Investigating Resistance and Resilience Mechanisms in Alzheimer’s Disease

研究阿尔茨海默病的抵抗力和恢复力机制

• 批准号: 10605784
• 负责人: PRASHANTHI VEMURI
• 金额: $ 81.03万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605784
• 关键词: Accounting; Address; Age; Age Factors; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Anterior; Area; Behavior; Biological; Biological Markers; Blood Pressure; Blood Vessels; Body mass index; Brain; Cardiovascular system; Cerebrovascular Disorders; Clinic; Clinical; Cognition; Cognitive; Cognitive aging; Complex; Corpus Callosum; Data; Dementia; Diffusion Magnetic Resonance Imaging; Education; Epidemiology; Evaluation; Genetic; Health; Hemorrhage; Heterogeneity; Image; Impaired cognition; Individual; Individual Adjustment; Infarction; Infrastructure; Intervention; Knowledge; Lipids; Magnetic Resonance Imaging; Maps; Measurement; Measures; Medical Record Linkage; Metabolic; Methods; Modeling; National Institute on Alcohol Abuse and Alcoholism; Nerve Degeneration; Neurites; Neurobehavioral Manifestations; Nomenclature; Occupations; Pathologic Processes; Pathway interactions; Peer Review; Physical activity; Plasma; Population; Positron-Emission Tomography; Predictive Factor; Prevention; Prevention strategy; Prevention trial; Proteins; Publications; Research; Resistance; Resolution; Risk Factors; Rural; Scanning; Sleep; Smoking; Social Identification; Social support; System; Testing; Thick; Translating; White Matter Hyperintensity; aged; bench-to-bedside translation; brain health; cohort; coping; density; deprivation; design; disability; entorhinal cortex; health literacy; imaging biomarker; improved; indexing; individual variation; machine learning method; microsystems; multimodality; perceived stress; polygenic risk score; population based; predictive marker; prevent; primary care visit; promote resilience; protective factors; research study; resilience; resistance mechanism; sex; social health determinants; success; tau Proteins; tau aggregation; therapeutically effective

PROJECT SUMMARY / ABSTRACT Cognitive Aging and risk of Alzheimer's disease, and Alzheimer's related dementias (AD/ADRD) is due to multiple aging and pathological processes that are driven by several upstream brain mechanisms and risk factors. The success of recent multi-domain interventions and our preliminary data suggests that multiple mechanisms need to be targeted for effective dementia prevention. In 2018, we proposed a simplistic conceptual framework that builds on existing concepts using the nomenclature of resistance in the context of avoiding AD pathology and resilience in the context of coping with AD pathology for investigating these distinct mechanisms. This proposal addresses an important barrier for developing effective therapeutic or preventive strategies for AD dementia - the poor understanding of how upstream risk factors and brain mechanisms (resistance and resilience) that could contribute to or protect from protein accumulation and neurodegeneration. Our central hypothesis is that identifying upstream brain mechanisms of resistance and resilience and modeling the complex inter-relationships between protective factors, brain mechanisms, and longitudinal changes in amyloid, tau, and cognition will aid in effective design of dementia prevention strategies. To test this hypothesis, our primary aim is to identify mechanisms of resistance and resilience using the existing infrastructure of the population-based Mayo Clinic Study of Aging (MCSA) (individuals aged ≥50 years) and Rochester Epidemiology Project (REP) which maintains a comprehensive medical records-linkage system. We will collect the following variables for this proposal: Genetics, Social Determinants of Health (SDoH), and systemic health (up to 20 years prior to scan from REP), longitudinal PiB and tau PET, baseline cutting edge MRI (high resolution T1/T2/FLAIR and multi-shell diffusion MRI to assess perivascular spaces, microstructural integrity, and cortical thickness), and cognitive decline. Our secondary aim is to develop and validate MRI- based resilience markers that can be used in the NIA-AA research framework alongside with AT(N) biomarkers to adjust for individual variability in cognition. Considering brain health measures (other than those included in the evaluation of N) as resilience markers will improve the prediction of cognitive decline across all aging and dementia studies. These measures will be able to capture biological variability due to SDoH and systemic health and facilitate better comparison of biomarkers across populations.

项目总结/摘要 认知老化和阿尔茨海默病的风险，以及阿尔茨海默病相关痴呆（AD/ADRD）是由于 多种老化和病理过程，由几个上游大脑机制和风险驱动 因素最近多领域干预的成功和我们的初步数据表明， 机制需要针对有效的痴呆症预防。在2018年，我们提出了一个简单的概念， 在避免AD的背景下，建立在现有概念基础上的框架，使用耐药性命名法 病理学和韧性的背景下，应对AD病理学调查这些不同的机制。 该提案解决了开发有效的AD治疗或预防策略的重要障碍 痴呆症-对上游风险因素和大脑机制（抵抗力和 弹性），可能有助于或保护蛋白质积累和神经变性。我们的中央 一种假说认为，识别抵抗力和恢复力的上游大脑机制， 保护因子、脑机制和淀粉样蛋白、tau蛋白和 认知将有助于痴呆症预防策略的有效设计。 为了验证这一假设，我们的主要目标是利用现有的 基于人群的马约诊所衰老研究（MCSA）的基础设施（年龄≥50岁的个体）和 罗切斯特流行病学项目（REP），该项目维护一个全面的医疗记录链接系统。我们 将为该提案收集以下变量：遗传学，健康的社会决定因素（SDoH），以及 全身健康（REP扫描前20年），纵向PiB和tau PET，基线前沿 MRI（高分辨率T1/T2/FLAIR和多壳扩散MRI，以评估血管周围间隙、微结构 完整性和皮质厚度）和认知能力下降。我们的第二个目标是开发和验证磁共振成像- 可与AT（N）生物标志物一起用于NIA-AA研究框架的基于弹性的标记物 以适应认知的个体差异。考虑脑健康措施（除 N）作为恢复力标记的评估将改善对所有年龄段认知下降的预测， 痴呆症研究这些措施将能够捕获由于SDoH和全身健康引起的生物变异性 并有助于更好地比较不同人群的生物标志物。