Frontiers in Aging Neuroscience最新文献

{"title":"Circulating and cerebrospinal fluid soluble TREM2 levels and risk of perioperative neurocognitive disorders in surgical patients: a systematic review and meta-analysis.","authors":"Haotian Wu, Yujie Wang, Zhifeng Gao, Huan Zhang","doi":"10.3389/fnagi.2026.1899745","DOIUrl":"10.3389/fnagi.2026.1899745","url":null,"abstract":"<p><strong>Background: </strong>Perioperative neurocognitive disorders (PND), including postoperative delirium (POD) and cognitive dysfunction (POCD), are common surgical complications in older adults. Neuroinflammation from microglial activation is a key mechanism. Soluble TREM2 (sTREM2) is a blood/CSF biomarker reflecting microglial activity. Existing studies on sTREM2 and PND risk have been inconsistent. We conducted the first meta-analysis to quantify this association.</p><p><strong>Methods: </strong>We searched PubMed, Web of Science, Scopus, APA PsycInfo, Embase, the Cochrane Library (CENTRAL), and https://www.ClinicalTrials.gov, CNKI, and Wanfang Data up to August 2026 for observational studies reporting perioperative sTREM2 levels in surgical patients with/without PND. Primary outcome was standardized mean difference (SMD) in sTREM2 between PND cases and controls, using a random-effects model. Heterogeneity was assessed via <i>I</i> ². Subgroup and sensitivity analyses were performed. PROSPERO: CRD420261386903.</p><p><strong>Results: </strong>Eight studies (1,154 patients) were included; seven with quantitative data (1,072 patients) were meta-analyzed. Patients with PND had higher sTREM2 levels than controls (SMD = 0.44, 95% CI: 0.02 to 0.87, <i>p</i> = 0.040; <i>I</i> ² = 86.5%). Subgroup analyses showed a positive direction of effect in CSF (SMD = 0.61, 95% CI: -0.02 to 1.23) but not in peripheral blood (SMD = 0.18, 95% CI: -0.13 to 0.49). Leave-one-out sensitivity analysis showed that the pooled estimate became non-significant after excluding the largest study, warranting cautious interpretation. One additional study reported that postoperative CSF sTREM2 elevation independently predicted POCD (adjusted OR = 1.07, 95% CI: 1.01-1.13).</p><p><strong>Conclusion: </strong>Elevated perioperative sTREM2 concentrations in cerebrospinal fluid, but not in peripheral blood, showed a modest positive association with PND risk. sTREM2 represents a candidate biomarker for perioperative cognitive complications; however, the very low certainty of the underlying evidence precludes definitive conclusions. Large-scale standardized studies are needed to validate its clinical utility.</p><p><strong>Systematic review registration: </strong>The systematic review was prospectively registered in PROSPERO (Unique Identifier: CRD420261386903), https://www.crd.york.ac.uk/prospero/.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1899745"},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13669114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215343","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":"Eye-movement-based machine learning for identifying Parkinson's disease dementia in a retrospective cohort: an interpretable model-development study.","authors":"Jing Wu, Qing Liu, Song Yang, Yuqing Zhang, Yuanlu Shu, Junwen Wang, Min Wu, Tian Tian","doi":"10.3389/fnagi.2026.1935091","DOIUrl":"10.3389/fnagi.2026.1935091","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease dementia (PDD) is a major non-motor complication of Parkinson's disease (PD), but conventional cognitive screening is influenced by education, language, motor impairment, fatigue, and testing conditions. We developed and interpreted machine-learning models using eye-movement and demographic features to identify PDD among patients with PD.</p><p><strong>Methods: </strong>In this retrospective single-center study, 486 patients were screened between December 2024 and February 2025. After exclusions, 297 patients with idiopathic PD were analyzed, including 84 without dementia and 213 with PDD. Thirteen machine-learning algorithms were trained using demographic and task-derived eye-movement variables. Performance was assessed using ROC AUC, PR AUC, classification metrics, calibration, the Brier score, and decision-curve analysis. SHapley Additive exPlanations (SHAP) were used to interpret the final model.</p><p><strong>Results: </strong>Patients with PDD showed poorer cognitive performance and abnormalities in antisaccade inhibition, saccade execution, and fixation stability. Seven predictors were retained: age, sex, education level, antisaccade accuracy, mean overlap-saccade completion duration, mean gap-saccade velocity, and lateral-gaze deviation duration >4°. Logistic regression and elastic net achieved the highest test-set ROC AUCs (both 0.962), while logistic regression had the lowest Brier score (0.077). A radial basis function support vector machine (SVM) was retained as the primary classifier for detailed evaluation because it provided balanced performance across threshold-dependent metrics and could capture potentially nonlinear relationships and interactions. In the test set, the SVM achieved a ROC AUC of 0.947 and PR AUC of 0.979. Accuracy, sensitivity, specificity, and F1 score were 0.867, 0.870, 0.857, and 0.904, respectively. SHAP identified education, antisaccade accuracy, mean overlap-saccade completion duration, mean gap-saccade velocity, and lateral-gaze deviation duration >4° as the leading contributors.</p><p><strong>Conclusion: </strong>A seven-feature model combining demographic and eye-movement measures showed promising internal discrimination of PDD from PD without dementia. Eye-movement-based machine learning may complement clinical cognitive assessment, but external validation in larger and more representative cohorts is required before clinical use.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1935091"},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13669113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215361","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":"Cardiorespiratory fitness is associated with cerebral oxygen extraction in Alzheimer's disease.","authors":"Paul J Kueck, Zachary D Green, Raechel Camones, Casey S John, Robyn A Honea, Jeffrey M Burns, Eric D Vidoni, Jill K Morris","doi":"10.3389/fnagi.2026.1943472","DOIUrl":"10.3389/fnagi.2026.1943472","url":null,"abstract":"<p><p>Cardiorespiratory fitness (CRF) is a modifiable determinant of brain health and has been associated with greater brain volume, improved cognition, and reduced dementia risk. However, whether CRF influences cerebral oxygen extraction fraction (OEF), a marker reflecting the balance between cerebral oxygen delivery and metabolic demand, remains poorly understood in aging and Alzheimer's disease (AD). We performed a secondary analysis of the Acute Exercise Response on Brain Imaging and Cognition (AEROBIC) study to investigate relationships among CRF, cerebral blood flow (CBF), and OEF in cognitively healthy older adults (CH) and individuals with AD. Multivariable linear regression demonstrated that higher CRF was independently associated with lower OEF. A significant CRF × diagnosis interaction indicated that this relationship was present in AD but not CH. Across the full cohort, higher CBF was strongly associated with lower OEF, and this relationship was preserved across diagnostic groups. Regional analyses demonstrated similar inverse associations between CBF and OEF in multiple cortical regions involved in cognitive and autonomic regulation. These findings suggest that greater CRF may reduce reliance on oxygen extraction by improving the adequacy of cerebral oxygen delivery in AD. Together, CRF, CBF, and OEF provide complementary physiological information regarding cerebral oxygen metabolism and may improve understanding of cerebrovascular physiology in aging and AD.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1943472"},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13668864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215265","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":"Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch.","authors":"Carlye Frisch, Lauren Baker, Gayathri Srinivasan, Albert E Mintah, Salma Leyasi, Morgan Pedroza, Brooke Galyon, David A Brafman","doi":"10.3389/fnagi.2026.1856154","DOIUrl":"10.3389/fnagi.2026.1856154","url":null,"abstract":"<p><strong>Introduction: </strong>Alzheimer's disease (AD) is a progressive neurodegenerative disorder influenced by both causal mutations and genetic modifiers. The rare APOE3 Christchurch (APOE3ch) variant has been associated with delayed disease onset in a familial Alzheimer's disease case, suggesting a potential protective role. However, the mechanisms underlying this protection, particularly across different genetic backgrounds, remain unclear.</p><p><strong>Methods: </strong>We generated isogenic human induced pluripotent stem cell (hiPSC)-derived neural cultures harboring either PSEN1 E280A or amyloid precursor protein duplication (APPdp) mutations, with and without the APOE3ch variant, using prime editing. Neural differentiation, amyloid-beta production, amyloid precursor protein processing, tau phosphorylation and transcriptomic profiles were assessed.</p><p><strong>Results: </strong>APOE3ch did not affect neural differentiation or apolipoprotein E secretion. However, it exhibited mutation-dependent effects on Alzheimer's disease phenotypes. In amyloid precursor protein duplication cultures, APOE3ch significantly reduced amyloid-beta production and shifted processing toward non-amyloidogenic pathways, accompanied by decreased phosphorylated tau. In contrast, in PSEN1 E280A cultures, APOE3ch had minimal impact on amyloid-beta levels but increased non-amyloidogenic processing and altered total tau without affecting phosphorylation. Transcriptomic analysis revealed both shared and mutation-specific effects, with consistent modulation of pathways related to synaptic function, including Wnt and cadherin signaling.</p><p><strong>Discussion: </strong>These findings demonstrate that APOE3ch acts as a context-dependent modifier of Alzheimer's disease pathology, with protective effects varying by genetic background. The variant consistently influences pathways associated with synaptic resilience while differentially modulating amyloid and tau pathology. This work provides mechanistic insight into APOE3ch-mediated protection and highlights the importance of genetic context in developing targeted therapeutic strategies for Alzheimer's disease.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1856154"},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13669193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215520","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":"No evidence that serum metabolite slopes improve held-out prediction of clinical progression in the Alzheimer's disease neuroimaging initiative.","authors":"Tia Warrick, Manali Misra, Stephen Kataria, Jahnavi Patel, Bhuvi Ajmera","doi":"10.3389/fnagi.2026.1942662","DOIUrl":"10.3389/fnagi.2026.1942662","url":null,"abstract":"<p><strong>Background: </strong>Repeated serum metabolite measurements may contribute to predicting clinical progression, but their incremental value requires evaluation beyond established clinical predictors.</p><p><strong>Methods: </strong>We linked Alzheimer's Disease Neuroimaging Initiative (ADNI) clinical data to Biocrates Quant 500 serum measurements. Annualized metabolite slopes were estimated from baseline through month 12, usually from two observations. At the month-12 landmark, participants without dementia were characterized by diagnosis, memory performance, and APOE ε4 status; progression was assessed at approximately month 36. Models were developed in ADNI1 (225 participants; 26 events) and applied without refitting to ADNI-GO/2 (269 participants; 50 events). We compared a clinical logistic model with a model that added a data-derived phosphatidylcholine (PC) aa C42:1 candidate slope. Models using 88 phosphatidylcholine-family metabolite slopes or 598 full-panel slopes were exploratory.</p><p><strong>Results: </strong>The clinical model achieved an area under the receiver operating characteristic curve (AUROC) of 0.758 (95% CI, 0.675-0.838). Adding PC aa C42:1 changed the AUROC by +0.0004 (-0.013 to 0.017). Both partially penalized lasso models retained no metabolite slopes at the selected penalty. A <i>post-hoc</i> evaluation restricted to 233 participants with mild cognitive impairment, including 38 events, also found no evidence of incremental discrimination. Other sensitivity analyses yielded similar results.</p><p><strong>Conclusion: </strong>We found no evidence that annualized serum metabolite slopes improved held-out prediction in this sample. The 26 development events limited estimation and feature selection, so these results cannot distinguish between a lack of incremental prognostic information and insufficient data to identify such information. Larger development samples and independent validation are needed to assess the value of serial metabolomics.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1942662"},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215538","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":"Selective autophagy inhibition alleviates oxidative stress-associated neurodegeneration in an AD+CCH model.","authors":"Xiaorui Huang, Jufang Chen, Zhicheng Lu, Jie Wang, Xuelian Luo, Qiuyan Qin, Qin Yang, Chongdong Jian, Xuebin Li, Jingwei Shang","doi":"10.3389/fnagi.2026.1870441","DOIUrl":"10.3389/fnagi.2026.1870441","url":null,"abstract":"<p><p>Dysregulated autophagy is increasingly implicated in the progression of Alzheimer's disease (AD), particularly when chronic cerebral hypoperfusion (CCH) coexists and exacerbates neurodegeneration. However, the relationship between autophagy dysregulation and oxidative stress responses under combined AD+CCH conditions remains incompletely understood. Here, APP/PS1 transgenic mice subjected to CCH were used to evaluate the effects of autophagy modulation with 3-methyladenine (3MA) and rapamycin (RAPA). CCH worsened cognitive impairment and neuronal injury in APP/PS1 mice and was accompanied by altered LC3-II and p62 expression, consistent with disturbed autophagy-related processing. These changes occurred together with increased expression of proteins associated with oxidative stress responses, including Keap1, Nrf2, HO-1, HIF-1α, and NOX-1. Notably, 3MA improved behavioral performance, reduced Aβ40 burden, and was associated with partial normalization of p62, Keap1, Nrf2, and downstream oxidative stress-related proteins. In contrast, RAPA did not confer detectable protection in this model. Age-stratified analyses further showed that abnormalities in autophagy- and oxidative stress-related markers were more severe at 12 months than at 9 months. Collectively, these findings support an association between altered autophagy-related processing and oxidative stress signaling in AD with chronic hypoperfusion and nominate the p62-Keap1-Nrf2 pathway as a candidate mechanism for further causal investigation.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1870441"},"PeriodicalIF":5.2,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13662021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180446","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":"Behavioral markers of motor reserve: stability, lateralization, and consistency.","authors":"David Vagni, Emanuela Principe, Melissa Pirrotta, Laura Catalano, Chiara Milasi, Morena De Francesco, Andreina Giustiniani, Chiara Arena, Francesco Scarfone, Angelo Quartarone, Domenico Bosco, Giovanni Pioggia, Antonio Cerasa","doi":"10.3389/fnagi.2026.1921302","DOIUrl":"10.3389/fnagi.2026.1921302","url":null,"abstract":"<p><strong>Background: </strong>Motor reserve has been phenomenologically defined as the capacity to maintain motor performance despite aging-related or disease-related changes, but its objective kinematic basis remains insufficiently characterized. We operationalized motor reserve using measures from a sensor-equipped glove and tested whether they capture inter-individual differences beyond chronological aging.</p><p><strong>Methods: </strong>We enrolled 100 healthy adults (50 older and 50 younger) with a deliberately bimodal age distribution contrasting a young baseline with an older sample of interest. The glove recorded finger-level contact events during four tapping tasks (self-paced, maximum-velocity, synchronization to a 2-Hz metronome, and continuation after metronome withdrawal), each performed under right-hand, left-hand, and bilateral conditions. Motor reserve was assessed with the Motor Reserve Index questionnaire. Candidate kinematic indices were constructed to capture endogenous timing stability, externally paced velocity, bimanual coordination, touch-duration lateralization, and cross-context consistency (ClinicalTrials.gov database n° NCT07634055).</p><p><strong>Results: </strong>The central finding concerns which kinematic dimensions survive adjustment for chronological age. Aging affected a broad set of glove-derived parameters, most strongly under external pacing. After formal assessment of age confounding, three of the five candidate axes-endogenous timing stability, touch-duration lateralization, and cross-context consistency-retained an association with the Motor Reserve Index questionnaire (MRIq) independent of age, whereas externally paced velocity tracked age rather than reserve. A residual index (rMR) combining the three retained axes was associated with MRIq within the older group and predicted it out-of-sample (leave-one-out <i>r</i> = +0.50; <i>r</i> = +0.42 under nested cross-validation). Supporting analyses showed that the association was absent in the younger group, that the group-by-index interaction was significant, and that rMR was related to MRIq but not to cognitive reserve (CRIq) or to general neuropsychological performance.</p><p><strong>Conclusion: </strong>These findings provide initial evidence for a candidate kinematic index of motor reserve in healthy aging. Motor reserve was not reducible to global motor speed or chronological age but expressed as a multidimensional profile of timing stability, lateralized motor organization, and consistency across task contexts.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1921302"},"PeriodicalIF":5.2,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179762","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":"Coordinated cellular architecture reveals weakened cortical structure-behavior coupling in normal aging.","authors":"Xiaoyi Zhan, Pengcheng Tan, Tirzah Tan, Chia-Chien Chen","doi":"10.3389/fnagi.2026.1932616","DOIUrl":"10.3389/fnagi.2026.1932616","url":null,"abstract":"<p><p>Normal aging compromises behavioral functions supported by cortical circuits, yet how age-related cellular reorganization relates to weakened circuit-behavior correspondence remains poorly defined. Here, we examined layer 4 (L4) of the mouse primary somatosensory barrel cortex, a thalamorecipient lamina in which dendritic organization, microglial process architecture, and whisker-dependent tactile function can be analyzed within the same sensory system. Aged mice showed impaired whisker-dependent texture discrimination. Using high-resolution three-dimensional cellular reconstructions, we quantified the morphology and spatial architecture of L4 pyramidal neurons and microglia in young and aged mice. We then applied within-domain principal component analysis (PCA) to derive architecture scores and tested how these scores mapped onto whisker-dependent behavior. Aging reduced the complexity and spatial extent of L4 pyramidal dendritic arbors, while microglia showed reduced process complexity and territorial occupancy. Across both cell types, these changes converged on a more spatially restricted local cellular architecture. PCA organized high-dimensional morphometric variables into dominant architecture scores that captured coordinated morphometric organization within the neuronal and microglial domains. In young animals, dominant architecture scores were associated with whisker-dependent tactile discrimination; residual scores and same-texture encoding indices did not show significant corresponding association. Within-age permutation analyses and direct Fisher r-to-z comparisons supported an age-dependent weakening of architecture-behavior correspondence. These findings identify parallel neuronal and microglial morphological changes as an anatomical axis of cortical aging, with restricted cellular architecture accompanied by weakened architecture-behavior correspondence in sensory cortex.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1932616"},"PeriodicalIF":5.2,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13662101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179989","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":"Prediction of cognitive impairment in Parkinson's disease using TabPFN: an integrative analysis of clinical data, longitudinal trajectories, and lipidomics.","authors":"Zikai Zhou, Jie Liu, Lijuan Wang, Hong Lv, Wencan Jiang, Ling Huang, Guojun Zhang, Ruimin Ma","doi":"10.3389/fnagi.2026.1905374","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1905374","url":null,"abstract":"<p><strong>Background: </strong>Cognitive impairment is a common and disabling non-motor manifestation of Parkinson's disease (PD). Early identification of patients at high risk remains challenging, and the metabolic mechanisms underlying cognitive decline are not fully understood.</p><p><strong>Methods: </strong>We conducted a retrospective cohort study including PD patients who were cognitively normal at baseline. A machine learning model based on a Tabular Prior-data Fitted Network (TabPFN) was developed using routinely collected clinical and laboratory data to predict future cognitive impairment. Model performance was evaluated using stratified group cross-validation and external validation in the Parkinson's Progression Markers Initiative (PPMI) cohort. Model interpretability was assessed using SHapley Additive exPlanations (SHAP). Longitudinal analyses and untargeted lipidomics were performed to explore temporal and molecular alterations associated with cognitive decline.</p><p><strong>Results: </strong>Among 91 patients in the internal cohort, 45 developed cognitive impairment during follow-up. The TabPFN model achieved an AUC of 0.822 (95% CI 0.709-0.889) in internal validation and 0.742 (95% CI 0.695-0.783) in external validation. In internal benchmark comparisons, TabPFN showed numerically higher discrimination than logistic regression (AUC = 0.728) and random forest (AUC = 0.787). MoCA and age were the most influential predictors, while triglycerides (TG) also contributed to model predictions. In the longitudinal analysis, TG trajectories differed between converters and stable participants after adjustment for relevant covariates (group-by-time interaction: β = -0.146, 95% CI - 0.248 to -0.044; <i>p</i> = 0.005). In the independent lipidomics cohort, although total TG abundance did not differ significantly between cognitive groups, several individual lipid species, including specific TG species, showed differential abundance.</p><p><strong>Conclusion: </strong>A TabPFN-based model using routinely available clinical and biochemical variables showed promising discrimination for future cognitive impairment in PD. TG contributed to prediction, and longitudinal analyses identified different TG trajectories between converters and stable participants. The cross-sectional lipidomics findings provide complementary, hypothesis-generating information about molecular lipid heterogeneity but do not establish the mechanism underlying the longitudinal TG pattern. Prospective multicenter validation is required before clinical implementation.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1905374"},"PeriodicalIF":5.2,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13662187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149192643","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":"Complement C4b and factor B in astrocyte-derived exosomes as novel biomarkers for amnestic mild cognitive impairment.","authors":"Yu Li, Menglu Zhang, Chao Ying, Chao Han, Qimeng Li, Yanning Cai","doi":"10.3389/fnagi.2026.1727449","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1727449","url":null,"abstract":"<p><p>Neuroinflammation represents a fundamental pathological mechanism underlying amnestic mild cognitive impairment (aMCI), with dysregulated activation of the complement system playing a pivotal role. Astrocyte-derived exosomes (ADEs), which are capable of traversing the blood-brain barrier (BBB), offer a non-invasive means to investigate central nervous system pathology. This study explored the diagnostic potential of two principal complement components, C4b and factor B (FB), within plasma-derived ADEs for aMCI and analyzed their interaction with the <i>ApoE</i> ε4 allele. We enrolled 99 aMCI patients and 96 demographically matched normal controls (NC). C4b and FB levels in plasma-derived ADEs were quantified using ELISA, and all participants underwent <i>ApoE</i> genotyping. In the total cohort, levels of both C4b and FB in ADEs were significantly elevated in the aMCI group compared to NC. Diagnostic model validation demonstrated that adding C4b alone or in combination with FB to a baseline model significantly improved diagnostic performance, whereas adding FB alone provided no significant benefit. Notably, the <i>ApoE</i> ε4 genotype exerted a precise modulatory effect: among <i>ApoE</i> ε4 non-carriers, C4b levels were elevated in the aMCI group but did not yield significant diagnostic improvement; in contrast, among <i>ApoE</i> ε4 carriers, both C4b and FB were specifically upregulated, and only their combination achieved excellent diagnostic performance (AUC = 0.833; DeLong's test, <i>P</i> = 0.017), whereas neither marker alone was effective. Furthermore, C4b exhibited broader and more significant correlations with cognitive function compared to FB. This study substantiates that ADE-derived C4b serves as a reliable diagnostic biomarker for aMCI, whereas the diagnostic efficacy of FB is contingent upon <i>ApoE</i> ε4 allele status. Consequently, we propose a precision diagnostic strategy that involves the concurrent assessment of C4b and FB specifically in individuals carrying the <i>ApoE</i> ε4 allele, thereby presenting a novel approach for the early detection of aMCI.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1727449"},"PeriodicalIF":5.2,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149192645","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}