Effects of Resonance-Frequency Breathing on Preclinical Alzheimer’s Disease Biomarkers and Cognition

共振频率呼吸对临床前阿尔茨海默病生物标志物和认知的影响

• 批准号: 10591329
• 负责人: MARA MATHER
• 金额: $ 78.85万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-15 至 2028-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591329
• 关键词: Abeta synthesis; Acceleration; Adrenergic Agents; Adult; Affect; African American; African American population; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Baroreflex; Biofeedback; Biological Markers; Blood; Blood Vessels; Brain; Brain Injuries; Breathing; Clinical Trials; Cognition; Cognitive; Discrimination; Disease; Double-Blind Method; Drug Targeting; Early Intervention; Elderly; Ethnic Origin; European; Foundations; Frequencies; Future; Genetic Transcription; Heart Rate; Hippocampus; Impaired cognition; Impairment; Influentials; Intervention; Learning; Measures; Mediating; Modeling; Neocortex; Neurobiology; Outcome; Participant; Pathologic; Pathologic Processes; Pathway interactions; Patients; Perception; Performance; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Plasma; Play; Production; Protein Fragment; Proteins; Randomized; Reporting; Research; Risk; Signal Transduction; Synaptic plasticity; System; Testing; Training; Vagus nerve structure; active control; active control group; aged; arm; cerebrospinal fluid flow; cognitive task; cohort; ethnic difference; glymphatic clearance; glymphatic system; heart rate variability; improved; innovation; intervention cost; intervention effect; middle age; neocortical; noradrenergic; personalized strategies; post intervention; pre-clinical; prevent; randomized trial; recruit; sex; side effect; success; tau Proteins; wasting; young adult

PROJECT SUMMARY The cascade of pathological changes involved in Alzheimer’s disease (AD) starts many years before AD diagnosis, suggesting that intervening with still-healthy adults will be most successful. According to the influential amyloid hypothesis, an imbalance between β-amyloid (Αβ) production and clearance initiates changes that lead to AD. This hypothesis suggests that early intervention targeting Αβ levels should be particularly effective in preventing AD, but the field has yet to test this core prediction of the hypothesis. A major obstacle is the lack of safe and low-cost interventions that reduce Αβ. Initial findings (N = 108) from our recently completed heart rate variability (HRV) biofeedback clinical trial indicate that daily sessions attempting to increase (via resonance-frequency breathing) vs. decrease (via personalized strategies) heart rate oscillations have significant opposing outcomes on plasma Αβ levels. Resonance-frequency breathing reduced overall plasma Αβ levels in both younger and older adults, and, among adults aged 55-70, increased Αβ42/Αβ40 ratios, a biomarker of reduced amyloid deposition in the brain. In this stage II double-blinded randomized trial, we aim to test hypotheses regarding the mechanisms behind this result as well as cognitive outcomes in African-American and European-American adults aged 50-70. Participants will complete ten weeks of daily paced breathing sessions, randomized to either a resonance-frequency breathing or a random- paced breathing condition. We hypothesize that resonance-frequency breathing reduces plasma biomarkers of AD risk via two synergistic pathways: 1) afferent vagus nerve activity suppresses noradrenergic activity that stimulates Aβ production; and 2) heart rate oscillations increase cerebrospinal fluid (CSF) flow, increasing brain clearance of Aβ42 in adults in their 50’s and 60’s in whom glymphatic clearance is declining. We will model how pre/post intervention change in plasma AD biomarkers relates to biomarkers associated with each of these hypothesized pathways. Compared with European Americans, African Americans have higher AD risk and higher noradrenergic/sympathetic system activity. They therefore may particularly benefit from resonance- frequency breathing. Across ethnicities, reduced levels of Αβ should especially benefit adults in their 50’s and 60’s, in whom amyloid is starting to aggregate in the brain as glymphatic clearance becomes less effective. The initial aggregative Αβ form (oligomeric Αβ) interferes with synaptic plasticity, so we will assess how much participants in the two conditions improve their performance on cognitive tasks they practice daily for 10 weeks. This innovative project will serve as a foundation for future long-term clinical trials to test the potential of resonance-frequency breathing to slow cognitive decline and prevent AD by reducing Αβ.

项目总结 阿尔茨海默病(AD)所涉及的一连串病理变化在AD之前许多年就开始了 诊断表明，对仍然健康的成年人进行干预将是最成功的。根据 有影响力的淀粉样蛋白假说，β-淀粉样蛋白(Αβ)的产生和清除启动之间的失衡 导致AD的变化。这一假设表明，针对Αβ水平的早期干预应该是 在预防AD方面特别有效，但该领域尚未检验这一假说的核心预测。一个 主要障碍是缺乏安全和低成本的干预措施来降低Αβ。我们的初步发现(N=108) 最近完成的心率变异性(HRV)生物反馈临床试验表明，每天的会议试图 增加(通过共振频率呼吸)与降低(通过个性化策略)心率 振荡对血浆Αβ水平有显著相反的结果。共振频率呼吸减少 年轻人和老年人的总体血浆Αβ水平，在55-70岁的成年人中都有所增加 Αβ42/Αβ40比率，大脑中淀粉样蛋白沉积减少的生物标志物。在这个阶段II中，双盲 随机试验，我们的目标是测试关于这一结果背后机制的假设以及认知 50-70岁的非洲裔美国人和欧洲裔美国人的结果。参赛者将完成十项 每天数周的有节奏的呼吸，随机分为共振频率呼吸或随机呼吸- 呼吸有节奏。我们假设，共振频率呼吸降低了血浆生物标记物 AD风险通过两个协同途径：1)传入迷走神经活动抑制去甲肾上腺素能活动 刺激Aβ的产生；2)心率振荡增加脑脊液流量，增加 50‘岁S和60’岁S淋巴清扫率下降的成人A-β-42脑清晰度。我们会 模拟干预前后血浆AD生物标记物的变化与相关生物标记物的关系 这些假想的路径。与欧洲裔美国人相比，非裔美国人患AD的风险更高 以及更高的去甲肾上腺素/交感神经系统活性。因此，他们可能特别受益于共振-- 频率呼吸。在不同种族中，降低Αβ水平尤其有利于50岁和50岁的成年人S和 60岁的S说，随着淋巴清除变得不那么有效，淀粉样蛋白开始在大脑中聚集。 最初的聚集性Αβ形式(寡聚体Αβ)干扰突触的可塑性，所以我们将评估有多大程度 这两种情况下的参与者提高了他们在认知任务中的表现，他们每天练习10次 几周。这一创新项目将作为未来长期临床试验的基础，以测试其潜力 利用共振频率呼吸来减缓认知衰退，并通过减少Αβ来预防AD。