Two Diseases or one? The early pathogenesis of vascular mediated cognitive decline and Alzheimer's Disease.

两种疾病还是一种？

• 批准号: 9191025
• 负责人: Sara Elizabeth Berman
• 金额: $ 3.35万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9191025
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Arteries; Autopsy; Biological Markers; Blood Vessels; Blood flow; Brain; Cause of Death; Cerebrospinal Fluid; Cerebrovascular Disorders; Cerebrum; Circle of Willis; Clinical; Clinical assessments; Cognition; Cognitive; Data; Dementia; Development; Diagnosis; Disease; Disease Progression; Elderly; Environment; Episodic memory; Family; Fellowship; Gene-Modified; Genes; Genetic; Genetic Risk; Health; Impaired cognition; Individual; Internal carotid artery structure; Late Onset Alzheimer Disease; Link; Magnetic Resonance Imaging; Marketing; Measurement; Measures; Mediating; Medical; Mentors; Metabolism; Methods; Modeling; Molecular; Nature; Nerve Degeneration; Neurobiology; Neurofibrillary Tangles; Neurons; Neuropsychological Tests; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Recording of previous events; Research; Research Personnel; Risk; Risk Factors; Senile Plaques; Statistical Models; Symptoms; Technology; Testing; Time; United States; Visit; Wisconsin; Work; abstracting; amyloid pathology; brain health; brain volume; cerebral atrophy; cognitive performance; cognitive testing; comorbidity; coping; executive function; experience; fight against; follow-up; genetic risk factor; hippocampal atrophy; indexing; middle age; mild cognitive impairment; mixed dementia; neuropsychological; non-demented; novel; pre-clinical; tau Proteins; tau-1

Project Summary/Abstract Alzheimer's disease (AD) is the only cause of death amongst the top ten in the United States which has no treatment. AD progression cannot be halted, and there are no disease-modifying drugs currently on the market (1). It is hypothesized that the reason many treatments have failed in the fight against AD is that once a person starts showing clinical cognitive decline, too many neurons are irreparably destroyed. Consequently, the prevailing notion in the field of AD research is that we must identify patients at risk for developing the disease, so we can treat them before symptoms manifest. In order to be successful in this endeavor, we must work to understand the etiopathogenesis of the disease. It is becomingly increasingly recognized that many cases of AD are multifactorial in nature; the most common mixed dementia pathology is standard AD amyloid and tau pathology in concert with vascular pathology. This proposal seeks to examine the relationship between vascular status, particularly arterial health metrics of the arteries of the Circle of Willis, and longitudinal metrics associated with AD progression, namely cognitive performance on neuropsychological tests and cerebrospinal fluid (CSF) analytes. Additionally, as AD is known to be genetically linked, this F30 project will also seek to investigate how differing genetic backgrounds interact with vascular and amyloid pathology. Specifically, this fellowship proposal will employ a newly developed 4D-Flow MRI method to characterize cerebrovascular disease in the major arteries of the brain. These metrics will be used as predictor variables in longitudinal linear mixed effects models to examine trajectories of cognitive decline. Furthermore, these arterial health metrics will be analyzed in concert with structural and molecular variables associated with AD, namely cortical atrophy, hippocampal atrophy, and CSF amyloid and tau, to determine whether poor vascular health is associated with a faster accumulation of AD-associated pathology. Lastly, a polygenic risk score representing the amyloid clearance pathway and metrics of arterial health will be studied in an interaction model to determine if optimal vascular health may be protective in those individuals with increased genetic risk for AD.

项目摘要/摘要 阿尔茨海默氏病（AD）是美国前十名中唯一的死亡原因 没有治疗。广告进展不能停止，并且目前没有疾病改良的药物 市场（1）。假设许多治疗方法在与AD斗争中失败的原因是 人开始表现出临床认知能力下降，太多的神经元被无法挽回地破坏。最后， 在广告研究领域，普遍的概念是，我们必须确定有风险的患者 疾病，因此我们可以在症状表现出来之前对其进行治疗。为了在这项工作中取得成功，我们必须 努力了解该疾病的病情发生。人们越来越认识到许多 AD的病例本质上是多因素的；最常见的混合痴呆病理学是标准AD淀粉样蛋白 和tau病理与血管病理结合在一起。该建议旨在检查 血管状态，尤其是威利斯圆动脉的动脉健康指标和纵向指标 与AD进展相关，即神经心理学测试和脑脊髓中的认知表现 流体（CSF）分析物。此外，正如广告相关的遗传链接，该F30项目也将寻求 研究不同的遗传背景如何与血管和淀粉样蛋白病理相互作用。具体来说，这是 奖学金提案将采用新开发的4D流MRI方法来表征脑血管 大脑主要动脉中的疾病。这些指标将用作纵向线性的预测变量 混合效应模型检查认知能力下降的轨迹。此外，这些动脉健康指标将 与与AD相关的结构和分子变量共同分析，即皮质萎缩， 海马萎缩以及CSF淀粉样蛋白和TAU，以确定较差的血管健康是否与 广告相关病理的更快积累。最后，代表淀粉样蛋白的多基因风险评分 将在相互作用模型中研究清除途径和动脉健康指标，以确定是否最佳 对于那些患有AD遗传风险增加的人的血管健康可能具有保护性。