1 Department of Pathology, Case Western Reserve University , Cleveland, Ohio.
Antioxid Redox Signal. 2013 Nov 10;19(14):1662-75. doi: 10.1089/ars.2012.5032. Epub 2013 Apr 16.
Most biomarkers used for the premortem diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) are surrogate in nature, and provide suboptimal sensitivity and specificity.
We report that CJD-associated brain iron dyshomeostasis is reflected in the cerebrospinal fluid (CSF), providing disease-specific diagnostic biomarkers. Analysis of 290 premortem CSF samples from confirmed cases of CJD, Alzheimer's disease, and other dementias (DMs), and 52 non-DM (ND) controls revealed a significant difference in ferroxidase (Frx) activity and transferrin (Tf) levels in sporadic Creutzfeldt-Jakob disease (sCJD) relative to other DM and ND controls. A combination of CSF Frx and Tf discriminated sCJD from other DMs with a sensitivity of 86.8%, specificity of 92.5%, accuracy of 88.9%, and area-under-the receiver-operating-characteristic (ROC) curve of 0.94. This combination provided a similar diagnostic accuracy in discriminating CJD from rapidly progressing cases who died within 6 months of sample collection. Surprisingly, ceruloplasmin and amyloid precursor protein, the major brain Frxs, displayed minimal activity in the CSF. Most of the Frx activity was concentrated in the <3-kDa fraction in normal and diseased CSF, and resisted heat and proteinase-K treatment.
(i) A combination of CSF Frx and Tf provides disease-specific premortem diagnostic biomarkers for sCJD. (ii) A novel, nonenzymatic, nonprotein Frx predominates in human CSF that is distinct from the currently known CSF Frxs.
The underlying cause of iron imbalance is distinct in sCJD relative to other DMs associated with the brain iron imbalance. Thus, change in the CSF levels of iron-management proteins can provide disease-specific biomarkers and insight into the cause of iron imbalance in neurodegenerative conditions.
大多数用于散发性克雅氏病（CJD）生前诊断的生物标志物都是间接的，其敏感性和特异性均不理想。
我们报告称，CJD 相关的脑铁动态失衡反映在脑脊液（CSF）中，提供了具有疾病特异性的诊断生物标志物。对 290 份来自确诊的 CJD、阿尔茨海默病和其他痴呆症（DM）病例以及 52 份非 DM（ND）对照者的生前 CSF 样本进行分析，发现铁氧化酶（Frx）活性和转铁蛋白（Tf）水平在散发性克雅氏病（sCJD）中与其他 DM 和 ND 对照组有显著差异。CSF Frx 和 Tf 的组合可将 sCJD 与其他 DM 区分开来，其敏感性为 86.8%，特异性为 92.5%，准确性为 88.9%，接受者操作特征（ROC）曲线下面积为 0.94。这种组合在区分 CJD 与在样本采集后 6 个月内死亡的快速进展病例方面提供了类似的诊断准确性。令人惊讶的是，铜蓝蛋白和淀粉样前体蛋白，这两种主要的脑 Frx，在 CSF 中显示出最小的活性。大多数 Frx 活性集中在正常和患病 CSF 的<3kDa 级分中，且对热和蛋白酶 K 处理具有抗性。
（i）CSF Frx 和 Tf 的组合为 sCJD 提供了具有疾病特异性的生前诊断生物标志物。（ii）在 CSF 中存在一种新型的、非酶、非蛋白 Frx，它与目前已知的 CSF Frx 不同。
与其他与脑铁失衡相关的 DM 相比，sCJD 中铁失衡的根本原因是不同的。因此，CSF 中铁代谢蛋白水平的变化可以提供具有疾病特异性的生物标志物，并深入了解神经退行性疾病中铁失衡的原因。
