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)带入了预防性治疗的时代 干预措施。研究人员现在认识到阿尔茨海默病是一个连续体，干预应该从 症状前阶段。为此，经皮迷走神经刺激(TVNS)是一种有希望的非 侵入性方法，因为其机制被归因于最初受AD影响的大脑系统 病理上，去甲肾上腺素蓝斑(LC)系统。动物实验和对患者的初步研究 我们组的健康人和其他人证明了tVNS改变了蓝斑(LC)和核 孤束(NTS)起作用并增强记忆力。这表明tVNS的目标是初始的 并有可能延缓AD相关的认知功能障碍。因此，TVNS可以 应对这一领域的一项重要挑战：在发病前以非侵入性方式延缓疾病进展 认知能力下降或明显的病理堆积。这项提案的首要目标是应用 在有不同程度AD病理的无症状老年人中，单一和重复的tVNS， 目的确定tVNS在领域和时间上对认知的影响程度，并与tVNS结果相关。 与LC和NTS的人口学、神经生理学特性以及AD生物标志物的负荷有关。我们的 在优化tVNS和敏感认知测量、超高场脑干成像和 基于血液的生物标记物允许我们检验我们的中心假设：序列tVNS增强记忆 功能不止单一，尤其是在AD病理负担较低的高危个体中 中度刺激，NTS-LC系统对刺激仍有反应。为此，140名有症状前期的老年人 个体(APOE-E4增强型)将参加双盲随机交叉刺激设计 在7T成像和采血过程中对比假TVNS。这之后将随机分配到 重复TVNS或SHAM 2周，2个月后进行认知功能评估。这样做的结果 这项研究将在三个重要方面为未来评估TVNS的试验提供重要信息：1)通过 研究TVNS在短期和长期对哪些认知领域进行调制，对 监测和确定成果措施，2)通过确定人口统计特征、职能 大脑和AD相关标记物预测对tVNS的有益反应，这对识别这一点将是重要的 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，并可能 监测进展情况(目标2和3)。提出的这项研究具有创新性，因为它旨在定义 基于两者已知的潜在生物学途径，tVNS可在其中有效的目标人群 TVNS和AD。细化目标人群至关重要，因为预计这将告知符合资格标准的大型- 扩大随机临床试验的规模，这反过来将有助于它们在延缓疾病进展方面的成功。

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.