Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.
PLoS One. 2011 Mar 9;6(3):e16804. doi: 10.1371/journal.pone.0016804.
Sporadic Creutzfeldt-Jakob-disease (sCJD) is a fatal neurodegenerative condition that escapes detection until autopsy. Recently, brain iron dyshomeostasis accompanied by increased transferrin (Tf) was reported in sCJD cases. The consequence of this abnormality on cerebrospinal-fluid (CSF) levels of Tf is uncertain. We evaluated the accuracy of CSF Tf, a 'new' biomarker, as a pre-mortem diagnostic test for sCJD when used alone or in combination with the 'current' biomarker total-tau (T-tau). Levels of total-Tf (T-Tf), isoforms of Tf (Tf-1 and Tf-β2), and iron saturation of Tf were quantified in CSF collected 0.3-36 months before death (duration) from 99 autopsy confirmed sCJD (CJD+) and 75 confirmed cases of dementia of non-CJD origin (CJD-). Diagnostic accuracy was estimated by non-parametric tests, logistic regression, and receiver operating characteristic (ROC) analysis. Area under the ROC curve (AUC), sensitivity, specificity, positive and negative predictive values (PV), and likelihood ratios (LR) of each biomarker and biomarker combination were calculated. We report that relative to CJD-, CJD+ cases had lower median CSF T-Tf (125,7093 vs. 217,7893) and higher T-tau (11530 vs. 1266) values. AUC was 0.90 (95% confidence interval (CI), 0.85-0.94) for T-Tf, and 0.93 (95% CI, 0.89-0.97) for T-Tf combined with T-tau. With cut-offs defined to achieve a sensitivity of ∼85%, T-Tf identified CJD+ cases with a specificity of 71.6% (95% CI, 59.1-81.7), positive LR of 3.0 (95% CI, 2.1-4.5), negative LR of 0.2 (95% CI, 0.1-0.3), and accuracy of 80.1%. The effect of patient age and duration was insignificant. T-Tf combined with T-tau identified CJD+ with improved specificity of 87.5% (95%CI, 76.3-94.1), positive LR of 6.8 (95% CI, 3.5-13.1), negative LR of 0.2 (95% CI, 0.1-0.3), positive-PV of 91.0%, negative-PV of 80.0%, and accuracy of 86.2%. Thus, CSF T-Tf, a new biomarker, when combined with the current biomarker T-tau, is a reliable pre-mortem diagnostic test for sCJD.
散发性克雅氏病（sCJD）是一种致命的神经退行性疾病，直到尸检才被发现。最近，在 sCJD 病例中报告了脑铁动态平衡失调伴转铁蛋白（Tf）增加。这种异常对脑脊液（CSF）Tf 水平的影响尚不确定。我们评估了 CSF Tf（一种“新型”生物标志物）作为 sCJD 生前诊断测试的准确性，单独使用或与“当前”生物标志物总 tau（T-tau）联合使用时的准确性。在 99 例经尸检证实的 sCJD（CJD+）和 75 例非 CJD 来源痴呆症（CJD-）确认病例中，我们在死亡前 0.3-36 个月（持续时间）收集了 CSF，并对总 Tf（T-Tf）、Tf 同工型（Tf-1 和 Tf-β2）和 Tf 的铁饱和度进行了定量。使用非参数检验、逻辑回归和接收器工作特征（ROC）分析来估计诊断准确性。计算每个生物标志物和生物标志物组合的曲线下面积（AUC）、敏感性、特异性、阳性和阴性预测值（PV）和似然比（LR）。我们报告与 CJD-相比，CJD+病例的 CSF T-Tf 中位数较低（125,7093 与 217,7893），T-tau 较高（11530 与 1266）。T-Tf 的 AUC 为 0.90（95%置信区间（CI），0.85-0.94），T-Tf 与 T-tau 联合的 AUC 为 0.93（95%CI，0.89-0.97）。通过定义达到约 85%敏感性的截止值，T-Tf 以 71.6%（95%CI，59.1-81.7）的特异性识别 CJD+病例，阳性 LR 为 3.0（95%CI，2.1-4.5），阴性 LR 为 0.2（95%CI，0.1-0.3），准确性为 80.1%。患者年龄和持续时间的影响无统计学意义。T-Tf 与 T-tau 联合使用可提高特异性至 87.5%（95%CI，76.3-94.1），阳性 LR 为 6.8（95%CI，3.5-13.1），阴性 LR 为 0.2（95%CI，0.1-0.3），阳性-PV 为 91.0%，阴性-PV 为 80.0%，准确性为 86.2%。因此，CSF T-Tf（一种新型生物标志物）与当前生物标志物 T-tau 联合使用，是 sCJD 的一种可靠的生前诊断测试。
