Frontiers in Aging Neuroscience最新文献

{"title":"From pathology to network failure: a Question-Model-Outcome framework for interpreting animal models of AD-related and dementia-relevant mechanisms.","authors":"Umut Şimşekçi, Yıldırım Cesaretli","doi":"10.3389/fnagi.2026.1882211","DOIUrl":"10.3389/fnagi.2026.1882211","url":null,"abstract":"<p><p>Animal studies remain indispensable for research on Alzheimer's disease (AD), vascular cognitive impairment, and other dementia-relevant mechanisms. Their value, however, is not that they reproduce human late-life dementia in miniature. A mouse line, vascular manipulation, or mixed-pathology preparation can make one aspect of the problem experimentally visible while not capturing the long preclinical course, clinical heterogeneity, and everyday functional consequences that define the human syndrome. This review therefore treats animal models as instruments for bounded inference. Drawing on translational, mechanistic, and methodological literature, we ask which biological question is posed, which outcome can legitimately answer it, and where the claim should be drawn back. The Question-Model-Outcome framework is developed around five recurrent problems: the loose relation between lesion burden and functional severity; vascular influences on proteinopathy and network injury; stage-dependent immune and glial responses; the narrow construct validity of many behavioral assays; and the interpretation of reported improvement after intervention. We argue that translational value arises when model biology, disease stage, and outcome level are aligned. In that role, animal studies can sharpen mechanistic reasoning and discipline clinical extrapolation without being treated as generic substitutes for human AD-related dementia.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1882211"},"PeriodicalIF":5.2,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13526821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148864105","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":"P2X7 receptor-dependent microglia-astrocyte coupling in Alzheimer's disease: from eATP sensing to synaptic and proteostatic failure.","authors":"Yiwen Li, Shiming Liu, Jiao Lan","doi":"10.3389/fnagi.2026.1915244","DOIUrl":"10.3389/fnagi.2026.1915244","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is characterized not only by amyloid-β and tau pathology but also by progressive failure of multicellular homeostasis. The P2X7 receptor (P2X7R), a low-affinity ATP-gated ion channel preferentially activated in extracellular ATP-rich pathological microenvironments, is well positioned to translate local tissue stress into sustained glial dysfunction. Although P2X7R has traditionally been studied as a microglial inflammasome-associated receptor, its broader significance may lie in coupling microglial activation to astrocytic loss of homeostatic support. In this review, we propose an integrative model in which P2X7R functions as a high-threshold inter-glial transducer through five interconnected axes: extracellular ATP amplification, cytokine relay, extracellular vesicle exchange, convergent synaptic modulation and circuit destabilization, and a coordinated clearance-to-retention switch. Microglial P2X7R activation promotes cytokine and reactive oxygen species production, vesicle and mitochondrial release, inflammatory reprogramming, and impaired phagocytic and lysosomal competence. Astrocytic P2X7R may reinforce this environment through feed-forward ATP release, altered gliotransmission, reactive transformation, extracellular vesicle shedding, and disrupted autophagic and lysosomal processing. We further situate this reciprocal loop within the amyloid plaque niche, where dystrophic neurites, stressed synapses, and reactive glia may create a spatially restricted P2X7R-sensitive ATP microdomain. The resulting cross-glial amplification is proposed to connect neuroinflammation with synaptic destabilization and defective proteostasis. This framework also suggests that brain-penetrant and pharmacologically selective P2X7R antagonists could complement protein-targeted therapies, particularly when guided by functional biomarkers of receptor activity. However, the proposed coupling architecture remains an integrative and testable hypothesis because much of the supporting evidence derives from non-AD models, <i>in vitro</i> studies, or correlative human tissue analyses. Cell-type-specific, temporally resolved studies are therefore required to establish whether P2X7R-dependent microglia-astrocyte coupling causally drives AD progression.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1915244"},"PeriodicalIF":5.2,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13527039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148864223","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":"Direct toll-like receptor 4 inhibition in Alzheimer's disease models: a focused scoping review of inflammatory, amyloid-handling, and functional outcomes.","authors":"Xiaolu Ren, Xinyu Jin, Ling Li, Fang Li","doi":"10.3389/fnagi.2026.1889254","DOIUrl":"10.3389/fnagi.2026.1889254","url":null,"abstract":"<p><strong>Objective: </strong>This focused scoping review evaluated whether direct toll-like receptor 4 (TLR4) inhibition, antagonism, or genetic suppression in Alzheimer's disease (AD)-related models was associated with concordant inflammatory, amyloid-β (Aβ)-handling, and functional outcomes.</p><p><strong>Methods: </strong>Original AD- or Aβ-related animal, cellular, and <i>ex vivo</i> studies were eligible when they directly inhibited, antagonized, or genetically suppressed TLR4 signaling using pharmacological approaches, including TAK-242/CLI-095/resatorvid, IAXO-101, RSLA, or related TLR4-targeting strategies, or genetic approaches such as TLR4 siRNA, knockdown, knockout, or loss-of-function mutation. Evidence was synthesized using a three-layer framework comprising inflammatory activation, Aβ handling, and neuronal, synaptic, or behavioral consequences.</p><p><strong>Results: </strong>Direct TLR4 suppression generally attenuated target-proximal inflammatory activation, including microglial activation, pro-inflammatory mediator expression, NF-κB signaling, NLRP3 inflammasome activation, and reactive microglial phenotypes. In contrast, amyloid-related and functional outcomes were heterogeneous. Some studies reported reduced Aβ pathology, enhanced phagocytosis, synaptic protection, or cognitive improvement, whereas others showed impaired amyloid clearance, increased Aβ deposition, or worsened memory-related outcomes. APOE genotype, sex, treatment window, model system, Aβ species, and intervention type appeared to modify the direction of downstream effects.</p><p><strong>Conclusion: </strong>Toll-like receptor 4 suppression relatively consistently attenuated inflammatory readouts, whereas amyloid-related and functional outcomes remained heterogeneous, supporting an exploratory, hypothesis-generating model of context-dependent inflammatory-amyloid-functional dissociation rather than a uniform therapeutic benefit.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1889254"},"PeriodicalIF":5.2,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13526921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148864068","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":"Exercise alone or combined with functional foods in aging and age-related diseases: targeting DNA damage, repair pathways, and genome integrity.","authors":"Ying Ma, Xuejun Li, He Chen, Rongchang Fan","doi":"10.3389/fnagi.2026.1772217","DOIUrl":"10.3389/fnagi.2026.1772217","url":null,"abstract":"<p><p>Aging is fundamentally associated with the gradual accumulation of DNA damage, which is instrumental in the initiation and advancement of age-associated pathologies, including neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease. Recent studies indicate that lifestyle modifications-especially the consumption of functional foods and participation in consistent physical exercise-can influence cellular and molecular processes related to DNA repair, reduction of oxidative stress, and maintenance of genomic integrity. This review consolidates contemporary research regarding how particular bioactive compounds (e.g., polyphenols, omega-3 fatty acids, and flavonoids) present in functional foods, in conjunction with diverse exercise interventions, affect DNA repair processes and diminish genotoxic stress. We examine evidence from exercise-only, nutrition-only, and combined lifestyle interventions, with particular attention to whether combined interventions show additive, complementary, or genuinely synergistic effects on oxidative stress, inflammatory responses, epigenetic aging, and DNA repair-related pathways. Particular emphasis is placed on the susceptibility of the brain to DNA damage and the significance of these interventions in safeguarding neuronal integrity and cognitive capabilities. By synthesizing evidence from molecular, animal, and human research, this review underscores the therapeutic promise of functional foods and physical activity as readily available, non-pharmacological approaches to ameliorate genomic integrity and postpone the onset or progression of aging-related and neurodegenerative disorders. In conclusion, we address prevailing limitations, deficiencies in translational research, and prospective avenues for personalized lifestyle medicine aimed at enhancing DNA integrity.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1772217"},"PeriodicalIF":5.2,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13522122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850262","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":"A male rat model integrating hypertension, chronic cerebral hypoperfusion, and aging recapitulates multimodal cerebral small vessel disease phenotypes.","authors":"Zhiwei Feng, Shan Han, Yanyi Li, Zhenzhen Li, Yige Tu, Bin Wu, Shengjie Zhu, Qin Zheng, Wenjun Sun","doi":"10.3389/fnagi.2026.1906043","DOIUrl":"10.3389/fnagi.2026.1906043","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Cerebral small vessel disease (CSVD) usually develops under the combined influence of vascular risk factors, chronic perfusion insufficiency, and age-related brain vulnerability; however, animal models driven by a single insult do not fully reproduce this multifactorial clinical context.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We established a composite CSVD rat model by combining spontaneous hypertension, bilateral common carotid artery stenosis (BCAS)-induced chronic cerebral hypoperfusion, and D-galactose (D-gal)-induced aging-related stress. Fourteen-week-old male Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) were assigned to the WKY, SHR, SHR+BCAS, and SHR+BCAS+D-gal groups. Spatial learning and memory, exploratory behavior, spontaneous locomotion, and motor coordination were assessed using the Morris water maze, open field test, and balance beam test. T2-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) were used to quantify regional brain volumes and white matter microstructural integrity. Luxol fast blue (LFB) staining and transmission electron microscopy (TEM) were performed to examine corpus callosum myelin pathology, and enzyme-linked immunosorbent assay (ELISA) was used to assess molecular markers related to the blood-brain barrier (BBB), neuroinflammation, oxidative stress, myelin injury, axonal injury, and neuronal damage.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Compared with WKY rats, SHR rats showed early spatial memory impairment, behavioral abnormalities, and structural brain changes. Superimposition of BCAS and D-gal progressively aggravated these abnormalities. SHR+BCAS+D-gal rats exhibited the longest escape latency, reduced target-quadrant dwell time and platform crossings, decreased locomotor and exploratory activity, prolonged balance beam crossing time, increased foot slips, and greater waiting/stopping behavior. MRI revealed ventricular enlargement and reduced hippocampal, cortical, and corpus callosum volumes. DTI showed lower fractional anisotropy in the genu of the corpus callosum, cingulum, dorsal hippocampus, and thalamic core region. LFB staining showed reduced myelin staining and disorganized fiber arrangement, whereas TEM revealed myelin lamellar loosening, irregularity, and deformation in the corpus callosum. Molecular analyses showed decreased Claudin-5, ZO-1, MBP, and SOD, and increased Iba1, GFAP, MDA, corpus callosum NfL, serum NfL, and serum NSE, especially in the SHR+BCAS+D-gal group.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;In male rats, the SHR+BCAS+D-gal composite model recapitulates the multifactorial background, chronic progression, and multimodal neurological impairment of clinical CSVD at behavioral, neuroimaging, histopathological, and molecular levels. This male rat model may provide a useful experimental platform for mechanistic and interventional studies targeting BBB protection, neuroinflammation, oxidative stress, and white matter repai","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1906043"},"PeriodicalIF":5.2,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13522228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850092","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":"Restoring anticipatory control through cognitive-motor dual-task training improves emotional and executive function in frail older adults.","authors":"Luca Boccacci, Martina Scalia, Riccardo Borzuola, Valentina Camomilla, Domenico Campagna, Andrea Casella, Imma Ceriello, Natalie Ferrulli, Margherita Filosa, Chiara Fossati, Federica Galli, Andrea Macaluso, William Manzon, Camilla Panacci, Martina Parrella, Fabio Pigozzi, Sabrina Pitzalis, Franco Pio Siciliano, Arnaldo Zelli, Francesco Di Russo","doi":"10.3389/fnagi.2026.1890281","DOIUrl":"10.3389/fnagi.2026.1890281","url":null,"abstract":"<p><strong>Background: </strong>Aging-related frailty is increasingly recognized as a multidimensional condition involving impairments in cognitive, emotional, and motor domains. Traditional interventions often fail to capture the complexity of real-world functioning, highlighting the need for more ecologically valid approaches.</p><p><strong>Objectives: </strong>This study investigated the effects of a structured Cognitive-Motor Dual-Task Training (CMDT) protocol, incorporating alternating bilateral stimulation (BAS), on emotional regulation, executive function, and anticipatory neural mechanisms in frail and pre-frail older adults.</p><p><strong>Methods: </strong>Thirty participants aged ≥ 65 years were enrolled in a randomized controlled trial and assigned to either a CMDT group or a motor-only control group. The intervention lasted 8 weeks (two sessions per week). Assessments were conducted at baseline, mid-intervention, and post-intervention, and included measures of anxiety (STAI-Y), depression (BDI-II), executive performance (reaction times, variability, and accuracy), functional mobility (BBS, TUG, 10mWT), and high-density EEG during a Go/No-go task to extract anticipatory event-related potentials (prefrontal negativity, pN; Bereitschaftspotential, BP).</p><p><strong>Results: </strong>The CMDT group showed significant reductions in anxiety and depressive symptoms, along with improved executive performance compared to the control group. At the neural level, CMDT enhanced anticipatory activity, reflected by increased pN and BP amplitudes. Mediation analyses revealed that changes in prefrontal anticipatory activity (pN) significantly mediated the relationship between CMDT and emotional improvements, with a full mediation pattern observed for self-reported depressive symptoms and a partial mediation pattern for anxiety.</p><p><strong>Conclusion: </strong>These findings indicate that CMDT enhances anticipatory control mechanisms linking brain function to behavior, supporting both emotional regulation and executive efficiency in frail older adults. By embedding cognitive demands within motor actions, this approach provides a low-cost and scalable intervention with increased ecological relevance, offering a promising strategy for addressing multidimensional vulnerability in aging.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1890281"},"PeriodicalIF":5.2,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850190","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":"Effects of Tai Chi on functional performance and fall-related psychological outcomes in Parkinson's disease: a systematic review and meta-analysis.","authors":"Fusen Wang, Tongtong Hao","doi":"10.3389/fnagi.2026.1860410","DOIUrl":"10.3389/fnagi.2026.1860410","url":null,"abstract":"<p><strong>Objective: </strong>To systematically evaluate the effects of Tai Chi on objective motor performance and subjective fall-related psychological outcomes in patients with Parkinson's disease (PD), and to examine whether intervention characteristics influence the magnitude of therapeutic effects.</p><p><strong>Methods: </strong>Randomized controlled trials (RCTs) investigating Tai Chi interventions in patients with PD were identified through searches of electronic databases from inception to April 2026. The methodological quality and risk of bias were assessed using the Cochrane Risk of Bias 2 (RoB 2) tool and the PEDro scale. Meta-analyses were performed to evaluate the effects of Tai Chi on balance function, motor function, mobility, balance confidence, and fear of falling. Subgroup analyses were conducted according to intervention duration, weekly frequency, and session length to explore potential sources of heterogeneity.</p><p><strong>Results: </strong>Seventeen RCTs involving 914 participants were included. Meta-analysis demonstrated that Tai Chi significantly improved balance function measured by the Berg Balance Scale (BBS) (MD = 3.35, 95% CI [1.40, 5.30], <i>p</i> < 0.001), motor function assessed by the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) (MD = -4.10, 95% CI [-6.34, -1.85], <i>p</i> < 0.001), and mobility measured by the Timed Up and Go Test (TUGT) (MD = -1.97, 95% CI [-3.30, -0.64], <i>p</i> < 0.001). Limited evidence suggested possible improvements in fall-related psychological outcomes, including balance confidence and fear of falling; however, these findings should be interpreted cautiously due to the small number of studies, heterogeneity, and limited precision.</p><p><strong>Conclusion: </strong>Tai Chi may improve balance, motor function, and mobility in patients with Parkinson's disease. Evidence regarding fall-related psychological outcomes remains limited and requires further investigation. However, the optimal intervention dosage remains unclear, and the findings should be interpreted cautiously due to heterogeneity among studies and limited evidence for subjective outcomes. Future large-scale, well-designed RCTs with standardized intervention protocols and longer follow-up periods are warranted.</p><p><strong>Systematic review registration: </strong>https://www.crd.york.ac.uk/PROSPERO/view/CRD420261371910, identifier CRD420261371910.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1860410"},"PeriodicalIF":5.2,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13522115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850098","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":"Multimodal characterization of cortical hyperexcitability as a driver of cognitive decline in neurocognitive disorders: study protocol for the LENDÜLET Neurocognitive Research Project.","authors":"András Attila Horváth","doi":"10.3389/fnagi.2026.1809381","DOIUrl":"10.3389/fnagi.2026.1809381","url":null,"abstract":"<p><strong>Introduction: </strong>Cognitive impairment is a major source of disability in neurodegenerative conditions, and it is also highly prevalent in autism spectrum disorder and attention-deficit/hyperactivity disorder. Across these conditions, subclinical epileptiform activity and resting-state functional hyperactivity have been repeatedly described, suggesting a shared state of cortical hyperexcitability. The LENDÜLET Neurocognitive Research Project aims to determine the incidence and multimodal characteristics of cortical hyperexcitability in multiple patient populations and to elucidate how hyperexcitability relates to cognitive performance, large-scale network connectivity, sleep-dependent memory consolidation, and tau/amyloid burden.</p><p><strong>Methods: </strong>In a prospective, multimodal observational study, we are recruiting 75 participants per group (patients with mild cognitive impairment, patients with autism spectrum disorder, patients with attention deficit/hyperactivity disorder, and healthy controls; total <i>N</i> = 300) at the National Institute of Psychiatry and Addictology (Budapest, Hungary). All participants are undergoing a harmonized diagnostic protocol including detailed neuropsychological assessment, structural MRI, resting-state functional MRI, and 24-h ambulatory electroencephalography. Patients with neurodegenerative conditions will additionally undergo CSF sampling. Individuals who exhibit markers of cortical hyperexcitability will be invited to an in-ward mechanistic substudy (3-day video-electroencephalography monitoring with repeated neuropsychological paradigms, overnight sleep recordings, and spindle analysis, and serial blood sampling to characterize circadian dynamics of tau and amyloid.</p><p><strong>Anticipated results: </strong>Primary outcome is the incidence and distribution of cortical hyperexcitability in each diagnostic group relative to controls. Secondary outcomes include relationships between hyperexcitability and (a) structural atrophy and white matter integrity; (b) functional connectivity within and between default mode, salience, and attention networks; (c) cerebrospinal and plasma tau/amyloid levels; and (e) domain-specific cognitive performance. The current paper describes the study design, while the results are not reported.</p><p><strong>Discussion: </strong>This study will provide the first systematic, multimodal assessment of cortical hyperexcitability across multiple neurocognitive disorders with shared vulnerability to epilepsy and cognitive decline. The resulting biomarker panel may support risk stratification, inform clinical trial design for anti-hyperexcitability interventions, and ultimately enable individualized prevention strategies for cognitive decline.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1809381"},"PeriodicalIF":5.2,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13521925/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850219","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 α-synuclein and QSM-derived susceptibility in Parkinson's disease: associations with clinical features.","authors":"Xingjun Li, Tianfei Luo, Jing Bai","doi":"10.3389/fnagi.2026.1740309","DOIUrl":"10.3389/fnagi.2026.1740309","url":null,"abstract":"<p><strong>Background: </strong>The pathological interplay between α-synuclein aggregation and iron dysregulation is central to the neurodegenerative process in Parkinson's disease (PD). Quantitative susceptibility mapping (QSM) allows <i>in vivo</i> assessment of regional brain iron burden, and blood assays enable measurement of plasma α-synuclein; however, their clinical relevance and mutual relationship remain insufficiently defined.</p><p><strong>Objective: </strong>To evaluate plasma α-synuclein as a diagnostic biomarker (against controls) and to explore whether regional brain iron deposition, measured by QSM, correlates with clinical features and plasma α-synuclein within the PD group.</p><p><strong>Methods: </strong>Fifty-two PD patients and sixty-two age- and sex-matched healthy controls were enrolled. Plasma α-synuclein concentrations were quantified by ELISA. Magnetic susceptibility values of seven deep gray-matter nuclei were obtained using QSM reconstructed from a multi-echo gradient-echo sequence on a 3.0 T MRI scanner. Motor and non-motor symptoms were assessed using MDS-UPDRS-III, H-Y staging, MoCA, MMSE, HAMD, and HAMA scales.</p><p><strong>Results: </strong>Plasma α-synuclein levels were significantly higher in PD than controls [median 54.9 (46.9-60.6) vs. 28.7 (24.4-33.7) pg/μL, <i>p</i> < 0.001]. ROC analysis showed strong diagnostic accuracy (AUC = 0.976, sensitivity = 100%, specificity = 88.7%). Within PD, plasma α-synuclein correlated inversely with Age (<i>r</i> = -0.371, <i>p</i> = 0.007) but not with other clinical parameters. In unadjusted analyses, regional QSM values showed nominal associations with motor severity and cognitive performance; however, these associations did not remain significant after adjustment for age and multiple comparisons.</p><p><strong>Conclusion: </strong>Elevated plasma α-synuclein provides a highly discriminative diagnostic biomarker for PD, while regional iron accumulation measured by QSM-derived magnetic susceptibility exhibited nominal associations with clinical and cognitive measures, although these relationships did not remain significant after age adjustment and correction for multiple comparisons. The absence of a direct association between peripheral α-synuclein levels and regional brain iron burden suggests that these biomarkers may reflect partially independent pathological processes in Parkinson's disease. Future longitudinal studies are warranted to clarify the temporal dynamics and potential complementary roles of these biomarkers in disease characterization.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1740309"},"PeriodicalIF":5.2,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13521921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850227","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":"Sex- and age-dependent associations between waist-to-hip ratio and cognitive impairment: a cross-sectional study of rural adults aged 40 years and older in northwestern China.","authors":"Simeng Cui, Yu Zhang, Qiqi Qiang, Ziyu Liu, Peijie Liu, Liangjun Dang, Jin Wang, Wenhui Lu, Kang Huo, Yu Jiang, Chen Chen, Ling Gao, Shan Wei, Junlong Feng, Suixia Cao, Suhang Shang, Qiumin Qu, Meng Zhang","doi":"10.3389/fnagi.2026.1835459","DOIUrl":"10.3389/fnagi.2026.1835459","url":null,"abstract":"<p><strong>Background: </strong>Obesity is a modifiable risk factor for cognitive impairment; however, body mass index fails to capture fat distribution. Waist-to-hip ratio (WHR), reflecting central adiposity, may better characterize obesity-related differences in cognitive impairment. Nevertheless, whether the association between WHR and cognitive impairment varies by sex and age remains unclear.</p><p><strong>Methods: </strong>This cross-sectional study included 1,792 adults aged ≥40 years from rural China. Cognitive impairment was defined using education-adjusted cutoffs on the Chinese Mini-Mental Status. WHR and clinical characteristics were collected by trained investigators. Multivariable logistic regression, restricted cubic splines, stratified analyses, and interaction analyses were performed.</p><p><strong>Results: </strong>In the total population, WHR was positively associated with the odds of cognitive impairment (OR = 1.245 per SD, 95% CI: 1.022-1.517, <i>P</i> = 0.029), with borderline evidence of nonlinearity (<i>P</i> _{<i>overall</i>} = 0.019, <i>P</i> _{<i>nonlinear</i>} = 0.090). In sex-stratified analyses, the association in females showed evidence of nonlinearity, with the estimated odds remaining relatively stable below a WHR of 0.88 and increasing at higher levels (<i>P</i> _{<i>overall</i>} = 0.014, <i>P</i> _{<i>nonlinear</i>} = 0.049), whereas no significant association was observed in males. Age-stratified analyses demonstrated a significant association in the middle-aged group (40-59 years, <i>P</i> _{<i>overall</i>} = 0.016, <i>P</i> _{<i>nonlinear</i>} = 0.143) but not in those ≥60 years. Further interaction analyses showed that age appeared to modify the association between WHR and cognitive impairment in males (OR = 0.462 per SD, 95% CI: 0.258-0.828, <i>P</i> _{<i>interaction</i>} = 0.010), but not in females. Specifically, the positive association between WHR and cognitive impairment was observed only in middle-aged males (OR = 1.652 per SD, 95% CI: 1.052-2.595, <i>P</i> = 0.029), but not in older males (OR = 0.804 per SD, 95% CI: 0.492-1.314, <i>P</i> = 0.384).</p><p><strong>Conclusion: </strong>Our findings show that WHR is associated with screening-defined cognitive impairment, with patterns that may differ by sex and age. Females exhibited a possible nonlinear association, whereas in males the association was mainly observed in midlife. These findings highlight central adiposity as an important correlate of cognitive impairment. Given the rural single-region sample, larger longitudinal studies with clinically adjudicated outcomes are warranted to assess generalizability and clarify temporal associations.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1835459"},"PeriodicalIF":5.2,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13518583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148839767","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}