A low-molecular-weight ferroxidase is increased in the CSF of sCJD cases: CSF ferroxidase and transferrin as diagnostic biomarkers for sCJD.
A low-molecular-weight ferroxidase is increased in the CSF of sCJD cases: CSF ferroxidase and transferrin as diagnostic biomarkers for sCJD.
复制标题
DOI：
10.1089/ars.2012.5032
复制
发表时间：
2013-10
影响因子：
6.6
通讯作者：
Swati Haldar;‘Alim J. Beveridge;Joseph Wong;A. Singh;D. Galimberti;B. Borroni;Xiongwei Zhu;
中科院分区：
文献类型：
--
作者：
Swati Haldar;‘Alim J. Beveridge;Joseph Wong;A. Singh;D. Galimberti;B. Borroni;Xiongwei Zhu;
目的：大多数用于散发性克雅氏病（CJD）死前诊断的生物标志物本质上是替代的，并且提供了次优的敏感性和特异性。结果：我们报道，cjd相关的脑铁失衡反映在脑脊液（CSF）中，提供了疾病特异性的诊断生物标志物。对克雅氏病、阿尔茨海默病和其他痴呆症（DMs）确诊病例的290例死前脑脊液样本和52例非糖尿病（ND）对照进行的分析显示，散发克雅氏病（sCJD）患者的铁氧化酶（Frx）活性和转铁蛋白（Tf）水平与其他糖尿病和ND对照相比存在显著差异。CSF Frx和Tf联合检测sCJD与其他dm的敏感性为86.8%，特异性为92.5%，准确度为88.9%，受试者工作特征曲线下面积为0.94。这一组合在区分克雅氏病和快速进展的病例方面提供了类似的诊断准确性，这些病例在采集样本的6个月内死亡。令人惊讶的是，铜蓝蛋白和淀粉样蛋白前体蛋白，主要的脑Frxs，在脑脊液中表现出最小的活性。Frx活性主要集中在正常和病变脑脊液<3-kDa部分，对高温和蛋白酶-k处理具有抗性。创新(i) CSF Frx和Tf的组合为sCJD提供了疾病特异性的死前诊断生物标志物。（ii）一种新的、非酶、非蛋白Frx在人脑脊液中占主导地位，与目前已知的脑脊液Frx不同。结论sCJD中铁失衡的潜在原因与其他与脑铁失衡相关的dm不同。因此，脑脊液中铁管理蛋白水平的变化可以提供疾病特异性生物标志物，并深入了解神经退行性疾病中铁失衡的原因。
AIMS Most biomarkers used for the premortem diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) are surrogate in nature, and provide suboptimal sensitivity and specificity. RESULTS 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. INNOVATION (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. CONCLUSION 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.