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

阿尔茨海默病相关痴呆症脉络丛功能和神经液循环的定量成像

基本信息

批准号：
10718346
负责人：
Manus J Donahue
金额：
$ 58.04万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10718346
关键词：
Address Adult Age Algorithms Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amyloid Anatomy Arachnoid mater Attention Biochemical Blood Blood Vessels Calibration Cerebral Ventricles Cerebral aqueduct Cerebrospinal Fluid Cerebrovascular Circulation Cerebrovascular Disorders Circadian Rhythms Circulation Clinical Communication Complement Complex Data Dementia Deposition Disease Diurnal Rhythm Elderly Female Foundations Functional disorder Future Goals Health Heart Atrium Human Hypertrophy Impairment Knowledge Light Link Liquid substance Literature Magnetic Resonance Imaging Measurement Measures Methodology Methods Modeling Molecular Nerve Degeneration Neurodegenerative Disorders Participant Partition Coefficient Pathway interactions Peptides Perfusion Physiology Positron-Emission Tomography Production Relaxation Reporting Reproducibility Resolution Resources Role Route Severities Signal Transduction Site Sleep Stress Structure of choroid plexus Suggestion Testing Time Tissues Variant Vascular Diseases Venous system Wakefulness Water Work arterial spin labeling biological sex cerebrospinal fluid flow circadian deep learning deep learning algorithm glymphatic system hemodynamics imaging modality improved in vivo kinetic model lateral ventricle lymphatic vessel male molecular marker neuroimaging novel perfusion imaging protein biomarkers quantitative imaging response symptomatology volunteer β-amyloid burden

项目摘要

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.

项目概要这项工作的目标是完善神经影像方法，以实现脉络丛 (ChP) 解剖结构的定量并在体内无创地发挥作用，然后使用这些方法来测试基本假设关于 ChP 活性、脑脊液 (CSF) 流量以及分子的解剖和蛋白质标记阿尔茨海默病相关痴呆症（ADRD）患者的清除功能障碍是其前提。该工作基于 ChP 复合物在 CSF 产生中的已知作用，以及最近之间的联系神经退行性疾病中脑脊液大量和血管周围血流功能障碍，但缺乏强大的我们已经证明了动脉自旋标记（ASL）对人类这些途径进行量化的方法。磁共振成像 (MRI) 方法和深度学习算法可以重新参数化，以实现以高空间分辨率和准确的自动化方式对 ChP 灌注 (ml/100g/min) 进行可重复的估计分别进行本地化：根据 139 名志愿者的初步数据，我们 (i) 展示了以下能力：在健康成人中获得可重复的 ChP 灌注估计值 (n=10)；(ii) 观察到改善情况；血管健康中的 ChP 活性降低 (n=23)，进行性颅内血管病变则增加 ChP 活性灌注（n = 75）；和（iii）在此报告，患有 ADRD 的老年人中，ChP 相对于年龄而言升高这些数据强调了评估 ChP 功能的可能性。然而，现有的方法需要改进。 ChP 定位和定量准确性，包括 ChP 生理学的扩展知识以及 ChP 如何活性与分子清除和症状学的解剖标志物有关。在这里，我们建议解决这一问题。我们理解中的这些差距在目标 (1) 中，我们将对 ChP MRI 弛豫进行系统测量。时间和循环动力学；研究结果将提高 ChP 灌注的准确性，超越目前的方法利用来自其他组织的便利校准值，我们将扩展先前的研究证明。 CSF 产生的昼夜变化可量化睡眠和清醒期间 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 ChP 功能作为替代或在目标 (3) 中，我们将量化参与者的 ChP 灌注。 ADRD 依次为通过脑导水管的大量 CSF 流速、矢状旁硬脑膜体积、数据将用于检验有关 ChP 活性和蛋白质病的相关性的基本假设。在正常和脂肪淀粉样蛋白负荷和临床痴呆的情况下跨分子通道受损。研究结果将提供关于如何从高浓度体内无创地量化 ChP 活性的第一个数据。空间分辨率灌注 MRI，反映了传统或新型流体流出成功的变化。完成后将提供新的采集和后处理资源，这将为这些方法在脑脊液清除功能障碍的应用中越来越多。