Biomarkers in Early Alzheimer's Disease (AD).

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。最近对老年正常人(NL)的研究表明，血浆淀粉样β1-40(A？40)水平升高的人患轻度认知障碍(MCI)和阿尔茨海默病(AD)的风险更高。在转基因AD(TG)和野生型小鼠模型中，血浆A？40升高与海马区(HIP)血管反应性(VR)降低相关，在TG中甚至在A？沉积或脑损伤之前就与此相关。我们的人类飞行员数据支持这些动物发现，表明血浆A？40是一种具有生物活性的脑血管收缩因子，对髋关节VR有显著的早期影响。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病理以及认知功能障碍。影响疾病进展的血管机制耐人寻味，并与神经病理学和流行病学相一致。然而，由于血浆A？40和心血管疾病(CVD)都损害了脑血管内皮细胞和平滑肌细胞的功能，因此对这两个因素及其相互作用进行纵向评估是至关重要的。我们的试点数据还显示，A？40和CVD-Risk独立地以VR-CO2为靶点，影响重叠和不同的脑血管区域。血浆A40升高和心血管疾病风险对认知、脑结构和AD生物标记物的联合影响尚不清楚。我们提出了两项关于NL老化的研究。在第一部分中，我们将在一个大的随机社区样本中，回顾建立血浆A？40、心血管疾病风险和认知能力下降之间的纵向关系。我们将从625名随机选择的居住在NL社区的老年受试者中检测1875份储存的血浆样本中的血浆A？40和A？42水平，每隔3年进行一次研究。在第二部分中，我们将对200名NL患者进行为期两年、三个时间点的前瞻性纵向研究，按A？40水平和心血管疾病风险分层。我们将研究A？40和心血管疾病危险因素之间的关系，作为VR-CO2减少和AD相关变化的预测因子。在资助周期中，所有必需的临床、核磁共振和生物标记物测量都进行了测试和验证。这包括一种新的动脉自旋标记(ASL)方法，它可以精确地测量髋部和皮质的血流灌注和VR-CO2，而不会出现传统回声平面ASL中典型的空间扭曲。我们将在横断面和纵向检验四个主要假说：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水平的升高与VR-CO2的降低一起预测与AD相关的一系列临床和生物学变化；3)CVD风险增加预示着新皮质VR-CO2的减少，以及言语流利性和工作记忆的进行性缺陷；4)对于CVD和高A？40合并风险的受试者，VR-CO2的协同减少以及认知和结构性大脑变化的增加。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。 公共卫生相关性：老年人血浆淀粉样β1-40(A？40)水平升高会增加未来记忆受损和阿尔茨海默病(AD)的风险。我们建议对正常老年人进行的MRI研究将检验这一假设，即血浆A？40是海马体和其他脑血管的血管收缩因子，它损害血管扩张并导致进行性AD相关变化。该项目可能导致对AD风险的新的血液和MRI评估，引导人们对调节A40的关注，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制的理解。

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.