Altered serum iron and copper homeostasis predicts cognitive decline in mild cognitive impairment.
Altered serum iron and copper homeostasis predicts cognitive decline in mild cognitive impairment.
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DOI：
10.3233/jad-2011-111841
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Kirsch W
中科院分区：
文献类型：
--
作者：
Mueller C;Schrag M;Crofton A;Stolte J;Muckenthaler MU;Magaki S;Kirsch W
阿尔茨海默病（AD）大脑的特征是严重的神经元死亡，部分原因是氧化应激增加。在这一点上，这种自由基损伤的病理生理学还没有得到很好的描述，但有一种假设是过渡金属代谢紊乱导致了这一过程。我们检验了这一假设，即周围的过渡金属代谢紊乱是目前在痴呆过程的早期。我们分析了非血红素铁和铜水平的受试者与正常的认知，轻度认知障碍，早期老年痴呆症，并跟踪这些科目超过5年。血清铜与非血红素铁水平比值的增加可预测轻度认知障碍受试者将进展为痴呆，而认知功能保持稳定的受试者将进展为痴呆。这种增加与铁调节蛋白2或外周淋巴细胞中选定的下游靶点的表达变化无关。一个基于cDNA的微阵列（IronChip）含有铁和铜代谢相关基因被用来评估过渡金属代谢循环淋巴细胞从认知正常和痴呆症的主题。没有基因被鉴定为失调超过2倍，并且使用定量RT-PCR的验证表明ALAS 2、FOS和CTR 1的表达没有显著变化。痴呆前血清铜与血清铁的比值升高可能作为认知功能下降的生物标志物，并反映了其他人先前报道的血清中的其他变化，但铁和铜代谢途径似乎在AD患者的外周血中基本不受影响。
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.