摘要
背景:阿尔茨海默病(AD)目前无法治愈,大部分研究药物临床试验失败。对这种失败的一种解释可能是关于淀粉样蛋白解释AD发病机理的假设的无效性。最近,以突触和代谢功能障碍为中心的假设越来越牵涉到AD。 目的:通过比较正常与AD脑脊液中的神经递质和代谢物标记物浓度来评估AD假说。 方法:Meta分析允许统计比较从多个出版物中提取的混合的,现有的脑脊液(CSF)标记数据,以获得更可靠的浓度估计。这种方法还提供了一个独特的机会,使用所得的CSF浓度数据快速验证AD假设。对于关键词“AD”,“CSF”和“human”以及为突触和代谢途径选择的标记,Hubmed,Pubmed和Google Scholar全面搜索了已发表的英文文章,没有日期限制。突触标记物是乙酰胆碱,γ-氨基丁酸(GABA),谷氨酰胺和甘氨酸。代谢标志物是谷胱甘肽,葡萄糖,乳酸盐,丙酮酸盐和其他8种氨基酸。只有在AD和对照(Ctl)中测量标记物的研究提供了方法,标准误差/偏差和受试者编号被包括在内。数据由六位作者提取,并由另外两位审查准确性。使用Cochrane协作网的Review Manager软件,使用平均比率(AD / Ctl的RoM)和随机效应荟萃分析汇集数据。 结果:在435份确定的出版物中,在排除和删除重复文献后,共纳入了35篇文章,共包括605名AD患者和585名对照者。以下标记的突触和代谢途径在AD /对照中显着改变:乙酰胆碱(RoM 0.36,95%CI 0.24-0.53,p <0.00001),GABA(0.74,0.58-0.94,p <0.01),丙酮酸盐(0.48, 0.24-0.94,p = 0.03),谷胱甘肽(1.11,1.01-1.21,p = 0.03),丙氨酸(1.10,0.98-1.23,p = 0.09),乳酸的显着性水平较低(1.2,1.00-1.47,p = 0.05)。值得注意的是,AD中CSF葡萄糖和谷氨酸水平与对照组相比没有显着差异。 结论:本研究为使用AD假说的荟萃分析验证提供了概念验证,特别是通过AD的胆碱能假说的有力证据。我们的数据不同意其他突触假说的谷氨酸兴奋性毒性和GABA能神经退行性,鉴于观察不变的谷氨酸水平和降低GABA水平。关于代谢假说,数据支持使用谷氨酸的无氧糖酵解,戊糖磷酸途径(谷胱甘肽)和三羧酸循环的复杂性上调。荟萃分析的未来应用表明进一步计算机评估和产生新型hy的可能性
关键词: 无氧糖酵解,谷氨酸兴奋毒性,CSF,GABA抗性,胆碱能假说,戊糖磷酸途径,谷氨酰胺解。
Current Alzheimer Research
Title:Evaluation of Metabolic and Synaptic Dysfunction Hypotheses of Alzheimer's Disease (AD): A Meta-Analysis of CSF Markers
Volume: 15 Issue: 2
关键词: 无氧糖酵解,谷氨酸兴奋毒性,CSF,GABA抗性,胆碱能假说,戊糖磷酸途径,谷氨酰胺解。
摘要: Background: Alzheimer's disease (AD) is currently incurable and a majority of investigational drugs have failed clinical trials. One explanation for this failure may be the invalidity of hypotheses focusing on amyloid to explain AD pathogenesis. Recently, hypotheses which are centered on synaptic and metabolic dysfunction are increasingly implicated in AD.
Objective: Evaluate AD hypotheses by comparing neurotransmitter and metabolite marker concentrations in normal versus AD CSF.
Methods: Meta-analysis allows for statistical comparison of pooled, existing cerebrospinal fluid (CSF) marker data extracted from multiple publications, to obtain a more reliable estimate of concentrations. This method also provides a unique opportunity to rapidly validate AD hypotheses using the resulting CSF concentration data. Hubmed, Pubmed and Google Scholar were comprehensively searched for published English articles, without date restrictions, for the keywords “AD”, “CSF”, and “human” plus markers selected for synaptic and metabolic pathways. Synaptic markers were acetylcholine, gamma-aminobutyric acid (GABA), glutamine, and glycine. Metabolic markers were glutathione, glucose, lactate, pyruvate, and 8 other amino acids. Only studies that measured markers in AD and controls (Ctl), provided means, standard errors/deviation, and subject numbers were included. Data were extracted by six authors and reviewed by two others for accuracy. Data were pooled using ratio of means (RoM of AD/Ctl) and random effects meta-analysis using Cochrane Collaboration’s Review Manager software.
Results: Of the 435 identified publications, after exclusion and removal of duplicates, 35 articles were included comprising a total of 605 AD patients and 585 controls. The following markers of synaptic and metabolic pathways were significantly changed in AD/controls: acetylcholine (RoM 0.36, 95% CI 0.24-0.53, p<0.00001), GABA (0.74, 0.58-0.94, p<0.01), pyruvate (0.48, 0.24-0.94, p=0.03), glutathione (1.11, 1.01- 1.21, p=0.03), alanine (1.10, 0.98-1.23, p=0.09), and lower levels of significance for lactate (1.2, 1.00-1.47, p=0.05). Of note, CSF glucose and glutamate levels in AD were not significantly different than that of the controls.
Conclusion: This study provides proof of concept for the use of meta-analysis validation of AD hypotheses, specifically via robust evidence for the cholinergic hypothesis of AD. Our data disagree with the other synaptic hypotheses of glutamate excitotoxicity and GABAergic resistance to neurodegeneration, given observed unchanged glutamate levels and decreased GABA levels. With regards to metabolic hypotheses, the data supported upregulation of anaerobic glycolysis, pentose phosphate pathway (glutathione), and anaplerosis of the tricarboxylic acid cycle using glutamate. Future applications of meta-analysis indicate the possibility of further in silico evaluation and generation of novel hypotheses in the AD field.
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Cite this article as:
Evaluation of Metabolic and Synaptic Dysfunction Hypotheses of Alzheimer's Disease (AD): A Meta-Analysis of CSF Markers, Current Alzheimer Research 2018; 15 (2) . https://dx.doi.org/10.2174/1567205014666170921122458
DOI https://dx.doi.org/10.2174/1567205014666170921122458 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
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