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

项目总结 这项工作的目标是改进神经成像方法，以便能够对脉络丛(CHP)解剖进行量化 并在体内非侵入性地发挥作用，随后使用这些方法来检验基本假设 关于CHP活性、脑脊液(CSF)流量以及分子的解剖和蛋白质标志物 阿尔茨海默病相关痴呆患者的清除功能障碍。这样做的前提是 这项工作是基于CHP复合体在脑脊液生产中的已知作用，以及最近 神经退行性疾病中的大量和血管周围脑脊液流动障碍，但缺乏稳健 在人类中量化这些途径的方法。我们已经证明动脉自旋标记(ASL) 磁共振成像(MRI)方法和深度学习算法可以重新参数化以实现 高空间分辨率和精确自动化的CHP血流灌注(ml/100g/min)的可重复性估计 本地化：在139名志愿者的初步数据中，我们(I)证明了以下能力 在健康成人(n=10)中获得可重复的CHP血流灌注估计；(Ii)观察到改善 血管健康患者CHP活性降低(n=23)，进行性颅内血管病变增加CHP 血流灌注(n=75)；和(Iii)这里报道，在患有ADRDS的老年人中，CHP相对于年龄- 匹配的非痴呆症成人(n=31)。这些数据突出了评估CHP功能的可能性 活体神经退行性疾病和脑血管疾病。然而，现有的方法需要改进才能改进。 CHP定位和定量准确性，包括对CHP生理学的扩展知识以及CHP如何 活性与分子清除和症状学的解剖学标志有关。在这里，我们建议解决 我们在理解上的这些差距。在Aim(1)中，我们将进行系统的CHP MRI松弛测量 时间和循环动力学；研究结果将提高CHP灌注的准确性，超过目前的方法 利用来自其他组织的方便的校准值。在AIM(2)中，我们将扩展先前的研究，证明 脑脊液产生的昼夜变化以量化睡眠和清醒期间CHP血流的日变化； 这些结果将作为未来研究的必要前提，这些研究将利用CHP作为替代或 补充淋巴或脑脊液流动功能障碍。在AIM(3)中，我们将量化参与者的CHP灌注量 ADRD的顺序为脑脊液通过导水管的体积流速、矢状面旁硬脑膜体积、 和蛋白质病。数据将被用来检验关于生防护中心活动和 在正常和淀粉样蛋白负荷升高和临床痴呆的背景下，跨分子通路受损。 这些发现将提供第一批关于CHP活性的数据，CHP活性是如何在体内从高 空间分辨率灌注MRI，反映了传统或新型液体外流的变化。成功 完成后将提供新的购置和后处理资源，这将为 在越来越多的脑脊液清除功能障碍的应用中使用了这些方法。

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.