Frontiers in Aging Neuroscience最新文献

{"title":"Integrated transcriptomic profiling combined with <i>in vitro</i> validation reveals the involvement of TMEM140 in the link between periodontitis and brain aging.","authors":"HaoRan Zhao, HongTao Wang, WangXing Li, Rui Su, Jing Li, Yan Liu, Lei Wang","doi":"10.3389/fnagi.2026.1761218","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1761218","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;Periodontitis (PD) is a prevalent chronic inflammatory disorder in adults, and moderate-to-severe PD (Stage II-III/IV) may accelerate brain aging and neurodegenerative changes via the peripheral-central immune-neural axis, although the molecular connections and mechanisms of interaction have yet to be fully elucidated. This study sought to identify senescence-associated molecules potentially shared by PD and Alzheimer's disease (AD) using integrated transcriptomic analysis, machine learning, and &lt;i&gt;in vitro&lt;/i&gt; RNA interference assays, and to further assess the role of TMEM140 in linking PD to brain aging.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Transcriptomic datasets related to PD and AD were retrieved from the GEO database, and differential gene expression analysis was performed following batch effect correction; shared aging-associated genes were subsequently identified by combining weighted gene co-expression network analysis (WGCNA) with aging gene databases (HAGR and aging Atlas). Four machine learning algorithms, namely random forest (RF), support vector machine (SVM), generalized linear model (GLM), and extreme gradient boosting (XGB), were further applied to identify key genes, and their diagnostic value was assessed using receiver operating characteristic (ROC) analysis and nomogram models. DSigDB was used to predict candidate small-molecule compounds. In the &lt;i&gt;in vitro&lt;/i&gt; experiments, a &lt;i&gt;Porphyromonas gingivalis&lt;/i&gt; lipopolysaccharide (PG-LPS)-induced inflammatory model in human gingival fibroblasts (HGFs) and an Aβ1-42 and D-galactose-induced senescence model in SH-SY5Y neuron-like cells were established; TMEM140 in SH-SY5Y cells was then silenced using small interfering RNA (siRNA), and the neuron-like cells were treated with the same batch of standardized conditioned medium (CM; prepared from the supernatant of PG-LPS-treated HGFs) to observe changes in cellular responses to inflammatory stimulation after TMEM140 downregulation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Seven aging-related genes common to PD and AD were identified, and comprehensive analysis using multiple algorithms selected TMEM140, TIMP1, and ALDH2 as key genes. Notably, TMEM140 was upregulated in PD and downregulated in AD, showed significant correlations with plasma cell and γδ T-cell infiltration, and single-cell analysis further revealed its cell type-specific expression in distinct brain cell subsets. &lt;i&gt;In vitro&lt;/i&gt; experiments demonstrated that PG-LPS treatment markedly increased TMEM140 expression in HGFs, whereas treatment with Aβ1-42 and D-galactose reduced TMEM140 expression in neuron-like cells. When exposed to the same batch of conditioned medium, neuron-like cells with TMEM140 knockdown displayed more evident injury and senescence-related phenotypes, including reduced cell viability, increased reactive oxygen species (ROS) production, a higher percentage of senescence-associated β-galactosidase (SA-β-Gal)-positive cells, and marked","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1761218"},"PeriodicalIF":4.5,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835921","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":"Limbic-predominant neuroimaging correlates of plasma p-Tau217 in preclinical and clinical Alzheimer's disease.","authors":"Ankit Patel, William Guiler, Sam Pepper, Riley E Kemna, Paul J Kueck, Ian W Weidling, Hana D Mayfield, Casey S John, Dinesh Pal Mudaranthakam, Heather M Wilkins, Russell H Swerdlow, Jeffrey M Burns, Jill K Morris, Robyn A Honea","doi":"10.3389/fnagi.2026.1748524","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1748524","url":null,"abstract":"<p><strong>Background: </strong>Plasma phosphorylated tau at threonine 217 (p-Tau217) has emerged as a highly sensitive and specific blood-based biomarker for Alzheimer's Disease (AD). However, its regional brain correlates with multimodal neuroimaging, beyond tau-PET, remain underexplored, particularly in early disease phases where limbic involvement may predominate. This study aimed to map the associations of plasma p-Tau217 with amyloid-PET burden, FDG-PET metabolism, and structural brain morphometry in a well-characterized cohort spanning cognitively unimpaired (CU) and cognitively impaired (CI) individuals across AD dementia stages, hypothesizing increased AD neuroimaging biomarkers in individuals with elevated p-Tau217.</p><p><strong>Methods: </strong>We analyzed data from 259 participants from the University of Kansas Alzheimer's Disease Research Center (KU ADRC) Clinical Cohort. Imaging outcomes included amyloid-PET, FDG-PET, gray matter volumetric regions of interest as well as whole brain voxel-based morphometry (VBM), and surface-based morphometry (SBM) for cortical thickness (CT), sulcal depth (SD), gyrification index (GI), fractal dimension (FD). Analyses were stratified by diagnostic and pTau-217 positivity (CU pTau + , CU pTau -, CI pTau + and CI pTau-). Spearman's correlations and voxel/surface-wise regressions evaluated p-Tau217 associations with imaging metrics, accounting for age and sex.</p><p><strong>Results: </strong>Plasma p-Tau217 was elevated in CI versus CU. Individuals with elevated plasma p-Tau217 had increased amyloid-PET deposition across the cortex, as well as significantly higher centiloids, both in CU and CI individuals. In CI individuals, elevated p-Tau217 was associated with reduced voxel-wise gray matter volume and cortical thickness in limbic, temporal, parietal, and frontal regions, plus increased cingulate FD. In both CU and CI pTau + individuals, p-Tau217 correlated with AD Signature gray matter decreases.</p><p><strong>Conclusion: </strong>These findings show that CU and CI individuals with elevated plasma p-Tau217 have both increased amyloid-PET burden but also temporolimbic gray matter atrophy and hypometabolism. This supports p-Tau217 as a minimally invasive, scalable biomarker for early AD detection, risk stratification, and prognostic monitoring in preclinical stages, potentially guiding trial enrichment and personalized interventions.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1748524"},"PeriodicalIF":4.5,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835947","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":"Secretory form of viral protease NIa ameliorates amyloid-β pathology and cognitive deficits in a mouse model of Alzheimer's disease.","authors":"Euy Jun Park, Bo-Ram Mun, Sung Yoon Kim, Muthukumar Elangovan, Sung Bin Kim, Won-Seok Choi, Woo Jin Park","doi":"10.3389/fnagi.2026.1720518","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1720518","url":null,"abstract":"<p><p>Alzheimer's disease (AD), the leading cause of dementia, is characterized by extracellular amyloid-β (Aβ) accumulation. Immunotherapies targeting Aβ clearance show promise, highlighting the therapeutic value of enhancing Aβ removal. We previously identified that nuclear inclusion a (NIa), a plant viral protease, fortuitously cleaves Aβ with strict sequence specificity. Here, we engineered a secretory form, SecNIa, to degrade extracellular Aβ. SecNIa was efficiently secreted from transfected cells while retaining potent Aβ-cleaving activity. Adeno-associated virus (AAV)-mediated delivery of SecNIa into 5xFAD mice resulted in robust hippocampal expression and cerebrospinal fluid secretion. SecNIa expression significantly reduced soluble and insoluble Aβ, decreased hippocampal plaques, and improved cognition, fully normalizing recognition memory and enhancing spatial learning. These findings establish SecNIa as a promising therapeutic strategy to directly target pathogenic extracellular Aβ in AD.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1720518"},"PeriodicalIF":4.5,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836200","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":"Feasibility study of differentiating patients with levodopa-induced dyskinesia using cerebellar gray and white matter radiomics features from 3DT1WI images.","authors":"Yi Chen, Yini Chen, Andong Lin, Li Ding, Linyou Wang, Zhelin Xia, Rujia Wang","doi":"10.3389/fnagi.2026.1796614","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1796614","url":null,"abstract":"<p><strong>Background: </strong>Levodopa therapy effectively treats Parkinson's disease (PD) motor symptoms but causes Levodopa-Induced Dyskinesia (LID) in some patients long-term. Cerebellar changes exist in LID cases; however, radiomics models based on this region haven't been evaluated for diagnostic use. We built diagnostic model using cerebellar structural radiomics from 3D T1WI to non-invasively diagnose LID.</p><p><strong>Methods: </strong>In this study, we retrospectively collected 3D T1WI data from the Parkinson's Progression Markers Initiative (PPMI) database, including data from 69 LID patients and 142 non-LID (N-LID) patients. These data were randomly split into a training set and a testing set at an 8:2 ratio. Using Fastsurfer segmentation, we identified four regions of interest (ROIs) corresponding to the left and right cerebellar gray matter and white matter. Python scripts were employed to independently extract radiomic features from each ROI. Subsequent steps involved feature selection and model construction. After selecting the optimal model, its performance was evaluated and validated. Finally, the SHAP method was used for model visualization.</p><p><strong>Results: </strong>Ultimately, the most representative 13 radiomic features were used for modeling. The model built based on the XGBoost algorithm achieved an AUC value of 0.962 on the training set and 0.849 on the testing set.</p><p><strong>Conclusion: </strong>The radiomic model extracted from the cerebellar gray and white matter effectively distinguishes between LID and N-LID patients. It offers a novel perspective on the heterogeneous characteristics of LID patients, significantly enhancing diagnostic performance and providing auxiliary support for clinical diagnosis.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1796614"},"PeriodicalIF":4.5,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835866","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":"Modulating the default mode network with deep TMS: a proof-of-concept framework with potential relevance to circuits implicated in lack of awareness of cognitive decline.","authors":"Youssef Bellaali, Dominika Sulcova, Adriana Salatino, Laurence Dricot, Bernard Jimmy Hanseeuw, John L Woodard, Adrian Ivanoiu","doi":"10.3389/fnagi.2026.1742759","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1742759","url":null,"abstract":"","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1742759"},"PeriodicalIF":4.5,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836012","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":"APOE ε4 as a predictor of cognitive decline and its interaction with hippocampal volume in Alzheimer's disease.","authors":"Faizaan Fazal Khan, Jun-Hyung Kim, Ji-In Kim, Goo-Rak Kwon","doi":"10.3389/fnagi.2026.1730265","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1730265","url":null,"abstract":"<p><strong>Background/introduction: </strong>The apolipoprotein E (APOE) ε4 allele is the strongest known genetic risk factor for late-onset Alzheimer's disease, and hippocampal atrophy is among the most reliable structural biomarkers of neurodegeneration. While both are independently associated with cognitive decline, whether APOE ε4 dose modulates the hippocampal volume-cognition relationship longitudinally in sporadic Alzheimer's disease remains underexplored at adequate statistical power.</p><p><strong>Methods: </strong>This study analyzed data from 2,417 Alzheimer's Disease Neuroimaging Initiative participants with complete APOE genotypes, intracranial volume-adjusted hippocampal volumes, and longitudinal cognitive assessments spanning a mean follow-up of 4.2 years and up to 19.3 years with an average of 4.9 visits per participant. Linear mixed-effects models with random intercepts and slopes per subject estimated cognitive trajectories across the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-SB), and Alzheimer's Disease Assessment Scale Cognitive Subscale 13 (ADAS-Cog13) as a function of time, APOE ε4 dose, and ICV-adjusted hippocampal volume, including their three-way interaction and adjusting for age, sex, education, baseline diagnosis, and depression. Cox proportional hazards models were used to assess conversion risk.</p><p><strong>Results: </strong>A clear APOE ε4 dose-response gradient was observed at baseline across all cognitive and hippocampal measures (all p < 0.001). Linear mixed-effects models revealed a significant three-way interaction of time × APOE ε4 dose × hippocampal volume on MMSE (<i>β</i> = -0.79, 95% CI [-1.51, -0.08], <i>p</i> = 0.030) and CDR-SB (<i>β</i> = +0.47, 95% CI [+0.03, +0.91], <i>p</i> = 0.037) trajectories, both significant under Bonferroni correction (<i>α</i> = 0.017), indicating that APOE ε4 amplifies the association between smaller hippocampal volume and faster cognitive deterioration over time. The time × hippocampal volume interaction was confirmed as highly significant by likelihood ratio test (LR = 3712.99, <i>p</i> < 0.001). Cox proportional hazards analyses of 845 conversion events showed that each additional ε4 allele conferred a 48% increase in conversion risk (HR = 1.48, 95% CI [1.29, 1.71], <i>p</i> < 0.001). Sensitivity analyses across diagnostic strata, after outlier exclusion, and in multi-visit subsamples confirmed the robustness of hippocampal volume effects.</p><p><strong>Discussion/conclusion: </strong>These findings demonstrate that APOE ε4 genotype significantly modulates the longitudinal relationship between hippocampal volume and cognitive decline, supporting the integration of APOE genotype and structural hippocampal imaging for refined individual risk stratification in Alzheimer's disease.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1730265"},"PeriodicalIF":4.5,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835899","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":"Magnetic resonance imaging volumetry in atypical parkinsonism: current evidence and neuroradiological perspectives.","authors":"Bartosz Migda, Natalia Madetko-Alster, Anna Migda, Michał Kutyłowski, Piotr Alster","doi":"10.3389/fnagi.2026.1816084","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1816084","url":null,"abstract":"<p><p>Atypical parkinsonism, including progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal syndrome (CBS), represents a major diagnostic challenge, particularly in the early stages of disease. Magnetic resonance imaging (MRI) plays a pivotal role in the differential diagnosis of these disorders. Beyond conventional qualitative assessment, quantitative MRI techniques, especially volumetry and planimetry, have gained increasing importance as objective tools for evaluating disease specific patterns of brain atrophy. This narrative review summarizes current evidence on MRI-based morphometric approaches in atypical parkinsonism, with a particular focus on brainstem, basal ganglia, cerebellar, and cortical measurements. The diagnostic value of established indices, including the Magnetic Resonance Parkinsonism Index (MRPI) and its updated version, MRPI 2.0, is discussed, along with advances in automated segmentation and machine learning based approaches. The potential role of MRI volumetry as both a diagnostic and progression biomarker is highlighted, together with current limitations and future perspectives relevant to neuroradiological practice.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1816084"},"PeriodicalIF":4.5,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836022","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":"Systematic proteomics reveals plasma NEFL as a robust predictor and pathological associate in <i>C9ORF72</i>-related neurodegeneration.","authors":"Zhen Hu, Jing-Jin Wan, Qin-Qin Yan, Yu Fan, Jun Liu","doi":"10.3389/fnagi.2026.1792887","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1792887","url":null,"abstract":"<p><strong>Background: </strong>The <i>C9ORF72</i> repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While neurofilament light chain (NEFL) is an established biomarker of neuroaxonal damage, its specific dose-response relationship with the <i>C9ORF72</i> expansion and its potential role beyond a passive bystander require systematic investigation. We performed a proteome-wide screen to identify plasma proteins linked to the <i>C9ORF72</i> expansion and evaluated their predictive value for motor neuron disease (MND).</p><p><strong>Methods: </strong>We utilized whole-genome sequencing and plasma proteomics from the UK Biobank, analyzing 106 individuals with <i>C9ORF72</i> expansions (defined as >30 repeats) and 212 age- and sex-matched controls. We screened ~3,000 proteins for associations with the continuous repeat count. The top candidate was evaluated using restricted cubic splines (RCS) to assess non-linearity and threshold effects. Its ability to independently predict MND risk was tested using regression models and a machine learning approach.</p><p><strong>Results: </strong>Our unbiased screen identified NEFL as the sole protein significantly associated with the <i>C9ORF72</i> repeat count (FDR-adjusted <i>P</i> = 8.39 × 10^-4). NEFL levels demonstrated a step-wise increase with expansion size, which followed a stable linear trajectory across the repeat spectrum (<i>P</i> _{non - linear} = 0.4435). Elevated NEFL independently predicted MND risk (OR = 2.42; HR = 2.90), even after adjusting for the <i>C9ORF72</i> repeat count. Our predictive model, combining NEFL and repeat count, achieved an AUC of 0.941 with 100% sensitivity. These findings align with emerging evidence that secreted NEFL may actively modulate neuroinflammation.</p><p><strong>Conclusions: </strong>NEFL emerges as a robust and specific plasma biomarker for <i>C9ORF72</i>-related neurodegeneration. Its strong linear association with repeat burden and independent predictive power, contextualized within its potential role in immune activation, suggest that NEFL is deeply integrated into the <i>C9ORF72</i> pathological landscape. These findings support NEFL-based screening and monitoring strategies for early intervention in <i>C9ORF72</i> carriers.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1792887"},"PeriodicalIF":4.5,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836192","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":"Plasma Aβ42/p-Tau217 ratio and p-Tau217 independently predict CSF-defined Alzheimer's disease pathology in a Brazilian admixed cohort.","authors":"Liara Rizzi, Isadora Cristina Ribeiro, Marjorie Cristina da Rocha Silva, Ítalo Karmann Aventurato, Luis Eduardo Santos, Ananssa Maíra Dos Santos Silva, Thaís Lopes Pinheiro, Gustavo Bruniera Peres Fernandes, Fernanda Guarino De Felice, Marcio L F Balthazar","doi":"10.3389/fnagi.2026.1773606","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1773606","url":null,"abstract":"<p><strong>Introduction: </strong>Blood-based biomarkers offer a promising, minimally invasive approach to Alzheimer's disease (AD) diagnosis, yet validation in admixed populations remains limited. We investigated whether plasma biomarkers predict CSF-defined AD pathology in a Brazilian cohort.</p><p><strong>Methods: </strong>Seventy-eight older adults [including individuals with mild cognitive impairment (MCI), subjective cognitive decline (SCD), and cognitively unimpaired controls] underwent cognitive testing, neuroimaging, and plasma biomarker assessment. CSF data were available for symptomatic participants (MCI and SCD; <i>n</i> = 61), and regression and ROC analyses were performed in the subset with both CSF and APOE genotyping data (<i>n</i> = 53). Plasma Aβ42, p-Tau181, p-Tau217, t-Tau, and derived ratios were quantified. Multivariable logistic regression and ROC analyses evaluated prediction of abnormal CSF p-Tau181/Aβ42 and t-Tau/Aβ42, adjusting for age, sex, and APOE ε4 status.</p><p><strong>Results: </strong>Approximately 25% of individuals with MCI exhibited abnormal CSF p-Tau181/Aβ42 and t-Tau/Aβ42 ratios. Moderate correlations were observed between plasma and CSF biomarkers (r > 0.4), particularly for Aβ42/p-Tau217 and p-Tau217. In adjusted models, plasma p-Tau217 and the Aβ42/p-Tau217 ratio independently predicted abnormal CSF pathology. Each one standard deviation increase in p-Tau217 was associated with 3.53-4.83-fold higher odds of abnormal CSF (<i>p</i> ≤ 0.003). In contrast, higher Aβ42/p-Tau217 ratios were associated with substantially lower odds of pathology, with each one standard deviation increase corresponding to a 91%-93% reduction in risk (<i>p</i> ≤ 0.002). The ratio showed stronger associations than p-Tau217 alone. ROC analyses demonstrated good discrimination. For CSF p-Tau181/Aβ42, Aβ42/p-Tau217 achieved an AUC of 0.88 (83% sensitivity, 85% specificity), compared with 0.83 for p-Tau217. For CSF t-Tau/Aβ42, both biomarkers yielded AUCs of 0.89.</p><p><strong>Discussion: </strong>Plasma Aβ42/p-Tau217 and p-Tau217 effectively identify CSF-defined AD pathology in an admixed cohort. While higher p-Tau217 levels were associated with increased odds of pathology, higher Aβ42/p-Tau217 ratios were associated with lower pathological burden and demonstrated stronger effect sizes, supporting the added value of combining amyloid and tau biomarkers. These findings provide initial evidence for local validation of blood-based AD biomarkers in Brazil.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1773606"},"PeriodicalIF":4.5,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836032","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":"Blood-brain barrier vulnerability and microcirculatory dysfunction as predictors of hemorrhagic transformation after endovascular treatment in acute ischemic stroke.","authors":"Yuchen Wang, Qiujin Du, Wenjie Zhu, Zhang Yang, Yuanyuan Zhang","doi":"10.3389/fnagi.2026.1783952","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1783952","url":null,"abstract":"<p><strong>Background: </strong>Hemorrhagic transformation (HT) after endovascular treatment (EVT) for acute ischemic stroke (AIS) remains a major clinical challenge, particularly in populations vulnerable to vascular and endothelial injury. Beyond conventional clinical predictors, microcirculatory dysfunction and blood-brain barrier (BBB) vulnerability may critically influence the risk of hemorrhagic complications following reperfusion. However, existing prediction models often rely on isolated imaging markers or basic clinical variables, failing to capture the integrated pathophysiological processes linking collateral circulation, microvascular perfusion, and BBB integrity.</p><p><strong>Methods: </strong>This retrospective study analyzed 202 consecutive AIS patients undergoing EVT (2021-2024). Collateral circulation was assessed via ASITN/SIR scale; CT perfusion (CTP)-derived parameters (rCBF, rCBV, rMTT, rTTP, rPS) quantified microcirculation and BBB integrity. Clinical/laboratory variables (including serum globulin) were collected. Multivariate logistic regression identified HT/parenchymal hematoma (PH) predictors; a nomogram was validated via ROC, calibration, bootstrap, DCA, and CIC. HT subtypes were correlated with functional outcomes.</p><p><strong>Results: </strong>HT occurred in 82 patients (40.6%, 37 PH cases). Higher ASITN/SIR grade (OR = 0.616), rCBF (OR = 0.053), and rCBV (OR = 0.204) were protective; rPS (OR = 2.624) and serum globulin (OR = 1.138) were risk factors for HT. The multimodal model (integrating three mechanistic pathways) showed excellent discrimination (AUC = 0.867) and superior net clinical benefit. For PH, ASITN/SIR was protective (AUC = 0.745). HT patients had poorer outcomes (<i>p</i> < 0.001), with PH worse than HI (<i>p</i> = 0.046).</p><p><strong>Conclusion: </strong>This study demonstrates that BBB vulnerability, microcirculatory dysfunction, and collateral status are key determinants of hemorrhagic transformation after endovascular treatment in acute ischemic stroke. By integrating these interrelated vascular and endothelial mechanisms, the proposed model provides insight into susceptibility to reperfusion-related hemorrhagic injury and offers a practical framework for individualized risk stratification in the peri-procedural setting.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1783952"},"PeriodicalIF":4.5,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835872","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}