Biomarkers in Early Alzheimer's Disease (AD).

描述（由申请人提供）：没有与AD进展相关的临床可识别机制。最近对老年正常人（NL）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A40升高与海马（HIP）血管反应性（VR）降低相关，即使在A40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研究结果，表明血浆A 40是脑血管的生物活性血管收缩剂，对HIP VR有明显的早期影响。然而，目前尚不清楚VR降低是否接近临床级联反应的来源，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是有趣的，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风险独立地靶向影响重叠和不同脑血管区域的VR-CO2。血浆A40升高和心血管病风险对认知、脑结构和AD生物标志物的综合影响仍不清楚。我们提出了两个NL老化研究。在第1部分中，我们将回顾性地建立一个大型随机社区样本中血浆A 40、心血管病风险和认知能力下降之间的纵向关系。我们将分析血浆A 40和A来自625名随机选择的社区居住NL老年受试者的1875份储存血浆样本中的42个水平，每年研究一次，为期3年。在第2部分中，我们将对200名NL个体进行一项前瞻性2年、3个时间点的纵向研究，按A <$40水平和CVD风险分层。我们将研究A40和CVD风险因素之间的关系，作为降低VR-CO2和AD相关变化的预测因子。所有要求的临床、MRI和生物标志物测量都在资助周期内进行了测试和验证。这包括一种新的动脉自旋标记（ASL）方法，该方法可精确测量HIP和皮质灌注以及VR-CO2，而不会出现传统回波平面ASL中典型的空间失真。我们将在横截面和纵向上测试四个主要假设：1）血浆A ² 40水平升高优先降低AD易感区域的VR-CO2; 2）血浆A ² 40升高与VR-CO2降低相关，预测与AD相关的一系列临床和生物学变化; 3）心血管疾病风险升高预示着新皮质VR-CO2降低，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的组合风险的受试者，VR-CO2协同降低，认知和结构性脑变化增加。这项研究有可能揭示与进展相关的AD相关的血管机制，并提高我们对AD和CVD之间相互作用的理解。 公共卫生相关性：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研究将检验血浆A 40是海马和其他脑血管的血管收缩剂的假设，该血管收缩剂损害血管舒张并导致进行性AD相关变化。该项目可能会导致新的血液和MRI评估AD风险，直接关注调节A40，并提高我们对AD和其他影响血管功能的疾病之间已知相互作用的机械理解。

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.