Aerobic fitness as a modifier of neurodegeneration and cognitive decline in preclinical Alzheimer's disease

有氧健身作为临床前阿尔茨海默病神经退行性变和认知能力下降的调节剂

• 批准号: 10165451
• 负责人: Edmarie Guzmán-Vélez
• 金额: $ 17.36万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165451
• 关键词: AD transgenic mice; Address; Adult; Aerobic Exercise; Affect; Age of Onset; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid; Animal Disease Models; Animal Model; Area; Biological Markers; Brain; Brain Injuries; Brain Pathology; CCL2 gene; Cardiovascular Pathology; Cessation of life; Chronic; Clinical; Cognition; Colombian; Data Collection; Dementia; Disease; Disease Progression; Ensure; Episodic memory; Exercise; Family; Family member; Functional Magnetic Resonance Imaging; Funding; Future; Genes; Goals; Gold; Health; Human; Image; Impaired cognition; Individual; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-6; Intervention; Knowledge; Link; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Memory; Memory Loss; Mentored Patient-Oriented Research Career Development Award; Mentorship; Modeling; Multimodal Imaging; Mutation; Nerve Degeneration; Neurofibrillary Tangles; Neuroglia; Neurophysiology - biologic function; Parietal; Participant; Pathologic; Pathology; Patient Self-Report; Performance; Physical activity; Population Heterogeneity; Positron-Emission Tomography; Prevalence; Research; Research Training; Rest; Role; Scientist; Senile Plaques; Spinal Puncture; Symptoms; Techniques; Testing; Time; Training; Universities; VO2max; autosomal dominant Alzheimer' s disease; brain health; career; career development; cognitive change; cognitive function; cognitive testing; cytokine; design; fitness; healthy aging; imaging modality; improved; in vivo; indexing; kindred; lifestyle factors; longitudinal analysis; mutation carrier; neurogenesis; neuroimaging; neuroinflammation; novel; pre-clinical; preclinical study; presenilin-1; prevent; relating to nervous system; response; skills; standard measure; tau Proteins; β-amyloid burden

PROJECT SUMMARY / ABSTRACT The prevalence of Alzheimer's disease (AD) is expected to rise significantly, reaching 15 million individuals by 2060 in the US. AD-related brain and cognitive changes are evident several years before symptom onset, in what is known as the preclinical stage. In the absence of disease-modifying treatments, it is imperative that we identify and characterize lifestyle factors that could modify the course of the disease. Greater aerobic fitness, objectively measured by VO2max, is considered a critical component of overall health and a strong predictor of cognitive functioning. It may prevent or modify the progression of AD, as it has been associated with stronger functional brain functioning and less amyloid and tau burden. It has also been shown to reduce neuroinflammation, which further contributes to disease progression and cognitive decline. While there is considerable evidence supporting the benefits of greater fitness in healthy aging, less is known about how it impacts the progression of AD. Specifically, there is paucity of research investigating, 1) the relation of fitness to AD-related brain pathology and functional connectivity; 2) the mechanisms that underlie the relationship between fitness and memory functioning in AD; and 3) changes in AD-related brain pathology, brain functioning and cognition associated with fitness overtime. The candidate will capitalize on an ongoing NIA-funded observational longitudinal biomarker study with a Colombian kindred with autosomal-dominant AD (ADAD), the world's largest family with a single mutation (E280A) in the Presenilin-1 gene that leads to dementia. She will test the hypothesis that greater aerobic fitness is associated with better brain functioning, less accumulation of brain pathology (tau and amyloid), and less neuroinflammation in presymptomatic mutation carriers. Some consider that ADAD is the ideal model to study preclinical changes associated with AD since mutation carriers, who are otherwise healthy (e.g. no cardiovascular pathology), will invariably develop dementia. Thus, this provides the opportunity to investigate the direct link between AD and aerobic fitness. To test the hypotheses, each participant will undergo PET PiB (amyloid) and 18F T807 (tau), functional MRI at rest, cognitive testing, and lumbar puncture to examine neuroinflammation as measured by a composite index of neuroinflammatory markers, at baseline and every 24 months. The candidate will obtain training in, (1) assessing aerobic fitness and understanding its relation to brain health, (2) longitudinal analytic approaches, (3) multimodal imaging methods, and (4) assessing and understanding the role of neuroinflammation in preclinical AD. She has gathered an exceptional team of experts in aging and AD from the MGH, Harvard University and Northeastern University, who are fully committed to helping her accomplish her research training and career development goals, as well as to ensure her successful transition to an independent and productive career in aging research.

项目总结/摘要 阿尔茨海默病（AD）患病率预计将大幅上升，达到1500万人 到2060年，在美国。AD相关的大脑和认知变化在几年前就很明显了 症状发作，即所谓的临床前阶段。在缺乏疾病修饰治疗的情况下， 我们必须确定和描述可能改变疾病进程的生活方式因素。 更好的有氧健身，通过VO 2 max客观测量，被认为是整体健康的关键组成部分 也是认知功能的重要预测指标它可以阻止或改变AD的进展，因为它已经 与更强的功能性脑功能和更少的淀粉样蛋白和tau蛋白负荷相关。还已经表明 以减少神经炎症，这进一步有助于疾病进展和认知能力下降。而 有相当多的证据支持健康老龄化中更大的健身益处，但对 如何影响AD的进展。具体而言，缺乏研究调查，1） 适应AD相关的大脑病理和功能连接; 2）基础的机制， AD中健康和记忆功能之间的关系;和3）AD相关脑病理学的变化， 大脑功能和认知与健身超时。 候选人将利用正在进行的由NIA资助的观察性纵向生物标志物研究， 哥伦比亚亲属患有常染色体显性AD（ADAD），这是世界上最大的单一突变家族 （E280 A）在早老素-1基因，导致痴呆症。她将检验更好的有氧运动的假设 健康与更好的大脑功能，更少的大脑病理（tau蛋白和淀粉样蛋白）积累有关， 症状前突变携带者的神经炎症较少。有些人认为ADAD是理想的模型， 研究与AD相关的临床前变化，因为突变携带者在其他方面是健康的（例如， 心血管病理学），将不可避免地发展成痴呆症。因此，这提供了调查的机会 AD和有氧健身之间的直接联系为了验证假设，每位参与者都将接受PET检查 PiB（淀粉样蛋白）和18F T807（tau），静息时功能性MRI，认知测试和腰椎穿刺检查 通过神经炎症标志物的复合指数测量的神经炎症，在基线和每个 24个月候选人将获得培训，（1）评估有氧健身和理解其关系， 脑健康，（2）纵向分析方法，（3）多模式成像方法，（4）评估和 了解神经炎症在临床前AD中的作用。她组建了一支出色的团队， 来自MGH、哈佛大学和东北大学的老龄化和AD专家，他们完全 致力于帮助她完成她的研究培训和职业发展目标，以及确保 她成功地过渡到一个独立的和富有成效的职业生涯在老龄化研究。