"What is N?" Towards operationalizing neurodegeneration in Alzheimer's and related dementias

项目总结/摘要 神经退行性变标志物（N标志物）与阿尔茨海默病（AD）的认知障碍相关 以及相关的痴呆症因为它们比AD特异性生物标志物更接近认知下降 （淀粉样蛋白和tau测量），它们已被提议作为临床试验中的替代终点，甚至用于 在临床环境中的预后。尽管N标记物有希望，但其实施的几个障碍 存在.主要的局限性包括：i）仅在排除那些具有显著性差异的便利样本中进行验证 脑血管疾病，而不是一般人群，ii）缺乏系统的比较，经常 使用了跨模态的N个标记（即，影像学、CSF、血液）来预测不同水平的认知结果。 AD和脑血管疾病病理学，以及iii）缺乏对相关病理特征的了解 每个N标记。在当前的应用中，我们的总体目标是了解每个N 标记物（成像、CSF、血液）提供关于认知下降和基础病理学的信息，以优化 它们在临床实践和临床试验中的应用。我们将利用马约诊所衰老研究（MCSA）a 一项基于人群的纵向研究，参与者接受心理测量、神经病学和神经影像学检查 检查（MRI，淀粉样蛋白和tau PET，FDG PET）和抽血;一个子集还具有CSF和/或术后 死亡数据作为此授权的主要数据集。在目标1中，我们将比较来自神经成像的N个标记物， 与人口统计学（包括社会经济状况）、体内AD（淀粉样蛋白） 和tau PET）和脑血管疾病生物标志物以及认知。我们将验证其中的一些 在Birmingham马约诊所杰克逊维尔样本和ADNI中的关系。在目标2中，我们将进行一次预先- 尸检N标记物-尸检验证研究，以确定与（每种 和N个标记的组合。研究结果的赠款将导致更好地了解N标记 与纵向认知衰退相关的神经元和与这些N标记相关的病理学。这些知识 将告知临床试验设计和指南，选择哪些N标记物用于未来AD的临床使用， ADRD。

PROJECT SUMMARY / ABSTRACT Neurodegeneration markers (N markers) are associated with cognitive impairment in Alzheimer's disease (AD) and related dementias. Since they are more proximally related to cognitive decline than AD-specific biomarkers (amyloid and tau measures), they have been proposed as surrogate endpoints in clinical trials and even for prognosis in the clinical setting. Despite the promise of N markers, several barriers to their implementation exist. The major limitations include i) only validation in convenience samples that exclude those with significant cerebrovascular disease rather than the general population, ii) lack of systematic comparison of the frequently used N markers across modalities (i.e., imaging, CSF, blood) to predict cognitive outcomes at varying levels of AD and cerebrovascular disease pathology, and iii) lack of understanding of the pathological profile associated with each N marker. In the current application, our overall goal is to understand the unique information each N marker (imaging, CSF, blood) provides with regards to cognitive decline and underlying pathology to optimize their use in clinical practice and clinical trials. We will utilize the Mayo Clinic Study of Aging (MCSA) a longitudinal population-based study where participants undergo psychometric, neurologic, and neuroimaging investigations (MRI, amyloid and tau PET, FDG PET), and blood draws; a subset also have CSF and/or post- mortem data as the primary dataset for this grant. In Aim 1, we will compare N markers from neuroimaging, CSF, and blood in MCSA in relation to demographics (including socioeconomic status), in vivo AD (amyloid and tau PET) and cerebrovascular disease biomarkers, and cognition. We will validate some of these relationships in a biracial Mayo Clinic Jacksonville sample and in ADNI. In Aim 2, we will conduct an ante- mortem N marker – post-mortem validation study to determine the pathological profiles associated with (each and combination of) N markers. The findings of the grant will lead to better understanding of N markers associated with longitudinal cognitive decline and the pathologies associated these N markers. This knowledge will inform clinical trial design and guidance of which N marker(s) to choose for future clinical use for AD and ADRD.