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

除中风之外的房颤中阿尔茨海默病的决定因素：提名研究

• 批准号: 10433238
• 负责人: Michelle C. Johansen
• 金额: $ 26.09万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433238
• 关键词: Accounting; Alleles; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer’s disease biomarker; American; Amyloid; Amyloid Proteins; Amyloid beta-42; Amyloid beta-Protein; Anticoagulation; Area; Atrial Fibrillation; Biological Markers; Blood; Blood Vessels; Brain; Cerebral Infarction; Cerebrovascular Disorders; Cerebrum; Characteristics; Clinical; Cognition; Cognitive; Consent; Control Groups; Data; Dementia; Development; Disease; Future; Goals; Grant; Hippocampus (Brain); Image; Impaired cognition; Infarction; Ischemic Stroke; Lead; Lesion; Life; Light; Link; Magnetic Resonance Imaging; Mediating; Memory; Myocardial dysfunction; Nerve Degeneration; Neuronal Injury; Outcome; Outpatients; Participant; Pathologic; Pathology; Pathway interactions; Patient risk; Patients; Plasma; Population; Public Health; Recording of previous events; Research; Risk; Risk Factors; Spinal Puncture; Stroke; Symptoms; Techniques; Testing; Time; Vascular Diseases; White Matter Disease; abeta deposition; apolipoprotein E-4; base; brain volume; cardiovascular risk factor; cerebral atrophy; cerebral hypoperfusion; cerebrovascular; clinical development; cohort; comorbidity; cost; dementia risk; demographics; disorder risk; high reward; high risk; high risk population; innovation; insight; interest; neurofilament; neuroinflammation; non-demented; prevent; recruit; screening; secondary analysis; specific biomarkers; stroke patient; stroke risk; stroke survivor; tau Proteins; treatment effect; vascular cognitive impairment and dementia; vascular contributions; vascular injury; vascular risk factor

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.

项目概要 痴呆症构成了严重的公共卫生问题，超过 200 万美国中风幸存者患有痴呆症 失智。心房颤动 (AF) 是一种特殊类型的不规则心跳，是心房颤动的最常见原因 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，房颤即使独立于临床卒中， 与认知能力下降和痴呆有关。房颤与认知障碍的关联机制 可能是多因素造成的，但 AF 和 AF 之间的独立通路背后的大脑病理学 除了临床中风之外，人们对痴呆症知之甚少。众所周知，导致 痴呆先于临床症状的出现，这表明这种病理学可能已经存在 存在于 AF 患者中，但没有普遍的痴呆症。痴呆症领域的快速发展带动了 能够使用基于血液（血浆）的生物标志物，而不是以前的更具侵入性的技术， 例如腰椎穿刺，以确定是否存在导致疾病的病理学 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 tau181 (pTau181)、血浆 β 淀粉样蛋白 (Aβ42/Aβ40) 和神经丝光 (NFL)，其中 被认为是三种主要病理成分（A/T/N；淀粉样蛋白/Tau/神经变性） 指导针对 AD 的研究。在本提案中，我们的目标是（目标 1）比较 AD- 的平均水平 一组无中风、非痴呆、高风险人群中的相关血浆生物标志物（p-tau181、Aβ42/Aβ40、NFL） 患有 AF 的心血管 (CVD) 门诊患者与无 AF 的高危 CVD 患者对照组。我们 还将根据生物标志物的特征确定这些生物标志物水平差异的可能性 AF 患者，例如患者患有 AF 的类型或与抗凝 (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 是否与脑萎缩相关 存在于患有 AF 的 CVD 患者与无 AF 的对照患者中，解释了无症状的脑血管病 疾病。该提案体现了 R21 高风险、高回报资助机制的目标，代表 一个创新项目，将开始了解 AF 患者的脑病理学 与普遍的临床中风不同，认知能力下降的相关风险是潜在的。它还具有 通过促进未来对预防、推迟潜在目标的研究，可能产生巨大的公共卫生影响 或治疗与房颤相关的痴呆症。