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

这项赠款申请解决了一个严重的健康问题-阿尔茨海默病(AD)-影响到约530万人 美国的人口和全球的2000-3000万人。随着人口老龄化，这些数字预计还会上升， 刺激对疾病预防和治疗疗法以及生物标志物的密集搜索 AD的早期识别。后者非常重要，因为存在一个很长的症状前期， 可用于在无症状个体中启动疾病修改疗法的预防试验， 预防认知衰退的目标，而不是治疗已经存在的症状。 本研究的主要目的是为使用创新的基于MRI的梯度回声提供基础 多元对比成像(GEPCI)技术可在体内识别AD脑内的早期病变。 我们实验室开发的这项名为GEPCI的技术为定量评估 在细胞水平上的脑组织结构的变化，已经成功地应用于评估 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，从老龄化研究中招募的具有良好特征的研究参与者获得 华盛顿大学奈特阿尔茨海默氏症研究中心的痴呆症使我们能够 首次证明在临床核磁共振扫描仪上获得的基于核磁共振的活体测量可以 提供有关人类参与者大脑淀粉样蛋白-β积累的信息，并区分健康的 对照组、临床期和轻度AD期。根据这些成果，我们计划实现以下具体目标： 1.我们的目标1是开发一种易于获得的、非侵入性的体内MRI生物标记物，该生物标记物可以 作为淀粉样蛋白-β在大脑中堆积的替代品(β在脑血管疾病的发展中起主要作用 阿尔茨海默氏症现在几乎被普遍接受)。 2.我们的目标2是建立GEPCI指标异常的具体数量和空间模式，这些模式将 区分正常大脑、临床前AD和非常轻微的AD。 3.我们的目标3是建立早期AD相关脑组织损伤的影响(由GEPCI替代者定义 生物标记物)对认知能力的影响，并检验以下假设 GEPCI指标可以预测疾病的进展。 4.我们的目标4是针对直接神经病理学验证GEPCI测量结果。 这项提议的总体目标是将GEPCI建立为一种活体非侵入性MRI技术 可在常规临床环境中用于筛查AD临床前病理和临床药物人群 审判。GEPCI数据是定量的，可重复性的，不依赖于MRI扫描仪，因此允许多中心 申请。我们方法的非侵入性特别重要，因为目前可用的大多数 用于鉴定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)”.