The wandering nerve: gateway to boost Alzheimer's disease related cognitive performance

游走神经：提高阿尔茨海默病相关认知能力的途径

• 批准号: 10210747
• 负责人: Heidi Irma Jacobs
• 金额: $ 83.84万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10210747
• 关键词: Acute; Address; Affect; Age; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Animals; Behavioral; Biological; Biological Markers; Blood specimen; Brain; Brain Stem; Cell Nucleus; Characteristics; Clinical; Clinical Trials; Cognitive; Crossover Design; Disease; Disease Progression; Double-Blind Method; Education; Elderly; Eligibility Determination; Enrollment; Exhibits; Exposure to; Face; Female; Functional Magnetic Resonance Imaging; Future; Genetic; Goals; Image; Impaired cognition; Impairment; Individual; Individual Differences; Inflammation; Inflammatory Response; Intervention; Intractable Epilepsy; Long-Term Effects; Long-Term Potentiation; Measures; Memory; Methodology; Methods; Monitor; Names; Nerve; Nerve Degeneration; Neuropsychological Tests; Norepinephrine; Outcome; Outcome Measure; Participant; Pathology; Pathway interactions; Patients; Performance; Phase; Physiology; Population; Preventive; Property; Public Health; Randomized; Randomized Clinical Trials; Research; Research Personnel; Risk; Series; Site; Stratification; System; Target Populations; Testing; Time; Validation; Work; abeta accumulation; apolipoprotein E-4; base; blood-based biomarker; cognitive change; cognitive performance; cognitive testing; cost; demographics; design; follow-up; innovation; locus ceruleus structure; molecular marker; neuroimaging; neurophysiology; noninvasive brain stimulation; pre-clinical; predictive marker; preventive intervention; primary outcome; randomized trial; relating to nervous system; respiratory; responders and non-responders; response; secondary outcome; sex; success; tau Proteins; vagus nerve stimulation

ABSTRACT Series of disappointing clinical trial outcomes have ushered the Alzheimer's field (AD) into an era of preventive interventions. Researchers now recognize that AD is a continuum and that interventions should start in the pre-symptomatic phase. To that end, transcutaneous vagus nerve stimulation (tVNS) is a promising non- invasive approach, as its mechanisms have been attributed to the brain system that is initially affected by AD pathology, the norepinephrine locus coeruleus (LC) system. Animal and preliminary studies in patients and healthy individuals from our group and others demonstrated that tVNS alters locus coeruleus (LC) and nucleus tractus solitarius (NTS) functioning and enhances memory. This indicates that tVNS targets the site of initial AD pathology and might have the potential to delay AD-related cognitive impairment. Thus, tVNS could address an important challenge in the field: non-invasively delaying disease progression prior to onset of cognitive decline or significant accumulation of pathology. The overarching goal of this proposal is to apply single and repeated tVNS in pre-symptomatic older individuals with varying degrees of AD pathology, with the aim to determine the extent of the cognitive effects of tVNS in domains and time, and to relate tVNS outcome to demographics, neurophysiological properties of the LC and NTS as well as burden of AD biomarkers. Our accomplishments in optimizing tVNS and sensitive cognitive measures, ultra-high field brainstem imaging and blood-based biomarkers allow us to examine our central hypothesis: that serial tVNS enhances memory functioning more than single, and in particular in at-risk individuals, in whom AD pathology burden is low to moderate and the NTS-LC system is still responsive to stimulation. To that end, 140 pre-symptomatic older individuals (APOE-E4 enriched) will be enrolled to a double-blind randomized cross-over design of stimulation versus sham tVNS during 7T imaging and blood sampling. This will be followed by randomized allocation to repeated tVNS or sham for 2 weeks and a follow-up cognitive assessment after 2 months. The results of this study will yield important information for future trials assessing tVNS in three important ways: 1) through investigating which cognitive domains are modulated by tVNS on the short and long-term, important for monitoring and determining outcome measures, 2) through identifying demographic characteristics, functional brain and AD-related markers that predict beneficial responses to tVNS, which will be important to identify trial eligibility (Aim 1 and 2) and 3) understanding biological pathways contributing to RAVANS success to confirm target engagement, aid in biomarker stratification or enrichment of the population, and which could serve to monitor progression (Aim 2 and 3). The research proposed is innovative because it aims to define the target population in whom tVNS can be efficacious, based on the known underlying biological pathways of both tVNS and AD. Refining the target population is critical as it is expected to inform eligibility criteria of large- scale randomized clinical trials, which in turn will contribute to their success in delaying disease progression.

抽象的 一系列令人失望的临床试验结果将阿尔茨海默病领域（AD）带入了预防时代 干预措施。研究人员现在认识到 AD 是一个连续体，干预措施应从 症状前阶段。为此，经皮迷走神经刺激（tVNS）是一种有前途的非 侵入性方法，因为其机制归因于最初受 AD 影响的大脑系统 病理学，去甲肾上腺素蓝斑（LC）系统。动物和患者的初步研究 我们组和其他人的健康个体证明 tVNS 改变蓝斑 (LC) 和细胞核 孤束 (NTS) 功能并增强记忆力。这表明 tVNS 的目标是初始位点 AD 病理学可能有可能延迟 AD 相关的认知障碍。因此，tVNS 可以 解决该领域的一个重要挑战：在疾病发作前以非侵入性方式延缓疾病进展 认知能力下降或病理的显着积累。该提案的总体目标是应用 对患有不同程度 AD 病理的症状前老年人进行单次和重复 tVNS 旨在确定 tVNS 在领域和时间上的认知影响程度，并将 tVNS 结果关联起来 人口统计学、LC 和 NTS 的神经生理学特性以及 AD 生物标志物的负担。我们的 在优化 tVNS 和敏感认知测量、超高场脑干成像和 基于血液的生物标志物使我们能够检验我们的中心假设：连续 tVNS 增强记忆 功能多于单一个体，尤其是高危个体，其中 AD 病理负担低至 中度且 NTS-LC 系统仍对刺激有反应。为此，140 名出现症状前的老年人 个体（APOE-E4 富集）将被纳入双盲随机交叉刺激设计 与 7T 成像和血液采样期间的假 tVNS 相比。随后将随机分配给 重复 tVNS 或假手术 2 周，并在 2 个月后进行后续认知评估。这样做的结果 研究将为未来以三种重要方式评估 tVNS 的试验提供重要信息：1）通过 研究哪些认知领域受到 tVNS 短期和长期的调节，对于 监测和确定结果措施，2) 通过确定人口特征、功能 预测对 tVNS 有益反应的大脑和 AD 相关标记物，这对于识别非常重要 试验资格（目标 1 和 2）和 3）了解有助于 RAVANS 成功的生物学途径 确认目标参与，帮助生物标志物分层或丰富人口，这可以 用于监测进展（目标 2 和 3）。所提出的研究具有创新性，因为它旨在定义 根据已知的潜在生物途径，tVNS 对哪些目标人群有效 tVNS 和 AD。细化目标人群至关重要，因为它有望为大型企业的资格标准提供信息。 规模随机临床试验，这反过来将有助于他们成功延缓疾病进展。