Department of Neurology, National Reference Centre for Transmissible Spongiform Encephalopathies, Georg-August-University, 37075 Göttingen, Germany.
Brain. 2012 Oct;135(Pt 10):3051-61. doi: 10.1093/brain/aws238. Epub 2012 Sep 25.
To date, cerebrospinal fluid analysis, particularly protein 14-3-3 testing, presents an important approach in the identification of Creutzfeldt-Jakob disease cases. However, one special point of criticism of 14-3-3 testing is the specificity in the differential diagnosis of rapid dementia. The constant observation of increased cerebrospinal fluid referrals in the national surveillance centres over the last years raises the concern of declining specificity due to higher number of cerebrospinal fluid tests performed in various neurological conditions. Within the framework of a European Community supported longitudinal multicentre study ('cerebrospinal fluid markers') we analysed the spectrum of rapid progressive dementia diagnoses, their potential influence on 14-3-3 specificity as well as results of other dementia markers (tau, phosphorylated tau and amyloid-β(1-42)) and evaluated the specificity of 14-3-3 in Creutzfeldt-Jakob disease diagnosis for the years 1998-2008. A total of 29 022 cerebrospinal fluid samples were analysed for 14-3-3 protein and other cerebrospinal fluid dementia markers in patients with rapid dementia and suspected Creutzfeldt-Jakob disease in the participating centres. In 10 731 patients a definite diagnosis could be obtained. Protein 14-3-3 specificity was analysed for Creutzfeldt-Jakob disease with respect to increasing cerebrospinal fluid tests per year and spectrum of differential diagnosis. Ring trials were performed to ensure the comparability between centres during the reported time period. Protein 14-3-3 test specificity remained high and stable in the diagnosis of Creutzfeldt-Jakob disease during the observed time period across centres (total specificity 92%; when compared with patients with definite diagnoses only: specificity 90%). However, test specificity varied with respect to differential diagnosis. A high 14-3-3 specificity was obtained in differentiation to other neurodegenerative diseases (95-97%) and non-neurological conditions (91-97%). We observed lower specificity in the differential diagnoses of acute neurological diseases (82-87%). A marked and constant increase in cerebrospinal fluid test referrals per year in all centres did not influence 14-3-3 test specificity and no change in spectrum of differential diagnosis was observed. Cerebrospinal fluid protein 14-3-3 detection remains an important test in the diagnosis of Creutzfeldt-Jakob disease. Due to a loss in specificity in acute neurological events, the interpretation of positive 14-3-3 results needs to be performed in the clinical context. The spectrum of differential diagnosis of rapid progressive dementia varied from neurodegenerative dementias to dementia due to acute neurological conditions such as inflammatory diseases and non-neurological origin.
迄今为止，脑脊液分析，特别是蛋白 14-3-3 检测，是识别克雅氏病病例的重要方法。然而，14-3-3 检测的一个特别值得批评的地方是在快速痴呆的鉴别诊断中的特异性。在过去几年中，国家监测中心不断观察到脑脊液检查的数量增加，这引起了人们的关注，即由于在各种神经疾病中进行了更多的脑脊液检查，特异性可能会下降。在一个欧洲共同体支持的纵向多中心研究（“脑脊液标志物”）框架内，我们分析了快速进行性痴呆诊断的范围，它们对 14-3-3 特异性的潜在影响，以及其他痴呆标志物（tau、磷酸化 tau 和淀粉样蛋白-β(1-42)）的结果，并评估了 1998-2008 年间 14-3-3 在克雅氏病诊断中的特异性。在参与中心的快速痴呆和疑似克雅氏病患者中，共分析了 29022 例脑脊液样本的 14-3-3 蛋白和其他脑脊液痴呆标志物。在 10731 例患者中获得了明确的诊断。分析了每年进行的脑脊液检查数量增加和鉴别诊断范围对克雅氏病 14-3-3 蛋白特异性的影响。为了确保在报告期间各中心之间的可比性，进行了环试验。在整个观察期间，14-3-3 检测的特异性在各中心的克雅氏病诊断中保持较高且稳定（总特异性为 92%；与明确诊断的患者相比：特异性为 90%）。然而，检测特异性因鉴别诊断而异。在与其他神经退行性疾病（95-97%）和非神经疾病（91-97%）的鉴别中，14-3-3 检测具有较高的特异性。在急性神经疾病（82-87%）的鉴别诊断中，特异性较低。所有中心的脑脊液检查数量逐年显著增加，但并未影响 14-3-3 检测的特异性，也未观察到鉴别诊断范围的变化。脑脊液蛋白 14-3-3 检测仍然是克雅氏病诊断的重要检测方法。由于在急性神经事件中特异性降低，因此需要在临床背景下解释阳性 14-3-3 结果。快速进行性痴呆的鉴别诊断范围从神经退行性痴呆到急性神经疾病引起的痴呆（如炎症性疾病和非神经源性疾病）不等。
