Frontiers in Aging Neuroscience最新文献

{"title":"Effects of dual-task training on health-related quality of life and cognitive function in people with Parkinson's disease: a systematic review and meta-analysis.","authors":"Leandro Cerda-Pérez, Catalina Gutiérrez-Rojas, Valentina Retamal-Salazar, Karina Rodríguez-Faúndez, Javiera Venegas-Alarcón, Jordan Hernandez-Martinez, Cristian Sandoval-Vásquez, Pablo Valdés-Badilla, Edgar Vásquez-Carrasco","doi":"10.3389/fnagi.2026.1939266","DOIUrl":"10.3389/fnagi.2026.1939266","url":null,"abstract":"<p><strong>Introduction: </strong>Dual-task training is proposed as a rehabilitative strategy to mitigate motor and cognitive impairments in patients with Parkinson's disease (PD). This systematic review and meta-analysis sought to consolidate existing information regarding the impact of dual-task therapies on health-related quality of life (HRQoL) and cognitive performance in middle-aged and older persons diagnosed with PD.</p><p><strong>Methods: </strong>A systematic review of randomized controlled trials (RCTs) published to May 2026 was performed utilizing PubMed, EBSCOhost, Scopus, and Web of Science. The chosen studies adhered to the PICOS framework. The Methodological quality and certainty of evidence were assessed using the Cochrane Risk of Bias 2 tool and GRADE framework, respectively. The review protocol is recorded in PROSPERO under the number CRD420251159680.</p><p><strong>Results: </strong>Out of 3,037 identified records, 10 RCTs met the eligibility criteria and were included in the systematic review, of which 9 contributed data to the meta-analysis. The meta-analysis showed a statistically significant but modest effect on HRQoL measured with the Parkinson's Disease Questionnaire-39 (SMD = 0.35; 95% CI: 0.03-0.67; <i>p =</i> 0.03). No significant between-group effects were observed for TMT-A (MD = 0.99; 95% CI: -3.38 to 5.37; <i>p =</i> 0.66), TMT-B (SMD = 0.02; 95% CI: -0.24 to 0.29; <i>p =</i> 0.86), or MoCA (SMD = 0.19; 95% CI: -0.26 to 0.64; <i>p =</i> 0.41).</p><p><strong>Conclusion: </strong>Dual-task interventions may produce a modest improvement in HRQoL in people with Parkinson's disease, whereas the current evidence does not demonstrate significant benefits for the cognitive outcomes assessed. These findings should be interpreted cautiously given the limited number of studies, methodological limitations, and clinical heterogeneity across interventions.</p><p><strong>Systematic review registration: </strong>https://www.crd.york.ac.uk/PROSPERO/view/CRD420251159680, identifier CRD420251159680.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1939266"},"PeriodicalIF":5.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13654966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of transcranial direct current stimulation on gait and balance under dual-task conditions in older adults: a systematic review and meta-analysis.","authors":"Yunxing Bi, Hongjie Ni, Ziqing Hou, Jinghua Qian","doi":"10.3389/fnagi.2026.1924261","DOIUrl":"10.3389/fnagi.2026.1924261","url":null,"abstract":"<p><strong>Objective: </strong>This systematic review and meta-analysis evaluated the effects of transcranial direct current stimulation (tDCS) on gait and balance outcomes measured under dual-task (DT) conditions in older adults.</p><p><strong>Methods: </strong>Following PRISMA guidance, four databases were searched through October 13, 2025. Random-effects meta-analyses used Hedges' <i>g</i>. Healthy older adults were prespecified as the primary population; clinical populations were analysed separately and mixed-population estimates were treated as exploratory. Multi-arm estimates were consolidated at the study level. Crossover trials used an assumed within-participant correlation (corr) of 0.50, with sensitivity analyses at 0.25 and 0.75. Risk of bias was assessed with RoB 2 and certainty with GRADE.</p><p><strong>Results: </strong>Fifteen studies involving 385 participants were included, and 12 contributed to quantitative synthesis. The forest plots present exploratory mixed-population estimates: dual-task gait speed was not significantly improved (Hedges' <i>g</i> = 0.071, 95% CI -0.199 to 0.340; <i>p</i> = 0.607), whereas the dual-task cost (DTC) of gait speed was reduced (Hedges' <i>g</i> = -0.362, 95% CI -0.538 to -0.185; <i>p</i> < 0.001). Exploratory reductions were also observed for DTC of sway speed, sway area, and DTC of sway area. In the prespecified healthy-older-adult primary analysis, gait speed (Hedges' <i>g</i> = 0.200, 95% CI 0.017 to 0.383; <i>p</i> = 0.032) and its DTC (Hedges' <i>g</i> = -0.368, 95% CI -0.557 to -0.179; <i>p</i> < 0.001) favoured tDCS. The gait-speed result was sensitive to the assumed crossover correlation, whereas gait-speed DTC remained significant across correlation assumptions.</p><p><strong>Conclusion: </strong>In healthy older adults, tDCS may improve gait speed and reduce its dual-task cost, but the gait-speed inference depends on the assumed crossover correlation and both estimates are based on only two studies. Evidence for other gait, variability, mobility, and standing-balance outcomes was inconclusive or could not be pooled within the healthy population. Evidence regarding falls, long-term benefit, and safety remains insufficient.</p><p><strong>Systematic review registration: </strong>https://www.crd.york.ac.uk/PROSPERO/view/CRD420251206965, PROSPERO Unique Identifier: CRD420251206965.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1924261"},"PeriodicalIF":5.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of globus pallidus internus deep brain stimulation on freezing of gait in Parkinson's disease: a prospective short-term single-arm study.","authors":"Pingchen Zhang, Linghao Cao, Tengjiao Wang, Dianyou Li, Shengdi Chen, Jun Liu, Hua He, Haiyan Zhou","doi":"10.3389/fnagi.2026.1848040","DOIUrl":"10.3389/fnagi.2026.1848040","url":null,"abstract":"<p><strong>Background: </strong>Freezing of gait (FoG) is a debilitating symptom in Parkinson's disease (PD), often resistant to medication. Deep brain stimulation (DBS) has emerged as an effective treatment for advanced PD, while its effect on FoG remains inconsistent. Specifically, the effect of globus pallidus internus deep brain stimulation (GPi-DBS) against FoG is inconclusive, and relevant studies are scarce.</p><p><strong>Objective: </strong>To describe the post-operative effect of GPi-DBS on FoG and identify pre-operative predictors of improvement.</p><p><strong>Methods: </strong>Forty-six PD patients undergoing GPi-DBS were assessed pre-operatively and at short-term follow-up (a median of 11 months) using the Gait and Falls Questionnaire (GFQ) and a comprehensive Timed Up and Go (TUG) test that quantified five FoG-related TUG indices. The primary outcome was the within-individual change in TUG total time, computed as the pre-operative med-off value minus the DBS-on med-off value. The secondary outcomes were changes of pre-operative med-off vs. med-on (the acute levodopa response) and pre-operative med-off vs. DBS-off med-off (a within-subject negative control for disease progression). Pre-operative predictors of FoG were assessed to predict the within-individual change in the TUG indices by performing forward stepwise Akaike Information Criterion (AIC) regression analysis.</p><p><strong>Results: </strong>At short-term follow-up, FoG measures (the TUG-derived indices and the self-reported GFQ) improved after GPi-DBS. TUG total time decreased by a median of 5.0 s (95% CI 1.5-14.5; FDR = 0.003), and the longest FoG duration by 1.0 s (95% CI 0-3.5; FDR = 0.030); the other three TUG indices improved in the same direction but did not survive correction (FDR 0.064-0.080). Additionally, GFQ total score decreased from a baseline median of 24 to 17 (Hodges-Lehmann median difference 4.0 points; 95% CI 0-8; <i>n</i> = 46; <i>p</i> = 0.036). In the forward-stepwise AIC regression (<i>n</i> = 40), the pre-operative axial levodopa response was the only pre-operative variable retained for the TUG changes; among the four motor components, only the DBS- related change in the axial subscore was significantly correlated with TUG improvement (Spearman ρ = 0.431, 95% CI 0.138-0.654, <i>p</i> = 0.006).</p><p><strong>Conclusions: </strong>Within this single-arm cohort, FoG measures improved over short-term follow-up after GPi-DBS, and greater pre-operative axial levodopa-responsiveness was associated with greater TUG improvement.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1848040"},"PeriodicalIF":5.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of 12-week 24-form Tai Chi on cognitive function, cerebral perfusion, and vascular function in postmenopausal women with mild cognitive impairment: an exploratory randomized controlled trial.","authors":"Yan Zheng, Lifen Hong, Lijuan Wu, Xinbei Chen, Qiaoling Hu, Liming Chen, Xuling Ni, Xiaojin Zhuang, Lianhua Yin","doi":"10.3389/fnagi.2026.1880915","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1880915","url":null,"abstract":"<p><strong>Background: </strong>Postmenopausal women are at increased risk of mild cognitive impairment (MCI). Vascular and cerebrovascular dysfunction may contribute to this increased vulnerability. Tai Chi has been shown to benefit cognitive function, but its effects on cerebrovascular health in this high-risk population remain poorly defined. This study aimed to evaluate the impact of a 12-week Tai Chi intervention on cognitive performance, cerebral perfusion, and circulating vasomotor and Alzheimer's disease (AD)-related biomarkers in postmenopausal women with MCI.</p><p><strong>Methods: </strong>This single-center, parallel-group, open-label exploratory randomized controlled trial was conducted from June 2023 to September 2024 in Fuzhou, China. Forty postmenopausal women with MCI were randomized in a 1:1 ratio using block randomization to either a 12-week supervised 24-form Tai Chi program or a health education control group. Primary and secondary outcomes included Montreal Cognitive Assessment (MoCA) total and domain-specific scores, cerebral blood flow in cognition-related brain regions, circulating vasomotor factors, and serum AD-related biomarkers.</p><p><strong>Results: </strong>Compared with the health education control group, the Tai Chi group showed greater improvement in MoCA total score (<i>β</i> = 4.95, <i>p</i> < 0.001) and in delayed recall (<i>β</i> = 1.50), visuospatial/executive function (<i>β</i> = 1.10), and attention (<i>β</i> = 1.05) (all <i>p</i> < 0.001). Tai Chi was also associated with greater increases in global and regional CBF, including a significant group-by-time interaction for global CBF (<i>β</i> = 15.29, <i>p</i> < 0.001), as well as increased plasma NO (<i>β</i> = 10.41, <i>p</i> < 0.001), a lower ET-1/NO ratio (<i>β</i> = -0.97, <i>p</i> = 0.004), and greater reductions in circulating T-tau (<i>β</i> = -255.45, <i>p</i> < 0.001), P-tau (<i>β</i> = -135.67, <i>p</i> < 0.001), and Aβ_1-42 (<i>β</i> = -169.41, <i>p</i> < 0.001). No intervention-related adverse events occurred.</p><p><strong>Conclusion: </strong>A 12-week program of standardized 24-form Tai Chi was associated with improvements in overall cognitive performance as assessed by the MoCA in postmenopausal women with MCI. These cognitive changes were accompanied by increased cerebral perfusion, a more favorable vasomotor profile, and reductions in circulating AD-related biomarkers. Tai Chi appears to be a feasible and well-tolerated non-pharmacological intervention for this vulnerable population.</p><p><strong>Clinical trial registration: </strong>ChiCTR2300068871.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1880915"},"PeriodicalIF":5.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tau protein in Parkinson's disease: advances in phosphoproteomics and molecular dynamics simulations.","authors":"Jessica Ledesma-Aparicio, Luis Alberto Caro-Gómez, Francisco Javier Padilla-Godínez, Omar Hernández-González, Luis O Soto-Rojas, Juan Pablo Reyes-Grajeda, Oscar Arias-Carrión, Marcela Palomero-Rivero, Brandt Bertrand, Carlos Munoz-Garay, Magdalena Guerra-Crespo","doi":"10.3389/fnagi.2026.1841131","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1841131","url":null,"abstract":"<p><p>Tau dysregulation, particularly abnormal phosphorylation, is increasingly implicated in Parkinson's disease (PD) and in the pathogenic interaction between Tau and α-synuclein. This review proposes an integrated PD-focused workflow connecting phosphoproteomic discovery, structural modeling, computational drug discovery, and experimental validation. Phosphoproteomic analyses of post-mortem brain tissue, biofluids, and patient-derived dopaminergic neuronal models can identify candidate Tau phosphosignatures associated with vulnerable brain regions, α-synuclein pathology, genetic background, or clinical progression. Molecular dynamics simulations can then evaluate how these signatures alter Tau conformation, microtubule binding, aggregation-prone motifs, membrane association, and pathogenic protein interactions. The resulting structural information can guide ensemble docking, chemoinformatics, and artificial intelligence approaches to prioritize conformer-selective ligands and regulatory targets. Candidate biomarkers should subsequently be validated in independent and longitudinal PD cohorts, whereas therapeutic candidates require mechanistic and functional validation in PD-relevant experimental models before clinical translation. This iterative framework may help distinguish mechanistically relevant Tau phosphoconformers from nonspecific phosphorylation changes, support biomarker-based patient stratification, and focus therapeutic development on structurally defined pathological states. Because much of the available structural evidence derives from Alzheimer's disease and other tauopathies, direct validation in PD remains essential. By linking PD-derived and disease-relevant molecular evidence with atomistic mechanisms and therapeutic prioritization, this workflow may support biomarker-informed strategies aimed at restoring Tau homeostasis and disrupting pathogenic Tau-α-synuclein interactions.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1841131"},"PeriodicalIF":5.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbial characteristics and kynurenine-related metabolism across sarcopenia groups: associations with neuromuscular and physical function.","authors":"Chang Fang, Chen Wang, Rui Wang, Yi-Fan Lu, Ling Ma","doi":"10.3389/fnagi.2026.1883616","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1883616","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Sarcopenia is characterized by heterogeneous alterations in muscle mass, strength, and physical performance and may involve interactions among the gut microbiota, tryptophan metabolism, and neuromuscular function. However, these biological characteristics across different sarcopenia stages remain incompletely understood. This study investigated gut microbial characteristics, kynurenine-related metabolism, circulating biomarkers, and physical function in older adults with different sarcopenia status.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In this cross-sectional study, 67 older adults were classified according to the Asian Working Group for Sarcopenia 2019 criteria as non-sarcopenia (NSG, &lt;i&gt;n&lt;/i&gt; = 17), possible sarcopenia (PSG, &lt;i&gt;n&lt;/i&gt; = 20), or sarcopenia (SG, &lt;i&gt;n&lt;/i&gt; = 30). Muscle mass, handgrip strength, and multidimensional physical performance were assessed. Serum C-terminal agrin fragment (CAF), tumor necrosis factor-α (TNF-α), amino acids, kynurenine (KYN), and tryptophan (Trp) were measured, and the KYN/Trp ratio was calculated. Gut microbiome composition was characterized by shotgun metagenomic sequencing. Differential abundance was evaluated using MaAsLin2 with adjustment for age and body mass index (BMI), and exploratory correlations among microbial genera, metabolites, circulating biomarkers, and physical function were examined with false discovery rate correction.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;ASMI was significantly lower in the SG group than in the NSG and PSG groups, whereas several measures of physical performance differed among groups without a uniform stepwise pattern. No significant differences were observed in alpha diversity, beta diversity, or the Firmicutes/Bacteroidetes ratio, and sarcopenia group explained only 3% of the variation in overall microbial community composition (PERMANOVA, &lt;i&gt;R&lt;/i&gt; &lt;sup&gt;2&lt;/sup&gt; = 0.03, &lt;i&gt;p&lt;/i&gt; = 0.226). Several genus-level associations were nominally significant after adjustment for age and BMI, but none remained significant after BH-FDR correction. After adjustment for age and BMI, serum KYN concentrations and the KYN/Trp ratio were significantly higher in the SG group than in the NSG group (&lt;i&gt;p&lt;/i&gt; = 0.011 and &lt;i&gt;p&lt;/i&gt; = 0.043, respectively), whereas Trp and the measured amino acids showed no significant pairwise differences. The unadjusted increase in CAF across sarcopenia groups was attenuated after covariate adjustment, and TNF-α did not differ significantly among groups. Exploratory correlation analyses identified several FDR-significant associations across microbial, metabolic, and functional domains, including negative associations of KYN and KYN/Trp with handgrip strength and a positive association between CAF and 6-m gait speed(GS).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Established sarcopenia was associated with altered circulating kynurenine-related metabolism despite the absence of pronounced differences in overall gut microbial community structure. Exp","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1883616"},"PeriodicalIF":5.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mediating effect of social frailty on oral frailty and cognitive function in older adults: a cross-sectional study in a rural Chinese community.","authors":"Zhiyue Jiang, Mei Wu, Ji Tang, Lingyao Xia, Jin Hu, Quanxiang Zhou, Xing Yang, Jingyuan Yang","doi":"10.3389/fnagi.2026.1826825","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1826825","url":null,"abstract":"<p><strong>Background: </strong>Cognitive function has been associated with both social and oral frailty. However, few studies have explored how social frailty and oral frailty jointly relate to cognitive function. This study aimed to explore whether social frailty plays a mediating role in the association between oral frailty and cognitive function and to examine potential gender differences in this pathway.</p><p><strong>Methods: </strong>This was a cross-sectional study design, and the data were obtained from the 2022 follow-up survey of the Health Status of Rural Older Adults (HSRO). The Mini-Mental State Examination (MMSE) was used to assess cognitive function, the Tanaka's Oral Frailty Index-8 (OFI-8) was used to assess the risk of oral frailty, and social frailty was assessed using an operational definition that included five items: going out less frequently, rarely visiting friends, feeling unhelpful to friends or family, living alone, and not talking with someone every day. Statistical analyses were performed using hierarchical multiple linear regression analysis and Hayes' PROCESS version 4.1 for mediation analysis in SPSS (IBM, Armonk, NY, United States).</p><p><strong>Results: </strong>Oral frailty, social frailty, and cognitive function were significantly related (<i>p</i> < 0.05). After adjusting for potential confounding variables, oral frailty and social frailty were negatively associated with cognitive function. The total effect of oral frailty on cognitive function was -0.089 (95% CI: -0.206, 0.028), and the indirect effect mediated by social frailty was -0.067 (95% CI: -0.103, -0.034), while the direct effect value was -0.022 (95% CI: -0.143, 0.098). The proportion of the indirect effect was 75%. In older men, the total effect of oral frailty on cognitive function was -0.206 (95% CI: -0.389, -0.024), and the indirect effect mediated by social frailty was -0.062 (95% CI: -0.119, -0.016). In older women, the total effect of oral frailty on cognitive function was not statistically significant, whereas the indirect effect through social frailty was -0.075 (95% CI: -0.139, -0.031).</p><p><strong>Conclusion: </strong>This cross-sectional study suggests that social frailty may mediate the association between oral frailty and cognitive function, providing statistical evidence of an association among these three factors. However, further prospective longitudinal studies are needed to validate these findings.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1826825"},"PeriodicalIF":5.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of unsupervised and supervised machine learning approaches to blood-based biomarkers of Alzheimer's disease in a memory clinic cohort.","authors":"Edoardo Guido Torrigiani, Davide Cianca, Lorenzo Gaetani, Giovanna Nardi, Federico Paolini Paoletti, Davide Chiasserini, Lucilla Parnetti, Luca Gammaitoni, Igor Neri, Giovanni Bellomo","doi":"10.3389/fnagi.2026.1922577","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1922577","url":null,"abstract":"<p><strong>Introduction: </strong>Blood-based biomarkers (BBMs) are promising tools to facilitate biological diagnosis of Alzheimer's Disease (AD). Establishing reliable cutoffs for BBMs represents a major issue for real-world implementation and the investigation of combined BBM approaches is limited. Our aim is to test different machine learning (ML) models for BBMs interpretation with respect to established gold-standard <i>in vivo</i> biomarkers, i.e., cerebrospinal fluid (CSF) biomarkers, to enhance their standalone and combined diagnostic value for AD.</p><p><strong>Methods: </strong>We selected 434 patients who referred to Perugia University Hospital for perceived cognitive decline with available CSF A β 42/40, pTau181 and tTau and plasma Aβ42, Aβ40, pTau217, pTau181 and NfL. Multiple unsupervised clustering algorithms for cutoff determination and supervised classification models were compared for the prediction of AD defined by a CSF A⁺/T ⁺ profile.</p><p><strong>Results: </strong>Different unsupervised clustering models obtained cutoffs with high performances in predicting an AD CSF profile (accuracy > 0.85). Each combination of cutoffs was tested, the best ones achieving A⁺/T⁺ CSF profile prevalences > 0.9 in BBM-positive subgroups. The best supervised ML models achieved accuracies up to 0.88 in 10-fold cross-validation.</p><p><strong>Discussion: </strong>Our results prove that clustering approaches can help in identifying reliable BBMs cutoffs for AD diagnosis even in the absence of CSF gold standard reference and that ML approaches combining multiple BBMs can strongly enhance their diagnostic accuracy.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1922577"},"PeriodicalIF":5.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differentiating early Parkinson's disease from multiple system atrophy on multimodal PET/MRI using atlas-guided segmentation and vision transformer classification.","authors":"Chao Cong, Xuewei Zhang, Shams Tabrez Rifat, Hongyun Tan, Jinju Sun, Wenping Peng, Xiao Chen","doi":"10.3389/fnagi.2026.1928959","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1928959","url":null,"abstract":"<p><strong>Introduction: </strong>Early differentiation between Parkinson's disease (PD) and multiple system atrophy-parkinsonian type (MSA-P) remains clinically challenging because of overlapping motor symptoms and subtle imaging abnormalities.</p><p><strong>Methods: </strong>We developed a fully automated multimodal PET/MRI framework for early PD-MSA-P differentiation that integrates atlas-guided subject-specific label generation, nnU-Net segmentation of the caudate nuclei and putamina, multimodal image fusion, and Vision Transformer classification with multi-slice voting (ViT+MSV). A total of 155 early-stage patients, including 121 with PD and 34 with MSA-P, were evaluated using patient-level stratified 4-fold cross-validation.</p><p><strong>Results: </strong>The segmentation model achieved an overall Dice score of 0.853 (95% CI, 0.830-0.877) and an IoU of 0.747 (95% CI, 0.725-0.770). ViT+MSV achieved a cross-validated AUC of 0.947 (95% CI, 0.905-0.981), an accuracy of 0.929 (95% CI, 0.890-0.968), a sensitivity of 0.942 (95% CI, 0.900-0.982), and a specificity of 0.882 (95% CI, 0.765-0.974). The combination of [¹⁸F]fluorodeoxyglucose (FDG) PET, [¹¹C]CFT dopamine-transporter PET, and T2-weighted imaging (T2WI) showed the best overall classification performance. Grad-CAM visualizations showed that class-discriminative gradient-based saliency was mainly concentrated on the bilateral putamen.</p><p><strong>Discussion: </strong>These findings suggest that anatomically guided multimodal PET/MRI analysis with transformer-based classification may support early PD-MSA-P differentiation while providing spatially interpretable evidence for model decisions.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1928959"},"PeriodicalIF":5.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MAPK3 as a ferroptosis driver in excitatory neurons in Alzheimer's disease: from genetic causal inference to <i>in vivo</i> functional validation.","authors":"Xiaoqiong An, Changge Wei, Manni Cao, Jianwei Xu, Wenfeng Yu, Zhenkui Ren","doi":"10.3389/fnagi.2026.1868908","DOIUrl":"10.3389/fnagi.2026.1868908","url":null,"abstract":"<p><strong>Introduction: </strong>Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and ferroptosis-an iron-dependent form of regulated cell death-has been increasingly implicated in AD-related neuronal loss. However, the causal relationship between specific ferroptosis-related genes and AD, particularly within defined neuronal subtypes, remains incompletely understood.</p><p><strong>Methods: </strong>We integrated two-sample Mendelian Randomization (MR) with single-cell expression quantitative trait locus (eQTL) analysis, followed by in vivo validation using AAV9-c-fos-mediated MAPK3 knockdown in APP/PS1 transgenic mice and in vitro validation using siRNA-mediated MAPK3 silencing in Aβ-treated HT22 neurons.</p><p><strong>Results: </strong>MR analysis of large-scale genetic datasets identified seven ferroptosis-related genes with causal associations with AD. Single-cell eQTL MR prioritized MAPK3 as a significant risk factor specifically within excitatory neurons. AAV9-c-fos-mediated MAPK3 knockdown in APP/PS1 mice significantly ameliorated cognitive deficits in the Morris water maze. Mechanistically, MAPK3 knockdown inhibited aberrant CaMKII phosphorylation, activated the Nrf2-GPX4 antioxidant axis (upregulation of GPX4, HO-1, and FTH1; downregulation of ACSL4 and KEAP1), and reestablished the Bax/Bcl-2 equilibrium, thereby reducing both ferroptosis and apoptosis. These effects were reproduced in Aβ-treated HT22 neurons following siRNA-mediated MAPK3 silencing.</p><p><strong>Discussion: </strong>Our findings identify MAPK3 in excitatory neurons as a potential causal link between genetic risk and AD pathogenesis, bridging population-level genetic risk and cellular vulnerability. Targeting the MAPK3-CaMKII-Nrf2 axis may represent a promising, cell-type-specific therapeutic strategy for AD.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1868908"},"PeriodicalIF":5.2,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13645776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}