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(超过乳腺癌和前列腺癌 癌症)，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年的医疗成本将达到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可用， 阿尔茨海默氏症仍然严重得不到几种药物的治疗 过去三十年在临床试验和/或实践中失败的化合物。 聚焦超声(FUS)与微泡结合仍然是唯一的 可诱导局部血脑屏障(BBB)开放的技术 非侵入性的、选择性的和安全的。尽管这项技术 最初打算打开BBB进行药物输送，我们小组是第一个 报告称，单独开放血脑屏障可以改善灵长类动物的认知能力。这个 由FUS启用的安全BBB开放可导致免疫级联，进而 与认知功能障碍的减少及病理改变相关。在我们学习之前 在此报道，FUS介导的血脑屏障的免疫治疗潜力 开幕式是未知的。在这项更新研究中，我们的目标是1)确定 目前尚不清楚FUS的神经保护和免疫治疗机制。 介导的血脑屏障开放以及上述作用的持续时间 多时段血脑屏障开放，2)联系认知改善和/或免疫 反应与突触密度增加，3)优化临床FUS系统 人类准确的海马区靶向，3)评估神经保护效果 无症状AD患者和4)评估免疫治疗效果 有症状的AD受试者。因此，潜在的假设是FUS调解的 血脑屏障单独开放可导致神经保护和免疫治疗 在AD中持续的记忆力改善。多学科团队 涵盖所有涉及的关键专业领域，例如超声波工程 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发展，因为它们属于神经科学 和神经学。在拟议的研究之后，这完全是非侵入性的，而且成本很高 高效的血脑屏障开放技术将转化为临床常规，从而 利用其在治疗阿尔茨海默氏症方面的临床潜力。