Biomarkers in Early Alzheimer's Disease (AD).

早期阿尔茨海默病 (AD) 的生物标志物。

• 批准号: 8532779
• 负责人: HENRY RUSINEK
• 金额: $ 61.83万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8532779
• 关键词: Affect; Aging; Agreement; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Animals; Biological; Biological Assay; Biological Markers; Blood; Blood Vessels; Blood flow; Brain; Brain Injuries; Carbon Dioxide; Cardiovascular Diseases; Cell physiology; Cerebrovascular Circulation; Cerebrum; Clinical; Cognition; Cognitive; Collaborations; Communities; Data; Delayed Memory; Deposition; Disease; Disease Progression; Elderly; Elements; Endothelial Cells; Enrollment; Epidemiology; Funding; Future; Goals; Health; Hippocampus (Brain); Human; Image; Impaired cognition; Individual; Lead; Longitudinal Studies; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Medical; Memory; Memory impairment; Methods; Morphologic artifacts; Neurons; Neuropsychological Tests; New York City; Pathology; Perfusion; Plasma; Procedures; Production; Quality Control; Registries; Research; Risk; Risk Factors; Sampling; Short-Term Memory; Site; Smooth Muscle Myocytes; Source; Spin Labels; Structure; Study Subject; Tauopathies; Testing; Time; Transgenic Organisms; United States National Institutes of Health; Vasoconstrictor Agents; Vasodilation; Wild Type Mouse; Work; base; brain volume; cardiovascular disorder risk; cell injury; cerebral atrophy; cerebrovascular; design; directed attention; executive function; follow-up; high risk; improved; mild cognitive impairment; mouse model; neocortical; neuropathology; normal aging; novel; prospective; public health relevance; response; tau Proteins; tool

DESCRIPTION (provided by applicant): There are no clinically recognizable mechanisms associated with AD progression. Recent studies of elderly normal (NL) subjects show that individuals with increased levels of plasma amyloid beta 1-40 (A¿40) are at higher risk for mild cognitive impairment (MCI) and Alzheimer's disease (AD). In transgenic AD (Tg) and wild type mice models, elevated plasma A¿40 is associated with decreased hippocampal (HIP) vasoreactivity (VR) and in Tg even prior to A¿ deposits or brain damage. Our human pilot data in support of these animal findings suggest that plasma A¿40 is a biologically active vasoconstrictor of cerebral blood vessels, with pronounced early effects on HIP VR. However, it remains unclear if reduced VR is near the source of a clinical cascade that includes progressive structural brain damage, amyloid and tau pathology, and cognitive impairment. A vascular mechanism influencing progression is intriguing and consistent with the neuropathology and the epidemiology. However, since both plasma A¿40 and cardiovascular disease (CVD) impair brain endothelial and smooth muscle cell function, it is crucial to evaluate both factors and their interaction longitudinally. Our pilot data also show that A¿40 and CVD-risk independently target VR-CO2 affecting both overlapping and different cerebrovascular regions. The combined effects of elevated plasma A¿40 and CVD-risk on cognition, brain structure, and AD biomarkers remains unknown. We propose two NL aging studies. In Part 1 we will retrospectively establish the longitudinal relationships between plasma A¿40, CVD-risk, and cognitive decline in a large random community sample. We will assay plasma A¿40 and A¿42 levels in 1875 stored plasma samples from 625 randomly selected community residing NL elderly subjects, studied annually over a 3-year interval. In Part 2, we will conduct a prospective 2-year, three time point, longitudinal study of 200 NL individuals stratified by A¿40 level and CVD-risk. We will examine the relationships between A¿40 and CVD- risk factors as predictors of reduced VR-CO2 and AD related changes. All the required clinical, MRI, and biomarker measures were tested and validated during the funded cycle. This includes a new arterial spin labeling (ASL) method that precisely measures HIP and cortical perfusion and VR-CO2 without the spatial distortions typical in conventional echo-planar ASL. We will test four major hypotheses in cross-section and longitudinally: 1) elevations in plasma A¿40 levels preferentially reduce VR-CO2 in AD-vulnerable regions; 2) elevated plasma A¿40, in association with reduced VR-CO2, predict a cascade of clinical and biological changes related to AD; 3) elevated CVD-risk predicts reduced neocortical VR-CO2, and progressive deficits in verbal fluency and working memory; 4) for subjects with combined risks of CVD and high plasma A¿40, there is a synergistic decrease in VR-CO2 and increased cognitive and structural brain changes. This study has the potential to reveal an AD-related vascular mechanism associated with progression and to improve our understanding of the interactions between AD and CVD. PUBLIC HEALTH RELEVANCE: Elevated plasma amyloid beta 1-40 (A¿40) levels in the elderly increase the risk of future memory impairment and Alzheimer's disease (AD). Our proposed MRI study of normal elderly will examine the hypothesis that plasma A¿40 is a vasoconstrictor of hippocampal and other cerebral blood vessels that impairs vasodilation and leads to progressive AD-related changes. This project could lead to new blood and MRI assessments for AD-risk, direct attention to modulating A¿40, and improve our mechanistic understandings of the known interactions between AD and other diseases that affect vascular function.

描述（由适用提供）：没有与AD进展相关的临床识别机制。对基本正常受试者（NL）受试者的最新研究表明，血浆淀粉样蛋白β1-40水平升高（A¿40）的个体对轻度认知障碍（MCI）和阿尔茨海默氏病（AD）的风险更高。在转基因AD（TG）和野生型小鼠模型中，升高的血浆a¿40与海马（髋关节）血管反应性（VR）的降低有关，甚至在A沉积或脑损伤之前，TG也是如此。我们的人类飞行员数据支持这些动物发现表明，血浆是脑血管的生物活性血管收缩剂，对髋关节VR有明显的早期作用。然而，尚不清楚VR减少是否在临床级联反应源附近，包括进行性结构性脑损伤，淀粉样蛋白和TAU病理学以及认知障碍。影响进展的血管机制很有趣，并且与神经病理学和流行病学一致。然而，由于血浆A 40和心血管疾病（CVD）都损害了脑内皮和平滑肌细胞功能，因此纵向评估这两个因素及其相互作用至关重要。我们的试点数据还表明，A 40和CVD风险独立靶向VR-CO2，影响重叠和不同的脑血管区域。升高血浆A a 40和CVD风险对认知，大脑结构和AD生物标志物的综合作用仍然未知。我们提出了两项​​NL衰老研究。在第1部分中，我们将回顾性地建立在大型随机社区样本中等离子体A级，CVD风险和认知能力下降之间的纵向关系。我们将在1875年的1875年中宣布血浆a贷和42个水平，从625个随机选择的社区中存储的血浆样品，每年居住在NL居住的NL，每年在3年的间隔内进行研究。在第2部分中，我们将对由A 40级别和CVD风险分层的200个个体进行了前瞻性2年，三个时间点，纵向研究。我们将研究A 40和CVD风险因素之间的关系，作为减少VR-CO2和AD相关变化的预测指标。在资助周期中测试和验证了所有所需的临床，MRI和生物标志物测量。这包括一种新的动脉自旋标记（ASL）方法，该方法精确地测量了常规回声平面ASL中典型的空间畸变，可精确测量髋关节和皮质灌注和VR-CO2。我们将在横截面和纵向上检验四个主要假设：1）血浆中的升高40级别优先降低Ad-vulnernerable区域中的VR-CO2； 2）与VR-CO2降低相关的血浆a§升高，预测与AD相关的一系列临床和生物学变化； 3）提高CVD风险预测减少了新皮质VR-CO2，以及言语荧光和工作记忆中的渐进定义； 4）对于具有CVD和高血浆风险合并风险的受试者，VR-CO2的协同下降并增加了认知和结构性大脑的变化。这项研究有可能揭示与进展相关的广告相关血管机制，并提高我们对AD与CVD之间相互作用的理解。 公共卫生相关性：基础上血浆淀粉样ββ1-40（A�40）水平升高，增加了未来记忆障碍和阿尔茨海默氏病（AD）的风险。我们提出的对正常基本的MRI研究将研究以下假设：血浆A 40是海马和其他大脑血管的血管收缩，会损害血管舒张并导致与AD相关的渐进性变化。该项目可能会导致广告风险的新血液和MRI评估，直接注意调节A 40，并提高我们对影响血管功能的AD与其他疾病之间已知相互作用的机械理解。