Quantitative imaging of choroid plexus function and neurofluid circulation in Alzheimer's Disease Related Dementia

项目摘要 这项工作的目标是完善神经影像学方法，使定量脉络丛（ChP）解剖 并在体内发挥非侵入性功能，随后使用这些方法来测试基本假设 关于ChP活性、脑脊液（CSF）流量以及分子生物学的解剖学和蛋白质标志物， 阿尔茨海默病相关性痴呆（ADRD）患者的清除功能障碍。这个前提是 这项工作是基于已知的ChP复合物对CSF生产的作用，以及最近的联系， 神经退行性疾病中的体积和血管周围CSF流动功能障碍，但缺乏稳健的 在人类中定量这些途径的方法。我们已经表明，动脉自旋标记（ASL） 磁共振成像（MRI）方法和深度学习算法可以被重新参数化， 在高空间分辨率和准确的自动化条件下，ChP灌注（ml/100 g/min）的可重现估计值 本地化，分别：在139名志愿者的初步数据，我们已经（i）证明了能力， 获得健康成人（n=10）的可重复ChP灌注估计值;（ii）观察到改善 在血管健康降低ChP活性（n=23）和进行性颅内血管病变增加ChP 灌注（n=75）;和（iii）在此报告，在ADRD的老年人中，ChP相对于年龄升高- 无痴呆的匹配成人（n=31）。这些数据突出了在以下情况下评价ChP功能的可能性： 在神经退行性疾病和脑血管疾病中。然而，现存的方法需要细化以改进 ChP定位和定量准确性，包括ChP生理学的扩展知识以及ChP如何 活性涉及分子清除和肿瘤学的解剖学标记。在此，我们建议解决 我们理解上的差距在目的（1）中，我们将进行ChP MRI弛豫的系统测量 时间和循环动力学;研究结果将提高ChP灌注准确性，超越目前的方法， 利用来自其他组织的便利校准值。在目标（2）中，我们将扩展先前的研究，证明 CSF产生的昼夜变化，以量化睡眠和觉醒期间ChP灌注的昼夜变化; 结果将作为未来研究的必要先决条件，利用中国药典功能作为替代品，或 补充胶质淋巴或CSF流动功能障碍。在目标（3）中，我们将量化参与者的ChP灌注 ADRD依次与通过大脑导水管的大量CSF流速，硬膜旁体积， 和蛋白质病。数据将用于检验关于中国药典活性相关性的基本假设， 在正常和升高的淀粉样蛋白负荷和临床痴呆的情况下受损的跨分子通道。 研究结果将提供关于ChP活性如何的第一个数据，在体内从高水平非侵入性定量， 空间分辨率灌注MRI反映了传统或新型液体流出的变化。成功 完成后将提供新的采集和后处理资源，这将为 在越来越多的CSF清除功能障碍的应用中使用这些方法。

PROJECT SUMMARY The goal of this work is to refine neuroimaging methods to enable quantitation of choroid plexus (ChP) anatomy and function non-invasively in vivo, and subsequently to use these methods to test fundamental hypotheses regarding ChP activity, cerebrospinal fluid (CSF) flow, and anatomical and protein markers of molecular clearance dysfunction in patients with Alzheimer’s Disease Related Dementias (ADRDs). The premise for this work is based on the known role of the ChP complexes for CSF production, and the recent link between bulk and perivascular CSF flow dysfunction in neurodegenerative disorders, yet a lack of robust methods for quantifying these pathways in humans. We have shown that arterial spin labeling (ASL) magnetic resonance imaging (MRI) methods and deep learning algorithms can be re-parameterized to enable reproducible estimates of ChP perfusion (ml/100g/min) at high spatial resolution and accurate automated localization, respectively: in preliminary data from 139 volunteers, we have (i) demonstrated abilities to obtain reproducible ChP perfusion estimates in healthy adults (n=10); (ii) observed that improvements in vascular health reduce ChP activity (n=23) and progressive intracranial vasculopathy increases ChP perfusion (n=75); and (iii) report here that in older adults with ADRDs, ChP is elevated relative to age- matched adults without dementia (n=31). These data highlight the possibility of evaluating ChP function in vivo in neurodegenerative and cerebrovascular disease. However, extant methods require refinement to improve ChP localization and quantitative accuracy, including an expanded knowledge of ChP physiology and how ChP activity relates to anatomical markers of molecular clearance and symptomatology. Here, we propose to address these gaps in our understanding. In Aim (1), we will perform systematic measurements of ChP MRI relaxation times and circulatory dynamics; findings will improve ChP perfusion accuracy beyond current approaches that utilize convenience calibration values from other tissues. In Aim (2), we will extend prior studies demonstrating circadian variation in CSF production to quantify diurnal variation in ChP perfusion during sleep and wakefulness; results will serve as a necessary prerequisite for future studies that utilize ChP function as a surrogate or complement to glymphatic or CSF flow dysfunction. In Aim (3), we will quantify ChP perfusion in participants with ADRD in sequence with bulk CSF flow velocity through the cerebral aqueduct, parasagittal dural volume, and proteinopathy. Data will be used to test fundamental hypotheses regarding the relevance of ChP activity and impaired trans-molecular passage in the setting of normal and heightened amyloid burden and clinical dementia. Findings will provide the first data on how ChP activity, quantified non-invasively in vivo from high spatial resolution perfusion MRI, reflects variation in traditional or novel fluid efflux. Successful completion will provide new acquisition and post-processing resources, which will provide a foundation for using these methods in the growing number of applications of CSF clearance dysfunction.