Relationships between clinicopathological features and cerebrospinal fluid biomarkers in Japanese patients with genetic prion diseases.
Relationships between clinicopathological features and cerebrospinal fluid biomarkers in Japanese patients with genetic prion diseases.
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DOI：
10.1371/journal.pone.0060003
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Mizusawa H
中科院分区：
文献类型：
--
作者：
Higuma M;Sanjo N;Satoh K;Shiga Y;Sakai K;Nozaki I;Hamaguchi T;Nakamura Y;Kitamoto T;Shirabe S;Murayama S;Yamada M;Tateishi J;Mizusawa H
日本于1999年4月建立了一个全国朊病毒疾病监测系统。在这里，我们分析了朊蛋白基因（PRNP）突变与临床特征，脑脊液（CSF）标志物，和遗传性PrDs（gPrDs）的主要基因型的病理特征之间的关系。我们回顾性分析了发病年龄和疾病持续时间; 309例携带P102 L、P105 L、E200 K、V180 I或M232 R突变的gPrD患者CSF中14-3-3蛋白、tau蛋白和异常朊蛋白（PrPSc）的浓度和发生率;以及32例尸检患者的脑病理学。观察到三种临床表型：快速进行性克雅氏病（CJD），包括100%的E200 K病例，70%的M232 R病例和21%的P102 L病例;缓慢进行性CJD，包括100%的V180 I病例和30%的M232 R病例; Gerstmann-Sträussler-Scheinker病，包括100%的P105 L病例和79%的P102 L病例。在超过80%的E200 K、M232 R或P102 L突变患者的CSF中检测到PrPSc，但在V180 I患者中仅检测到39%。V180 I在脑内伴有较弱的PrP免疫反应。脑脊液中PrPSc阴性的患者在发病时比阳性患者年龄大。具有与CSF中高14-3-3蛋白水平相关的突变的患者通常在脑中具有PrP的突触沉积和快速病程。小PrP蛋白片段在脑匀浆中的存在与其他临床病理特征无关。脑脊液中PrPSc阳性可能反映了疾病发作前或发作时的病理过程，或PrPSc分泌或代谢的异常。CSF中14-3-3蛋白的量可能指示病理过程的严重性和伴随的神经元损伤。在gPrD病例中CSF的这些特征性特征可能有助于各种疾病亚型的准确诊断和临床病理学研究。
A national system for surveillance of prion diseases (PrDs) was established in Japan in April 1999. Here, we analyzed the relationships among prion protein gene (PRNP) mutations and the clinical features, cerebrospinal fluid (CSF) markers, and pathological characteristics of the major genotypes of genetic PrDs (gPrDs). We retrospectively analyzed age at onset and disease duration; the concentrations and incidences of 14-3-3 protein, tau protein, and abnormal prion protein (PrPSc) in the CSF of 309 gPrD patients with P102L, P105L, E200K, V180I, or M232R mutations; and brain pathology in 32 autopsied patients. Three clinical phenotypes were seen: rapidly progressive Creutzfeldt-Jakob disease (CJD), which included 100% of E200K cases, 70% of M232R, and 21% of P102L; slowly progressive CJD, which included 100% of V180I and 30% of M232R; and Gerstmann-Sträussler-Scheinker disease, which included 100% of P105L and 79% of P102L. PrPSc was detected in the CSF of more than 80% of patients with E200K, M232R, or P102L mutations but in only 39% of patients with V180I. V180I was accompanied by weak PrP immunoreactivity in the brain. Patients negative for PrPSc in the CSF were older at disease onset than positive patients. Patients with mutations associated with high 14-3-3 protein levels in the CSF typically had synaptic deposition of PrP in the brain and a rapid course of disease. The presence of small PrP protein fragments in brain homogenates was not correlated with other clinicopathological features. Positivity for PrPSc in the CSF may reflect the pathological process before or at disease onset, or abnormality in the secretion or metabolism of PrPSc. The amount of 14-3-3 protein in the CSF likely indicates the severity of the pathological process and accompanying neuronal damage. These characteristic features of the CSF in cases of gPrD will likely facilitate accurate diagnosis and clinicopathological study of the various disease subtypes.
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