Early diagnostic marker for Alzheimer's disease

我们有三个主要目的在发展可靠的生物学标记在阿尔茨海默病（AD）。首先，它是必要的，以确定特定的生物标志物，区分AD从非AD痴呆症的老年人，使更准确的检测可以开发可靠的诊断AD。第二，我们需要的生物标志物，使我们能够尽早检测AD，使AD患者获得最大的好处从治疗。最后，生物标志物可用于监测患者对潜在神经保护药物的反应。因此，迫切需要开发AD的生物标记物，其具有足够的灵敏度和特异性以确认AD的死前诊断并尽可能早地鉴定合适的患者用于新兴的治疗干预。这种挑衅性的 ...更多信息 这项研究促使其他研究小组检查AD中的CSF-tau水平，以确定其潜在的诊断用途。迄今为止，来自几个独立小组的一系列研究得出了相同的结论，即与其他神经系统疾病患者和对照组相比，AD受试者的CSF-tau水平显著升高（5.7-9.14）。我们已经通过使用ELISA定量来自97名AD患者的CSF-tau水平来扩展我们的初始研究（5（平均年龄：74岁），12例帕金森病患者（PD，平均年龄：67岁），12例运动神经元病患者（MND，平均年龄：66岁），10例非急性脑血管病患者（CDV，平均年龄：67），27例其他神经系统疾病患者（其他，平均年龄：55），15例无任何神经精神疾病证据的正常对照受试者（正常，平均年龄：56）。其他组包括具有以下临床诊断的受试者：脑膜脑炎（n=5），癫痫（n=4），多发性硬化（n=3），正常压力脑积水（n=2），贝尔麻痹（n =2），Gerstmann-Strauser-Scheinker病（n=2），Creutzfeldt-Jacob病（n= 1），小脑炎（n = 1），多发性肌炎（n =1），慢性炎性去环化多神经根神经病（n=1），维生素B<@D212@>D2缺乏所致痴呆（n=1）、横肌萎缩症（n=1）和系统性红斑狼疮脑炎（n=1）。获得知情同意后，通过常规腰椎穿刺采集CSF，并以1500 rpm离心10 min，等分试样，并储存在-80 ℃直至分析。通过商业夹心ELISA（Innogenetics，Belgium）定量CSF-tau水平。在AD中CSF-tau水平显著增加（95.6（± 0.01）SY）。105.3pg/mL）与PD组（19.0 ± 0.5pg/mL）比较，P < 0.01。[）9.0），MND（26.1（]SY. ±. [] 21.1），CDV（26.0（]SY. [）40.2），其他（31.5（]SY.+-.（31.1）和正常（32. (]SY.+-. [）7（）SY. ±-.（见第43.2段）。值得注意的是，重要的是要指出，在AD患者中发现的CSF-tau水平升高与发病年龄、种族背景、ApoE、α <@D21@>-抗胰凝乳蛋白酶和早老素-1多态性以及痴呆的临床严重程度无关。受试者操作特征分析表明，CSF-tau测定的诊断特异性为75%，敏感性为93.8%。此外，当CSF-tau与CSF-Abeta联合使用时，诊断特异性和灵敏度分别提高到86.8%和94.8%（6）。然而，应该注意的是，升高的CSF-tau水平不仅在某些急性神经系统疾病中也被检测到（5，10），即，脑膜脑炎、缺氧性脑损伤、维生素B<@D212@>D2缺乏症、AIDS和Creutzeno-Jacob病，但也可用于一些慢性神经退行性疾病，包括弥漫性路易体病和额颞叶痴呆（1）。我们报告了两名患有非常轻度记忆障碍的患者的CFS-tau水平升高，这些患者随后在随访时进展至符合AD的诊断标准，这表明CSF-tau对于早期检测该疾病的临床效用要高得多（11）。事实上，我们表明CSF-tau可能被用作CDR 0.5患者痴呆的预测因子（3）。最近，Galasko等人报道了类似的观察结果（6）.与这个问题相关的未来方向是CSF-tau是否在AD症状发作前增加。在2年随访期间，从同一AD患者获得的两个单独CSF样本的结果显示，随着疾病进展，CSF-tau水平持续异常（2）。将来，在AD的所有阶段以周期性间隔从同一患者获得的多次CSF采样可能会产生用于监测AD进展及其对新型治疗药物的反应的强大的新策略（12）。少

WE have three major purposes in the development of reliable biological markers in Alzheimer's discase (AD). First, it is necessary to identify specific biological markers that distinguish AD from non-AD dementing desorders of the elderly so that more accurate assays can be developed for the reliable diagnosis of AD.Second, we need biological markers that enable us to detect AD as early as possible so that AD patients obtain maximum benefit from therapy. Finally, the biological markers can be used to monitor the response of patients to potential neuroprotective drugs. Therefore, there is a compelling need to develop biological markers for AD that have adequate sensitivity and specificity to confirm the antemortem diagnosis of AD and identify appropriate patients as early as possible for emerging therapcutic interventions.In 1993, Vandermeeien et al.reported the presence of micro-tubule-associated-protein tau in cerebrospinal fluid (CSF) of AD and non-AD subjects (13). This provocative s … More tudy prompted other research groups to examine the CSF-tau levels in AD for its potential diagnostic use. To date, a series of studies from several independent groups have reached the same conclusion that CSF-tau levels are significantly increased in subjects with AD compared with patients with other neurological discases and controls (5.7-9.14). We have extended our initial study (5) by quantitating CSF-tau levels using an ELISA from 97 AD patients (mean age : 74), 12 patients with Parkinson's discase (PD,mean age : 67), 12 patients with motor neuron discase (MND,mean age : 66), 10 patients with non-acute cerebrovascular discase (CDV,mean age : 67), 27 patients with other miscellaneous neurological discases (OTHERS,mean age : 55), and 15 normal control subjects without evidence of any neuropsychiatric discase (NORMAL,mean age : 56). The OTHERS group included subjects with the following clinical diagnoses : meningoencephalitis (n=5), epilepsy (n=4), multiple selerosis (n=3), normal pressure hydrocephalus (n=2), Bell's palsy (n=2), Gerstmann-Strauser-Scheinker discase (n=2), Creutzfeldt-Jacob discase (n=1), cerebellitis (n=1), polymyositis (n=1), chronic inflammatory demyclinating polyradiculoneuropathy (n=1), dementia due to vitamin B<@D212@>D2 deficiency (n=1), transverse myelitis (n=1), and systemic lupus erythematosus encephalitis (n=1). After obtaining informed consent, CSF was taken by routine lumbar puncture and centrifuged at 1500 rpm for 10 min., aliquoted, and stored at-80ﾟC until analysis. CSF-tau levels were quantitated by a commercial sandwich ELISA (Innogenetics, Belgium). The CSF-tau levels are significantly increased in AD (95.6(]SY.+-。[)105.3pg/mL) compared with those in PD (19.0(]SY.+-。[)9.0), MND (26.1(]SY.+-。[)21.1), CDV (26.0(]SY.+-。[)40.2), OTHERS(31.5(]SY.+-。[)31.1), and NORMAL(32.(]SY.+-。[)7(]SY.+-。[)43.2). Notably, it is important to point out that an increased CSF-tau level found in AD patients inespective of age at onset, racial background, ApoE,alpha<@D21@>D2-antichy-motrypsin, and presenilin-1 polymorphism, and clinical severity of dementia. Receiver Operating Characteristics analysis indicated that the CSF-tau determination had a diagnostic specificity of 75% and sensitivity of 93.8%. Furthermore, when the CSF-tau was taken in combination with CSF-Abeta, the diagnostic specificity and sensitivity have been improved to 86.8% and 94.8%, respectively (6). However, it should be noted that the elevated CSF-tau levels were also detected not only in certain acute neurological conditions (5,10), i.e., meningo-encephalitis, hypoxic brain injury, vitamin B<@D212@>D2 deficiency, AIDS and Creutzfeld-Jacob disease, but also in some chronic neurodegenerative diseases including diffuse Lewy body disease and frontotemporal dementia (1). This might suggest that it wouldWe reported an elevated CFS-tau level in two patients with very mild memory impairment who subsequently progressed to meet the diagnostic criteria for AD on follow-up, suggesting much higher clinical utility of CSF-tau for the early detection of the disease (11). Indeed, we showed that CSF-tau might be used as a predictor of dementia in patients with CDR0.5 (3). Recently, Galasko et al.have reported a similar observation (6). A future direction related to this issue is whether CSF-tau increases before the onset of AD symptoms. Results from two separate CSF samples obtained from the same AD patient during 2-year follow-up showed that CSF-tau levels continued to be abnormal as the disease progressed (2). In the future, multiple CSF samplings from the same patient obtained at periodic intervals spanning all stages of AD may yield powerful new strategics for monitoring the progression of AD and its response to novel therapeutic agents (12). Less