Frontiers in Aging Neuroscience最新文献

{"title":"The estrogen-brain interface in neuroinflammation: a multidimensional mechanistic insight.","authors":"Jie Lu, Tie-Jun Xian, Cheng-Jun Li, Yang Wang","doi":"10.3389/fnagi.2025.1671552","DOIUrl":"10.3389/fnagi.2025.1671552","url":null,"abstract":"<p><p>Neuroinflammation plays a dual role in the central nervous system, offering protection in acute phases but contributing to chronic damage in neurodegenerative diseases. Estrogen, traditionally recognized for its reproductive functions, exerts extensive neuroprotective effects by modulating neuroinflammatory processes across multiple levels. This review explores the actions of estrogen through its receptors in astrocytes, microglia, and neurons, emphasizing its regulation of signaling pathways such as PI3K/Akt, NF-κB, and WNT/<i>β</i>-catenin. Estrogen also enhances mitochondrial function, promotes DNA repair, and interacts with the gut microbiota to influence systemic inflammation. Furthermore, sex-specific responses to 17<i>α</i>-estradiol highlight the importance of hormonal context. Together, these findings underscore estrogen's potential as a multifaceted modulator of neuroinflammation and provide insight for precision therapeutic strategies.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1671552"},"PeriodicalIF":4.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12434045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074862","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":"Influence of biological sex on neuroinflammatory dynamics in the aging brain.","authors":"Ludmila Müller, Svetlana Di Benedetto, Viktor Müller","doi":"10.3389/fnagi.2025.1670175","DOIUrl":"10.3389/fnagi.2025.1670175","url":null,"abstract":"<p><p>The aging brain undergoes complex neuroinflammatory changes that are increasingly recognized as contributing factors to the development and progression of neurodegenerative diseases. Emerging research reveals that biological sex profoundly shapes these neuroinflammatory dynamics, resulting in distinct trajectories of immune function, glial activity, and neural vulnerability in males and females. This mini-review focuses on recent advances in understanding the interplay of hormonal, genetic, and epigenetic factors that drive sex-specific differences of neuroinflammatory processes in aging brain. We begin by describing the hallmarks of neuroinflammation, including chronic activation of glial cells and the loss of inflammatory resolution. We provide a brief overview of age-related changes in microglial and astrocyte function, along with systemic influences such as immunosenescence, inflammaging, dysbiosis, and increased blood-brain barrier permeability. Building on this foundation, we examine sex-dependent differences in immune aging, CNS immune surveillance, and hormonal regulation of glial activity, particularly in the context of menopause and andropause. Particular attention is given to how these mechanisms drive sex-specific differences in the pathophysiology of neuroinflammation-a key contributor to many neurodegenerative diseases. Finally, we address key methodological challenges-such as the underrepresentation of females in preclinical models and limited sex-stratified clinical analyses-that constrain our understanding of sex-specific neuroinflammation in aging. By integrating sex as a critical biological variable and exploring systems-based approaches such as multilayer network models, this review highlights the importance of sex-informed research to better understand, prevent, and treat neuroinflammatory and neurodegenerative conditions in aging populations.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1670175"},"PeriodicalIF":4.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12426254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064027","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":"Association between shift work and brain age gap: a neuroimaging study using MRI-based brain age prediction algorithms.","authors":"Youjin Kim, Joon Yul Choi, Evgeny Petrovskiy, Wanhyung Lee","doi":"10.3389/fnagi.2025.1650497","DOIUrl":"10.3389/fnagi.2025.1650497","url":null,"abstract":"<p><strong>Background: </strong>Shift work is increasingly common and associated with numerous adverse health effects. Although studies show that shift work affects brain structure and neurological stress, its direct impact on brain aging remains unclear. Therefore, this study aims to investigate the association between shift work and brain aging using the brain age gap (BAG)-a neuroimaging biomarker calculated by comparing predicted brain age derived from structural magnetic resonance imaging (MRI) scans to chronological age.</p><p><strong>Methods: </strong>Structural MRI data (T1-weighted and T2-weighted) were collected from 113 healthcare workers, including 33 shift workers and 80 fixed daytime workers. Brain age was estimated using seven validated machine learning models. BAG was calculated as the difference between predicted brain age and chronological age. Statistical analyses, including ANCOVA, adjusted for chronological age, sex, intracranial volume (ICV), education level, and occupational type.</p><p><strong>Results: </strong>The association between BAG and shift work duration was also evaluated. Model performance varied (maximum R² = 0.79) and showed systematic age-related bias, typically underestimating brain age in older participants. Unadjusted analyses initially indicated lower BAG values in younger shift workers. However, after covariate adjustments, shift workers consistently exhibited significantly higher BAG values, suggesting accelerated brain aging. Two models retained statistical significance despite adjustment for potential confounders. Longer shift work duration correlated with a decreasing BAG trend, suggesting potential neuroadaptive changes or selective retention of resilient workers.</p><p><strong>Conclusion: </strong>These findings demonstrate that shift work is associated with accelerated apparent brain aging, even after controlling for systematic model bias and demographic covariates. The observed reduction in BAG with extended shift work exposure may reflect adaptive or selective effects, emphasizing the need for longitudinal studies to clarify these mechanisms. This research highlights the importance of incorporating occupational exposures in neuroimaging and brain health investigations.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1650497"},"PeriodicalIF":4.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12425934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063890","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":"Emerging biomarkers of postoperative delirium at the intersection of neuroinflammation and neurodegeneration.","authors":"Kun Leng, Mervyn Maze, Odmara L Barreto Chang","doi":"10.3389/fnagi.2025.1632947","DOIUrl":"10.3389/fnagi.2025.1632947","url":null,"abstract":"<p><p>Postoperative delirium (POD) is a common and severe neuropsychiatric complication affecting older adults after surgery. POD is characterized by fluctuating cognitive disturbances, impaired attention, and altered consciousness, resulting in increased morbidity and mortality, prolonged hospital stays, and higher healthcare costs. Systemic inflammation induced by surgical trauma is implicated in the pathophysiology of POD, although the subsequent mechanisms that produce blood-brain barrier (BBB) dysfunction, neuroinflammation, and interactions with underlying dementia neuropathology have not been resolved. Recent advances in biomarker research have shed light on predictive and diagnostic tools for POD. Biomarkers linked to dementia neuropathology (e.g., hyperphosphorylated tau, amyloid beta), neuronal injury (e.g., total tau, neurofilament light chain), glial activation (e.g., glial fibrillary acidic protein), and systemic inflammation (e.g., interleukin-6) have shown promise. The feasibility of measuring the above biomarkers in easy-to-obtain biofluids such as blood is enhanced by technologies like single-molecule array immunoassays, enabling sensitive detection of central nervous system markers at femtomolar concentrations. Emerging evidence highlights associations between POD risk and these biomarkers, although findings often vary due to cohort heterogeneity and methodological differences. This review critically examines the existing literature on POD biomarkers, focusing on their relevance to dementia neuropathology, neuronal injury, neuroinflammation, and BBB integrity. While significant strides have been made, gaps in knowledge persist, emphasizing the need for larger, more standardized studies. Developing robust biomarkers could transform POD prediction, diagnosis, and management, ultimately improving outcomes for vulnerable surgical populations.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1632947"},"PeriodicalIF":4.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12426202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064050","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":"Abnormal sleep blood pressure patterns are associated with the diffusion tensor imaging along the perivascular space index in cognitively impaired individuals.","authors":"Mariateresa Buongiorno, Gonzalo Sánchez-Benavides, Giovanni Caruana, Andrea Elias-Mas, Cristina Artero, Natalia Cullell, Pilar Delgado, Darly Milena Giraldo, Clara Marzal-Espí, Oriol Grau-Rivera, Alejandro de la Sierra, Ariane Delgado-Sanchez, Nicola J Ray, Jerzy Krupinski","doi":"10.3389/fnagi.2025.1578270","DOIUrl":"10.3389/fnagi.2025.1578270","url":null,"abstract":"<p><strong>Introduction: </strong>Blood pressure (BP) physiologically dips during sleep, and a lack of dipping is associated with adverse health outcomes and cognitive decline. Vascular pulsatility is the primary driver of glymphatic cerebrospinal fluid (CSF) transport, which removes metabolic waste products from the brain during sleep. We hypothesized that abnormal sleep BP patterns may affect glymphatic system health and that this relationship may result in lower diffusion tensor imaging along the perivascular space (DTI-ALPS) indices, a proposed neuroimaging index of glymphatic health.</p><p><strong>Methods: </strong>A total of 21 participants with mild-to-moderate cognitive impairment underwent 24-h ambulatory BP monitoring (ABPM), DTI-MRI, and Alzheimer's disease (AD) biomarker assessments. Of them, eight participants were classified as dippers (≥10%) and 13 as non-dippers (< 10%), using the sleep/awake systolic BP (SBP) percentage of change.</p><p><strong>Results: </strong>We found that the non-dippers had lower DTI-ALPS indices, even after adjusting for age and clinical stage (<i>p</i> = 0.013). Stiffness measures (pulse wave velocity) were negatively correlated with DTI-ALPS (<i>r</i> = -0.5), but the association disappeared after adjusting for age. Positive AD biomarkers were more frequently observed in the individuals who were classified as non-dippers for both systolic and diastolic BP (DBP), compared to the systolic and diastolic dippers (<i>p</i> = 0.041).</p><p><strong>Discussion: </strong>Our findings suggest that deviations from the physiological BP dipping sleep pattern may be related to poorer glymphatic function and increased AD pathology.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1578270"},"PeriodicalIF":4.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12426274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063947","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":"Systemic inflammation versus clinical demographics: patient age surpasses the platelet-to-lymphocyte ratio in differentiating secondary trigeminal neuralgia.","authors":"Zihao Zhang, Qingpei Hao, Tao Wang, Shijun Peng, Xin Chang, Yuepeng Wang, Jia Ouyang, Ruen Liu","doi":"10.3389/fnagi.2025.1658854","DOIUrl":"10.3389/fnagi.2025.1658854","url":null,"abstract":"<p><strong>Background: </strong>Objective biomarkers to differentiate trigeminal neuralgia (TN) subtypes are lacking. This study aimed to evaluate the utility of the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) for distinguishing primary TN from secondary TN caused by meningiomas (STN-M) or epidermoid cysts (STN-E).</p><p><strong>Methods: </strong>In this retrospective study of 53 patients, analysis of covariance (ANCOVA) was used to compare adjusted biomarker levels while controlling for confounders. The diagnostic performance of these hematological markers and patient age was assessed using receiver operating characteristic (ROC) curve analysis, and their independent predictive values were determined by multivariable logistic regression to differentiate the two secondary TN types.</p><p><strong>Results: </strong>After adjusting for confounders, the mean PLR was significantly lower in the STN-M group compared to the STN-E group (<i>p</i> = 0.036), while NLR showed no significant difference. Notably, when comparing diagnostic performance for the secondary etiologies, patient age demonstrated a higher area under the curve (AUC = 0.962; 95% CI: 0.897-1.000) than PLR (AUC = 0.793; 95% CI: 0.614-0.972). Multivariable regression identified age as the most influential variable, showing a strong trend toward significance (<i>p</i> = 0.051), while PLR was not an independent predictor (<i>p</i> = 0.197).</p><p><strong>Conclusion: </strong>While this study identified PLR as a potential auxiliary biomarker, its most crucial finding is that the simple demographic feature of patient age is the primary and more powerful discriminator for differentiating STN-M from STN-E. This highlights that while novel biomarkers should be explored, the foundational importance of basic clinical parameters must not be overlooked in the pursuit of diagnostic precision.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1658854"},"PeriodicalIF":4.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12426273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064035","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":"HDL from 36-h fasted participants potently promotes efflux of cholesteryl ester from activated microglia.","authors":"Joanne K Agus, Oscar M Muñoz Herrera, Christopher H Rhodes, Jack Jingyuan Zheng, Chenghao Zhu, Maurice Wong, Xinyu Tang, Izumi Maezawa, Lee-Way Jin, Carlito B Lebrilla, Danielle J Harvey, Angela M Zivkovic","doi":"10.3389/fnagi.2025.1629496","DOIUrl":"10.3389/fnagi.2025.1629496","url":null,"abstract":"<p><p>The potential impact of lifestyle changes such as prolonged fasting on brain health still remains unclear. Neurodegenerative diseases often exhibit two key hallmarks: accumulation of misfolded proteins such as amyloid beta oligomers (AβO) and intracellular cholesterol accumulation. In this study, we investigate how a 36-h fast affects the capacity of isolated high-density lipoproteins (HDLs) to modulate the effects of AβO and excess cholesterol in microglia. HDL from 36-h fasted individuals were significantly more effective in effluxing cholesteryl esters from treated microglia, showing a remarkable 10-fold improvement compared to HDL from the postprandial state. Furthermore, the ability of 36-h fasted HDL to mitigate the reduction of apolipoprotein E secretion in AβO- and cholesterol-loaded microglia surpassed that of postprandial HDL. In exploring differences among HDL parameters from postprandial, overnight fasted, and 36-h fasted individuals, we observed that plasma HDL-cholesterol and apolipoprotein A-I concentrations remained unchanged. However, nuclear magnetic resonance (NMR) analysis revealed reduced total HDL particle count, a decrease in the smallest HDL particles (HDL1, 7.4 nm diameter), and an increase in the largest HDL particles (HDL7, 12 nm) after the 36-h fast. Transmission electron microscopy (TEM) analysis further found an increase in even larger HDL particles (12-14 nm) in 36-h fasted individuals. Targeted mass spectrometry (MS)-based proteomics and glycoproteomics unveiled a reduction in HDL-associated apolipoprotein A-IV and disialylated apolipoprotein C-III content following the 36-h fast. These findings collectively suggest that prolonged fasting induces structural, compositional, and functional alterations in HDL particles, and influences their capacity to attenuate the effects of excess cholesterol and AβO in microglia.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1629496"},"PeriodicalIF":4.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039560","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":"The expression and association of MATK in chronic hypoperfusion patients with white matter hyperintensity.","authors":"Ming Zhao, Jiayue Zhang, Qianqian Yang, Lei Chen, Hongjian Shen, Yingyan Pu, Wei Wei, Yi Han, Ping Zhang","doi":"10.3389/fnagi.2025.1570482","DOIUrl":"10.3389/fnagi.2025.1570482","url":null,"abstract":"<p><strong>Background: </strong>Chronic cerebral hypoperfusion (CCH) is a key contributor to vascular cognitive impairment (VCI). Patients with CCH frequently exhibit white matter hyperintensities (WMH) on MRI. This study investigated the expression and clinical relevance of megakaryocyte-associated tyrosine kinase (MATK) in CCH patients with WMH.</p><p><strong>Methods: </strong>We recruited 42 anterior circulation stenosis patients with CCH and WMH (CCH-WMH group) and 45 age-matched healthy controls. MATK mRNA expression in peripheral blood mononuclear cells (PBMCs) was quantified using qPCR. WMH severity was graded using the Fazekas scale. Correlations between MATK expression and imaging/clinical parameters were analyzed using Pearson's correlation and logistic regression. Diagnostic performance was assessed via ROC analysis.</p><p><strong>Results: </strong>Megakaryocyte-associated tyrosine kinase expression was significantly downregulated in the CCH-WMH group versus controls (1.20 ± 0.99 vs. 1.84 ± 0.87; <i>P</i> < 0.01). MATK levels showed a strong negative correlation with Fazekas scores (R² = 0.3405, <i>P</i> < 0.001). Multivariate regression identified MATK as independently associated with WMH (aOR = 0.492; 95% CI: 0.262-0.923; <i>P</i> = 0.027). ROC analysis demonstrated moderate diagnostic accuracy for WMH (AUC = 0.743; 95% CI: 0.637-0.849).</p><p><strong>Conclusion: </strong>Reduced peripheral MATK expression correlates with WMH severity in CCH patients and may serve as a potential diagnostic biomarker.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1570482"},"PeriodicalIF":4.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039705","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":"Cognitive flexibility in aging: the impact of age range and task difficulty on local switch costs in task switching.","authors":"Tara Radović, Sebastian Kübler, Rafael Mikolajczyk, Alexander Kluttig, Viktoria Maydych, Torsten Schubert","doi":"10.3389/fnagi.2025.1619441","DOIUrl":"10.3389/fnagi.2025.1619441","url":null,"abstract":"<p><strong>Introduction: </strong>Previous studies provided inconclusive results regarding the effects of aging on the ability to flexibly switch between task rules (local switch cost). The goal of the present study was to investigate the influence of age on the local switch costs at two levels of difficulty (easy task switching: two task rules vs. difficult task switching: four task rules).</p><p><strong>Methods: </strong>The local switch costs, i.e., reaction time and error differences between trials with a task switch and task repetition relative to the previous trial, were compared in a group of young adults (19 to 33 years) and three groups of older adults (64-72; 73-80; 82-97 years).</p><p><strong>Results: </strong>The analysis of the switch costs showed significantly higher switch costs of the three groups of older adults compared to the younger adults and the effect was more pronounced in the difficult task switching than in the easy task switching. At the same time, there were no clear differences in the local switch costs between the three groups of older adults.</p><p><strong>Discussion: </strong>The results showed that even after the age-related slowdown was taken into account, age differences in local switch costs will emerge when the age range of older adults is extended and task difficulty is sufficiently high. These findings contribute to our understanding of how and when age differences in cognitive flexibility emerge and suggest that complex multitasking environments may disproportionately challenge older adults.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1619441"},"PeriodicalIF":4.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039595","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":"Cognitive training gain transfer in cognitively healthy aging: per protocol results of the German AgeGain study.","authors":"Florian U Fischer, Bianca Kollmann, Dominik Wolf, Alexandra Sebastian, Kristel Knaepen, David Riedel, Andreas Mierau, Nicolas Ruffini, Kristina Endres, Jennifer Winter, Heiko K Strüder, Gerard N Bischof, Sofia Faraza, Bernhard Baier, Harald Binder, Alexander Drzezga, Stefan Teipel, Andreas Fellgiebel, Oliver Tüscher","doi":"10.3389/fnagi.2025.1587395","DOIUrl":"10.3389/fnagi.2025.1587395","url":null,"abstract":"<p><strong>Introduction: </strong>Cognitive decline is part of the normal aging process, but also a major risk factor for dementia. Cognitive training interventions aim to attenuate cognitive decline, but training gains need to be transferable to untrained cognitive abilities to influence everyday function. Furthermore, the neurobiological basis of cognitive training gain transfer remains elusive. A possible candidate is increased bilateral hemisphere usage enabled by efficient structural connectivity, especially of prefrontal regions. Therefore, the present multicentric study used a cognitive training intervention to demonstrate training transfer and identify neurobiological modulators of successful transfer.</p><p><strong>Methods: </strong>In total 235 subjects were enrolled in AgeGain; 180 underwent a broad 4-week cognitive training intervention at three study sites. Pre- and post-training neuropsychological testing was conducted and successful transferers were identified according to preregistered definitions. Pre-training, subjects underwent diffusion and functional MRI to assess interhemispheric connectivity, measured as microstructural integrity of the corpus callosum and lateralization of functional activation patterns during a cognitive control task. Logistic regression models were estimated to predict successful transfer based on structural connectivity and bilateralization of activation patterns.</p><p><strong>Results: </strong>Out of 180 subjects, 74 showed short-term training gain transfer that was maintained over 3 months in 19 subjects. Neither microstructural integrity of the corpus callosum, nor bilateralized activation predicted training gain transfer alone. However, their interaction was associated with long-term transfer over 3 months: subjects with higher mean diffusivity of the corpus callosum and more bilateral functional activity or conversely with lower diffusivity of the corpus callosum and more lateral functional activity were more likely successful long-term transferers.</p><p><strong>Discussion: </strong>We demonstrated successful training gain transfer in 41.1% of subjects, among whom 25.7% maintained the transfer over 3 months. Successful long-term transfer of training gains may depend on divergent mechanisms of structural and functional connectivity, which may explain previous heterogeneous results in the literature.</p><p><strong>Trial register: </strong>German Clinical Trials Register (DRKS), ID: DRKS00013077. Registered on November 19th 2017.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1587395"},"PeriodicalIF":4.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039554","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}