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        <title>Frontiers in Aging Neuroscience | New and Recent Articles</title>
        <link>https://www.frontiersin.org/journals/aging-neuroscience</link>
        <description>RSS Feed for Frontiers in Aging Neuroscience | New and Recent Articles</description>
        <language>en-us</language>
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        <pubDate>2026-05-13T16:13:05.372+00:00</pubDate>
        <ttl>60</ttl>
        <item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1823372</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1823372</link>
        <title><![CDATA[Stereoselective effects of nicotine enantiomers on the gut-brain axis and neuroinflammation in a mouse model of Parkinson’s disease]]></title>
        <pubdate>2026-05-13T00:00:00Z</pubdate>
        <category>Original Research</category>
        <author>Ruixia Liu</author><author>Yunu Ma</author><author>Yingyan Li</author><author>Xia Gao</author><author>Shu Wang</author><author>Lutao Xu</author><author>Guanglin Liu</author><author>Huan Chen</author><author>Min Ji</author><author>Hongwei Hou</author>
        <description><![CDATA[IntroductionParkinson’s disease (PD) is characterized by progressive dopaminergic neurodegeneration, neuroinflammation, and emerging evidence of gut microbiota dysbiosis. Although nicotine has been implicated in neuroprotection, whether its enantiomers exert stereoselective effects on the gut-brain axis remains unknown.MethodsWe systematically compared the effects of S-nicotine and R-nicotine in an MPTP-induced mouse model of PD. Motor function, nigrostriatal dopaminergic neuronal loss, neuroinflammatory responses, intestinal barrier integrity, and gut microbiota composition were assessed.ResultsBoth enantiomers ameliorated motor deficits, attenuated nigrostriatal dopaminergic neuronal loss, and suppressed neuroinflammatory responses, yet exhibited markedly different efficacy profiles. S-nicotine produced robust neuroprotection at a lower effective dose (1 mg/kg), associated with improved motor performance, reduced central and peripheral inflammation, preservation of intestinal barrier integrity, and coordinated remodeling of the gut microbiota characterized by enrichment of Akkermansiaceae (notably Akkermansia). In contrast, R-nicotine required a higher dose (3 mg/kg) to achieve comparable neuroprotection and induced weaker and more heterogeneous microbiota alterations. Correlation analyses further revealed that S-nicotine-associated enrichment of Akkermansia was closely linked to improvements in motor function, reduced inflammatory status, and enhanced intestinal integrity.DiscussionThese findings demonstrate pronounced stereoselective and dose-dependent effects of nicotine enantiomers on neuroimmune modulation and identify gut microbiota remodeling as a functionally relevant correlate of nicotine-mediated neuroprotection in PD. Our results highlight the therapeutic potential of targeting the microbiota-gut-brain axis through chiral interventions and support S-nicotine as a promising candidate for neuroprotective strategies in aging-related neurodegenerative disorders.]]></description>
      </item><item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1776156</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1776156</link>
        <title><![CDATA[Functional autonomy, comorbidities and cognitive decline: a mediation analysis in neurocognitive disorders]]></title>
        <pubdate>2026-05-13T00:00:00Z</pubdate>
        <category>Original Research</category>
        <author>Giuseppe Valente</author><author>Claudia Bauco</author><author>Carmela Bucca</author><author>Francesca Corte</author><author>Alessandra Petrillo</author><author>Daniele Tonietti</author><author>Nadia Di Sturco</author><author>Pierluigi Diotaiuti</author>
        <description><![CDATA[BackgroundNeurocognitive Disorders (NCDs) represent a growing global health concern, significantly impacting both quality of life and healthcare systems. Emerging evidence suggests that functional autonomy, measured through Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL), as well as comorbidity and educational attainment, influence the trajectory of cognitive decline. However, the interplay among these factors remains insufficiently understood. This study investigates the mediating role of IADL between comorbidity and disorder severity, while examining the direct and IADL-mediated effects of educational attainment (as a proxy of cognitive reserve).ObjectivesTo explore the interrelationships between comorbidity (Cumulative Illness Rating Scale—CIRS), functional autonomy (ADL and IADL), educational attainment, and the severity of Neurocognitive Disorders. Specifically, the study aims to assess the mediating effect of IADL and examine how demographic and clinical variables (including age, gender, and education level) are associated with cognitive impairment.MethodsAn observational study was conducted on a sample of 1,033 individuals, including patients diagnosed with major or mild Neurocognitive Disorder, as well as individuals without dementia but reporting subjective memory complaints. Functional autonomy was assessed using the ADL and IADL scales, comorbidity through the Cumulative Illness Rating Scale (CIRS), and educational attainment was measured in total years of formal schooling. Multiple linear regression analyses and mediation testing were carried out using Structural Equation Modeling (SEM).ResultsComorbidity (CIRS) was the strongest predictor of disorder severity (B = 0.259, p = 0.001), followed by age (B = 0.012, p < 0.001), educational attainment (B = −0.018, p = 0.003), and IADL scores (B = −0.109, p < 0.001). In multiple regression, diagnostic severity was significantly associated with comorbidity (CIRS; B = 0.259), age (B = 0.012), educational attainment (B = −0.018), and functional autonomy (IADL; B = −0.109). SEM supported partial mediation of the CIRS–severity association via IADL (indirect effect = 0.222), with excellent model fit (CFI = 0.95; RMSEA = 0.03).ConclusionComorbidity, functional autonomy, and educational attainment play critical roles in the progression of Neurocognitive Disorders. Higher comorbidity is linked to more severe cognitive deficits, whereas greater functional independence and educational background are protective factors. Incorporating ADL, IADL, and CIRS assessments into diagnostic and care planning, alongside demographic profiling, may enhance the precision of clinical interventions, support functional independence, and reduce caregiver burden.]]></description>
      </item><item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1816702</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1816702</link>
        <title><![CDATA[Nuclear accumulation of PANK4 in hippocampal astrocytes aggravates cuproptosis in association with mild cognitive impairment in aged mice]]></title>
        <pubdate>2026-05-13T00:00:00Z</pubdate>
        <category>Original Research</category>
        <author>Bo Wang</author><author>Jing Zhang</author><author>Chang-Hong Li</author><author>Xiao Huang</author><author>Ruo-Bing Gao</author><author>Yan Peng</author><author>Qing Xie</author><author>Ya-Lei Ning</author><author>Yan Zhao</author><author>Nan Yang</author><author>Xing Chen</author><author>Yang-Li Xie</author><author>Yuan-Guo Zhou</author><author>Sen Lin</author><author>Lin Chen</author><author>Ping Li</author>
        <description><![CDATA[BackgroundMild cognitive impairment (MCI), a condition that falls somewhere between normal aging and severe cognitive dysfunction (e.g., Alzheimer’s disease), is a common manifestation of the neurocognitive function decline that seniors encounter as they age. The fundamental processes causing its beginning are still not well understood yet.MethodsWe employed aged (18-month-old) male C57BL/6J mice, including astrocyte-specific Pantothenate kinases 4 (PANK4) conditional knockout (Pank4f/f;Gfap-Cre, Pank4-CKO) mice. Cognitive function was assessed using the Barnes maze, Y-maze (spatial novelty preference, spontaneous alternation), novel object recognition (NOR) test, and open field test (OFT). Hippocampal PANK4 localization was analyzed via immunofluorescence (IF) and subcellular fractionation/western blotting (WB). Cuproptosis markers (FDX1, LIAS, DLAT), copper transporters (ATP7A, ATP7B, SLC31A1), and copper content (ICP-MS) were quantified in hippocampal tissue. In vitro studies used LPS-stimulated primary astrocytes for RNA-seq and qPCR validation.ResultsAged wild-type (18M+WT) mice exhibited specific deficits in Barnes maze retention and reversal learning, indicative of mild cognitive impairment, while Pank4-CKO mice showed significant rescue. We discovered a novel age-dependent nuclear accumulation of PANK4 in hippocampal cells, which was absent in Pank4-CKO mice. Aged hippocampi displayed upregulated pro-cuproptotic factors (FDX1, LIAS) and reduced DLAT, alongside decreased expression of the copper exporter ATP7A, ATP7B, SLC31A1 and increased copper accumulation. Astrocyte-specific Pank4 knockout reversed these changes: it suppressed FDX1/LIAS upregulation, restored ATP7B expression and DLAT levels, and normalized hippocampal copper content. In vitro, LPS-induced neuroinflammation triggered PANK4 nuclear translocation and selectively downregulated Atp7b expression in astrocytes. Small interfering RNA (siRNA)-mediated knockdown of Pank4 significantly upregulated Atp7b expression.ConclusionThis study identifies a novel pathological mechanism in age-related MCI: the nuclear accumulation of PANK4 in hippocampal exacerbates cuproptosis susceptibility by specifically impairing ATP7B-dependent copper efflux, leading to copper overload. Astrocyte-specific PANK4 ablation mitigates these effects, highlighting PANK4 as a potential therapeutic target for preventing or treating age-associated cognitive decline.]]></description>
      </item><item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1808824</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1808824</link>
        <title><![CDATA[Efficacy of repeated external cueing training on freezing of gait and gait performance in Parkinson’s disease: a systematic review and meta-analysis]]></title>
        <pubdate>2026-05-13T00:00:00Z</pubdate>
        <category>Systematic Review</category>
        <author>Qingling Sun</author><author>Wangfang Yu</author><author>Huafu Ni</author>
        <description><![CDATA[BackgroundFreezing of gait (FOG) is a disabling gait disturbance in Parkinson’s disease (PD) that responds poorly to pharmacological treatment. External cueing has been proposed as a non-pharmacological strategy to improve gait and mobility; however, the effectiveness of repeated external cueing training on FOG-related outcomes remains uncertain, particularly across different cueing modalities.MethodsWe conducted a systematic review and meta-analysis of randomized controlled trials (RCTs), with a specific focus on repeated external cueing interventions (≥2 weeks). PubMed, Web of Science, Embase, the Cochrane Library, CNKI, Wanfang, and VIP databases were searched from inception to November 10, 2025. RCTs evaluating external cueing interventions in individuals with PD were included. Primary outcomes were FOG severity assessed by the Freezing of Gait Questionnaire (FOGQ) or New FOGQ (NFOGQ). Secondary outcomes included Timed Up and Go (TUG), MDS–UPDRS part III, and Berg Balance Scale (BBS). Risk of bias was assessed using ROB 2.0, and evidence certainty using GRADE.ResultsNine RCTs involving patients with PD were included. Pooled analysis showed no statistically significant reduction in FOG severity following external cueing interventions compared with control conditions (SMD = −0.30, 95% CI: −0.68 to 0.09), with substantial heterogeneity. In contrast, external cueing significantly improved functional mobility as measured by the TUG test (SMD = −0.65, 95% CI: −1.15 to −0.15), although heterogeneity remained high. No consistent benefits were observed for overall motor symptoms or balance outcomes. Exploratory analysis incorporating short-term follow-up data suggested a modest improvement in FOG severity; however, these findings should be interpreted with caution due to persistent heterogeneity. The certainty of evidence for all outcomes was rated as low according to the GRADE framework. The observed heterogeneity was likely attributable to variations in intervention protocols, cueing modalities, and outcome assessment methods.ConclusionExternal cueing interventions may improve functional mobility in individuals with PD, particularly for tasks involving gait initiation and turning. However, current evidence does not support consistent benefits for FOG severity, overall motor symptoms, or balance. Given the low certainty of evidence, further high-quality, multicenter RCTs with standardized outcome measures and longer follow-up are needed to clarify the clinical role of cueing-based interventions in FOG. These findings highlight important limitations in the current evidence base and provide directions for future research.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420261280910, identifier CRD420261280910.]]></description>
      </item><item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1630798</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1630798</link>
        <title><![CDATA[From muscle to brain: the mediating effect of vitamin D in the relationship between muscle loss and cognitive function in Alzheimer’s disease]]></title>
        <pubdate>2026-05-13T00:00:00Z</pubdate>
        <category>Original Research</category>
        <author>Xiaoting Ma</author><author>Linlin Yao</author><author>Fangbo Li</author><author>Chong Cui</author><author>Erlei Wang</author><author>Caishan Wang</author><author>Ping Zhao</author><author>Xiaofen Weng</author><author>Chunfeng Liu</author><author>Shanwen Liu</author><author>Hua Hu</author>
        <description><![CDATA[ObjectiveTo investigate the association among Vitamin D (VD), muscle loss and cognitive function, and further analyze the possible role of VD in the association between muscle loss and cognitive function in patients with Alzheimer’s disease (AD).MethodsThis cross-sectional study included 58 patients with AD (30 mild and 28 moderate) and 30 neurotypical controls (NC). Demographic data, neuropsychological tests, and serum VD levels were collected. Muscle loss related indicators, including both clinical macroscopic and morphological microstructural indicators, were measured.ResultsThe differences among 3 groups in different cognitive domains, muscle loss related indicators and serum VD levels were statistically significant (P < 0.05). Adjusted for age, sex and BMI, correlations were observed among broad cognitive domains, muscle loss related indicators (especially muscle mass and upper limb muscle strength) and serum VD levels in patients with AD (P < 0.05). Mediation analyses revealed that muscle loss, particularly muscle mass reduction, significantly impacted cognitive function in patients with AD (P < 0.05). This effect remained statistically significant after accounting for VD levels (P < 0.05), and VD deficiency partially mediated the effect of muscle loss on cognitive function (P < 0.05).ConclusionVD level, muscle loss, and cognitive dysfunction are closely related, and VD partially mediated the association between muscle mass reduction and cognitive dysfunction in patients with AD. These preliminary findings highlight the importance of assessing muscle loss and VD deficiency, and suggest that targeted intervention may be a valuable management strategy for the AD population.]]></description>
      </item><item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1779861</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1779861</link>
        <title><![CDATA[Dopamine 2 receptor ablation from cholinergic neurons attenuates L-DOPA induced dyskinesias]]></title>
        <pubdate>2026-05-12T00:00:00Z</pubdate>
        <category>Original Research</category>
        <author>Santiago Uribe-Cano</author><author>Lauren Malave</author><author>Andreas H. Kottmann</author>
        <description><![CDATA[IntroductionL-DOPA-induced dyskinesia (LID) formation requires prominent dopamine oscillations over hours, across years of treatment. Striatal cholinergic interneurons (CIN) have been implicated in both the facilitation and attenuation of LID, but how CIN sense and respond to striatal dopamine levels in this context remains incompletely understood. CIN express both the inhibitory, Gαi-coupled dopamine D2 receptor and the facilitatory, Gαs-coupled dopamine D5 receptor. Although systemic ablation of D5 exacerbates LID, the contribution of CIN-specific D2 expression to LID has not been studied.MethodsWe generated mice with conditional ablation of D2 from choline acetyltransferase-expressing cells (D2ChATKO) and subjected them to unilateral 6-hydroxydopamine lesions followed by chronic L-DOPA dosing. We assessed dyskinetic behaviors across escalating L-DOPA doses and performed postmortem analyses of LID-associated signaling markers in dorsal striatal CIN. Specifically, we quantified p-ERK expression and phosphorylated rpS6240/244, a marker of translational activity, in CIN from mice examined in the L-DOPA ON and OFF states.ResultsD2ChATKO mice exhibited attenuated LID across escalating L-DOPA doses. Postmortem analyses suggested reduced expression of the LID-associated marker p-ERK among CIN of the dorsal striatum. In control mice, L-DOPA increased phosphorylated rpS6240/244 in a subset of CIN located in the dorsolateral striatum, indicating increased translational activity during the L-DOPA ON state. Ablation of D2 from CIN prevented this L-DOPA-associated increase in CIN phosphorylated rpS6240/244.DiscussionTogether, these findings indicate that D2 signaling in CIN promotes LID formation and suggest that CIN D2 is a potential molecular target for mitigating dyskinesias while preserving the therapeutic efficacy of L-DOPA. These results are discussed in the context of recently refined models of how CIN may contribute to aberrant plasticity in the basal ganglia of the Parkinsonian mouse brain.]]></description>
      </item><item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1824113</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1824113</link>
        <title><![CDATA[Decreases in the sustained firing capacity of layer 2/3 pyramidal neurons in the anterior cingulate cortex of aged rats]]></title>
        <pubdate>2026-05-11T00:00:00Z</pubdate>
        <category>Original Research</category>
        <author>Taketoshi Sugimura</author><author>Yasuhiko Saito</author>
        <description><![CDATA[The anterior cingulate cortex (ACC) is particularly vulnerable to aging, which impairs cognitive functions such as attention and working memory. Although aging is known to alter intrinsic electrophysiological properties in other brain regions, the differences in the properties of aged ACC neurons and young adult neurons remain uninvestigated. In this study, we compared the intrinsic membrane properties and firing characteristics of aged layer 2/3 pyramidal neurons (26-month-old rats) with those of young adult neurons (6-month-old rats) using whole-cell patch-clamp recordings in acute slices from male Long-Evans rats. Although the distribution of the aged neurons based on the firing patterns did not significantly differ from that of the young adult neurons, the aged neurons exhibited depolarized resting membrane potentials, decreased input capacitance, and increased input resistance. In regular-spiking neurons, compared with young adult neurons, aged ACC neurons presented higher action potential thresholds, smaller action potential amplitudes, narrower action potential half-widths, and smaller slow afterhyperpolarization (sAHP) amplitudes. While basic excitability under standard step currents was preserved, aged regular-spiking neurons did not show sustained firing under ramp or triangular current stimulation, with rapid decreases in the firing frequency following the ramp peak and premature spike termination during the triangular descending phase, respectively. These results indicate that the intrinsic membrane properties of aged ACC neurons differ from those of young adult neurons and that aged neurons exhibit a reduced capacity for sustained firing. This cellular dysfunction in aged neurons provides a potential physiological mechanism underlying the age-related decline in ACC-dependent cognitive functions.]]></description>
      </item><item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1797674</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1797674</link>
        <title><![CDATA[Route efficiency in spatial navigation as an early indicator of cognitive decline in amnestic mild cognitive impairment]]></title>
        <pubdate>2026-05-08T00:00:00Z</pubdate>
        <category>Original Research</category>
        <author>Nicole Rogers</author><author>Carol Dazil SanMartín</author><author>Jamileth More</author><author>César Romero</author><author>Daniela Paz Ponce</author><author>José Luis Valdés</author><author>María Isabel Behrens</author>
        <description><![CDATA[IntroductionThe hippocampus is one of the brain regions most affected by neurodegeneration in Alzheimer’s disease (AD). This structure and its neural circuits are critically involved in spatial learning and memory. Poor spatial navigation performance in virtual environments such as the Virtual Morris Water Navigation Task (VMWNT) may precede other clinical findings in amnestic mild cognitive impairment (aMCI), a pre-dementia stage of AD. To explore this idea, we correlated aMCI and cognitively healthy control (HC) performance in the VMWNT with Montreal Cognitive Assessment (MoCA) and Memory Index Score (MoCA-MIS), testing whether navigation-derived metrics are associated with cognitive performance within a framework of shared medial temporal lobe vulnerability.MethodsThirty-eight participants (18 aMCI, 20 HC) were assessed for neurologic evaluation and VMWNT performance. Neuropsychological tests, including MoCA, MoCA-MIS, Clinical Dementia Rating (CDR), CDR sum of boxes (CDR-SOB) and AD8, were performed. Group differences were assessed using Mann–Whitney U tests on participant-level means and complemented with mixed-effects models to account for the repeated-measures structure of trial-level data. All behavioral parameters obtained in the VMWNT were reduced to a single variable, “Route Efficiency,” through Principal Component Analysis (PCA) on five navigation variables, with the aim to correlate spatial memory performance with clinical findings.ResultsSignificant differences in VMWNT performance were observed. aMCI patients displayed longer path lengths (p = 0.006), more quadrant crossings (p = 0.010), reduced time in target quadrant (p < 0.001), and fewer target crossings (p = 0.006), with group differences most evident in Stage 2; Stage 3 showed no significant differences for most variables. Route Efficiency was significantly lower in aMCI than HC (p < 0.001); correlations with MoCA and MoCA-MIS were observed across the full sample but were nonsignificant within groups. Stage 3 allocentric navigation did not reveal consistent group differences. Using nested cross-validation, the AUC for aMCI detection was 0.78 (95% CI: 0.63–0.91).DiscussionGroup differences in Route Efficiency and correlations with cognitive measures were observed, though these associations primarily reflected between-group rather than individual variation. Allocentric significant findings were not observed. These preliminary results support further exploration of virtual navigation paradigms in clinical settings.]]></description>
      </item><item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1791756</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1791756</link>
        <title><![CDATA[Entorhinal cortex atrophy mediates the association of plasma p-tau181, GFAP, and NfL with cognitive impairment in Parkinson’s disease]]></title>
        <pubdate>2026-05-08T00:00:00Z</pubdate>
        <category>Original Research</category>
        <author>Qiangqiang Wan</author><author>Xinyu Dai</author><author>Zhongwen Zhang</author><author>Ping Shan</author><author>Gui Mei</author><author>Luqi Huang</author><author>Lan Wang</author><author>Hongfen Peng</author>
        <description><![CDATA[BackgroundCognitive impairment is a major determinant of disability in Parkinson’s disease (PD), underscoring the need for biomarkers that reflect its underlying pathophysiology. Plasma biomarkers, including phosphorylated tau at threonine 181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL), are promising candidates, yet their independent predictive value and the pathways by which they relate to cognitive function in PD remain unclear.MethodsWe enrolled 89 PD patients without dementia (37 with normal cognition and 52 with mild cognitive impairment) and 40 healthy controls. Plasma biomarkers were measured using single-molecule array technology. All participants underwent high-resolution structural magnetic resonance imaging and cognitive assessment with the Montreal Cognitive Assessment (MoCA). Hierarchical regression evaluated the independent contribution of each biomarker to MoCA scores. Mediation and moderated mediation analyses were then conducted to test whether atrophy in brain regions of interest mediates the effects of biomarkers on cognitive function and whether these pathways were moderated by cognitive status.ResultsPlasma p-tau181, GFAP, and NfL were each independently associated with worse global cognition. The effects of all three biomarkers were significantly and specifically mediated by atrophy of the entorhinal cortex (ERC), but not by other tested regions. Critically, the mediation pathway for NfL was specifically moderated by cognitive status, being significant only in PD patients with mild cognitive impairment.ConclusionThe associations of plasma p-tau181, GFAP, and NfL on cognitive impairment in PD converges on ERC atrophy. The association between NfL and cognition via ERC atrophy is dynamically potentiated at the mild cognitive impairment stage, positioning NfL as a stage-specific biomarker. An integrative model combining these plasma biomarkers with ERC integrity could enhance risk stratification for cognitive impairment in PD.]]></description>
      </item><item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1778992</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1778992</link>
        <title><![CDATA[Transcranial magnetic stimulation from healthy brain aging to Alzheimer’s disease: a review on mechanisms, therapeutic potential, and future clinical directions]]></title>
        <pubdate>2026-05-08T00:00:00Z</pubdate>
        <category>Review</category>
        <author>Faddi Saleh Velez</author><author>Maria Cedeno-Bruzual</author><author>Melba Zuniga-Gutierrez</author><author>Daniela Mercado Pena</author><author>Cade L. Ballard</author><author>Jeng S. Kong</author><author>Ana Clara Da C. Pinaffi-Langley</author><author>Cameron D. Owens</author><author>Zsuzsanna TucsekCardon</author><author>Zsofia Szarvas</author><author>Mihaly Muranyi</author><author>Zalan Kaposzta</author><author>Peter Mukli</author><author>Laura Boada Robayo</author><author>Stefano Tarantini</author><author>Zoltan Ungvari</author><author>Andriy Yabluchanskiy</author><author>Camila B. Pinto</author>
        <description><![CDATA[Transcranial magnetic stimulation (TMS), a non-invasive and non-pharmacological intervention, is increasingly being explored for mitigating age-related cognitive decline and dementia. Its therapeutic potential is largely attributed to its capacity to modulate neuronal firing rates and induce neuroplastic changes and modulate neurovascular coupling within distributed neural networks that support memory, attention, and executive function. Despite growing interest, gaps remain in understanding how specific stimulation parameters engage in neural circuits and translate into meaningful cognitive outcomes in aging and neurodegeneration. This narrative review synthesizes current evidence on the neurophysiological and hemodynamic mechanisms and clinical effects of repetitive TMS (rTMS) across the spectrum of cognitive aging, from healthy older adults to those experiencing age-related cognitive decline and Alzheimer’s disease. By integrating mechanistic and clinical perspectives, this review bridges basic neuroscience and clinical practice, highlighting rTMS’s emerging role in promoting cognitive resilience and healthier brain aging.]]></description>
      </item><item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1801267</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1801267</link>
        <title><![CDATA[Aging modulates amyloid clearance kinetics during anti-amyloid therapy: evidence from real-world serial amyloid PET]]></title>
        <pubdate>2026-05-08T00:00:00Z</pubdate>
        <category>Original Research</category>
        <author>Tomomichi Iizuka</author><author>Toshiaki Watanabe</author><author>Masashi Kameyama</author>
        <description><![CDATA[BackgroundAnti-amyloid antibodies have been shown to reduce cerebral amyloid burden in early Alzheimer’s disease (AD), yet considerable interindividual variability in treatment-associated amyloid reduction has been observed. The biological factors underlying this variability remain unclear. In particular, the influence of aging on amyloid clearance dynamics during anti-amyloid therapy has not been well characterized in real-world clinical settings.MethodsWe conducted a prospective observational study of 23 patients with early-stage AD receiving lecanemab who underwent serial 18F-flutemetamol amyloid PET at baseline and after 6 and 12 months. Amyloid burden was quantified in centiloid units. Cognitive outcomes were assessed using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating–Sum of Boxes (CDR-SB). Baseline cerebral perfusion was evaluated using 123I-IMP SPECT with three-dimensional stereotactic surface projection (3D-SSP) analysis.ResultsAll participants showed reductions in amyloid burden on serial PET; however, the magnitude of reduction varied substantially across individuals. Older patients tended to exhibit larger and more rapid reductions in amyloid burden, whereas younger patients demonstrated more modest decreases despite comparable baseline amyloid levels and standardized dosing. Amyloid reduction at 6 months strongly predicted the magnitude of reduction at 12 months, suggesting that early PET changes capture subsequent amyloid clearance trajectories. Cognitive decline occurred in a subset of patients despite substantial amyloid reduction and was associated with marked baseline temporo-parietal hypoperfusion on SPECT rather than insufficient amyloid removal.ConclusionIn this real-world cohort, aging appeared to influence the observable kinetics of amyloid reduction during anti-amyloid therapy. Early serial amyloid PET may provide useful information regarding longer-term amyloid dynamics, while baseline perfusion imaging may help identify patients with substantial downstream neurodegenerative burden who remain at risk for cognitive decline despite amyloid clearance. These findings highlight biological heterogeneity in treatment response and underscore the value of multimodal imaging for monitoring disease-modifying therapies in AD.]]></description>
      </item><item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1797960</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1797960</link>
        <title><![CDATA[Potential for distinguishing the parkinsonian subtype of multiple system atrophy from Parkinson’s disease: a three-dimensional gait analysis study]]></title>
        <pubdate>2026-05-07T00:00:00Z</pubdate>
        <category>Original Research</category>
        <author>Reyisha Taximaimaiti</author><author>Sheng Cai</author><author>Hongyan Li</author>
        <description><![CDATA[ObjectiveDistinguishing the parkinsonian subtype of multiple system atrophy (MSA-P) from Parkinson’s disease (PD) at an early stage was a challenge, and gait analysis based on wearable sensors offers a reliable method to quantify gait parameters. In this study, we used a three-dimensional gait motion capture system based on wearable sensors to identify potential gait-based biomarkers that might assist in distinguishing MSA-P from PD.MethodsParticipants were enrolled in this observational study from the Department of Neurology at the People’s Hospital of Xinjiang Uygur Autonomous Region from June 2024 to October 2025 and were required to complete the timed up and go (TUG) test, Cognitive Load Test, and Endogenous Beat Test according to our instructions. Multivariate analysis of covariance (MANCOVA) was used to conduct overall comparisons of gait characteristics among groups, and predictive ability was tested through 5-fold cross-validated receiver operating characteristic curves and sensitivity analysis.ResultsA total of 74 PD patients, 33 MSA-P patients, and 79 healthy controls (HCs) were enrolled in this study. When PD patients and MSA-P patients exhibited similar clinical performance and drug dosage, MSA-P patients had a 4.9-year younger age of symptom onset and a duration of symptoms that was 19.4 months shorter. Both PD patients and MSA-P patients exhibited reduced stride length, reduced velocity, reduced bilateral step length, anterior pelvic tilt, and broadly reduced range of motion (ROM) of the pelvis and the lower limb joints compared to HCs. The negative impact of the Cognitive Load Test on gait seemed to be far greater than that of the Endogenous Beat Test, and PD patients might be more sensitive to the Endogenous Beat Test than MSA-P patients. The ROM of hip flexion–extension in the Endogenous Beat Test demonstrated the most favorable discriminative and potential predictive capacity for distinguishing MSA-P patients from PD patients, and the results were stable across different subgroups of patients according to sensitivity analysis.DiscussionThe ROM of hip flexion–extension in the Endogenous Beat Test might have a potential capacity to distinguish MSA-P patients from PD patients. Three-dimensional gait analysis based on wearable sensors might hold considerable application potential for the clinical differential diagnosis of neurodegenerative diseases.]]></description>
      </item><item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1831973</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1831973</link>
        <title><![CDATA[Investigating hepatitis E virus seroprevalence in patients with Alzheimer’s disease]]></title>
        <pubdate>2026-05-07T00:00:00Z</pubdate>
        <category>Brief Research Report</category>
        <author>Tiberiu Daniel Capraru</author><author>Tim Christopher Bauer</author><author>Paula Jordan</author><author>Niklas M. Weidner</author><author>Melisa Oensal</author><author>Lutz Froelich</author><author>Claudia Beisel</author><author>Lucrezia Hausner</author><author>Viet Loan Dao Thi</author>
        <description><![CDATA[BackgroundHepatitis E virus (HEV) exposure has been linked to neurologic manifestations and dementia. This study aims to clarify a possible association between HEV and Alzheimer’s disease (AD).MethodsWe performed a single-center retrospective case–control study of 453 cognitively impaired adults from southern Germany, comparing anti-HEV IgG seropositivity between patients with AD and those with non-AD cognitive impairment. Associations were evaluated using chi-square testing and multivariable logistic regression, including age-stratified analyses.ResultsOverall HEV IgG seroprevalence was higher in the AD group than in the non-AD group (44.5% vs. 37.7%, p = 0.138), with a significant difference in patients aged 60–69 years (46.5% vs. 35.1%, p = 0.040) but not in those aged 70–79 years (46.7% vs. 50.0%, p = 0.646).ConclusionThese findings suggest that anti-HEV antibodies are more frequent in younger elderly AD patients compared with cognitively impaired individuals of the same age without AD, raising the hypothesis that prior HEV infection may represent a candidate environmental risk factor for AD.]]></description>
      </item><item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1834543</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1834543</link>
        <title><![CDATA[Intranasal administration of stem cells and their derivatives for neurological and respiratory disorders: a systematic review of human clinical trials]]></title>
        <pubdate>2026-05-07T00:00:00Z</pubdate>
        <category>Systematic Review</category>
        <author>Umm E. Habiba</author><author>Roshini Sathyanarayanan</author><author>Sabiha Shamim</author><author>Aishwarya Manian</author><author>Ammar Haider</author><author>Iqra Sarwar</author><author>David Lawrence Greene</author>
        <description><![CDATA[ObjectiveThis systematic review evaluates the safety, feasibility, tolerability, and efficacy outcomes of intranasally administered stem cells and their derivatives (MSCs, NSCs, secretome, and EVs) for the treatment of neurological and respiratory disorders.MethodsA literature search was conducted across PubMed, Google Scholar, Web of Science, Scopus, and ClinicalTrials.gov for published research from January 2011 to December 2025. A total of 19 studies were included (7 published articles, 12 registry-only or grey literature records). Risk of bias was assessed using two complementary Cochrane tools, the RoB 2 tool for all 19 studies and the ROBINS-I tool for the 6 n-RCTs. Sources of heterogeneity were systematically characterized across 5 clinical dimensions, and structural publication bias was evaluated against a 30% registry-only threshold. A random-effects model was selected for pooled analyses, with a planned subgroup analysis of treatment dosage against adverse events. Effect sizes were extracted using SMD, mean differences, risk ratios, and odds ratios as appropriate per outcome type.ResultsThis systematic review was conducted in accordance with PRISMA 2020 guidelines. A total of 104 participants were enrolled in 7 published studies, with one completed registry trial (NCT04602104) confirming actual enrolment of an additional 18 participants. No study achieved an overall low risk of bias under either assessment tool. Under RoB 2, 1 published study was rated as having some concerns, others were rated high risk or some concerns. Under ROBINS-I, 3 n-RCT studies were rated critical overall. The remaining 3 were rated serious. Across the 7 published studies, 98 participants contributed to the analyzed outcomes. Structural publication bias was confirmed. Substantial clinical heterogeneity was identified across 9 conditions, multiple cell product categories, and mixed intranasal and intravenous delivery routes.ConclusionAlthough current evidence suggests that intranasal administration of stem cells, particularly MSCs and NSCs, in humans is a safe and feasible approach, with possible therapeutic improvements in CNS disorders. However, there is a serious risk of bias, critically small sample sizes, and pervasive publication bias in the available literature. Adequately powered, quadruple-blinded, placebo-controlled randomized trials need to be conducted before clinical translation can be considered.]]></description>
      </item><item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1798699</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1798699</link>
        <title><![CDATA[Food-chain spirochetes: a unified hypothesis for Parkinson’s disease and dementia risk]]></title>
        <pubdate>2026-05-07T00:00:00Z</pubdate>
        <category>Hypothesis and Theory</category>
        <author>Linda M. Sweeney</author>
        <description><![CDATA[Parkinson’s disease (PD) and dementia have risen markedly in many regions. While aging, genetics, toxicants, and protein misfolding explain key aspects of pathology, they do not fully account for synchronized temporal trends or pronounced regional heterogeneity in recent increases. This hypothesis and theory article proposes that persistent microorganisms in industrial food systems—particularly biofilm-forming spirochetes in high-throughput poultry processing—may represent an under-recognized upstream contributor via the gut–brain axis. Analysis of Global Burden of Disease and FAOSTAT data reveals a population-level temporal alignment between rising PD incidence and poultry consumption in the United States and China, with a multi-year lag consistent with prodromal disease phases. In contrast, countries with differing sanitation and feed-chain policies (e.g., Israel’s kosher salting and Germany’s oxidative/thermal methods) show more stable neurodegenerative trends despite high poultry intake. These patterns suggest that sanitation chemistry, processing throughput, and animal-protein recycling may influence long-term microbial exposure risk. The proposed model integrates infection, gut–brain signaling, and protein-misfolding pathways by positioning chronic microbial persistence as a plausible initiating or amplifying factor. Supporting observations include spirochete detection in neurodegenerative tissue, biofilm adaptation under disinfection stress, and experimental evidence linking intestinal bacteria to α-synuclein pathology. Testable predictions include detection of resilient spirochetes or related taxa in post-sanitation products and higher microbial signatures in relevant patient samples.]]></description>
      </item><item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1729134</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1729134</link>
        <title><![CDATA[No associations between blood pressure and brain volumes in a convenience sample of Hispanic/Latino middle-aged and older adults]]></title>
        <pubdate>2026-05-05T00:00:00Z</pubdate>
        <category>Original Research</category>
        <author>Carolina L. Costa</author><author>Carlos E. E. Araujo-Menendez</author><author>Alyssa Lawrence</author><author>Alonzo Mendoza</author><author>Wassim Tarraf</author><author>Ariana M. Stickel</author>
        <description><![CDATA[BackgroundHigh blood pressure (BP) is a known risk factor for dementia, but the relationships between BP and gross brain volumes are mixed and are understudied in groups who are at particularly high risk for dementia, such as Hispanic/Latino adults. Therefore, we aimed to investigate the relationships between BP and brain volumes, among Hispanic/Latino older adults.MethodsParticipants included 122 cognitively healthy Hispanic/Latino late middle-aged and older adults ages (mean age = 73.48 years, SD = 7.32) from the National Alzheimer’s Coordinating Center. Data were collected from 2005 to 2024 from 20 Alzheimer’s Disease Research Centers. BP measures included systolic (SBP), diastolic (DBP), and pulse pressure (PP). Brain outcomes included total, hippocampal, gray matter, and white matter hyperintensity volumes. Covariates included age, sex, Hispanic/Latino heritage, hypertension, diabetes, hypercholesterolemia, body mass index, hypotensive status, and smoking status.ResultsNo BP measure was significantly associated with brain outcomes (all p > 0.05).DiscussionOverall, we found no relationships between BP measures and brain volumes in this sample of late middle-aged and older Hispanic/Latino adults. Our findings warrant longitudinal studies to better characterize the relationships between BP and other cardiovascular disease risk factors with brain health in this population.]]></description>
      </item><item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1859014</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1859014</link>
        <title><![CDATA[Correction: Elevated gonadotropins and risk of dementia in Chinese adults aged over 80: a cross-sectional study]]></title>
        <pubdate>2026-05-05T00:00:00Z</pubdate>
        <category>Correction</category>
        <author>Yunxia Zhu</author><author>Youyi Tu</author><author>Chenxi Ren</author><author>Yingying Ke</author><author>Qihao Guo</author>
        <description></description>
      </item><item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1791352</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1791352</link>
        <title><![CDATA[Integrative bibliometric and transcriptomic analyses identify selenium-associated molecular signatures in the aging brain]]></title>
        <pubdate>2026-05-04T00:00:00Z</pubdate>
        <category>Original Research</category>
        <author>Shan Liu</author><author>Bo Yan</author><author>Han Gao</author><author>Lin Zhang</author><author>Zihan Zhang</author><author>Yaru Liu</author><author>Fanglian Chen</author><author>Ping Lei</author>
        <description><![CDATA[Background and purposeThe aging brain is particularly sensitive to alterations in selenium status. Selenium deficiency has been associated with impaired neural function, cognitive decline, and increased vulnerability to neurodegeneration. However, the molecular mechanisms that link selenium biology to brain aging remain poorly understood.MethodsWe conducted a bibliometric analysis of 1,826 publications and identified brain-aging DEGs from public datasets. After intersecting these with selenium-related gene sets, we used machine-learning feature selection and SHAP/nomogram evaluation to prioritize core genes, validated findings in an independent cohort, performed immune-infiltration and gene-drug enrichment analyses, and confirmed age-related transcriptional and protein changes in mouse brain tissue.ResultsBibliometric analysis showed a steady increase in publications on selenium and aging over the past two decades, with major research hotspots focusing on oxidative stress, selenoproteins, and cognitive function, while the selenium-cognition relationship remains relatively underexplored. Intersection analysis identified seven potential targets linking selenium to brain aging, from which machine-learning feature selection prioritized three core genes (SP1, SEPHS2, and MSRB1) that were significantly differentially expressed in aged samples. SHAP and nomogram analyses indicated that SP1 and SEPHS2 were the main contributors to model discrimination. Animal experiments further confirmed increased SP1 and decreased SEPHS2 expression at both mRNA and protein levels in aged mouse brains, consistent with the bioinformatic findings.ConclusionThis study identifies SP1 and SEPHS2 as key genes linking selenium to brain aging, providing new insights into the role of selenium in brain aging and suggesting that these genes may represent potential biomarkers or therapeutic targets for brain aging and aging-related brain disorders.]]></description>
      </item><item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1781503</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1781503</link>
        <title><![CDATA[Intracisternal IGF-1 gene delivery attenuates early anxiety-like behavior but not dopaminergic neurodegeneration in a 6-OHDA rat model of parkinsonism]]></title>
        <pubdate>2026-05-04T00:00:00Z</pubdate>
        <category>Original Research</category>
        <author>Leandro Gabriel Champarini</author><author>Macarena Lorena Herrera</author><author>Matías Jávega Cometto</author><author>Rocío del Valle Bartolozzi</author><author>Aracely Janneth Naranjo Viteri</author><author>Rosana Crespo</author><author>Gastón Diego Calfa</author><author>Claudia Beatriz Hereñú</author>
        <description><![CDATA[BackgroundParkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons, leading to a spectrum of motor and non-motor symptoms. In addition to the motor deficits serving as the primary criteria for diagnosis, mood and anxiety disorders also play a significant role in shaping the prognosis and overall disease progression in PD.ObjectivesIn this study, our aim was to characterize the progression of anxiety-like behavioral deficits in a rat model of neurotoxicity induced by 6-hydroxydopamine (6-OHDA) and to investigate insulin-like growth factor 1 (IGF-1) potential therapeutic effects on these pathological markers.MethodsBehavioral changes were evaluated in male Wistar rats at 1, 2, and 3 weeks post-lesion using the elevated plus maze and dark–light box tests. Anxiety-like behaviors emerged as early as week 1 post-lesion and persisted through week 3. Following 6-OHDA infusion, immunohistochemical analysis revealed a decrease in tyrosine hydroxylase (TH) immunoreactivity within the ventral tegmental area (VTA) indicating a partial lesion of the nigrostriatal dopaminergic system. As a therapeutic approach we performed the intracisternal administration of a recombinant adenoviral vector encoding IGF-1 (RAd IGF-1) one week after 6-OHDA-induced neurotoxicity.ResultsAt a behavioral level, IGF-1 treatment effectively prevented anxiety-like behavior by the third week of neurotoxicity. Nevertheless, IGF-1 overexpression was not able to modulate VTA dopaminergic neuron loss. These results reveal a dissociation between the behavioral effects of IGF-1 and its impact on dopaminergic neurodegeneration.DiscussionThese findings emphasize time-dependent alterations in anxiety-like behavior and dopaminergic neurodegeneration. In addition, these data support the potential use of IGF-1 as a therapeutic molecule and its novel administrations for future gene transfer interventions, which will shed light on the progressive nature of neurodegenerative mechanisms.]]></description>
      </item><item>
        <guid isPermaLink="true">https://www.frontiersin.org/articles/10.3389/fnagi.2026.1787430</guid>
        <link>https://www.frontiersin.org/articles/10.3389/fnagi.2026.1787430</link>
        <title><![CDATA[An eye-tracking-based Stroop test: an efficient method for evaluating frontal lobe function]]></title>
        <pubdate>2026-05-04T00:00:00Z</pubdate>
        <category>Original Research</category>
        <author>Sho Yamamoto</author><author>Shuko Takeda</author><author>Sho Miki</author><author>Shin Teshirogi</author><author>Yoshinobu Kishino</author><author>Mizuki Katsuhisa</author><author>Momoko Okawara</author><author>Akane Oyama</author><author>Yuki Ito</author><author>Tsuneo Nakajima</author><author>Yoichi Takami</author><author>Yasushi Takeya</author><author>Koichi Yamamoto</author><author>Ryuichi Morishita</author>
        <description><![CDATA[IntroductionAssessing attention and frontal lobe function is essential for diagnosing dementia. The Stroop test is widely used for these purposes, and its validity and reliability have been verified. Nevertheless, test-related burdens and procedural complexity have prevented their use as a screening tool. We developed a novel Stroop test using eye-tracking technology and evaluated its validity and utility in a clinical setting.MethodsThe study included 97 older adults at a memory clinic. Participants completed both the eye-tracking-based and conventional paper-based Stroop tests, along with MMSE, FAB, and TMT-A/B.ResultsScores on the eye-tracking-based Stroop test significantly correlated with the paper-based test (r = 0.634), FAB (r = 0.480), and TMT-B (r = −0.536). It achieved an AUC–ROC of 0.701 for frontal lobe dysfunction and 0.708 for dementia.DiscussionThe eye-tracking-based Stroop test has the potential to efficiently assess frontal lobe function and serve as a screening tool for dementia.]]></description>
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