Leveraging simultaneous BOLD-fMRI and wide-field Ca2+ imaging to reveal measures of neurovascular health that cross scales and species which have AD symptom and treatment response prognostic utility

利用同步 BOLD-fMRI 和广域 Ca2 成像来揭示具有 AD 症状和治疗反应预后效用的跨尺度和跨物种的神经血管健康指标

• 批准号: 10370675
• 负责人: Evelyn MR Lake
• 金额: $ 46.06万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370675
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease therapeutic; Alzheimer’s disease biomarker; Animal Model; Animals; Astrocytes; Basic Science; Behavioral; Biological Factors; Biological Markers; Brain; Calcium; Cell Communication; Clinical; Data; Diagnosis; Disease; Disease Progression; Disease model; Equipment; Fluorescence; Functional Magnetic Resonance Imaging; Functional disorder; Future; Health; Human; Image; Impaired cognition; Knowledge; Link; Literature; Longitudinal Studies; Magnetic Resonance Imaging; Measurement; Measures; Methods; Modality; Modeling; Multimodal Imaging; Mus; Pathology; Patients; Performance; Pericytes; Prediction of Response to Therapy; Process; Protocols documentation; Publishing; Research Personnel; Resolution; Severities; Signal Transduction; Specificity; Stimulus; Structure; Symptoms; Synapses; Translating; Treatment Protocols; Work; awake; behavioral impairment; behavioral outcome; biomedical imaging; blood oxygen level dependent; brain cell; brain health; burden of illness; cell type; clinically actionable; density; experimental analysis; imaging approach; imaging biomarker; imaging modality; improved; innovation; insight; mouse model; multimodality; neurovascular; neurovascular coupling; pre-clinical; preclinical study; predictive modeling; prognostic value; prognostication; relating to nervous system; spatiotemporal; symptom treatment; therapeutic development; tool; treatment response; two photon microscopy

PROJECT SUMMARY There is still little we can do to effectively treat patients with Alzheimer’s disease (AD). In part, this is due to the lack of a comprehensive disease model, clinically actionable biomarkers, and the challenge of translating findings between basic science and patients. To interrogate disease processes, researchers use a variety of methods – each with relative strengths and weaknesses – that specialize in capturing one or a few aspects of AD pathology within an optimized, but confined, spatiotemporal milieu. To close knowledge gaps across scales, and species, we can develop simultaneous multi-modal imaging approaches that leverage the strengths of complementary modalities. These approaches will help to deepen our understanding of how the pathophysiological mechanism that influence AD progression and treatment response, evident in animal models at the micro- or meso-scale, manifest clinically. Further, the use of multi-modal imaging methods allows us to interrogate changes in spontaneous activity (brain function in the absence of presented stimuli) which constitutes the vast majority of all brain activity, is boundless in that it emerges across the whole-brain and has been shown to provide insight into brain health that is independent from stimulus-evoked activity. Fully aligned with NOT-AG-19-033, our objective is to use our recently published method of simultaneous blood- oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) and wide-field calcium (WF- Ca2+) imaging, to study multi-modal predictive modeling of AD progression and treatment response in a murine disease model. We propose to conduct a longitudinal study which will include both an awake and anesthetized multi-modal imaging protocol. WF-Ca2+ imaging provides a cell-type specific high spatiotemporal resolution measurement of cortex-wide activity, while BOLD-fMRI is a whole-brain cell-type agnostic measure with limited specificity but high sensitivity. Where WF-Ca2+ imaging is limited to a preclinical setting, BOLD-fMRI is a routine clinical measure. Together, BOLD-fMRI and WF-Ca2+ imaging can advance our understanding of the cellular origins of AD-related BOLD-fMRI signal changes and provide a direct link between animal and human studies. Our overarching hypothesis is that our multi-modal approach can provide direct evidence of regional and circuit- level neurovascular coupling health from measures of spontaneous activity that can be used for AD-symptom severity (Aim 1) and treatment-response (Aim 2) prediction. The significance of this proposal lies in advancing our understanding of the mechanisms which drive BOLD- fMRI signal changes, which helps to validate clinically accessible imaging biomarkers of AD and contributes to a more comprehensive understanding of AD pathology. The innovation of this proposal lies in establishing an experimental and analysis framework which enables the study of AD-related changes in spontaneous activity that are predictive of behavioral outcome through the simultaneous acquisition of cell-type specific WF-Ca2+ imaging and whole-brain BOLD-fMRI data in awake mice.

项目总结 在有效治疗阿尔茨海默病(AD)患者方面，我们仍然几乎无能为力。在一定程度上，这是由于 缺乏全面的疾病模型、临床可操作的生物标记物，以及转化研究结果的挑战 在基础科学和病人之间。为了询问疾病过程，研究人员使用了各种方法- 每一个都有相对的优势和劣势--专门捕捉AD病理的一个或几个方面 在一个优化但受限的时空环境中。为了缩小不同规模、不同物种之间的知识差距， 我们可以开发同时的多模式成像方法，利用互补的优势 医疗模式。这些方法将有助于加深我们对病理生理机制的理解 影响AD进展和治疗反应的因素，在微观或中观尺度的动物模型中很明显， 在临床上表现出来。此外，多模式成像方法的使用使我们能够询问 自发活动(在没有呈现刺激的情况下大脑功能)，它构成了绝大多数 所有的大脑活动都是无限的，因为它出现在整个大脑中，并已被证明提供洞察力 独立于刺激诱发的活动的大脑健康。 与NOT-AG-19-033完全一致，我们的目标是使用我们最近发表的同步血液- 氧水平依赖(BOLD)功能磁共振成像(FMRI)和广域钙(WF- 在小鼠中研究AD进展和治疗反应的多模式预测模型 疾病模型。我们建议进行一项纵向研究，包括清醒和麻醉两种情况。 多模式成像协议。WF-Ca~(2+)成像提供了细胞类型特定的高时空分辨率 测量整个皮质的活动，而BOLD-fMRI是一种全脑细胞类型的不可知性测量，具有有限的 特异度高，但敏感性高。在WF-Ca~(2+)成像仅限于临床前环境的情况下，BOLD-fMRI是常规检查 临床测量。BOLD-fMRI和WF-Ca~(2+)成像结合起来可以提高我们对细胞 阿尔茨海默病相关的BOLD-fMRI信号改变的起源，为动物和人类的研究提供了直接的联系。 我们的主要假设是，我们的多模式方法可以提供区域和巡回的直接证据- 可用于AD症状的自发活动测量的神经血管偶联健康水平 严重程度(目标1)和治疗反应(目标2)预测。 这项建议的意义在于增进了我们对推动大胆- FMRI信号改变，这有助于验证临床可获得的AD成像生物标志物，并有助于 对AD病理有更全面的了解。这一建议的创新之处在于建立了一个 实验和分析框架，使研究AD相关的自发活动变化成为可能 通过同时获取细胞类型特定的WF-钙离子来预测行为结果 清醒小鼠的成像和全脑BOLD-fmri数据。