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Title: A low molecular-weight ferroxidase is increased in the CSF of sCJD cases: CSF ferroxidase and transferrin as diagnostic biomarkers for sCJD

Author
item HALDAR, SWATI - Case Western Reserve University (CWRU)
item BEVERIDGE, ALIM - Case Western Reserve University (CWRU)
item WONG, JOSEPH - Case Western Reserve University (CWRU)
item SINGH, AJAY - Case Western Reserve University (CWRU)
item GALIMBERTI, DANIELA - Case Western Reserve University (CWRU)
item BORRONI, BARBARA - Case Western Reserve University (CWRU)
item ZHU, XIONGWEI - Case Western Reserve University (CWRU)
item WANG, XINLONG - Case Western Reserve University (CWRU)
item Greenlee, Justin
item SINGH, NEENA - Case Western Reserve University (CWRU)

Submitted to: Antioxidants and Redox Signaling
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/4/2013
Publication Date: 11/10/2013
Citation: Haldar, S., Beveridge, A.J., Wong, J., Singh, A.J., Galimberti, D., Borroni, D., Zhu, X., Blevins, J., Greenlee, J., Perry, G., Mukhopadhyay, C.K., Schmotzer, C., Singh, N. 2014. A low-molecular-weight ferroxidase is increased in the CSF of sCJD Cases: CSF ferroxidase and transferrin as diagnostic biomarkers for sCJD. Antioxidants & Redox Signaling. 19(14):1662-1675.

Interpretive Summary: Many neurodegenerative diseases share the common feature of imbalanced regulation of iron within the cells of the brain. Since cerebrospinal fluid (CSF) and the fluid between cells within the brain form a continuous compartment, these changes are reflected in the CSF. The purpose of this work was to determine if changes in levels of different compounds within the CSF related to the regulation of iron within the cells of the brain occur in disease specific patterns. Results of this study show that two of the proteins (ferroxidase and transferrin) could be used in combination to differentiate sporadic Creutzfeldt-Jakob disease (sCJD) from other neurologic disease in specimens collected prior to death of the patients. This is interesting because it suggests that the reason for loss of the ability to regulate cellular iron in sCJD may have a different cause than other neurologic diseases. Until now, differentiation of these diseases in clinical patients was done postmortem by examining microscopic sections of brain tissue. This information will be used in the human medical field to provide a diagnosis earlier in the course of disease than previously possible.

Technical Abstract: Imbalance of brain iron homeostasis is a common feature of neurodegenerative conditions that include sporadic Creutzfeldt-Jakob disease (sCJD), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease, among others. However, the mechanisms underlying this change are unclear. In sCJD, sequestration of iron in stable protein complexes is believed to create functional iron deficiency, while in AD and PD iron accumulation is suggested to occur due to compromised ferroxidase activity of Alzheimer precursor protein (APP) and ceruloplasmin (Cp), respectively. In this study, we explored whether the change in brain iron homeostasis is reflected in the cerebrospinal fluid (CSF) in a disease specific manner. Accordingly, 282 pre-mortem CSF samples from sCJD, AD, PD, and other dementias were compared to 52 non-dementia cases and evaluated for changes in ferroxidase activity and levels of iron modulating proteins. Of these, ferroxidase activity and transferrin (Tf) differed significantly in sCJD relative to dementia and non-dementia cases. Rigorous statistical analysis demonstrated that a combination of ferroxidase and Tf discriminated sCJD from other dementias with a sensitivity of 86.8%, specificity of 92.5%, accuracy of 88.9%, and area under the receiver operating characteristic curve (ROC) of 0.94. Similar diagnostic accuracy was achieved in discriminating sCJD from rapidly progressing cases that died within 6 months of sample collection. Surprisingly, almost all ferroxidase activity in the CSF was concentrated in the <3kDa fraction and was resistant to heat and detergent treatment. Neither Cp nor APP contributed to the ferroxidase activity of normal or diseased CSF. Together, these observations suggest that the underlying cause of iron dyshomeostasis in sCJD is distinct from other dementias, and CSF ferroxidase and Tf are disease specific biomarkers of sCJD with a superior diagnostic accuracy than currently used biomarkers. Moreover, these data identify a novel non-protein ferroxidase in human CSF that is increased in sCJD.