Characterizing Alzheimer's disease molecular and anatomical imaging markers and their relationships with cognition and genetics using machine learning

项目摘要 淀粉样蛋白-β和tau是轻度认知障碍（MCI）/阿尔茨海默病（AD）的标志。的 体内淀粉样蛋白β、tau蛋白和神经变性与认知、临床和遗传标记的关系 并没有得到很好的理解。AD病理学患者的临床症状和疾病表现出异质性 当然了了解AD潜在的神经生物学异质性机制， 成果一直是中心目标。该提案利用了体内淀粉样蛋白的补充信息， β正电子发射断层扫描（淀粉样蛋白PET），tau PET，结构磁共振成像（sMRI）， 通过先进的机器学习方法进行认知、临床和遗传测量，并研究 MCI/AD患者相对于正常对照的这些测量之间的关系。该提案将 研究阿尔茨海默病神经影像学倡议（ADNI; N = 898）和华盛顿的数据， Knight阿尔茨海默病研究中心（Knight ADRC; N = 1，121）。这项研究将是第一个 检查局部淀粉样蛋白PET、tau PET和sMRI标记物及其与认知、临床和 在AD研究中使用机器学习预测建模和异质性分析进行遗传表型分析。的 建议将区域PET结果量化为分布容积比（DVR），将sMRI量化为容积， 研究他们与认知[简易精神状态检查（MMSE）]、临床[临床痴呆] 方框（CDR-SB）和CDR评分总和]和遗传[多基因风险评分（PRS）和载脂蛋白E（APOE）] 测量. Aim 1将开发机器学习建模方法来研究淀粉样蛋白之间的关系 PET、tau PET和sMRI与认知和临床表型的关系，并检验是否存在区域性 基于脑的成像测量显示出与认知和临床 MCI/AD患者和对照组的表型。目的2：研究淀粉样蛋白PET、tau蛋白在脑内的区域异质性， PET和sMRI结果通过半监督机器学习方法。这项研究将比较 确定的患者亚组或对照组与每个患者亚组之间的结局，以检验 假设患者亚组之间的成像标记物是否不同。目标3将审查 淀粉样蛋白PET、tau PET和sMRI异质性特征与认知和遗传学的关系，以测试 在MCI/AD亚组中，成像特征是否与认知和遗传学差异相关 相对于对照。总的来说，这一创新提案将产生关于AD异质性的关键信息 机制，有助于AD的诊断和治疗的精准医学。 1

Project Summary Amyloid-beta and tau are hallmarks of mild cognitive impairment (MCI)/Alzheimer’s disease (AD). The relationships of in-vivo amyloid-beta, tau, and neurodegeneration with cognitive, clinical, and genetic markers are not well understood. Patients with AD pathology exhibit heterogeneity in their clinical symptoms and illness course. Understanding the underlying neurobiological heterogeneity mechanisms of AD and improving the outcomes have been the central goals. This proposal leverages complementary information of in-vivo amyloid- beta positron emission tomography (amyloid PET), tau PET, structural magnetic resonance imaging (sMRI), cognitive, clinical, and genetic measurements via advanced machine learning methods and investigates the relationships among these measurements in patients with MCI/AD relative to normal controls. The proposal will study the data from the Alzheimer Disease Neuroimaging Initiative (ADNI; N = 898) and the Washington University’s Knight Alzheimer Disease Research Center (Knight ADRC; N = 1,121). This study will be the first to examine regional amyloid PET, tau PET, and sMRI markers and their relationships with cognitive, clinical, and genetic phenotypes using machine learning predictive modeling and heterogeneity analytics in AD research. The proposal will quantify regional PET outcomes as distribution volume ratio (DVR) and sMRI as the volumes and investigate their associations with cognitive [Mini-mental state examination (MMSE)], clinical [clinical dementia rating sum of boxes (CDR-SB) and CDR], and genetic [polygenic risk scores (PRS) and apolipoprotein E (APOE)] measurements. Aim 1 will develop machine learning modeling methods to study the relationships of amyloid PET, tau PET, and sMRI with cognitive and clinical phenotypes and test the hypothesis of whether regional brain-based imaging measurements exhibit multivariate predictive associations with cognitive and clinical phenotypes in MCI/AD patients and controls. Aim 2 will study the regional heterogeneity of amyloid PET, tau PET, and sMRI outcomes via semi-supervised machine learning methods. The study will compare the imaging outcomes between identified subgroups of patients or controls vs. each subgroup of patients to test the hypothesis of whether imaging markers differ between subgroups of patients. Aim 3 will examine the relationships of amyloid PET, tau PET, and sMRI heterogeneity signatures with cognition and genetics to test whether imaging signatures associate differentially with cognition and genetics in the subgroups of MCI/AD relative to controls. Overall, this innovative proposal will yield critical information on AD heterogeneity mechanisms, and contribute to precision medicine of diagnosis and treatment of AD. 1