三重确认：认知正常的人脑脊液中的AD足迹
2012-07-09 17:17:53   来源：   作者：  评论：0 点击：

15 2010年8月 在临床研究中，首次发现可能振奋的阴谋，但它是一般的数据，给他们留下了不可磨灭的印记潜在的独立确认。这就是为什么脑脊液（CSF）在这个月的神经学档案阿尔茨海默病的生物标志物的研究应该进行更多的重量，足以保证在覆盖纽约时报。几个关键的调查结果比认知正常老年人的三分之一，实际数字定义此病理读确认此前公布的数据存在一个AD签名。雨果Vanderstichele Innogenetics公司，根特，比利时，和同事在最新出版的研究，不仅确定参加的长者1 AD样脑脊液签名阿尔茨海默氏病影像学倡议（ADNI），但也验证2独立的欧洲人群中这些数据。（Innogenetics 公司是1比利时公司，生产CSF的测试套件和立场，以争取它们的广泛使用。）在另一项研究报告上个月的阿尔茨海默氏病在檀香山，夏威夷，史蒂芬 Edland，美国加州圣迭戈国际会议，和同事得出了类似的的脑脊液签名，广泛的年龄分析公元五个研究中心在美国的参与者

之前在欧洲和美国的研究建立低脑脊液Aβ1-42和AD发病的早期指标升高脑脊液tau蛋白磷酸化tau-181P（P-tau蛋白）（见，例如，东盟地区论坛有关的新闻报道，费根等人，2007年） 。最近，ADNI流体生物化学研究，由莱斯利·肖，宾夕法尼亚大学，费城，脊髓液中Aβ42和tau定义的阈值浓度，相关疾病（Shaw等，2009）。Shaw和他的同事发现公元192皮克/毫升或更低的Aβ42的切点作为诊断分析预验脑脊液标本尸检证实AD患者和年龄匹配的认知正常的研究参与者，在大学的AD研究中心。应用的ADNI集，这些脑脊液标准正确识别AD患者超过96％的时间。

在目前的纸张，第一作者，比利时根特大学，和他的同事，包括邵氏，海尔特德迈耶选择了不同的策略，解决同样的问题确定脑脊液阈值的判别与公元人民团体。他们对资本从肖氏2009年的研究数据的离奇模式：法线陷入两个相当不同的群一个一个AD的CSF的个人资料，没有其他。这促使德•梅耶尔和他的同事们使用混合模型，以确定自然发生公元签名，或切点，基于CSFAβ42及P-tau181，在400多个ADNI 55至90岁的参与者，与AD，统计方法，轻度认知障碍（MCI），或认知功能正常。这里的新颖性，是德•梅耶尔和他的同事们决心，没有任何临床或诊断信息，对受试者的诊断切点。他们这样做是为了避免偏见有关的问题，更常用的方法评估生物标志物。

为了验证脑脊液阈值，从这个临床盲目进场，研究人员分析了两个单独的ADNI人群：在比利时的尸检证实的队列，从一个不同的欧洲纵向研究患者的一个子集。在比利时的队列中，65人中有73人有一个AD的诊断，尸检和脑脊液标准的94％，这些患者正确分类。在欧洲的研究（汉森等人，2006年），五年内转换到公元175 MCI的患者，57和脑脊液阈值确定了100％，这些皈依。此外，36％ADNI认知正常的老年人有类似的AD-CSF的读取，“强调在症状出现之前的AD病理的存在，”作者写道。

也许是令人印象深刻的事实，由De Meyer等人的研究。到达CSF切点了188皮克/毫升，192皮克/毫升，从邵氏的早期作品，它使用了不同的研究设计和统计方法几乎相同。“曾经是一个巨大的问题是，所有的地方不同的数值（为脑脊液阈值），”肖说，东盟地区论坛。“我们开始看到更好的定量结果的复制，这是非常重要的。”这两项研究使用相同Innogenetics公司平台，为他们的免疫，每发现脑脊液数据落入两个垃圾桶整齐，那些使用和不使用公元签名即使在正常组。

在ICAD中，Edland报告惊人地相似，从CSF中与伊莱恩Peskind，华盛顿大学，西雅图，担任小组成员，东盟地区论坛在最近的一次网络研讨会（见脑脊液分析的价值合作完成的生物标志物分析结果东盟地区论坛现场讨论）。edland和他的同事们也用Innogenetics公司的平台，即使采用相同的公正的统计方法，分析303认知正常公元五个研究中心招募志愿者。这些都不是ADNI参与者。其脑脊液Aβ42的截止值190和200皮克/毫升之间，Edland告诉东盟地区论坛，这是由De Meyer等人在报纸上报道的门槛接近。Shaw等。

edland的研究是独特的，它包括年轻的成年人。他的志愿者中，有125分别为20和55岁之间。“所有这些年轻的法线的重要性是，它真的指甲一个'正常'CSF的个人资料是什么，”Edland在接受电话采访时说。这为中老年人群的发现的“戏剧性”的阶段。“许多人可能会猜测，你有年轻的成年人的正常脑脊液Aβ水平，为您获得疾病，[脑脊液读数]漂流到一个AD水平一样，”他说。然而，在56和老年人组的脑脊液Aβ42的水平明显双峰，确认2009年邵氏的纸，首先描述这脑脊液Aβ42的分布在法线的结果。Edland，说：“”一个模式，看起来就像年轻的法线，和其他看起来就像公元。“关于双峰分布的迷人之处在于，它表明，正常和AD脑脊液型材之间的过渡很快发生。这不是一个数据涂片。从一个分配到其他人跳。我认为这里是最重要的信息。“

当他们认为ApoE基因E4类认知正常的携带者之间，研究人员发现，年龄70岁及以上，有三分之二像一个AD-CSF的个人资料，Edland说。相比之下，只有第四个同样年龄E4非携带者有AD的签名。

两者合计，最近的调查结果应推动越来越多的运动，以支持脑脊液分析，多年来得到的冷遇，因为有些医生不愿意执行脊髓水龙头（又名“腰椎穿刺”）和患者不愿接受手术过程。在这一点上，由De Meyer等的纸张上的神经评论。注 意到，脊髓水龙头是“没有更多的比，如内窥镜，数百万美国人的容忍每年其他门诊程序侵入。”此外，脑脊液的Aβ和tau蛋白读数的成本相形见绌“的咨询医 生的法案，神经心理测试费比较，磁共振脑扫描在大多数中心“的费用，写A.扎拉Herskovits布里格姆和妇女医院，马萨诸塞州总医院，无论是在波士 顿和约翰Growdon。

常规临床使用仍然是一个办法，部分原因是由于质量控制和生产问题。然而，专家纷纷推出全球倡议，来应对这些挑战（见ARF的相关新闻报道），包括一系列的修订草案中的生物标志物之 ​​间的的脑脊液措施公元诊断标准（见ARF的相关新闻报道）。

作为生物标志物研究在温和的人口快速推进（ARF的覆盖面，在今年的阿尔茨海默氏病国际会议介绍），有些人认为脑脊液检测保证在一些研究设置更多的关注。“我觉得测试是在治疗试验中的黄金时间做好准备，例如，”肖说东盟地区论坛，指出脑脊液生物标记物可以帮助确定疾病的风险高或低的参与者。

此外，“凝视着未来时，有AD的神经保护药物，我们可以设想，脑脊液分析可以作为筛选试验，以确定在MCI和AD的临床健康风险的个人实施的建议”Herskovits和Growdon写。“获得的信息将有助于延缓认知功能障碍的症状或进展缓慢的发病早期应用的治疗。”以斯帖Landhuis。

参考：
德•梅耶尔G，F·夏皮罗，范德SticheleĤVanmechelenéEngelborghs小号，德Deyn的聚丙烯，CoartéØ汉森，大号 Minthon，ZetterbergĤ，Blennowķ肖大号，Trojanowski阿尔茨海默氏症的影像学倡议疾病J。独立诊断的生物标志物在阿尔茨海默氏症的认知正常老人签名。拱桥“神经病学神经。2010年8月67（8）:949-956。摘要

15 August 2010. In clinical research, a first-time finding may rouse intrigue, but it’s generally independent confirmations of the data that give them potential to leave an indelible mark. That’s why a study of cerebrospinal fluid (CSF) biomarkers of Alzheimer disease in this month’s Archives of Neurology should carry all the more weight—enough to warrant coverage in The New York Times. Several key findings—the presence of an AD signature in more than a third of cognitively normal seniors, and the actual figures that define this pathological read—confirm previously published data. In the newly published study, Hugo Vanderstichele, Innogenetics, Gent, Belgium, and colleagues not only identified an AD-like CSF signature in seniors enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), but also validated these data in two independent European populations. (Innogenetics is a Belgian company that manufactures CSF test kits and stands to gain from their widespread use.) In a separate study reported last month at the International Conference on Alzheimer’s Disease in Honolulu, Hawaii, Steven Edland, University of California, San Diego, and colleagues derived a similar CSF signature, analyzing participants of wide-ranging age from five AD research centers in the U.S.

Prior research in Europe and the U.S. established low CSF Aβ1-42 and elevated CSF tau and phosphorylated tau-181P (p-tau) as early indicators of AD pathogenesis (see, e.g., ARF related news story on Fagan et al., 2007). More recently, the ADNI fluid biochemistry study, led by Leslie Shaw, University of Pennsylvania, Philadelphia, defined threshold concentrations of spinal fluid Aβ42 and tau that associated with disease (Shaw et al., 2009). Shaw and colleagues identified an Aβ42 cut point of 192 pg/ml or lower as diagnostic for AD, by analyzing pre-mortem CSF samples from autopsy-confirmed AD patients and age-matched cognitively normal research participants at the university’s AD research center. Applied to the ADNI dataset, these CSF criteria correctly identified AD patients more than 96 percent of the time.

In the current paper, first author Geert De Meyer, Ghent University, Belgium, and colleagues, including Shaw, chose a different strategy to tackle the same problem of identifying CSF thresholds that discriminate groups of people with and without AD. They capitalized on an uncanny pattern in the data from Shaw’s 2009 study: the normals fell into two fairly distinct subgroups—one with an AD-like CSF profile, the other without. This prompted De Meyer and colleagues to use a statistical approach known as mixture modeling to identify naturally occurring AD signatures, or cut points, based on CSF Aβ42 and p-tau181, in more than 400 ADNI participants, aged 55 to 90, with AD, mild cognitive impairment (MCI), or normal cognition. The novelty here is that De Meyer and colleagues determined their diagnostic cut points without any clinical or diagnostic information on the subjects. They did this to avoid bias-related problems with more commonly used methods for assessing biomarkers.

To validate the CSF threshold values coming from this clinically blind approach, the researchers analyzed two separate populations outside of ADNI: an autopsy-proven cohort in Belgium, and a subset of patients from a different European longitudinal study. In the Belgian cohort, 65 of 73 people had an AD diagnosis at autopsy, and the CSF criteria correctly classified 94 percent of these patients. In the European study (Hansson et al., 2006), 57 of 175 MCI patients converted to AD within five years, and the CSF threshold values identified 100 percent of these converts. Furthermore, 36 percent of cognitively normal ADNI seniors had AD-like CSF reads, which “underscores the presence of AD pathology before the onset of symptoms,” the authors write.

Perhaps as impressive was the fact that the study by De Meyer et al. arrived at a CSF cut point of 188 pg/ml, virtually identical to the 192 pg/ml coming from Shaw’s earlier work, which used a different study design and statistical methods. “What had been a huge issue is that numerical values (for CSF thresholds) varied all over the place,” Shaw told ARF. “We're starting to see better replication of the quantitative results, and that's very important.” Both studies used the same Innogenetics platform for their immunoassays, and each found the CSF data falling neatly into two bins, those with and without an AD signature, even within the normal groups.

At ICAD, Edland reported strikingly similar findings from a CSF biomarkers analysis done in collaboration with Elaine Peskind, University of Washington, Seattle, who served as a panelist in a recent ARF Webinar on the value of CSF analysis (see ARF Live Discussion). Edland and colleagues also used the Innogenetics platform, even applying the same unbiased statistical methods, to analyze 303 cognitively normal volunteers recruited at five AD research centers. These are not ADNI participants. Their CSF Aβ42 cut-off value came out between 190 and 200 pg/ml, Edland told ARF, which is in close proximity to the thresholds reported in the papers by De Meyer et al. and Shaw et al.

Edland’s study was unique in that it included younger adults. Of his volunteers, 125 were between the ages of 20 and 55. “The importance of having all those young normals is that it really nails down what a ‘normal’ CSF profile is,” Edland said in a phone interview. This set the stage for the “dramatic” finding in the older subgroup. “Many might guess that you've got normal CSF Aβ levels as young adults, and as you acquire disease, the [CSF readout] would drift to an AD-like level,” he said. However, CSF Aβ42 levels in the 56-and-older group were clearly bimodal, confirming the results of Shaw’s 2009 paper, which first described this CSF Aβ42 distribution in normals. “One mode looks just like the young normals, and the other looks just like AD,” said Edland. “The fascinating thing about the bimodal distribution is that it suggests the transition between normal and AD CSF profiles happens very quickly. It's not a smear of data. People jump from one distribution to the other. I think that is the most important message here.”

When they considered ApoE genotype, the researchers found that, among cognitively normal E4 carriers ages 70 and up, two-thirds have an AD-like CSF profile, Edland said. By contrast, only a fourth of similarly aged E4 non-carriers had the AD signature.

Taken together, the recent findings should fuel a growing movement to support CSF analysis, which has for years gotten short shrift because of some doctors’ reluctance to perform spinal taps (aka “lumbar punctures”) and patients’ unwillingness to receive the invasive procedure. On this point, an Archives of Neurology commentary on the paper by De Meyer et al. notes that spinal taps are “no more invasive than other outpatient procedures such as endoscopies that millions of Americans tolerate each year.” Moreover, the cost of CSF Aβ and tau readouts pales in comparison to “the consulting physician’s bill, the charge for neuropsychological testing, and the cost of a magnetic resonance brain scan” at most centers, write A. Zara Herskovits of Brigham and Women’s Hospital, and John Growdon of Massachusetts General Hospital, both in Boston.

Routine clinical use is still a way off, partly due to quality control and manufacturing issues. However, experts have launched worldwide initiatives to address these challenges (see ARF related news story), and included CSF measures among a set of biomarkers in a draft revision of AD diagnostic criteria (see ARF related news story).

As biomarker studies in milder populations proceed apace (see ARF coverage of presentations at this year’s International Conference on Alzheimer’s Disease), some think CSF assays warrant more attention in some research settings. “I feel the tests are ready for prime time for inclusion in treatment trials, for example,” Shaw told ARF, noting that CSF biomarkers could help identify participants at high or low disease risk.

Furthermore, “gazing into the future when there are neuroprotective medications for AD, we can envision a recommendation that CSF analyses be implemented as a screening test to identify clinically healthy individuals at risk for MCI and AD,” Herskovits and Growdon write. “The information gained would enable early application of treatments to delay onset of symptoms or slow progression of cognitive impairments.”—Esther Landhuis.

References:
De Meyer G, Shapiro F, Vanderstichele H, Vanmechelen E, Engelborghs S, De Deyn PP, Coart E, Hansson O, Minthon L, Zetterberg H, Blennow K, Shaw L, Trojanowski J for the Alzheimer’s Disease Neuroimaging Initiative. Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. Arch Neurol. August 2010;67(8):949-956. Abstract

Herskovits AZ and Growdon JH. Sharpen that needle. Arch Neurol. August 2010;67(8):918-920. Abstract