Quantitative MRI of Iron Homeostasis, Atrophy and Tissue Structure in AD Brain

项目概述：阿尔茨海默病（AD）是最常见的痴呆症类型，目前仅在美国就有400多万人受到影响。据估计，仅将该病的发病推迟5年就可使发病率降低50%。因此，由于治疗或预防干预的潜在益处，在痴呆症临床出现之前识别高危人群已成为优先事项。最近，我们的实验室和其他实验室已经证明，在老年人达到轻度认知障碍阶段的前几年，脑萎缩的区域发生率增加了。尽管这些观察结果与阿尔茨海默病临床前阶段的存在一致，但导致这种观察结果的机制尚不清楚。在本研究中，我们将探讨脑萎缩率、铁稳态和组织微观结构复杂性之间的关系。具体来说，我们感兴趣的是，在临床相关脑萎缩发病之前，脑铁稳态的破坏和组织微观结构复杂性的降低是否明显。为了验证这些假设，我们将在认知完整个体、轻度认知障碍（MCI）受试者和轻度AD患者中进行纵向和横断面研究。我们将使用成熟的MRI技术（T2， T2*和DTI）以及两种新的定量MRI技术；磁场相关成像（MFC）和扩散峰度成像（OKI）。相关性：本提案中需要解决的问题是，AD病理的复杂方面是否可以给出适合定量评估的精确定义，以及这样的评估可以有助于我们对疾病的理解。无创、纵向定量评估AD患者局部脑铁稳态和组织微观结构复杂性的能力在以下方面具有潜在的用途：(a)研究AD的发病机制，(b)监测疾病进展，(c)帮助AD的鉴别诊断。此外，这项工作将使我们能够识别最有可能从早期干预中受益的症状前患者，帮助开发替代标记物，加速药物发现，并提供客观，非侵入性的方法来监测治疗试验。鉴于神经退行性疾病的发病率，本研究的潜在影响是相当大的。

DESCRIPTION (provided by applicant): Project Summary: Alzheimer's disease (AD) is the most common type of dementia currently affecting more than 4 million people in the United States alone. It has been estimated that delaying the onset of the disease by only 5 years could result in a 50% decrease in disease prevalence. Therefore, identification of people at risk prior to the clinical appearance of dementia has become a priority due to the potential benefit from therapeutic or preventative intervention. Recently, our lab and others have demonstrated regional increased rates of cerebral atrophy several years before elderly people reach the stage known as mild cognitive impairment. Although these observations are consistent with the presence of a preclinical stage of AD, the mechanism(s) responsible for this observation are unknown. In this proposal we will investigate the relationship between cerebral atrophy rates, iron homeostasis and tissue micro structural complexity. Specifically, we are interested in whether disruption of brain iron homeostasis and reduction in tissue micro structural complexity are evident prior to the onset of clinically relevant cerebral atrophy. To test these hypotheses, we will conduct longitudinal and cross-sectional studies in cognitively intact individuals, subjects with mild cognitive impairment (MCI), and patients with mild AD. We will use well established MRI techniques (T2, T2* and DTI) along with two novel quantitative MRI techniques; Magnetic Field Correlation (MFC) imaging and Diffusional Kurtosis Imaging (OKI). Relevance: The questions to be addressed in this proposal are whether complex aspects of AD pathology can be given a precise definition suitable for quantitative evaluation, and what such an evaluation can contribute to our understanding of the disease. The ability to quantitatively assess regional brain iron homeostasis and tissue micro structural complexity in AD patients noninvasively and longitudinally has potential use in (a) studying the pathogenesis of AD, (b) monitoring disease progression, and (c) aiding in the differential diagnosis of AD. Moreover, this work will allow us to identify presymptomatic persons who are most likely to benefit from early intervention, help develop surrogate markers, accelerate drug discovery, and provide an objective, noninvasive means to monitor therapeutic trials. Given the incidence of neurodegenerative disease, the potential impact of this study is considerable.