Neurobiology of Aging最新文献_第3页

Depressive symptoms and plasma AT(N) biomarkers among cognitively healthy and mild cognitively impaired in a diverse cohort 认知健康和轻度认知受损人群的抑郁症状和血浆AT(N)生物标志物

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2025-11-13 DOI: 10.1016/j.neurobiolaging.2025.11.005

Christina S. Dintica , Leigh Johnson , Melissa Petersen , Sid O’Bryant , Kristine Yaffe

Depression is a known risk factor for dementia and MCI, but its associations with AT(N) biomarkers remain inconsistent and may differ by cognitive status. We cross-sectionally studied 2929 dementia-free participants from the Health & Aging Brain Study—Health Disparities (HABS-HD). Mild cognitive impairment (MCI) was identified as having cognitive complaints, Clinical Dementia Rating scores between 0.5 and 2.0, and at least one cognitive test ≤ 1.5 SD below norms. We defined AT (N) with plasma biomarkers amyloid-β 42/40 (Aβ42/40), phosphorylated tau (p-tau181), neurofilament light (NfL), assessed using SIMOA technology and magnetic resonance imaging (MRI) based Alzheimer disease (AD) signature cortical thickness. Depressive symptoms were measured with the Geriatric Depression Scale (GDS), categorized as high (≥10) or low (<10). We used linear regression to determine association between depressive symptoms and biomarkers, adjusting for age, sex, education, kidney function, and body mass index. High depressive symptoms (19 %) were linked to higher NfL (standardized mean differences [SMD] = 0.10, 95 % confidence interval [CI: 0.02–0.18] and p-tau181 (SMD = 0.15, 95 % CI: 0.07–0.22) levels compared to low symptoms but not with Aβ42/40 or AD cortical thickness. Participants with both MCI and high depressive symptoms had higher NfL (SMD = 0.19, 95 % CI: 0.05–0.33) and p-tau181 (SMD = 0.30, 95 % CI: 0.16–0.45), and lower AD signature cortical thickness (SMD = –0.30, 95 % CI: –0.48 to –0.11). No group differences were found for Aβ42/40. Depressive symptoms, particularly among those with MCI, were linked to greater tau and neurodegeneration; longitudinal studies are needed to clarify this clinical significance.

抑郁症是痴呆和轻度认知障碍的已知危险因素，但其与AT(N)生物标志物的关联仍然不一致，可能因认知状态而异。我们横断面研究了2929名来自健康与衰老大脑研究-健康差异（HABS-HD）的无痴呆参与者。轻度认知障碍（MCI）被确定为有认知主诉，临床痴呆评分在0.5到2.0之间，至少有一项认知测试≤ 1.5 SD低于规范。我们用血浆生物标志物淀粉样蛋白-β 42/40 （Aβ42/40）、磷酸化tau蛋白（p-tau181）、神经丝光（NfL）来定义AT (N)，并使用SIMOA技术和基于阿尔茨海默病（AD）特征的磁共振成像（MRI）皮质厚度进行评估。用老年抑郁量表（GDS）测量抑郁症状，分为高（≥10）和低（<10）。我们使用线性回归来确定抑郁症状与生物标志物之间的关系，调整年龄、性别、教育程度、肾功能和体重指数。与低症状相比，高抑郁症状（19 %）与较高的NfL(标准化平均差异[SMD] = 0.10, 95 %可信区间[CI: 0.02-0.18]和p-tau181 （SMD = 0.15, 95 % CI: 0.07-0.22）水平相关，但与Aβ42/40或AD皮质厚度无关。MCI和高抑郁症状的参与者具有较高的NfL （SMD = 0.19, 95 % CI: 0.05-0.33）和p-tau181 （SMD = 0.30, 95 % CI: 0.16-0.45）和较低的AD特征皮质厚度（SMD = -0.30, 95 % CI: -0.48至-0.11）。Aβ42/40无组间差异。抑郁症状，尤其是轻度认知障碍患者，与较大的tau蛋白和神经变性有关；需要纵向研究来阐明这一临床意义。

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引用次数: 0

1H-MR spectroscopy biomarkers are associated with plasma-derived biomarkers of amyloid-β and tau in the early phase of AD continuum 在AD连续体的早期阶段，1H-MR光谱生物标志物与血浆来源的淀粉样蛋白-β和tau生物标志物相关

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2025-11-10 DOI: 10.1016/j.neurobiolaging.2025.11.003

Firat Kara , James M. Joers , Scott A. Przybelski , Alicia Algeciras-Schimnich , Jeffrey L. Gunter , Clifford R. Jack Jr , Ronald C. Petersen , Gülin Öz , Kejal Kantarci

The objective of the study was to evaluate the relationship of plasma biomarkers of Alzheimer’s disease (AD) with in vivo proton magnetic resonance spectroscopy (¹H-MRS) markers, and their association with cognitive function across the early stages of the AD continuum. Determining these associations may clarify the AD-related biological pathways and support the development of integrated AD blood and ¹H-MRS biomarkers for early detection of these pathways. Fifty-five older adults (40 cognitively unimpaired; 15 mild cognitive impairment) from the Mayo Clinic Study of Aging underwent single-voxel ¹H-MRS (sLASER) at 3T in the posterior cingulate gyrus (PCG) and left hippocampus (LH), along with plasma assays for Aβ42/40, phosphorylated tau (p-tau181), and the p-tau181/Aβ42 ratio. Associations between plasma biomarkers and ¹H-MRS metabolites (myo-inositol [mIns]/total creatine [tCr], total N-acetylaspartate [tNAA]/tCr, and tNAA/mIns) were examined using partial Spearman correlations (rho, ρ) adjusted for age and sex. Next, associations of the Mini-Mental State Examination with p-tau181/Aβ42 and tNAA/mIns were examined adjusting for the same covariates plus education. In both PCG and LH regions, lower tNAA/mIns was associated with higher p-tau181/Aβ42 (PCG:ρ=−0.59; LH:ρ=−0.54) and p-tau181 (PCG: ρ=−0.38; LH:ρ =−0.39), as well as with lower Aβ42/40 (PCG:ρ=0.40; LH:ρ=0.32). Higher mIns/tCr was associated with higher p-tau181/Aβ42 (PCG: ρ=0.56; LH:ρ=0.46) and p-tau181 (PCG:ρ=0.37; LH:ρ=0.31). Lower PCG and LH tNAA/mIns ratios were associated with lower MMSE (PCG:ρ=0.53; LH:ρ=0.46), while higher p-tau181/Aβ42 was associated with lower MMSE (ρ=−0.49). ¹H-MRS-derived gliosis and neuronal injury biomarkers are associated with early AD pathology, and cognitive performance, supporting their use as noninvasive biomarkers in early AD.

该研究的目的是评估阿尔茨海默病（AD）血浆生物标志物与体内质子磁共振波谱（H-MRS）标志物的关系，以及它们在AD连续体早期阶段与认知功能的关系。确定这些关联可以澄清AD相关的生物学途径，并支持开发整合AD血液和H-MRS生物标志物，用于早期检测这些途径。来自梅奥诊所衰老研究的55名老年人（40名认知未受损，15名轻度认知障碍）在3T时接受了后扣带回（PCG）和左海马（LH）的单体素¹H-MRS (sLASER)，并进行了a - β42/40、磷酸化tau （p-tau181）和p-tau181/ a - β42比值的血浆检测。血浆生物标志物与H-MRS代谢物（肌醇[mIns]/总肌酸[tCr]、总n -乙酰天冬氨酸[tNAA]/tCr和tNAA/mIns）之间的关系采用调整年龄和性别的部分Spearman相关性（ρ, ρ）进行检验。接下来，对p-tau181/ a - β42和tNAA/ min与迷你精神状态检查的关联进行检查，调整相同的协变量加上教育。在PCG和LH区域，较低的tNAA/ min与较高的p-tau181/ a - β42 （PCG:ρ=−0.59;LH:ρ=−0.54）和p-tau181 （PCG:ρ=−0.38;LH:ρ=−0.39）以及较低的a - β42/40 （PCG:ρ=0.40; LH:ρ=0.32）相关。较高的min /tCr与较高的p-tau181/ a - β42 （PCG:ρ= 0.56; LH:ρ=0.46）和p-tau181 （PCG:ρ=0.37; LH:ρ=0.31）相关。较低的PCG和LH tNAA/ min比值与较低的MMSE相关（PCG:ρ=0.53; LH:ρ=0.46），而较高的p-tau181/ a - β42与较低的MMSE相关（ρ= - 0.49）。¹h - mrs衍生的神经胶质瘤和神经元损伤生物标志物与早期阿尔茨海默病病理和认知表现相关，支持它们作为早期阿尔茨海默病的无创生物标志物。

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引用次数: 0

Optimized atlas for early tau-PET staging via native space segmentations 通过原生空间分割优化早期tau-PET分期图谱

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2025-11-06 DOI: 10.1016/j.neurobiolaging.2025.11.002

Etienne Aumont , Brandon J. Hall , Tevy Chan , Lydia Trudel , Gleb Bezgin , Seyyed Ali Hosseini , Joseph Therriault , Arthur C. Macedo , Jaime Fernández Arias , Nesrine Rahmouni , Stijn Servaes , Paolo Vitali , Jenna Stevenson , Vladimir Fonov , Maxime Montembeault , Jesse Klostranec , Yasser Iturria-Medina , Serge Gauthier , Pedro Rosa-Neto , for the Alzheimer’s Disease Neuroimaging Initiative

Positron Emission Tomography (PET) early Braak staging might be susceptible to anatomical variability and atrophy in the medial temporal lobe (MTL) structures. These factors should be accounted for in an optimized atlas to improve staging accuracy. This study aimed to compare the accuracy of early tau detection using traditional standard space methods versus using a native space MTL segmentations. Twelve native space MTL structures were used as regions of interest (ROI) for [¹⁸F]MK6240 tau-PET images and compared with standard space Braak stage ROIs for 333 participants aged over 55. We used the Rey Auditory Verbal Learning Test (RAVLT) to assess memory function. Native and standard space tau-PET stage ROIs were compared, then combined with anatomical constraints into an optimized standard space MTL atlas. The native space MTL tau-PET staging identified 34 participants with significantly more advanced tau accumulation. Of these, 14 had significant entorhinal and transentorhinal tau despite being classified as Braak stage I when using the original standard space method (here called pre-I stage). In addition, 19 were classified as Braak stage III despite being at Braak stage II using standard space methods (here called pre-III stage). These pre-III participants displayed a significant memory impairment. We found that a standard space spatial smoothing to 6 mm at FWHM best allowed to replicate native space results, resulting in the optimized atlas identifying 29 of these 33 more advanced cases. Therefore, standard space approaches can be improved to better capture early AD tau pathology and be more sensitive to cognitive impairment.

正电子发射断层扫描（PET）早期Braak分期可能易受解剖变异和内侧颞叶（MTL）结构萎缩的影响。在优化的图谱中应考虑这些因素，以提高分期准确性。本研究旨在比较使用传统标准空间方法与使用本地空间MTL分割的早期tau检测的准确性。使用12个原生空间MTL结构作为[18F]MK6240 tau-PET图像的感兴趣区域（ROI），并与333名年龄在55岁以上的参与者的标准空间Braak阶段ROI进行比较。我们使用Rey听觉语言学习测试（RAVLT）来评估记忆功能。将原生和标准空间tau-PET阶段roi进行比较，然后结合解剖约束形成优化的标准空间MTL图谱。原生空间MTL tau- pet分期鉴定出34名tau积累明显更晚期的参与者。其中，14例具有显著的内嗅和经内嗅tau，尽管使用原始标准空间法（这里称为前I期）时被归类为Braak期。此外，19个被归类为Braak III级，尽管使用标准空间方法（这里称为pre-III级）处于Braak II级。这些iii前的参与者表现出明显的记忆障碍。我们发现，在FWHM处，标准空间平滑至6 mm最能复制本地空间结果，从而使优化的图谱识别出33例晚期病例中的29例。因此，可以改进标准空间方法，以更好地捕捉早期AD tau病理，并对认知障碍更敏感。

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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 : 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

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2025-11-03 DOI: 10.1016/j.neurobiolaging.2025.10.007

Emily M. Fabrizio-Stover , James W. Dias , Carolyn M. McClaskey , Kelly C. Harris

There is growing evidence that perceptual difficulties associated with age-related hearing loss are not solely due to cochlear damage and are exacerbated by central nervous system changes. We examined electrophysiological (EEG) responses to clicks and diffusion kurtosis imaging in 49 older (29 female) and 26 younger (20 female) adults to determine the extent to which auditory nerve (AN) deficits in older adults contributed to functional and structural changes throughout the auditory system. Older adults exhibited smaller AN responses, similar brainstem responses, and larger auditory cortex (AC) responses, demonstrating progressive “central gain.” Audiometric thresholds were not predictive of EEG measures. Reduced AN function predicted deficits in cortical microstructure (lower AC fractional anisotropy) in older adults, consistent with microstructure degeneration. These lower fractional anisotropy values in the AC of older adults also predicted larger AC responses and more central gain. Older adults exhibited significantly lower AC fractional anisotropy and kurtosis fractional anisotropy coupled with higher mean and radial diffusivity compared to younger adults. AC fractional anisotropy, radial diffusivity, axial diffusivity, and mean diffusivity were all significant predictors of speech-in-noise (SIN) recognition in older adults. The results suggest that reduced afferent input in older adults not only results in functional changes throughout the auditory system consistent with progressive gain but also contributes to deficits in AC structure beyond those explained by age alone, contributing to SIN recognition deficits. Understanding the complex effects of age, reduced AN input, central gain, and AC microstructure on SIN recognition may provide potential therapeutic targets for intervention.

越来越多的证据表明，与年龄相关的听力损失相关的感知困难不仅仅是由于耳蜗损伤，而且还会因中枢神经系统的变化而加剧。我们检测了49名老年人（29名女性）和26名年轻人（20名女性）对咔嚓声和弥散峰度成像的电生理（EEG）反应，以确定老年人听神经（AN）缺陷在多大程度上导致了整个听觉系统的功能和结构变化。老年人表现出较小的AN反应，类似的脑干反应和较大的听觉皮层（AC）反应，表现出进行性的“中枢增益”。听力阈值不能预测脑电图。AN功能降低预示着老年人皮层微结构缺陷（AC分数各向异性降低），与微结构退化相一致。老年人AC的低分数各向异性值也预示着更大的AC反应和更多的中心增益。与年轻人相比，老年人表现出明显较低的AC分数各向异性和峰度分数各向异性，同时具有较高的平均扩散系数和径向扩散系数。交流分数各向异性、径向扩散率、轴向扩散率和平均扩散率都是老年人语音噪声识别的显著预测因子。结果表明，老年人传入输入的减少不仅导致整个听觉系统的功能变化与进行性增益一致，而且还导致AC结构的缺陷，而不仅仅是年龄的原因，从而导致SIN识别缺陷。了解年龄、AN输入减少、中枢增益和AC微观结构对SIN识别的复杂影响可能为干预提供潜在的治疗靶点。

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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 : 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

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 : 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

Identifying a proteomics signature of cognitive impairment and dementia in blood and cerebrospinal fluid through a mediation analysis framework 通过中介分析框架确定血液和脑脊液中认知障碍和痴呆的蛋白质组学特征

IF 3.5 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging

Pub Date : 2025-10-28 DOI: 10.1016/j.neurobiolaging.2025.10.004

Gabriel Torrealba-Acosta , Shu Yang , Javier Calvo-Marín , Abhay R. Moghekar , Aida Kamalian , Michael W. Lutz , for the Alzheimer’s Disease Neuroimaging Initiative

This study aimed to identify CSF and plasma proteins that mediate the association between age and mild cognitive impairment (MCI) and Alzheimer’s disease using mediation analysis. By focusing on proteins significantly associated in both CSF and plasma, we sought to identify biomarkers accessible for clinical applications. Proteomic measurements were obtained from CSF and plasma from a cohort of cognitively normal and MCI patients at the Johns Hopkins Alzheimer’s Disease Research Center using Olink Proximity Extension Assay technology. Mediation effects were estimated using single- and multiple-mediator models and validated in three independent datasets: Duke (CSF), ADNI (CSF), and UK Biobank (plasma). Over 3000 proteins in 86 patients were analyzed. Three candidates, leiomodin-1 (LMOD1), glial fibrillary acidic protein (GFAP), and elastin (ELN), met the criteria for mediation in both CSF and plasma. Multiple mediator models demonstrated a significant combined mediation effect on MCI in CSF (OR: 1.122, 95 % CI: 1.026–1.439) and plasma (OR: 1.142, 95 % CI: 1.058–1.410). Across validation cohorts, GFAP consistently showed significant mediation effects (Duke CSF: OR: 1.114, 95 % CI: 1.069–1.206; ADNI: OR: 1.004, 95 % CI: 1.000–1.009; UK Biobank: OR: 1.030, 95 % CI: 1.026–1.034). In contrast, ELN and LMOD1 demonstrated mediation effects in the discovery dataset but were not consistently reproduced in external cohorts. Our findings highlight GFAP as a robust mediator of age-related risk of cognitive impairment across CSF and plasma, supporting its utility as a practical biomarker. ELN and LMOD1 may represent exploratory candidates reflecting extracellular matrix and vascular processes requiring further validation.

本研究旨在通过中介分析确定介导年龄与轻度认知障碍（MCI）和阿尔茨海默病之间关联的CSF和血浆蛋白。通过关注脑脊液和血浆中显著相关的蛋白质，我们试图确定可用于临床应用的生物标志物。蛋白质组学测量来自约翰霍普金斯阿尔茨海默病研究中心的一组认知正常和轻度认知障碍患者的脑脊液和血浆，使用Olink接近扩展测定技术。使用单介质和多介质模型估计中介效应，并在三个独立的数据集中进行验证：Duke （CSF）、ADNI （CSF）和UK Biobank（血浆）。分析了86例患者的3000多种蛋白质。三种候选药物，leomotin -1 (LMOD1)，胶质纤维酸性蛋白（GFAP）和弹性蛋白（ELN），符合CSF和血浆调解的标准。多个中介模型显示，对脑脊液（OR: 1.122, 95 % CI: 1.026-1.439）和血浆（OR: 1.142, 95 % CI: 1.058-1.410）的MCI有显著的联合中介作用。在验证队列中，GFAP一致显示出显著的中介效应（Duke CSF: OR: 1.114, 95 % CI: 1.069-1.206; ADNI: OR: 1.004, 95 % CI: 1.000-1.009; UK Biobank: OR: 1.030, 95 % CI: 1.026-1.034）。相比之下，ELN和LMOD1在发现数据集中表现出中介效应，但在外部队列中并不一致地再现。我们的研究结果强调GFAP是脑脊液和血浆中与年龄相关的认知障碍风险的强大中介，支持其作为实用生物标志物的实用性。ELN和LMOD1可能是反映细胞外基质和血管过程的探索性候选物，需要进一步验证。

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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 : 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

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 : 2025-10-16 DOI: 10.1016/S0197-4580(25)00176-9

引用次数: 0