Frontiers in Aging Neuroscience最新文献

{"title":"Persistent Alzheimer-related molecular dysregulation after cerebral ischemia: a hierarchical-circular hypothesis of impaired allostatic recovery.","authors":"Samuel Ruesga Mundo","doi":"10.3389/fnagi.2026.1938670","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1938670","url":null,"abstract":"<p><strong>Introduction: </strong>Growing evidence suggests a consistent association between brain ischemia and the subsequent development of Alzheimer's disease (AD)-related molecular changes. Experimental and clinical studies have demonstrated that ischemic episodes trigger the overexpression of genes associated with AD pathology, including amyloid precursor protein (APP), β-secretase (BACE1), presenilin 1 and 2 (PSEN1, PSEN2), and MAPT (tau). However, the mechanisms by which transient or chronic ischemic events convert transient gene dysregulation into sustained neurodegenerative pathology remain poorly understood. We acknowledge that current evidence, largely derived from animal models, does not establish that ischemia alone is sufficient to initiate AD as defined by the 2024 NIA-AA biological criteria (core amyloid and tau biomarkers); rather, ischemia may act as a significant contributor that accelerates or exacerbates AD-related molecular changes in vulnerable individuals.</p><p><strong>Objective: </strong>To propose a multilevel reconceptualization of the ischemic contribution to AD within the hierarchical-circular model of biological memory and the construct of allostatic integrity, integrating recent evidence on post-ischemic gene expression, neuroinflammation, oxidative stress, and epigenetic mechanisms.</p><p><strong>Hypothesis and synthesis: </strong>We propose that cerebral ischemia acts as a high-intensity allostatic challenge that may \"freeze\" biological memory into a pathological configuration. Within this framework, ischemic episodes are not merely transient vascular events but rather serve as biological \"programmers\" that dysregulate AD-associated genes across multiple levels of biological organization: genetic-epigenetic (DNA methylation, microRNA dysregulation), cellular-mitochondrial (oxidative stress, mitophagy failure), synaptic-neurotrophic (loss of plasticity), neuroimmune-proteostatic (chronic neuroinflammation, protein misfolding), and behavioral-cognitive (progressive dementia). The persistent overexpression of APP, BACE1, PSEN1, PSEN2, and MAPT represents a failure of the system's capacity to restore adaptive circular information flow after an ischemic insult.</p><p><strong>Implications: </strong>This model reframes the ischemic contribution to AD from a linear cause-effect relationship to a dynamic, multilevel failure of allostatic adaptation. It provides a conceptual roadmap for understanding why ischemic events may predispose to sporadic AD and suggests that therapeutic strategies should target the restoration of allostatic integrity across multiple levels rather than single molecular pathways.</p><p><strong>Testable predictions: </strong>The framework generates falsifiable predictions, including: (1) composite indices of allostatic integrity will predict post-ischemic AD progression better than single biomarkers; (2) interventions that restore allostatic integrity (e.g., anti-inflammatory agents, epigenetic modul","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1938670"},"PeriodicalIF":5.2,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180496","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":"Muscle quality index combined with plasma metabolomics: enhancing risk stratification for post-stroke dementia.","authors":"Zhen Tan, Shuang Li, Tianjiao Li, Lei Liu, Xinrui Xue, Xiaoping Li, Hongqiang Ren","doi":"10.3389/fnagi.2026.1837030","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1837030","url":null,"abstract":"<p><strong>Objective: </strong>Post-stroke dementia is a severe long-term stroke complication with heavy medical burdens, and early risk identification is critical. This study explored the association of muscle quality index (MQI) and plasma metabolomics with dementia among stroke survivors.</p><p><strong>Methods: </strong>This study included 7,047 UK Biobank participants with a history of stroke who were free of dementia at the baseline assessment. MQI was defined as dominant handgrip strength (HGS) divided by corresponding arm fat-free mass. Plasma metabolomics was analyzed via high-throughput nuclear magnetic resonance (NMR). Metabolomics risk scores (MRS-ACD, MRS-AD, and MRS-VaD) were constructed using metabolite features screening with LASSO regression and XGBoost algorithms. Statistical analyses included Cox proportional hazards models, time-dependent receiver operating characteristic (TD-ROC), restricted cubic spline (RCS) regression, interaction analyses, Mendelian randomization (MR), and several sensitivity analyses.</p><p><strong>Results: </strong>Higher MQI was associated with lower risks of all-cause dementia (ACD), Alzheimer's disease (AD) and vascular dementia (VaD) (all <i>p</i> for trend <0.05). Each 1-SD increment in MRS was associated with a higher risk of ACD (HR = 1.63, 95% CI: 1.36-1.96), AD (HR = 2.40, 95% CI: 1.74-3.31), and VaD (HR = 1.92, 95% CI: 1.46-2.54). Individuals with high MRS and lowest MQI had the highest ACD (HR = 3.29, 95% CI: 1.91-5.68), AD (HR = 5.83, 95% CI: 1.75-19.37), and VaD (HR = 4.57, 95% CI: 2.28-9.14) risk. MQI was linearly negatively associated with ACD (<i>p</i> for non-linear = 0.240) and VaD (<i>p</i> for non-linear = 0.665), and non-linearly associated with AD (<i>p</i> for non-linear = 0.013). Two-sample MR using genetically proxied grip strength and lean mass provided suggestive genetic evidence for muscle-dementia relationships: higher genetically predicted lean mass reduced AD risk (OR = 0.92, 95% CI 0.86-0.99, <i>p</i> = 0.027), while grip strength showed an independent protective effect on VaD after accounting for lean mass (OR = 0.16, 95% CI 0.04-0.64, <i>p</i> = 0.009). Extensive sensitivity analyses confirmed the robustness of the main findings.</p><p><strong>Conclusion: </strong>Joint assessment of MQI and plasma metabolomics provides suggestive evidence for stratifying post-stroke dementia risk and may assist early risk screening in stroke survivors.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1837030"},"PeriodicalIF":5.2,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658159/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180513","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":"Evaluation of peripheral and intranigral AAV-mediated Irisin delivery in a chronic AAV-A53T α-Synuclein overexpression mouse model of Parkinson's disease.","authors":"Chunyan Shu, Jiehong Huang, Wandi Pu, Haoyuan Liang, Zucai Xu, Xijin Wang, Lixi Li","doi":"10.3389/fnagi.2026.1918326","DOIUrl":"10.3389/fnagi.2026.1918326","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD) is characterized by progressive loss of dopaminergic neurons in the substantia nigra and pathological aggregation of α-Synuclein (α-Syn). Although Irisin has shown neuroprotective effects in acute MPTP-induced and α-Syn preformed fibrils (PFFs) propagation models, its therapeutic effects in a chronic α-Syn overexpression model remain incompletely defined.</p><p><strong>Methods: </strong>In the present study, we evaluated the effects of AAV8-Irisin delivered either peripherally via tail vein injection or centrally via direct intranigral co-administration in the AAV9-A53T mouse model.</p><p><strong>Results: </strong>Under the tested doses, routes, and intervention schedule, neither peripheral nor intranigral AAV8-Irisin delivery produced statistically significant improvements in behavioral performance, dopaminergic neuron survival, α-Synuclein pathology, glial activation, or AQP4 polarization; however, numerical trends were observed in select measures, including motor coordination and TH-positive neuron counts.</p><p><strong>Conclusion: </strong>These findings suggest that, under the current experimental conditions, a clear neuroprotective benefit of Irisin was not readily detectable in this model. Whether modest effects might emerge under different exposure levels, intervention windows, or adequately powered designs remains unknown.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1918326"},"PeriodicalIF":5.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164216","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":"Unraveling changes in mitochondrial processes influenced by ancestry in <i>APOEε</i>4 carriers with Alzheimer disease.","authors":"M D M Muniz Moreno, K Celis, F Rajabli, P L Whitehead, K L Hamilton-Nelson, D M Dykxhoorn, K Nuytemans, M M Mesulam, D A Bennett, T Schuck, S Weintraub, C Geula, M Gearing, C Alba, C L Dalgard, D A Davis, W K Scott, J L Haines, M A Pericak-Vance, A J Griswold, J M Vance, J I Young","doi":"10.3389/fnagi.2026.1888862","DOIUrl":"10.3389/fnagi.2026.1888862","url":null,"abstract":"<p><strong>Introduction: </strong>The <i>APOEε4</i> allele is the strongest known genetic risk factor for late-onset Alzheimer disease (AD). However, the risk effect of <i>APOEε4</i> varies substantially by ancestry, with individuals of African ancestry (AF) demonstrating markedly lower risk compared to those of European ancestry (EU). This difference in risk is associated with distinct levels of <i>APOE</i> gene expression. Here, we investigate whether mitochondrial processes in brain cells are also influenced by ancestry in AD <i>APOEε4</i> carriers, potentially contributing to the observed risk differences.</p><p><strong>Methods: </strong>Single nuclei RNA sequencing was performed on frontal cortex from 17 AD patients homozygous for <i>APOEe4</i> with either African Local Ancestry (AF-LA; <i>N</i> = 7) or European Local Ancestry (EU-LA; <i>N</i> = 10). Differential gene expression was compared between AF and EU samples, with particular focus on mitochondrial pathways. Differential expression and functional enrichment analyses were performed using MAST and PathFindR, respectively. MitoXplorer was used to identify differential mitochondrial processes, while REACTOME facilitated the building of regulatory networks.</p><p><strong>Results: </strong>Multiple cell types and biological processes contribute to the differences in <i>APOEe4</i> risk seen between individuals of AF and EU ancestry. AF astrocytes show a less reactive phenotype and L6 and L5/6 excitatory neurons appear to be less vulnerable in AF compared to EU samples. Mitochondrial alterations were more pronounced in EU-LA <i>APOEe4</i> AD carriers relative to their AF counterparts. Cells highly expressing <i>APOE</i> (astrocytes, microglia, and vascular leptomeningeal cells) showed increased expression of mitochondrial genes, particularly in EU-LA samples. We observed increased expression of pro-apoptotic, oxidative phosphorylation, and mitophagy-related genes in EU samples. Regulatory network analysis identified the transcription factor PPARG as a potential mediator linking <i>APOEε4</i> expression to mitochondrial gene programs in a cell-type- and ancestry-dependent manner.</p><p><strong>Conclusion: </strong>Our snRNA-seq analysis demonstrates that ancestry-linked regulation of <i>APOEε4</i> expression influences mitochondrial transcriptome and astrocyte activation in AD. The stronger <i>APOE-PPARG</i>-mitochondrial gene coupling in EU ancestry particularly in astrocytes may underlie increased AD risk, while AF ancestry confers partial decoupling of these pathways. These results underscore the importance of considering ancestry in AD research and suggest that precision therapeutic strategies targeting mitochondrial and glial pathways should account for <i>APOE</i> local ancestry.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1888862"},"PeriodicalIF":5.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655079/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165832","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 p-tau181 moderates the association between ten-year atherosclerotic cardiovascular disease risk and mild cognitive impairment - HABS-HD.","authors":"Joey A Contreras, Nancy E Ortega, Raymond Jones, Roland J Thorpe, Cellas A Hayes","doi":"10.3389/fnagi.2026.1870150","DOIUrl":"10.3389/fnagi.2026.1870150","url":null,"abstract":"<p><strong>Introduction: </strong>This study examined cross-sectional associations between ten-year American Heart Association (AHA) atherosclerotic cardiovascular disease (ASCVD) risk and plasma Alzheimer's disease (AD) biomarkers in relation to cognitive outcomes and to determine whether ASCVD risk modifies biomarker-cognition relationships.</p><p><strong>Methods: </strong>Baseline data were analyzed from cognitively unimpaired and mild cognitive impaired (MCI) participants enrolled in the Health and Aging Brain Study-Health Disparities (HABS-HD), a large, community-based cohort enriched for racial and ethnic diversity. Plasma biomarkers included amyloid-β42/40 (Aβ42/Aβ40), phosphorylated tau (p-tau181 and p-tau217), and neurofilament light (NfL). Ten-year ASCVD risk was calculated using pooled cohort equations. Multivariable logistic regression models examined associations of ten-year ASCVD risk and plasma biomarkers with MCI, while multivariable linear regression models evaluated associations with Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) Sum of Boxes scores. Separate models were constructed for Aβ42/40, p-tau217, p-tau181, NfL, and apolipoprotein (<i>APOE</i>) ε4 carrier status, and analyses were stratified by race and ethnicity. ASCVD × biomarker interaction terms were tested to evaluate effect modification.</p><p><strong>Results: </strong>Increased ten-year ASCVD risk was consistently associated with increased odds of MCI, ranging from OR = 2.62 (95% CI: 1.31-5.17) to OR = 4.22 (95% CI: 2.04-8.64), lower MMSE scores, ranging from <i>β</i> = -1.90 (95% CI: -2.62 to -1.18) to <i>β</i> = -2.56 (95% CI: -3.30 to -1.82), and increased CDR Sum of Boxes scores, ranging from <i>β</i> = 0.28 (95% CI: 0.09-0.46) to <i>β</i> = 0.39 (95% CI: 0.20-0.58). The ASCVD × p-tau181 interaction was significant for MCI (OR = 1.91; 95% CI: 1.26-2.95) and CDR Sum of Boxes (<i>β</i> = 0.27; 95% CI: 0.16-0.39). ASCVD associations with CDR Sum of Boxes ranged from <i>β</i> = 0.11 (95% CI: -0.08 to 0.30) to <i>β</i> = 0.24 (95% CI: 0.04-0.43) among non-Hispanic White participants, <i>β</i> = 0.80 (95% CI: 0.10-1.51) to <i>β</i> = 1.17 (95% CI: 0.49-1.86) among non-Hispanic Black participants, and <i>β</i> = 0.36 (95% CI: 0.08-0.65) to <i>β</i> = 0.52 (95% CI: 0.25-0.80) among Hispanic participants.</p><p><strong>Conclusion: </strong>Greater ten-year ASCVD risk was consistently associated with cognitive impairment independent of plasma AD biomarkers, with evidence that p-tau181 modifies these associations and that their magnitude varies across racial and ethnic groups.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1870150"},"PeriodicalIF":5.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165213","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":"Olfactory context and memory across the adult lifespan: effects on mnemonic discrimination and olfactory function.","authors":"Renae Mannion, Alexis Bailey, Stephanie L Leal","doi":"10.3389/fnagi.2026.1917760","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1917760","url":null,"abstract":"<p><p>Odor is a powerful contextual cue that can influence memory and is closely linked to brain regions involved in episodic memory, including the hippocampus. Age-related olfactory dysfunction is among the earliest behavioral changes associated with cognitive decline and may contribute to memory impairments in older adults. Hippocampal pattern separation, or the process of reducing interference among similar experiences, provides a sensitive measure of age-related memory decline, yet little is known about how olfactory context influences mnemonic discrimination. In the present study, we examined whether odor context during encoding affects subsequent mnemonic discrimination in young and older adults. Participants completed a mnemonic similarity task in which object stimuli were encoded in both odor (lavender) and no-odor contexts prior to a memory test. Across participants, odor context did not significantly influence target recognition or mnemonic discrimination. Consistent with prior work, older adults exhibited poorer mnemonic discrimination and reduced olfactory function relative to young adults. However, odor presentation order influenced mnemonic discrimination in older adults, such that performance was better when the odor context was encountered during the first encoding block compared to the second. Additionally, poorer olfactory function was associated with reduced mnemonic discrimination, and this relationship was largely explained by age-related differences in olfactory ability. These findings suggest that the influence of olfactory context on memory depends on both age and the timing of odor exposure, highlighting the importance of individual differences in olfactory function when evaluating odor-based approaches to support memory in aging.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1917760"},"PeriodicalIF":5.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180463","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 biomarker strategies to reduce diagnostic uncertainty in p-tau217-based assessment of CSF amyloid positivity in secondary-care patients with MCI.","authors":"María Pascual-Lucas, Leticia Sarasa, Noelia Fandos, Jorge Loscos, Judith Romero, Adrián Sánchez, Jose Terencio, Isabel Ortega-Madueño, María Cruz Cárdenas, Fernando Cava-Valenciano, María José Gil-Moreno, Jordi A Matias-Guiu, José Antonio Allué","doi":"10.3389/fnagi.2026.1918304","DOIUrl":"10.3389/fnagi.2026.1918304","url":null,"abstract":"<p><strong>Introduction: </strong>Plasma p-tau217 accurately reflects amyloid pathology, but dual-cutoff strategies leave a non-negligible grey zone requiring confirmatory testing. We evaluated whether integrating plasma Aβ measurements could reduce diagnostic uncertainty in patients with mild cognitive impairment (MCI).</p><p><strong>Methods: </strong>Plasma p-tau217 was measured using the Lumipulse platform, and plasma Aβ40 and Aβ42 were quantified by liquid chromatography-mass spectrometry (ABtest-MS) in 186 secondary-care MCI patients. CSF Aβ42/Aβ40 defined amyloid status. Logistic regression models were compared, and dual-cutoff strategies targeting 95% predictive values were applied.</p><p><strong>Results: </strong>p-tau217 was the strongest individual biomarker. Models incorporating plasma Aβ measures improved AUC, model fit, and reduced the grey zone from 27.4% with p-tau217 alone to 12.3%. A sequential two-step strategy restricted additional Aβ testing to p-tau217-indeterminate cases and reduced the final grey zone to 13.4%.</p><p><strong>Discussion: </strong>Plasma Aβ measurements complement p-tau217 by reducing the indeterminate results, with the potential to improve diagnostic efficiency and streamline diagnostic workflows.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1918304"},"PeriodicalIF":5.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166187","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":"Dysfunction of lipid metabolism and lysosomal capacity: at the core of microglial aging?","authors":"Eva Šimončičová, Marie-Ève Tremblay","doi":"10.3389/fnagi.2026.1884230","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1884230","url":null,"abstract":"<p><p>As primary immune cells of the central nervous system (CNS), microglia maintain immune surveillance, inflammation regulation, cell interactions and debris clearance. These dynamic and adaptive effector functions are reciprocally sustained by microglial metabolism. Lipids are emerging as a key programmer of microglial metabolic and functional flexibility in conditions of homeostasis, cellular stress, and pathology. The delicate equilibrium in microglial lipid homeostasis is dependent on the integrated activity of all cellular components, including the lysosome-lipophagy pathway. Continuous adaptations in microglial metabolism contribute to a cumulative imbalance between lysosomal network capacity and the efficacy of lipid turnover in aged microglia. The disequilibrium contributes to microglial fatigue and detrimental homeostatic activity associated with aging. Lipid droplet-accumulating microglia (LDAM) emerged as an age-associated example of these lysosome-lipid flux alterations. While characterized by dysregulated phagocytosis and pro-inflammatory intercellular signaling, the role of LDAM in the contexts of neuroplasticity, aging-related cognitive decline and frailty remains undetermined. This review discusses the immunometabolic profile of aging LDAM and their interactions with neurons and synapses, highlighting the impact of intercellular lipid signaling route.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1884230"},"PeriodicalIF":5.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179974","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":"Home-administered unfocused transcranial ultrasound in subjective cognitive decline and dementia: an open-label, uncontrolled feasibility pilot study.","authors":"Helané Wahbeh, Sterling Cooley, Steven Russell Chamberlin, Thomas Brophy, Stuart Hameroff","doi":"10.3389/fnagi.2026.1937897","DOIUrl":"10.3389/fnagi.2026.1937897","url":null,"abstract":"<p><strong>Background: </strong>Memory and cognitive impairments remain disabling, with few effective treatments. Low-intensity transcranial ultrasound (TUS) is a non-invasive neuromodulation approach with a favorable safety profile and preliminary evidence of cognitive benefit, with one hypothesized but unproven mechanism involving microtubule resonance and reassembly.</p><p><strong>Objectives: </strong>This open-label pilot study evaluated the safety and preliminary efficacy of the US Pro2000 unfocused ultrasound device in adults with memory or cognitive difficulties, a sample spanning subjective cognitive decline among self-administering participants to diagnosed dementia among caregiver-rated recipients, and described self-reported symptom trajectories.</p><p><strong>Methods: </strong>In a within-participant design, adults with self-reported cognitive impairment, or their caregivers, applied the device at the right temporal window for 5 min three times daily (target 15 min/day), in cycles of 3 weeks on and 1 week off. Outcomes (GAD-7, CESD-5, Inoue battery, and caregiver-rated MDS 3.0) and adverse events were collected online. Mixed-effects models with age and device-use covariates assessed change over time, with False Discovery Rate correction within aim.</p><p><strong>Results: </strong>Twenty-seven participants enrolled and 26 initiated treatment. Across 2,174 daily assessments, no serious or unanticipated adverse events occurred; only headache (15.4%) and transient jaw clenching (3.8%) were possibly related, and none caused discontinuation. Among self-administered participants, depression (CESD-5) declined significantly (<i>p</i>_FDR = 0.016) and five of eight monthly self-report symptoms improved, including memory, word-finding, and problem-solving (all <i>p</i>_FDR ≤ 0.040); anxiety trended downward, and the objective cognitive battery, near ceiling at baseline, did not change. Caregiver-rated outcomes were stable. Device use showed no dose response, and sensitivity analyses were consistent.</p><p><strong>Conclusion: </strong>Home-based self-administered low-intensity TUS was well tolerated, with only mild transient events, although adverse-event ascertainment relied on unblinded self-report and relatedness judgments were made by unblinded investigators. Efficacy signals were confined to self-report, while objective cognition and caregiver ratings were unchanged. The uncontrolled design, small subgroups, and reliance on self-report preclude causal inference. These findings support the safety and feasibility of TUS and justify an adequately powered, double-blind, sham-controlled trial.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1937897"},"PeriodicalIF":5.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165038","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":"Childhood trauma and cognitive decline in women: an empirical analysis of cognitive vulnerability in later life.","authors":"Mai A Salem, Eid Abo Hamza, Dalia Bedewy, Reham A Amer, Abdalla A R M Hamid, Emad Mahgoub, Ahmed A Moustafa","doi":"10.3389/fnagi.2026.1848025","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1848025","url":null,"abstract":"<p><p>Childhood trauma has lasted consequences for women's cognitive health and this may contribute to memory decline and increased vulnerability to cognitive impairment in later life. A cross sectional study was carried out to assess the correlation between childhood trauma and cognitive status among 55 women aged 58-79 years were selected from Departments of Psychiatry and General Medicine, Tanta University Hospital, Egypt. The Montreal Cognitive Assessment (MoCA) was used to evaluate cognitive performance, the Global Deterioration Scale (GDS) for global clinical staging, and the Childhood Trauma Questionnaire (CTQ) for childhood adversity. Overall, emotional abuse was exposed the most with a high mean score on the CTQ subscale. Pearson correlations and multiple linear regression models (controlling for age) showed that emotional neglect and physical neglect were the strongest predictors across both outcomes. For MoCA performance, emotional neglect (β = -0.0877, <i>r</i> = -0.85, <i>p</i> < 0.01) and physical neglect (β = -0.0100, <i>r</i> = -0.80, <i>p</i> < 0.01) showed the largest effects. GDS coefficients had an absolute value that was proportionately smaller (emotional neglect: β = 0.0112; physical neglect: β = 0.0013) and, consistent with the higher-is-worse nature of the GDS, were positive in direction. Additional findings show a greater amount of neglect predicted more advanced clinical staging, and that there was no change to the relative order of effects by predictor compared to the MoCA model. The regression model accounted for 72.5% of the variance (R² = 0.725) in MoCA. The results indicate that childhood neglect, especially emotional neglect, might be an important risk factor for cognitive vulnerability in adulthood and highlight the necessity to intervene early in childhood to promote cognitive health in women.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1848025"},"PeriodicalIF":5.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179807","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}