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: 9979722
• 负责人: Edmarie Guzmán-Vélez
• 金额: $ 17.78万
• 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/9979722
• 关键词: 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; Transgenic Organisms; Universities; VO2max; 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.

项目摘要/摘要 阿尔茨海默病(AD)的患病率预计将大幅上升，达到1500万人 到2060年，美国的个人数量。广告相关的大脑和认知变化在几年前就很明显了 症状出现，处于所谓的临床前阶段。在缺乏改善疾病的治疗方法的情况下， 当务之急是，我们必须识别和描述可能改变疾病进程的生活方式因素。 更好的有氧健身被认为是整体健康的关键组成部分，这是由VO2max客观衡量的 也是认知功能的有力预测指标。它可能会阻止或改变AD的进展，就像它已经发生的那样 与更强的大脑功能和较少的淀粉样蛋白和tau负担有关。它也被展示出来 以减少神经炎症，这进一步促进了疾病的进展和认知能力下降。而当 有相当多的证据支持更健康的身体对健康衰老的好处，但对此知之甚少 它如何影响AD的进展。具体地说，缺乏研究考察，1)与经济发展的关系 适应AD相关的脑病理和功能连接；2)基础机制 阿尔茨海默病患者体能与记忆功能的关系；3)AD相关脑病理改变， 大脑功能和认知与健身加班有关。 候选人将利用NIA资助的正在进行的观察性纵向生物标记物研究， 哥伦比亚人与常染色体显性AD(ADAD)有亲属关系，ADAD是世界上最大的单一突变家庭 导致痴呆的早老素-1基因(E280A)。她将测试更多有氧运动的假说 健康与更好的大脑功能、较少的大脑病理堆积(tau和淀粉样蛋白)有关，以及 症状前突变携带者的神经炎症较少。一些人认为ADAD是 研究突变携带者以来与AD相关的临床前变化，这些携带者在其他方面是健康的(例如，没有 心血管病理学)，总会发展成痴呆症。因此，这提供了调查的机会 AD和有氧健身之间的直接联系。为了检验假设，每个参与者都要接受PET检查 PIB(淀粉样蛋白)和18F T807(Tau)，静息功能磁共振，认知测试，腰椎穿刺术检查 通过神经炎性标记物的综合指数在基线和每个时间点测量神经炎症 24个月。应聘者将接受以下方面的培训：(1)评估有氧体能并了解其与 脑健康，(2)纵向分析方法，(3)多模式成像方法，以及(4)评估和 了解神经炎症在临床前AD中的作用。她聚集了一支出色的团队 来自麻省理工学院、哈佛大学和东北大学的老龄化和AD专家，他们充分 致力于帮助她完成她的研究培训和职业发展目标，并确保 她在老龄化研究方面成功地过渡到了独立和富有成效的职业生涯。