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Longitudinal relationships between Aβ and tau to executive function and memory in cognitively normal older adults 认知正常老年人的 Aβ 和 tau 与执行功能和记忆的纵向关系
IF 3.7 3区 医学 Q2 GERIATRICS & GERONTOLOGY Pub Date : 2024-10-19 DOI: 10.1016/j.neurobiolaging.2024.10.004
Xi Chen , Alexis Juarez , Suzanne Mason , Sarah Kobayashi , Suzanne L. Baker , Theresa M. Harrison , Susan M. Landau , William J. Jagust
The early accumulation of AD pathology such as Aβ and tau in cognitively normal older people is predictive of cognitive decline, but it has been difficult to dissociate the cognitive effects of these two proteins. Early Aβ and tau target distinct brain regions that have different functional roles. Here, we assessed specific longitudinal pathology-cognition associations in seventy-six cognitively normal older adults from the Berkeley Aging Cohort Study who underwent longitudinal PiB PET, FTP PET, and cognitive assessments. Using linear mixed-effects models to estimate longitudinal changes and residual approach to characterizing cognitive domain-specific associations, we found that Aβ accumulation, especially in frontal/parietal regions, was associated with faster decline in executive function, not memory, whereas tau accumulation, especially in left entorhinal/parahippocampal regions, was associated with faster decline in memory, not executive function, supporting an “Aβ-executive function, tau-memory” double-dissociation in cognitively normal older people. These specific relationships between accumulating pathology and domain-specific cognitive decline may be due to the particular vulnerabilities of the frontal-parietal executive network to Aβ and temporal memory network to tau.
在认知能力正常的老年人中,Aβ和tau等AD病理蛋白的早期积累可预测认知能力的下降,但这两种蛋白对认知能力的影响一直难以区分。早期的Aβ和tau针对不同的大脑区域,具有不同的功能作用。在此,我们对伯克利老龄队列研究(Berkeley Aging Cohort Study)中76名认知正常的老年人进行了纵向PiB PET、FTP PET和认知评估,评估了特定的纵向病理-认知关联。我们使用线性混合效应模型来估计纵向变化,并使用残差法来描述认知领域的特异性关联,结果发现,Aβ的积累(尤其是在额叶/顶叶区域)与执行功能(而非记忆)的快速衰退有关,而tau的积累(尤其是在左侧内侧/副海马区域)与记忆(而非执行功能)的快速衰退有关,这支持了认知正常老年人的 "Aβ-执行功能,tau-记忆 "双重关联。病理累积与特定领域认知能力下降之间的这些特殊关系可能是由于额叶-顶叶执行网络对Aβ和颞叶记忆网络对tau的特殊脆弱性。
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引用次数: 0
Editorial Advisory Board 编辑顾问委员会
IF 3.7 3区 医学 Q2 GERIATRICS & GERONTOLOGY Pub Date : 2024-10-18 DOI: 10.1016/S0197-4580(24)00176-3
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引用次数: 0
Hearing loss and its relation to longitudinal changes in white matter microstructure in older adults: The Rotterdam Study 听力损失及其与老年人白质微结构纵向变化的关系:鹿特丹研究
IF 3.7 3区 医学 Q2 GERIATRICS & GERONTOLOGY Pub Date : 2024-10-18 DOI: 10.1016/j.neurobiolaging.2024.10.003
Jordi H.C. Boons , Elisabeth J. Vinke , Gertjan Dingemanse , Bernd Kremer , André Goedegebure , Meike W. Vernooij
Hearing loss is considered a potentially modifiable risk factor for dementia. The sensory deprivation theory postulates that hearing loss adversely affects cognition in older adults through structural brain changes, but longitudinal studies are scarce. To find evidence for a possible detrimental effect of hearing loss on white matter microstructure, we carried out a longitudinal study in the population-based Rotterdam Study. A total of 1877 participants with a median age at baseline of 56.4 years (IQR: [52.2–60.0]) underwent audiometry and had longitudinal diffusion imaging data available with a mean follow-up of 4.0 years. A lower level of hearing acuity was associated with worse white matter microstructure in the left uncinate fasciculus and superior longitudinal fasciculus at baseline. Poorer hearing acuity was also associated with faster microstructural deterioration over time in the left superior longitudinal fasciculus. The strongest effects were observed for low-frequency hearing thresholds, while the high-frequency thresholds showed the weakest associations. These results suggest that hearing loss may contribute to the age-related decline in brain structure, consistent with the sensory deprivation theory.
听力损失被认为是痴呆症的潜在风险因素。感觉剥夺理论推测,听力损失会通过大脑结构变化对老年人的认知能力产生不利影响,但纵向研究却很少。为了寻找听力损失可能对白质微结构产生不利影响的证据,我们在基于人群的鹿特丹研究中开展了一项纵向研究。共有 1877 名基线年龄中位数为 56.4 岁(IQR:[52.2-60.0])的参与者接受了听力测定,并获得了纵向扩散成像数据,平均随访时间为 4.0 年。听力敏锐度较低与基线时左侧钩状筋膜和上纵筋膜的白质微结构较差有关。随着时间的推移,听力敏锐度越低,左上纵筋膜的微结构退化越快。低频听阈的影响最强,而高频听阈的影响最弱。这些结果表明,听力损失可能会导致与年龄相关的大脑结构衰退,这与感觉剥夺理论是一致的。
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引用次数: 0
Alcohol consumption confers lasting impacts on prefrontal cortical neuron intrinsic excitability and spontaneous neurotransmitter signaling in the aging brain in mice 饮酒对小鼠衰老大脑前额叶皮质神经元固有兴奋性和自发神经递质信号转导产生持久影响。
IF 3.7 3区 医学 Q2 GERIATRICS & GERONTOLOGY Pub Date : 2024-10-15 DOI: 10.1016/j.neurobiolaging.2024.09.014
Grace C. Smith , Keith R. Griffith , Avery R. Sicher , Dakota F. Brockway , Elizabeth A. Proctor , Nicole A. Crowley
Both alcohol use disorder (AUD) and cognitive decline include disruption in the balance of excitation and inhibition in the cortex, but the potential role of alcohol use on excitation and inhibition on the aging brain is unclear. We examined the effect of moderate voluntary binge alcohol consumption on the aged, pre-disease neuronal environment by measuring intrinsic excitability and spontaneous neurotransmission on prefrontal cortical pyramidal (excitatory, glutamatergic) and non-pyramidal (inhibitory, GABAergic) neurons following a prolonged period of abstinence from alcohol in mice. Results highlight that binge alcohol consumption has lasting impacts on the electrophysiological properties of prefrontal cortical neurons. A profound increase in excitatory events onto layer 2/3 non-pyramidal neurons following alcohol consumption was seen, along with altered intrinsic excitability of pyramidal neurons, which could have a range of effects on cognitive disorder progression, such as Alzheimer’s Disease, in humans. These results indicate that moderate voluntary alcohol influences the pre-disease environment in aging and highlight the need for further mechanistic investigation into this risk factor.
酒精使用障碍(AUD)和认知能力下降都包括大脑皮层兴奋和抑制平衡的破坏,但酒精使用对老化大脑兴奋和抑制的潜在作用尚不清楚。我们通过测量小鼠长期戒酒后前额叶皮层锥体(兴奋性,谷氨酸能)和非锥体(抑制性,GABA能)神经元的内在兴奋性和自发神经传递,研究了中度自愿暴饮对老化、病前神经元环境的影响。研究结果表明,酗酒会对前额叶皮质神经元的电生理特性产生持久影响。饮酒后,第 2/3 层非锥体神经元的兴奋事件显著增加,锥体神经元的固有兴奋性也发生了改变,这可能会对人类认知障碍(如阿尔茨海默病)的发展产生一系列影响。这些结果表明,适度自愿饮酒会影响衰老过程中的病前环境,并强调了对这一风险因素进行进一步机理研究的必要性。
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引用次数: 0
Increased inflammation in older high-pressure glaucoma mice 老年高压青光眼小鼠炎症加剧
IF 3.7 3区 医学 Q2 GERIATRICS & GERONTOLOGY Pub Date : 2024-10-09 DOI: 10.1016/j.neurobiolaging.2024.10.001
Sabrina Reinehr , M. Rahim Pamuk , Rudolf Fuchshofer , H. Burkhard Dick , Stephanie C. Joachim
Besides an elevated intraocular pressure (IOP), advanced age is one of the most crucial risk factors for developing glaucoma. βB1-Connective Tissue Growth Factor (βB1-CTGF) high-pressure glaucoma mice were used in this study to assess whether glaucoma mice display more inflammatory and aging processes than age-matched controls. Therefore, 20-month-old βB1-CTGF and corresponding wildtype (WT) controls were examined. After IOP measurements, retinas were processed for (immuno-)histological and quantitative real-time PCR analyses. A significantly higher IOP and diminished retinal ganglion cell numbers were noted in βB1-CTGF mice compared to WT. An enhanced macrogliosis as well as an increased number of microglia/macrophages and microglia was detected in retinas of old glaucoma mice. Interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and transforming growth factor-β2 were upregulated, suggesting an ongoing inflammation. Moreover, βB1-CTGF retinas displayed an increased senescence-associated β-galactosidase staining accompanied by a downregulation of Lmnb1 (laminin-B1) mRNA levels. Our results provide a deeper insight into the association between inflammation and high-pressure glaucoma and thus might help to develop new therapy strategies.
除了眼内压(IOP)升高外,高龄也是罹患青光眼的最关键风险因素之一。本研究利用βB1-结缔组织生长因子(βB1-CTGF)高压青光眼小鼠来评估青光眼小鼠是否比年龄匹配的对照组表现出更多的炎症和衰老过程。因此,研究人员对 20 个月大的βB1-CTGF 小鼠和相应的野生型(WT)对照组进行了检查。测量眼压后,对视网膜进行(免疫)组织学和实时定量 PCR 分析。与 WT 相比,βB1-CTGF 小鼠的眼压明显升高,视网膜神经节细胞数量减少。在老年性青光眼小鼠的视网膜中,检测到大胶质细胞增多以及小胶质细胞/巨噬细胞和小胶质细胞数量增加。白细胞介素(IL)-1β、IL-6、肿瘤坏死因子-α和转化生长因子-β2上调,表明炎症正在持续。此外,βB1-CTGF 视网膜显示衰老相关的 β-半乳糖苷酶染色增加,同时 Lmnb1(层粘连蛋白-B1)mRNA 水平下调。我们的研究结果让我们更深入地了解了炎症与高压性青光眼之间的关联,从而可能有助于开发新的治疗策略。
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引用次数: 0
The histone acylation reader ENL/AF9 regulates aging in Drosophila melanogaster 组蛋白酰化阅读器ENL/AF9调控黑腹果蝇的衰老
IF 3.7 3区 医学 Q2 GERIATRICS & GERONTOLOGY Pub Date : 2024-10-09 DOI: 10.1016/j.neurobiolaging.2024.10.002
Ranchana Yeewa , Sureena Pohsa , Titaree Yamsri , Wasinee Wongkummool , Phatcharida Jantaree , Saranyapin Potikanond , Wutigri Nimlamool , Vorasuk Shotelersuk , Luca Lo Piccolo , Salinee Jantrapirom
Histone acylation plays a pivotal role in modulating gene expression, ensuring proper neurogenesis and responsiveness to various signals. Recently, the evolutionary conserved YAF9, ENL, AF9, TAF41, SAS5 (YEATS) domain found in four human paralogs, has emerged as a new class of histone acylation reader with a preference for the bulkier crotonyl group lysine over acetylation. Despite advancements, the role of either histone crotonylation or its readers in neurons remains unclear. In this study, we employed Drosophila melanogaster to investigate the role of ENL/AF9 (dENL/AF9) in the nervous system. Pan-neuronal dENL/AF9 knockdown not only extended the lifespan of flies but also enhanced their overall fitness during aging, including improved sleep quality and locomotion. Moreover, a decreased activity of dENL/AF9 in neurons led to an up-regulation of catalase gene expression which combined with reduced levels of malondialdehyde (MDA) and an enhanced tolerance to oxidative stress in aging flies. This study unveiled a novel function of histone crotonylation readers in aging with potential implications for understanding age-related conditions in humans.
组蛋白酰化在调节基因表达、确保适当的神经发生和对各种信号的响应方面起着关键作用。最近,进化保守的 YAF9、ENL、AF9、TAF41、SAS5(YEATS)结构域在四个人类旁系亲属中被发现,成为一类新的组蛋白酰化阅读器,它偏爱体积较大的巴豆酰基赖氨酸而非乙酰化。尽管取得了进展,但组蛋白巴豆酰化或其阅读器在神经元中的作用仍不清楚。在这项研究中,我们利用黑腹果蝇研究了ENL/AF9(dENL/AF9)在神经系统中的作用。泛神经元dENL/AF9敲除不仅延长了果蝇的寿命,还提高了它们在衰老过程中的整体适应能力,包括改善睡眠质量和运动能力。此外,神经元中dENL/AF9活性的降低导致过氧化氢酶基因表达的上调,这与丙二醛(MDA)水平的降低以及衰老苍蝇对氧化应激的耐受性增强相结合。这项研究揭示了组蛋白巴豆酰化阅读器在衰老过程中的新功能,对理解人类与衰老相关的疾病具有潜在的意义。
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引用次数: 0
Midlife dynamics of white matter architecture in lexical production 词汇生成中白质结构的中年动态变化
IF 3.7 3区 医学 Q2 GERIATRICS & GERONTOLOGY Pub Date : 2024-09-28 DOI: 10.1016/j.neurobiolaging.2024.09.013
Clément Guichet , Élise Roger , Arnaud Attyé , Sophie Achard , Martial Mermillod , Monica Baciu
We aimed to examine the white matter changes associated with lexical production difficulties, beginning in midlife with increased naming latencies. To delay lexical production decline, middle-aged adults may rely on domain-general and language-specific compensatory mechanisms proposed by the LARA model (Lexical Access and Retrieval in Aging). However, the white matter changes supporting these mechanisms remains largely unknown. Using data from the CAMCAN cohort, we employed an unsupervised and data-driven methodology to examine the relationships between diffusion-weighted imaging and lexical production. Our findings indicate that midlife is marked by alterations in brain structure within distributed dorsal, ventral, and anterior cortico-subcortical networks, marking the onset of lexical production decline around ages 53–54. Middle-aged adults may initially adopt a “semantic strategy” to compensate for lexical production challenges, but this strategy seems compromised later (ages 55–60) as semantic control declines. These insights underscore the interplay between domain-general and language-specific processes in the trajectory of lexical production performance in healthy aging and hint at potential biomarkers for language-related neurodegenerative pathologies.
我们的目的是研究从中年开始随着命名潜伏期的延长而出现的与词汇生成困难相关的白质变化。为了延缓词汇生成能力的衰退,中年人可能会依赖 LARA 模型(老龄词汇存取和检索)提出的领域通用和语言特异性补偿机制。然而,支持这些机制的白质变化在很大程度上仍不为人所知。利用 CAMCAN 队列的数据,我们采用了一种无监督和数据驱动的方法来研究扩散加权成像与词汇生成之间的关系。我们的研究结果表明,中年时期分布在背侧、腹侧和前部皮质-皮质下网络中的大脑结构发生了变化,这标志着词汇生成能力在 53-54 岁左右开始下降。中年人最初可能会采用 "语义策略 "来弥补词汇生成方面的挑战,但随着语义控制能力的下降,这种策略似乎会在后期(55-60 岁)受到影响。这些见解强调了在健康老龄化过程中词汇生成能力的轨迹中领域一般过程和语言特异过程之间的相互作用,并暗示了与语言相关的神经退行性病变的潜在生物标记物。
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引用次数: 0
Corrigendum to: A clinical, molecular genetics and pathological study of a FTDP-17 family with a heterozygous splicing variant c.823-10 G>T at the intron 9/exon 10 of the MAPT gene. 更正:一个患有 MAPT 基因内含子 9/ 外显子 10 的杂合剪接变异 c.823-10 G>T 的 FTDP-17 家族的临床、分子遗传学和病理学研究。
IF 3.7 3区 医学 Q2 GERIATRICS & GERONTOLOGY Pub Date : 2024-09-23 DOI: 10.1016/j.neurobiolaging.2024.09.011
Diana A Olszewska, Conor Fearon, Christopher McGuigan, Terri P McVeigh, Henry Houlden, James M Polke, Brian Lawlor, Robert Coen, Michael Hutchinson, Michael Hutton, Alan Beausang, Isabelle Delon, Francesca Brett, Ioanna Sevastou, Nuria Seto-Salvia, Rohan de Silva, Tim Lynch
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引用次数: 0
Modeling the progression of neuropsychiatric symptoms in Alzheimer’s disease with PET-based Braak staging 利用基于 PET 的布拉克分期模拟阿尔茨海默病神经精神症状的发展过程
IF 3.7 3区 医学 Q2 GERIATRICS & GERONTOLOGY Pub Date : 2024-09-20 DOI: 10.1016/j.neurobiolaging.2024.09.009
Arthur C. Macedo , Joseph Therriault , Cécile Tissot , Étienne Aumont , Stijn Servaes , Nesrine Rahmouni , Jaime Fernandez-Arias , Firoza Z. Lussier , Yi-Ting Wang , Kok Pin Ng , Marie Vermeiren , Gleb Bezgin , Kely Quispialaya Socualaya , Jenna Stevenson , Seyyed Ali Hosseini , Mira Chamoun , João Pedro Ferrari-Souza , Pâmela C.L. Ferreira , Bruna Bellaver , Douglas Teixeira Leffa , Pedro Rosa-Neto
In Alzheimer’s disease (AD), neuropsychiatric symptoms (NPS) correlate with tau deposition in the brain. Here, we investigated the association of PET-based Braak stages with NPS and assessed whether they predict annual changes in NPS. We evaluated 231 individuals in the aging and AD continuum. Participants were assigned a Braak stage at baseline and followed for 1.97 (s.d. 0.62) years. NPS were investigated using the Mild Behavioral Impairment Checklist (MBI-C) and the Neuropsychiatric Inventory Questionnaire severity (NPI-Q-S) and distress (NPI-Q-D) scales. Multiple linear regressions (MLR) assessed the association of Braak stages with baseline NPS and the annual change in NPS scores. At baseline, stages I-II, III-IV, and V-VI were associated with higher MBI-C, NPI-Q-S, and NPI-Q-D scores. Stages V-VI were associated with a significant annual increase in MBI-C scores. These findings suggest that tau accumulation may manifest clinically with an increase in NPS, which seems to be an early event in AD pathophysiology. Moreover, PET-based Braak staging appears to be a good predictor of NPS severity progression.
在阿尔茨海默病(AD)中,神经精神症状(NPS)与大脑中的 tau 沉积相关。在此,我们研究了基于 PET 的 Braak 阶段与 NPS 的关联,并评估了它们是否能预测 NPS 的年度变化。我们对 231 名处于衰老和注意力缺失症连续体中的人进行了评估。参与者在基线时被分配了一个布拉克分期,并随访了 1.97 年(标准差为 0.62)。使用轻度行为损害核对表(MBI-C)和神经精神量表问卷严重程度(NPI-Q-S)和痛苦程度(NPI-Q-D)量表对NPS进行调查。多重线性回归(MLR)评估了布拉克分期与基线 NPS 和 NPS 分数年度变化之间的关系。基线时,I-II、III-IV 和 V-VI 阶段与较高的 MBI-C、NPI-Q-S 和 NPI-Q-D 分数相关。第V-VI期与MBI-C评分每年显著增加有关。这些发现表明,tau积累在临床上可能表现为NPS的增加,这似乎是AD病理生理学中的早期事件。此外,基于 PET 的 Braak 分期似乎可以很好地预测 NPS 的严重程度。
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引用次数: 0
Auditory distraction, time perception, and the role of age: ERP evidence from a large cohort study 听觉分心、时间感知和年龄的作用:来自大型队列研究的 ERP 证据
IF 3.7 3区 医学 Q2 GERIATRICS & GERONTOLOGY Pub Date : 2024-09-20 DOI: 10.1016/j.neurobiolaging.2024.09.012
Stephan Getzmann , Stefan Arnau , Patrick D. Gajewski , Edmund Wascher
Cognitive aging is typically associated with a higher susceptibility to distraction by concurrent, but task-irrelevant stimuli. Here, we studied the cognitive sub-processes involved in a sample of 484 healthy adults aged 20–70 years from the Dortmund Vital Study (Clinicaltrials.gov NCT05155397). Participants judged the duration of tone stimuli of a random sequence of long and short tones, having either a regular (standard) pitch or rare (deviant) pitch. Deviance-related ERPs were explored, reflecting neuro-cognitive correlates of pre-attentive deviance detection (MMN), attention allocation toward (P3a) and processing of (P3b) the deviance, and re-orienting toward the task-relevant stimulus feature (RON). Accuracy was reduced for deviant long tones, possibly due to withdrawing attention from processing the time information, making long stimuli appear shorter. This effect increased with age, and cluster-based permutation tests on the correlation of ERPs and age as well as linear mixed modeling indicated a decrease in MMN, an increase in P3a with long tones, and decreases in P3b and RON. This suggests a greater attentional orienting to the deviant stimulus feature and a reduced re-orienting to the task-relevant feature with increasing age.
认知老化通常与更易受同时出现但与任务无关的刺激干扰有关。在此,我们研究了多特蒙德生命研究(Clinicaltrials.gov NCT05155397)中 484 名 20-70 岁健康成年人的认知子过程。受试者对音调刺激的持续时间进行判断,这些音调刺激由随机序列的长音和短音组成,音调要么是规则(标准)音调,要么是罕见(偏差)音调。研究人员探讨了与偏差相关的ERP,这些ERP反映了注意前偏差检测(MMN)、对偏差的注意分配(P3a)和处理(P3b)以及对任务相关刺激特征的重新定向(RON)的神经认知相关性。对偏差长音的准确度降低,可能是由于注意力从处理时间信息中撤出,使长刺激显得更短。这种效应随着年龄的增长而增加,对 ERPs 和年龄的相关性进行的基于聚类的置换检验以及线性混合模型表明,MMN 下降,P3a 随长音增加,P3b 和 RON 下降。这表明随着年龄的增长,对偏离刺激特征的注意定向增加,而对任务相关特征的重新定向减少。
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引用次数: 0
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Neurobiology of Aging
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