This study explored free-water diffusion tensor imaging (FW-DTI) in the basal ganglia as a biomarker for mild cognitive impairment (MCI) in Parkinson’s disease (PD). One hundred and fourteen drug-naïve PD patients (without MCI at baseline) and 102 healthy controls (HC) from Parkinson’s Progression Markers Initiative (PPMI) were included, and FW-DTI metrics were extracted from the bilateral putamen, caudate, external globus pallidus (GPe), and internal globus pallidus (GPi). The result showed that PD-MCI convertors had significantly higher FW in GPe and GPi. Cox regression identified that GPe FW, MDS-UPDRS Part I score, and CSF Aβ42/pTau were significantly associated with MCI conversion in PD during 5-year follow-up. GPe FW > 0.328 predicted a 4.698-fold increased MCI risk (95% CI: 1.974–11.179) in PD in 5 years, after adjusting for CSF Aβ42/pTau value and MDS-UPDRS part I score. Furthermore, higher GPe FW correlated with executive dysfunction (symbol digit modalities: R = -0.272, P = 0.004; letter number sequencing: R = -0.199, P = 0.035) and elevated serum neurofilament light chain (R = 0.322, P < 0.001) in PD, but not HC. In conclusion, GPe FW may serve as a sensitive imaging biomarker reflecting neuronal injury and MCI conversion risk in PD.
本研究探讨了基底节区自由水扩散张量成像（FW-DTI）作为帕金森病（PD）轻度认知障碍（MCI）的生物标志物。纳入了114名drug-naïve PD患者（基线时无MCI）和102名来自帕金森进展标志物计划（PPMI）的健康对照（HC），并从双侧壳核、尾状核、外苍白球（GPe）和内苍白球（GPi）中提取了wi - dti指标。结果表明，PD-MCI转化器在GPe和GPi方面的FW显著高于其他转化器。Cox回归发现，GPe FW、MDS-UPDRS第一部分评分和CSF a - β42/pTau与PD患者5年随访期间MCI转换显著相关。在调整CSF a - β42/pTau值和MDS-UPDRS第一部分评分后，GPe FW > 0.328预测PD患者5年内MCI风险增加4.698倍（95% CI: 1.974-11.179）。此外，较高的GPe FW与PD的执行功能障碍（符号数字模式：R = -0.272, P = 0.004；字母数字序列：R = -0.199, P = 0.035）和血清神经丝轻链升高（R = 0.322, P < 0.001）相关，但与HC无关。综上所述，GPe FW可能是反映PD患者神经元损伤和MCI转化风险的敏感成像生物标志物。
{"title":"Free water in the external globus pallidus predicts mild cognitive impairment in Parkinson’s disease and is associated with serum neurofilament light chain levels","authors":"Huimin Chen, Huijing Liu, Wenyi Kou, Xinxin Ma, Yunfei Long, Dongdong Wu, Wei Du, Jing He, Shuhua Li, Haibo Chen, Wen Su","doi":"10.1038/s41531-026-01291-1","DOIUrl":"https://doi.org/10.1038/s41531-026-01291-1","url":null,"abstract":"This study explored free-water diffusion tensor imaging (FW-DTI) in the basal ganglia as a biomarker for mild cognitive impairment (MCI) in Parkinson’s disease (PD). One hundred and fourteen drug-naïve PD patients (without MCI at baseline) and 102 healthy controls (HC) from Parkinson’s Progression Markers Initiative (PPMI) were included, and FW-DTI metrics were extracted from the bilateral putamen, caudate, external globus pallidus (GPe), and internal globus pallidus (GPi). The result showed that PD-MCI convertors had significantly higher FW in GPe and GPi. Cox regression identified that GPe FW, MDS-UPDRS Part I score, and CSF Aβ42/pTau were significantly associated with MCI conversion in PD during 5-year follow-up. GPe FW > 0.328 predicted a 4.698-fold increased MCI risk (95% CI: 1.974–11.179) in PD in 5 years, after adjusting for CSF Aβ42/pTau value and MDS-UPDRS part I score. Furthermore, higher GPe FW correlated with executive dysfunction (symbol digit modalities: R = -0.272, P = 0.004; letter number sequencing: R = -0.199, P = 0.035) and elevated serum neurofilament light chain (R = 0.322, P < 0.001) in PD, but not HC. In conclusion, GPe FW may serve as a sensitive imaging biomarker reflecting neuronal injury and MCI conversion risk in PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"45 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152247","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 : 2026-02-11DOI: 10.1038/s41531-026-01289-9
Julia Chocarro, Sergio Marana, Maria Espelosin, Alberto J. Rico, Goiaz Ariznabarreta, Elena Lorenzo-Ramos, Mario M. Ilarduya, Ruben Hernandez-Alcoceba, Miquel Chillón, Miquel Vila, Jeffrey H. Kordower, Anthony H. V. Schapira, Ana Garcia-Osta, Maria del Mar Cuadrado-Tejedor, Jose L. Lanciego
There is a pressing need for the development, characterization, and standardization of animal models of Parkinson’s disease (PD) that properly mimic the cardinal features of this disorder, comprising both the motor phenotype and neuropathological signatures. In the past few years, animal modeling has moved from neurotoxin-based approaches toward viral vectors carrying a given genetic payload of interest. Here, to induce pigmentation of the mouse brain upon systemic delivery, we took advantage of a modified adeno-associated viral vector capsid engineered to bypass the blood-brain barrier and coding for the human tyrosinase gene (AAV9-P31-hTyr). Obtained results revealed an ongoing pigmentation of catecholaminergic centers related to the pathophysiology of PD, such as the substantia nigra pars compacta, ventral tegmental area, and locus coeruleus. Moreover, pigmented dopaminergic neurons exhibited Lewy body-like intracytoplasmic inclusions, a progressive nigrostriatal degeneration, and a time-dependent PD motor phenotype. The bilateral pigmented model of PD generated in this way does not require stereotactic surgery for viral vector delivery, opening up unprecedented possibilities for preclinical testing of therapeutic candidates designed to reduce disease progression rates.
{"title":"Introducing PIGMO, a novel PIGmented MOuse model of Parkinson’s disease","authors":"Julia Chocarro, Sergio Marana, Maria Espelosin, Alberto J. Rico, Goiaz Ariznabarreta, Elena Lorenzo-Ramos, Mario M. Ilarduya, Ruben Hernandez-Alcoceba, Miquel Chillón, Miquel Vila, Jeffrey H. Kordower, Anthony H. V. Schapira, Ana Garcia-Osta, Maria del Mar Cuadrado-Tejedor, Jose L. Lanciego","doi":"10.1038/s41531-026-01289-9","DOIUrl":"https://doi.org/10.1038/s41531-026-01289-9","url":null,"abstract":"There is a pressing need for the development, characterization, and standardization of animal models of Parkinson’s disease (PD) that properly mimic the cardinal features of this disorder, comprising both the motor phenotype and neuropathological signatures. In the past few years, animal modeling has moved from neurotoxin-based approaches toward viral vectors carrying a given genetic payload of interest. Here, to induce pigmentation of the mouse brain upon systemic delivery, we took advantage of a modified adeno-associated viral vector capsid engineered to bypass the blood-brain barrier and coding for the human tyrosinase gene (AAV9-P31-hTyr). Obtained results revealed an ongoing pigmentation of catecholaminergic centers related to the pathophysiology of PD, such as the substantia nigra pars compacta, ventral tegmental area, and locus coeruleus. Moreover, pigmented dopaminergic neurons exhibited Lewy body-like intracytoplasmic inclusions, a progressive nigrostriatal degeneration, and a time-dependent PD motor phenotype. The bilateral pigmented model of PD generated in this way does not require stereotactic surgery for viral vector delivery, opening up unprecedented possibilities for preclinical testing of therapeutic candidates designed to reduce disease progression rates.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"31 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152273","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 : 2026-02-11DOI: 10.1038/s41531-026-01283-1
Sarah Meglaj Bakrač, Katarina Mandić, Lidija Cvetko Krajinović, Željka Mačak Šafranko, Fran Borovečki, Anja Barešić, Antonela Blažeković
Parkinson’s disease (PD) is characterised by α-synuclein aggregation, dopaminergic neuron loss and chronic neuroinflammation. Disruption of the blood-brain barrier enables immune cell infiltration, including dendritic cells (DCs) and CD4+ T-cells, contributing to disease progression. To explore peripheral immune mechanisms in PD, we isolated DCs and CD4+ T-cells from the blood of 17 PD patients and 10 controls using magnetic separation, followed by flow cytometry and single-cell RNA sequencing. Cell-type annotation identified CD4+ T-cell and DC subtypes, including rare DC3 cells. PD patients showed reduced circulating DCs, with no change in CD4+ T-cell levels. Differential gene expression and pathway analysis suggest CD4+ effector memory T-cells (TEMs) and cDC2s as important mediators of immune responses in PD, enriched for immune-related pathways including T-cell activation and antigen presentation. Our findings implicate specific immune subsets in PD-associated neuroinflammation, suggesting cDC2s and CD4+ TEMs as potential targets for immunomodulatory strategies.
{"title":"Single-cell analysis of the peripheral immune landscape in Parkinson’s disease: insights into dendritic cell and CD4+ T-cell transcriptomics","authors":"Sarah Meglaj Bakrač, Katarina Mandić, Lidija Cvetko Krajinović, Željka Mačak Šafranko, Fran Borovečki, Anja Barešić, Antonela Blažeković","doi":"10.1038/s41531-026-01283-1","DOIUrl":"https://doi.org/10.1038/s41531-026-01283-1","url":null,"abstract":"Parkinson’s disease (PD) is characterised by α-synuclein aggregation, dopaminergic neuron loss and chronic neuroinflammation. Disruption of the blood-brain barrier enables immune cell infiltration, including dendritic cells (DCs) and CD4+ T-cells, contributing to disease progression. To explore peripheral immune mechanisms in PD, we isolated DCs and CD4+ T-cells from the blood of 17 PD patients and 10 controls using magnetic separation, followed by flow cytometry and single-cell RNA sequencing. Cell-type annotation identified CD4+ T-cell and DC subtypes, including rare DC3 cells. PD patients showed reduced circulating DCs, with no change in CD4+ T-cell levels. Differential gene expression and pathway analysis suggest CD4+ effector memory T-cells (TEMs) and cDC2s as important mediators of immune responses in PD, enriched for immune-related pathways including T-cell activation and antigen presentation. Our findings implicate specific immune subsets in PD-associated neuroinflammation, suggesting cDC2s and CD4+ TEMs as potential targets for immunomodulatory strategies.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"393 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152246","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 : 2026-02-10DOI: 10.1038/s41531-026-01279-x
Valeria Orrù, Michele Marongiu, Maristella Steri, Mara Marongiu, Carlo Sidore, Valentina Serra, Mauro Pala, Stefania Olla, Noemi Toggia, Matteo Floris, Monia Lobina, Maria Grazia Piras, Antonella Mulas, Andrea Maschio, Mariano Dei, Marina Parolini, Cinzia Dellanoce, Alessandro Delitala, 23andMe Research Team, David Schlessinger, Jonica Campolo, Marcella Devoto, Magdalena Zoledziewska, Francesco Cucca, Edoardo Fiorillo
Neopterin is a pro-inflammatory molecule upregulated in several diseases; however, its role in pathophysiology is unclear and its genetic regulation is unexplored. We observed that neopterin levels increase during senescence (P-value = 1.88×10-13, beta = 0.96) and positively correlate with age-related neurodegeneration and inflammation markers. The heritability estimation of neopterin variation was 35%. We then conducted a genome-wide association study on 999 Sardinians, identifying two signals in the GTP cyclohydrolase (GCH1) gene that were suggestively associated with neopterin levels. The first signal, led by rs140884539-C (P-value = 7.05×10-08, beta = 0.59), was in strong linkage disequilibrium with variants associated with predisposition to rheumatoid arthritis, decrease in dopamine, increased levels of GCH1 transcript, dopamine metabolites, and galectin-3. The second signal, represented by rs12323905-T (P-value = 8.17×10-08, beta = 0.30), colocalised with GCH1 splicing and Parkinson’s disease signals. Transcriptome analysis of 605 Sardinians showed that the Parkinson’s disease-predisposing variant was significantly associated with an increase in a shorter and inactive form of GCH1, whose presence is predicted to reduce the GCH1 decamer stability. The GCH1 homo-decamer regulates neopterin and tetrahydrobiopterin production, a cofactor required for the synthesis of dopamine and serotonin. Our data motivate experimental work to test whether modulating GCH1 expression or isoform ratio alters dopaminergic function in Parkinson’s disease models.
{"title":"Genetic co-regulation of neopterin and Parkinson’s disease","authors":"Valeria Orrù, Michele Marongiu, Maristella Steri, Mara Marongiu, Carlo Sidore, Valentina Serra, Mauro Pala, Stefania Olla, Noemi Toggia, Matteo Floris, Monia Lobina, Maria Grazia Piras, Antonella Mulas, Andrea Maschio, Mariano Dei, Marina Parolini, Cinzia Dellanoce, Alessandro Delitala, 23andMe Research Team, David Schlessinger, Jonica Campolo, Marcella Devoto, Magdalena Zoledziewska, Francesco Cucca, Edoardo Fiorillo","doi":"10.1038/s41531-026-01279-x","DOIUrl":"https://doi.org/10.1038/s41531-026-01279-x","url":null,"abstract":"Neopterin is a pro-inflammatory molecule upregulated in several diseases; however, its role in pathophysiology is unclear and its genetic regulation is unexplored. We observed that neopterin levels increase during senescence (P-value = 1.88×10-13, beta = 0.96) and positively correlate with age-related neurodegeneration and inflammation markers. The heritability estimation of neopterin variation was 35%. We then conducted a genome-wide association study on 999 Sardinians, identifying two signals in the GTP cyclohydrolase (GCH1) gene that were suggestively associated with neopterin levels. The first signal, led by rs140884539-C (P-value = 7.05×10-08, beta = 0.59), was in strong linkage disequilibrium with variants associated with predisposition to rheumatoid arthritis, decrease in dopamine, increased levels of GCH1 transcript, dopamine metabolites, and galectin-3. The second signal, represented by rs12323905-T (P-value = 8.17×10-08, beta = 0.30), colocalised with GCH1 splicing and Parkinson’s disease signals. Transcriptome analysis of 605 Sardinians showed that the Parkinson’s disease-predisposing variant was significantly associated with an increase in a shorter and inactive form of GCH1, whose presence is predicted to reduce the GCH1 decamer stability. The GCH1 homo-decamer regulates neopterin and tetrahydrobiopterin production, a cofactor required for the synthesis of dopamine and serotonin. Our data motivate experimental work to test whether modulating GCH1 expression or isoform ratio alters dopaminergic function in Parkinson’s disease models.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"46 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152249","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 : 2026-02-10DOI: 10.1038/s41531-026-01288-w
K. C. Biju, Enrique Torres Hernandez, Alison Michelle. Stallings, Ada C. Felix-Ortiz, Skanda K. Hebbale, Robert A. Clark
Olfactory dysfunction, often the earliest symptom of Parkinson’s disease (PD), can precede clinical diagnosis by over 20 years, yet its mechanism and link to α-synuclein pathology remain unclear. To understand the impact of α-synuclein pathology on the topographic olfactory sensory map that supports the detection and discrimination of particular odors, we created two double transgenic mouse models (α-Syn/M72 and α-Syn/P2) expressing tagged-M72 or tagged-P2 odor receptors in a human wild-type α-synuclein over-expressing background. We demonstrated that the sensory map is disrupted in these mice. Histological analysis showed a significant reduction in M72 and P2 olfactory sensory neurons (OSNs), with altered glomerular topographies as axons converged into supernumerary glomeruli of varying size and location. These findings suggest that α-synuclein overexpression impairs the mechanism guiding the convergence of OSN axons and thus formation of a precise olfactory sensory map. As OSNs in the nasal epithelium are accessible via non-invasive biopsy, they are a potential source of prodromal PD biomarkers.
{"title":"Olfactory sensory map is perturbed in a human wild-type α-synuclein overexpressing transgenic mouse model of Parkinson’s disease","authors":"K. C. Biju, Enrique Torres Hernandez, Alison Michelle. Stallings, Ada C. Felix-Ortiz, Skanda K. Hebbale, Robert A. Clark","doi":"10.1038/s41531-026-01288-w","DOIUrl":"https://doi.org/10.1038/s41531-026-01288-w","url":null,"abstract":"Olfactory dysfunction, often the earliest symptom of Parkinson’s disease (PD), can precede clinical diagnosis by over 20 years, yet its mechanism and link to α-synuclein pathology remain unclear. To understand the impact of α-synuclein pathology on the topographic olfactory sensory map that supports the detection and discrimination of particular odors, we created two double transgenic mouse models (α-Syn/M72 and α-Syn/P2) expressing tagged-M72 or tagged-P2 odor receptors in a human wild-type α-synuclein over-expressing background. We demonstrated that the sensory map is disrupted in these mice. Histological analysis showed a significant reduction in M72 and P2 olfactory sensory neurons (OSNs), with altered glomerular topographies as axons converged into supernumerary glomeruli of varying size and location. These findings suggest that α-synuclein overexpression impairs the mechanism guiding the convergence of OSN axons and thus formation of a precise olfactory sensory map. As OSNs in the nasal epithelium are accessible via non-invasive biopsy, they are a potential source of prodromal PD biomarkers.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"92 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152248","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 : 2026-02-07DOI: 10.1038/s41531-026-01280-4
Elisa Lilly Garulli, Timon Merk, Ghadi El Hasbani, Burçe Kabaoğlu, Rafaël De Sa, Ruben Behrsing, Dennis Doll, Michael Franz-Josef Schellenberger, Ibrahem Hanafi, Arend Vogt, Wolf-Julian Neumann, Chiara Palmisano, Ioannis Ugo Isaias, Yangfan Peng, Matthias Endres, Christoph Harms, Nikolaus Wenger
Gait deficits present an unresolved therapeutic challenge in Parkinson’s disease. At the behavioral level, symptoms exhibit heterogeneity, including bradykinesia and hypokinesia during cyclical limb movements, and sudden, involuntary interruptions in the gait sequence, known as freezing of gait. The neural activities driving these various deficits remain largely unknown. Here, we investigated the neural correlates of gait sequence interruptions with a deep phenotyping approach. For this, we transformed kinematic trajectories and cortical oscillations into continuous time series of neurobehavioral features. Next, we combined low-dimensional embedding with supervised classification to identify cortical oscillation features that drive gait deficits. In a rodent Parkinson’s disease model, our approach revealed that gait, akinesia, and stationary movements occupy distinct regions in the low-dimensional embedding space. Among the predominant features separating the states, Hjorth complexity and mobility modulated at akinesia onset. Additionally, we validated our findings in two Parkinson’s patients with freezing of gait, where neural features in STN recordings partially reflected the results in rodents. The presented neurobehavioral phenotyping approach is translational and can easily be generalized to the analysis of other complex movement disorders. Together, our results highlight specific neural features as potential biomarkers that may support the development of adaptive closed-loop algorithms for gait therapy in PD.
{"title":"Deep neurobehavioral phenotyping uncovers neural fingerprints of locomotor deficits in Parkinson’s disease","authors":"Elisa Lilly Garulli, Timon Merk, Ghadi El Hasbani, Burçe Kabaoğlu, Rafaël De Sa, Ruben Behrsing, Dennis Doll, Michael Franz-Josef Schellenberger, Ibrahem Hanafi, Arend Vogt, Wolf-Julian Neumann, Chiara Palmisano, Ioannis Ugo Isaias, Yangfan Peng, Matthias Endres, Christoph Harms, Nikolaus Wenger","doi":"10.1038/s41531-026-01280-4","DOIUrl":"https://doi.org/10.1038/s41531-026-01280-4","url":null,"abstract":"Gait deficits present an unresolved therapeutic challenge in Parkinson’s disease. At the behavioral level, symptoms exhibit heterogeneity, including bradykinesia and hypokinesia during cyclical limb movements, and sudden, involuntary interruptions in the gait sequence, known as freezing of gait. The neural activities driving these various deficits remain largely unknown. Here, we investigated the neural correlates of gait sequence interruptions with a deep phenotyping approach. For this, we transformed kinematic trajectories and cortical oscillations into continuous time series of neurobehavioral features. Next, we combined low-dimensional embedding with supervised classification to identify cortical oscillation features that drive gait deficits. In a rodent Parkinson’s disease model, our approach revealed that gait, akinesia, and stationary movements occupy distinct regions in the low-dimensional embedding space. Among the predominant features separating the states, Hjorth complexity and mobility modulated at akinesia onset. Additionally, we validated our findings in two Parkinson’s patients with freezing of gait, where neural features in STN recordings partially reflected the results in rodents. The presented neurobehavioral phenotyping approach is translational and can easily be generalized to the analysis of other complex movement disorders. Together, our results highlight specific neural features as potential biomarkers that may support the development of adaptive closed-loop algorithms for gait therapy in PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"182 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135598","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}
Chronic intestinal inflammation is a key precursor to Parkinson’s disease (PD). Leucine-rich repeat kinase 2 R1628P variant (LRRK2R1628P) is a risk factor for PD in Asians. However, whether it drives the occurrence of intestinal inflammation remains elusive. Here, we report that LRRK2R1627P (the rat homolog) disrupts intestinal homeostasis during aging and toxin exposure in rats. Compared with age-matched wild-type rats, aging LRRK2R1627P rats exhibited shortened small intestine, reduced goblet cells, and abnormal epithelial cell junction structures. Mechanistically, these changes were induced by macrophage polarization toward a pro-inflammatory phenotype via TLR4/MyD88/NF-κB pathway, resulting in PD-associated intestinal pathology, including chronic inflammatory, decreased microbial diversity, and increased p-α-synuclein aggregation. LRRK2R1627P also enhanced susceptibility to lipopolysaccharide-induced intestinal inflammation. Remarkably, TLR4 inhibitor ameliorated the age-related disruption of intestinal homeostasis mediated by LRRK2R1627P. Using the LRRK2R1627P rats, this study reveals a cascading interplay among genetic susceptibility, age-related internal imbalance, and exogenous toxin exposure in PD pathology. These findings provide critical insights into how the dynamic interplay of multiple risk factors overwhelms the body’s compensatory thresholds, ultimately initiating the pathological process of neurodegeneration.
{"title":"LRRK2R1627P mutation amplifies environmental risk factors induced chronic inflammation and α-synuclein aggregation in the gut of rats","authors":"Shimin Pang, Jing Lu, Yanyan Wang, Chao Ying, Chunsong Zhao, Zhenyu Yue, Qiumei Yang, Piu Chan","doi":"10.1038/s41531-026-01281-3","DOIUrl":"https://doi.org/10.1038/s41531-026-01281-3","url":null,"abstract":"Chronic intestinal inflammation is a key precursor to Parkinson’s disease (PD). Leucine-rich repeat kinase 2 R1628P variant (LRRK2R1628P) is a risk factor for PD in Asians. However, whether it drives the occurrence of intestinal inflammation remains elusive. Here, we report that LRRK2R1627P (the rat homolog) disrupts intestinal homeostasis during aging and toxin exposure in rats. Compared with age-matched wild-type rats, aging LRRK2R1627P rats exhibited shortened small intestine, reduced goblet cells, and abnormal epithelial cell junction structures. Mechanistically, these changes were induced by macrophage polarization toward a pro-inflammatory phenotype via TLR4/MyD88/NF-κB pathway, resulting in PD-associated intestinal pathology, including chronic inflammatory, decreased microbial diversity, and increased p-α-synuclein aggregation. LRRK2R1627P also enhanced susceptibility to lipopolysaccharide-induced intestinal inflammation. Remarkably, TLR4 inhibitor ameliorated the age-related disruption of intestinal homeostasis mediated by LRRK2R1627P. Using the LRRK2R1627P rats, this study reveals a cascading interplay among genetic susceptibility, age-related internal imbalance, and exogenous toxin exposure in PD pathology. These findings provide critical insights into how the dynamic interplay of multiple risk factors overwhelms the body’s compensatory thresholds, ultimately initiating the pathological process of neurodegeneration.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"161 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135599","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 : 2026-02-03DOI: 10.1038/s41531-026-01275-1
Harini Sarva, Rajesh Pahwa, Jorge Hernandez-Vara, Mark A. Goldstein, Rupam Borgohain, Stewart A. Factor, Sandeep Inamdar, Damon Love, Carrie Hames, Yiyong Fu, Victor Mergel, Andrew Goldfine, Chandra Kumar, Steven P. Piccoli, Siu-Long Yao, Orest Hurko
Inhibition of cAbl tyrosine kinase reduces α-synuclein aggregation, protects dopaminergic neurons, and improves motor function in animal models of Parkinson’s Disease (PD). PROSEEK was a Phase 2, randomized, double-blind, placebo-controlled study of the effects on disease progression of Vodobatinib, a brain-penetrant c-Abl inhibitor, in 513 participants with early PD not on symptomatic treatment other than a stable dose of a MAO-B inhibitor. Recently diagnosed subjects with confirmatory Dopamine Transporter Single Photon Emission Computed Tomography (DaT-SPECT) scans were randomized to daily Vodobatinib 384 mg, 192 mg, or placebo. The primary endpoint in Part 1 was the change from baseline to Week 40 in the Movement Disorder Society – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III total score; Part 2 was an optional 36-week extension. There was a high, dose-related rate of early withdrawal. The mean score of completers in the placebo group was slightly lower than at baseline of the entire cohort. Comparisons with either dose group favored the placebo. Serum neurofilament light chains increased significantly in both Vodobatinib groups, supporting inefficacy in PD.
{"title":"Evaluation of c-Abl inhibitor vodobatinib in subjects with early Parkinson’s disease: a phase 2, randomized, double-blind, placebo-controlled study","authors":"Harini Sarva, Rajesh Pahwa, Jorge Hernandez-Vara, Mark A. Goldstein, Rupam Borgohain, Stewart A. Factor, Sandeep Inamdar, Damon Love, Carrie Hames, Yiyong Fu, Victor Mergel, Andrew Goldfine, Chandra Kumar, Steven P. Piccoli, Siu-Long Yao, Orest Hurko","doi":"10.1038/s41531-026-01275-1","DOIUrl":"https://doi.org/10.1038/s41531-026-01275-1","url":null,"abstract":"Inhibition of cAbl tyrosine kinase reduces α-synuclein aggregation, protects dopaminergic neurons, and improves motor function in animal models of Parkinson’s Disease (PD). PROSEEK was a Phase 2, randomized, double-blind, placebo-controlled study of the effects on disease progression of Vodobatinib, a brain-penetrant c-Abl inhibitor, in 513 participants with early PD not on symptomatic treatment other than a stable dose of a MAO-B inhibitor. Recently diagnosed subjects with confirmatory Dopamine Transporter Single Photon Emission Computed Tomography (DaT-SPECT) scans were randomized to daily Vodobatinib 384 mg, 192 mg, or placebo. The primary endpoint in Part 1 was the change from baseline to Week 40 in the Movement Disorder Society – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III total score; Part 2 was an optional 36-week extension. There was a high, dose-related rate of early withdrawal. The mean score of completers in the placebo group was slightly lower than at baseline of the entire cohort. Comparisons with either dose group favored the placebo. Serum neurofilament light chains increased significantly in both Vodobatinib groups, supporting inefficacy in PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"97 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102076","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 : 2026-02-02DOI: 10.1038/s41531-026-01265-3
Kai Shi Lim, Maria Teresa Periñan, Elaine Guo Yan Chew, Paul Suhwan Lee, Fulya Akçimen, Jia Lun Lim, Mathew J. Koretsky, Manabu Funayama, Hiroyo Yoshino, Nobutaka Hattori, Rauan Kaiyrzhanov, Henry Houlden, Mariam Isayan, Yi Wen Tay, Tzi Shin Toh, Lei-Cheng Lit, Anis Nadhirah Khairul Anuar, Hans Xing Ding, Laurel Screven, Norlinah Mohamed Ibrahim, Chin-Hsien Lin, Han-Joon Kim, Jee-Young Lee, Sun Ju Chung, Jia Nee Foo, Eng-King Tan, Shen-Yang Lim, Ai Huey Tan, Sara Bandres-Ciga, Azlina Ahmad-Annuar, the Global Parkinson’s Genetics Program (GP2)
Common and rare variants in LRRK2 influence Parkinson’s disease (PD) risk across diverse populations, and in this study, the rare p.A419V variant was investigated across multiple ancestry cohorts comprising over 200,000 PD cases and controls. In cases of East Asian (EAS) ancestry, p.A419V was significantly associated with increased risk of PD (OR = 2.9; 95% CI: 1.66–5.10; p = 0.0002), and was not in linkage disequilibrium with other LRRK2 coding variants. The variant was significantly associated with a lower age at PD onset in the study cohort, while a meta-analysis of the EAS cases indicated a similar, albeit non-significant trend. LRRK2 protein modelling prediction indicated that binding sites for RAB8A, RAB29 and RAB32 were in close proximity to the p.A419V variant within the ARM domain. Together, these findings confirm the p.A419V as a significant PD risk factor in EAS populations, as well as highlight disease-relevant variants in the ARM domain and the link with LRRK2-RAB signaling.
LRRK2的常见和罕见变异影响不同人群的帕金森病（PD）风险，在本研究中，罕见的p.A419V变异在多个祖先队列中进行了调查，包括超过20万PD病例和对照组。在东亚（EAS）血统的病例中，p.A419V与PD风险增加显著相关（OR = 2.9; 95% CI: 1.66-5.10; p = 0.0002），并且与其他LRRK2编码变体不存在连锁不平衡。在研究队列中，该变异与较低的PD发病年龄显著相关，而对EAS病例的荟萃分析显示了类似的趋势，尽管不显著。LRRK2蛋白模型预测表明，RAB8A、RAB29和RAB32的结合位点在ARM结构域内与p.A419V变异位点非常接近。总之，这些发现证实了p.A419V在EAS人群中是一个重要的PD危险因素，并强调了ARM域中的疾病相关变异以及与LRRK2-RAB信号传导的联系。
{"title":"Association of LRRK2 p.A419V with Parkinson’s Disease in East Asians and analysis of age at onset","authors":"Kai Shi Lim, Maria Teresa Periñan, Elaine Guo Yan Chew, Paul Suhwan Lee, Fulya Akçimen, Jia Lun Lim, Mathew J. Koretsky, Manabu Funayama, Hiroyo Yoshino, Nobutaka Hattori, Rauan Kaiyrzhanov, Henry Houlden, Mariam Isayan, Yi Wen Tay, Tzi Shin Toh, Lei-Cheng Lit, Anis Nadhirah Khairul Anuar, Hans Xing Ding, Laurel Screven, Norlinah Mohamed Ibrahim, Chin-Hsien Lin, Han-Joon Kim, Jee-Young Lee, Sun Ju Chung, Jia Nee Foo, Eng-King Tan, Shen-Yang Lim, Ai Huey Tan, Sara Bandres-Ciga, Azlina Ahmad-Annuar, the Global Parkinson’s Genetics Program (GP2)","doi":"10.1038/s41531-026-01265-3","DOIUrl":"https://doi.org/10.1038/s41531-026-01265-3","url":null,"abstract":"Common and rare variants in LRRK2 influence Parkinson’s disease (PD) risk across diverse populations, and in this study, the rare p.A419V variant was investigated across multiple ancestry cohorts comprising over 200,000 PD cases and controls. In cases of East Asian (EAS) ancestry, p.A419V was significantly associated with increased risk of PD (OR = 2.9; 95% CI: 1.66–5.10; p = 0.0002), and was not in linkage disequilibrium with other LRRK2 coding variants. The variant was significantly associated with a lower age at PD onset in the study cohort, while a meta-analysis of the EAS cases indicated a similar, albeit non-significant trend. LRRK2 protein modelling prediction indicated that binding sites for RAB8A, RAB29 and RAB32 were in close proximity to the p.A419V variant within the ARM domain. Together, these findings confirm the p.A419V as a significant PD risk factor in EAS populations, as well as highlight disease-relevant variants in the ARM domain and the link with LRRK2-RAB signaling.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"147 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102080","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 : 2026-01-31DOI: 10.1038/s41531-026-01273-3
Guan-Yu Zhu, Timon Merk, Konstantin Butenko, Zi-Xiao Yin, Ying-Chuan Chen, Ning-Fei Li, Thomas Binns, Ruo-Yu Ma, Ting-Ting Du, Yu-Ye Liu, Hu-Tao Xie, Lin Shi, An-Chao Yang, Fan-Gang Meng, Andrea A. Kühn, Jian-Guo Zhang, Wolf-Julian Neumann
We investigated the impact of visual states on basal ganglia oscillatory biomarkers, comparing local field potentials (LFPs) dynamics between Parkinson’s disease (PD) and dystonia and developing a decoding model for state identification. Simultaneous LFPs recordings from the subthalamic nucleus (STN) or globus pallidus internus (GPi), and cortex were obtained from 18 PD and 18 dystonia patients. In the eyes-closed state, theta and alpha power increased in the basal ganglia, with stronger coherence to the central cortex, more pronounced in the STN than in the GPi. Machine learning models identified the eyes-closed state with 88% accuracy for STN and 77% for GPi. The sensorimotor STN and GPi were most informative. The present findings provide proof-of-concept that basal ganglia LFPs can reliably predict a physiological state, highlighting the potential influence of physiological oscillatory activity on pathological bands and its relevance for adaptive stimulation paradigms.
{"title":"Decoding the impact of visual states on adaptive deep brain stimulation feedback signals in movement disorders","authors":"Guan-Yu Zhu, Timon Merk, Konstantin Butenko, Zi-Xiao Yin, Ying-Chuan Chen, Ning-Fei Li, Thomas Binns, Ruo-Yu Ma, Ting-Ting Du, Yu-Ye Liu, Hu-Tao Xie, Lin Shi, An-Chao Yang, Fan-Gang Meng, Andrea A. Kühn, Jian-Guo Zhang, Wolf-Julian Neumann","doi":"10.1038/s41531-026-01273-3","DOIUrl":"https://doi.org/10.1038/s41531-026-01273-3","url":null,"abstract":"We investigated the impact of visual states on basal ganglia oscillatory biomarkers, comparing local field potentials (LFPs) dynamics between Parkinson’s disease (PD) and dystonia and developing a decoding model for state identification. Simultaneous LFPs recordings from the subthalamic nucleus (STN) or globus pallidus internus (GPi), and cortex were obtained from 18 PD and 18 dystonia patients. In the eyes-closed state, theta and alpha power increased in the basal ganglia, with stronger coherence to the central cortex, more pronounced in the STN than in the GPi. Machine learning models identified the eyes-closed state with 88% accuracy for STN and 77% for GPi. The sensorimotor STN and GPi were most informative. The present findings provide proof-of-concept that basal ganglia LFPs can reliably predict a physiological state, highlighting the potential influence of physiological oscillatory activity on pathological bands and its relevance for adaptive stimulation paradigms.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"86 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089881","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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