Journal of Alzheimer's Disease最新文献_第10页

Type 2 Diabetes and Biomarkers of Brain Structure, Perfusion, Metabolism, and Function in Late Mid-Life: A Multimodal Discordant Twin Study 2 型糖尿病与中年后期大脑结构、灌注、新陈代谢和功能的生物标志物：多模态不和谐双胞胎研究

IF 4 3区医学 Q1 Psychology

Journal of Alzheimer's Disease

Pub Date : 2024-01-06 DOI: 10.3233/jad-230640

C. Karayiannis, V. Srikanth, R. Beare, Hemal Mehta, Mark Gillies, Thanh G. Phan, Zheng Yang Xu, Christine Chen, Chris Moran

Background: Type 2 diabetes (T2D) is associated with an increased risk of dementia and early features may become evident even in mid-life. Characterizing these early features comprehensively requires multiple measurement modalities and careful selection of participants with and without T2D. Objective: We conducted a cross-sectional multimodal imaging study of T2D-discordant twins in late mid-life to provide insights into underlying mechanisms. Methods: Measurements included computerized cognitive battery, brain MRI (including arterial spin labelling, diffusion tensor, resting state functional), fluorodeoxyglucose (FDG)-PET, and retinal optical coherence tomography. Results: There were 23 pairs, mean age 63.7 (±6.1) years. In global analyses, T2D was associated with poorer attention (β= –0.45, p <0.001) and with reduced FDG uptake (β= –5.04, p = 0.02), but not with cortical thickness (p = 0.71), total brain volume (p = 0.51), fractional anisotropy (p = 0.15), mean diffusivity (p = 0.34), or resting state activity (p = 0.4). Higher FDG uptake was associated with better attention (β= 3.19, p = 0.01) but not with other cognitive domains. In regional analyses, T2D was associated with lower accumbens volume (β= –44, p = 0.0004) which was in turn associated with poorer attention. Conclusion: T2D-related brain dysfunction in mid-life manifests as attentional loss accompanied by evidence of subtle neurodegeneration and global reduction in cerebral metabolism, in the absence of overt cerebrovascular disease.

背景：2 型糖尿病（T2D）与痴呆症风险的增加有关，其早期特征甚至在中年时期就已显现。要全面描述这些早期特征，需要采用多种测量方式，并对患有和未患有 T2D 的参与者进行仔细筛选。研究目的我们对中年后期患有 T2D 的不一致双胞胎进行了横断面多模态成像研究，以深入了解其潜在机制。研究方法测量包括计算机认知电池、脑磁共振成像（包括动脉自旋标记、弥散张量、静息状态功能）、氟脱氧葡萄糖（FDG）-PET 和视网膜光学相干断层扫描。研究结果23对患者的平均年龄为63.7（±6.1）岁。在总体分析中，T2D与注意力较差（β= -0.45，p <0.001）和FDG摄取减少（β= -5.04，p = 0.02）有关，但与皮质厚度（p = 0.71）、大脑总体积（p = 0.51）、分数各向异性（p = 0.15）、平均扩散率（p = 0.34）或静息状态活动（p = 0.4）无关。较高的 FDG 摄取与较好的注意力相关（β= 3.19，p = 0.01），但与其他认知领域无关。在区域分析中，T2D 与较低的腰果体积相关（β= -44，p = 0.0004），而较低的腰果体积又与较差的注意力相关。结论在没有明显脑血管疾病的情况下，与 T2D 相关的中年脑功能障碍表现为注意力减退，同时伴有微妙的神经变性和整体脑代谢降低的证据。

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引用次数: 0

Interaction Between Arteriosclerosis and -β on Cognitive Function 动脉硬化与-β对认知功能的相互作用

IF 4 3区医学 Q1 Psychology

Journal of Alzheimer's Disease

Pub Date : 2024-01-05 DOI: 10.3233/jad-230604

I. Frentz, Joyce van Arendonk, A. Leeuwis, Meike W. Vernooij, W. M. van der Flier, Daniel Bos, P. P. De Deyn, F. Wolters, M. Ikram

Background: Dementia is a multifactorial disease, with Alzheimer’s disease (AD) and vascular pathology often co-occurring in many individuals with dementia. Yet, the interplay between AD and vascular pathology in cognitive decline is largely undetermined. Objective: The aim of the present study was to examine the joint effect of arteriosclerosis and AD pathology on cognition in the general population without dementia. Methods: We determined the interaction between blood-based AD biomarkers and CT-defined arteriosclerosis on cognition in 2,229 dementia-free participants of the population-based Rotterdam Study (mean age: 68.9 years, 52% women) cross-sectionally. Results: Amyloid-β (Aβ)42 and arterial calcification were associated with cognitive performance. After further adjustment for confounders in a model that combined all biomarkers, only arterial calcification remained independently associated with cognition. There was a significant interaction between arterial calcification and Aβ 42 and between arterial calcification and the ratio of Aβ 42/40. Yet, estimates attenuated, and interactions were no longer statistically significant after adjustment for cardio metabolic risk factors. Conclusions: Arteriosclerosis and AD display additive interaction-effects on cognition in the general population, that are due in part to cardio metabolic risk factors. These findings suggest that joint assessment of arteriosclerosis and AD pathology is important for understanding of disease etiology in individuals with cognitive impairment.

背景：痴呆症是一种多因素疾病，在许多痴呆症患者中，阿尔茨海默病（AD）和血管病变往往同时存在。然而，认知能力下降过程中阿尔茨海默病和血管病理学之间的相互作用在很大程度上尚未确定。研究目的本研究旨在探讨动脉硬化和 AD 病变对无痴呆症的普通人群认知能力的共同影响。研究方法我们通过横截面研究确定了基于血液的注意力缺失症生物标志物和 CT 定义的动脉硬化对基于人群的鹿特丹研究中 2,229 名无痴呆症参与者（平均年龄：68.9 岁，52% 为女性）认知能力的交互作用。结果显示淀粉样蛋白-β（Aβ）42和动脉钙化与认知能力有关。在结合所有生物标志物的模型中进一步调整混杂因素后，只有动脉钙化仍与认知能力独立相关。动脉钙化与 Aβ 42 之间以及动脉钙化与 Aβ 42/40 的比率之间存在明显的交互作用。然而，在对心血管代谢风险因素进行调整后，估计值减弱，相互作用不再具有统计学意义。结论在普通人群中，动脉硬化和注意力缺失症对认知能力的交互影响是相加的，部分原因在于心脏代谢风险因素。这些发现表明，联合评估动脉硬化和注意力缺失症的病理变化对于了解认知障碍患者的疾病病因非常重要。

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引用次数: 0

The Role of Impaired Receptor Trafficking in Mediating the Pathological Effects of APOE4 in Alzheimer’s Disease 受体贩运受损在阿尔茨海默病中介导 APOE4 病理效应的作用

IF 4 3区医学 Q1 Psychology

Journal of Alzheimer's Disease

Pub Date : 2024-01-05 DOI: 10.3233/jad-230514

Mirna Safieh, Ori Liraz, Maayan Ovadia, Danny M. Michaelson

Background: Apolipoprotein E4 (APOE4) is the most prevalent genetic risk factor of Alzheimer’s disease. Several studies suggest that APOE4 binding to its receptors is associated with their internalization and accumulation in intracellular compartments. Importantly, this phenomenon also occurs with other, non-ApoE receptors. Based on these observations, we hypothesized that APOE4 pathological effects are mediated by impairment in the life cycle of distinct receptors (APOER2, LRP1, IR, VEGFR). Objective: To examine the effects of APOE genotype on receptors protein levels and compartmentalization. Methods: Primary mouse neurons were prepared from APOE3 or APOE4 targeted replacement mice, or APOE-KO mice. Specific receptors protein levels were evaluated in these neurons, utilizing immunofluorescent staining. Additionally, surface membrane protein levels of those receptors were assessed by cell surface biotinylation assay and ELISA. Receptors’ colocalization with intracellular compartments was assessed by double staining and confocal microscopy, followed by colocalization analysis. Finally, LRP1 or APOER2 were knocked-down with CRISPR/Cas9 system to examine their role in mediating APOE4 effects on the receptors. Results: Our results revealed lower receptors’ levels in APOE4, specifically on the membrane surface. Additionally, APOE4 affects the compartmentation of these receptors in two patterns: the first was observed with LRP1 and was associated with decreased receptor levels in numerous intracellular compartments. The second was obtained with the other receptors and was associated with their accumulation in early endosomes and their decrease in the late endosomes. Conclusions: These results provide a unifying mechanism, in which APOE4 drives the down regulation of various receptors, which plays important roles in distinct APOE4 related pathological processes.

背景：载脂蛋白 E4（APOE4）是阿尔茨海默病最普遍的遗传风险因素。多项研究表明，载脂蛋白 E4 与其受体结合与受体内化和在细胞内积累有关。重要的是，这种现象也发生在其他非载脂蛋白E受体上。基于这些观察结果，我们假设 APOE4 的病理效应是由不同受体（APOER2、LRP1、IR、VEGFR）的生命周期受损介导的。研究目的研究 APOE 基因型对受体蛋白水平和分区的影响。方法：制备小鼠原代神经元：制备 APOE3 或 APOE4 靶向替代小鼠或 APOE-KO 小鼠的原代小鼠神经元。利用免疫荧光染色法评估这些神经元中的特定受体蛋白水平。此外，还通过细胞表面生物素化试验和酶联免疫吸附试验评估了这些受体的表面膜蛋白水平。通过双重染色和共聚焦显微镜，然后进行共聚焦分析，评估受体与细胞内分区的共聚焦情况。最后，用CRISPR/Cas9系统敲除LRP1或APOER2，以研究它们在介导APOE4对受体的影响中的作用。结果：我们的研究结果表明，APOE4 的受体水平较低，特别是在膜表面。此外，APOE4 还以两种模式影响这些受体的分区：第一种模式是在 LRP1 中观察到的，与许多细胞内分区中受体水平的降低有关。第二种是对其他受体的影响，与它们在早期内体中的积累和在晚期内体中的减少有关。结论：这些结果提供了一个统一的机制，即 APOE4 驱动各种受体的下调，而这些受体在不同的 APOE4 相关病理过程中发挥着重要作用。

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引用次数: 0

The Catastrophe of Intracerebral Hemorrhage Drives the Capillary-Hemorrhage Dementias, Including Alzheimer’s Disease 脑出血的灾难性后果导致了包括阿尔茨海默病在内的毛细血管出血性痴呆症的发生

IF 4 3区医学 Q1 Psychology

Journal of Alzheimer's Disease

Pub Date : 2024-01-05 DOI: 10.3233/jad-231202

Jonathan Stone, John Mitrofanis, Daniel M. Johnstone, Stephen R. Robinson

This review advances an understanding of several dementias, based on four premises. One is that capillary hemorrhage is prominent in the pathogenesis of the dementias considered (dementia pugilistica, chronic traumatic encephalopathy, traumatic brain damage, Alzheimer’s disease). The second premise is that hemorrhage introduces four neurotoxic factors into brain tissue: hypoxia of the tissue that has lost its blood supply, hemoglobin and its breakdown products, excitotoxic levels of glutamate, and opportunistic pathogens that can infect brain cells and induce a cytotoxic immune response. The third premise is that where organisms evolve molecules that are toxic to itself, like the neurotoxicity ascribed to hemoglobin, amyloid- (A), and glutamate, there must be some role for the molecule that gives the organism a selection advantage. The fourth is the known survival-advantage roles of hemoglobin (oxygen transport), of A (neurotrophic, synaptotrophic, detoxification of heme, protective against pathogens) and of glutamate (a major neurotransmitter). From these premises, we propose 1) that the brain has evolved a multi-factor response to intracerebral hemorrhage, which includes the expression of several protective molecules, including haptoglobin, hemopexin and A; and 2) that it is logical, given these premises, to posit that the four neurotoxic factors set out above, which are introduced into the brain by hemorrhage, drive the progression of the capillary-hemorrhage dementias. In this view, A expressed at the loci of neuronal death in these dementias functions not as a toxin but as a first responder, mitigating the toxicity of hemoglobin and the infection of the brain by opportunistic pathogens.

这篇综述基于四个前提，加深了人们对几种痴呆症的理解。其一，毛细血管出血在所研究的痴呆症（搏动性痴呆症、慢性外伤性脑病、外伤性脑损伤、阿尔茨海默病）的发病机制中占据重要地位。第二个前提是，出血会给脑组织带来四种神经毒性因素：失去血液供应的组织缺氧、血红蛋白及其分解产物、兴奋性毒性谷氨酸水平以及可感染脑细胞并诱发细胞毒性免疫反应的机会性病原体。第三个前提是，当生物进化出对自身有毒的分子时，如血红蛋白、淀粉样蛋白（A）和谷氨酸的神经毒性，该分子一定有某种作用，使生物具有选择优势。第四，血红蛋白（氧运输）、淀粉样蛋白（A）（神经营养、突触营养、血红素解毒、抵御病原体）和谷氨酸（一种主要的神经递质）具有已知的生存优势作用。从这些前提出发，我们提出：1）大脑已进化出一种对脑出血的多因素反应，其中包括几种保护性分子的表达，包括血红蛋白、血卟啉和 A；2）鉴于这些前提，合乎逻辑的假设是，因出血而进入大脑的上述四种神经毒性因素推动了毛细血管出血性痴呆症的发展。根据这一观点，在这些痴呆症的神经元死亡部位表达的 A 的功能不是毒素，而是第一反应器，可减轻血红蛋白的毒性和机会性病原体对大脑的感染。

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引用次数: 0

High-Fat Diets in Animal Models of Alzheimer’s Disease: How Can Eating Too Much Fat Increase Alzheimer’s Disease Risk? 阿尔茨海默病动物模型中的高脂饮食：摄入过多脂肪如何增加阿尔茨海默病风险？

IF 4 3区医学 Q1 Psychology

Journal of Alzheimer's Disease

Pub Date : 2024-01-04 DOI: 10.3233/jad-230118

Josue Valentin-Escalera, M. Leclerc, Frédéric Calon

High dietary intake of saturated fatty acids is a suspected risk factor for neurodegenerative diseases, including Alzheimer’s disease (AD). To decipher the causal link behind these associations, high-fat diets (HFD) have been repeatedly investigated in animal models. Preclinical studies allow full control over dietary composition, avoiding ethical concerns in clinical trials. The goal of the present article is to provide a narrative review of reports on HFD in animal models of AD. Eligibility criteria included mouse models of AD fed a HFD defined as > 35% of fat/weight and western diets containing > 1% cholesterol or > 15% sugar. MEDLINE and Embase databases were searched from 1946 to August 2022, and 32 preclinical studies were included in the review. HFD-induced obesity and metabolic disturbances such as insulin resistance and glucose intolerance have been replicated in most studies, but with methodological variability. Most studies have found an aggravating effect of HFD on brain Aβ pathology, whereas tau pathology has been much less studied, and results are more equivocal. While most reports show HFD-induced impairment on cognitive behavior, confounding factors may blur their interpretation. In summary, despite conflicting results, exposing rodents to diets highly enriched in saturated fat induces not only metabolic defects, but also cognitive impairment often accompanied by aggravated neuropathological markers, most notably Aβ burden. Although there are important variations between methods, particularly the lack of diet characterization, these studies collectively suggest that excessive intake of saturated fat should be avoided in order to lower the incidence of AD.

从膳食中摄入大量饱和脂肪酸被怀疑是包括阿尔茨海默病（AD）在内的神经退行性疾病的危险因素。为了破译这些关联背后的因果联系，人们在动物模型中对高脂饮食（HFD）进行了反复研究。临床前研究可以完全控制饮食成分，避免了临床试验中的伦理问题。本文旨在对有关高脂饮食在 AD 动物模型中应用的报道进行叙述性综述。资格标准包括以脂肪含量大于 35%/ 重量的高脂饮食和胆固醇含量大于 1%或糖含量大于 15%的西式饮食喂养的 AD 小鼠模型。我们检索了1946年至2022年8月的MEDLINE和Embase数据库，共纳入了32项临床前研究。大多数研究都证实了高密度脂蛋白胆固醇诱发的肥胖和代谢紊乱，如胰岛素抵抗和葡萄糖不耐受，但研究方法存在差异。大多数研究发现，高频分解膳食对大脑 Aβ 病理学有加重作用，而对 tau 病理学的研究要少得多，结果也比较模糊。虽然大多数报告显示高氟酸脱氢引发的认知行为障碍，但混杂因素可能会模糊其解释。总之，尽管结果相互矛盾，但将啮齿类动物暴露于富含饱和脂肪的饮食中，不仅会诱发代谢缺陷，而且还会诱发认知障碍，通常还伴随着神经病理学标志物的加重，其中最显著的是 Aβ 负担。尽管不同研究方法之间存在很大差异，尤其是缺乏饮食特征描述，但这些研究共同表明，应避免摄入过量饱和脂肪，以降低注意力缺失症的发病率。

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引用次数: 0

Erratum to: Shifting the Paradigm of Nursing Home Care for People with Dementia: The Italian Experience of Il Paese Ritrovato and the Impact of SARS-CoV-2. 勘误：转变养老院对痴呆症患者的护理模式：意大利的 "Il Paese Ritrovato "经验和 SARS-CoV-2 的影响。

IF 4 3区医学 Q1 Psychology

Journal of Alzheimer's Disease

Pub Date : 2024-01-01 DOI: 10.3233/JAD-249006

引用次数: 0

Suspecting Non-Alzheimer's Pathologies and Mixed Pathologies: A Comparative Study Between Brain Metabolism and Tau Images. 怀疑非阿尔茨海默病病症和混合病症：大脑新陈代谢与 Tau 图像的比较研究》。

IF 4 3区医学 Q1 Psychology

Journal of Alzheimer's Disease

Pub Date : 2024-01-01 DOI: 10.3233/JAD-230696

Vincent Malotaux, Lise Colmant, Lisa Quenon, Lara Huyghe, Thomas Gérard, Laurence Dricot, Adrian Ivanoiu, Renaud Lhommel, Bernard Hanseeuw

Background: Alzheimer's disease (AD) pathology can be disclosed in vivo using amyloid and tau imaging, unlike non-AD neuropathologies for which no specific markers exist.

Objective: We aimed to compare brain hypometabolism and tauopathy to unveil non-AD pathologies.

Methods: Sixty-one patients presenting cognitive complaints (age 48-90), including 32 with positive AD biomarkers (52%), performed [18F]-Fluorodeoxyglucose (FDG)-PET (brain metabolism) and [18F]-MK-6240-PET (tau). We normalized these images using data from clinically normal individuals (n = 30), resulting in comparable FDG and tau z-scores. We computed between-patients correlations to evaluate regional associations. For each patient, a predominant biomarker (i.e., Hypometabolism > Tauopathy or Hypometabolism≤Tauopathy) was determined in the temporal and frontoparietal lobes. We computed within-patient correlations between tau and metabolism and investigated their associations with demographics, cognition, cardiovascular risk factors (CVRF), CSF biomarkers, and white matter hypointensities (WMH).

Results: We observed negative associations between tau and FDG in 37 of the 68 cortical regions-of-interest (average Pearson's r = -0.25), mainly in the temporal lobe. Thirteen patients (21%) had Hypometabolism > Tauopathy whereas twenty-five patients (41%) had Hypometabolism≤Tauopathy. Tau-predominant patients were more frequently females and had greater amyloid burden. Twenty-three patients (38%) had Hypometabolism≤Tauopathy in the temporal lobe, but Hypometabolism > Tauopathy in the frontoparietal lobe. This group was older and had higher CVRF than Tau-predominant patients. Patients with more negative associations between tau and metabolism were younger, had worse cognition, and greater amyloid and WMH burdens.

Conclusions: Tau-FDG comparison can help suspect non-AD pathologies in patients presenting cognitive complaints. Stronger Tau-FDG correlations are associated with younger age, worse cognition, and greater amyloid and WMH burdens.

背景：阿尔茨海默病（AD）的病理变化可通过淀粉样蛋白和 tau 蛋白成像技术在体内显示出来：阿尔茨海默病（AD）病理可通过淀粉样蛋白和tau成像在体内揭示，而非AD神经病理则不同，它们没有特定的标记物：我们旨在比较大脑代谢低下和 tau 蛋白病变，以揭示非 AD 病变：61名出现认知症状的患者（48-90岁），包括32名AD生物标志物阳性者（52%），进行了[18F]-氟脱氧葡萄糖（FDG）-PET（脑代谢）和[18F]-MK-6240-PET（tau）检查。我们使用临床正常人（n = 30）的数据对这些图像进行了归一化处理，得出了具有可比性的 FDG 和 tau z 分数。我们计算了患者之间的相关性，以评估区域关联。我们为每位患者确定了颞叶和顶叶的主要生物标记物（即代谢亢进>Tau病或代谢亢进≤Tau病）。我们计算了患者体内 tau 和代谢之间的相关性，并研究了它们与人口统计学、认知、心血管风险因素（CVRF）、CSF 生物标志物和白质低密度（WMH）之间的关联：我们在68个皮质感兴趣区中的37个观察到了tau和FDG之间的负相关（平均Pearson's r = -0.25），主要集中在颞叶。13名患者（21%）代谢亢进>Tau病，而25名患者（41%）代谢亢进≤Tau病。以Tau为主的患者多为女性，且淀粉样蛋白负荷较大。23名患者（38%）颞叶的代谢≤Tau病变，但额叶的代谢≤Tau病变>Tau病变。这组患者年龄较大，CVRF高于Tau占主导地位的患者。tau和代谢之间存在更多负相关的患者更年轻，认知能力更差，淀粉样蛋白和WMH负担更大：结论：Tau-FDG对比有助于怀疑出现认知症状的患者是否患有非AD病变。较强的Tau-FDG相关性与年龄较小、认知能力较差、淀粉样蛋白和WMH负荷较大有关。

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引用次数: 0

Communication Regarding the Myocardial Ischemia/Reperfusion and Cognitive Impairment: A Narrative Literature Review. 关于心肌缺血/再灌注与认知障碍的交流：叙述性文献综述》。

IF 3.4 3区医学 Q2 NEUROSCIENCES

Journal of Alzheimer's Disease

Pub Date : 2024-01-01 DOI: 10.3233/JAD-230886

Haiqing Chang, Erya Chen, Tao Zhu, Jin Liu, Chan Chen

Coronary artery disease is a prevalent ischemic disease that results in insufficient blood supply to the heart muscle due to narrowing or occlusion of the coronary arteries. Various reperfusion strategies, including pharmacological thrombolysis and percutaneous coronary intervention, have been developed to enhance blood flow restoration. However, these interventions can lead to myocardial ischemia/reperfusion injury (MI/RI), which can cause unpredictable complications. Recent research has highlighted a compelling association between MI/RI and cognitive function, revealing pathophysiological mechanisms that may explain altered brain cognition. Manifestations in the brain following MI/RI exhibit pathological features resembling those observed in Alzheimer's disease (AD), implying a potential link between MI/RI and the development of AD. The pro-inflammatory state following MI/RI may induce neuroinflammation via systemic inflammation, while impaired cardiac function can result in cerebral under-perfusion. This review delves into the role of extracellular vesicles in transporting deleterious substances from the heart to the brain during conditions of MI/RI, potentially contributing to impaired cognition. Addressing the cognitive consequence of MI/RI, the review also emphasizes potential neuroprotective interventions and pharmacological treatments within the MI/RI model. In conclusion, the review underscores the significant impact of MI/RI on cognitive function, summarizes potential mechanisms of cardio-cerebral communication in the context of MI/RI, and offers ideas and insights for the prevention and treatment of cognitive dysfunction following MI/RI.

冠状动脉疾病是一种常见的缺血性疾病，由于冠状动脉狭窄或闭塞，导致心肌供血不足。目前已开发出各种再灌注策略，包括药物溶栓和经皮冠状动脉介入治疗，以加强血流恢复。然而，这些干预措施可能会导致心肌缺血/再灌注损伤（MI/RI），从而引发不可预知的并发症。最近的研究强调了心肌缺血/再灌注损伤与认知功能之间令人信服的联系，揭示了可能导致大脑认知改变的病理生理机制。MI/RI 后大脑的病理表现与阿尔茨海默病（AD）的病理表现相似，这意味着 MI/RI 与阿尔茨海默病的发展之间存在潜在联系。心肌梗死/脑梗死后的促炎症状态可能会通过全身炎症诱发神经炎症，而心脏功能受损会导致脑灌注不足。这篇综述深入探讨了细胞外囊泡在 MI/RI 情况下将有害物质从心脏输送到大脑的作用，这可能会导致认知功能受损。针对心肌梗死/脑梗死的认知后果，综述还强调了在心肌梗死/脑梗死模型中潜在的神经保护干预措施和药物治疗。总之，综述强调了 MI/RI 对认知功能的重大影响，总结了 MI/RI 情况下心脑沟通的潜在机制，并为预防和治疗 MI/RI 后的认知功能障碍提供了思路和见解。

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引用次数: 0

Senescence Targeting Methods Impact Alzheimer's Disease Features in 3xTg Mice. 衰老靶向方法影响 3xTg 小鼠的阿尔茨海默病特征

IF 3.4 3区医学 Q2 NEUROSCIENCES

Journal of Alzheimer's Disease

Pub Date : 2024-01-01 DOI: 10.3233/JAD-230465

Pei Y Ng, Cheng Zhang, Hu Li, Darren J Baker

Background: Cellular senescence has been associated with neurodegenerative disease and clearance of senescent cells using genetic or pharmaceutical strategies (senolytics) has demonstrated beneficial effects in mouse models investigating individual disease etiologies of Alzheimer's disease (AD). However, it has remained unclear if senescent cell clearance in a mouse model exhibiting both plaque and tau pathologies modifies the disease state (3xTg).

Objective: To investigate the effects of senescent cell clearance in the 3xTg mouse model.

Methods: 3xTg mice were treated with senolytics (ABT263 (navitoclax; NAVI), a combination of dasatinib and quercetin (D+Q)), or subjected to transgene-mediated removal of p16-expressing cells (via INK-ATTAC).

Results: Senolytic treatments consistently reduced microgliosis and ameliorated both amyloid and tau pathology in 3xTg mice. Using RNA sequencing, we found evidence that synaptic dysfunction and neuroinflammation were attenuated with treatment. These beneficial effects were not observed with short-term senolytic treatment in mice with more advanced disease.

Conclusions: Overall, our results further corroborate the beneficial effects senescent cell clearance could have on AD and highlight the importance of early intervention for the treatment of this debilitating disease.

背景：细胞衰老与神经退行性疾病有关，在研究阿尔茨海默病（AD）个别病因的小鼠模型中，利用基因或药物策略（衰老剂）清除衰老细胞已显示出有益的效果。然而，在同时表现出斑块和 tau 病理学的小鼠模型（3xTg）中，衰老细胞的清除是否会改变疾病状态仍不清楚：方法：用衰老剂（ABT263（navitoclax；NAVI）、达沙替尼和槲皮素的组合（D+Q））治疗 3xTg 小鼠，或通过转基因介导清除 p16 表达细胞（通过 INK-ATTAC）：结果：在3xTg小鼠中，衰老治疗可持续减少小胶质细胞增多，并改善淀粉样蛋白和tau病理学。通过 RNA 测序，我们发现有证据表明，治疗可减轻突触功能障碍和神经炎症。在对晚期疾病小鼠进行短期溶老治疗时，并没有观察到这些有益的影响：总之，我们的研究结果进一步证实了清除衰老细胞可对老年痴呆症产生有益影响，并强调了早期干预对治疗这种使人衰弱的疾病的重要性。

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引用次数: 0

Neuropsychological Profiles, Etiologies, and Medical Comorbidities in Early-Onset Dementia and Cognitive Impairment: A Memory Outpatient Clinic Cohort Study. 早发性痴呆和认知障碍的神经心理学特征、病因和并发症：记忆门诊队列研究》。

IF 3.4 3区医学 Q2 NEUROSCIENCES

Journal of Alzheimer's Disease

Pub Date : 2024-01-01 DOI: 10.3233/JAD-230877

Anna-Leena Heikkinen, Teemu I Paajanen, Tuomo Hänninen, Veera Tikkanen, Christer Hublin, Anne M Koivisto, Anne M Remes, Johanna Krüger

Background: Although early-onset dementia (EOD) is associated with diagnostic challenges that differ from those of related to late-onset dementia, only limited studies have addressed the neuropsychological and health characteristics or specified the diagnoses underlying early-onset cognitive impairment in a real-world clinical setting.

Objective: To investigate the neuropsychological profiles, etiologies, and comorbidities of an unselected cohort of memory clinic patients (≤65 years at symptom onset).

Methods: The patients' (n = 210) diagnoses were determined based on comprehensive diagnostic workup. Medical comorbidities and neuropsychological profiles were compared between clinically relevant patient groups, namely early-onset dementia (n = 55), mild cognitive impairment due to vascular or suspected neurodegenerative (MCI-n, n = 35) or non-neurodegenerative (MCI-o, n = 106) etiologies, and subjective cognitive decline (n = 14).

Results: The most prevalent diagnoses were Alzheimer's disease (AD, 14%) and depression (11%). Multiple prior medical conditions were common (67%); however, EOD patients had fewer other diagnoses (p = 0.008) than MCI-o patients. Compared to other groups, EOD patients had more severe deficits (p < 0.001) on immediate and delayed memory, processing speed, symptom awareness, and global cognition. AD patients had weaker memory retention ability but less behavioral symptoms than frontotemporal dementia (FTD) patients (p≤0.05). Depression was associated with better immediate memory, symptom awareness, and global cognition than AD and FTD (p < 0.05).

Conclusions: EOD is associated with more severe and widespread neuropsychological deficits but fewer prior medical diagnoses than nondegenerative etiologies of cognitive impairment. AD and depression are common etiologies and the neuropsychological profiles are partly overlapping; however, memory, symptom awareness and global cognitive impairment measures may help in the differential diagnosis.

背景：尽管早发性痴呆（EOD）在诊断方面面临着不同于晚发性痴呆的挑战，但在真实世界的临床环境中，针对早发性认知障碍的神经心理学和健康特征或明确诊断的研究却非常有限：目的：调查一组未经筛选的记忆门诊患者（症状出现时年龄小于 65 岁）的神经心理学特征、病因和合并症：方法：患者（n = 210）的诊断是根据综合诊断结果确定的。比较了临床相关患者组（即早发痴呆（n = 55）、血管性或疑似神经退行性疾病引起的轻度认知障碍（MCI-n，n = 35）或非神经退行性疾病引起的轻度认知障碍（MCI-o，n = 106）以及主观认知能力下降（n = 14））的合并症和神经心理学特征：最常见的诊断是阿尔茨海默病（AD，14%）和抑郁症（11%）。之前患有多种疾病的患者很常见（67%）；然而，与 MCI-o 患者相比，EOD 患者的其他诊断较少（p = 0.008）。与其他组别相比，EOD 患者的缺陷更为严重（p 结论：EOD 与更严重和更复杂的疾病相关：与认知障碍的非退行性病因相比，EOD 与更严重、更广泛的神经心理障碍相关，但与更少的既往医疗诊断相关。注意力缺失症和抑郁症是常见的病因，其神经心理学特征有部分重叠；然而，记忆、症状意识和整体认知障碍测量有助于鉴别诊断。

{"title":"Neuropsychological Profiles, Etiologies, and Medical Comorbidities in Early-Onset Dementia and Cognitive Impairment: A Memory Outpatient Clinic Cohort Study.","authors":"Anna-Leena Heikkinen, Teemu I Paajanen, Tuomo Hänninen, Veera Tikkanen, Christer Hublin, Anne M Koivisto, Anne M Remes, Johanna Krüger","doi":"10.3233/JAD-230877","DOIUrl":"10.3233/JAD-230877","url":null,"abstract":"Background: Although early-onset dementia (EOD) is associated with diagnostic challenges that differ from those of related to late-onset dementia, only limited studies have addressed the neuropsychological and health characteristics or specified the diagnoses underlying early-onset cognitive impairment in a real-world clinical setting.Objective: To investigate the neuropsychological profiles, etiologies, and comorbidities of an unselected cohort of memory clinic patients (≤65 years at symptom onset).Methods: The patients' (n = 210) diagnoses were determined based on comprehensive diagnostic workup. Medical comorbidities and neuropsychological profiles were compared between clinically relevant patient groups, namely early-onset dementia (n = 55), mild cognitive impairment due to vascular or suspected neurodegenerative (MCI-n, n = 35) or non-neurodegenerative (MCI-o, n = 106) etiologies, and subjective cognitive decline (n = 14).Results: The most prevalent diagnoses were Alzheimer's disease (AD, 14%) and depression (11%). Multiple prior medical conditions were common (67%); however, EOD patients had fewer other diagnoses (p = 0.008) than MCI-o patients. Compared to other groups, EOD patients had more severe deficits (p < 0.001) on immediate and delayed memory, processing speed, symptom awareness, and global cognition. AD patients had weaker memory retention ability but less behavioral symptoms than frontotemporal dementia (FTD) patients (p≤0.05). Depression was associated with better immediate memory, symptom awareness, and global cognition than AD and FTD (p < 0.05).Conclusions: EOD is associated with more severe and widespread neuropsychological deficits but fewer prior medical diagnoses than nondegenerative etiologies of cognitive impairment. AD and depression are common etiologies and the neuropsychological profiles are partly overlapping; however, memory, symptom awareness and global cognitive impairment measures may help in the differential diagnosis.","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139671847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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