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

摘要 一系列令人失望的临床试验结果将阿尔茨海默病（AD）领域带入了预防性治疗的时代。 干预措施。研究人员现在认识到，AD是一个连续体，干预措施应该从 症状前阶段为此，经皮迷走神经刺激（tVNS）是一种有前途的非电刺激疗法。 侵入性方法，因为其机制已被归因于最初受AD影响的脑系统 病理学，去甲肾上腺素蓝斑（LC）系统。在患者中进行的动物和初步研究， 我们组和其他健康人证实，tVNS改变了蓝斑（LC）和核 孤束（NTS）功能和增强记忆。这表明，tVNS靶向的网站最初 AD病理学改变，并可能具有延缓AD相关认知功能障碍的潜力。因此，TVNS可以 解决了该领域的一个重要挑战：非侵入性延迟疾病进展之前， 认知能力下降或病理学显著积累。本提案的总体目标是 单次和重复tVNS在症状前老年人与不同程度的AD病理，与 目的是确定tVNS在领域和时间上的认知效应的程度，并将tVNS结果 LC和NTS的人口统计学、神经生理学特性以及AD生物标志物的负担。我们 在优化tVNS和敏感的认知措施，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核心假设：连续tVNS增强记忆 功能超过单一，特别是在高危人群中，其中AD病理负担低， 中度，NTS-LC系统仍然对刺激有反应。为此，140名症状前老年人 个体（APOE-E4富集）将入组双盲随机交叉刺激设计 在7 T成像和血液采样期间与假tVNS比较。随后将随机分配至 重复tVNS或假手术2周，并在2个月后进行随访认知评估。的结果 这项研究将为未来的试验提供重要信息，以三种重要方式评估tVNS：1）通过 调查哪些认知领域是由tVNS调制的短期和长期， 监测和确定结果措施，2）通过确定人口统计学特征，功能 大脑和AD相关的标志物，预测对tVNS的有益反应，这将是重要的，以确定 试验合格性（目标1和2）和3）了解有助于RAVANS成功的生物学途径， 确认目标接合，帮助生物标志物分层或人群富集，并且可以 用于监测进展（目标2和3）。这项研究是创新的，因为它旨在定义 根据已知的潜在生物学途径，tVNS可以有效的目标人群， TVNS和AD。细化目标人群至关重要，因为预计将为大规模残疾人的资格标准提供信息， 大规模随机临床试验，这反过来将有助于他们在延缓疾病进展方面取得成功。

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.