from controls, suggesting a more prominent role early in progression. Gene expression variability in prodromal PD was high at baseline but decreased over time, indicating convergence as disease advances. Notably, 50% of DNA repair genes and 74% of ISR genes showed non-linear patterns, suggesting a transient adaptive response fading with progression. Feature importance analysis highlighted several predictors of prodromal PD, including ERCC6, PRIMPOL, NEIL2, and NTHL1. These findings indicate that DNA repair and ISR dysregulation are relevant in prodromal PD and may be biomarkers for early detection and intervention. Future research should validate these results in larger cohorts and evaluate diagnostic and therapeutic potential.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"22 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680367","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}
This study aimed at: (1) assessing microstructural MRI and glymphatic flow alterations in isolated REM sleep behavioral disorder (iRBD) subjects relative to controls; (2) comparing sub-groups of iRBD patients with different levels of disease severity; and (3) studying the correlations between clinical alterations and MRI changes. 44 iRBD subjects and 52 controls underwent clinical and MRI evaluations. Gray and white-matter microstructural alterations were studied. Diffusion-tensor image analysis along the perivascular space (DTI-ALPS) index was obtained for the evaluation of glymphatic flow functionality. Cluster analysis was applied to divide iRBD patients in sub-groups. IRBD subjects showed worse sleep quality, reduced manual dexterity and gait alterations relative to controls. IRBD had alterations in the gray matter of fronto-parietal lobes and in the white matter of brainstem and frontal lobe, and a lower DTI-ALPS index relative to controls. Correlation analyses in the iRBD group showed that worse gray-matter microstructural alterations correlated with worse manual dexterity, lower peak turning velocity during dual-task mobility and worse sleep quality. Cluster analysis identified two clusters, one with worse clinical, neuropsychological, gait performances and DTI-ALPS index. The study detected early neurodegeneration in iRBD, subtle clinical deficits, microstructural gray/white-matter changes, and lower DTI-ALPS scores hinting at glymphatic dysfunction.
{"title":"Unveiling hidden neurodegeneration in isolated REM sleep behavior disorder through MRI microstructure and glymphatic flow.","authors":"Silvia Basaia,Elisabetta Sarasso,Andrea Gardoni,Andrea Grassi,Alejandro Enrique Brivio,Sara Marelli,Roberta Balestrino,Lucia Zenere,Alessandra Castelnuovo,Massimo Malcangi,Elisa Canu,Luigi Ferini-Strambi,Federica Agosta,Massimo Filippi","doi":"10.1038/s41531-025-01193-8","DOIUrl":"https://doi.org/10.1038/s41531-025-01193-8","url":null,"abstract":"This study aimed at: (1) assessing microstructural MRI and glymphatic flow alterations in isolated REM sleep behavioral disorder (iRBD) subjects relative to controls; (2) comparing sub-groups of iRBD patients with different levels of disease severity; and (3) studying the correlations between clinical alterations and MRI changes. 44 iRBD subjects and 52 controls underwent clinical and MRI evaluations. Gray and white-matter microstructural alterations were studied. Diffusion-tensor image analysis along the perivascular space (DTI-ALPS) index was obtained for the evaluation of glymphatic flow functionality. Cluster analysis was applied to divide iRBD patients in sub-groups. IRBD subjects showed worse sleep quality, reduced manual dexterity and gait alterations relative to controls. IRBD had alterations in the gray matter of fronto-parietal lobes and in the white matter of brainstem and frontal lobe, and a lower DTI-ALPS index relative to controls. Correlation analyses in the iRBD group showed that worse gray-matter microstructural alterations correlated with worse manual dexterity, lower peak turning velocity during dual-task mobility and worse sleep quality. Cluster analysis identified two clusters, one with worse clinical, neuropsychological, gait performances and DTI-ALPS index. The study detected early neurodegeneration in iRBD, subtle clinical deficits, microstructural gray/white-matter changes, and lower DTI-ALPS scores hinting at glymphatic dysfunction.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"115 1","pages":"346"},"PeriodicalIF":8.7,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664276","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 : 2025-12-03DOI: 10.1038/s41531-025-01195-6
Yu Fan,Zhen Hu,Qin-Qin Yan,Jing-Jin Wan,Jun Liu
Parkinson's Disease (PD) is a complex neurodegenerative disorder with a largely undefined genetic architecture, particularly regarding the role of rare coding variants. We performed a large-scale exome-wide association study to systematically identify rare genetic risk factors for PD. We analyzed whole-exome sequencing (WES) data from 3,602 PD patients and a strictly defined control group of 145,496 individuals of European ancestry from the UK Biobank. We focused on identifying high-confidence protein-truncating variants (PTVs) and used a rigorous gene-based association analysis to find genes significantly associated with PD risk. Our analysis identified PTVs in nine genes that were significantly more frequent in PD cases. These include three previously reported genes for PD/parkinsonism (ATP5F1C, COMMD9, and OPA1) and six novel genes (RGMB, SNX13, MGST2, NMBR, RCBTB1, and JAG1). Following sensitivity analyses, eight genes remained significant. Functional enrichment analysis highlighted pathways related to Notch binding and glutathione transferase activity. This study significantly expands the known genetic landscape of PD by identifying six novel candidate risk genes. Our findings underscore the importance of rare, high-impact PTVs in PD pathogenesis and provide new avenues for mechanistic research and the development of targeted therapeutics.
{"title":"Whole-exome sequencing and burden analysis identify six novel candidate risk genes and expand the genetic landscape of Parkinson's disease.","authors":"Yu Fan,Zhen Hu,Qin-Qin Yan,Jing-Jin Wan,Jun Liu","doi":"10.1038/s41531-025-01195-6","DOIUrl":"https://doi.org/10.1038/s41531-025-01195-6","url":null,"abstract":"Parkinson's Disease (PD) is a complex neurodegenerative disorder with a largely undefined genetic architecture, particularly regarding the role of rare coding variants. We performed a large-scale exome-wide association study to systematically identify rare genetic risk factors for PD. We analyzed whole-exome sequencing (WES) data from 3,602 PD patients and a strictly defined control group of 145,496 individuals of European ancestry from the UK Biobank. We focused on identifying high-confidence protein-truncating variants (PTVs) and used a rigorous gene-based association analysis to find genes significantly associated with PD risk. Our analysis identified PTVs in nine genes that were significantly more frequent in PD cases. These include three previously reported genes for PD/parkinsonism (ATP5F1C, COMMD9, and OPA1) and six novel genes (RGMB, SNX13, MGST2, NMBR, RCBTB1, and JAG1). Following sensitivity analyses, eight genes remained significant. Functional enrichment analysis highlighted pathways related to Notch binding and glutathione transferase activity. This study significantly expands the known genetic landscape of PD by identifying six novel candidate risk genes. Our findings underscore the importance of rare, high-impact PTVs in PD pathogenesis and provide new avenues for mechanistic research and the development of targeted therapeutics.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"113 1","pages":"347"},"PeriodicalIF":8.7,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664275","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 : 2025-12-02DOI: 10.1038/s41531-025-01180-z
Wenhua Sun, Claudia Schulte, Thomas Gasser, Manuela Tan
Genome-wide association study of Parkinson's disease (PD) identified common variants associated with lysosomal mechanism, including TMEM175, SCARB2, and CTSB. We investigated the association between common and rare variants across populations using cohorts from the Global Parkinson's Genetics Program (GP2) (33,733 cases and 18,703 controls from ten ancestries). In the European cohort, we confirmed significant associations with PD risk for all known genetic risk variants across the three genes and TMEM175 p. Met393Thr as an independent genome-wide significant signal. Additionally, a novel independent signal, SCARB2 rs11547135, was detected. The burden analysis linked PD to SCARB2 in African American, Ashkenazi Jewish and East Asian cohorts. Single variants-based tests identified rare missense variants in SCARB2 in several populations. Our study reinforces the association of lysosomal genetic variants with PD risk, revealing genetic heterogeneity across populations.
帕金森病（PD）的全基因组关联研究发现了与溶酶体机制相关的常见变异，包括TMEM175、SCARB2和CTSB。我们使用来自全球帕金森遗传学计划（GP2）的队列（来自10个祖先的33,733例病例和18,703例对照）调查了人群中常见和罕见变异之间的关系。在欧洲队列中，我们证实了三个基因中所有已知的遗传风险变异与PD风险的显著关联，TMEM175 p. Met393Thr是一个独立的全基因组显著信号。此外，还检测到一个新的独立信号SCARB2 rs11547135。在非裔美国人、德系犹太人和东亚人群中，负担分析将PD与SCARB2联系起来。基于单变异的检测在几个人群中发现了罕见的SCARB2错义变异。我们的研究强调了溶酶体遗传变异与帕金森病风险的关联，揭示了人群之间的遗传异质性。
{"title":"TMEM175, SCARB2 and CTSB associations with Parkinson's disease risk across populations.","authors":"Wenhua Sun, Claudia Schulte, Thomas Gasser, Manuela Tan","doi":"10.1038/s41531-025-01180-z","DOIUrl":"10.1038/s41531-025-01180-z","url":null,"abstract":"<p><p>Genome-wide association study of Parkinson's disease (PD) identified common variants associated with lysosomal mechanism, including TMEM175, SCARB2, and CTSB. We investigated the association between common and rare variants across populations using cohorts from the Global Parkinson's Genetics Program (GP2) (33,733 cases and 18,703 controls from ten ancestries). In the European cohort, we confirmed significant associations with PD risk for all known genetic risk variants across the three genes and TMEM175 p. Met393Thr as an independent genome-wide significant signal. Additionally, a novel independent signal, SCARB2 rs11547135, was detected. The burden analysis linked PD to SCARB2 in African American, Ashkenazi Jewish and East Asian cohorts. Single variants-based tests identified rare missense variants in SCARB2 in several populations. Our study reinforces the association of lysosomal genetic variants with PD risk, revealing genetic heterogeneity across populations.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":" ","pages":"348"},"PeriodicalIF":8.2,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12678402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661212","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 : 2025-12-02DOI: 10.1038/s41531-025-01155-0
Xuan Li,Si-Jia Peng,Yu Wang,Xin Chen,Ting-Ting Wu,Ya Feng,Xi-Xi Wang,Huiyong Yin,Yun-Cheng Wu
Emerging evidence suggests that ferroptosis is probably involved in the selective loss of dopaminergic neurons in Parkinson's disease (PD). Acetaldehyde dehydrogenase 2 (ALDH2) plays an important role in detoxifying lipid aldehydes derived from lipid peroxidation, a process that is closely linked to ferroptosis. In our study, ALDH2 knockout (KO) mice were more susceptible to the loss of tyrosine hydroxylase-positive neurons and behavioral changes in a PD mouse model. Similar observations were made in a knock-in (KI) mouse model with one of the most common single-nucleotide polymorphisms of ALDH2, rs671. Interestingly, ALDH2 KO or KI mice showed enhanced ferroptosis in the SN. Moreover, expression of ALDH2 modified the sensitivity of SH-SY5Y cells to ferroptosis inducers. Mechanistic studies have shown that ALDH2 regulates neuronal cell ferroptosis by interacting with the antioxidant enzyme peroxiredoxin 6 (PRDX6) to enhance its enzymatic activity, whereas the ALDH2 rs671 variant weakens its binding to PRDX6.
{"title":"ALDH2 protects against dopaminergic neuronal cell ferroptosis by enhancing the enzyme activity of PRDX6 in Parkinson's disease.","authors":"Xuan Li,Si-Jia Peng,Yu Wang,Xin Chen,Ting-Ting Wu,Ya Feng,Xi-Xi Wang,Huiyong Yin,Yun-Cheng Wu","doi":"10.1038/s41531-025-01155-0","DOIUrl":"https://doi.org/10.1038/s41531-025-01155-0","url":null,"abstract":"Emerging evidence suggests that ferroptosis is probably involved in the selective loss of dopaminergic neurons in Parkinson's disease (PD). Acetaldehyde dehydrogenase 2 (ALDH2) plays an important role in detoxifying lipid aldehydes derived from lipid peroxidation, a process that is closely linked to ferroptosis. In our study, ALDH2 knockout (KO) mice were more susceptible to the loss of tyrosine hydroxylase-positive neurons and behavioral changes in a PD mouse model. Similar observations were made in a knock-in (KI) mouse model with one of the most common single-nucleotide polymorphisms of ALDH2, rs671. Interestingly, ALDH2 KO or KI mice showed enhanced ferroptosis in the SN. Moreover, expression of ALDH2 modified the sensitivity of SH-SY5Y cells to ferroptosis inducers. Mechanistic studies have shown that ALDH2 regulates neuronal cell ferroptosis by interacting with the antioxidant enzyme peroxiredoxin 6 (PRDX6) to enhance its enzymatic activity, whereas the ALDH2 rs671 variant weakens its binding to PRDX6.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"51 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145656830","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 : 2025-12-01DOI: 10.1038/s41531-025-01181-y
Bahaaeddin Attaallah, Sheena Waters, Charles Marshall, Alastair Noyce
Neuropsychiatric symptoms are a significant yet often overlooked aspect of Parkinson’s disease (PD). Using UK Biobank data, we examined associations between neuropsychiatric dimensions and PD risk markers. Factor analysis identified four dimensions—Depression, Anxiety, Adult Stress-Adversity, and Alcohol- and Substance-Related Behaviours (ASRB) —across three groups: PD, healthy controls, and cerebrovascular disease (CVD) as neurological controls. These dimensions showed distinct patterns in PD. Depression scores were significantly elevated, while ASRB scores were consistently lower. Neuroimaging linked ASRB to subcortical changes specific to PD, particularly quantitative susceptibility mapping in the substantia nigra, consistent with the dopaminergic system’s role in goal-directed behaviour. GBA1 carrier status was linked to age-related changes in this dimension. Furthermore, PD patients with higher ASRB showed greater volatility in cognitive and motor function, with worsening before diagnosis and subsequent improvement. These findings highlight the complex interplay between psychiatric symptoms, neurobiological changes, and genetic factors in PD, suggesting that specific neuropsychiatric profiles may serve as early indicators of disease risk and progression.
{"title":"The relationship between neuropsychiatric dimensions and markers of Parkinson’s disease risk in the UK Biobank","authors":"Bahaaeddin Attaallah, Sheena Waters, Charles Marshall, Alastair Noyce","doi":"10.1038/s41531-025-01181-y","DOIUrl":"https://doi.org/10.1038/s41531-025-01181-y","url":null,"abstract":"Neuropsychiatric symptoms are a significant yet often overlooked aspect of Parkinson’s disease (PD). Using UK Biobank data, we examined associations between neuropsychiatric dimensions and PD risk markers. Factor analysis identified four dimensions—Depression, Anxiety, Adult Stress-Adversity, and Alcohol- and Substance-Related Behaviours (ASRB) —across three groups: PD, healthy controls, and cerebrovascular disease (CVD) as neurological controls. These dimensions showed distinct patterns in PD. Depression scores were significantly elevated, while ASRB scores were consistently lower. Neuroimaging linked ASRB to subcortical changes specific to PD, particularly quantitative susceptibility mapping in the substantia nigra, consistent with the dopaminergic system’s role in goal-directed behaviour. <jats:italic>GBA1</jats:italic> carrier status was linked to age-related changes in this dimension. Furthermore, PD patients with higher ASRB showed greater volatility in cognitive and motor function, with worsening before diagnosis and subsequent improvement. These findings highlight the complex interplay between psychiatric symptoms, neurobiological changes, and genetic factors in PD, suggesting that specific neuropsychiatric profiles may serve as early indicators of disease risk and progression.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"72 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145645151","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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