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

项目摘要 痴呆症构成了一个重大的公共卫生问题，超过200万的美国中风幸存者患有痴呆症。 痴呆心房颤动（AF）是一种特殊类型的不规则心跳，是最常见的原因， 心源性卒中，研究表明，在卒中患者中，心源性卒中 患者认知能力下降的风险最大。然而，即使与临床卒中无关， 与认知能力下降和痴呆症有关。房颤与认知功能障碍的相关机制 可能是多因素的，但作为AF和AF之间独立通路基础的大脑病理学 除了临床中风之外，对痴呆症的了解很少。据了解，大脑病理，导致 痴呆先于临床症状的发展，这表明这种病理学可能已经是 存在于AF患者中，但没有普遍的痴呆。痴呆症领域的快速发展导致了 使用基于血液（血浆）的生物标志物的能力，而不是以前的更具侵入性的技术， 例如腰椎穿刺，以确定导致 临床阿尔茨海默病（AD）的发展。AD病理学的此类血浆生物标志物包括 磷酸化tau 181（pTau 181）、血浆β淀粉样蛋白（Aβ42/Aβ40）和神经丝轻蛋白（NFL）， 已被认为是三个主要的病理组分（A/T/N;淀粉样蛋白/Tau/神经变性）， 以指导具体的AD研究。在本建议中，我们的目标是（目标1）比较AD的平均水平- 无卒中、非痴呆、高危人群队列中相关血浆生物标志物（p-tau 181、Aβ42/Aβ40、NFL） 心血管（CVD）门诊房颤患者与对照组无房颤的高风险CVD患者。 还将确定这些生物标志物水平差异的可能性， AF患者，例如患者的AF类型或抗凝（AC）相关的可能性 治疗效果最后，（目的2）我们将确定这些患者的一个子集是否与AD相关的脑萎缩 与无AF的对照患者相比，CVD伴AF患者中存在无症状脑血管 疾病该提案体现了R21高风险、高回报赠款机制的目标， 这是一个创新项目，将开始建立对AF患者大脑病理学的理解 与普遍的临床中风不同，这是认知能力下降的相关风险的基础。它也有 通过促进未来对潜在目标的研究，以预防、推迟和消除疾病， 或治疗房颤相关痴呆。

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.