Frontiers in Aging Neuroscience最新文献

{"title":"Reconsideration of the DTI-ALPS index as a glymphatic surrogate: disease-specific findings in small vessel disease due to cerebral amyloid angiopathy or arteriolosclerosis.","authors":"Yaping Zhou, Xingqi Pan, Ziyi Xia, Yuhui Sha, Gan Sun, Fei Han, Ming Yao, Lixin Zhou, Liyun Tu, Feng Feng, Joanna M Wardlaw, Yi-Cheng Zhu, Jun Ni","doi":"10.3389/fnagi.2026.1933808","DOIUrl":"10.3389/fnagi.2026.1933808","url":null,"abstract":"<p><strong>Objectives: </strong>To explore the disease-specific performance of diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index in cerebral amyloid angiopathy (CAA) and arteriolosclerosis CSVD (aCSVD).</p><p><strong>Methods: </strong>We retrospectively enrolled probable CAA or aCSVD patients who underwent 5.0T MRI. Disease-specific DTI-ALPS characteristics and the correlations with clinical, imaging markers, and cognition were evaluated. Regression models were applied according to outcome distributions. Multiple comparisons were controlled using the Benjamini-Hochberg false discovery rate (FDR) procedure.</p><p><strong>Results: </strong>A total of 134 participants (56 probable CAA and 78 arteriolosclerosis, mean age 64.9 ± 10.0 years, 64.9% males) were enrolled. DTI-ALPS index was significantly lower in aCSVD than in CAA (<i>p</i> < 0.001). After adjustment for age and sex and FDR correction, no clinical factors remained significantly associated with DTI-ALPS index. In aCSVD, DTI-ALPS was significantly associated with cognitive performance, whereas these associations did not reach statistical significance in CAA. Across both groups, DTI-ALPS was significantly associated with white matter hyperintensity volume, skeletonized fractional anisotropy, skeletonized mean diffusivity, and peak width of skeletonized mean diffusivity (all FDR-adjusted <i>p</i> < 0.05). Associations with PVS burden and established CAA imaging markers did not reach statistical significance.</p><p><strong>Conclusion: </strong>DTI-ALPS index is heterogenous across distinct angiopathies but consistently associated with white matter microstructural damage. These subtype-specific findings question the relevance of DTI-ALPS index and caution against using DTI-ALPS index as a universal glymphatic surrogate.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1933808"},"PeriodicalIF":5.2,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105895","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":"Average performance and performance variability on a brief functional fine motor test reflect distinct behavioral constructs in aging.","authors":"Chung-Fu Sun, Kylie B Tomlin, Jennapher Lingo VanGilder, Andrew Hooyman, Alexandra M Reed, Jessica L Trevino, Sydney Y Schaefer","doi":"10.3389/fnagi.2026.1957422","DOIUrl":"10.3389/fnagi.2026.1957422","url":null,"abstract":"<p><p>Prior work in older adults has developed a brief functional fine motor test, which involves repeated timed trials of an upper-limb task. Performance has been associated with global and domain-specific neuropsychological tests as well as putative markers of Alzheimer's disease when scored using variability in trial time; however, the extent to which task performance depends on motor ability has not been established nor quantified. This retrospective study examined whether mean trial time and trial time variability (measured as intrasubject standard deviation in trial time) were differentially associated with standard assessments of motor and cognitive function. Forty-eight older adults with no functional impairment completed the functional fine motor test, which was compared to grooved pegboard test performance, grip strength, and Rey-Osterrieth complex figure test (RCFT) delayed recall. Generalized linear models included age, sex, education, and both scoring methods on the functional fine motor test (mean trial time and trial time variability) as predictors. Longer mean trial time was associated with slower grooved pegboard performance and lower grip strength, whereas trial time variability was not associated with either standard motor assessment. These findings, along with patterns of partial correlations, suggest that mean trial time may predominantly reflect motor function while trial time variability does not. Together, these findings highlight the value of considering both mean performance and performance variability in tasks that include multiple trials, offering an efficient approach to assessing multiple domains in older adults.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1957422"},"PeriodicalIF":5.2,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106567","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 impairment and probable REM sleep behavior disorder in Parkinson's disease: clinical relevance to the single- and dual-hit hypotheses.","authors":"Chia-Yen Lin, Ting-Hsin Chang, Ling-Yu Lin, Ming-Hong Chang","doi":"10.3389/fnagi.2026.1778012","DOIUrl":"10.3389/fnagi.2026.1778012","url":null,"abstract":"<p><strong>Background: </strong>Rapid eye movement (REM) sleep behavior disorder (RBD) and olfactory impairment are common prodromal features of Parkinson's disease (PD), but the implications of their coexistence remain uncertain. The dual-hit hypothesis proposes concomitant olfactory and enteric involvement, whereas the revised single-hit framework proposes predominantly brain-first or body-first routes. We examined whether probable RBD (pRBD)/anosmia-defined subgroups exhibit distinct clinical profiles.</p><p><strong>Methods: </strong>In this cross-sectional study, 201 individuals with PD underwent olfactory, cognitive, motor, non-motor, and quality-of-life assessments. Anosmia was defined as a University of Pennsylvania Smell Identification Test score <19 and pRBD as an RBD Screening Questionnaire score ≥6 supplemented by participant and informant interviews. Multivariable models evaluated the main and interactive effects of anosmia and pRBD.</p><p><strong>Results: </strong>Of 201 participants, 95 (47.3%) were pRBD-positive (pRBD+), 135 (67.2%) had anosmia, and 68 (33.8%) had both. Anosmia prevalence did not differ between the pRBD+ and pRBD-negative (pRBD-) groups (71.6% vs. 63.2%; <i>p</i> = 0.208). After adjustment for age, sex, and disease duration, pR+A+ and pR+A- (subgroups defined by probable RBD status [pR+/pR-] and anosmia status [A+/A-]) did not differ in any assessed outcome. The anosmia-by-pRBD interaction was negative for MDS-UPDRS part III (β = -8.3, 95% CI -15.2 to -1.4; <i>p</i> = 0.019). Within the pRBD- subgroup, pR-A+ participants had lower MoCA scores than pR-A- participants (β = -2.6; 95% CI -4.1 to -1.0; <i>p</i> = 0.001), and the anosmia-by-pRBD interaction was positive for MoCA (β = 2.3, 95% CI 0.0 to 4.5; <i>p</i> = 0.049). Anosmia was associated with cognitive impairment in pRBD- participants (OR 2.53, 95% CI 1.00-6.37; <i>p</i> = 0.049), but not in pRBD+ participants (OR 1.65, 95% CI 0.60-4.50; <i>p</i> = 0.331).</p><p><strong>Conclusion: </strong>In pRBD+ participants, anosmia was not associated with greater motor severity; in pRBD- participants, it was instead linked to cognitive impairment. Concurrent assessment of olfaction and pRBD may improve clinical phenotyping, but longitudinal validation is required.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1778012"},"PeriodicalIF":5.2,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638651/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105880","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":"Kinestesia: the prefrontal EEG response to a cognitive-motor intervention is graded by baseline cognitive status.","authors":"Jorge F Bosch-Bayard, Judith Guerrero-Sauzameda, Laura Navarrete-Torres, Liane Aguilar-Fabre, Rene F Rodriguez-Valdes, Rodolfo I Bosch-Bayard, Andrei Martinez-Finkelstein, Gracia Castro-Luna, Giuseppe A Chiarenza","doi":"10.3389/fnagi.2026.1931028","DOIUrl":"10.3389/fnagi.2026.1931028","url":null,"abstract":"<p><strong>Background: </strong>This is a companion neurophysiological study (<i>N</i> = 19) to a recently published exploratory pilot of the Kinestesia intervention - combining therapeutic videogames, rhythmic gait, and sensory stimulation - in older adults spanning the cognitively healthy (HC, <i>n</i> = 10) to mild cognitive impairment (MCI, <i>n</i> = 9) spectrum. That paper, published in Archives of Gerontology and Geriatrics, reported BH-corrected behavioural gains; here we ask whether the resting-state electrocortical response is graded by baseline cognitive status.</p><p><strong>Methods: </strong>Resting-state EEG was recorded before and after 30 sessions in 19 participants (9 MCI, MoCA < 26; 10 HC, MoCA 26-29). Age-referenced Z-scores were computed for eleven pre-specified clinical EEG indices using the Harmonized Functional EEG Derived Phenotypes normative pipeline (HarFEDPNorms). The primary analysis treated the 19 participants as a single sample and correlated baseline MoCA with the pre-to-post change in each index (Spearman ρ), with Benjamini-Hochberg (BH) FDR correction. We assessed robustness to educational attainment using partial correlation.</p><p><strong>Results: </strong>Eight of the eleven pre-specified indices showed a BH-corrected continuous association with baseline MoCA. The strongest were the Engagement Index (EI) and the Alpha/Beta Ratio (ABR) at Fp2 (EI: ρ = +0.704, <i>q</i> = 0.008; ABR: ρ = -0.687, <i>q</i> = 0.008): higher baseline cognitive status was associated with greater prefrontal activation after the intervention, and lower status with the reverse. MoCA and education were substantially correlated at the sample level (<i>r</i> = 0.596; 36% shared variance, driven by the HC/MCI contrast), and the primary prefrontal effect (EI Fp2) remained significant after adjusting for education (partial ρ = 0.50, <i>p</i> = 0.033).</p><p><strong>Conclusion: </strong>In this small, uncontrolled sample, the electrocortical response to Kinestesia was graded by baseline cognitive status, with a robust prefrontal engagement effect (EI and ABR at Fp2; BH <i>q</i> < 0.01). Findings are exploratory and hypothesis-generating, pending a randomised controlled trial. The HarFEDPNorms pipeline offers a device-independent framework for individualised EEG tracking in intervention research.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1931028"},"PeriodicalIF":5.2,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638596/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106642","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":"Deep cervical lymphovenous reconstruction in Alzheimer's disease: three target-defined interfaces with distinct mechanistic implications.","authors":"Kuisheng Sun, Youmao Zheng, Li Deng, Wenhua Huang, Wanli Lin","doi":"10.3389/fnagi.2026.1945322","DOIUrl":"10.3389/fnagi.2026.1945322","url":null,"abstract":"<p><p>Age-related impairment of brain solute clearance has been implicated in Alzheimer's disease (AD), yet procedures described as deep cervical lymphovenous reconstruction do not necessarily target the same lymphatic structure. This review examines glymphatic exchange, meningeal lymphatic drainage, cervical outflow, human lymphatic imaging, lymphatic surgery, early clinical studies, registered trials, and reported harms. Three interfaces can be distinguished: lymphatic flap-vein, lymph node-vein, and collecting lymphatic vessel-vein anastomosis. They differ in the reconstructed structure, pressure-flow conditions, sensitivity to nodal resistance and venous back pressure, likely failure modes, and the extent to which patency can be tested directly. Human evidence remains largely uncontrolled, short term, and incompletely reported. Recent mouse, cadaveric, proteomic, and retrospective clinical reports broaden the evidence base but do not establish a human cervical bottleneck or clinical efficacy. Biomarker changes are hypothesis-generating rather than evidence of enhanced cerebral clearance, and a delayed report of neurological, infectious, and immune events indicates the need for surveillance beyond the perioperative period. Credible evaluation requires biological confirmation of AD, a measurable clearance-axis phenotype, a suitable cervical target, explicit operative reporting, directional target-level flow with durable patency, concordant imaging and biomarker findings, perioperative and long-term neurological and systemic safety assessment, a controlled longitudinal design, and blinded patient-level outcomes. Collecting lymphatic vessel-vein anastomosis is the most anatomically defined construct for standardized mechanistic testing; lymph node-vein anastomosis depends on functional nodal screening and sustained flow; and lymphatic flap-vein anastomosis remains an exploratory mixed interface. This is a research-design ordering based on target definition and testability, not a therapeutic ranking, evidence of efficacy, or evidence of clinical superiority.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1945322"},"PeriodicalIF":5.2,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106522","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 atherogenic dyslipidemia and DBS-derived p-tau217 in older adults: evidence from SHARE DBS data.","authors":"Zunwei Wang, Yanyan Liu, Xiaofei Sun, Yitong Ling","doi":"10.3389/fnagi.2026.1948518","DOIUrl":"10.3389/fnagi.2026.1948518","url":null,"abstract":"<p><strong>Background: </strong>Atherogenic dyslipidemia has been associated with adverse cognitive and dementia-related outcomes, but its relationship with Alzheimer's disease-related blood biomarkers remains unclear.</p><p><strong>Objective: </strong>To examine whether the atherogenic index of plasma (AIP) is associated with dried blood spot (DBS)-derived phosphorylated tau 217 (p-tau217) in older adults from Germany, Sweden, and Denmark.</p><p><strong>Materials and methods: </strong>This cross-sectional analysis included adults aged ≥50 years from Germany, Sweden, and Denmark in the Survey of Health, Ageing and Retirement in Europe DBS biomarker substudy. AIP was calculated as log10(triglycerides/high-density lipoprotein cholesterol). Multivariable linear regression with robust standard errors evaluated standardized natural log-transformed p-tau217, with additional dose-response analyses, comparisons across neurological biomarkers, and sensitivity analyses.</p><p><strong>Results: </strong>Among 2,676 participants, a 1-SD higher AIP was associated with a 0.074-SD higher ln(p-tau217) (95% CI, 0.034-0.115; <i>p</i> < 0.001), corresponding after back-transformation to a 5.2% higher adjusted geometric mean DBS-derived p-tau217 concentration (95% CI, 2.3-8.1%). The highest versus lowest AIP quartile was associated with higher p-tau217 (β, 0.162; 95% CI, 0.052-0.272; <i>p</i> = 0.004), although estimates across quartiles were not strictly monotonic. Associations were statistically supported for p-tau217 and total tau, but not for GFAP or NfL after FDR correction. Results were robust in sensitivity analyses.</p><p><strong>Conclusion: </strong>In this cross-sectional analysis, higher AIP, reflecting atherogenic dyslipidemia, was associated with a modestly higher DBS-derived p-tau217 concentration in older adults. The biological and clinical significance of this association remains to be established in longitudinal and multimodal studies.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1948518"},"PeriodicalIF":5.2,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106538","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":"Multi-omics identification of novel biomarkers and therapeutic targets for Parkinson's disease: from transcriptome to drug interaction.","authors":"Bingbing Zhao, Zhe Shi, Xiuming Pang, Yue Qi","doi":"10.3389/fnagi.2026.1870056","DOIUrl":"10.3389/fnagi.2026.1870056","url":null,"abstract":"<p><strong>Introduction: </strong>Parkinson's disease (PD) is a progressive neurodegenerative disorder with limited therapeutic options. Acupuncture may serve as a complementary intervention, but its molecular mechanisms remain unclear. This study integrated bulk and single-cell transcriptomic datasets to identify PD-associated diagnostic candidate genes and explore their relationship with acupuncture-related temporal expression patterns.</p><p><strong>Methods: </strong>PD-associated differentially expressed genes were identified from GSE68719. Time-series analysis of GSE178470 characterized ascending or descending expression trajectories in longitudinal blood transcriptomes from one patient with PD sampled at baseline and after 5 and 8 acupuncture sessions. Genes showing directionally opposite patterns between PD-associated dysregulation and post-acupuncture temporal changes were intersected, followed by feature selection using LASSO, Random Forest, Boruta, and XGBoost. Diagnostic performance was evaluated in GSE68719. Single-cell transcriptomic analysis, molecular docking, and MPP+-treated SH-SY5Y cells were used for further exploratory characterization and validation.</p><p><strong>Results: </strong>Eleven candidate genes were identified, of which four were prioritized by machine-learning approaches. The four-gene panel discriminated patients with PD from healthy controls in GSE68719, with an apparent AUC of 0.873, sensitivity of 0.690, specificity of 0.864, accuracy of 0.795, precision of 0.769, F1 score of 0.727, and Brier score of 0.134. These metrics reflect PD-versus-control classification rather than prediction of acupuncture response. Single-cell analysis mapped cell type-specific expression across human midbrain populations. Molecular docking provided exploratory predicted binding poses. BAG3 and HSPB1 were upregulated in MPP+-treated SH-SY5Y cells.</p><p><strong>Discussion: </strong>These findings provide an integrative framework for prioritizing PD-associated candidate genes with exploratory acupuncture-related temporal patterns. Further validation in larger longitudinal cohorts and functional studies is required.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1870056"},"PeriodicalIF":5.2,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106794","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 computational-first proof-of-concept for dual-function metal chelation and aggregate neutralization in an Aβ42 <i>Drosophila</i> model.","authors":"Edric Tsai, Zimu Wang, James Truglio","doi":"10.3389/fnagi.2026.1912315","DOIUrl":"10.3389/fnagi.2026.1912315","url":null,"abstract":"<p><p>Alzheimer's disease (AD) pathology is amplified by a self-reinforcing metal-Aβ-ROS axis, in which redox-active Cu and Fe bound to Aβ N-terminal histidines catalyze Fenton-like ROS generation and accelerate aggregation. Existing single-target interventions - anti-amyloid antibodies, antioxidants, metal-protein attenuating compounds, aggregation inhibitors, and photooxygenation catalysts - each address only one node of this loop. We used a computational-first framework to evaluate a dual-function strategy targeting two connected points of the axis: upstream redox-active metal sequestration by maltol, and downstream photodynamic modification of Aβ aggregates via endogenous protoporphyrin IX (PpIX), generated from 5-aminolevulinic acid (5-ALA) under 400 nm illumination. <i>Drosophila</i> experiments served as functional validation, testing whether this combined intervention improved Aβ42-associated behavioral and survival outcomes and was tolerated in wild-type (WT) flies. DFT calculations (B3LYP-D3BJ/def2-SVP//def2-TZVP, CPCM/SMD water) showed deprotonated maltol localizes oxygen-donor electron density comparable to deprotonated deferiprone, and forms a converged, solvent-stabilized Fe(III)-maltol complex. Cu(II) and Zn(II) coordination was weak and geometrically incomplete, indicating an Fe-preferential rather than broadly nonspecific chelation profile; the study does not demonstrate protection against Cu(II)-mediated ROS. Time-dependent DFT predicted PpIX excitations spanning the visible/near-UV range consistent with photosensitizer behavior, and docking against Aβ42 fibril 5OQV showed PpIX engaged the central hydrophobic/turn surface more strongly than chlorin e6 or maltol. In a pan-neuronal Aβ42 <i>Drosophila</i> model, dual treatment improved climbing performance (<i>p</i> = 2.39 × 10^-3 vs. untreated Aβ42) and extended lifespan (log-rank <i>p</i> = 6.04 × 10^-13; median survival ∼40 d); WT + Treatment flies appeared tolerant, though no formal statistical contrast was pre-specified. Treatment-group ThT amyloid burden was not measured, so no amyloid-reduction claim is made. Because chelation-only and 5-ALA/light-only arms were not included, we cannot attribute improvement to either intervention alone and cannot make a formal claim of additive or interactive effects between the two intervention components. The combined intervention was associated with improved behavioral and survival outcomes in the Aβ42 <i>Drosophila</i> model. Because the present study lacks single-intervention controls and treatment-group pathological measurements, these findings do not establish the mechanism responsible for the observed functional improvement. The study illustrates how ground-state, excited-state, and docking calculations can jointly inform a computationally motivated intervention tested in a tractable organismal model.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1912315"},"PeriodicalIF":5.2,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106525","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":"Epigenetic memory and allostatic integrity: a theoretical integration of the hierarchical-circular model using a longitudinal methylation signature of dementia.","authors":"Samuel Ruesga Mundo","doi":"10.3389/fnagi.2026.1919708","DOIUrl":"10.3389/fnagi.2026.1919708","url":null,"abstract":"<p><strong>Introduction: </strong>The Hierarchical-Circular Model of Biological Memory (HCM) proposes that dementia results from disrupted circular information flow across five levels: genetic, epigenetic, allostatic, PNEI network, and interoceptive. Allostatic integrity-the adaptive capacity for circular flow-determines whether pathology translates into dementia.</p><p><strong>Objective: </strong>To evaluate whether a recently published blood DNA methylation signature for incident dementia is consistent with the predictions of the HCM.</p><p><strong>Methods: </strong>We systematically mapped Zhang et al.'s findings (44 CpGs, 44 DMRs, pathway enrichments, methylation risk score) to HCM levels and predictions. We interpreted these findings as providing indirect and conceptual support for the model rather than direct empirical validation.</p><p><strong>Results: </strong>The 44 CpGs/DMRs linked to dementia were enriched in immune and metabolic pathways. Their methylation risk score predicted cognitive decline independently of age, sex, APOEε4, education, and MMSE. These findings are consistent with the HCM's Level 2 (epigenetic memory), Levels 3-4 (allostatic load/PNEI), and Predictions 1 (composite biomarkers outperform single) and 4 (allostatic integrity moderates reserve).</p><p><strong>Discussion: </strong>Epigenetic changes precede dementia, supporting Level 2 as an early event. Immune/metabolic pathways link to allostatic load. Independence from APOEε4/education is consistent with allostatic integrity being distinct from genetic risk and reserve.</p><p><strong>Conclusion: </strong>Zhang et al.'s study provides large-scale evidence that blood DNA methylation may serve as a peripheral biomarker of lost allostatic integrity, consistent with the HCM and supporting a shift from linear to circular, multilevel frameworks for dementia.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1919708"},"PeriodicalIF":5.2,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106589","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":"Distinct brain activation patterns linked to clinical symptoms during hand grasping in Parkinson's disease.","authors":"Kaili Wang, Jing Guo, Dan Liu, Qiong Wu, Jin Qiao","doi":"10.3389/fnagi.2026.1895333","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1895333","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to investigate the characteristics of brain functional activation during a hand grasping task in patients with Parkinson's Disease (PD) using functional near-infrared spectroscopy (fNIRS), and to further explore the clinical factors associated with the level of regional brain activation.</p><p><strong>Methods: </strong>Fifty-nine PD patients were enrolled. Demographic data (age, sex, education level) and clinical characteristics (disease duration, Hoehn-Yahr stage, UPDRS-III score, side of onset, motor complications, cognitive function, activities of daily living, non-motor symptoms, and levodopa equivalent daily dose) were collected for all participants. Oxygenated hemoglobin (HbO₂) signals from multiple brain regions were acquired using fNIRS during a hand grasping task. With sex, age, and disease duration as covariates, multiple linear regression analysis was used to examine the relationships between clinical variables-including side of onset, constipation, REM sleep behavior disorder (RBD), Freezing of Gait (FOG), UPDRS-III, Montreal Cognitive Assessment (MoCA), and Hoehn-Yahr stage-and brain activation metrics (both temporal-domain and advanced features).</p><p><strong>Results: </strong>Among the 59 PD patients, 38 (64.4%) had constipation and 17 (28.8%) had freezing of gait (FOG). Under the left-hand task, constipation was significantly positively correlated with parameters in 13 brain regions (pFDR < 0.05), mainly including the bilateral dorsolateral prefrontal cortex, left frontal eye field, and left premotor area (regression coefficients: 0.0033-0.8538). No other clinical variables showed significant associations. Under the right-hand task, FOG was significantly negatively correlated with the full width at half maximum (FWHM) of the right primary motor cortex (β = -8.52, 95% CI: -12.98 to -4.06, pFDR = 0.010). No other clinical variables showed significant associations; however, larger studies are needed to confirm these findings and to evaluate potential subtle effects, particularly for RBD.</p><p><strong>Conclusion: </strong>In PD patients, constipation is associated with cortical hyperactivation in the prefrontal-premotor areas during the non-dominant hand task. Conversely, FOG correlates with reduced hemodynamic persistence and shortened activation duration in the right primary motor cortex (M1) during the dominant hand task. fNIRS can act as an objective tool to explore the cortical mechanisms of motor and non-motor symptoms in PD, providing hypothesis-generating evidence for potential targets that warrant further investigation in future repetitive transcranial magnetic stimulation (rTMS) intervention trials.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1895333"},"PeriodicalIF":5.2,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106559","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}