Neuromodulation of brain network function in preclinical and prodromal Alzheimer's Disease

神经调节方式，如重复的经颅磁刺激(RTMS)可以诱导长期的 可塑性改变和选择性改变功能性网络连接，进而可能改善症状 阿尔茨海默病(AD)。然而，尽管rTMS在人类中得到了广泛应用，但其机制 RTMS在健康衰老和AD中诱导的可塑性仍然不确定。来自一家公司的初步证据 对认知正常的老年人的研究表明，rTMS可以调节大脑皮质的动力学- 海马区网络被称为默认模式网络(DMN)，在AD时受损。然而，有一种 迫切需要复制这些影响。此外，因为之前没有一项研究测量到淀粉样蛋白 目前还不清楚rTMS对认知正常的脑淀粉样蛋白升高的成年人是否有效。 (临床前AD)。我们在一名AD病理患者身上的初步数据也显示rTMS可能会改善 受损的大脑网络的异常。虽然这些发现令人鼓舞，但我们需要更多的证据。 关于rTMS改变网络功能的机制，以及这些影响在 时间到了。这项建议的总体目标是确定调制是否存在差异 RTMS检测AD患者与健康老年人脑网络功能的比较。该提案正在提交于 对PAR 22-094和NOT-AG-21-039的响应，以表征潜在的神经电路机制 脑老化背景下阿尔茨海默病的脑可塑性。我们建议进行一项受试者内部实验。 15名认知正常、无阿尔茨海默病证据的老年人使用rTMS 10天 生物标志物(Aβ-)，15例淀粉样蛋白阳性(Aβ+)认知正常老年人(临床前AD)和15例患者 患有前驱AD(Aβ+，临床诊断为遗忘性轻度认知障碍)的患者 通过单独资助的研究进行PET成像。我们将使用基准功能连接MRI来 瞄准DMN的左侧顶叶结节。我们的中心假设是，针对DMN的rTMS将 提高正常运行的网络完整性。我们将追求三个具体目标：1)建立RTMS对以下方面的影响 临床前阿尔茨海默病的神经可塑性，2)建立rTMS对先兆AD神经可塑性的影响，3) 确定与衰老和AD相关的生物学特征，预测神经可塑性是否可以通过 RTMS。结果将在即刻、1周和2周后测量DMN功能连接性 刺激。我们将使用淀粉样蛋白和tau PET扫描(通过另一项研究获得)进行AOS结构 神经变性标记物，以量化AD病理和萎缩对rTMS诱导的可塑性的影响。 我们的方法是创新的，因为它专注于AD病理生理变化之间的关系 RTMS诱导的可塑性。这项拟议的研究意义重大，因为它将更好地阐明 以及rTMS如何改善临床前和先兆AD患者的大脑功能，以及谁最有可能受益于 RTMS。一个长期目标是使用这些数据来计划未来的临床试验，并对AD的行为结果进行研究。

Neuromodulation modalities, such as repetitive transcranial magnetic stimulation (rTMS) can induce long-term plastic changes and selectively alter functional network connectivity which in turn may improve symptoms in Alzheimer’s disease (AD). However, despite the wide application of rTMS in humans, the mechanisms underlying rTMS-induced plasticity in healthy aging and AD remain uncertain. Preliminary evidence from one study with cognitively normal older adults suggests that rTMS can modulate dynamics in a cortical- hippocampal network known as the default mode network (DMN), which is impaired in AD. Yet there is a critical need for replication of these effects. Furthermore, because none of the prior studies measured amyloid beta, it is still unknown whether rTMS is effective in cognitively normal adults with elevated cerebral amyloid (preclinical AD). Our preliminary data in a single patient with AD pathology also show that rTMS may improve abnormalities in the impaired brain network. While these findings are encouraging, we need more evidence regarding the mechanisms through which rTMS alters network function, and the durability of these effects over time. The overall objective of this proposal is to determine whether there are differences in the modulation of brain network function by rTMS in AD compared to healthy aging. This proposal is being submitted in response to PAR 22-094 and NOT-AG-21-039 to characterize neural circuitry mechanisms underlying brain plasticity in AD in the context of the aging brain. We propose to conduct a within-subjects experiment using rTMS administration for 10 days in 15 cognitively unimpaired older adults with no evidence of AD biomarkers (Aβ-), 15 amyloid positive (Aβ+) cognitively normal older adults (preclinical AD) and 15 patients with prodromal AD (Aβ+ and a clinical diagnosis of amnestic mild cognitive impairment) who have already undergone PET imaging through separately funded studies. We will use baseline functional connectivity MRI to target the left lateral parietal node of the DMN . Our central hypothesis is that rTMS targeting the DMN will improve functional network integrity. We will pursue three specific aims: 1) establish the effects of rTMS on neural plasticity in preclinical AD, 2) establish the effects of rTMS on neural plasticity in prodromal AD and 3) identify the aging- and AD-related biological features that predict whether neural plasticity can be induced by rTMS. Outcomes will be measures of DMN functional connectivity immediately and 1 week and 2 weeks after stimulation. We will aos use amyloid and tau PET scans (acquired through another study) with structural markers of neurodegeneration to quantify the impact of AD pathology and atrophy on rTMS-induced plasticity. Our approach is innovative because it focuses on the relationship between AD pathophysiological changes and rTMS-induced plasticity. The proposed research is significant because it will better elucidate whether and how rTMS improves brain function in preclinical and prodromal AD and who is most likely to benefit from rTMS. A long-term goal is to use these data to plan a future clinical trial with behavioral outcomes in AD.