Frontiers in Aging Neuroscience最新文献

{"title":"Hippocampal iron patterns in aging and mild cognitive impairment.","authors":"Sonja M Kagerer, Laetitia Vionnet, Jiri M G van Bergen, Rafael Meyer, Anton F Gietl, Klaas P Pruessmann, Christoph Hock, Paul G Unschuld","doi":"10.3389/fnagi.2025.1598859","DOIUrl":"10.3389/fnagi.2025.1598859","url":null,"abstract":"<p><strong>Introduction: </strong>The entorhinal cortex (EC)-hippocampus system is critical for memory and affected early in Alzheimer's disease (AD). Cognitive dysfunction in AD is linked to neuropathological changes, including non-heme iron accumulation in vulnerable brain regions. This study characterized iron distribution in the EC-hippocampus system using ultra-high field (UHF) magnetic resonance imaging (MRI) at 7 Tesla (T) in aging and mild cognitive impairment (MCI), an AD at-risk state.</p><p><strong>Methods: </strong>40 participants (mean age [SD] 69.2 [7.42] years; 12 mild cognitive impairment (MCI), 28 cognitively healthy controls (HC)) underwent UHF MRI at 7 T with turbo spin echo and quantitative susceptibility mapping (QSM). Gray matter segmentation was performed using FreeSurfer software. Intraclass correlation coefficients (ICCs) were calculated for hippocampal and EC measures.</p><p><strong>Results: </strong>ICCs for mean susceptibilities were 0.61 overall, 0.58 for HC, and 0.69 for MCI, with significant group differences between HC and MCI (Kolmogorov-Smirnov test, <i>k</i> = 0.625, <i>p</i> ≤ 0.05).</p><p><strong>Discussion: </strong>Our findings suggest a higher coherence of non-heme iron distribution in MCI. An increasingly uniform distribution of iron in MCI could reflect a clinical continuum ranging from healthy aging to pathologic brain change and cognitive disorder. This highlights the potential of non-heme iron as a biomarker for early AD co-pathology.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1598859"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648917","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":"Serum uric acid to creatinine ratio in patients with early-onset post-stroke cognitive impairment: a retrospective cohort study.","authors":"Libin Liao, Weiquan Huang, Rongchao Ma, Wentong Hu, Hui Wu, Moxi Su, Dujuan Sha","doi":"10.3389/fnagi.2025.1580722","DOIUrl":"10.3389/fnagi.2025.1580722","url":null,"abstract":"<p><strong>Background: </strong>Cognitive impairment is the major complication of acute ischemic stroke, which is a significant health concern imposing a heavy economic burden on families and society. Studies have shown that the serum uric acid (SUA) level is correlated to clinical outcomes of stroke and neurogenerative diseases. The serum uric acid to serum creatinine ratio (SUA/SCr) is an independent risk factor for poor outcomes of acute ischemic stroke and can potentially become an effective diagnostic indicator for cognitive decline. In this study, we aimed to investigate the association between SUA/SCr and early-onset post-stroke cognitive impairment.</p><p><strong>Methods: </strong>Consecutive acute ischemic stroke patients from our hospital were enrolled between June 2023 and September 2024. All blood samples were collected within 24 h after admission, and the cognitive function of patients was assessed within 2 weeks using the Chinese version of the Montreal Cognitive Assessment (MoCA). SUA/SCr was calculated by serum uric acid (umol/L)/serum creatinine (umol/L) and was split into three layers according to tertiles. The subjects were divided into a post-stroke cognitive impairment group and a non-post-stroke cognitive impairment group based on cognitive assessment. Binary logistic regression with different models, multivariate logistic regression analysis, and receiver operating characteristic (ROC) curves were adopted to evaluate the predictive ability of SUA/SCr in early-onset post-stroke cognitive impairment.</p><p><strong>Results: </strong>The current study showed that the post-stroke cognitive impairment group had lower SUA/SCr (<i>p</i> = 0.005) and the lower tertile of SUA/SCr is associated with a higher prevalence of post-stroke cognitive impairment (<i>p</i> = 0.008). The multivariate logistic analysis indicated that SUA/SCr (OR = 0.560, 95% CI = 0.321-0.976, <i>p</i> = 0.024) was independently associated with early-onset post-stroke cognitive impairment, and the lowest tertile was independently associated with a 5.903-fold increased risk of post-stroke cognitive impairment after adjusting for confounders. The optimal cutoff value of SUA/SCr to predict post-stroke cognitive impairment was 4.874, which gave a sensitivity of 72.22% and a specificity of 63.16%.</p><p><strong>Conclusion: </strong>Our study revealed that SUA/SCr can be a potential indicator for post-stroke cognitive impairment in the early phase, a lower level of SUA/SCr upon admission was independently correlated to cognitive dysfunction after stroke.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1580722"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648945","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":"Nurr1 deficiency impairs autophagy-lysosomal function through GBA-dependent transcriptional regulation in Parkinson's disease pathogenesis.","authors":"Cheng Cheng, Huijia Yang, Lulu Tian, Yang Ni, Congcong Jia, Weidong Le, Qingshan Wang","doi":"10.3389/fnagi.2025.1612389","DOIUrl":"10.3389/fnagi.2025.1612389","url":null,"abstract":"<p><strong>Introduction: </strong>The autophagy-lysosomal pathway (ALP) dysfunction and lysosomal impairment contribute to the pathogenesis of Parkinson's disease (PD). Nuclear receptor related protein 1 (Nurr1) maintains the differentiation and maturation of dopaminergic neurons, and mutants or polymorphism in Nurr1 is associated with familial and sporadic PD. Previous studies on Nurr1 have mainly focused on the development and maintenance of midbrain dopaminergic neurons, while the potential involvement of Nurr1 in ALP regulation remains uncharacterized.</p><p><strong>Methods: </strong>Stable Nurr1 knockdown cells and inducible Nurr1 knockout mice were generated. Transcriptome sequencing and analysis was utilized to confirm the altered pathways and differentially expression genes associated with ALP. Transmission electron microscopy observation was conducted to find the ultrastructure differences between the Nurr1 knockdown cells and the controls. The expression of LC3B and the colocalization of LC3B and Lamp1 were assessed. Lysosomal acidity in the Nurr1 knockdown cells and the controls was measured. The expression of lysosomal proteins (Lamp 1/2, CTSD, and GBA) was determined <i>in vitro</i> and <i>in vivo</i> in the Nurr1-deficient models. Dual-luciferase reporter gene assay was performed to detect the transcriptional activity of GBA. The key lysosomal proteins (Lamp 1/2 and CTSD) were assessed after GBA overexpression.</p><p><strong>Results: </strong>Twenty-two terms and 45 differentially expression genes associated with ALP were identified by transcriptome analysis. Knockdown of Nurr1 induced intracellular aggregation of autophagosomes, increased endogenous expression of LC3B II and elevated colocalization of exogenous GFP-LC3B with Lamp1. Lysosome dysfunction has been implicated with lysosomal alkalization and deprived level of lysosomal marker proteins with Nurr1 deficiency. GBA was transcriptionally downregulated by Nurr1 and Nurr1 deficiency-triggered lysosomal dysfunction were attenuated by GBA overexpression in the Nurr1 knockdown cells.</p><p><strong>Discussion: </strong>Our study provided the first experimental evidence that Nurr1 deficiency induced lysosomal dysfunction by alkalizing the lumen of lysosomes and downregulating the key lysosomal protein (Lamp1, CTSD, and Lamp2) expression <i>in vivo</i> and <i>in vitro</i>. Defective lysosomal function compromised lysosomal mediated autophagic vesicle clearance. Mechanistically, Nurr1 transcriptionally regulated GBA expression, which in turn governed lysosomal marker protein homeostasis through a GBA-dependent axis. This study illuminated the involvement of Nurr1 in the ALP and the interaction between PD-related genes in the pathogenesis of PD.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1612389"},"PeriodicalIF":4.1,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636604","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":"Intermittent supplementation with <i>Akkermansia muciniphila</i> and galactooligosaccharides modulates Alzheimer's disease progression, gut microbiota, and colon short-chain fatty acid profiles in mice.","authors":"Arnas Kunevičius, Akshay Kumar Vijaya, Alessandro Atzeni, Jonas Mingaila, Ieva Šimoliūnė, Rapolas Jamontas, Emilija Keževičiūtė, Miguel Gueimonde, Rolandas Meškys, Daiva Baltriukienė, Silvia Arboleya, Aurelijus Burokas","doi":"10.3389/fnagi.2025.1617980","DOIUrl":"10.3389/fnagi.2025.1617980","url":null,"abstract":"<p><strong>Background: </strong>Bidirectional communication and mutual regulation between the gastrointestinal tract and the CNS is facilitated through the gut-brain axis. Recent studies have found reduced diversity of the gut microbiota in Alzheimer's disease (AD) patients, and animal models suggest microbial involvement in amyloid beta peptide (Aβ) accumulation. Modulation of the gut microbiota by new-generation probiotics represents a novel treatment strategy to alleviate the symptoms and slow the progression of AD.</p><p><strong>Methods: </strong>In this study, the therapeutic effect of the probiotic <i>Akkermansia muciniphila</i> and the prebiotic galactooligosaccharides (GOS) was investigated in the APP/PS1 mouse model. After 7 months of triweekly administration, we evaluated physiological parameters, glucose metabolism, and behavioral outcomes. Additionally, we assessed gut microbiota diversity and composition, short-chain fatty acid (SCFA) concentrations in the cecum, Aβ load in the hippocampus and prefrontal cortex, and microglial abundance in the hippocampus.</p><p><strong>Results: </strong><i>A. muciniphila</i> and GOS administration normalized fasting glucose levels, glucose metabolism, and intestinal transit time to wild-type levels. Furthermore, supplementation reduced anxiety, improved long-and short-term memory, and partially restored activity levels. It also regulated SCFA concentrations in the cecum, improved the richness of the gut microbiota, and normalized abundance of microglia in the hippocampus, indicating reduced neuroinflammation.</p><p><strong>Conclusion: </strong>These findings suggest that long-term administration of <i>A. muciniphila</i> and GOS effectively improves metabolic health and modulates symptoms of AD in the APP/PS1 mouse model.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1617980"},"PeriodicalIF":4.1,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636603","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":"Examining the independent and moderating effects of arterial stiffness and cerebral blood flow on total hippocampal and hippocampal subfield volumes.","authors":"Michelle Horan, Daniel Carey, Silvin Knight, A Fagan, James F M Meaney, Rose Anne Kenny, Céline De Looze","doi":"10.3389/fnagi.2025.1466294","DOIUrl":"10.3389/fnagi.2025.1466294","url":null,"abstract":"<p><strong>Introduction: </strong>There is a critical link between vascular disease and the progression to dementia. The hippocampus has been implicated in memory and cognitive decline. In this study, we investigate the independent and moderating effects of increased arterial stiffness (AS) and reduced cerebral blood flow (CBF) on hippocampal volume (HV) in a large MRI sample of community-dwelling older adults from the Irish Longitudinal Study on Ageing (TILDA).</p><p><strong>Methods: </strong>Longitudinal data from study participants for Wave 1 (2009-2011) and Wave 3 (2014-2015) were included. This included health and social information as well as a nurse-administered health assessment. Patients who had complete AS, CBF and MR-hippocampal measurements were included. Pseudo-continuous arterial spine labelling was performed to quantify whole CBF. Volumetric analysis was performed using FreeSurfer 6.0 recon-all processing pipeline.</p><p><strong>Results: </strong>395 patients met inclusion criteria. This four-year follow up longitudinal study demonstrated that (i) prolonged elevated AS (at wave 1 and wave 3), (ii) the interaction between higher AS at wave 1 and lower CBF at wave 3 and (iii) the interaction between prolonged elevated AS (at wave 1 and wave 3) and reduced CBF at wave 3 were associated with smaller HV.</p><p><strong>Conclusion: </strong>Increased arterial stiffness and reduced CBF were not independently associated with smaller HV. However, in combination, persistently elevated AS and reduced CBF is associated with smaller HV. These effects were equally exerted across all hippocampal subfields tested. Our findings suggest a lag effect in the arterial stiffness and hippocampal volume relationship. We propose that the subsequent reduction in cerebral blood flow observed with elevated arterial stiffness may be the missing link in the pathway associating arterial stiffness with hippocampal atrophy.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1466294"},"PeriodicalIF":4.1,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648916","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":"Age-sex differences in Alzheimer's and related dementias burden and risk factors in east and Southeast Asia: results from the 2021 GBD study.","authors":"Tengyu Zhao, Pengyu Pan, Yuhan Zhou, Xinyue Zhang, Quan Li, Yanyan Zhou","doi":"10.3389/fnagi.2025.1562148","DOIUrl":"10.3389/fnagi.2025.1562148","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease and related dementias (ADRD) significant global public health challenges, leading to severe disability in patients and placing a heavy burden on caregivers. However, epidemiological studies focusing on ADRD in specific regions remain limited. This study aims to comprehensively analyze and describe the current status and changing trends of ADRD in Non-High-income East Asia (NHIEA), Non-High-income Southeast Asia (NHISEA), and High-income Asia Pacific (HIAP), providing more detailed real-world data to inform policymaking.</p><p><strong>Methods: </strong>The data for ADRD used in this study were extracted from the 2021 Global Burden of Disease (GBD) database. We employed three major indicators of disease burden-prevalence, incidence, and years lived with disability (YLD)-and explored associated risk factors, further analyzing trends by age and sex. The results are presented as mean values with 95% uncertainty intervals (UIs). Additionally, we explored the differences between NHIEA, NHISEA, HIAP and other regions, as well as the potential associations between the disease burden of Alzheimer's and other dementias and socioeconomic factors.</p><p><strong>Results: </strong>The findings indicate that the burden of dementia is rising in East and Southeast Asia, with women showing a higher burden across all indicators. Notably, in NHIEA, particularly in China, the burden of dementia has increased with the rising Social Demographic Index (SDI). China experienced a 27.3% increase in Alzheimer's disease and other dementia ASYRs from 1990 to 2021, with a sharp 7.6% annual surge in 2021 alone, outpacing regional averages. Gender analysis revealed that women bear a disproportionate burden of Alzheimer's disease and related dementias, especially after menopause, when the risk increases significantly. The study also identified smoking, high blood sugar, and high body mass index as important risk factors affecting the disease burden. The contribution of these risk factors varies across regions, genders, and age groups.</p><p><strong>Conclusion: </strong>The health burden of ADRD remains substantial, with distinct patterns observed across NHIEA, NHISEA, and HIAP, including regional variations in gender, age, and risk factors. These findings highlight the need for tailored approaches to allocate healthcare resources and implement appropriate control measures based on the specific conditions of each region to address this growing public health challenge. Future research should prioritize comparative analyses across continents and within regions to inform the development of more region-specific prevention strategies for ADRD.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1562148"},"PeriodicalIF":4.1,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12245908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625867","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":"Editorial: Advances in Parkinson's Disease Research: Exploring Biomarkers and Therapeutic Strategies for Halting Disease Progression.","authors":"Anastasia Bougea, Yildiz Degirmenci","doi":"10.3389/fnagi.2025.1640566","DOIUrl":"10.3389/fnagi.2025.1640566","url":null,"abstract":"","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1640566"},"PeriodicalIF":4.1,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12245866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625868","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":"Metformin improves age-related visual cortex dysfunction in mice by reducing noise correlation in the primary visual cortex.","authors":"Xiaoming Liu, Yifeng Zhou, Jiachen Liu, Guangwei Xu","doi":"10.3389/fnagi.2025.1572653","DOIUrl":"10.3389/fnagi.2025.1572653","url":null,"abstract":"<p><strong>Introduction: </strong>Age-related decline in visual processing has been observed in association with reduced orientation selectivity and decreased signal-to-noise ratios in the primary visual cortex (V1). Elevated noise correlations between neurons are associated with impaired visual discrimination in aging; however, less is known about therapeutic interventions that could preserve visual cortical function during aging. In this study, we investigated the effects of metformin treatment on age-related changes in visual processing and neuronal correlations in V1.</p><p><strong>Methods: </strong>We conducted <i>in vivo</i> electrophysiological recordings to investigate whether 3 weeks of acute gavage with metformin improves visual processing in 12-month-old mice compared to 8-week-old mice by modulating neural noise in the V1, and used western blot analysis to investigate the molecular mechanism of the effect of metformin.</p><p><strong>Results: </strong><i>In vivo</i> electrophysiological recordings revealed that aging led to V1 neuronal hyperactivity, accompanied by reduced orientation selectivity, a decreased signal-to-noise ratio, and increased response variability. Notably, aged mice exhibited increased noise correlation, response covariance, and population variability. Analysis of fast-spiking interneurons revealed impaired noise suppression in the inhibitory circuits of aged mice. Daily metformin treatment reversed these age-related alterations by improving fast-spiking neuron-mediated decorrelation and reducing noise correlation. Mechanistically, metformin upregulated the protein expression levels of glutamic acid decarboxylase 67 and gephyrin, key components of inhibitory synapses, suggesting that metformin enhances visual processing by strengthening inhibitory signaling and reducing the correlated variability in the V1.</p><p><strong>Discussion: </strong>Metformin treatment effectively ameliorated these deficits through enhanced GABAergic signaling; however, the broader therapeutic mechanisms across sensory systems remain unclear. In this study, we demonstrate that metformin preserves visual function by restoring excitatory-inhibitory balance, suggesting a promising approach for age-related sensory decline.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1572653"},"PeriodicalIF":4.1,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12241007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607961","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":"Reduced synaptic tagging by complement protein C3 is associated with elevated extracellular matrix in the middle-aged cerebellum of mice.","authors":"Henning Peter Düsedau, Carla Cangalaya, Stoyan Stoyanov, Alexander Dityatev, Ildiko Rita Dunay","doi":"10.3389/fnagi.2025.1616390","DOIUrl":"10.3389/fnagi.2025.1616390","url":null,"abstract":"<p><strong>Background: </strong>Aging of the brain is associated with cognitive decline and recognized as a major risk factor for the development of neurodegenerative diseases. On a cellular level, brain aging is accompanied by a progressive increase of the basal pro-inflammatory tonus, leading to the activation of phagocytic pathways in brain-resident microglia and disruptive effects on synaptic neurotransmission. While the aging process affects all brain compartments at different velocities and one of the particularly affected regions is the cerebellum (CB), the underlying effects remain elusive.</p><p><strong>Methods: </strong>In the present study, we harnessed a murine model of natural aging in males combined with orthogonal experimental approaches comprising of cytokine gene expression analysis, flow cytometry, immunohistochemistry, and flow synaptometry.</p><p><strong>Results: </strong>We report age-dependent morphological and phenotypic changes in microglia that are distinct in the cortex (CTX) and CB. Furthermore, we show an increased expression of cytokines and complement factors upon aging and a decline of C3-tagged VGLUT1⁺ presynaptic puncta in the CB. Using flow synaptometry to quantify the composition of synapses in more detail, we validated the reduction of C3b-labeled excitatory synaptosomes while the overall frequency of glutamatergic synaptosomes remained unaffected by aging. Notably, proteoglycans brevican and aggrecan, key components of the neural extracellular matrix, were significantly upregulated in the middle-aged CB.</p><p><strong>Discussion: </strong>The data presented herein suggests the ECM-mediated shielding of synapses from complement-tagging and subsequent engulfment by microglia. Thus, we provide novel insights into mechanisms that may confer resilience in the brain by modulating synapse removal in the context of aging.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1616390"},"PeriodicalIF":4.1,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12240999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607962","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":"Regional network covariance patterns of white matter integrity related to cardiorespiratory fitness in healthy aging.","authors":"Samantha G Smith, Pradyumna K Bharadwaj, David A Raichlen, Matthew D Grilli, Jessica R Andrews-Hanna, Georg A Hishaw, Matthew J Huentelman, Theodore P Trouard, Gene E Alexander","doi":"10.3389/fnagi.2025.1542458","DOIUrl":"10.3389/fnagi.2025.1542458","url":null,"abstract":"<p><p>Cardiorespiratory fitness (CRF), measured by VO₂max, is an indicator of vascular functioning that can influence the integrity of brain microstructural white matter tracts in aging. How CRF is related to regional patterns of white matter bundles for magnetic resonance imaging (MRI) diffusion metrics (axial diffusivity, AD; radial diffusivity, RD; mean diffusivity, MD; fractional anisotropy, FA) has been less studied. We used a multivariate analysis method, the Scaled Subprofile Model (SSM), to identify network patterns of MRI tract-specific white matter integrity (WMI) for AD, RD, MD, and FA related to VO₂max and to evaluate their relation to demographic, vascular health, and dementia risk factors in 167 cognitively unimpaired older adults, ages 50 to 88. We identified four CRF-related regional patterns of WMI characterized by enhanced integrity in commissural pathways that connect areas within anterior brain regions (prefrontal body of the corpus callosum), connect subcortical regions to one another (fornix), and include selected association tracts (arcuate fasciculus, superior longitudinal fasciculus). Greater white matter lesion load, in addition to age, was associated with reduced expression of all four CRF-WMI patterns, while high vascular risk level was further associated with reduced expression of the RD, MD, and FA patterns. The regional patterns of RD and FA were most strongly associated with CRF. The results suggest that in healthy older adults, enhanced CRF is differentially associated with regional patterns of WMI, which are related to age and further impacted by macrostructural white matter lesion load and vascular risk. These findings support the use of the multivariate SSM in identifying regional patterns of white matter tracts that may provide markers of brain aging and cerebrovascular health.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1542458"},"PeriodicalIF":4.1,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12241056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607963","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}