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.

项目概要 阿尔茨海默病 (AD) 涉及的一系列病理变化早在 AD 发生前许多年就开始了 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 (Aβ) 产生和清除之间的不平衡启动 导致 AD 的变化。这一假设表明，针对 Aβ 水平的早期干预应该 在预防 AD 方面特别有效，但该领域尚未检验这一假设的核心预测。一个 主要障碍是缺乏减少 Aβ 的安全且低成本的干预措施。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，每日训练尝试 增加（通过共振频率呼吸）与减少（通过个性化策略）心率 振荡对血浆 Aβ 水平具有显着相反的结果。呼吸共振频率降低 年轻人和老年人的总体血浆 Aβ 水平，以及 55-70 岁的成年人中，均升高 Aβ42/Aβ40 比率，大脑中淀粉样蛋白沉积减少的生物标志物。在这个第二阶段双盲 随机试验，我们的目的是测试有关该结果背后的机制以及认知的假设 50-70 岁非裔美国人和欧洲裔美国人的结果。参与者将完成十 数周的每日定速呼吸课程，随机分为共振频率呼吸或随机呼吸 有节奏的呼吸状况。我们假设共振频率呼吸会减少血浆生物标志物 AD 风险通过两种协同途径产生：1) 传入迷走神经活动抑制去甲肾上腺素能活动， 刺激 Aβ 产生； 2) 心率振荡会增加脑脊液 (CSF) 流量，从而增加 50 多岁和 60 多岁的成年人大脑中 Aβ42 的清除率下降，这些人的类淋巴清除率正在下降。我们将 模型干预前后血浆 AD 生物标志物的变化如何与每个相关的生物标志物相关 这些假设的途径。与欧洲裔美国人相比，非洲裔美国人的 AD 风险更高 和更高的去甲肾上腺素能/交感系统活动。因此，他们可能特别受益于共振 频率呼吸。在各个种族中，降低 Aβ 水平尤其有利于 50 多岁的成年人 60 年代，随着类淋巴清除的效率降低，淀粉样蛋白开始在大脑中聚集。 最初的聚集 Aβ 形式（寡聚 Aβ）会干扰突触可塑性，因此我们将评估有多少干扰 两种条件下的参与者在每天练习 10 次的认知任务中的表现都有所提高 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 共振频率呼吸可减缓认知能力下降，并通过减少 Aβ 来预防 AD。