Frontiers in Aging Neuroscience最新文献

Introduction: Previous studies have illuminated a significant genetic component in motor neuron disease (MND) pathogenesis, with several causative genes identified. However, a substantial proportion of MND cases remain genetically unexplained, particularly regarding the comprehensive contribution of rare, high-impact variants across the exome.

Methods: Leveraging whole-exome sequencing data from nearly half a million UK Biobank participants, we systematically investigated the association between high-confidence protein-truncating variants (HC PTVs) and MND risk in a Caucasian subset. Our large-scale gene-based association analysis utilized REGENIE software and LOFTEE-defined HC PTVs.

Results: We identified significant preliminary associations between HC PTVs in 14 genes and an increased risk of MND. Notably, while NEK1 has been previously implicated in ALS, the remaining 13 genes (BLVRB, KLHL32, RIMS2, DYDC2, DCBLD1, ANXA4, COMP, TRIM42, ANO4, NFX1, CFAP206, CKAP2L, and ANGPTL4) show preliminary associations as novel candidate loci for the disease. Functional enrichment analyses further indicated that these genes are significantly involved in critical biological pathways, including collagen-containing extracellular matrix organization and ciliary function. Furthermore, tissue specificity analysis highlighted a strong enrichment of these genes' expression in brain regions, with the hypothalamus showing the highest specificity.

Discussion: These findings suggest a potential expansion of the known genetic landscape of MND, and highlight novel biological pathways implicated in its pathogenesis. This study underscores the power of large-scale population genetics in uncovering critical disease mechanisms and offers new avenues for mechanistic research and therapeutic development for MND, pending independent validation.

Background: The rising global burden of Parkinson's disease (PD) is often related to cognitive decline. Exploring neuroimaging biomarkers is crucial for early diagnosis.

Methods: The purpose of the exploratory research was to look at the differences in cortical activation and functional connectivity between PD patients and healthy controls (HC), as well as among cognitive subgroups of PD, using multichannel functional near-infrared spectroscopy (fNIRS) during a verbal fluency task. A total of 39 PD patients and 20 age-matched HC were assessed.

Results: Results showed significantly reduced oxygenated hemoglobin (oxy-Hb) concentrations in PD patients, particularly in the right temporal lobe, compared to HC. Among PD cognitive subgroups, patients with Parkinson's disease dementia (PDD) displayed notably lower oxy-Hb levels in key brain regions compared to PD with normal cognition (PD-NC) and PD with mild cognitive impairment (PD-MCI). The analysis among the four groups showed that the HC group and the PDD group had the most differences in activation. Functional connectivity analyses between PD subgroups revealed that PD-NC patients had stronger connectivity between prefrontal regions than PD-MCI and PDD groups.

Conclusion: Our findings generate the hypothesis that PD is associated with altered neurovascular responses and disrupted cortical network organization in the frontal and temporal lobes, especially in cognitively impaired subgroups. These results support the potential utility of fNIRS for characterizing cognition-related neural alterations in PD and provide a basis for future hypothesis-driven and longitudinal investigations.

Objective: Microglia are the primary immune cells in the central nervous system (CNS); however, their temporal and spatial responses to traumatic brain injury (TBI) at the single-cell level remain poorly defined. This study aimed to map the dynamic microglial responses to TBI using single-cell transcriptomics and validate key signaling pathways in vitro.

Methods: A single-cell transcriptomic atlas was reconstructed from publicly available datasets comprising cortical, hippocampal, and blood samples from 35 mice (11 blood, 12 cortex, and 12 hippocampus) subjected to TBI or sham treatment at 24 h and after 7 days. Comparative analyses were conducted to investigate the heterogeneity of myeloid cells, including monocytes, macrophages, and microglia, with a particular focus on activated microglia. The key findings were further validated using quantitative PCR (qPCR) in an in vitro TBI-mimicking model, employing lipopolysaccharide (LPS)-stimulated microglial cell lines to assess changes in gene expression.

Results: TBI induced rapid immune remodeling, including an increase in activated microglia in the cortex, enriched in leukocyte differentiation pathways, and elevated macrophage populations in the cortex and hippocampus, enriched in chemotaxis functions at 24 h. Ligand-receptor (LR) analysis revealed three major signaling axes-Ccl2/Ccl7-Ccr2, Tnf-Tnfrsf1b, and Grn-Flna-associated with monocyte recruitment, M1 polarization, and macrophage differentiation. Validation using qPCR confirmed significant upregulation of Ccl2, Tnf, and Grn in LPS-stimulated microglia, which is consistent with single-cell findings.

Conclusion: This study provides the first integrative single-cell transcriptomic map of microglial-myeloid interactions after TBI across multiple tissues and time points, linking microglial signaling to mitochondrial dysfunction and neuroinflammation. These findings lay the foundation for therapeutic strategies targeting myeloid-driven immune regulation in TBI.

Background: Inflammation plays a critical role in post-stroke mortality. However, identification of robust and generalizable inflammatory biomarkers for post-stroke mortality remains a challenge. We conducted a comprehensive analysis of various composite inflammatory indices, evaluating the associations between these indices and post-stroke mortality by examining two cohorts, to discover trans-situationally robust indices.

Methods: Data were sourced from the National Health and Nutrition Examination Survey (NHANES) circles of 1999-2010 and 2015-2018, as well as from our stroke center. Twelve composite inflammatory indices were calculated based on peripheral blood cell, C-reactive protein, and albumin. The correlations between these indices and post-stroke mortality were evaluated using multivariate Cox proportional hazards regression analyses, with the false discovery rate (FDR) correction applied for multiple testing. The neutrophil-to-lymphocyte ratio (NLR), which demonstrated consistent significance in both NHANES and clinical cohorts, was further subjected to subgroup analyses to elucidate its relationship with post-stroke mortality across various conditions.

Results: This study included 1,152 participants from NHANES cohort, followed until December 31, 2019, and 2,540 patients with acute ischemic stroke (AIS) from the clinical cohort with 90-day follow-up. The NLR, whether treated as a continuous or categorical variable (classified into tertiles), was significantly associated with mortality in both NHANES (per unit increase: hazard ratio [HR] 1.101, 95% confidence interval [CI] 1.043-1.163, P_-FDR  = 0.001; T3 vs. T1: HR 2.002, 95% CI 1.555-2.577, P_-FDR < 0.001) and clinical cohort (per unit increase: HR 1.023, 95% CI 1.010-1.037, P_-FDR  = 0.002; T3 vs. T1: HR 1.939, 95% CI 1.342-2.804, P_-FDR  = 0.009). Subgroup analyses revealed a significant interaction between NLR and time from AIS onset to admission in clinical cohort (P for interaction = 0.017), demonstrating the association was particularly strong in patients admitted within 24 h of AIS onset (HR 1.024, 95% CI 1.011-1.038, p < 0.001).

Conclusion: The NLR may serve as a generalizable biomarker of post-stroke mortality assessment across both community and clinical settings. The correlation with mortality is pronounced in patients during early stage of AIS, underscoring the time-sensitive prognostic value of NLR.

Background: Parkinson's disease (PD) is a chronic neurodegenerative disorder that is closely associated with neuroinflammation, yet effective anti-inflammatory therapies remain limited. This study aimed to elucidate the potential mechanisms of Cassia obtusifolia in mitigating PD-associated neuroinflammatory responses.

Methods: Network pharmacology was employed to identify bioactive compounds, candidate targets, and enriched pathways, followed by protein-protein interaction (PPI) analysis and molecular docking. Rhein, a representative compound, was further validated in LPS-induced BV2 microglial cells using CCK-8, NO detection, ELISA, and Western blot assays.

Results: A total of 114 candidate targets were identified, with enrichment highlighting NF-κB, MAPK, and NLRP3 inflammasome pathways. Molecular docking revealed strong binding affinity between rhein and NF-κB p65. In vitro, rhein significantly reduced the production of inflammatory mediators and suppressed p65 phosphorylation in BV2 cells.

Conclusion: Cassia obtusifolia exerts multi-target anti-neuroinflammatory effects, supporting its potential as a therapeutic candidate for PD and providing a foundation for further translational studies.

Background: Acute ischemic stroke with large vessel occlusion (AIS-LVO) poses a grave threat to the health of the elderly, exhibiting a high degree of disability and mortality. Post-stroke ventilator-associated pneumonia (VAP) significantly impairs neurological recovery and worsens clinical outcomes. This study aimed to construct and validate a prognostic nomogram to forecast VAP risk in elderly patients who underwent endovascular therapy (EVT) with AIS-LVO.

Methods: We retrospectively analyzed a total of 536 patients with AIS-LVO who endured EVT under mechanical ventilation at the Dongguan Hospital of Guangzhou University of Chinese Medicine from August 2018 to March 2025. After applying inclusion/exclusion criteria, 240 elderly patients were randomly split into two groups: training (n = 168) and validation (n = 72), maintaining a 7:3 ratio. Using the least absolute shrinkage and selection operator regression (LASSO) for feature selection followed by multivariable logistic regression, we identified independent predictors for nomogram construction. Model performance was assessed through the area under receiver operating characteristic (ROC), calibration curves, decision curve analysis (DCA), and clinical impact curves (CIC).

Results: Six independent predictors were identified: gender (OR 0.34, 95% CI 0.13∼0.85), nasogastric intubation (OR 7.56, 95% CI 1.77∼32.25), postoperative platelet-to-lymphocyte ratio(PLR) (OR 1.01, 95% CI 1.01∼1.02), postoperative neutrophil-to-lymphocyte ratio (NLR) (OR 1.22, 95% CI 1.02∼1.45), admission white blood cell(WBC) (OR 1.25, 95% CI 1.04∼1.49)and prognostic nutritional index (PNI) (OR 0.85, 95% 0.79∼0.92). The nomogram demonstrated excellent discrimination (AUROC 0.880, 95% CI 0.826∼0.933) and good calibration. DCA and CIC confirmed clinical utility across a wide probability threshold range.

Conclusion: We developed and validated an effective nomogram incorporating six clinically accessible parameters to forecast VAP risk in elderly stroke patients post-EVT. This tool has the potential to expedite early high-risk patient identification and conduct preventive measures to enhance patient clinical outcomes.

[This corrects the article DOI: 10.3389/fnagi.2025.1692414.].

Background: Mild Cognitive Impairment (MCI) and dementia are distinguished by whether cognitive deficits interfere with independent performance of instrumental activities of daily living (iADLs). In Parkinson's disease (PD) this distinction is challenging due to the combined impact of motor and cognitive symptoms on autonomy. To address this, we examine two methods aimed at isolating these contributions using the Functional Activities Questionnaire (FAQ): (1) a modified scoring method that classifies items as motor or cognitive to compute a ratio of the two contributors (FAQ_Q), and (2) a novel, extended FAQ that captures patients' and care-partners' perspective to elucidate the cognitive burden experienced.

Methods: We conducted a retrospective chart review of PD patients (n = 283) prior to Deep Brain Stimulation. We extracted ratings from the standardized and extended FAQ, cognitive diagnoses [PD-MCI: n = 164; cognitively normal (PD-CN) n = 119], neuropsychological test scores, and demographic and clinical variables. We examined the degree to which respondents attributed iADL difficulties to motor and cognitive symptoms, and whether these ratings matched the modified scoring method's categorization. To validate this scoring method in our sample, we examined each standardized FAQ item's relationship with measures of motor symptoms (UPDRS-III) and global cognition (DRS-II). Lastly, we derived a Reported Cognitive Burden (RCB) score from the extended FAQ and examined how it, and the FAQ_Q, relate to cognitive status (PD-CN vs. PD-MCI) and performance on neuropsychological tests.

Results: Patients and care-partners reported that iADLs were more limited by motor symptoms, even for items categorized as "cognitive." Regression models did not achieve the same item classification as prior research using the modified scoring method. The RCB, but not the FAQ_Q, was higher in PD-MCI than PD-CN and related to performance in attention and executive domains regardless of who provided the ratings.

Conclusion: Patient's and care-partner's appraisal of the source of iADL difficulties was inconsistent with previous categorization of FAQ items in patients with more advanced PD. Our novel RCB offers a sensitive means of detecting mild functional changes related to cognition even in the presence of highly disabling motor symptoms, and may aid in establishing cognitive diagnoses in PD and other neurodegenerative disorders.