Neuroepidemiology of the vascular contribution to cognitive impairment and Alzheimer's disease

 描述（由申请人提供）：血管风险因素和血管疾病越来越被认为是认知障碍和痴呆（包括阿尔茨海默病（AD））的主要贡献者，但尽管其作为预防目标的潜在作用，但往往研究不足。作为一名接受过临床研究博士培训的卒中神经科医生，PI建议评价一种特殊形式的血管疾病-充血性心力衰竭（CHF）-与认知能力和β-淀粉样蛋白沉积（主要假设为AD的病因）的相关性。在一个已经收集的社区队列中，（社区神经认知研究中的动脉粥样硬化风险（ARIC-NCS），由NHLBI和NINDS资助，Gottesman博士担任联合研究者）及其辅助R 01子队列（ARIC-PET研究，由NIA R 01资助，Gottesman博士作为PI），Gottesman博士将评估亚临床心功能障碍与认知能力下降和β-淀粉样蛋白沉积之间的相关性，每个.此外，在一项正在进行的前瞻性临床心力衰竭队列（利尿临床认知队列）中，Gottesman博士将评价与认知损害相关的CHF特征，将评价在失代偿性CHF治疗背景下认知缺陷是否可逆，并将探索在这种背景下任何一过性认知缺陷的机制（特别是脑血流量和炎症的变化）。这些研究将为PI提出的指导计划提供结构，她在血管对认知障碍和AD的贡献领域的其他正在进行的研究也将如此，重点是神经流行病学方法。作为职业生涯中期指导奖的一部分，PI将专注于培训未来对血管对AD的贡献感兴趣的研究者。因为这是一个可以进行干预或预防性治疗的领域，可以直接减少AD负担，或者可以识别可能从未来AD特异性治疗中受益的高风险人群，因此显然需要了解如何测量和定义血管风险因素和疾病的重要性的受训者，以及如何解决与认知障碍和痴呆症患者相关的分析中的潜在偏见。指导计划将侧重于直接接触临床队列和流行病学队列内的原始数据收集、流行病学数据的二级数据分析以及跨学科的研究方法。这项K-24申请中的拟议研究使用了一种特殊的血管疾病模型（CHF），该模型可能是认知障碍和痴呆的重要贡献者，并且其中的损伤可能是可逆或可预防的。该K-24应用程序的具体目标是：（1）表征和探索与充血性心力衰竭相关的认知功能障碍的机制;（2）招募和指导来自约翰霍普金斯大学医学院和公共卫生学院的一系列学科的新研究人员，包括但不限于神经病学，精神病学，神经心理学，老年病学，流行病学和生物统计学。

 DESCRIPTION (provided by applicant): Vascular risk factors and vascular disease are increasingly recognized as major contributors to cognitive impairment and dementia, including Alzheimer's disease (AD), but tend to be understudied despite their potential role as a target for prevention. As a stroke neurologist, with doctoral training in Clinical Investigation, the PI proposes to evaluate a particular form of vascular disease-congestive heart failure (CHF)-in association with cognitive performance and β-amyloid deposition, which by leading hypotheses is the cause of AD. In one already-collected community-based cohort (The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), funded through NHLBI and NINDS with Dr. Gottesman as a coinvestigator) and its ancillary R01 sub-cohort (The ARIC-PET study, funded through an NIA R01 with Dr. Gottesman as PI), Dr. Gottesman will evaluate associations between subclinical cardiac dysfunction and cognitive decline and β- amyloid deposition, each. In addition, in an ongoing prospective clinical heart failure cohort (Diuresis Clinic Cognitive Cohort), Dr. Gottesman will evaluate the features of CHF that are associated with cognitive impairment, will evaluate if cognitive deficits are reversible in the setting of treatment of decompensated CHF, and will explore mechanism for any transient cognitive deficits in this setting (particularly, changes in cerebral blood flow and in inflammation). These studies will provide the structure for the PI's proposed mentoring plan, as will her other ongoing research in the area of the vascular contribution to cognitive impairment and AD, with an emphasis on neuroepidemiologic approaches. As part of this mid-career mentoring award, the PI will focus on training future investigators interested in the vascular contribution to AD. Because this is an area in which interventions or preventive therapies might be undertaken that could either directly reduce AD burden, or could identify persons at high risk who might benefit from future AD-specific treatments, it is clear that trainees are needed who understand the importance of how to measure and define vascular risk factors and disease, and how to address potential biases in analyses related to persons with cognitive impairment and dementia. The mentoring plan will focus on direct exposure to primary data collection within clinical cohorts and within epidemiologic cohorts, secondary data analysis of epidemiologic data, and an interdisciplinary approach to research. The proposed research in this K-24 application uses a particular vascular disease model (CHF) that is a likely important contributor to cognitive impairment and dementia, and in which impairments might be reversible or preventable. The specific goals of this K-24 application are: (1) to characterize and explore mechanisms for cognitive dysfunction associated with congestive heart failure; and (2) to recruit and mentor new investigators in a range of disciplines from the Schools of Medicine and Public Health at Johns Hopkins, to include, but not limited to, neurology, psychiatry, neuropsychology, geriatrics, epidemiology, and biostatistics.