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

使用 ADNI 数据集验证阿尔茨海默病的新型前瞻性循环生物标志物。

• 批准号: 9717641
• 负责人: Blaise deBonneval Frederick
• 金额: $ 29.96万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-11 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9717641
• 关键词: Addendum; Alzheimer disease detection; Alzheimer' s Disease; Amyloid; Arteries; Biological Markers; Blood; Blood Circulation; Blood Vessels; Blood Volume; Blood capillaries; Blood flow; Brain; Cerebrovascular Disorders; Cerebrum; Clinical; Data; Data Set; Databases; Dementia; Diagnosis; Disease; Disease Progression; Equipment; Evaluation; Functional Magnetic Resonance Imaging; Functional disorder; Gases; Grant; Health; Hypercapnia; Image; Intracranial Arterial Stenosis; Lead; Longevity; Machine Learning; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Maps; Measurement; Measures; Metabolic; Methods; Moyamoya Disease; Near-Infrared Spectroscopy; Nerve Degeneration; Neurologic Effect; Neurons; Nutrient; Oxygen; Parietal; Pathology; Patients; Pattern; Perfusion; Physiological; Play; Positron-Emission Tomography; Procedures; Protocols documentation; Proxy; Reaction Time; Rest; Risk; Role; Running; Scanning; Schedule; Signal Transduction; Stenosis; Stroke; Study Subject; Symptoms; Techniques; Testing; Time; Tissues; Training; Validation; Vascular Diseases; Vasodilation; Visit; Work; cerebral blood volume; cerebral hemodynamics; cerebrovascular; cerebrovascular pathology; cohort; comparison group; deep learning; design; early detection biomarkers; fluorodeoxyglucose positron emission tomography; gray matter; hemodynamics; interest; longitudinal dataset; mild cognitive impairment; neuroimaging; novel; parent grant; prospective; response; single photon emission computed tomography; stroke risk; tau Proteins; temporal measurement; tool; white matter

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.

总结 本补充将评估从静息状态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物。我们开发了一种方法， 从静息状态数据中得出脑血管功能和功能障碍图，包括通过回顾性 分析现有的公共数据集。这些指标对大血管和微血管都很敏感 变化在健康组织中，血管舒张调节脑灌注，以响应不断变化的需求， 氧气和营养素;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）是脑血管舒张能力的量度，其提供了 关于局部脉管系统健康的有用信息。高碳CVR数据的传统分析方法 低估了响应相对于气体管理延迟的区域的CVR幅度 时间表，并没有提供任何信息，血流延迟，一个重要的特点，血管功能障碍。我们 已经验证了一种方法来定量地绘制血流到达的延迟，以及其他血液动力学参数， 即使在没有外部操作的情况下，也使我们能够区分循环和代谢 仅从静息状态数据中就可以看出脑血管损害的组成部分。我们已经展示了 这种方法在主要循环系统疾病中的效用，如中风和烟雾病;这种补充 试图建立这种方法的实用性，以探讨早期循环功能障碍的AD。 循环中局部改变的特定模式可能先于（或甚至导致）神经元变性，并且可能 作为跟踪疾病进展的有效生物标志物。这一补充将用于测试这一点 假设有两种方式。首先，我们将增加一个有轻度认知障碍或可能有认知障碍的患者的重点队列， 轻度阿尔茨海默病（16名受试者）与我们研究中风风险受试者的活性方案相比。我们将执行 我们广泛的循环评估方案的简化版本，以确定早期 AD相对于我们的对照组。其次，我们将对静息状态进行广泛的回顾性分析， ADNI（阿尔茨海默病神经成像倡议）数据库中的fMRI数据， 参数在一个非常大的组，其中包括一系列的诊断，和纵向数据的子集， 受试者，以确定区域血流如何随疾病进展而变化。最后，我们将设计和测试 机器学习分类器，以评估这些循环标志物检测早期AD/PRAD的能力。 这些互补的努力将测试的假设，具体的，区域模式的循环改变 阿尔茨海默病的进展，事实上可能先于其他症状，允许早期，客观， AD的定量检测和疾病进展的跟踪。此外，这将作为优秀的 初步数据，以设计更全面的努力，发展这种技术作为一种有效的临床工具。