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

项目摘要 我们仍然几乎无法有效地治疗阿尔茨海默病（AD）患者。在某种程度上，这是由于 缺乏全面的疾病模型，临床上可操作的生物标志物，以及转化研究结果的挑战 基础科学和病人之间的关系为了探究疾病过程，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病理学的一个或几个方面 在一个优化但受限的时空环境中为了缩小不同尺度和物种之间的知识差距， 我们可以开发同时多模态成像方法， 方式。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，在微观或中尺度的动物模型中很明显， 临床表现。此外，多模态成像方法的使用使我们能够询问 自发活动（在没有刺激的情况下的大脑功能），它构成了绝大多数的 所有的大脑活动，是无限的，因为它出现在整个大脑，并已被证明提供洞察力 独立于刺激诱发活动的大脑健康。 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时采血的方法， 氧水平依赖性（BOLD）功能磁共振成像（fMRI）和宽场钙（WF- Ca 2+）成像，以研究在小鼠中AD进展和治疗反应的多模式预测建模。 疾病模型我们建议进行一项纵向研究，其中包括清醒和麻醉的 多模式成像协议。WF-Ca 2+成像提供细胞类型特异性高时空分辨率 测量皮质范围的活动，而BOLD-fMRI是一种全脑细胞类型的不可知测量， 特异性强，灵敏度高。在WF-Ca 2+成像仅限于临床前环境的情况下，BOLD-fMRI是常规的 临床测量BOLD-fMRI和WF-Ca 2+成像可以共同推进我们对细胞内钙离子的理解。 AD相关BOLD-fMRI信号变化的起源，并提供动物和人类研究之间的直接联系。 我们的总体假设是，我们的多模式方法可以提供区域和电路的直接证据- 从可用于AD症状的自发活动的测量水平神经血管耦合健康 严重程度（目标1）和治疗反应（目标2）预测。 这一建议的意义在于推进我们对BOLD驱动机制的理解- fMRI信号变化，这有助于验证临床上可获得的AD成像生物标志物，并有助于 更全面地了解AD病理学。该提案的创新之处在于建立了一个 实验和分析框架，使研究AD相关的自发活动的变化 通过同时获得细胞类型特异性WF-Ca 2+来预测行为结果 清醒小鼠的成像和全脑BOLD-fMRI数据。

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.