Neurobiology of Aging最新文献_第4页

Hippocampal 1H-MR spectroscopy metabolites are linked to CSF tau pathology in cognitively unimpaired older adults along the Alzheimer’s continuum 海马1H-MR谱代谢物与认知功能未受损的老年人在阿尔茨海默病连续体中的脑脊液tau病理有关。

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2026-01-01 Epub Date: 2025-10-30 DOI: 10.1016/j.neurobiolaging.2025.10.005

Jessica N. Lingad , Casey R. Vanderlip , Sierra Wright , Lorena Sordo , Elizabeth Head , Craig E.L. Stark

Relationships between Alzheimer’s disease (AD) pathologies in cognitively unimpaired adults and in vivo neurometabolic properties measured directly from the hippocampus, a vulnerable region early along the AD continuum, are not well-understood in the earliest stages of AD. In a 3T ¹H-MRS study, we assessed age and AD-related changes in estimates of absolute concentrations of neurometabolites in the right hippocampus. Participants included older adults (age range: 60–85, n = 19) primarily cognitively unimpaired (CU, n = 16), as well as some with cognitive impairment (n = 3). All participants previously received a lumbar puncture for AD disease staging from cerebrospinal fluid (CSF) AD biomarkers (Aβ42, p-tau181 and t-tau), where all were amyloid positive (A+) and most had subthreshold tau pathology (T-). Hippocampal ¹H-MRS metabolites included total N-acetylaspartate (tNAA), myo-inositol (mIns), total creatine (tCr) and total choline (tCho). Regression analyses were performed for assessing relationships among CSF biomarkers, age, and ¹H-MRS metabolites measured as tissue-corrected estimates of absolute concentrations (millimoles/kilogram) and as ratios (/tCr and tNAA/mIns). We identified age-related decreases to mIns/tCr, where estimated absolute concentrations revealed that tCr increased while mIns remained stable. Concentrations for tNAA and mIns were positively associated with CSF p-tau181 and t-tau. Levels of tCr and tCho were not associated with any CSF biomarkers. Overall, our results demonstrate that sub-threshold tau pathologies in cognitively unimpaired A+ individuals are associated with hippocampal metabolite changes related to neural metabolism and glial reactivity early in disease progression.

认知功能未受损的成人阿尔茨海默病（AD）病理与直接从海马体（AD连续体早期的一个脆弱区域）测量的体内神经代谢特性之间的关系，在AD的早期阶段尚未得到很好的理解。在一项3T 1H-MRS研究中，我们评估了右海马神经代谢物绝对浓度的年龄和ad相关变化。参与者包括老年人（年龄范围：60-85岁，n = 19），主要是认知障碍（CU, n = 16），以及一些认知障碍（n = 3）。所有参与者之前都接受了腰椎穿刺，从脑脊液（CSF） AD生物标志物（a β42， p-tau181和T- tau）来判断AD疾病分期，其中所有人都是淀粉样蛋白阳性（a +），大多数人有阈下tau病理（T-）。海马1H-MRS代谢产物包括总n -乙酰天冬氨酸（tNAA）、肌醇（mIns）、总肌酸（tCr）和总胆碱（tCho）。进行回归分析，评估脑脊液生物标志物、年龄和1H-MRS代谢物之间的关系，以组织校正的绝对浓度（毫摩尔/千克）和比率（/tCr和tNAA/ min）进行测量。我们确定了与年龄相关的min /tCr下降，其中估计的绝对浓度显示tCr增加而min保持稳定。tNAA和mIns浓度与CSF p-tau181和t-tau呈正相关。tCr和tCho的水平与任何脑脊液生物标志物无关。总体而言，我们的研究结果表明，认知未受损的A+ 个体的亚阈值tau病理与疾病进展早期与神经代谢和神经胶质反应性相关的海马代谢物变化有关。

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引用次数: 0

Targeting neuronal activity and neuroinflammation for the treatment of Alzheimer’s disease in a mouse model 靶向神经元活动和神经炎症治疗阿尔茨海默病的小鼠模型

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2026-01-01 Epub Date: 2025-11-01 DOI: 10.1016/j.neurobiolaging.2025.10.006

Chongzhen Yuan , Long Li , Hsiao-yun Lin , Antonio v. Aubry , Lyonna F. Parise , Carole Morel , Fiona Chen , Jean Wong , Scott J. Russo , Jun Wang

Alzheimer’s disease (AD) is characterized by progressive cognitive decline driven by complex pathological processes, including tau hyperphosphorylation (p-Tau), amyloid-beta (Aβ) accumulation, and neuroinflammation. In this study, we investigated the effects of two bioactive compounds, dihydrocaffeic acid (DHCA) and malvidin-glucoside (Mal-gluc), targeting inflammation and neuronal activity, respectively, on cognitive function and AD pathology in a mouse model of AD. Our results demonstrate that chronic DHCA/Mal-gluc treatment significantly improves recognition memory in 3xTg-AD mice without reducing p-Tau or Aβ burden. Employing a newly developed whole-brain cFOS and IBA-1 mapping technique, we found that this combination treatment enhances neuronal activity and promotes microglial homeostasis across multiple brain regions in 3xTg-AD mice. These findings underscore the potential of restoring neuronal function and immune homeostasis as a therapeutic approach for AD. Future study will explore the underlying mechanisms and evaluate whether DHCA/Mal-gluc, combined with currently approved Aβ monoclonal therapy, can synergistically prevent or delay AD onset and progression.

阿尔茨海默病（AD）的特点是由复杂的病理过程驱动的进行性认知能力下降，包括tau过度磷酸化（p-Tau）、β淀粉样蛋白（Aβ）积累和神经炎症。在这项研究中，我们研究了两种生物活性化合物，二氢咖啡酸（DHCA）和malvidin-glucoside (Mal-gluc)，分别针对炎症和神经元活性，对AD小鼠模型的认知功能和AD病理的影响。我们的研究结果表明，慢性DHCA/Mal-gluc治疗显著改善3xTg-AD小鼠的识别记忆，但不减少p-Tau或a - β负担。采用新开发的全脑cFOS和IBA-1定位技术，我们发现这种联合治疗增强了3xTg-AD小鼠的神经元活性，并促进了多个大脑区域的小胶质稳态。这些发现强调了恢复神经元功能和免疫稳态作为AD治疗方法的潜力。未来的研究将探索潜在的机制，并评估DHCA/Mal-gluc联合目前批准的Aβ单克隆治疗是否能协同预防或延缓AD的发病和进展。

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引用次数: 0

EEG slow waves and cognitive decline in Isolated Rapid Eye Movements Behavior Disorder: A multicenter longitudinal study 孤立性快速眼动行为障碍的脑电图慢波与认知能力下降：一项多中心纵向研究

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2026-01-01 Epub Date: 2025-11-04 DOI: 10.1016/j.neurobiolaging.2025.11.001

Caterina Leitner , Dario Arnaldi , Francesca Casoni , Michela Figorilli , Beatrice Orso , Pietro Mattioli , Valter Rustioni , Monica Puligheddu , Luigi De Gennaro , Michele Terzaghi , Luigi Ferini-Strambi , Andrea Galbiati

This multicenter retrospective longitudinal study aims to evaluate the association between electroencephalographic slow oscillations (0.3–1 Hz) and slow waves (1–4 Hz) with cognitive performance, and their impact on phenoconversion in patients affected by isolated rapid eye movement (REM) sleep behavior disorder (iRBD). 69 iRBD patients underwent baseline overnight video-polysomnography, clinical assessment, and a neuropsychological evaluation. Phenoconversion was assessed with a follow-up clinical evaluation. Automatic detection of slow oscillations and slow waves was performed during non-REM sleep stage 2 (N2) and 3 (N3) on frontal and central derivations. Clinical, neuropsychological and electrophysiological measures were compared between converters and non-converters. Correlations were computed between cognitive performance and slow oscillations and slow wave densities, as well as between N2 slow oscillation density and N3 slow/fast wave densities. Time-to-event analyses, including Kaplan-Meier and Cox proportional hazards model were performed to assess phenoconversion risk and potential predictors. 30.36 % of patients phenoconverted to an overt alpha-synucleinopathy with a mean follow-up of 45.57 ± 37.26 months. Both slow wave and slow oscillation densities were significantly associated with cognitive performance. Moreover, slow oscillation density in N2 positively correlated with slow oscillation and slow wave density in N3. At baseline, patients who phenoconverted at follow-up showed significantly lower executive function performance and reduced N2 slow oscillation density. In the Cox model including covariates, only executive functions remained a significant predictor. Baseline differences in executive functions may help identify iRBD patients at greater risk of phenoconversion, whereas reduced N2 slow oscillation density may reflect early neurophysiological alterations preceding overt disease.

本多中心回顾性纵向研究旨在评估脑电图慢振荡（0.3-1 Hz）和慢波（1-4 Hz）与孤立性快速眼动（REM）睡眠行为障碍（iRBD）患者认知表现的关系及其对表型转化的影响。69例iRBD患者接受了基线夜间视频多导睡眠图、临床评估和神经心理学评估。表型转化通过随访临床评估进行评估。在非快速眼动睡眠阶段2 （N2）和3 （N3）对额叶和中枢衍生进行慢振荡和慢波的自动检测。比较两组患者的临床、神经心理和电生理指标。计算认知能力与慢振荡和慢波密度之间的相关性，以及N2慢振荡密度与N3慢/快波密度之间的相关性。时间-事件分析，包括Kaplan-Meier和Cox比例风险模型来评估表型转化风险和潜在的预测因素。30.36 %的患者表型转化为明显的α -突触核蛋白病，平均随访45.57 ± 37.26个月。慢波和慢振荡密度都与认知能力显著相关。N2的慢振荡密度与N3的慢振荡和慢波密度呈正相关。在基线时，随访时表型转化的患者表现出明显较低的执行功能表现和N2慢振荡密度降低。在包含协变量的Cox模型中，只有执行功能仍然是显著的预测因子。执行功能的基线差异可能有助于识别具有更高表型转化风险的iRBD患者，而N2慢振荡密度降低可能反映了显性疾病之前的早期神经生理改变。

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引用次数: 0

Zinc transporter proteins in the retina as potential biomarkers for staging early Alzheimer’s disease: Comparative analysis in human and mouse models 视网膜中的锌转运蛋白作为早期阿尔茨海默病分期的潜在生物标志物：人类和小鼠模型的比较分析

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2026-01-01 Epub Date: 2025-10-01 DOI: 10.1016/j.neurobiolaging.2025.09.010

Seyed Mostafa Hosseinpour Mashkani , David Bishop , Paul A. Adlard , S. Mojtaba Golzan

Zinc plays a critical role in memory, learning, and neuronal function, with dysregulation increasingly implicated in neurodegenerative diseases such as Alzheimer’s disease (AD). This study aimed to investigate whether changes in the expression of zinc transporter proteins, ZnT3 and ZIP3, in the retina mirror those in the brain, and to explore their potential as non-invasive biomarkers for early AD detection. Immunofluorescence and Western blotting were used to assess ZnT3 and ZIP3 expression in the retina and hippocampus of APP/PS1 and WT mice (9 and 18 months), as well as in human post-mortem tissues (9 AD and 6 control cases). To further investigate the regulatory role of ZnT3 in zinc homeostasis and its influence on tissue zinc concentrations, we quantified zinc levels in retinal and hippocampal tissues from WT and ZnT3 knockout mice using inductively coupled plasma-mass spectrometry (ICP-MS). ZnT3 and ZIP3 levels were significantly higher in the retina and hippocampus of healthy controls compared to AD cases across both mouse and human samples. ICP-MS analysis confirmed significantly lower zinc concentrations in ZnT3 knockout mice compared to WT controls in both the These findings demonstrate that retinal ZnT3 and ZIP3 expression changes mirror those observed in the hippocampus during AD progression. This suggests their potential as retinal biomarkers for Alzheimer's disease. Notably, ZnT3 shows strong promise for early, non-invasive detection of AD. Further validation in larger cohorts is warranted.

锌在记忆、学习和神经元功能中起着至关重要的作用，其失调与阿尔茨海默病（AD）等神经退行性疾病的关系越来越密切。本研究旨在探讨锌转运蛋白ZnT3和ZIP3在视网膜中的表达变化是否反映了大脑中的表达变化，并探索它们作为早期阿尔茨海默病非侵入性生物标志物的潜力。应用免疫荧光和Western blotting检测APP/PS1和WT小鼠（9个月和18个月）视网膜和海马以及人死后组织（9例AD和6例对照）中ZnT3和ZIP3的表达。为了进一步研究ZnT3在锌稳态中的调节作用及其对组织锌浓度的影响，我们使用电感耦合等离子体质谱（ICP-MS）定量了WT和ZnT3敲除小鼠视网膜和海马组织中的锌水平。健康对照的视网膜和海马体中ZnT3和ZIP3水平明显高于阿尔茨海默病小鼠和人类样本。ICP-MS分析证实，与WT对照组相比，ZnT3基因敲除小鼠的锌浓度显著降低。这些发现表明，视网膜ZnT3和ZIP3表达的变化与AD进展过程中海马中观察到的变化相一致。这表明它们有可能成为阿尔茨海默病的视网膜生物标志物。值得注意的是，ZnT3在早期、无创检测AD方面显示出强大的前景。需要在更大的队列中进一步验证。

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引用次数: 0

Verbal learning in logopenic variant Primary Progressive Aphasia: An EEG investigation 语词缺失型原发性进行性失语症的语言学习：脑电图研究。

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2026-01-01 Epub Date: 2025-10-10 DOI: 10.1016/j.neurobiolaging.2025.10.002

Kyriaki Neophytou , Panteleimon Chriskos , Jessica Gallegos , Alexandros Afthinos , Constantine E. Frangakis , Nathan E. Crone , Panagiotis D. Bamidis , Argye E. Hillis , Kyrana Tsapkini

The logopenic variant of PPA (lvPPA) is characterized by impaired single-word retrieval and impaired repetition, which suggests a phonological working memory impairment. Phonological working memory is an essential mechanism for verbal learning; thus, one would expect that the verbal learning skills of this population would be thoroughly investigated. Nonetheless, the relevant research is scarce. As a preliminary investigation aiming to deepen our understanding of verbal learning in lvPPA, we studied how resting-state electroencephalographic (EEG) activity relates to the verbal learning abilities in this group. Specifically, short low-density (i.e., 8 channels, bilaterally) EEG recordings were collected from nine lvPPA individuals at resting-state. Activity at the five frequency bands (delta, theta, alpha, beta, gamma) was extracted and correlated with Sum of Trials performance on the Rey Auditory Verbal Learning Test (RAVLT). Our results showed a statistically significant association between delta band activity and verbal learning across the brain, particularly in the left parietal region. Specifically, higher delta power (on average across channels, as well as at each of the eight channels separately) was associated with lower RAVLT scores. EEG activity at the other frequency bands did not show a statistically significant association with verbal learning. These findings provide the first insights into the association of resting-state electrophysiological activity with verbal learning in lvPPA. The findings of this preliminary investigation can be used as guiding evidence in future neuromodulation studies to target activity at specific frequency bands for electrical stimulation both in lvPPA, as well as in other populations with similar learning impairments.

PPA的词性变异体（lvPPA）表现为单字检索功能受损和重复功能受损，提示存在语音工作记忆障碍。语音工作记忆是语言学习的重要机制；因此，人们会期望对这一人群的语言学习技能进行彻底的调查。然而，相关的研究却很少。作为一项旨在加深我们对lvPPA中言语学习的理解的初步研究，我们研究了静息状态脑电图（EEG）活动与这一群体的言语学习能力之间的关系。具体而言，收集了9名lvPPA个体静息状态下的短低密度（即8通道，双侧）脑电图记录。提取5个频带（delta, theta, alpha, beta, gamma）的活动，并将其与Rey听觉言语学习测试（RAVLT）的试验总和成绩相关联。我们的研究结果显示，在整个大脑中，特别是在左顶叶区域，delta波段活动与语言学习之间存在统计学上显著的关联。具体来说，较高的δ功率（平均跨通道，以及分别在八个通道中的每个通道）与较低的RAVLT分数相关。其他频带的脑电图活动与语言学习没有统计学上显著的关联。这些发现首次揭示了lvPPA静息状态电生理活动与言语学习之间的关系。这项初步研究的结果可以作为未来神经调节研究的指导性证据，在lvPPA以及其他具有类似学习障碍的人群中，针对特定频段的活动进行电刺激。

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引用次数: 0

Editorial Advisory Board 编辑顾问委员会

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2026-01-01 Epub Date: 2025-11-18 DOI: 10.1016/S0197-4580(25)00194-0

引用次数: 0

Apraxic deficits in Alzheimer’s disease are associated with altered dynamic connectivity in praxis-related networks 阿尔茨海默病的失用缺陷与实践相关网络的动态连接改变有关。

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2026-01-01 Epub Date: 2025-09-18 DOI: 10.1016/j.neurobiolaging.2025.09.007

Taylan D. Kuzu , Elena Brinkmann , Anna K. Bonkhoff , Veronika Wunderle , Gérard N. Bischof , Kathrin Giehl , Maximilian H.T. Schmieschek , Oezguer A. Onur , Frank Jessen , Gereon R. Fink , Alexander Drzezga , Peter H. Weiss

Apraxia is a common symptom in Alzheimer’s disease (AD) that reduces autonomy and quality of life. However, the neural basis underlying apraxia in AD, for example, reflected by functional connectivity (FC) alterations, remains unexplored. We investigated static and dynamic FC using resting-state functional imaging in 14 patients with biomarker-confirmed AD pathology and 14 matched healthy participants. FC was estimated as average (static) and short-term (dynamic) connectivity strengths between motor- and praxis-related functional networks. Recurring connectivity patterns were clustered into dynamic states to compute temporal connectivity measures. Connectivity measures were used for correlations with apraxic deficits. In AD patients, static connectivity between visual and inferior parietal networks correlated with apraxic imitation (r = 0.762, P_FDR = 0.043) and arm/hand gesture deficits (r = 0.848, P_FDR = 0.020), while dynamic connectivity between these networks correlated with apraxic imitation deficits (r = 0.851, P_FDR = 0.020). Dynamic FC analysis revealed a segregated and integrated state. AD patients spent more time overall (fraction time, P_FDR < 0.001) and remained longer without switching (dwell time, P_FDR = 0.004) in the segregated state. Both fraction (ρ = –0.858, P_FDR = 0.015) and dwell time (ρ = –0.914, P_FDR = 0.003) correlated with apraxic imitation deficits. Connectivity strengths between visual and inferior parietal networks and fraction time in the segregated state predicted apraxic imitation deficits (adjusted R² = 0.782, P < 0.001). We conclude that apraxia in AD patients is associated with altered FC in praxis-related networks, suggesting FC as a potential clinical indicator for predicting motor-cognitive deficits.

失用症是阿尔茨海默病（AD）的常见症状，它会降低自主性和生活质量。然而，阿尔茨海默症失用的神经基础，例如，通过功能连接（FC）改变所反映的神经基础，仍未被探索。我们使用静息状态功能成像研究了14名生物标志物证实的AD病理患者和14名匹配的健康参与者的静态和动态FC。FC被估计为运动和实践相关功能网络之间的平均（静态）和短期（动态）连接强度。将重复出现的连接模式聚类为动态状态，以计算时间连接度量。连通性测量用于与失用性缺陷的相关性。在AD患者中，视觉和下顶网络之间的静态连通性与失用模仿（r = 0.762,PFDR = 0.043）和手臂/手势缺陷（r = 0.848,PFDR = 0.020）相关，而这些网络之间的动态连通性与失用模仿缺陷相关（r = 0.851,PFDR = 0.020）。动态FC分析显示了分离和集成状态。AD患者在隔离状态下总体停留时间更长（分数时间，PFDR < 0.001），未切换的停留时间更长（停留时间，PFDR = 0.004）。分数（ρ = -0.858, PFDR = 0.015）和停留时间（ρ = -0.914, PFDR = 0.003）与失用模仿缺陷相关。视觉和下顶叶网络的连接强度与分离状态下的分数时间预测失用模仿缺陷(调整R2 = 0.782， P

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引用次数: 0

Proteomic polygenic risk scores of age-related plasma protein levels reveal a role for Metalloproteinase inhibitor 2 (TIMP2) in cognitive performance 年龄相关血浆蛋白水平的蛋白质组学多基因风险评分揭示了金属蛋白酶抑制剂2 （TIMP2）在认知表现中的作用。

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2026-01-01 Epub Date: 2025-10-23 DOI: 10.1016/j.neurobiolaging.2025.10.003

Federica Anastasi , Patricia Genius , Blanca Rodriguez-Fernandez , Chengran Yang , Priyanka Gorijala , Jigyasha Timsina , Felipe Hernández-Villamizar , Luigi Lorenzini , Marta del Campo , Gonzalo Sánchez-Benavides , Carolina Minguillon , Arcadi Navarro , Carlos Cruchaga , Marc Suárez-Calvet , Natalia Vilor-Tejedor

Several studies in mice have identified blood proteins that influence brain aging, yet translating these findings into humans remains challenging. To address this gap, we conducted a systematic review that identified 12 proteins reported to have an aging or rejuvenating effect in murine brains. Using protein quantitative trait loci data, we computed proteomic polygenic risk scores (protPRSs) capturing the lifelong genetic predisposition to higher or lower plasma protein levels and their regulation. We first validated the prediction accuracy of these protPRSs in two independent cohorts: 10 protPRSs in the Knight-ADRC and 7 protPRSs in the ALFA+ cohort significantly predicted their corresponding protein levels, although effect sizes were modest. We then examined their association with cognitive performance in cognitively unimpaired individuals at risk of Alzheimer’s disease of the ALFA+ cohort. Among the protPRSs tested, the metalloproteinase inhibitor 2 (TIMP2) protPRS was significantly associated with better global cognition and episodic memory. These associations were consistent across stratifications by sex, APOE-ε4, and amyloid-β status, although some did not survive multiple testing corrections. TIMP2 protPRS correlated with measured TIMP2 levels, but actual plasma concentrations were not significantly related to cognition. This finding aligns with murine evidence of TIMP2's brain-rejuvenating role. By leveraging genetic predisposition to protein abundance and regulation, protPRSs may provide complementary insight into long-term biological processes not captured by single protein measurements. Our results support TIMP2 as a candidate for further investigation in the context of brain aging and cognitive decline.

在老鼠身上进行的几项研究已经确定了影响大脑衰老的血液蛋白，但将这些发现转化为人类仍然具有挑战性。为了填补这一空白，我们进行了一项系统综述，确定了12种据报道在小鼠大脑中具有衰老或返老还童作用的蛋白质。利用蛋白质数量性状位点数据，我们计算了蛋白质组学多基因风险评分（protprs），该评分捕获了血浆蛋白水平升高或降低及其调控的终生遗传易感性。我们首先在两个独立的队列中验证了这些protPRSs的预测准确性：Knight-ADRC队列中的10个protPRSs和ALFA+队列中的7个protPRSs显著预测了相应的蛋白质水平，尽管效应大小不大。然后，我们研究了ALFA+队列中具有阿尔茨海默病风险的认知功能未受损个体的认知表现与它们的关系。在测试的protPRS中，金属蛋白酶抑制剂2 (TIMP2) protPRS与更好的全局认知和情景记忆显著相关。这些关联在不同性别、APOE-ε4和淀粉样蛋白-β状态的分层中是一致的，尽管有些没有经过多次测试修正。TIMP2 protPRS与测量的TIMP2水平相关，但实际血浆浓度与认知无显著相关性。这一发现与TIMP2的大脑恢复作用的小鼠证据一致。通过利用蛋白质丰度和调节的遗传易感性，protprs可以为单蛋白测量无法捕获的长期生物过程提供补充见解。我们的研究结果支持TIMP2在大脑衰老和认知能力下降的背景下作为进一步研究的候选者。

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引用次数: 0

Identification of circular RNAs associated with ageing of the dorsolateral prefrontal cortex across the adult lifespan 鉴定与成年期间背外侧前额叶皮层衰老相关的环状rna

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2026-01-01 Epub Date: 2025-10-09 DOI: 10.1016/j.neurobiolaging.2025.10.001

Fatemeh Amjadi-Moheb , Sumangali Gobhidharan , Adith Mohan , Perminder S. Sachdev , Anbupalam Thalamuthu , Karen A. Mather

Circular RNAs (circRNAs) are emerging as crucial regulators of biological processes and have been implicated in age-related diseases. Few studies have explored age-related circRNA expression in the human brain across the adult lifespan. This study aims to identify age-related differentially expressed circRNAs in human post-mortem dorsolateral prefrontal cortex (DLPFC) samples, a region critically involved in cognition that exhibits early signs of age-related changes. Total RNA sequencing was conducted on a discovery cohort of 67 post-mortem DLPFC samples, from individuals with no neurological disease diagnosis at the time of death (35–103 years). CircRNAs were identified using CIRCexplorer2, with 11,907 circRNAs available for analyses. Linear regression was used to analyse the relationships between circRNA expression and age at death. Replication of the results was performed in an independent neurologically healthy dataset from the CommonMind Consortium (n = 321, age at death: 35–91 years). Co-expression network analysis was performed to identify modules of highly co-expressed circRNAs associated with age. Potential microRNA and RNA-binding protein target sites were predicted. In the discovery dataset, 37 circRNAs were age-associated (FDR <0.05). Seven out of the 37 were successfully replicated. The host genes of replicated age-associated circRNAs are implicated in synapse regulation. Co-expression analysis revealed two circRNA modules significantly correlated with age. We identified 484 microRNA and 99 RNA-binding protein target sites on the replicated circRNAs. In conclusion, seven age-associated circRNAs were identified as important candidates for involvement in post-transcriptional regulatory networks in the DLPFC. Future studies should aim to elucidate their functional roles in brain ageing.

环状rna （circRNAs）正在成为生物过程的关键调节因子，并与年龄相关疾病有关。很少有研究探索成年期人脑中与年龄相关的circRNA表达。本研究旨在确定人类死后背外侧前额叶皮层（DLPFC）样本中与年龄相关的差异表达环状rna， DLPFC是一个与认知有关的区域，表现出与年龄相关变化的早期迹象。对67个死后DLPFC样本的发现队列进行了总RNA测序，这些样本来自死亡时（35-103岁）未诊断出神经系统疾病的个体。使用CIRCexplorer2鉴定circrna，有11,907个circrna可用于分析。采用线性回归分析circRNA表达与死亡年龄之间的关系。在来自CommonMind Consortium的独立神经健康数据集中（n = 321，死亡年龄：35-91岁）对结果进行了复制。进行共表达网络分析以鉴定与年龄相关的高度共表达circrna模块。预测潜在的microRNA和rna结合蛋白靶点。在发现数据集中，37个circrna与年龄相关（FDR <0.05）。37个实验中有7个被成功复制。复制年龄相关环状rna的宿主基因参与突触调控。共表达分析显示两个circRNA模块与年龄显著相关。我们在复制的环状rna上鉴定了484个microRNA和99个rna结合蛋白靶点。总之，七个与年龄相关的环状rna被确定为参与DLPFC转录后调控网络的重要候选者。未来的研究应致力于阐明它们在脑老化中的功能作用。

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引用次数: 0

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2026-01-01 Epub Date: 2025-09-20 DOI: 10.1016/j.neurobiolaging.2025.09.008

Dakota Z. Smallridge , Kylee Tenney , Gillian L. Barach , Gurveer Singh , Erin N. Beskitt , Justine Busby , Syllissa Duncan , Alexa Wawrzyniak , Brenda Vega , Nick J. Tokar , Andrew P. Ohl , Jesse W. Young , Jeffrey G. Mellott

The inferior colliculus (IC) is a nucleus in the auditory midbrain that plays an important role in sound and speech processing through how it encodes temporal precision. Temporal precision depends on the balance of inhibition and excitation within the IC. This balance degrades during aging. Age-related changes in synapses have been described in the lemniscal IC as a contributing factor for this imbalance. However, it is unknown if aging affects synapses throughout the non-lemniscal IC in a similar manner. We sought to determine this by examining the dorsal cortex of the IC (ICd). The ICd is a non-lemniscal nucleus that is well known for its extensive innervation by the auditory cortex. Electron microscopy techniques were used across age groups of younger age (2–3 months), middle age (19–21 months) and older age (27–29 months) Fischer Brown Norway rats. Our data demonstrates a small loss of GABAergic synaptic density in middle age, with a significant (34 %) loss during older age. Unlike previous reports of the aging ultrastructure of the IC, asymmetric synaptic density in the ICd remained unchanged. We also demonstrate decreases with age in terminal area and mitochondrial ultrastructure across both synaptic types. Lastly, far fewer asymmetric inputs were observed onto larger GABAergic dendrites. Collectively our data suggest a net loss of inhibition in the ICd. Thus, the balance of excitation and inhibition in the ICd is likely altered and may contribute to factors underlying age-related hearing loss.

下丘（IC）是听觉中脑中的一个核，通过编码时间精度在声音和言语处理中起重要作用。时间精度取决于IC内抑制和激发的平衡。这种平衡随着老化而退化。年龄相关的突触变化已被描述为这种不平衡的一个促成因素。然而，尚不清楚衰老是否以类似的方式影响整个非锁骨IC的突触。我们试图通过检查IC （ICd）的背侧皮质来确定这一点。ICd是一种非锁骨核，因其广泛受听觉皮层的神经支配而闻名。采用电镜技术对年龄较小（2-3个月）、中年（19-21个月）和老年（27-29个月）的Fischer Brown Norway大鼠进行观察。我们的数据显示，gaba能突触密度在中年时有少量的损失，在老年时有显著的损失（34% %）。与以往报道的IC老化超微结构不同，ICd中的不对称突触密度保持不变。我们还发现，两种突触类型的终端区和线粒体超微结构随着年龄的增长而减少。最后，在较大的gaba能树突上观察到的不对称输入要少得多。总的来说，我们的数据表明ICd中抑制作用的净损失。因此，ICd中兴奋和抑制的平衡可能被改变，并可能导致与年龄相关的听力损失。

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