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Field: Neuroscience & Behavior
Article Title: Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer's disease
Authors: Georganopoulou, DG;Chang, L;Nam, JM;Thaxton, CS;Mufson, EJ;Klein, WL;Mirkin, CA
Journal: PROC NAT ACAD SCI USA
Volume: 102
Issue: 7
Page: 2273-2276
Year: FEB 15 2005

William L. Klein answers a few questions about this month's fast breaking paper in the field of Neuroscience & Behavior.

Q： Why do you think your paper is highly cited?

A：Our paper is about Alzheimer's disease (AD), and there's tremendous interest in this subject. The story in our paper is very novel and very significant, which is why both the National Science Foundation and the Proceedings of the National Academy of Sciences promoted it's and why the media coverage was high. We offer hope of a lab test for AD there's none currently available?but, with continued effort, our work potentially could rectify that.

Q:Does it describe a new discovery or a new methodology that's useful to others?

A：Both. Our findings establish that spinal fluid (CSF) contains "ADDLs" (amyloid-derived diffusible ligands), which are a new type of neurotoxin that we previously discovered and found in brain tissue affected by Alzheimer,s. It seems increasingly likely that ADDLs, cause AD memory loss. The new findings show that ADDLs in CSF show a striking AD-dependence. This suggests that ADDLs might provide, for the first time, a real biomarker for the disease.

The methology is incredible! Our measurements depended entirely on a novel nanotechnology invented in Chad Mirkin,s laboratory. His "Biobarcode?" is orders of magnitude more sensitive than the best ELISAs (Enzyme linked immunosorbent assays) and it retains the specificity of immunassays. It can be adapted to other diseases and applications and is a real breakthrough. NSF has been a real force in helping to develop this technology through its support of Northwestern?s Nanoscale Science and Engineering Center.

Q：Could you summarize the significance of your paper in layman's terms?

A：The conclusions are exciting because they lay the foundation for lab tests that could provide a definitive diagnosis for AD. Right now, AD is diagnosed by clinical interviews and the diagnosis accuracy is less than 90%.

Q：How did you become involved in this research, and were there successes or failures along the way?

A：We discovered ADDLs a number of years ago in biochemical experiments. When we found that ADDLs could inhibit memory mechanisms experimentally, it became crucial to determine whether they actually occurred in AD brain tissue. Assessment of CSF was part of the effort. However, prior to the Biobarcode?, we couldn't measure levels of CSF-ADDLs.

Q：If applicable, what are the social or political implications of your research?

A：Given our aging population and the incredible financial burden of AD, it's going to be important to find an effective AD treatment. As of now, none exists. We're hopeful that our findings and methods will accelerate drug discovery by providing reliable assessments of the disease, in addition to validating our concepts concerning disease mechanisms.

William L. Klein
Professor of Neurobiology & Physiology
Cognitive Neurology and Alzheimer's Disease Center
Northwestern University Institute for Neuroscience
Northwestern University
Evanston, IL, USA


这是一篇里程碑式的重要突破，文章得到高度评价和重视。

以下是TS记者与论文作者的访谈录：

问：你认为你的文章引用率为什么如此高?
答：我们的论文是有关老年痴呆症的研究，医学界具有极大的兴趣。我们在论文中所描述的“故事”很新颖，意义重大，所以国家科学基金会和美国国家科学院报如此推崇，媒体报道和覆盖率如此高。目前还没有在实验室检测老年痴呆症的可靠方法，我们的研究成果以及后续的努力，有望提供这样一种检测方法和手段。

问：论文是否描述了一种新发现或对其他学者有用的新方法？
答：两方面都有。我们的研究结果证实脊髓液中含有淀粉样蛋白可扩散配体（amyloid衍生diffusible ligands，简称“ADDLs”），这是我们以前在老年痴呆症患者脑组织中已发现的一种新型神经毒素。越来越多的证据表明，ADDLs很可能造成记忆丧失问题。我们的最新研究结果显示，在ADDLs在脊髓液中的出现明显与老年痴呆症相关。这表明ADDLs可能首次提供了真正的诊断老年痴呆症的生物标记biomarker。

这一新颖的方法是不可思议的！我们的测定完全取决于Chad Mirkin实验室发明的一种新的纳米技术，这种被称为生物条玛（Biobarcode）显示技术，灵敏度要比传统的最佳免疫酶标ELISAs方法要高出好几个数量级，其专一性与免疫酶标相仿。它可以同样应用到检测其他疾病，这真是一项重大突破！美国国家科学基金是这项技术开发的真正推手，主要通过其西北纳米级科技工程中心给予我们支持。

问：你能用最通俗的语言概述一下你的论文意义何在？
答：我们的研究（成果）结论是令人振奋的，因为这项研究为实验室准确检测老年痴呆症奠定了基础。现在的检测方法是基于临床面谈（试），准确诊断率不到90%。

问：您如何涉足这项研究的？在研究过程中有什么成功或失败之处可以与大家分享？
答：在多年前，我们通过生化实验发现了ADDLs。当我们用实验证明了ADDLs可抑制记忆的机制，尤其重要的是，需要进一步确定其机制是否真正发生在脑细胞组织中。评测CSF的工作就是其中的部分（努力）工作，然而，在biobarcode我们无法测定CSF-ADDLs水准。

问：适用哪些政治或社会问题研究？
答：由于我们的人口老龄化问题和由于老年痴呆症多带来的巨大财政负担，使找出有效的治疗药物和方法变得极为重要或迫在眉睫。至今为至，没有任何可靠的方法和治疗存在。我们希望，我们的调查结果和方法将会加速药物的发现，除了进一步了解和完善我们对该疾病的机制的了解外，也希望帮助临床医生提供了可靠的评价疾病方法。

背景介绍

老年痴呆症是最常见的神经退行性疾病，在世界范围内使大约一千六百万人遭受折磨，并且诊断后平均存活期为九年。它是一种中枢神经（大脑皮层）退行性疾病，主要表现为进行性记忆的丧失和认知能力损害的症状。这种疾病以轻微的认知损害为开端，但与其他与年龄有关的痴呆症的良性症状不能相区别。目前除了在患者死后通过大脑中衰老斑和神经纤维混乱的出现这些指标进行疾病确认外还没有公认的诊断标准。而生前的诊断精确度只有85%。临床诊断主要根据病人的病史；大脑影像学；还有心理学，认知和神经学测试。实验室辅助诊断方法主要是检测体液中含有的可溶性标志物。检测老年痴呆症的可溶性的标志物有两种常用的方法。一种方法是测量脑脊液或血浆中的总TAU蛋白总量或淀粉体浓度。因为这些标志物水平在正常个体和患病个体间有显著的重叠，特异性不高，容易造成漏诊和误诊，这种方法的使用受到了限制。另一种方法专注于检测那些值得怀疑的病理标志物，如粘着TAU蛋白，磷酸化TAU蛋白和ADDL的浓度。尽管这种检测病理性标志物的方法将会有更加准确的结论，但是由于在发病的早期这些标志物在脑脊液中浓度太低，而不能用通常的的ELISA或免疫印迹方法进行检测。最近研究发现的脑脊液（cerebrospinal fluid，CSF）中ADDL水平与疾病的相关性，有望早期确立AD诊断和早期治疗。Chad Mirkin博士和他的学生应用生物条形码检测技术（Bio-barcode Assay，BCA）早期诊断AD显然是一聪明的设计和可行的方案。这种技术根据免疫学原理，应用特异性抗ADDL的单克隆抗体，特异性结合脑脊液中微量的ADDL，通过生物条形码DNA的准确而特异地放大，间接定量检测ADDL，从而诊断AD。

研究表明，ADDL、贝塔淀粉体的小的可溶性的低聚物，可能是与AD相关联的记忆损失的病理因子。这种观点基于ADDL的神经毒性作用，它在AD病人的大脑中的含量水平高于年龄相仿的对照组。小白鼠实验表明，经注射贝塔淀粉体的抗体，记忆损伤发生了逆转。这暗示ADDL可作为一种新的老年痴呆症的病理标志物。本研究的目的即是利用生物条形码放大测定原理发展一种检测脑脊液中可溶性病理标志物ADDL蛋白的诊断工具，将有利于早期诊断老年痴呆症。

请参见
http://bioteq.bokee.com/2124306.html


编辑：西门吹血