Brain Iron in Aging Adults

描述（由申请人提供）：大量证据表明，铁参与了许多与年龄相关的神经退行性疾病的机制。脑铁水平随着年龄的增长而增加，并有助于自由基毒性和与几种常见的与年龄相关的神经退行性疾病(如阿尔茨海默病（AD）、帕金森病（PD）和路易体痴呆（DLB）相关的蛋白质病变（蛋白质异常沉积）的发展。现有的关于脑铁的研究在设计上完全是横断面的，大部分是死后的，因此不足以公正地评估与年龄相关的变化，这对于理解铁储备（铁蛋白铁）对这些疾病发生风险的贡献是必要的。本研究通过几种新颖的方法解决了这一空白，包括前瞻性设计，具有大队列规模和长随访间隔的独特数据集，评估影响铁代谢的高度流行基因，以及高度特异性的体内MRI测量脑铁蛋白铁的方法，该方法已通过死后和体外数据得到验证。该项目测试了脑铁蛋白铁序列转移的理论模型，该模型始于中年早期，髓磷脂逐渐分解，并反映在铁蛋白铁从白质区域向灰质区域的持续转移中。这些变化导致脆弱的灰质区域（如海马体）中与年龄相关的铁蛋白铁增加，促进毒性作用，导致可测量的与年龄相关的认知和功能下降，并最终导致导致蛋白质病变的疾病。多种因素可以通过影响髓磷脂发育和分解的终生轨迹来影响这一过程，并可能表现为减缓或促进发生认知障碍和神经退行性疾病的风险。两个这样的因素，性别和遗传性血色素沉着症等位基因，将检查作为本研究的一部分。该项目将提供必要的数据，以优化设计有针对性的治疗研究和初级预防干预措施（使用铁螯合剂以及其他更容易获得的治疗方法，如改变饮食和/或静脉切开术），这些措施可能有助于延缓甚至预防这些与年龄有关的神经退行性疾病。

DESCRIPTION (provided by applicant): A great deal of evidence suggests that iron is involved in the mechanisms that underlie many age related neurodegenerative diseases. Brain iron levels increase with age and contribute to free radical toxicity and the development of proteinopathies (abnormal deposits of proteins) associated with several prevalent age-related neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Dementia with Lewy Bodies (DLB). Existing studies on brain iron are entirely cross sectional in design, largely post-mortem, and therefore inadequate for unbiased assessment of age-related changes necessary for understanding of the contribution of iron stores (ferritin iron) to the risk of developing these diseases. This study addresses this void through several novel approaches including its prospective design, unique dataset with large cohort size and long follow-up interval, assessment of highly prevalent genes that impact iron metabolism, and its highly specific in vivo MRI methodology of measuring brain ferritin iron that has been validated against post mortem and in vitro data. This project tests a theoretical model of sequential shifts in brain ferritin iron that begin in early middle age with progressive myelin breakdown and are reflected in continual shifts of ferritin iron from white matter regions to gray matter regions. These shifts contribute to age-related increases of ferritin iron in vulnerable gray matter regions such as the hippocampus, promoting toxic effects that result in measurable age-related cognitive and functional declines and culminate in disease causing proteinopathies. Multiple factors can impact this process through their effects on the life-long trajectory of myelin development and breakdown and may manifest as mitigators or promoters of risk for developing cognitive impairments and neurodegenerative diseases. Two such factors, gender and hereditary hemochromatosis alleles, will be examined as part of this study. This project will provide the data necessary to optimally design targeted treatment studies and primary prevention interventions (using iron chelators as well as other more readily available treatments such as changes in diet and/or phlebotomy) that may help delay or even prevent these age-related neurodegenerative diseases.