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Immunosenescence of Natural Killer Cells, Inflammation, and Alzheimer's Disease. 自然杀伤细胞的免疫衰老、炎症和阿尔茨海默病。
Q1 Neuroscience Pub Date : 2018-11-01 eCollection Date: 2018-01-01 DOI: 10.1155/2018/3128758
Corona Solana, Raquel Tarazona, Rafael Solana

Alzheimer's disease (AD) represents the most common cause of dementia in the elderly. AD is a neurodegenerative disorder characterized by progressive memory loss and cognitive decline. Although the aetiology of AD is not clear, both environmental factors and heritable predisposition may contribute to disease occurrence. In addition, inflammation and immune system alterations have been linked to AD. The prevailing hypothesis as cause of AD is the deposition in the brain of amyloid beta peptides (Aβ). Although Aβ have a role in defending the brain against infections, their accumulation promotes an inflammatory response mediated by microglia and astrocytes. The production of proinflammatory cytokines and other inflammatory mediators such as prostaglandins and complement factors favours the recruitment of peripheral immune cells further promoting neuroinflammation. Age-related inflammation and chronic infection with herpes virus such as cytomegalovirus may also contribute to inflammation in AD patients. Natural killer (NK) cells are innate lymphoid cells involved in host defence against viral infections and tumours. Once activated NK cells secrete cytokines such as IFN-γ and TNF-α and chemokines and exert cytotoxic activity against target cells. In the elderly, changes in NK cell compartment have been described which may contribute to the lower capacity of elderly individuals to respond to pathogens and tumours. Recently, the role of NK cells in the immunopathogenesis of AD is discussed. Although in AD patients the frequency of NK cells is not affected, a high NK cell response to cytokines has been described together with NK cell dysregulation of signalling pathways which is in part involved in this altered behaviour.

阿尔茨海默病(AD)是老年痴呆症最常见的病因。AD是一种以进行性记忆丧失和认知能力下降为特征的神经退行性疾病。尽管AD的病因尚不清楚,但环境因素和遗传易感性都可能导致疾病的发生。此外,炎症和免疫系统的改变也与AD有关。AD的主要原因是淀粉样β肽(Aβ)在大脑中的沉积。尽管Aβ在保护大脑免受感染方面发挥作用,但它们的积累促进了小胶质细胞和星形胶质细胞介导的炎症反应。促炎细胞因子和其他炎症介质如前列腺素和补体因子的产生有利于外周免疫细胞的募集,进一步促进神经炎症。年龄相关的炎症和巨细胞病毒等疱疹病毒的慢性感染也可能导致AD患者的炎症。自然杀伤细胞(NK)是参与宿主防御病毒感染和肿瘤的先天性淋巴细胞。一旦激活,NK细胞就会分泌IFN-γ和TNF-α等细胞因子和趋化因子,并对靶细胞发挥细胞毒性活性。在老年人中,已经描述了NK细胞区室的变化,这可能导致老年人对病原体和肿瘤的反应能力降低。最近,人们讨论了NK细胞在AD免疫发病中的作用。尽管在AD患者中,NK细胞的频率没有受到影响,但已经描述了NK细胞对细胞因子的高反应,以及NK细胞对信号通路的失调,这在一定程度上与这种改变的行为有关。
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引用次数: 0
Development of Regional Disparities in Alzheimer's Disease Mortality in the Slovak Republic from 1996 to 2015. 1996年至2015年斯洛伐克共和国阿尔茨海默病死亡率区域差异的发展
Q1 Neuroscience Pub Date : 2018-10-11 eCollection Date: 2018-01-01 DOI: 10.1155/2018/3149495
Beáta Gavurová, Viliam Kováč, Dominika Jarčušková

Alzheimer's disease-subsequently as AD in the text-represents a chronic neurodegenerative disease discussed very often in the recent period. It involves the G30 diagnosis expressing exactly AD and also the F00 diagnosis epitomising dementia in AD. The Slovak Republic has a very various population in terms of the disparities of the population localisation. The analysis is executed on the basement of the standardised mortality rate. It is calculated for the individual districts of the Slovak Republic to get a detailed spatial view and for each year of the explored period from 1996 to 2015 to get a time development. It has a considerably rising tendency. Therefore, the regional disparities of the standardised mortality rate of AD are analysed from an angle of view of its similarity, by its measurement in a form of a Euclidean distance approach. The results of the analysis offer the heat maps as the distance matrices in a graphic form and the maps of the individual districts too. These outputs reveal a very heterogeneous structure of the standardised mortality rate. Another graphic outcome demonstrates a distribution of its values among the districts throughout the whole Slovak Republic for the whole observed period. The results offer a comparison among the districts of the Slovak Republic too. The highest values and also the lowest values are reached in the different districts for the both sexes. Even, one district reaches the opposite result for the individual sexes. The age structure of the deceased population on the G30 diagnosis is also executed and the extreme values from an angle of a view of the districts are picked up. There are evident high differentiations between the individual districts of the Slovak Republic. The conclusion section involves the several key points and the potential suggestions for further research.

阿尔茨海默病(下文简称AD)是近年来经常讨论的一种慢性神经退行性疾病。它包括准确表达AD的G30诊断和体现AD痴呆的F00诊断。斯洛伐克共和国在人口本地化方面的差异非常大。该分析是在标准化死亡率的基础上进行的。对斯洛伐克共和国的各个地区进行了计算,以获得详细的空间视图,并对1996年至2015年期间的每一年进行了计算,以获得时间发展。它有相当大的上升趋势。因此,本文从相似度的角度,利用欧几里得距离法对AD标准化死亡率进行测量,分析AD标准化死亡率的地区差异。分析结果提供了以图形形式作为距离矩阵的热图和各区的地图。这些产出显示出标准化死亡率的结构非常不均匀。另一个图表结果显示了整个观察期间整个斯洛伐克共和国各区间的数值分布情况。结果也提供了斯洛伐克共和国各地区之间的比较。在不同的地区,男女都达到了最高和最低的值。甚至,有一个地区在两性方面得出了相反的结果。还执行了G30诊断中死亡人口的年龄结构,并从地区的角度提取了极值。斯洛伐克共和国各区之间的差别明显很大。结语部分包括本文的几个关键点和进一步研究的建议。
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引用次数: 3
Impaired Cerebral Vasomotor Reactivity in Alzheimer's Disease. 阿尔茨海默病的脑血管舒缩反应性受损。
Q1 Neuroscience Pub Date : 2018-09-09 eCollection Date: 2018-01-01 DOI: 10.1155/2018/9328293
Fernando Gongora-Rivera, Adolfo Cordero-Perez, Alejandro Gonzalez-Aquines, Antonio Anaya-Escamilla, Eduardo Villarreal-Garza, Meztli Espinosa-Ortega, Mario C Salinas-Carmona, Xochilt Ortiz-Jimenez

Background: Recent studies have shown that cerebral vascularity may be impaired in Alzheimer's disease. Cerebral vasomotor reactivity could be an important biomarker for this pathology.

Aims: The aim of this study was to investigate the alterations in cerebral vascular motor reactivity in Alzheimer's disease subjects and to associate these changes with their cognitive scores.

Methods: We recruited subjects with a diagnosis of Alzheimer's disease and healthy controls. Demographic, clinical, imaging, and cognitive test were obtained. Then all participants performed a cerebral vascular motor reactivity test with 7% CO2 and cerebral blood flow velocities (CBFV) were recorded with transcranial doppler ultrasound before and after the test.

Results: We recruited 45 subjects, 26 (21 female) Alzheimer's disease participants and 19 (15 female) healthy controls. There were no differences in baseline cerebral blood flow velocities between the groups. After the cerebral vasomotor reactivity test, absolute mean difference in mean CBFV (ΔCBFV-m) was 8.70±4.14 versus 4.81±6.96 (p<0.01), respectively. Calculated percentage of change (%CVMR) was lower in the AD group 7.45±18.25 versus 23.29±17.48, and there was a positive but weak correlation with mini-mental scores (ρ=0.337, p=0.023).

Conclusions: In this study, Alzheimer's disease subjects showed significant changes in all absolute cerebral blood flow velocities after the cerebral vasomotor reactivity test with CO2, but only diastolic phase responses were statistically significant. There was a positive but weak correlation between cerebral vasomotor reactivity and cognitive scores. Further studies are needed to investigate these effects in larger Latin-American samples.

背景:最近的研究表明,阿尔茨海默病可能导致脑血管功能受损。脑血管舒缩反应性可能是该病理的重要生物标志物。目的:本研究的目的是研究阿尔茨海默病患者脑血管运动反应性的变化,并将这些变化与他们的认知评分联系起来。方法:我们招募了诊断为阿尔茨海默病的受试者和健康对照者。进行人口学、临床、影像学和认知测试。然后在7% CO2条件下进行脑血管运动反应性测试,测试前后用经颅多普勒超声记录脑血流速度(CBFV)。结果:我们招募了45名受试者,26名阿尔茨海默病患者(21名女性)和19名健康对照者(15名女性)。两组之间的基线脑血流速度没有差异。脑血管舒缩反应性试验后,平均CBFV (ΔCBFV-m)的绝对平均差值为8.70±4.14 vs 4.81±6.96 (p =0.337, p=0.023)。结论:本研究中,阿尔茨海默病患者在CO2脑血管舒缩反应性试验后,所有脑绝对血流速度均有显著变化,但只有舒张期反应有统计学意义。脑血管舒缩反应性与认知评分呈正相关,但相关性较弱。需要进一步的研究在更大的拉丁美洲样本中调查这些影响。
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引用次数: 5
The Effect of 40-Hz Light Therapy on Amyloid Load in Patients with Prodromal and Clinical Alzheimer's Disease. 40Hz光疗法对原发性和临床阿尔茨海默病患者淀粉样蛋白负荷的影响。
Q1 Neuroscience Pub Date : 2018-07-30 eCollection Date: 2018-01-01 DOI: 10.1155/2018/6852303
Rola Ismail, Allan K Hansen, Peter Parbo, Hans Brændgaard, Hanne Gottrup, David J Brooks, Per Borghammer

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. AD pathology is characterized by abnormal aggregation of the proteins amyloid-β (Aβ) and hyperphosphorylated tau. No effective disease modifying therapies are currently available. A short-duration intervention with 40 Hz light flicker has been shown to reduce brain Aβ load in transgenic mice. We aimed to test the effect of a similar short-duration 40 Hz light flicker regime in human AD patients. We utilized a Light Emitting Diode (LED) light bulb with a 40 Hz flicker. Six Aβ positive patients received 10 days of light therapy, had 2 hours of daily exposure, and underwent a postintervention PiB PET on day 11. After 10 days of light therapy, no significant decrease of PiB SUVR values was detected in any volumes of interest tested (primary visual cortex, visual association cortex, lateral parietal cortex, precuneus, and posterior cingulate) or in the total motor cortex, and longer treatments may be necessary to induce amyloid removal in humans.

阿尔茨海默病(AD)是一种进行性神经退行性疾病。AD的病理特征是淀粉样蛋白-β(Aβ)和过度磷酸化的tau蛋白异常聚集。目前尚无有效的疾病改良疗法。40Hz光闪烁的短时间干预已被证明可以降低转基因小鼠的大脑Aβ负荷。我们旨在测试人类AD患者中类似的短持续时间40Hz光闪烁方案的效果。我们使用了一个闪烁频率为40赫兹的发光二极管(LED)灯泡。6名Aβ阳性患者接受了10天的光照治疗,每天暴露2小时,并在干预后第11天接受了PiB PET。在光治疗10天后,在任何感兴趣的测试体积(初级视觉皮层、视觉联想皮层、顶叶外侧皮层、楔前叶和后扣带)或整个运动皮层中都没有检测到PiB-SUVR值的显著降低,可能需要更长的治疗来诱导人类淀粉样蛋白的去除。
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引用次数: 0
Cognitive Assessment Test: Validation of a Short Cognitive Test for the Detection of Mild Cognitive Disorder. 认知评估测试:一种检测轻度认知障碍的简短认知测试的验证。
Q1 Neuroscience Pub Date : 2018-07-02 eCollection Date: 2018-01-01 DOI: 10.1155/2018/3280621
Kelly Estrada-Orozco, Kely Bonilla-Vargas, Francy Cruz, Oscar Mancera, Miguel Ruiz, Laura Alvarez, Rodrigo Pardo, Humberto Arboleda

Introduction: Cognitive disorders are a clinical and research challenge; in particular, the mild cognitive disorder (MiCD) requires diagnostic suspicion and tools with adequate performance for its detection. The objective of this study was the validation of a short cognitive test (CATest) for the detection of MiCD in population of 50 years or more.

Methods: A diagnostic accuracy study was assembled and performed in a prospective cohort. A consecutive sample of 200 Colombian subjects who represented the whole spectrum of the condition of interest allowed us to reach the objective. Validity was determined by concurrent criteria. The cut points were determined by the ROC curves considering the best overall performance and accuracy of the test.

Results: CATest was validated to detection of MiCD at a cut-off point of 18. As a result, scores lower than 18 classified the participants as MiCD. At this cut-off point, CATest showed sensitivity of 84.3% (CI 76 to 90.16), specificity of 71.4% (CI 95% 61.8 to 79.43), positive predictive value of 75% ( 95% CI 66.79 to 82.42), and area under curve AUC 0.8518 (standard error SE 0.0265).

Discussion: CATest has an adequate performance as a short cognitive test for the detection of MiCD. Its performance is superior to MiniMental and similar to Montreal Cognitive test (MoCA) according to the data reported in the literature. The advantages over other tests are the evaluation of all cognitive domains, time of application, and easy interpretation of results. CATest is a free use alternative for MiCD detection.

引言:认知障碍是一项临床和研究挑战;特别是,轻度认知障碍(MiCD)需要诊断怀疑和具有足够性能的检测工具。本研究的目的是验证一种短认知测试(CATest)在50岁或以上人群中检测MiCD的有效性。方法:在前瞻性队列中进行诊断准确性研究。连续抽样200名哥伦比亚受试者,他们代表了所有感兴趣的条件,使我们能够达到目标。有效性由并发标准确定。切割点由ROC曲线确定,考虑测试的最佳整体性能和准确性。结果:CATest在截断点为18的情况下能够检测到MiCD。因此,得分低于18分的参与者被归类为MiCD。在该截止点,CATest的敏感性为84.3% (CI 76 ~ 90.16),特异性为71.4% (CI 95% 61.8 ~ 79.43),阳性预测值为75% (95% CI 66.79 ~ 82.42),曲线下面积AUC为0.8518(标准误差SE 0.0265)。讨论:CATest作为一种简短的认知测试,在检测MiCD方面有足够的表现。从文献数据来看,其性能优于MiniMental,与Montreal Cognitive test (MoCA)相近。与其他测试相比,其优点是评估所有认知领域,应用时间短,结果易于解释。CATest是一种免费的MiCD检测替代品。
{"title":"Cognitive Assessment Test: Validation of a Short Cognitive Test for the Detection of Mild Cognitive Disorder.","authors":"Kelly Estrada-Orozco,&nbsp;Kely Bonilla-Vargas,&nbsp;Francy Cruz,&nbsp;Oscar Mancera,&nbsp;Miguel Ruiz,&nbsp;Laura Alvarez,&nbsp;Rodrigo Pardo,&nbsp;Humberto Arboleda","doi":"10.1155/2018/3280621","DOIUrl":"https://doi.org/10.1155/2018/3280621","url":null,"abstract":"<p><strong>Introduction: </strong>Cognitive disorders are a clinical and research challenge; in particular, the mild cognitive disorder (MiCD) requires diagnostic suspicion and tools with adequate performance for its detection. The objective of this study was the validation of a short cognitive test (CATest) for the detection of MiCD in population of 50 years or more.</p><p><strong>Methods: </strong>A diagnostic accuracy study was assembled and performed in a prospective cohort. A consecutive sample of 200 Colombian subjects who represented the whole spectrum of the condition of interest allowed us to reach the objective. Validity was determined by concurrent criteria. The cut points were determined by the ROC curves considering the best overall performance and accuracy of the test.</p><p><strong>Results: </strong>CATest was validated to detection of MiCD at a cut-off point of 18. As a result, scores lower than 18 classified the participants as MiCD. At this cut-off point, CATest showed sensitivity of 84.3% (CI 76 to 90.16), specificity of 71.4% (<b>CI</b> 95% 61.8 to 79.43), positive predictive value of 75% ( 95% CI 66.79 to 82.42), and area under curve AUC 0.8518 (standard error SE 0.0265).</p><p><strong>Discussion: </strong>CATest has an adequate performance as a short cognitive test for the detection of MiCD. Its performance is superior to MiniMental and similar to Montreal Cognitive test (MoCA) according to the data reported in the literature. The advantages over other tests are the evaluation of all cognitive domains, time of application, and easy interpretation of results. CATest is a free use alternative for MiCD detection.</p>","PeriodicalId":13802,"journal":{"name":"International Journal of Alzheimer's Disease","volume":"2018 ","pages":"3280621"},"PeriodicalIF":0.0,"publicationDate":"2018-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2018/3280621","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36354327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 5
Amyloid-Beta 1-42 Cross-Reactive Antibody Prevalent in Human Sera May Contribute to Intraneuronal Deposition of A-Beta-P-42. 人类血清中普遍存在的淀粉样β1-42交叉反应抗体可能有助于A-Beta-P-42的神经元内沉积。
Q1 Neuroscience Pub Date : 2018-06-21 DOI: 10.1155/2018/1672568
Aristo Vojdani, Elroy Vojdani

Antibodies against many neural antigens are detected in the sera of both patients with Alzheimer's disease (AD) and some healthy individuals. Blood-brain barrier dysfunction could make it possible for brain-reactive autoantibodies to reach the brain, where they can react with amyloid ß peptide (AßP). The origin of these autoreactive antibodies in the blood is unclear. The goals of this study were as follows: (1) to examine the immune reactivity of anti-AßP-42 with 22 neuronal and other associated antigens, some of which are involved in the pathophysiology of AD; (2) to classify antibodies to these 22 different antigens into those that cross-react with AßP-42 and those that do not; (3) to determine whether these antibodies react with BBB proteins, nerve growth factors, and enteric neuronal antigens. Using monoclonal AßP-42 antibody and ELISA methodology, we found that the antibody was highly reactive with Aß protein, tau protein, presenilin, rabaptin-5, β-NGF, BDNF, mTG, and enteric nerve. The same antibody produced equivocal to moderate reactions with glutamate-R, S100B, AQP4, GFAP, MBP, α-synuclein, tTG-2, and tTG-3, and not with the rest. These antibodies were also measured in blood samples from 47 AD patients and 47 controls. IgG antibodies were found to be elevated against AßP-42 and many other antigens in a significant percentage of controls. Overall, the mean OD values were significantly higher against 9/23 tested antigens (p <0.001) in the samples with AD. We were indeed able to classify the detected neuronal antibodies into those that cross-react with AßP-42 and those that do not. Our main finding is that although these antibodies may be harmless in a subgroup of controls, in individuals with compromised BBBs these antibodies that cross-react with AßP-42 can reach the brain, where their cross-reactivity with AßP-42 may contribute to the onset and progression of AD, and perhaps other neurodegenerative disorders.

在阿尔茨海默病(AD)患者和一些健康人的血清中都检测到了针对许多神经抗原的抗体。血脑屏障功能障碍可能使大脑反应性自身抗体到达大脑,在那里它们可以与淀粉样蛋白ß肽(Aß; P)反应。血液中这些自身反应抗体的来源尚不清楚。本研究的目的如下:(1)检测抗AßP-42与22种神经元和其他相关抗原的免疫反应性,其中一些抗原参与AD的病理生理学;(2) 将针对这22种不同抗原的抗体分为与AßP-42交叉反应的抗体和不与AłP-42A交叉反应的抗原;(3) 以确定这些抗体是否与血脑屏障蛋白、神经生长因子和肠道神经元抗原反应。使用单克隆AßP-42抗体和ELISA方法,我们发现该抗体与A 223蛋白、tau蛋白、早老素、rabatin-5、β-NGF、BDNF、mTG和肠神经具有高度反应性。同一抗体与戊二酸-R、S100B、AQP4、GFAP、MBP、α-突触核蛋白、tTG-2和tTG-3产生模棱两可到中等程度的反应,而与其他抗体不产生反应。这些抗体也在47名AD患者和47名对照的血液样本中测得。在对照组中,发现抗AßP-42和许多其他抗原的IgG抗体显著升高。总的来说,针对9/23测试抗原的平均OD值显著更高(p
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引用次数: 12
Analysis of Association of Genetic Markers in the LUZP2 and FBXO40 Genes with the Normal Variability in Cognitive Performance in the Elderly. LUZP2和FBXO40基因遗传标记与老年人认知表现正常变异性的关联分析
Q1 Neuroscience Pub Date : 2018-04-19 eCollection Date: 2018-01-01 DOI: 10.1155/2018/2686045
Vadim Stepanov, Kseniya Vagaitseva, Anna Bocharova, Andrey Marusin, Valentina Markova, Larisa Minaycheva, Oksana Makeeva

Cognitive performance is an important endophenotype for various neurodegenerative and neuropsychiatric traits. In the present study two genetic variants in the leucine-zipper protein (LUZP2) and the F-box 40 protein (FBXO40) genes, previously reported to be genome-wide significant for Alzheimer's diseases and schizophrenia, were examined for an association with cognitive abilities in normal elderly from the Russian population. Rs1021261 in the LUZP2 and rs3772130 in the FBXO40 were genotyped by multiplex PCR and MALDI-TOF mass spectrometry in a sample of 708 normal elderly subjects tested for cognitive performance using the Montreal Cognitive Assessment (MoCA). Association of genetic variability with the MoCA scores was estimated by parametric and nonparametric analysis of variance and by the frequency comparison between upper and lower quartiles of MoCA distribution. Significantly higher frequency of "TT" genotype of rs1021261 in the LUZP2 gene as well as "A" allele and "AA" genotype of rs3772130 in the FBXO40 gene was found in a subsample of individuals with the MoCA score less than 20 comparing to the fourth quartile's subsample (MoCA > 25). The data of the present study suggests that genetic variability in the LUZP2 and FBXO40 loci associated with neurodegenerative and neuropsychiatric diseases is also contributed to the normal variability in cognitive performance in the elderly.

认知表现是各种神经退行性和神经精神特征的重要内表型。在目前的研究中,亮氨酸拉链蛋白(LUZP2)和F-box 40蛋白(FBXO40)基因的两个遗传变异,先前报道在全基因组范围内对阿尔茨海默病和精神分裂症具有重要意义,研究了与俄罗斯人群正常老年人认知能力的关联。采用多重PCR和MALDI-TOF质谱技术,对708例使用蒙特利尔认知能力评估(MoCA)进行认知能力测试的正常老年受试者的LUZP2基因中的Rs1021261和FBXO40基因中的rs3772130进行基因分型。通过参数和非参数方差分析以及MoCA分布上下四分位数的频率比较,估计遗传变异与MoCA评分的关联。LUZP2基因中rs1021261的“TT”基因型以及FBXO40基因中rs3772130的“A”等位基因和“AA”基因型在MoCA评分低于20分的个体亚样本中出现的频率显著高于第四四分位数的亚样本(MoCA > 25)。本研究的数据表明,与神经退行性疾病和神经精神疾病相关的LUZP2和FBXO40基因座的遗传变异也有助于老年人认知能力的正常变异。
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引用次数: 7
Oil Palm Phenolics Inhibit the In Vitro Aggregation of β-Amyloid Peptide into Oligomeric Complexes. 油棕酚类物质抑制β-淀粉样肽在体外聚集成寡聚物。
Q1 Neuroscience Pub Date : 2018-01-31 eCollection Date: 2018-01-01 DOI: 10.1155/2018/7608038
Robert P Weinberg, Vera V Koledova, Hyeari Shin, Jennifer H Park, Yew Ai Tan, Anthony J Sinskey, Ravigadevi Sambanthamurthi, ChoKyun Rha

Alzheimer's disease is a severe neurodegenerative disease characterized by the aggregation of amyloid-β peptide (Aβ) into toxic oligomers which activate microglia and astrocytes causing acute neuroinflammation. Multiple studies show that the soluble oligomers of Aβ42 are neurotoxic and proinflammatory, whereas the monomers and insoluble fibrils are relatively nontoxic. We show that Aβ42 aggregation is inhibited in vitro by oil palm phenolics (OPP), an aqueous extract from the oil palm tree (Elaeis guineensis). The data shows that OPP inhibits stacking of β-pleated sheets, which is essential for oligomerization. We demonstrate the inhibition of Aβ42 aggregation by (1) mass spectrometry; (2) Congo Red dye binding; (3) 2D-IR spectroscopy; (4) dynamic light scattering; (5) transmission electron microscopy; and (6) transgenic yeast rescue assay. In the yeast rescue assay, OPP significantly reduces the cytotoxicity of aggregating neuropeptides in yeast genetically engineered to overexpress these peptides. The data shows that OPP inhibits (1) the aggregation of Aβ into oligomers; (2) stacking of β-pleated sheets; and (3) fibrillar growth and coalescence. These inhibitory effects prevent the formation of neurotoxic oligomers and hold potential as a means to reduce neuroinflammation and neuronal death and thereby may play some role in the prevention or treatment of Alzheimer's disease.

阿尔茨海默病是一种严重的神经退行性疾病,其特征是淀粉样蛋白-β肽(a β)聚集成有毒的低聚物,激活小胶质细胞和星形胶质细胞,引起急性神经炎症。多项研究表明,Aβ42的可溶性低聚物具有神经毒性和促炎作用,而其单体和不溶性原纤维则相对无毒。我们发现a - β42的聚集在体外被油棕酚类物质(OPP)抑制,这是一种来自油棕树(Elaeis guineensis)的水提取物。数据表明,OPP抑制β-褶片的堆积,这是寡聚化所必需的。我们通过(1)质谱法证明了a - β42聚集的抑制作用;(2)刚果红染料装订;(3) 2D-IR光谱;(4)动态光散射;(5)透射电镜;(6)转基因酵母拯救试验。在酵母拯救实验中,OPP显著降低了酵母基因工程中聚集神经肽的细胞毒性,使这些肽过表达。数据表明,OPP抑制(1)Aβ聚集成低聚物;(2) β-褶片的堆叠;(3)纤维的生长和合并。这些抑制作用可防止神经毒性低聚物的形成,并有可能作为减少神经炎症和神经元死亡的手段,从而可能在预防或治疗阿尔茨海默病中发挥一定作用。
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引用次数: 21
Regional Cerebral Blood Flow in Mild Cognitive Impairment and Alzheimer's Disease Measured with Arterial Spin Labeling Magnetic Resonance Imaging. 用动脉自旋标记磁共振成像测量轻度认知障碍和阿尔茨海默病的局部脑血流。
Q1 Neuroscience Pub Date : 2017-01-01 Epub Date: 2017-03-01 DOI: 10.1155/2017/5479597
Alba Sierra-Marcos

Alzheimer's disease (AD) depicts dynamic changes in regional brain function from early stages of the disease. Arterial spin labeling- (ASL-) based MRI methods have been applied for detecting regional cerebral blood flow (rCBF) perfusion changes in patients with AD and mild cognitive impairment (MCI). Nevertheless, the results obtained from ASL studies in AD and MCI are still controversial, since rCBF maps may show both hypoperfusion or hyperperfusion areas in brain structures involved in different cognitive functions. The goal of this review is to provide the current state of the art regarding the role of ASL for detecting distinctive perfusion patterns in subjects with MCI and/or AD. The ability to obtain this information using a noninvasive and widely available modality such as ASL should greatly enhance the knowledge into the broad range of hemodynamically related changes taking place during the cognitive decline process in AD.

阿尔茨海默病(AD)描述了该疾病早期区域脑功能的动态变化。基于动脉自旋标记(ASL)的MRI方法已被应用于检测AD和轻度认知障碍(MCI)患者的局部脑血流(rCBF)灌注变化。然而,从AD和MCI的ASL研究中获得的结果仍然存在争议,因为rCBF图可能显示涉及不同认知功能的脑结构中的低灌注或高灌注区域。本综述的目的是提供ASL在MCI和/或AD患者中检测不同灌注模式的作用的最新技术。通过非侵入性和广泛可用的方式(如ASL)获得这些信息的能力,将极大地增强对AD患者认知能力下降过程中发生的血流动力学相关变化的认识。
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引用次数: 49
Seeking a New Paradigm for Alzheimer's Disease: Considering the Roles of Inflammation, Blood-Brain Barrier Dysfunction, and Prion Disease. 寻找阿尔茨海默病的新范式:考虑炎症、血脑屏障功能障碍和朊病毒病的作用。
Q1 Neuroscience Pub Date : 2017-01-01 Epub Date: 2017-12-05 DOI: 10.1155/2017/2438901
Mark E McCaulley, Kira A Grush

There is no effective etiologic treatment for Alzheimer's disease, nor is there a prophylactic medication which delays or prevents its onset. The lack of an accurate paradigm is undoubtedly related to the lack of effective means of prophylaxis and treatment. The current paradigm of beta amyloid in Alzheimer's brains causing cognitive dysfunction must be modified. Despite failed clinical trials, research continues into amyloid-oriented treatments. The persistence of the amyloid hypothesis/paradigm is an example of anchoring and representativeness heuristics described by Kahneman and Tversky in their classic 1974 Science paper. Economic factors also contribute to the persistence of this paradigm. Paradigms impact the scientific process by the following: (1) what is studied; (2) the types of questions that are asked; (3) the structure and nature of the questions; (4) the interpretations of research findings. We review the contribution of inflammation, malfunction of the neurovascular unit, and prion disease to Alzheimer's disease manifestations. Any or all of these are candidates for inclusion into a more accurate, inclusive, and useful new paradigm. By incorporating emerging facts and understanding into a new paradigm, we will enhance our ability to move toward effective prophylaxis and therapy for this tragic disease.

目前还没有治疗阿尔茨海默病的有效病因,也没有延缓或防止其发病的预防性药物。缺乏准确的范式无疑与缺乏有效的预防和治疗手段有关。目前关于阿尔茨海默氏症患者大脑中的β淀粉样蛋白会导致认知功能障碍的模式必须改变。尽管临床试验失败了,但以淀粉样蛋白为导向的治疗研究仍在继续。淀粉样蛋白假说/范式的持续存在是卡尼曼(Kahneman)和特维尔斯基(Tversky)在其 1974 年的经典科学论文中描述的锚定和代表性启发式的一个例子。经济因素也促成了这一范式的持续存在。范式对科学进程的影响如下:(1) 研究的内容;(2) 提出的问题类型;(3) 问题的结构和性质;(4) 对研究结果的解释。我们回顾了炎症、神经血管功能失调和朊病毒疾病对阿尔茨海默病表现的影响。任何或所有这些都可以纳入一个更准确、更包容、更有用的新范式。通过将新出现的事实和认识纳入新范式,我们将提高我们的能力,为这种悲剧性疾病提供有效的预防和治疗。
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International Journal of Alzheimer's Disease
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