Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis
Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis
复制标题
DOI：
10.1007/s00401-008-0456-1
复制
发表时间：
2009-01-01
影响因子：
12.7
通讯作者：
Nakagawa, Masanori
中科院分区：
文献类型：
--
作者：
Kasai, Takashi;Tokuda, Takahiko;Nakagawa, Masanori
越来越多的病理学、生物化学和遗传学证据表明，43-kDa反式反应（TAR）-DNA结合蛋白（TDP-43）的代谢和聚集在散发性和某些形式的家族性肌萎缩侧索硬化（ALS）的发病机制中起着至关重要的作用。最近，据报道，使用ELISA系统，与健康对照相比，在阿尔茨海默病和额颞叶痴呆患者的血浆样品中检测到TDP-43水平升高。为了确定脑脊液（CSF）中TDP-43的定量是否在ALS的诊断中具有潜在的信息性，我们通过类似的ELISA方法测量了30名ALS患者（根据修订的埃尔埃斯科里亚标准诊断）和29名年龄匹配的没有任何神经退行性疾病的对照患者的CSF中TDP-43的浓度。我们发现，作为一个群体，ALS患者的CSF中TDP-43的水平明显高于年龄匹配的对照组（ALS中为6.92 +/- 3.71 ng/ml，对照组为5.31 +/- 0.94 ng/ml，p < 0.05），在6名（20%）散发性ALS患者中，CSF中TDP-43水平升高超过对照组的95%置信水平上限。所有6例脑脊液TDP-43水平较高的患者均在发病后10个月内进行了检查。在发病10个月内检查的患者显示CSF TDP-43水平（8.24 +/- 4.72 ng/ml）显著高于发病11个月或更长时间后检查的患者（5.41 +/- 0.66 ng/ml，p < 0.05）。提示ALS患者脑脊液中TDP-43水平在发病早期可能升高。我们还证实了TDP-43蛋白在CSF中的存在，从一些ALS患者，和对照组，从CSF样品免疫捕获的蛋白质的蛋白质印迹。CSF中升高的TDP-43水平可以抢先于中枢神经系统中TDP-43病理的形成，或者与早期TDP-43病理相关，因此是ALS早期的生物标志物。
There is mounting pathological, biochemical and genetic evidence that the metabolism and aggregation of the 43-kDa transactive response (TAR)-DNA-binding protein (TDP-43) play a crucial role in the pathogenesis of sporadic and some forms of familial amyotrophic lateral sclerosis (ALS). Recently, it was reported using an ELISA system that elevated levels of TDP-43 were detected in plasma samples from patients with Alzheimer's disease and frontotemporal dementia, compared to healthy controls. To determine whether quantification of TDP-43 in cerebrospinal fluid (CSF) is potentially informative in the diagnosis of ALS, we measured the concentration, by a similar ELISA method, of TDP-43 in CSF from 30 patients with ALS (diagnosed according to the revised El Escorial criteria) and 29 age-matched control patients without any neurodegenerative disease. We found that, as a group, the ALS patients had significantly higher levels of TDP-43 in their CSF than the age-matched controls (6.92 +/- 3.71 ng/ml in ALS versus 5.31 +/- 0.94 ng/ml in controls, p < 0.05), with levels of TDP-43 in CSF elevated beyond 95% upper confidence level for the control group in six (20%) of the patients with sporadic ALS. All the six patients with higher levels of CSF TDP-43 were examined within 10 months of the onset of illness. The patients examined within 10 months of onset showed significantly higher levels of CSF TDP-43 (8.24 +/- 4.72 ng/ml) than those examined after 11 months or more of onset (5.41 +/- 0.66 ng/ml, p < 0.05). These results suggest that the levels of TDP-43 in CSF may increase in the early stage of ALS. We also confirmed the existence of the TDP-43 protein in CSF from some patients with ALS, and a control subject, by western blotting of proteins immunocaptured from the CSF samples. Raised TDP-43 levels in the CSF may preempt the formation of TDP-43 pathology in the central nervous system, or correlate with early-stage TDP-43 pathology, and accordingly be a biomarker for the early stage of ALS.