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.

项目摘要 阿尔茨海默病（AD）的病理变化级联早于AD多年 这表明，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（A β）产生和清除之间的不平衡引发 导致AD的变化。这一假设表明，针对A β水平的早期干预应该是有效的。 特别有效地预防AD，但该领域尚未测试这一假设的核心预测。一 主要障碍是缺乏减少A β的安全和低成本干预措施。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， 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A β水平具有显著相反的结果。共振频率呼吸减少 年轻人和老年人的总体血浆A β水平，以及55-70岁的成年人中， A β42/A β40比率，大脑中淀粉样蛋白沉积减少的生物标志物。在本阶段II中，双盲 随机试验，我们的目标是测试关于这一结果背后的机制以及认知的假设。 在50-70岁的非洲裔美国人和欧洲裔美国人中的结果。参与者将完成10个 数周的每日节奏呼吸疗程，随机分为共振频率呼吸或随机频率呼吸。 节奏呼吸条件。我们假设共振频率呼吸减少了血浆中的生物标志物， 通过两种协同途径的AD风险：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）心率振荡增加脑脊液（CSF）流量， Aβ42在50岁和60岁的成年人中的脑清除率，其中胶质淋巴清除率正在下降。我们将 模拟干预前/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 这些假设的路径。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/交感神经系统活性。因此，它们可能特别受益于共振- 频率呼吸在不同种族中，A β水平的降低尤其有益于50多岁的成年人， 60年代，淀粉样蛋白开始在大脑中聚集，因为胶质淋巴清除变得不那么有效。 最初的聚集性A β形式（寡聚A β）干扰突触可塑性，因此我们将评估 在这两种情况下，参与者提高了他们在认知任务中的表现，他们每天练习10 周这一创新项目将作为未来长期临床试验的基础， 共振频率呼吸，以减缓认知能力下降，并通过减少A β来预防AD。