Alzheimer Biomarker Consortium - Down Syndrome (ABC-DS)-04 Supplement 4

摘要 这是一份U19 AG068054“阿尔茨海默病”为期一年的行政补充申请 生物标记物联合体-唐氏综合症“(ABC-DS，PI：B.Handen，E.Head)。这种“仅限分析” 提案将建立在利用正电子发射的令人印象深刻的多学科工作的基础上 对唐氏综合征(DS)患者进行断层扫描(PET)成像，以揭示与年龄相关的、DS特有的、 与阿尔茨海默病(AD)相关的FDG代谢和神经病理生理变化 淀粉样β蛋白(Aβ)和tau蛋白沉积。阿尔茨海默病在DS中的出现和发展一直是一个 许多这些研究的重要焦点，主要由ABC-DS的成员进行 财团。在这项研究中，我们将开发一个多变量多模式分析框架，该框架将 更好地利用多模式神经成像数据集的复杂性和丰富性，以提供改进的 β和tau蓄积的时空映射，使早期和 相对于先前的评估，DS的进行性病理生理学变化。其具体目的是 对获得的基线和纵向A-β和tau-PET神经成像数据进行联合模式分析 在兄弟姐妹对照和DS患者中，以确定Aβ和tau摄取的时空模式 比以前的方法对进行性的大脑病理生理变化更敏感。我们会申请 A-β和Tau的多集典型相关分析和正交信号校正 兄弟姐妹对照和患有DS的个体在基线和16个月纵向随访时获得的数据 (跨越认知稳定、轻度认知障碍和AD的连续体)。我们会 评估这些模式时要考虑其他病理生理标记、认知状态和 人口统计和遗传变量。评估早期/临床前变化将包括检查 β纹状体纹状体模式和早期检测内嗅皮层tau沉积 检测到tau随着疾病的进展扩散到皮质区。我们还将评估两国关系 β和tau对其他病理生理标记物(例如磁共振容积测量)的影响，对认知的影响 表现，并包括协变量(例如，年龄、教育程度和遗传风险因素)，考虑到 导致DS生物学和临床异质性的因素。这项工作将提供更多的 对个人状态进行全面和个性化的评估。分析平台将是 共享以促进可行的多模式分析并促进新的多模式科学、多模式 假设的发展和多学科的ABC-DS合作。这项研究与以下方面高度相关 母公司ABC-DS基金(U19 AG068054，阿尔茨海默病生物标记物)的目标和优先事项 财团-唐氏综合症“)和纳入项目。

ABSTRACT This is an application for a 1-year administrative supplement to U19 AG068054 “Alzheimer Biomarker Consortium – Down Syndrome” (ABC-DS, PI: B. Handen, E. Head). This “analysis-only” proposal will build upon an impressive body of multidisciplinary work that has utilized Positron Emission Tomography (PET) imaging of individuals with Down Syndrome (DS) to reveal age-related, DS-specific, and Alzheimer’s disease (AD)-related neuropathophysiological changes in FDG metabolism and amyloid-beta (Aβ) and tau protein deposition. The emergence and progression of AD in DS has been an important focus of many of these studies that were performed in large part by members of the ABC-DS consortium. In this research, we will develop a multivariate multimodal analysis framework that will better leverage the complexity and richness of multimodal neuroimaging datasets to provide improved spatiotemporal mapping of Aβ and tau accumulation and enable more sensitive detection of early and progressive pathophysiological changes in DS, relative to prior assessments. The specific aim is to perform joint pattern analyses of baseline and longitudinal Aβ and tau PET neuroimaging data acquired in sibling controls and individuals with DS to identify spatiotemporal patterns of Aβ and tau uptake that are more sensitive to progressive pathophysiological brain changes, than prior methods. We will apply multiset canonical correlational analysis (MCCA) and orthogonal signal correction (OSC) to Aβ and tau data acquired at baseline and 16-month longitudinal follow-up in sibling controls and individuals with DS (across the continuum of cognitively stable, mild cognitive impairment, and AD continuum). We will evaluate these patterns with consideration of other pathophysiological markers, cognitive status, and demographic and genetic variables. Assessment of early/preclinical change will include examination of Aβ striatal patterns and early detection of tau deposition in entorhinal cortex in the context of subsequent detection of tau spread to cortical areas with disease progression. We will also evaluate the relationship of Aβ and tau to other pathophysiological markers (e.g., MRI volumetric measures), to cognitive performance and include covariates (e.g., age, education, and genetic risk factors), in consideration of factors contributing to the biological and clinical heterogeneity in DS. This work will provide a more comprehensive and personalized evaluation of the individual’s status. The analysis platform will be shared to facilitate feasible multimodal analyses and promote novel multimodal science, multimodal hypothesis development, and multidisciplinary ABC-DS collaboration. This research is highly relevant to the goals and priorities of both the parent ABC-DS grant (U19 AG068054, “Alzheimer Biomarker Consortium – Down Syndrome”) and the INCLUDE project.