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

项目摘要/摘要 神经变性标记物(N标记物)与阿尔茨海默病(AD)认知损害相关 以及相关的痴呆症。因为与AD特异性生物标志物相比，它们与认知功能减退关系更密切 (淀粉样蛋白和tau指标)，它们已被提议作为临床试验的替代终点，甚至用于 临床环境中的预后。尽管N标记有希望，但实施它们的几个障碍 是存在的。主要限制包括：i)仅在方便的样本中验证，排除那些显著 脑血管疾病而不是一般人群，二)缺乏系统的频度比较 使用N个标记物(例如，成像、脑脊液、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个标记。在当前的应用程序中，我们的总体目标是了解每个N的唯一信息 标记物(成像、脑脊液、血液)提供关于认知衰退和潜在病理的优化 它们在临床实践和临床试验中的应用。我们将利用梅奥衰老临床研究(MCSA)a 以人群为基础的纵向研究，参与者接受心理测量、神经学和神经成像 检查(MRI，淀粉样蛋白和tau-PET，FDG-PET)和抽血；一个子集也有脑脊液和/或术后 尸检数据作为此授权的主要数据集。在目标1中，我们将比较神经成像的N个标记物， 脑脊液和MCSA中的血液与人口学(包括社会经济地位)、活体AD(淀粉样蛋白)的关系 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内容 在杰克逊维尔梅奥诊所的混血样本和ADNI中的关系。在目标2中，我们将进行一场赌注- 死亡N标记-尸检研究，以确定与(每个)相关的病理特征 和)N个标记的组合。这项资助的发现将有助于更好地理解N标记 与纵向认知衰退和病理相关的N个标记物。这一知识 将告知临床试验设计和指导选择哪个N标志物(S)用于未来临床治疗AD和 阿德勒。

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.