Pub Date : 2025-12-13DOI: 10.1038/s41531-025-01206-6
Susan H Fox,Daniel G Luca,Ronald B Postuma,Roongroj Bhidayasiri,Francisco Cardoso,Gabor G Kovacs,Regina Katzenschlager,Claudia Trenkwalder
The 2015 International Parkinson and Movement Disorder Society (MDS) Diagnostic criteria for Parkinson Disease are based on expert consensus opinion and defines core motor features, 'Absolute Exclusion Criteria' and a balance of 'Supportive Criteria' and 'Red Flags'. To assess validity of each criterion in pathologically-confirmed cases, a scoping literature review between 1988-2024 using search terms for clinicopathological PD and atypical parkinsonian disorders identified 28 articles. Supportive criteria were higher in PD, with excellent levodopa response and rest tremor most useful. Absolute exclusion criteria and red flags were present more often in atypical parkinsonian disorders. However, supranuclear gaze palsy, rapid progression of gait impairment to wheelchair requirement and bilateral symptoms were reported in >5% PD. Data was limited by few appropriate pathological studies with sufficient clinical data; challenges in applying highly-specific definitions to retrospective studies and likely co-pathologies. This review provides empiric data to support some items of the MDS Criteria with future potential refinement.
{"title":"Revisiting the 2015 MDS diagnostic criteria for Parkinson disease: insights from autopsy-confirmed cases.","authors":"Susan H Fox,Daniel G Luca,Ronald B Postuma,Roongroj Bhidayasiri,Francisco Cardoso,Gabor G Kovacs,Regina Katzenschlager,Claudia Trenkwalder","doi":"10.1038/s41531-025-01206-6","DOIUrl":"https://doi.org/10.1038/s41531-025-01206-6","url":null,"abstract":"The 2015 International Parkinson and Movement Disorder Society (MDS) Diagnostic criteria for Parkinson Disease are based on expert consensus opinion and defines core motor features, 'Absolute Exclusion Criteria' and a balance of 'Supportive Criteria' and 'Red Flags'. To assess validity of each criterion in pathologically-confirmed cases, a scoping literature review between 1988-2024 using search terms for clinicopathological PD and atypical parkinsonian disorders identified 28 articles. Supportive criteria were higher in PD, with excellent levodopa response and rest tremor most useful. Absolute exclusion criteria and red flags were present more often in atypical parkinsonian disorders. However, supranuclear gaze palsy, rapid progression of gait impairment to wheelchair requirement and bilateral symptoms were reported in >5% PD. Data was limited by few appropriate pathological studies with sufficient clinical data; challenges in applying highly-specific definitions to retrospective studies and likely co-pathologies. This review provides empiric data to support some items of the MDS Criteria with future potential refinement.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"1 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145746704","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}
Brain accumulation of toxic soluble α-synuclein (α-syn) oligomers represents a prodromal marker of synucleinopathies in Parkinson's disease (PD), contributing to progressive nigrostriatal neurodegeneration. Dysfunction in beta-glucocerebrosidase (GCase) and leucine-rich repeat kinase 2 (LRRK2) mutation are genetic risks for developing synucleinopathies. However, whether pharmacological GCase activation ameliorated synucleinopathies in LRRK2-PD was unexplored. Here, we showed that long-term treatment of ambroxol (ABX), a brain-penetrant GCase activator, reduced α-syn oligomer accumulation in aged mutant LRRK2R1441G mouse striatum. Acute ABX treatment (50 µM) increased cellular GCase enzymatic activity and reduced Ser129-α-syn phosphorylation in human SH-SY5Y cells and mutant LRRK2 mouse fibroblasts, independent to LRRK2 kinase activity. Real-time DQ-BSA assay revealed lysosomal dysfunction in mutant MEFs, which was partially attenuated by ABX treatment. Lysosomal stress by bafilomycin-A1 induced endogenous GCase activity in wildtype (WT) MEFs, which was not observed in the LRRK2 mutant. Single gavage of ABX (400 mg/kg) in aged mice achieved peak drug level in serum and brain within 6 h post-administration. Ad libitum feeding of ABX (in food pellets) over 18 weeks (average dose: 45.9 mg/kg/day) elevated brain GCase activity in both WT and mutant striatum without affecting body weight. This regimen significantly reduced α-syn oligomer level in mutant striatum to a comparable physiological level in age-matched WT without altering total α-syn and Ser129-phosphorylation levels. This is the first study demonstrating reduced α-syn oligomer accumulation by chronic treatment of GCase activator in aged mouse brains vulnerable to PD, suggesting early intervention to alter progression of synucleinopathies as a key determinant of clinical outcomes of PD.
{"title":"Long-term oral glucocerebrosidase activator reduces soluble α-synuclein oligomer accumulation in Parkinsonian LRRK2 mutant mouse brain.","authors":"Zoe Yuen-Kiu Choi,Huifang Liu,Eunice Eun-Seo Chang,Shirley Yin-Yu Pang,Ivy Lingyi Luo,Yuefei Ruan,Qi Wang,Yasine Malki,Steffi Xi-Yue Zhang,Kerry Yupeng Weng,Benson Wui-Man Lau,Roy Chun-Laam Ng,Zaijun Zhang,Shu-Leong Ho,Philip Wing-Lok Ho","doi":"10.1038/s41531-025-01205-7","DOIUrl":"https://doi.org/10.1038/s41531-025-01205-7","url":null,"abstract":"Brain accumulation of toxic soluble α-synuclein (α-syn) oligomers represents a prodromal marker of synucleinopathies in Parkinson's disease (PD), contributing to progressive nigrostriatal neurodegeneration. Dysfunction in beta-glucocerebrosidase (GCase) and leucine-rich repeat kinase 2 (LRRK2) mutation are genetic risks for developing synucleinopathies. However, whether pharmacological GCase activation ameliorated synucleinopathies in LRRK2-PD was unexplored. Here, we showed that long-term treatment of ambroxol (ABX), a brain-penetrant GCase activator, reduced α-syn oligomer accumulation in aged mutant LRRK2R1441G mouse striatum. Acute ABX treatment (50 µM) increased cellular GCase enzymatic activity and reduced Ser129-α-syn phosphorylation in human SH-SY5Y cells and mutant LRRK2 mouse fibroblasts, independent to LRRK2 kinase activity. Real-time DQ-BSA assay revealed lysosomal dysfunction in mutant MEFs, which was partially attenuated by ABX treatment. Lysosomal stress by bafilomycin-A1 induced endogenous GCase activity in wildtype (WT) MEFs, which was not observed in the LRRK2 mutant. Single gavage of ABX (400 mg/kg) in aged mice achieved peak drug level in serum and brain within 6 h post-administration. Ad libitum feeding of ABX (in food pellets) over 18 weeks (average dose: 45.9 mg/kg/day) elevated brain GCase activity in both WT and mutant striatum without affecting body weight. This regimen significantly reduced α-syn oligomer level in mutant striatum to a comparable physiological level in age-matched WT without altering total α-syn and Ser129-phosphorylation levels. This is the first study demonstrating reduced α-syn oligomer accumulation by chronic treatment of GCase activator in aged mouse brains vulnerable to PD, suggesting early intervention to alter progression of synucleinopathies as a key determinant of clinical outcomes of PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"16 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732825","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 : 2025-12-11DOI: 10.1038/s41531-025-01228-0
Ida H. Klæstrup, Line S. Reinert, Sara A. Ferreira, Johanne Lauritsen, Gitte U. Toft, Hjalte Gram, Poul H. Jensen, Søren R. Paludan, Marina Romero-Ramos
Microglia response is proposed to be relevant in the neurogenerative process associated with alpha-synuclein (α-syn) pathology in Parkinson’s disease (PD). STING is a protein related to the immune sensing of DNA and autophagy, and it has been proposed to be involved in PD neurodegeneration. To investigate this, we injected 10 µg of murine pre-formed fibrils (PFFs) of α-syn (or monomeric and PBS as controls) into the striatum of wild-type (WT) and STINGgt/gt mice, which lack functional STING. We examined motor behavior and brain pathology at 1- and 6-month post-injection. STINGgt/gt mice showed more motor changes associated with PFF injection than WT mice. STINGgt/gt mice had a differential immune response to PFF with early and sustained increased microglia numbers and higher macrophagic CD68 response, but milder changes in the expression of immune-relevant markers such as TLR2, TLR4, IL1ß, and TREM2. However, the lack of STING did not induce changes in the extent of α-syn pathology nor the p62 accumulation seen in the model. Altogether, this resulted in a faster but similar degree of nigrostriatal dopaminergic degeneration after 6 months. Therefore, the data do not support a necessary role for STING in the α-syn-induced nigral neuronal loss in the PFF-PD mouse model used here. However, the results suggest a functional relevance for STING in the brain response to the excess and aggregation of amyloidogenic proteins such as α-syn that can contribute to symptomatic changes.
{"title":"Lack of functional STING modulates immunity but does not protect dopaminergic neurons in the alpha-synuclein pre-formed fibrils Parkinson’s disease mouse model","authors":"Ida H. Klæstrup, Line S. Reinert, Sara A. Ferreira, Johanne Lauritsen, Gitte U. Toft, Hjalte Gram, Poul H. Jensen, Søren R. Paludan, Marina Romero-Ramos","doi":"10.1038/s41531-025-01228-0","DOIUrl":"https://doi.org/10.1038/s41531-025-01228-0","url":null,"abstract":"Microglia response is proposed to be relevant in the neurogenerative process associated with alpha-synuclein (α-syn) pathology in Parkinson’s disease (PD). STING is a protein related to the immune sensing of DNA and autophagy, and it has been proposed to be involved in PD neurodegeneration. To investigate this, we injected 10 µg of murine pre-formed fibrils (PFFs) of α-syn (or monomeric and PBS as controls) into the striatum of wild-type (WT) and STINGgt/gt mice, which lack functional STING. We examined motor behavior and brain pathology at 1- and 6-month post-injection. STINGgt/gt mice showed more motor changes associated with PFF injection than WT mice. STINGgt/gt mice had a differential immune response to PFF with early and sustained increased microglia numbers and higher macrophagic CD68 response, but milder changes in the expression of immune-relevant markers such as TLR2, TLR4, IL1ß, and TREM2. However, the lack of STING did not induce changes in the extent of α-syn pathology nor the p62 accumulation seen in the model. Altogether, this resulted in a faster but similar degree of nigrostriatal dopaminergic degeneration after 6 months. Therefore, the data do not support a necessary role for STING in the α-syn-induced nigral neuronal loss in the PFF-PD mouse model used here. However, the results suggest a functional relevance for STING in the brain response to the excess and aggregation of amyloidogenic proteins such as α-syn that can contribute to symptomatic changes.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"20 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718489","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 : 2025-12-11DOI: 10.1038/s41531-025-01226-2
Yuyuan Lin, Kimberly C. Paul, Dean P. Jones, Douglas I. Walker, Aline Duarte Folle, Irish Del Rosario, Yu Yu, Keren Zhang, Adrienne M. Keener, Jeff Bronstein, Beate Ritz
Depression is a common non-motor symptom of Parkinson’s disease (PD), with poorly understood mechanisms. To explore whether there are dysregulated metabolic pathways among PD patients with depression, we analyzed serum samples of PD patients from a population-based case-control study (total n = 635) and performed metabolome-wide association and pathway analyses of depression in PD. We identified 212 metabolomic features associated with having ever received a depression diagnosis before PD and 213 features with higher Geriatric Depression Scale (GDS) scores (129 were annotated). Metabolic features we identified belonged to 14 pathways: glycerophospholipid metabolism for both outcomes and tryptophan, tyrosine, folate, biopterin, and sialic acid metabolism for those with higher GDS scores. An association with 6-hydroxy-1H-indole-3acetamide we observed likely indicates recent antidepressant treatment. These findings suggest that dysregulation in lipid and amino acid pathways, including tryptophan and tyrosine metabolism involved in neurotransmitter synthesis, may reflect altered neurochemical signaling and systemic metabolic changes related to depression in PD.
{"title":"Metabolomic profiles of depression in Parkinson’s disease patients","authors":"Yuyuan Lin, Kimberly C. Paul, Dean P. Jones, Douglas I. Walker, Aline Duarte Folle, Irish Del Rosario, Yu Yu, Keren Zhang, Adrienne M. Keener, Jeff Bronstein, Beate Ritz","doi":"10.1038/s41531-025-01226-2","DOIUrl":"https://doi.org/10.1038/s41531-025-01226-2","url":null,"abstract":"Depression is a common non-motor symptom of Parkinson’s disease (PD), with poorly understood mechanisms. To explore whether there are dysregulated metabolic pathways among PD patients with depression, we analyzed serum samples of PD patients from a population-based case-control study (total n = 635) and performed metabolome-wide association and pathway analyses of depression in PD. We identified 212 metabolomic features associated with having ever received a depression diagnosis before PD and 213 features with higher Geriatric Depression Scale (GDS) scores (129 were annotated). Metabolic features we identified belonged to 14 pathways: glycerophospholipid metabolism for both outcomes and tryptophan, tyrosine, folate, biopterin, and sialic acid metabolism for those with higher GDS scores. An association with 6-hydroxy-1H-indole-3acetamide we observed likely indicates recent antidepressant treatment. These findings suggest that dysregulation in lipid and amino acid pathways, including tryptophan and tyrosine metabolism involved in neurotransmitter synthesis, may reflect altered neurochemical signaling and systemic metabolic changes related to depression in PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"112 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718486","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 : 2025-12-10DOI: 10.1038/s41531-025-01230-6
Laura Camacho-Meño,Carmen M Labandeira,Susana B Bravo,Mateo V Torres,Helena Bejr-Kasem,Angela Molina-Crespo,Mercedes Atienza,Jose L Lanciego,Jose L Cantero,Jaime Kulisevsky,Jose Luis Labandeira-Garcia,Ana I Rodriguez-Perez
In models of Parkinson's disease (PD), angiotensin-II type-1 receptor (AT1) blockers (ARBs) mitigated the vulnerability of dopaminergic neurons, which aligns with recent transcriptomic studies of human brains showing increased susceptibility of dopaminergic neurons with high AGTR1 expression, and with epidemiological data indicating an ARB-related reduction in PD incidence. However, there is no experimental evidence in PD patients. Using a minimally invasive strategy based on the isolation of blood extracellular vesicles (EVs) from neuronal, microglial/macrophage, astrocytic, and oligodendrocytic origin, we report proteomic profiles from patients treated with the ARB candesartan. Candesartan treatment led to the differential expression of key proteins involved in PD pathogenesis: 46 in neuron-derived EVs, 48 in microglia/macrophage-derived EVs, 22 in astrocyte-derived EVs, and 92 in oligodendrocyte-derived EVs. Our findings provide the first direct molecular evidence of neuroprotective mechanisms triggered by ARBs in PD patients and support the rationale for larger clinical trials on ARB repurposing.
{"title":"Brain-derived extracellular vesicle proteomics reveals neuroprotection induced by the ARB candesartan in Parkinson's disease patients.","authors":"Laura Camacho-Meño,Carmen M Labandeira,Susana B Bravo,Mateo V Torres,Helena Bejr-Kasem,Angela Molina-Crespo,Mercedes Atienza,Jose L Lanciego,Jose L Cantero,Jaime Kulisevsky,Jose Luis Labandeira-Garcia,Ana I Rodriguez-Perez","doi":"10.1038/s41531-025-01230-6","DOIUrl":"https://doi.org/10.1038/s41531-025-01230-6","url":null,"abstract":"In models of Parkinson's disease (PD), angiotensin-II type-1 receptor (AT1) blockers (ARBs) mitigated the vulnerability of dopaminergic neurons, which aligns with recent transcriptomic studies of human brains showing increased susceptibility of dopaminergic neurons with high AGTR1 expression, and with epidemiological data indicating an ARB-related reduction in PD incidence. However, there is no experimental evidence in PD patients. Using a minimally invasive strategy based on the isolation of blood extracellular vesicles (EVs) from neuronal, microglial/macrophage, astrocytic, and oligodendrocytic origin, we report proteomic profiles from patients treated with the ARB candesartan. Candesartan treatment led to the differential expression of key proteins involved in PD pathogenesis: 46 in neuron-derived EVs, 48 in microglia/macrophage-derived EVs, 22 in astrocyte-derived EVs, and 92 in oligodendrocyte-derived EVs. Our findings provide the first direct molecular evidence of neuroprotective mechanisms triggered by ARBs in PD patients and support the rationale for larger clinical trials on ARB repurposing.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"5 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145710893","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 : 2025-12-10DOI: 10.1038/s41531-025-01224-4
Elena Vacchi, Arianna Giani, Nunzio Perta, Sara Turchetti, Laura Pasetto, Valentina Bonetto, Maria Giulia Bacalini, Luca Baldelli, Federica Provini, Sandra Hackethal, Silvia Riccardi, Silvia Miano, Mauro Manconi, Georg Kägi, Ilaria Bertaina, Giovanni Bianco, Salvatore Galati, Alain Kaelin-Lang, Domenico Raimondo, Mariaelena Repici, Mauro Tettamanti, Giorgia Melli, Tiziana Borsello
Diagnosis of Parkinson’s disease (PD) remains challenging due to the lack of reliable biomarkers. To address this need, we quantified plasma levels of brain-specific c-Jun N-terminal kinase 3 (JNK3), a protein involved in neurodegeneration. A total of 108 participants were enrolled, including 25 individuals with isolated REM sleep behavior disorder (iRBD), 26 patients with De Novo PD, 29 with Late PD, and 28 age-matched healthy controls (HC). All subjects underwent clinical assessment, blood sampling, and skin biopsy. Plasma JNK3 levels were significantly elevated in PD and iRBD compared to HC, a finding that remained robust after adjustment for age and sex in multivariate logistic regression. ROC analysis demonstrated that JNK3 levels distinguished PD from HC with 100% specificity and 65% sensitivity in Late PD. In contrast, Neurofilament Light Chain showed non-significant group differences and weak discriminative performance. Notably, while JNK3 declined with age in HC, it increased with age in Late PD (P = 0.048, B = 0.105) and negatively correlated with motor impairment. Elevated JNK3 was also associated with pathological α-Synuclein in skin biopsy. These findings highlight JNK3 as a promising blood biomarker for PD, with meaningful diagnostic and prognostic value, suggesting that its implementation could refine patient stratification and improve clinical trial efficiency.
由于缺乏可靠的生物标志物，帕金森病（PD）的诊断仍然具有挑战性。为了满足这一需求，我们量化了脑特异性c-Jun n-末端激酶3 （JNK3）的血浆水平，JNK3是一种参与神经变性的蛋白质。共纳入108名参与者，包括25名孤立性快速眼动睡眠行为障碍（iRBD）患者，26名新生PD患者，29名晚期PD患者和28名年龄匹配的健康对照（HC）。所有受试者均接受了临床评估、血液取样和皮肤活检。与HC相比，PD和iRBD的血浆JNK3水平显著升高，在多因素logistic回归中调整了年龄和性别后，这一发现仍然强劲。ROC分析表明，JNK3水平在晚期PD中区分PD和HC的特异性为100%，敏感性为65%。而神经丝轻链组间差异不显著，辨别能力弱。值得注意的是，JNK3在HC中随着年龄的增长而下降，而在PD晚期随着年龄的增长而增加（P = 0.048, B = 0.105），并且与运动障碍呈负相关。在皮肤活检中，JNK3的升高也与病理性α-突触核蛋白有关。这些发现突出了JNK3作为PD的一种有前景的血液生物标志物，具有有意义的诊断和预后价值，表明其实施可以细化患者分层，提高临床试验效率。
{"title":"JNK3 quantification in plasma: a novel biomarker for neuronal damage in Parkinson’s disease","authors":"Elena Vacchi, Arianna Giani, Nunzio Perta, Sara Turchetti, Laura Pasetto, Valentina Bonetto, Maria Giulia Bacalini, Luca Baldelli, Federica Provini, Sandra Hackethal, Silvia Riccardi, Silvia Miano, Mauro Manconi, Georg Kägi, Ilaria Bertaina, Giovanni Bianco, Salvatore Galati, Alain Kaelin-Lang, Domenico Raimondo, Mariaelena Repici, Mauro Tettamanti, Giorgia Melli, Tiziana Borsello","doi":"10.1038/s41531-025-01224-4","DOIUrl":"https://doi.org/10.1038/s41531-025-01224-4","url":null,"abstract":"Diagnosis of Parkinson’s disease (PD) remains challenging due to the lack of reliable biomarkers. To address this need, we quantified plasma levels of brain-specific c-Jun N-terminal kinase 3 (JNK3), a protein involved in neurodegeneration. A total of 108 participants were enrolled, including 25 individuals with isolated REM sleep behavior disorder (iRBD), 26 patients with De Novo PD, 29 with Late PD, and 28 age-matched healthy controls (HC). All subjects underwent clinical assessment, blood sampling, and skin biopsy. Plasma JNK3 levels were significantly elevated in PD and iRBD compared to HC, a finding that remained robust after adjustment for age and sex in multivariate logistic regression. ROC analysis demonstrated that JNK3 levels distinguished PD from HC with 100% specificity and 65% sensitivity in Late PD. In contrast, Neurofilament Light Chain showed non-significant group differences and weak discriminative performance. Notably, while JNK3 declined with age in HC, it increased with age in Late PD (P = 0.048, B = 0.105) and negatively correlated with motor impairment. Elevated JNK3 was also associated with pathological α-Synuclein in skin biopsy. These findings highlight JNK3 as a promising blood biomarker for PD, with meaningful diagnostic and prognostic value, suggesting that its implementation could refine patient stratification and improve clinical trial efficiency.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"39 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711542","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 : 2025-12-10DOI: 10.1038/s41531-025-01231-5
Xiaxuan Huang, Yitong Ling, Shanyuan Tan, Zihong Bai, Si Shen, Hao Wang, Jun Lyu
Cognitive frailty has emerged as an important concept in research and clinical practice, yet the combined effect of cognitive reserve and frailty on neurodegenerative disease risk remains unexplored. This study included 346,025 UK Biobank participants followed for up to 15 years. Cognitive reserve indicators were generated using latent class analysis based on educational level, occupational achievement, confiding in others, social contact, leisure activities, and television viewing time. The primary outcome was neurodegenerative disease, with secondary outcomes including Parkinson’s disease, Alzheimer’s disease, and all-cause dementia. During a median follow-up of 13.7 years, 5,590 new cases of neurodegenerative diseases were diagnosed. Compared to non-frail individuals, pre-frail and frail individuals had 1.47-fold (95% CI: 1.39-1.55) and 2.74-fold (95% CI: 2.46-3.06) increased risk, respectively, while high cognitive reserve conferred protection (HR = 0.82, 95% CI: 0.76-0.87). In joint effect analysis, individuals with low levels of cognitive reserve and frailty had the highest risk (HR = 3.13, 95% CI: 2.70-3.63), demonstrating significant additive interaction. Cross-sectional neuroimaging analyses showed that lower cognitive reserve levels was associated with reduced total brain volume (β = -0.161), reduced hippocampal volumes (βleft = -0.085, βright = -0.097), and increased white matter hyperintensities (β = 0.045). These findings emphasize maintaining cognitive reserve and managing frailty as modifiable factors for preventing neurodegenerative diseases.
{"title":"Cognitive reserve, frailty status, and risk of neurodegenerative diseases: a prospective cohort study","authors":"Xiaxuan Huang, Yitong Ling, Shanyuan Tan, Zihong Bai, Si Shen, Hao Wang, Jun Lyu","doi":"10.1038/s41531-025-01231-5","DOIUrl":"https://doi.org/10.1038/s41531-025-01231-5","url":null,"abstract":"Cognitive frailty has emerged as an important concept in research and clinical practice, yet the combined effect of cognitive reserve and frailty on neurodegenerative disease risk remains unexplored. This study included 346,025 UK Biobank participants followed for up to 15 years. Cognitive reserve indicators were generated using latent class analysis based on educational level, occupational achievement, confiding in others, social contact, leisure activities, and television viewing time. The primary outcome was neurodegenerative disease, with secondary outcomes including Parkinson’s disease, Alzheimer’s disease, and all-cause dementia. During a median follow-up of 13.7 years, 5,590 new cases of neurodegenerative diseases were diagnosed. Compared to non-frail individuals, pre-frail and frail individuals had 1.47-fold (95% CI: 1.39-1.55) and 2.74-fold (95% CI: 2.46-3.06) increased risk, respectively, while high cognitive reserve conferred protection (HR = 0.82, 95% CI: 0.76-0.87). In joint effect analysis, individuals with low levels of cognitive reserve and frailty had the highest risk (HR = 3.13, 95% CI: 2.70-3.63), demonstrating significant additive interaction. Cross-sectional neuroimaging analyses showed that lower cognitive reserve levels was associated with reduced total brain volume (β = -0.161), reduced hippocampal volumes (βleft = -0.085, βright = -0.097), and increased white matter hyperintensities (β = 0.045). These findings emphasize maintaining cognitive reserve and managing frailty as modifiable factors for preventing neurodegenerative diseases.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"142 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711546","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 : 2025-12-09DOI: 10.1038/s41531-025-01196-5
Diego L. Guarín
We developed a method to quantify hand postural tremor amplitude and frequency from standard videos without external calibration. Using iris-based scaling and deep-learning models for 3D pose estimation and hand tracking, the automatic approach demonstrated excellent agreement with manual measures. Clinical validation in persons with Parkinson’s disease demonstrated sensitivity to treatment effects and strong correlation with clinician-provided scores. The proposed method, available as part of VisionMD, enables objective, scalable assessment of postural tremor from standard videos.
{"title":"Video-based quantification of hand postural tremor without external references. Integrating postural tremor quantification into visionMD","authors":"Diego L. Guarín","doi":"10.1038/s41531-025-01196-5","DOIUrl":"https://doi.org/10.1038/s41531-025-01196-5","url":null,"abstract":"We developed a method to quantify hand postural tremor amplitude and frequency from standard videos without external calibration. Using iris-based scaling and deep-learning models for 3D pose estimation and hand tracking, the automatic approach demonstrated excellent agreement with manual measures. Clinical validation in persons with Parkinson’s disease demonstrated sensitivity to treatment effects and strong correlation with clinician-provided scores. The proposed method, available as part of VisionMD, enables objective, scalable assessment of postural tremor from standard videos.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"140 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145705081","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 : 2025-12-09DOI: 10.1038/s41531-025-01213-7
Guendalina Bastioli, Maria Mancini, Jyoti C. Patel, Begoña Gamallo-Lana, Jennifer C. Arnold, Adam C. Mar, Margaret E. Rice
Aging is often accompanied by a decline in mobility across species, which can be improved by aerobic exercise, even in individuals with Parkinson’s disease. We showed previously that 30 days of voluntary wheel-running exercise in young male mice leads to enhanced release of the motor-system transmitter, dopamine (DA), in ex vivo corticostriatal slices. Here we tested whether voluntary exercise also increases DA release in aging (12 months old) mice of both sexes, and whether this is associated with improved motor performance. Mice were allowed unlimited access to a rotating (runners) or a locked (controls) wheel for 30 days. Motor behavior was then assessed, and electrically evoked DA release was quantified in slices from these animals using fast-scan cyclic voltammetry. Although daily running distance for females was nearly twice that of males, runners of both sexes showed comparable increases in evoked DA release in dorsolateral striatum and in nucleus accumbens core and shell compared to age- and sex-matched controls. Runners of both sexes showed an increase in locomotion velocity and improved motor coordination. Thus, voluntary exercise boosts striatal DA release and improves motor performance in aging mice, providing new insights into the benefits of exercise in aging humans.
{"title":"Voluntary exercise increases striatal dopamine release and improves motor performance in aging mice","authors":"Guendalina Bastioli, Maria Mancini, Jyoti C. Patel, Begoña Gamallo-Lana, Jennifer C. Arnold, Adam C. Mar, Margaret E. Rice","doi":"10.1038/s41531-025-01213-7","DOIUrl":"https://doi.org/10.1038/s41531-025-01213-7","url":null,"abstract":"Aging is often accompanied by a decline in mobility across species, which can be improved by aerobic exercise, even in individuals with Parkinson’s disease. We showed previously that 30 days of voluntary wheel-running exercise in young male mice leads to enhanced release of the motor-system transmitter, dopamine (DA), in ex vivo corticostriatal slices. Here we tested whether voluntary exercise also increases DA release in aging (12 months old) mice of both sexes, and whether this is associated with improved motor performance. Mice were allowed unlimited access to a rotating (runners) or a locked (controls) wheel for 30 days. Motor behavior was then assessed, and electrically evoked DA release was quantified in slices from these animals using fast-scan cyclic voltammetry. Although daily running distance for females was nearly twice that of males, runners of both sexes showed comparable increases in evoked DA release in dorsolateral striatum and in nucleus accumbens core and shell compared to age- and sex-matched controls. Runners of both sexes showed an increase in locomotion velocity and improved motor coordination. Thus, voluntary exercise boosts striatal DA release and improves motor performance in aging mice, providing new insights into the benefits of exercise in aging humans.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"56 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145705160","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 : 2025-12-09DOI: 10.1038/s41531-025-01197-4
Morvarid Ghamgosar Shahkhali, Lang Liu, Emma N. Somerville, Alastair J. Noyce, Ziv Gan-Or, Konstantin Senkevich
Tumor necrosis factor (TNF) inhibition is under investigation as a therapeutic strategy for Parkinson’s disease (PD) and REM sleep behavior disorder (RBD), yet supporting genetic evidence is limited. We used Summary-data-based Mendelian Randomization (SMR) to test whether expression level of ten TNF-related genes were causally linked to PD risk, PD progression, or RBD risk. We also analyzed associations between common and rare variants in these genes, and performed pathway specific polygenic risk score analysis, with PD. Overall, our findings do not support a genetic link between the TNF signaling and PD or RBD, arguing against this pathway as a genetically validated therapeutic target.
{"title":"No evidence for genetic role of the tumor necrosis factor pathway in Parkinson’s disease","authors":"Morvarid Ghamgosar Shahkhali, Lang Liu, Emma N. Somerville, Alastair J. Noyce, Ziv Gan-Or, Konstantin Senkevich","doi":"10.1038/s41531-025-01197-4","DOIUrl":"https://doi.org/10.1038/s41531-025-01197-4","url":null,"abstract":"Tumor necrosis factor (TNF) inhibition is under investigation as a therapeutic strategy for Parkinson’s disease (PD) and REM sleep behavior disorder (RBD), yet supporting genetic evidence is limited. We used Summary-data-based Mendelian Randomization (SMR) to test whether expression level of ten TNF-related genes were causally linked to PD risk, PD progression, or RBD risk. We also analyzed associations between common and rare variants in these genes, and performed pathway specific polygenic risk score analysis, with PD. Overall, our findings do not support a genetic link between the TNF signaling and PD or RBD, arguing against this pathway as a genetically validated therapeutic target.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"5 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145705083","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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