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

 描述(申请人提供)：血管风险因素和血管疾病日益被认为是认知障碍和痴呆症的主要因素，包括阿尔茨海默病(AD)，但尽管它们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中风神经学家，PI建议评估一种特殊形式的血管疾病-充血性心力衰竭(CHF)-与认知表现和β-淀粉样蛋白沉积有关，通过引导性假设，这是AD的原因。在一个已经收集到的以社区为基础的队列(社区动脉粥样硬化风险神经认知研究，由NHLBI和NINDS资助，戈特斯曼博士担任协作者)及其附属的R01子队列(ARIC-PET研究，由美国心脏病学会R01资助，戈特斯曼博士担任PI)中，戈特斯曼博士将评估亚临床心脏功能障碍与认知功能下降和β-淀粉样蛋白沉积之间的关系。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博士将评估与认知障碍相关的CHF的特征，评估失代偿性CHF治疗中的认知障碍是否可逆，并将探索这种情况下任何一过性认知障碍的机制(尤其是脑血流和炎症的变化)。这些研究将为PI提出的指导计划提供结构，以及她在血管对认知障碍和AD的贡献领域正在进行的其他研究，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将专注于培训对AD的血管贡献感兴趣的未来研究人员。由于这是一个可以采取干预措施或预防性治疗的领域，既可以直接减轻AD负担，也可以确定可能从未来针对AD的治疗中受益的高危人群，因此显然需要了解如何衡量和定义血管风险因素和疾病以及如何在与认知障碍和痴呆者相关的分析中解决潜在偏见的受训者。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初级数据收集，流行病学数据的二级数据分析，以及研究的跨学科方法。在这项K-24申请中提出的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症的重要贡献者，其中损伤可能是可逆的或可以预防的。这项K-24应用的具体目标是：(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；以及(2)从约翰霍普金斯大学医学院和公共卫生学院招募和指导一系列学科的新研究人员，包括但不限于神经学、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.