Frontiers in Aging Neuroscience最新文献

Introduction: Alzheimer's disease (AD) is marked by the accumulation of fibrillary aggregates composed of pathological tau protein. Although neuroinflammation is frequently observed in conjunction with tau pathology, current preclinical evidence does not sufficiently establish a direct causal role in tau tangle formation. This study aimed to evaluate whether chronic Toll-like receptor 4 (TLR4) stimulation, induced by a high dose of lipopolysaccharide (LPS, 5 mg/kg), exacerbates neurofibrillary tangle (NFT) pathology in a transgenic mouse model of tauopathy that expresses human truncated 151-391/3R tau, an early feature of sporadic AD.

Methods: We utilized a transgenic mouse model of tauopathy subjected to chronic TLR4 stimulation via weekly intraperitoneal injections of LPS over nine consecutive weeks. Neurofibrillary tangle formation, microglial activation, and tau hyperphosphorylation in the brainstem and hippocampus were assessed through immunohistochemistry, immunofluorescence, and detailed morphometric analysis of microglia.

Results: Chronic LPS treatment led to a significant increase in the number of Iba-1⁺ microglia in the LPS-treated group compared to the sham group (p < 0.0001). Notably, there was a 1.5- to 1.7-fold increase in microglia per tangle-bearing neuron in the LPS-treated group. These microglia exhibited a reactive yet exhausted phenotype, characterized by a significant reduction in cell area (p < 0.0001) without significant changes in other morphometric parameters, such as perimeter, circumference, solidity, aspect ratio, or arborization degree. Despite extensive microglial activation, there was no observed reduction in tau hyperphosphorylation or a decrease in tangle formation in the brainstem, where pathology predominantly develops in this model.

Discussion: These findings suggest that chronic TLR4 stimulation in tau-transgenic mice results in significant microglial activation but does not influence tau tangle formation. This underscores the complexity of the relationship between neuroinflammation and tau pathology, indicating that additional mechanisms may be required for neuroinflammation to directly contribute to tau tangle formation.

Objectives: To explore the relationship between glymphatic dysfunction and cognitive impairment in unilateral temporal lobe epilepsy (TLE).

Methods: This study retrospectively included 38 patients with unilateral TLE and 26 age- and gender-matched healthy controls (HCs). The diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, choroid plexus volume (CPV), and cognitive assessment were obtained for each participant. Neuropsychological test batteries included Montreal Cognitive Assessment (MoCA), Minimum Mental State Examination, Arithmetic Test (AT), Digit Symbol Substitution Test (DSST), Digit Span Test (DST), Boston Naming Test, Block design, Phonological Fluency Test (PFT), and Semantic Verbal Fluency (SVF).

Results: Compared to HCs, TLE patients had lower scores of MoCA, AT, DSST, DST, Block design, PFT and SVF (all p < 0.05) and lower values of mean DTI-ALPS index (1.491 ± 0.142 vs. 1.642 ± 0.123, p < 0.001). Significantly lower DTI-ALPS index values were observed in the ipsilateral hemisphere than in the contralateral hemisphere (1.466 ± 0.129 vs. 1.517 ± 0.175, p = 0.013) for patients with unilateral TLE. Correlation analyses found that SVF performance was significantly or borderline significantly associated with glymphatic function (FDR-corrected p < 0.05 for all DTI-ALPS index and FDR-corrected p = 0.057 for CPV) in TLE patients. Linear regression analyses showed that increased CPV and decreased DTI-ALPS index were independent risk factors for semantic fluency impairment (all p < 0.05). Furthermore, mediation analyses found the mediator role of the mean DTI-ALPS index in the relationship between choroid plexus enlargement and semantic fluency impairment (indirect effect: β = -0.182, 95%CI = -0.486 to -0.037).

Conclusion: These findings reveal the important role of the DTI-ALPS index and CPV in SVF performance in unilateral TLE. Decreased DTI-ALPS index and increased CPV are the independent risk factors for semantic fluency impairment. The DTI-ALPS index may fully mediate the relationship between CP enlargement and SVF performance. These insights provide a radiological foundation for further investigations into the mechanism of the glymphatic system in TLE pathophysiology.

The early detection of cognitive decline in older adults is crucial for preventing dementia. This mini-review focuses on electroencephalography (EEG) markers of early dementia-related precursors, including subjective cognitive decline, subjective memory complaints, and cognitive frailty. We present recent findings from EEG analyses identifying high dementia risk in older adults, with an emphasis on conditions that precede mild cognitive impairment. We also cover event-related potentials, quantitative EEG markers, microstate analysis, and functional connectivity approaches. Moreover, we discuss the potential of these neurophysiological markers for the early detection of cognitive decline as well as their correlations with related biomarkers. The integration of EEG data with advanced artificial intelligence technologies also shows promise for predicting the trajectory of cognitive decline in neurodegenerative disorders. Although challenges remain in its standardization and clinical application, EEG-based approaches offer non-invasive, cost-effective methods for identifying individuals at risk of dementia, which may enable earlier interventions and personalized treatment strategies.

Introduction: Recent research has recognized executive dysfunction as another component affected in Primary Progressive Aphasia (PPA). This systematic review aimed to examine what information distinctive neurophysiological markers can provide in the evaluation of executive function (EF) deficits in PPA, and to what effect executive function deficits can be assessed through the characteristics of functional markers.

Methods: We conducted a systematic literature search following the PRISMA guidelines across studies that employed neuropsychological assessments and neurophysiological imaging techniques (EEG, MEG; PET, SPECT, fMRI, fNIRS) to investigate executive dysfunction correlates in PPA.

Results: Findings from nine articles including a total number of 111 individuals with PPA met our inclusion criteria and were synthesized. Although research on the neural correlates of EF deficits is scarce, MEG studies revealed widespread oscillatory slowing, with increased delta and decreased alpha power, where alterations in alpha, theta, and beta activities were significant predictors of executive function deficits. PET findings demonstrated significant correlations between executive dysfunction and hypometabolism in frontal brain regions. fMRI results indicated elevated homotopic connectivity in PPA patients, with a broader and more anterior distribution of abnormal hippocampal connections of which were associated with reduced executive performance.

Conclusion: Our study provides indirect support for the assumption regarding the significance of the frontal regions and inferior frontal junction in executive control and demonstrates that neurophysiological tools can be a useful aid to further investigate clinical-neurophysiological correlations in PPA.

Background and aims: The relationship between the ABCA7 gene and Alzheimer's disease (AD) has been widely studied across various populations. However, the results have been inconsistent. This meta-analysis aimed to evaluate the association of ABCA7 polymorphisms with AD risk, including specific subtypes such as late-onset Alzheimer's disease (LOAD).

Methods: Relevant studies were identified through comprehensive database searches, and the quality of each study was assessed using the Newcastle-Ottawa Scale (NOS). Allele and genotype frequencies were extracted from the included studies. The pooled odds ratios (OR) with corresponding 95% confidence intervals (CI) were calculated using random-effects or fixed-effects models. Multiple testing corrections were conducted using the false discovery rate (FDR) method. The Cochran Q statistic and I² metric were used to evaluate heterogeneity between studies, while Egger's test and funnel plots were employed to assess publication bias.

Results: A total of 36 studies, covering 21 polymorphisms and involving 31,809 AD cases and 44,994 controls, were included in this meta-analysis. NOS scores ranged from 7 to 9, indicating high-quality studies. A total of 11 SNPs (rs3764650, rs3752246, rs4147929, rs3752232, rs3752243, rs3764645, rs4147934, rs200538373, rs4147914, rs4147915, and rs115550680) in ABCA7 were significantly associated with AD risk. Among these SNPs, two (rs3764650 and rs3752246) were also found to be related to the late-onset AD (LOAD) subtype. In addition, two SNPs (rs4147929 and rs4147934) were associated with the susceptibility to AD only in non-Hispanic White populations. A total of 10 SNPs (rs3764647, rs3752229, rs3752237, rs4147932, rs113809142, rs3745842, rs3752239, rs4147918, rs74176364, and rs117187003) showed no significant relationship with AD risk. Sensitivity analyses confirmed the reliability of the original results, and heterogeneity was largely attributed to deviations from Hardy-Weinberg equilibrium, ethnicity, and variations between individual studies.

Conclusion: The available evidence suggests that specific ABCA7 SNPs may be associated with AD risk. Future studies with larger sample sizes will be necessary to confirm these results.

Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42024540539.

Background: This study utilized recent advancements in electroencephalography (EEG) technology that enable the measurement of prefrontal event-related potentials (ERPs) to facilitate the early detection of mild cognitive impairment (MCI). We investigated two-channel prefrontal ERP signals obtained from a large cohort of elderly participants and compare among cognitively normal (CN), subjective cognitive decline (SCD), amnestic MCI (aMCI), and nonamnestic MCI (naMCI) groups.

Methods: Signal processing and ERP component analyses, specifically adapted for two-channel prefrontal ERP signals evoked by the auditory oddball task, were performed on a total of 1,754 elderly participants. Connectivity analyses were conducted to assess brain synchronization, especially in the beta band involving the phase locking value (PLV) and coherence (COH). Time-frequency, time-trial, grand average, and further statistical analyses of the standard and target epochs were also conducted to explore differences among the cognition groups.

Results: The MCI group's response to target stimuli was characterized by greater response time variability (p < 0.001) and greater variability in the P300 latency (p < 0.05), leading to less consistent responses than those of the healthy control (HC) group (CN+SCD subgroups). In the connectivity analyses of PLV and COH waveforms, significant differences were observed, indicating a loss of synchronization in the beta band in response to standard stimuli in the MCI group. In addition, the absence of event-related desynchronization (ERD) indicated that information processing related to readiness and task performance in the beta band was not efficient in the MCI group. Furthermore, the observed decline in the P200 amplitude as the standard trials progressed suggests the impaired attention and inhibitory processes in the MCI group compared to the HC group. The aMCI subgroup showed high variability in COH values, while the naMCI subgroup showed impairments in their overall behavioral performance.

Conclusion: These findings highlight the variability and connectivity measures can be used as markers of early cognitive decline; such measures can be assessed with simple and fast two-channel prefrontal ERP signals evoked by both standard and target stimuli. Our study provides deeper insight of cognitive impairment and the potential use of the prefrontal ERP connectivity measures to assess early cognitive decline.

Background/objective: To examine the cognitive benefits of 6 months of prescribed intermittent exercise (10-min bouts totaling 150 weekly minutes) in community-dwelling older adults, comparing effects of low-intensity movement (LIM) and moderate-intensity aerobic exercise (aerobic exercise; AE) training; and exploring biological mechanisms of exercise-related cognitive improvement.

Method: Twenty-five adults (>60 years old) participated in a 6-month controlled trial and were randomized into LIM or AE intermittent training. Cognition was assessed using a neuropsychological test battery including the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), California Verbal Learning Test, 2nd Edition (CVLT-II), and Delis-Kaplan Executive Function System (D-KEFS). Neuroimaging measures were collected using a 7 T human MRI scanner. Serologic neurotrophic and inflammatory factors were analyzed using Luminex multiplex assays [brain derived neurotrophic factor (BDNF); vascular endothelial growth factor (VEGF)]; interleukin-6 (IL-6), C-reactive protein (CRP), plasminogen activator inhibitor (PAI-1).

Results: LIM and AE intermittent training had dissociable effects on cognition, with LIM resulting in improved learning and memory and AE resulting in improved executive functioning. Intervention groups differed on change in cognitive performance on CVLT-II learning and D-KEFS trail making test. Increase in right dorsolateral prefrontal cortex (DLPFC) surface area was linked to executive improvement (i.e., phonemic fluency) regardless of intervention group. A decline in circulating PAI-1 was linked to learning and memory improvement in response to LIM over 6 months.

Conclusion: Moderate-intensity AE and LIM intermittent training likely have distinct cognitive benefits, though low-intensity activity is often included as a control group in exercise trials in aging.

Background: Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressively worsening cognitive decline and memory loss. Excessive iron accumulation produces severe cognitive impairment. However, there are no uniform conclusions about changes in brain iron content in AD. This study aimed to investigate the iron content of the deep brain nuclei in AD, and its correlation with cognitive function.

Methods: Thirty-one patients with mild to moderate AD, 17 patients with mild cognitive impairment (MCI), and 20 age-, sex-, and education-matched healthy controls (HC) were collected. The QSM was used to quantify the magnetic susceptibility values of the caudate nucleus, putamen, globus pallidus, substantia nigra, red nucleus, and dentate nucleus, and to analyze the differences that existed between the three groups. As well as the correlation between the magnetic susceptibility values and cognitive function was calculated.

Results: The magnetic susceptibility values of bilateral globus pallidus, left putamen, and bilateral substantia nigra were significantly higher in AD patients than in HC, and the magnetic susceptibility values of the right globus pallidus were significantly higher in AD patients than in MCI (all p < 0.05). The magnetic susceptibility values of the left dentate nucleus in the AD group were negatively correlated with the writing function of the MMSE subitem (r = -0.42, p = 0.020), and the magnetic susceptibility values of the left caudate nucleus and right dentate nucleus were significantly and negatively correlated with the naming function and language function of the MoCA subitem, respectively (r = -0.43, p = 0.019; r = -0.36, p = 0.048).

Conclusion: Magnetic susceptibility values based on QSM correlate with cognitive function are valuable in discriminating AD from MCI and AD from HC.

Background: Deep Brain Stimulation (DBS) has been widely applied and accepted in the treatment of neurological and psychiatric disorders. Despite numerous studies exploring the effects of DBS on the progression of neurodegenerative diseases and the treatment of advanced Parkinson's disease (PD), there is a limited number of articles summarizing this research. The purpose of this study is to investigate the current trends, hot topics, and potential in research surrounding DBS therapy for PD, as well as to anticipate the challenges of such research.

Methods: We searched the Web of Science Core Collection database (WoSCC) for DBS research literature related to PD published from January 2014 to January 2024, utilized CiteSpace, VOS viewer, the bibliometric online analysis platform, Scimago Graphica, Microsoft Excel 2021, and R software version 4.2.3 for data analysis. And we conducted quantitative research on publications, citations, journals, authors, countries, institutions, keywords, and references, visualized the results in network graphs.

Results: From 2014 to 2024, papers from 39 journals from 11 countries were among the top 100 cited. Most papers were published in Neurology, with the highest average citations per paper in Nature Neuroscience. The United States (US) contributed the most publications, followed by the United Kingdom (UK) and Germany. In terms of total publications, University College London (UCL) contributed the most papers. The primary classifications of articles were Clinical Neurology, Neurosciences, and Surgery. The top five keywords were subthalamic nucleus, DBS, PD, medical therapy, and basal ganglia. Cluster analysis indicates that DBS research focus on improving quality of life and applying computational models.

Conclusion: Through bibliometric analysis, researchers could quickly and clearly understand the hotspots and boundaries of their research field, thus guiding their research direction and scope to improve research efficiency and the quality of outcomes. Although studies indicate that DBS is currently a crucial method for treating advanced PD, in the long run, creating a personalized, low-cost treatment regimen with precise targeting and long-term efficacy poses a challenge.