Validation of a novel prospective circulatory biomarker for Alzheimer's Disease using the ADNI dataset.

摘要 本补充资料将评估从静息状态fMRI数据中提取的血流动力学参数图的实用性， 作为阿尔茨海默病(AD)脑血管功能障碍的早期标志。我们已经开发出一种方法来 从静息状态数据中获取脑血管功能和功能障碍的地图，包括通过回顾 对现有公共数据集的分析。这些指标对大血管和微血管都很敏感。 改变。在健康组织中，血管扩张调节大脑灌注，以响应不断变化的需求 氧气和营养物质；这种能力在许多形式的脑血管病变中降低或缺失。 脑血管反应性(CVR)是衡量脑血管扩张能力的指标，它为 关于局部血管系统健康的有用信息。高碳酸盐CVR数据的传统分析方法 低估了响应相对于天然气管理延迟的地区的CVR大小 时间表，并且根本没有提供关于血流延迟的信息，这是血管功能障碍的一个关键特征。我们 验证了一种定量绘制血流到达延迟和其他血流动力学参数的方法， 即使在没有外部操作的情况下，也允许我们区分循环和新陈代谢 仅从静息状态数据来看，脑血管的组成部分就会受到损害。我们已经演示了 这种方法在主要循环系统疾病中的应用，如中风和烟雾病；本增补件 寻求建立这一方法的效用，以探索AD的早期循环功能障碍。 循环中局部改变的特定模式可能先于(甚至导致)神经元退化，并可能 作为跟踪疾病进展的有效生物标志物。这一补充将被用来测试这一点 假设有两种方式。首先，我们将增加一组有轻度认知障碍或可能 轻度阿尔茨海默病(16名受试者)加入我们的积极方案，研究中风的风险受试者。我们将表演 我们广泛的循环评估方案的简略版本，用于确定早期循环标志物 AD与我们的对照组相比。其次，我们将对休息状态进行广泛的回顾分析 ADNI(阿尔茨海默病神经成像计划)数据库中的fMRI数据用于测量循环 一个非常大的组中的参数，包括一系列诊断和来自子集的纵向数据 受试者，以确定区域血流如何随着疾病进展而变化。最后，我们将进行设计和测试 机器学习分类器评估这些循环标志物检测早期AD/PRAD的能力。 这些相辅相成的努力将检验这样一个假设，即特定的、区域性的循环改变模式 阿尔茨海默病的进展，实际上可能先于其他症状，允许早期、客观和 AD的定量检测和疾病进展的跟踪。此外，这将是一个极好的 为设计更全面的努力将这项技术发展为有效的临床工具提供初步数据。

Summary This supplement will evaluate the utility of hemodynamic parameter maps extracted from resting state fMRI data, as early markers of cerebrovascular dysfunction in Alzheimer’s Disease (AD). We have developed a method to derive maps of cerebrovascular function and dysfunction from resting state data, including through retrospective analysis of existing public datasets. These metrics are sensitive to both macrovascular and microvascular changes. In healthy tissue, vasodilation modulates cerebral perfusion in response to changing demands for oxygen and nutrients; this ability is reduced or absent in many forms of cerebrovascular pathology. Cerebrovascular reactivity (CVR), is a measure of brain blood vessels’ capacity for vasodilation, which offer useful information on the health of local vasculature. Traditional analysis methods of hypercarbic CVR data underestimate CVR magnitude in regions where the response is delayed with respect to the gas administration schedule, and give no information at all about blood flow delay, a crucial feature of vascular dysfunction. We have validated a method to quantitatively map delays in blood flow arrival, and other hemodynamic parameters, even in the absence of external manipulations, allowing us to differentiate the circulatory and metabolic components of cerebrovascular compromise from resting state data alone. We have already demonstrated the utility of this approach in primarily circulatory disorders, such as stroke and moyamoya disease; this supplement seeks to establish the utility of this approach to probe early circulatory dysfunction in AD. Specific patterns of local alteration in circulation may precede (or even lead to) neuronal degeneration, and may serve as an effective biomarker for following disease progression. This supplement would be used to test this hypothesis in two ways. First, we will add a focused cohort of patients with mild cognitive impairment or probable mild Alzheimer’s Disease (16 subjects) to our active protocol studying subjects at risk for stroke. We will perform an abbreviated version of our extensive circulatory evaluation protocol to determine circulatory markers of early AD relative to our comparison group. Second, we will perform a broad retrospective analysis on the resting state fMRI data in the ADNI (Alzheimer’s Disease Neuroimaging Initiative) database to measure circulatory parameters in a very large group that includes a range of diagnoses, and longitudinal data from a subset of subjects, to determine how regional bloodflow changes with disease progress. Finally, we will design and test machine learning classifiers to evaluate the ability of these circulatory markers to detect early AD/PRAD. These complementary efforts will test the hypothesis that specific, regional patterns of circulatory alteration progress with Alzheimer’s Disease, and may in fact precede other symptoms, allowing early, objective and quantitative detection of AD, and tracking of disease progression. Furthermore, this will serve as excellent preliminary data for designing more comprehensive efforts to develop this technique as an effective clinical tool.