Assessment of ultrasound-facilitated neurotherapeutics in Alzheimer's disease

超声辅助神经疗法治疗阿尔茨海默病的评估

• 批准号: 10901036
• 负责人: Elisa E. Konofagou
• 金额: $ 79.82万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10901036
• 关键词: 3-Dimensional; 3xTg-AD mouse; Aftercare; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Area; Astrocytes; Behavioral; Blood - brain barrier anatomy; Blood Tests; Brain; COVID-19 pandemic; Central Nervous System Diseases; Clinical; Clinical Trials; Code; Cognition; Cognitive; Cognitive deficits; Dependence; Drug Delivery Systems; Engineering; Episodic memory; Focused Ultrasound; Funding; Health Care Costs; Hippocampus; Human; Immune; Immune response; Immunotherapeutic agent; Immunotherapy; Infrastructure; Journals; Link; Longitudinal Studies; Macrophage; Magnetic Resonance Imaging; Malignant neoplasm of prostate; Maps; Mediating; Memory; Memory impairment; Microbubbles; Microglia; Monitor; Mus; National Institute on Aging; Neurodegenerative Disorders; Neurology; Neuronavigation; Neurosciences; Onset of illness; Outcome; Pathology; Peer Review; Peripheral; Pharmacological Treatment; Phenotype; Positron-Emission Tomography; Prefrontal Cortex; Primates; Progress Reports; Publications; Reporting; Short-Term Memory; Site; Synapses; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Translating; Translations; asymptomatic Alzheimer' s disease; clinical practice; clinical translation; cohort; cost efficient; density; effective therapy; immune activation; improved; malignant breast neoplasm; medical specialties; model development; mouse model; multidisciplinary; nervous system disorder; neuroimmunology; neuroprotection; nonhuman primate; patient safety; pharmacologic; recruit; response; sex; simulation; tau Proteins; timeline; transcriptomics; ultrasound

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.

阿尔茨海默病 (AD) 导致三分之一的老年人死亡（多于乳腺癌和前列腺疾病） 癌症合并），在 2020 年 covid-19 大流行期间增加了 16%， 是最昂贵的疾病，预计 2021 年医疗费用将达到 3,550 亿美元 到 2050 年将达到 1.1 万亿美元。尽管有一些有效的治疗方法， 阿尔茨海默病的几种药物治疗仍然严重不足 过去三十年来，化合物在临床试验和/或实践中失败。 聚焦超声 (FUS) 与微泡相结合，仍然是唯一的 可以诱导局部血脑屏障（BBB）打开的技术 尽管该技术是非侵入性的、选择性的和安全的。 最初打算打开血脑屏障进行药物输送，我们组是第一个 报告称，仅打开血脑屏障就可以改善灵长类动物的认知能力。 FUS 实现的安全 BBB 打开可导致免疫级联反应，进而产生免疫级联反应 在我们的研究之前，这与认知缺陷和病理学的减少相关。 本文报道了 FUS 介导的 BBB 的免疫治疗潜力 在这项更新研究中，开口是未知的，我们的目标是确定 1) 目前尚不清楚 FUS 的神经保护和免疫治疗机制 介导的 BBB 打开以及上述效应的持续时间 多节 BBB 开放，2) 将认知改善和/或免疫联系起来 突触密度增加的反应，3) 优化临床 FUS 系统 准确地针对人类海马体，3) 评估神经保护功效 无症状 AD 受试者和 4) 评估免疫治疗效果 因此，潜在的假设是 FUS 介导的有症状的 AD 受试者。 单独打开血脑屏障可产生神经保护和免疫治疗作用 AD 记忆力的持续改善。 涵盖所有涉及的关键专业领域，例如超声工程 以及 MRI、PET 和 AD 病理学、神经免疫学、认知和 与神经科学相关的记忆测试和小鼠模型开发 根据拟议的研究，这完全是无创且昂贵的。 高效BBB开放技术将转化为临床常规，以期 利用其治疗阿尔茨海默病的临床潜力。