Kasai Takashi, Tokuda Takahiko, Ishigami Noriko, Sasayama Hiroshi, Foulds Penelope, Mitchell Douglas J, Mann David M A, Allsop David, Nakagawa Masanori
Department of Neurology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-0841, Japan.
Acta Neuropathol. 2009 Jan;117(1):55-62. doi: 10.1007/s00401-008-0456-1. Epub 2008 Nov 7.
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.
越来越多的病理学、生物化学和遗传学证据表明，43 kDa反式激活应答（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症（ALS）的发病机制中起关键作用。最近，有报道称，使用酶联免疫吸附测定（ELISA）系统检测发现，与健康对照相比，阿尔茨海默病和额颞叶痴呆患者血浆样本中TDP-43水平升高。为了确定脑脊液（CSF）中TDP-43的定量检测对ALS诊断是否具有潜在参考价值，我们采用类似的ELISA方法，检测了30例ALS患者（根据修订的埃斯科里亚尔标准诊断）和29例年龄匹配的无任何神经退行性疾病的对照患者脑脊液中TDP-43的浓度。我们发现，总体而言，ALS患者脑脊液中TDP-43水平显著高于年龄匹配的对照患者（ALS患者为6.92±3.71 ng/ml，对照患者为5.31±0.94 ng/ml，p<0.05），6例（20%）散发性ALS患者脑脊液中TDP-43水平超过对照组95%置信上限。脑脊液中TDP-43水平较高的6例患者均在发病1个月内接受检查。发病1个月内接受检查的患者脑脊液中TDP-43水平（8.24±4.72 ng/ml）显著高于发病11个月或更长时间后接受检查的患者（5.41±0.66 ng/ml，p<0.05）。这些结果表明，ALS早期脑脊液中TDP-43水平可能升高。我们还通过对从脑脊液样本中免疫捕获的蛋白质进行蛋白质印迹分析，证实了部分ALS患者和1例对照受试者的脑脊液中存在TDP-43蛋白。脑脊液中TDP-43水平升高可能先于中枢神经系统中TDP-43病理改变的形成，或与早期TDP-病理改变相关，因此可能成为ALS早期的生物标志物。
