title: A low-molecular-weight ferroxidase is increased in the CSF of sCJD cases: CSF ferroxidase and transferrin as diagnostic biomarkers for sCJD.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  (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.
  
  
  CONCLUSIONS
  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.
authors: 1 Department of Pathology, Case Western Reserve University , Cleveland, Ohio.
authors: Swati
authors: S
authors: Haldar
authors: 'alim J
authors: 'J
authors: Beveridge
authors: Joseph
authors: J
authors: Wong
authors: Ajay
authors: A
authors: Singh
authors: Daniela
authors: D
authors: Galimberti
authors: Barbara
authors: B
authors: Borroni
authors: Xiongwei
authors: X
authors: Zhu
authors: Janis
authors: J
authors: Blevins
authors: Justin
authors: J
authors: Greenlee
authors: George
authors: G
authors: Perry
authors: Chinmay K
authors: CK
authors: Mukhopadhyay
authors: Christine
authors: C
authors: Schmotzer
authors: Neena
authors: N
authors: Singh
mesh_terms: D015415:Biomarkers / Q000134:cerebrospinal fluid* / Q000378:metabolism; D002570:Ceruloplasmin / Q000134:cerebrospinal fluid* / Q000378:metabolism*; D007562:Creutzfeldt-Jakob Syndrome / Q000175:diagnosis / Q000201:enzymology* / Q000378:metabolism*; D006801:Humans; D014168:Transferrin / Q000134:cerebrospinal fluid* / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D014168:Transferrin; D002570:Ceruloplasmin
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