In vivo MRI Biomarkers of Microstructural Correlates of Brain Pathology in Preclinical and Early Alzheimer Disease

这项拨款申请解决了一个重大的健康问题-阿尔茨海默病（AD）-影响约530万 在美国和全世界有2000万到3000万人。随着人口老龄化，这些数字预计将上升， 刺激了对疾病预防和治疗疗法以及生物标志物的强烈探索， 早期诊断AD。后者是非常重要的，因为存在很长的症状前时期， 可用于在无症状个体中启动疾病修饰疗法的预防试验， 目的是预防认知能力下降，而不是治疗已经存在的症状。 本研究的主要目标是为使用创新的基于MRI的梯度回波提供基础 多元对比成像（GEPCI）技术用于在体内识别AD脑中的早期病理变化。 这种技术，GEPCI，在我们的实验室开发，提供了定量评估的替代品， 在细胞水平上改变脑组织结构，并已成功地应用于评估 多发性硬化症和一些精神疾病的组织损伤。 我们的初步数据，获得了良好的特点，研究参与者招募的研究老化 华盛顿大学奈特阿尔茨海默病研究中心的阿尔茨海默病和痴呆症，使我们能够 首次证明在临床MRI扫描仪上获得的基于MRI的体内测量结果可以 提供人类参与者大脑淀粉样蛋白-β积累的信息，并区分健康和肥胖之间的差异。 对照、临床前和轻度AD阶段。根据这些结果，我们计划实现以下具体目标： 1.我们的目标1是开发一种容易获得的、非侵入性的、基于MRI的体内定量生物标志物， 作为脑中淀粉样蛋白-β积累的替代物（Aβ在脑发育中的主要作用）， 阿尔茨海默病现在几乎被普遍接受）。 2.我们的目标2是建立GEPCI指标异常的特定定量和空间模式， 区分正常脑、临床前AD和非常轻度AD。 3.我们的目的3是确定早期AD相关脑组织损伤（由GEPCI替代定义）的影响 生物标志物）对认知表现的影响，并检验GEPCI指标和/或 GEPCI指标可以预测疾病进展。 4.我们的目标4是验证GEPCI测量对直接神经病理学。 该提案的总体目标是将GEPCI确立为体内非侵入性MRI技术 在常规临床环境中可用于筛选临床前AD病理学和临床药物 审判GEPCI数据是定量的、可再现的，并且不依赖于MRI扫描仪，因此允许多中心 应用.我们的方法的非侵入性性质特别重要，因为目前大多数可用的 用于识别AD的生物标志物“在某种程度上是侵入性的（NIH PAR-15-359）"。

This grant application addresses a significant health problem - Alzheimer’s disease (AD) - that affects ~5.3 million people in the US and 20-30 million worldwide. As the population ages, these numbers are anticipated to rise, stimulating an intense search for disease prevention and treatment therapies as well as for biomarkers allowing early identification of AD. The latter is very important due to the existence of a long pre-symptomatic period that can be used for the initiation of prevention trials of disease-modifying therapies in asymptomatic individuals, with the goal of preventing cognitive decline as opposed to treating of symptoms that are already present. The main goal of this study is to provide a groundwork for using the innovative MRI-based Gradient Echo Plural Contrast Imaging (GEPCI) technique for in vivo identifying early pathological changes in the AD brain. This technique, GEPCI, developed in our laboratory, provides surrogates for quantitative assessments of changes in the brain tissue structure at the cellular level and has been already successfully applied to evaluating tissue damage in multiple sclerosis and some psychiatric diseases. Our preliminary data, obtained on well-characterized research participants recruited from studies of aging and dementia at the Washington University Knight Alzheimer’s Disease Research Center, allowed us to demonstrate for the first time that in vivo MRI-based measurements obtained on a clinical MRI scanner can provide information on brain amyloid-β accumulation in human participants, and to distinguish between healthy control, preclinical and mild AD stages. Based on these results, we plan to achieve the following Specific Aims: 1. Our Aim 1 is to develop a readily available, non-invasive quantitative in vivo MRI-based biomarker that can serve as a surrogate for amyloid-β accumulation in the brain (a primary role of Aβ in the development of Alzheimer's disease is now almost universally accepted). 2. Our Aim 2 is to establish specific quantitative and spatial patterns of GEPCI metrics abnormalities that would distinguish between normal brain, preclinical AD, and very mild AD. 3. Our Aim 3 is to establish the effect of early AD-related brain tissue damage (defined by GEPCI surrogate biomarkers) on cognitive performance and to test the hypothesis that the GEPCI metrics and/or changes in GEPCI metrics can be predictors of the disease progression. 4. Our Aim 4 is to validate GEPCI measurements against direct neuropathology. The overarching goal of this proposal is to establish GEPCI as an in vivo non-invasive MRI technique available in a conventional clinical setting for screening population for preclinical AD pathology and clinical drug trials. GEPCI data are quantitative, reproducible and MRI scanner independent, thus allowing multi-center applications. The non-invasive nature of our approach is especially important since most of currently available biomarkers for identifying AD “are invasive, to one degree or another (NIH PAR-15-359)”.