Altered Serum Iron and Copper Homeostasis Predicts Cognitive Decline in Mild Cognitive Impairment

Article type: Research Article

Authors: Mueller, Claudius^{a; b; 1} | Schrag, Matthew^{a; c; 1} | Crofton, Andrew^{a; d} | Stolte, Jens^e | Muckenthaler, Martina U.^e | Magaki, Shino^{a; f} | Kirsch, Wolff^{a; *}

Affiliations: [a] Neurosurgery Center for Research, Loma Linda University, Loma Linda, CA, USA | [b] Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA | [c] Department of Neurology, Yale University, New Haven, CT, USA | [d] Department of Human Anatomy and Pathology, Loma Linda University, Loma Linda, CA, USA | [e] Molecular Medicine, University of Heidelberg, Heidelberg, Germany | [f] Department of Pathology, University of California, Los Angeles, CA, USA

Correspondence: [*] Correspondence to: Wolff Kirsch, Neurosurgery Center for Research, Loma Linda University, 11175 Campus St, Loma Linda, CA 92350, USA. Tel.: +1 909 558 7070; Fax: +1 909 558 0472; E-mail: wkirsch@llu.edu.

Note: [1] These authors contributed equally to the study.

Abstract: Alzheimer's disease (AD) brain is marked by severe neuronal death which has been partly attributed to increased oxidative stress. The pathophysiology accounting for this free radical injury is not well-delineated at this point, but one hypothesis is that a derangement in transition metal metabolism contributes to the process. We tested the hypothesis that peripheral derangement of transition metal metabolism is present early in the dementing process. We analyzed non-heme iron and copper levels in serum from subjects with normal cognition, mild cognitive impairment, and early stage senile dementia and followed these subjects over 5 years. An increase in the ratio of serum copper to non-heme iron levels predicted which subjects with mild cognitive impairment would progress to dementia versus those that would remain cognitively stable. This increase did not correlate with changes in expression of iron regulatory protein 2 or selected downstream targets in peripheral lymphocytes. A cDNA-based microarray (IronChip) containing genes relevant to iron and copper metabolism was used to assess transition metal metabolism in circulating lymphocytes from cognitively normal and demented subjects. No gene was identified as being dysregulated more than 2-fold, and verification using quantitative RT-PCR demonstrated no significant changes in expression for ALAS2, FOS, and CTR1. The increased ratio of serum copper to serum iron prior to dementia has potential as a biomarker for cognitive decline and mirrors other changes in serum previously reported by others, but iron and copper metabolism pathways appear to be broadly unaffected in peripheral blood in AD.

Keywords: ALAS, CTR1, FOS, IronChip, oxidative stress, biomarker, iron, copper, Alzheimer's disease

DOI: 10.3233/JAD-2011-111841

Journal: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 341-350, 2012