Midlife Vascular Risk Factors for Alzheimer's Disease in Persons with HFpEF

摘要 本研究的目的是确定血管危险因素与 阿尔茨海默病（AD）风险的生物标志物随着时间的推移，在中年人的心脏衰竭， 射血分数（HFpEF）。中年心血管危险因素有助于老年AD的发展 以及AD进展。HFpEF的病理生理机制与AD的机制途径相同 在某些实施方案中，所述方法可用于治疗脑发育，例如脑灌注不足、血脑屏障（BBB）破坏、全身和中枢神经系统损伤。 炎症和神经激素失调。这些AD途径导致AD生物标志物的积累 在脑脊液（CSF）和血液中。本研究将招募HFpEF患者，以阐明血管风险 这一未充分研究人群的特定因素与血管功能障碍相关的病理生理驱动因素 AD风险。拟议的纵向研究将检验中年血管危险因素预测 HFpEF患者AD风险的生物标志物。我们将在一个高风险队列中测试以下特定目标： 80例中年（45- 65岁）非西班牙裔白色（n =40）和黑人/非裔美国人（n=40） 诊断HFpEF超过2年的患者：1）评估血管风险与CSF生物标志物的相关性 2）评估血管风险与HFpEF的关系， 在HFpEF中年成人中两年以上AD风险的血液生物标志物，和3）评估 在HFpEF中年患者中，血管风险与认知功能的关系超过两年。这个职业 发展奖建立在以前开发的研究心血管机制的优势之上 疾病病理生理学，并旨在填补申请人在阿尔茨海默病研究方面的差距。 训练具体的职业发展目标包括：1）获得AD科学的专业知识， AD生物标志物，包括收集和分析来自血液和脑脊液的AD生物标志物， 血管功能测量，2）获得认知功能测量方面的高级培训和经验，3）获得 临床试验实施方面的专业知识，4）完善健康差异研究方面的知识，以及5）过渡到 独立性，并为我的翻译研究计划的下一阶段做准备。从这个研究结果 将导致识别可能适合于改善血管的干预的途径， 在HFpEF患者中发挥作用，目的是降低这一高发病率人群中的AD风险。

ABSTRACT The purpose of this study is to determine the extent to which vascular risk factors are associated with biomarkers of Alzheimer’s disease (AD) risk over time in middle aged adults with heart failure with preserved ejection fraction (HFpEF). Mid-life cardiovascular risk factors contribute to the development of AD in later life and to AD progression. Pathophysiologic mechanisms in HFpEF share mechanistic pathways implicated in AD development, such as cerebral hypoperfusion, blood brain barrier (BBB) disruption, systemic and central inflammation, and neurohormonal dysregulation. These AD pathways lead to accumulation of AD biomarkers in cerebral spinal fluid (CSF) and blood. This study will enroll persons with HFpEF to elucidate vascular risk factors specific to this understudied population with pathophysiologic drivers of vascular dysfunction associated with AD risk. The proposed longitudinal study will test the hypothesis that midlife vascular risk factors predict biomarkers of AD risk in persons with HFpEF. We will test the following Specific Aims in a high-risk cohort of 80 non-Hispanic White (n=40) and Black/African American (n=40) individuals during middle age (45-65yrs) who have a diagnosis of HFpEF over 2 years: 1) assess the association of vascular risks with CSF biomarkers of AD risk over two years in middle aged adults with HFpEF, 2) assess the association of vascular risks with blood biomarkers of AD risk over two years in middle aged adults with HFpEF, and 3) assess the association of vascular risks with cognitive function over two years in middle aged adults with HFpEF. This career development award builds on previously developed strengths in studying mechanisms in cardiovascular disease pathophysiology and aims to fill the gap related to Alzheimer’s disease research in the applicant’s training. Specific career development goal included in this plan are: 1) gain expertise in the science of AD and AD biomarkers, including collecting and analyzing AD biomarkers from blood and cerebrospinal fluid and vascular function measures, 2) gain advanced training and experience in cognitive function measures, 3) gain expertise in clinical trial implementation, 4) refine knowledge in health disparities research, and 5) transition to independence and prepare for the next stage of my translational research program. Findings from this study will lead to the identification of pathways that might be amenable to interventions that improve vascular function for persons with HFpEF, with the goal of decreasing AD risk in this high morbidity population.