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（由申请人提供）：没有临床上可识别的与 AD 进展相关的机制。最近对老年正常 (NL) 受试者的研究表明，血浆淀粉样蛋白 β 1-40 (A¿40) 水平升高的个体患轻度认知障碍 (MCI) 和阿尔茨海默病 (AD) 的风险较高。在转基因 AD (Tg) 和野生型小鼠模型中，血浆 A¿40 升高与海马 (HIP) 血管反应性 (VR) 降低有关，并且在 Tg 中甚至在 A¿ 沉积或脑损伤之前。我们支持这些动物研究结果的人类试验数据表明，血浆 A¿40 是一种具有生物活性的脑血管收缩剂，对 HIP VR 具有明显的早期影响。然而，目前尚不清楚 VR 的减少是否是临床级联反应的根源，包括进行性结构性脑损伤、淀粉样蛋白和 tau 蛋白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) 都会损害脑内皮细胞和平滑肌细胞功能，因此纵向评估这两个因素及其相互作用至关重要。 我们的试验数据还表明，A¿40 和 CVD 风险独立地针对影响重叠和不同脑血管区域的 VR-CO2。血浆 A¿40 升高和 CVD 风险对认知、大脑结构和 AD 生物标志物的综合影响仍不清楚。我们提出了两项​​ NL 老化研究。在第 1 部分中，我们将在大型随机社区样本中回顾性地建立血浆 A¿40、CVD 风险和认知能力下降之间的纵向关系。我们将检测来自 625 名随机选择的 NL 社区老年受试者的 1875 个储存血浆样本中的血浆 A¿40 和 A¿42 水平，每年进行一次为期 3 年的研究。在第 2 部分中，我们将对 200 名 NL 个体进行一项为期 2 年、三个时间点的纵向研究，按 A¿40 水平和 CVD 风险进行分层。我们将研究 A¿40 和 CVD 风险因素之间的关系，作为 VR-CO2 减少和 AD 相关变化的预测因素。所有必需的临床、MRI 和生物标志物测量均在资助周期内进行了测试和验证。其中包括一种新的动脉自旋标记 (ASL) 方法，可精确测量 HIP 和皮质灌注以及 VR-CO2，而不会出现传统回波平面 ASL 中典型的空间扭曲。我们将在横截面和纵向上测试四个主要假设：1）血浆 A¿40 水平的升高优先减少 AD 易感区域的 VR-CO2； 2) 血浆 A¿40 升高与 VR-CO2 减少相关，可预测与 AD 相关的一系列临床和生物学变化； 3）CVD风险升高预示着新皮质VR-CO2减少，以及言语流畅性和工作记忆的进行性缺陷； 4) 对于具有 CVD 和高血浆 A¿40 综合风险的受试者，VR-CO2 会协同减少，认知和大脑结构变化也会增加。这项研究有可能揭示与进展相关的 AD 相关血管机制，并提高我们对 AD 和 CVD 之间相互作用的理解。 公共健康相关性：老年人血浆淀粉样蛋白 β 1-40 (A¿40) 水平升高会增加未来记忆障碍和阿尔茨海默病 (AD) 的风险。我们提出的对正常老年人的 MRI 研究将检验以下假设：血浆 A¿40 是海马和其他脑血管的血管收缩剂，会损害血管舒张并导致进行性 AD 相关变化。该项目可能会带来针对 AD 风险的新血液和 MRI 评估，直接关注调节 A¿40，并提高我们对 AD 与影响血管功能的其他疾病之间已知相互作用的机制理解。