Brain Iron in Aging Adults

描述(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发病机制。脑铁水平随着年龄的增长而增加，并导致自由基毒性和蛋白质病(蛋白质异常沉积)的发展，这些疾病与几种普遍存在的与年龄相关的神经退行性疾病有关，如阿尔茨海默病(AD)、帕金森病(PD)和路易体痴呆(DLB)。现有的关于脑铁的研究在设计上完全是横断面的，主要是在死后进行的，因此不足以公正地评估与年龄相关的变化，这对于了解铁储存(铁蛋白铁)对这些疾病的风险的贡献是必要的。这项研究通过几种新的方法来解决这一空白，包括其前瞻性设计，具有大队列大容量和长跟踪间隔的独特数据集，对影响铁代谢的高度流行的基因的评估，以及其高度特异性的体内MRI方法，该方法已与尸检和体外数据相验证。该项目测试了大脑铁蛋白铁顺序转移的理论模型，该模型始于中年早期，伴随着进行性的髓鞘破坏，并反映在铁蛋白铁从白质区域向灰质区域的连续转移中。这些变化导致海马体等灰质脆弱区域的铁蛋白铁随年龄增加，从而促进毒性效应，导致可测量的与年龄相关的认知和功能下降，并最终导致疾病导致蛋白质病。多种因素可以通过影响髓鞘发育和分解的终生轨迹来影响这一过程，并可能表现为认知障碍和神经退行性疾病风险的缓解或促进因素。性别和遗传性血色沉着症等位基因这两个因素将作为这项研究的一部分进行检查。该项目将提供必要的数据，以便优化设计有针对性的治疗研究和初级预防干预措施(使用铁络合剂以及其他更容易获得的治疗方法，如改变饮食和/或抽血)，以帮助延缓甚至预防这些与年龄相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.