Assessment of ultrasound-facilitated neurotherapeutics in Alzheimer's disease

阿尔茨海默病（AD）导致三分之一的老年人死亡（超过乳腺癌和前列腺癌 癌症合并），在2020年新冠肺炎大流行期间增加了16%， 是最昂贵的疾病，预计2021年的医疗费用为3550亿美元 到2050年将达到1.1万亿美元虽然有一些有效的治疗方法， 阿尔茨海默氏症仍然严重治疗不足的几个药理学 在过去的三十年中，在临床试验和/或实践中失败的化合物。 聚焦超声（FUS），结合微泡，仍然是唯一的 可诱导局部血脑屏障（BBB）开放技术 非侵入性的，有选择性的，安全的尽管这项技术 最初打算打开BBB进行药物递送，我们的小组是第一个 报告说，血脑屏障开放单独可以导致灵长类动物的认知改善。的 通过FUS实现的安全BBB开放可导致免疫级联反应， 与认知缺陷和病理学的减少相关。在我们的研究之前 本文报道，FUS介导的BBB的免疫抑制潜力 开放是未知的。在这项更新研究中，我们的目标是确定1） 目前未知的FUS的神经保护和免疫机制- 介导的血脑屏障开放以及上述作用的持续时间， 多阶段BBB开放，2）链接认知改善和/或免疫 反应与突触密度增加，3）优化临床FUS系统， 在人类中准确的海马靶向，3）评估神经保护功效， 无症状AD受试者和4）评估免疫功效， 症状性AD受试者。因此，潜在的假设是，FUS介导的 单独打开BBB可产生神经保护和免疫治疗作用， 持续记忆改善AD。多学科团队 涵盖所有涉及的关键专业领域，如超声工程 以及MRI、PET和AD病理学、神经免疫学、认知和 记忆测试和小鼠模型开发，因为它们与神经科学有关 和神经学根据拟议的研究，这完全是非侵入性的， 有效的血脑屏障开放技术将在临床常规中转化， 利用其治疗阿尔茨海默氏症的临床潜力。

Alzheimer’s disease (AD) kills 1 in 3 seniors (more than breast and prostate cancer combined), increased by 16% during the covid-19 pandemic in 2020 and is the costliest condition with an expected $355 billion in healthcare costs in 2021 and $1.1 trillion in 2050. Although some effective treatments are available, Alzheimer’s remains severely undertreated with several pharmacological compounds failing in clinical trials and/or practice over the past three decades. Focused Ultrasound (FUS), in conjunction with microbubbles, remains the sole technique that can induce localized blood-brain barrier (BBB) opening noninvasively, selectively and safely. Despite the fact that the technology was initially intended to open the BBB for drug delivery, our group was the first to report that BBB opening alone can lead to cognitive amelioration in primates. The safe BBB opening enabled by FUS can lead to an immune cascade that is in turn correlated with reduction of cognitive deficits and pathology. Prior to our studies reported herein, the immunotherapeutic potential of the FUS-mediated BBB opening was unknown. in this renewal study, we aim to determine 1) the currently unknown neuroprotective and immunotherapeutic mechanisms of FUS- mediated BBB opening as well as the duration of the aforementioned effects in multi-session BBB opening, 2) link cognitive improvement and/or immune response with synaptic density increase, 3) optimize the clinical FUS system for accurate hippocampal targeting in humans, 3) assess neuroprotection efficacy in asymptomatic AD subjects and 4) assess immunotherapeutic efficacy in symptomatic AD subjects. The underlying hypothesis is thus that FUS-mediated BBB opening alone leads to neuroprotective and immunotherapeutic with sustained mnemonic amelioration in AD. The multi-disciplinary team encompasses all critical specialty areas involved, such as ultrasound engineering as well as MRI, PET and AD pathology, neuroimmunology, cognitive and memory testing and mouse model development as they pertain to neuroscience and neurology. Following the proposed studies, this entirely noninvasive and cost efficient BBB opening technology will be translated in the clinical routine so as to harness its clinical potential in the treatment of Alzheimer’s.