Early diagnostic marker for Alzheimer's disease

我们在开发可靠的阿尔茨海默病（AD）生物标志物方面有三个主要目的。首先，有必要确定区分老年痴呆症与非老年痴呆症的特异性生物标志物，以便开发更准确的检测方法，可靠地诊断老年痴呆症。其次，我们需要生物标志物，使我们能够尽早发现阿尔茨海默病，使阿尔茨海默病患者从治疗中获得最大的益处。最后，生物标记物可用于监测患者对潜在神经保护药物的反应。因此，迫切需要开发具有足够敏感性和特异性的阿尔茨海默病生物标志物，以确认阿尔茨海默病的生前诊断，并尽早确定合适的患者，以便进行新的治疗干预。1993年，Vandermeeien等人报道了阿尔茨海默病和非阿尔茨海默病受试者脑脊液（CSF）中存在微管相关蛋白tau（13）。更多的研究促使其他研究小组检查阿尔茨海默病的CSF-tau水平，以寻找其潜在的诊断用途。迄今为止，来自几个独立研究小组的一系列研究都得出了相同的结论，即与其他神经系统疾病患者和对照组相比，AD患者的CSF-tau水平显著升高（5.7-9.14）。扩展我们的初步研究(5)量化中CSF-tau水平使用ELISA从公元97年患者(平均年龄:74),12个帕金森患者除去外罩(PD,平均年龄:67),12个患者运动神经元除去外罩(MND,平均年龄:66),10表示脑血管患者除去外罩(CDV,平均年龄:67),27日与其他杂项神经病人除去外罩(其他人,平均年龄:55),以及正常对照组15没有任何的证据神经除去外罩(正常,平均年龄:56)。OTHERS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）、多发性脊髓硬化（n=3）、常压性脑水（n=2）、贝尔氏麻痹（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）、慢性炎性脱髓鞘性多根神经病变（n=1）、维生素B<@D212@>D2缺乏症所致痴呆（n=1）、横脊髓炎（n=1）、系统性红斑狼疮脑炎（n=1）。在获得知情同意后，常规腰椎穿刺取脑脊液，1500rpm离心10min， ali引述，并在80c下保存直至分析。采用商用夹心ELISA （Innogenetics，比利时）测定CSF-tau水平。CSF-tau水平显著增加在广告(95.6 (SY。+ -。[)105.3 pg / mL)相比,那些在PD (19.0 (SY。+ -。(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。+ - 43.2())。值得注意的是，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@> d2 -抗胰蛋白酶和早老素-1多态性以及痴呆的临床严重程度无关。受试者工作特征分析显示CSF-tau检测诊断特异性为75%，敏感性为93.8%。此外，当CSF-tau与CSF-Abeta联合使用时，诊断特异性和敏感性分别提高到86.8%和94.8%(6)。然而，值得注意的是，CSF-tau水平升高不仅在某些急性神经系统疾病（如脑膜脑炎、缺氧脑损伤、维生素B<@D212@>D2缺乏症、艾滋病和克雅氏病）中发现，而且在一些慢性神经退行性疾病（如弥散性路易体病和额颞叶痴呆）中也发现(1)。我们报道了两名非常轻微的记忆障碍患者的CFS-tau水平升高，他们随后在随访中进展到符合AD的诊断标准，这表明CSF-tau在疾病的早期检测中具有更高的临床效用（11）。事实上，我们发现CSF-tau可能被用作CDR0.5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)。与该问题相关的未来方向是CSF-tau是否在AD症状出现之前增加。在2年的随访中，从同一AD患者获得的两个单独的CSF样本的结果显示，随着疾病的进展，CSF-tau水平继续异常(2)。在未来，在AD的所有阶段，从同一患者中定期获得多个CSF样本，可能会为监测AD的进展及其对新型治疗剂的反应提供强有力的新策略（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