Determinants of Alzheimer's Disease in Atrial Fibrillation apart from Stroke: The NOMINATE Study

项目总结 痴呆症是一个重大的公共卫生问题，超过200万美国中风幸存者患有痴呆症 痴呆症。房颤(房颤)是一种特殊类型的不规则心跳，是导致 心栓性中风，研究表明，在中风患者中，心栓性中风 患者认知能力下降的风险最大。然而，房颤，即使独立于临床中风，也有 与认知能力下降和痴呆症有关。房颤与认知功能障碍的联系机制 可能是多因素的，但作为房颤和房颤之间这一独立通路的基础的大脑病理 痴呆症，除了临床中风外，人们对此知之甚少。众所周知，导致脑部病变的原因是 痴呆症先于临床症状的发展，表明这种病理可能已经 存在于房颤患者中，但不存在普遍的痴呆。痴呆症领域的快速发展导致了 使用基于血液的(血浆)生物标记物的能力，而不是以前更具侵入性的技术， 例如腰椎穿刺术，以确定是否存在导致 临床阿尔茨海默病(AD)的发展。阿尔茨海默病的这些血浆生物标志物包括 磷酸化tau181(PTau181)、血浆β淀粉样蛋白(Aβ42/Aβ40)和神经丝光(NFL)，其中 已被认为是三个主要的病理成分(A/T/N；淀粉样蛋白/Tau/神经变性)，由 以指导特定于AD的研究。在这项建议中，我们的目标是(目标1)比较AD的平均水平- 无卒中、非痴呆、高危人群中的相关血浆生物标志物(p-tau181，Aβ42/Aβ40，NFL) 有房颤的心血管(CVD)门诊患者与无房颤的高危CVD患者的对照组比较。我们 还将根据这些生物标志物的特征确定这些生物标志物水平的差异 房颤患者，例如患者的房颤类型或与抗凝(AC)相关的可能性 治疗效果。最后，(目标2)我们将在这些患者的子集中确定AD相关的脑萎缩 在有房颤的CVD患者和没有房颤的对照组患者中存在，这是无症状脑血管的原因 疾病。这项提案体现了R21高风险、高回报赠款机制的目标，通过代表 一个创新的项目，将开始建立对房颤患者脑病理的理解 与普遍存在的临床中风不同，认知功能下降的相关风险是潜在的。它还拥有 通过促进未来对潜在预防目标的研究，推迟对公共卫生的潜在影响 或治疗房颤相关的痴呆症。

PROJECT SUMMARY Dementia poses a significant public health problem, and over 2 million American stroke survivors suffer from dementia. Atrial fibrillation (AF), which is a particular type of irregular heartbeat, is the most common cause of cardioembolic stroke, and studies have demonstrated that, among stroke patients, cardioembolic stroke patients are at the greatest risk for cognitive decline. However, AF, even independent of clinical stroke, has been associated with cognitive decline and dementia. The mechanisms linking AF and cognitive impairment are likely multifactorial, but the cerebral pathology that underlies this independent pathway between AF and dementia, apart from clinical stroke, is poorly understood. It is known that the cerebral pathology that leads to dementia precedes the development of clinical symptoms, suggesting that such pathology may already be present in patients with AF, but without prevalent dementia. Rapid developments in the dementia field have led to the ability to use blood-based (plasma) biomarkers, rather than the previous, more invasive, techniques, such as a lumbar puncture, to determine the presence of disease-causing pathology that contribute to the development of clinical Alzheimer’s disease (AD). Such plasma biomarkers of AD pathology include phosphorylated-tau181 (pTau181), plasma beta Amyloid (Aβ42/Aβ40) and neurofilament light (NFL), which has been suggested as the three primary pathologic components (A/T/N; Amyloid/Tau/Neurodegeneration) by which to guide AD-specific research. In this proposal, we aim to (Aim 1) compare the mean level of AD- associated plasma biomarkers (p-tau181, Aβ42/Aβ40, NFL) in a cohort of stroke-free, non-demented, high-risk cardiovascular (CVD) outpatients with AF to those in a control group of high-risk CVD patients without AF. We also will determine the potential for differences in the levels of these biomarkers based on characteristics of the AF patient, such as the type of AF a patient has or the possibility of an anticoagulation (AC) associated treatment effect. Finally, (Aim 2) we will determine in a sub-set of those patients if AD associated brain atrophy is present in CVD patients with AF versus in control patients without AF, accounting for silent cerebrovascular disease. This proposal embodies the goals of the R21 high-risk, high-reward grant mechanism by representing an innovative project that will begin to establish an understanding of the cerebral pathology in AF patients underlying the associated risk for cognitive decline, distinct from prevalent clinical stroke. It also has the potential for great public health impact by facilitating future research on potential targets to prevent, postpone or treat AF-related dementia.