Neurobiology of Aging最新文献_第5页

Corrigendum to “The moderating effect of cognitive reserve on the association between neuroimaging biomarkers and cognition: A systematic review” [Neurobiology of Aging, Volume 156, December 2025, Pages 10–29] “认知储备对神经成像生物标志物和认知之间关联的调节作用：系统综述”的更正[衰老神经生物学，156卷，2025年12月，第10-29页]。

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2025-09-10 DOI: 10.1016/j.neurobiolaging.2025.08.007

Lizhi Guo , Yajing Zhou , Hanna Lu , Helene H. Fung

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 : 2025-09-06 DOI: 10.1016/S0197-4580(25)00158-7

引用次数: 0

Cognitive resilience in preclinical Alzheimer’s disease: Higher NPTX2 and VGF levels are associated with reduced cognitive decline 临床前阿尔茨海默病的认知恢复能力：较高的NPTX2和VGF水平与认知能力下降的减少有关

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2025-09-04 DOI: 10.1016/j.neurobiolaging.2025.09.002

Claire L. Anderson , Alden L. Gross , Corinne Pettigrew , Juan P. Vazquez , Abhay Moghekar , Sungtaek Oh , Chan Hyun Na , Marilyn Albert , Paul Worley , Anja Soldan , the BIOCARD Research Team

Prior work suggests higher levels of the synaptic proteins neuronal pentraxin 2 (NPTX2) and neurosecretory protein VGF (VGF) may confer cognitive resilience to Alzheimer’s disease (AD) pathology. Little is known about how these measures relate to long-term cognitive trajectories among individuals initially cognitively unimpaired. This study examined how rates of cognitive decline (mean follow-up=16 years) among 269 initially cognitively unimpaired individuals from the BIOCARD study (M baseline age=57.7 years, 59 % female) are associated with baseline levels of three synaptic proteins measured in cerebrospinal fluid (CSF), using parallel reaction monitoring mass spectrometry: VGF, NPTX2, and the associated AMPA glutamate receptor subunit 4 (GluA4). Baseline CSF biomarker levels of AD pathology (e.g., Aβ_1–42/Aβ_1–40 and p-tau₁₈₁) were measured using the Fujirebio Lumipulse G1200 assays. Linear mixed effects models evaluated associations between baseline NPTX2, GluA4, and VGF with level and rate of change in global, executive function, and episodic memory cognitive composite scores. Lower baseline Aβ_1–42/Aβ_1–40 and higher p-tau₁₈₁ were associated with greater cognitive decline. When accounting for AD biomarker levels, higher baseline NPTX2 and VGF levels were associated with less decline in the global (both p ≤ 0.002) and episodic memory (both p < 0.03) scores. Higher VGF was associated (p = 0.03) with less executive function decline, with a similar pattern for NPTX2 (p = 0.06). GluA4 was not associated with level or change in cognition (all p > 0.08). These results support the hypothesis that higher levels of NPTX2 and VGF may be associated with cognitive resilience to AD pathology and be potential therapeutic targets for reducing cognitive decline.

先前的研究表明，较高水平的突触蛋白神经元戊烷素2 （NPTX2）和神经分泌蛋白VGF （VGF）可能赋予阿尔茨海默病（AD）病理的认知弹性。对于这些测量与最初认知未受损个体的长期认知轨迹之间的关系，我们知之甚少。本研究检测了来自BIOCARD研究的269名最初认知功能未受损个体（M基线年龄=57.7岁，59% %为女性）的认知衰退率（平均随访=16年）与脑脊液（CSF）中测量的三种突触蛋白基线水平的关系，使用平行反应监测质谱法：VGF， NPTX2和相关的AMPA谷氨酸受体亚基4 （GluA4）。使用Fujirebio Lumipulse G1200测定AD病理的基线CSF生物标志物水平（例如a - β1 - 42/ a - β1 - 40和p-tau181）。线性混合效应模型评估基线NPTX2、GluA4和VGF与整体、执行功能和情景记忆认知综合评分水平和变化率之间的关系。较低的基线Aβ1-42 / Aβ1-40和较高的p-tau181与认知能力下降有关。当考虑到AD生物标志物水平时，较高的基线NPTX2和VGF水平与总体评分（p ≤ 0.002）和情景记忆评分（p <； 0.03）下降较少相关。较高的VGF与较少的执行功能下降相关（p = 0.03），与NPTX2相似（p = 0.06）。GluA4与认知水平或改变无关（p均为 >； 0.08）。这些结果支持了较高水平的NPTX2和VGF可能与AD病理的认知恢复能力相关的假设，并且是减少认知能力下降的潜在治疗靶点。

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A synthetic nonapeptide, JAL-TA9, inhibits neuronal cytotoxicity caused by Aβ25–35 aggregation with proteolytic activity 合成的非肽JAL-TA9具有蛋白水解活性，可抑制Aβ25 - 35聚集引起的神经元细胞毒性

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2025-09-03 DOI: 10.1016/j.neurobiolaging.2025.09.001

Rina Nakamura , Momoka Okada , Asuka Takahashi , Yoshihiro Hayashi , Motomi Konishi , Fumiaki Ito , Ichiro Murakami , Motoaki Saito , Toshifumi Akizawa

Due to the growing number of Alzheimer’s disease (AD) patients, new drugs are urgently required. A synthetic nonapeptide, JAL-TA9 (YKGSGFRMI), derived from Transducer of ErbB-2.1 (Tob1) protein, cleaves amyloid β (Aβ) 42 with serine protease-like activity. Aβ25–35 was chosen because it is the shortest fragment that forms fibrils and is cytotoxic. Aβ25–35 has been used to create AD model mice, and it appears to be an attractive target for AD therapeutics. Using Thioflavin-T assays, the fluorescence intensity of the reaction of Aβ25–35 and JAL-TA9 was lower than that of Aβ25–35 without JAL-TA9, and the same result was obtained with aggregated Aβ25–35. These data showed that JAL-TA9 inhibits aggregation of Aβ25–35 and dissolves its aggregates. Furthermore, electron microscopy showed that amyloid fibrils of both Aβ25–35 and aggregated Aβ25–35 are reduced in the presence of JAL-TA9. The proteolytic activity of JAL-TA9 against Aβ25–35 was evaluated using HPLC and mass spectrometry. These data showed that JAL-TA9 cleaves both soluble and aggregated forms of Aβ25–35. JAL-TA9 inhibits neuronal cytotoxicity caused by Aβ25–35 aggregation by cleaving Aβ25–35 and its aggregated form. These results suggest that JAL-TA9 is a promising candidate for developing novel drugs against AD.

由于阿尔茨海默病（AD）患者数量的不断增加，迫切需要新药。合成的非肽JAL-TA9 （YKGSGFRMI）来源于ErbB-2.1 （Tob1）蛋白的换能器，具有丝氨酸蛋白酶样活性，可切割淀粉样蛋白β (Aβ) 42。选择Aβ25-35是因为它是形成原纤维的最短片段，并且具有细胞毒性。a - β25 - 35已被用于创建AD模型小鼠，它似乎是AD治疗的一个有吸引力的靶点。通过硫黄素- t实验，a - β25 - 35与JAL-TA9反应的荧光强度低于不含JAL-TA9的a - β25 - 35，与聚集的a - β25 - 35反应的荧光强度相同。这些数据表明，JAL-TA9抑制a - β25 - 35的聚集并溶解其聚集物。此外，电镜显示，在JAL-TA9存在下，a - β25 - 35和聚集的a - β25 - 35的淀粉样蛋白原纤维都减少。采用HPLC和质谱法评价JAL-TA9对a - β25 - 35的蛋白水解活性。这些数据表明，JAL-TA9可以切割a - β25 - 35的可溶性和聚集形式。JAL-TA9通过切割Aβ25-35及其聚集形态，抑制Aβ25-35聚集引起的神经元细胞毒性。这些结果表明，JAL-TA9是开发抗阿尔茨海默病新药的一个有希望的候选者。

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引用次数: 0

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2025-09-03 DOI: 10.1016/j.neurobiolaging.2025.08.008

Emilio J. Galván , Ernesto Griego

The physiological decline associated with aging is often accompanied by a progressive deterioration in cognitive processing abilities driven by a series of cellular dysfunctions that remain poorly understood. In the hippocampus, a critical area for learning and memory, aging affects the functional expression of ionotropic and metabotropic receptors, including the metabotropic glutamate receptors (mGluRs). mGluRs play a critical role in multiple cellular functions, including modulation of ion channels and intrinsic excitability, synaptic transmission, and induction of synaptic plasticity, processes considered part of the cellular substrates for learning and memory. This study used patch-clamp recordings and pharmacological tools in acute hippocampal slices to uncover the aging-related disruption in the mGluR-dependent modulation of area CA3 pyramidal neurons. Pharmacological stimulation of group I mGluRs triggers rhythmic firing discharge in CA3 pyramidal neurons of young rats (5 ± 1 weeks of age) and a reduction in the afterhyperpolarization. By contrast, in older adult rats (20–24 months of age), stimulation of group I mGluRs causes a switch from afterhyperpolarization to an afterdepolarization plateau that eases a persistent but non-rhythmic firing discharge. In young animals, postsynaptic activation of group II mGluRs enhances the intrinsic excitability of CA3 pyramidal neurons, and an exacerbated response is observed in older adult rats. By contrast, in older adult animals, the presynaptic inhibition of glutamate release by pharmacological stimulation of group II mGluRs from mossy fibers was significantly reduced. These findings support the notion of older adult-related changes in the functional expression of mGluRs within the hippocampal area CA3 that may contribute to the cognitive alterations commonly associated with aging.

与衰老相关的生理衰退通常伴随着认知处理能力的进行性恶化，这是由一系列细胞功能障碍引起的，但我们对这些功能障碍知之甚少。海马是学习和记忆的关键区域，衰老会影响电离性和代谢性受体的功能表达，包括代谢性谷氨酸受体（mGluRs）。mGluRs在多种细胞功能中发挥关键作用，包括离子通道和内在兴奋性的调节、突触传递和突触可塑性的诱导，这些过程被认为是学习和记忆的细胞基质的一部分。本研究使用膜片钳记录和药理学工具在急性海马切片中揭示了mglur依赖的CA3区锥体神经元调节的衰老相关破坏。1组mGluRs的药物刺激可触发幼龄大鼠（5 ± 1周龄）CA3锥体神经元的节律放电，并减少后超极化。相比之下，在年龄较大的成年大鼠（20-24个月大）中，刺激I组mGluRs会导致从后超极化到后去极化平台的转换，从而缓解持续但无节奏的放电。在幼龄动物中，II组mGluRs的突触后激活增强了CA3锥体神经元的固有兴奋性，并且在老年成年大鼠中观察到这种反应加剧。相比之下，在老年成年动物中，苔藓纤维药理刺激II组mGluRs对谷氨酸释放的突触前抑制显著降低。这些发现支持了老年海马区CA3内mGluRs功能表达变化可能导致与衰老相关的认知改变的观点。

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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 : 2025-08-31 DOI: 10.1016/S0197-4580(25)00147-2

引用次数: 0

Relationship between inner hair cell synaptopathy and outer hair cell loss in two mouse models of accelerated age-related hearing loss 两种老年性加速听力损失小鼠模型中内毛细胞突触病变与外毛细胞损失的关系

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2025-08-26 DOI: 10.1016/j.neurobiolaging.2025.08.006

Tuuli Lankinen, Saija Leinonen, Kuu Ikäheimo , Ulla Pirvola

Hallmarks of sensorineural hearing loss are elevated hearing thresholds and defects in temporal auditory processing, the former being often caused by outer hair cell (OHC) damage, and the latter by the loss of synapses between inner hair cells (IHCs) and spiral ganglion neurons. In the well-studied CBA/CaJ mouse strain, these impairments are disconnected, IHC synaptopathy preceding OHC loss. We have investigated the relationship between IHC synaptopathy and OHC loss in the C57BL/6J (B6) and ICR mouse strains that model accelerated age-related hearing loss. Regression analysis revealed a strong correlation between these variables across the high-to-low frequency axis of the cochlea. Using the fluorescent dye FM1–43 as a proxy for mechanotransduction (MET) in the hair-cell stereocilia bundle, we found that MET malfunction coexisted with synaptopathy in IHCs. Thus, our results suggest that a MET defect drives IHC synaptopathy in the B6 and ICR strains known to carry a missense mutation of Cadherin 23, encoding a stereocilia bundle protein. Previous data have suggested that OHC stereocilia abnormalities could trigger OHC death. Therefore, stereocilia defect could be a trigger of intracellular stress that drives both IHC synaptopathy and OHC loss. To determine whether tauroursodeoxycholic acid (TUDCA), known to target several stress signalling pathways, could influence cochlear pathology, we conducted long-term TUDCA delivery to ICR mice. TUDCA provided partial protection against IHC synaptopathy but did not prevent OHC loss. These results in two mouse models of accelerated cochlear pathology provide novel insights into the mechanisms behind age-related hearing loss.

感音神经性听力损失的特征是听力阈值升高和时间听觉处理缺陷，前者通常是由外毛细胞（OHC）损伤引起的，后者是由内毛细胞（ihc）和螺旋神经节神经元之间的突触丧失引起的。在充分研究的CBA/CaJ小鼠品系中，这些损伤是断开的，IHC突触病先于OHC损失。我们在C57BL/6J （B6）和ICR小鼠品系中研究了IHC突触病与OHC损失之间的关系，这些品系模拟了加速年龄相关性听力损失。回归分析显示，这些变量在耳蜗的高频到低频轴上有很强的相关性。使用荧光染料FM1-43作为毛细胞立体纤毛束机械转导（MET）的代理，我们发现在ihc中MET功能障碍与突触病变共存。因此，我们的研究结果表明，MET缺陷驱动了B6和ICR菌株的IHC突触病，这些菌株已知携带编码立纤毛束蛋白的钙粘蛋白23错义突变。先前的数据表明，OHC偏纤毛异常可引发OHC死亡。因此，纤毛立体缺陷可能是细胞内应激的触发因素，从而驱动IHC突触病和OHC损失。为了确定牛磺酸去氧胆酸（TUDCA）是否会影响耳蜗病理，我们对ICR小鼠进行了长期的TUDCA给药。TUDCA对IHC突触病变提供部分保护，但不能防止OHC损失。在两种加速耳蜗病理的小鼠模型中，这些结果为年龄相关性听力损失背后的机制提供了新的见解。

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引用次数: 0

In vivo growth trajectories of regional brain volumes in the Wistar rat Wistar大鼠局部脑容量的体内生长轨迹

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2025-08-26 DOI: 10.1016/j.neurobiolaging.2025.08.005

Qingyu Zhao , Natalie M. Zahr

Normative, longitudinal data are necessary for effective modeling of factors underlying disease processes on the brain. Large scale national and international consortium data have characterized human regional brain volume trajectories as complex and prolonged gray and white matter maturation through the third decade of life followed by progressive senescence of cortical and then subcortical gray matter. By middle age (>40 years), white matter volume is also in decline. Although rodents are the mainstay of experimental gerontology, the few studies on brain volume trajectories are based on small samples. Here, 16 longitudinal neuroimaging experiments in Wistar rats were merged to describe regional brain volume growth from peripuberty (32 days, human equivalent ∼12 years) to late middle age (18.8 months, human equivalent ∼60 years). As female relative to male rodents are significantly smaller in weight, brain growth was expected to scale to smaller female size. In a total sample of 1009 male and female wildtype Wistar rats and male, alcohol-preferring P rats derived from the Wistar strain, regional brain volumes peaked at different ages: the cortex, for example, reached a vertex at 6.4 months, and the ventral hippocampus at 13.6 months, but thalamus had yet to plateau at 18.8 months. Age at which regional volumes peaked was differentially modulated by strain and sex. These data provide empirical evidence to recommend that preclinical experiments consider distinct patterns of regional brain volume growth and that studies on senescence, at least in Wistar rats, focus on animals older than 18 months.

规范的，纵向的数据是必要的有效建模的因素，潜在的疾病过程的大脑。大规模的国家和国际联盟数据表明，人类区域脑容量轨迹是复杂而漫长的灰质和白质成熟，贯穿生命的第三个十年，随后是皮层和皮层下灰质的渐进性衰老。到了中年（40岁），白质体积也在下降。虽然啮齿类动物是实验老年学的支柱，但少数关于脑容量轨迹的研究是基于小样本的。在这里，合并了16个Wistar大鼠的纵向神经成像实验，以描述从青春期（32天，相当于人类~ 12年）到中年晚期（18.8个月，相当于人类~ 60年）的区域脑容量增长。由于雌性啮齿类动物相对于雄性啮齿类动物的体重要小得多，因此预计雌性的大脑发育会更小。在1009只雄性和雌性野生型Wistar大鼠以及来自Wistar品系的雄性偏好酒精的P大鼠的样本中，区域脑容量在不同的年龄达到峰值：例如，皮层在6.4个月时达到顶点，而腹侧海马在13.6个月时达到顶点，但丘脑在18.8个月时尚未达到平稳。区域体积达到峰值的年龄因菌株和性别而有差异调节。这些数据提供的经验证据表明，临床前实验考虑了不同的区域脑容量增长模式，而衰老研究，至少在Wistar大鼠中，主要集中在18个月以上的动物身上。

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引用次数: 0

Degeneration of the stria vascularis in quiet-aged gerbils: Linking structural, cellular and molecular changes to cochlear function 静龄沙鼠血管纹退化：结构、细胞和分子变化与耳蜗功能的联系

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2025-08-14 DOI: 10.1016/j.neurobiolaging.2025.08.004

Sonny Bovee , Carolin Jüchter , Georg M. Klump , Christine Köppl , Sonja J. Pyott

Presbycusis, or age-related hearing loss, is a prevalent condition characterized by progressive auditory decline, significantly impacting quality of life in older adults. While sensorineural damage has been widely studied, degeneration of the stria vascularis (SV) remains underexplored despite its essential role in cochlear ion homeostasis. The SV is organized into three cellular layers—marginal, intermediate, and basal cells—each with distinct functions critical for maintaining the endocochlear potential. Using the quiet-aged Mongolian gerbil—a well-established model of metabolic presbycusis—we systematically mapped the structural and cellular degeneration of the SV and linked these changes to cochlear function. We assessed cochlear function using auditory brainstem response (ABR) measurements and quantified age-related atrophy of the strial cell layers using immunofluorescence, confocal microscopy, and 3D reconstruction. We identified a striking, region-specific pattern of degeneration, with the greatest atrophy occurring in ATP1A1-expressing marginal cells, followed by KCNJ10-expressing intermediate cells, and comparatively little atrophy in CLDN11-expressing basal cells. Notably, atrophy was most pronounced in the cochlear apex and base, regions critical for low- and high-frequency hearing. We further established a significant correlation between the decline in cochlear function and the extent of atrophy of the individual strial cell layers, especially in the cochlear base. By moving beyond traditional cross-sectional assessments of age-related degeneration of the SV, this work provides a more nuanced understanding of how strial pathology contributes to age-related decline in cochlear function and may inform therapeutic interventions targeting strial function to mitigate age-related hearing loss even when sensorineural function is compromised.

老年性耳聋，或与年龄相关的听力损失，是一种以进行性听力下降为特征的普遍疾病，严重影响老年人的生活质量。虽然感觉神经损伤已被广泛研究，但血管纹变性（SV）在耳蜗离子稳态中起着重要作用，但仍未得到充分研究。SV由三层细胞组成：边缘细胞、中间细胞和基底细胞，每层细胞在维持耳蜗电位方面都具有不同的功能。利用蒙古沙鼠（一种成熟的代谢性老年病模型），我们系统地绘制了SV的结构和细胞变性，并将这些变化与耳蜗功能联系起来。我们使用听觉脑干反应（ABR）测量来评估耳蜗功能，并使用免疫荧光、共聚焦显微镜和3D重建来量化审状细胞层的年龄相关萎缩。我们发现了一种显著的区域特异性退化模式，表达atp1a1的边缘细胞萎缩最严重，其次是表达kcnj10的中间细胞，而表达cldn11的基底细胞萎缩相对较小。值得注意的是，萎缩在耳蜗尖端和基部最为明显，这两个区域对低频和高频听力至关重要。我们进一步证实了耳蜗功能的下降与单个审状细胞层，特别是耳蜗基底的萎缩程度之间的显著相关性。通过超越传统的与年龄相关的SV变性的横断面评估，这项工作提供了更细致入微的理解试验病理如何导致与年龄相关的耳蜗功能下降，并可能为针对试验功能的治疗干预提供信息，以减轻与年龄相关的听力损失，即使在感觉神经功能受损的情况下。

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引用次数: 0

Choroid plexus volume and its association with cognitive performance across the lifespan: Links to sleep quality and healthy brain aging 脉络膜丛体积及其与一生中认知表现的关系：与睡眠质量和健康的大脑老化有关

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2025-08-13 DOI: 10.1016/j.neurobiolaging.2025.08.003

Julia L. Becker , M. Ethan MacDonald , Kirstan A. Vessey , Rebecca J. Williams

The choroid plexus (ChP) is implicated in inflammation and supports the clearance of waste byproducts, particularly those related to the pathogenesis of Alzheimer’s disease. Increases in ChP volume have been associated with older age and cognitive decline in both clinical and healthy cohorts. However, the clearance of waste products in the brain is also related to sleep, and sleep quality may contribute to ChP dysfunction and cognitive decline. In the present work, it was therefore hypothesized that the association between age and cognitive performance is mediated by ChP volume, however this is conditional on sleep quality. A moderated-mediation model was tested on a sample (N = 590) of healthy adults aged 18–87 years from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN). Results showed that the relationship between increasing age and decreased cognitive performance was partially mediated by ChP volume, however, this was not conditional on sleep quality. A moderation analysis indicated that the relationship between ChP volume and cognitive performance was moderated by age, with ChP enlargement associated with worse cognitive performance in participants older than 62 years. In participants younger than 62 years, sleep duration was associated with cognitive performance, but ChP volume was not. These findings provide support for the sensitivity of ChP volume to cognitive performance in older adults.

脉络膜丛（ChP）与炎症有关，并支持废物副产物的清除，特别是与阿尔茨海默病的发病机制有关的废物副产物。在临床和健康人群中，ChP体积的增加与年龄增大和认知能力下降有关。然而，大脑中废物的清除也与睡眠有关，睡眠质量可能导致ChP功能障碍和认知能力下降。因此，在目前的工作中，假设年龄和认知表现之间的关联是由ChP量介导的，然而这是有条件的睡眠质量。在剑桥老龄化与神经科学中心（Cam-CAN）的18-87岁健康成人样本（N = 590）上测试了一个有调节的中介模型。结果表明，年龄增长和认知能力下降之间的关系部分由ChP量介导，但这与睡眠质量无关。一项调节分析表明，ChP体积与认知表现之间的关系受年龄的调节，在62岁以上的参与者中，ChP增大与认知表现较差相关。在年龄小于62岁的参与者中，睡眠时间与认知能力有关，但ChP量与认知能力无关。这些发现为老年人ChP容量对认知能力的敏感性提供了支持。

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引用次数: 0