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.

项目摘要这项工作的目的是完善神经影像学方法以实现脉络丛（CHP）解剖并在体内发挥非侵入性，随后使用这些方法来检验基本假设关于CHP活性，脑脊液（CSF）流以及分子的解剖学和蛋白质标记阿尔茨海默氏病与痴呆症（ADRDS）患者的清除功能障碍。这个前提工作基于CHP复合物在CSF生产中的已知作用，以及最近的联系神经退行性疾病中的散装和血管周CSF流动功能障碍，但缺乏健壮性量化人类这些途径的方法。我们已经证明了动脉自旋标记（ASL）可以重新参数以启用磁共振成像（MRI）方法和深度学习算法高空间分辨率和准确自动化的CHP灌注（ML/100G/min）的可再现估计值本地化分别：在来自139名志愿者的初步数据中，我们（i）证明了能力在健康成年人中获得可重复的CHP灌注估计值（n = 10）；（ii）观察到改进在血管健康中，CHP活性（n = 23）和进行性颅内血管病增加了CHP 灌注（n = 75）; （iii）在这里报告说，在患有ADRDS的老年人中，CHP相对于年龄升高不含痴呆症的成年人（n = 31）。这些数据突出了评估CHP功能的可能性神经退行性和脑血管疾病的体内。但是，现存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的方式活性涉及分子清除和症状学的解剖标记。在这里，我们建议解决这些差距在我们的理解中。在AIM（1）中，我们将对CHP MRI松弛进行系统测量时间和电路动力学；发现将提高CHP灌注精度，而不是当前的方法利用其他组织的便利校准值。在AIM（2）中，我们将扩展先前的研究证明 CSF产生的昼夜节律变化，以量化睡眠和清醒期间CHP灌注的昼夜变化；结果将是将来利用CHP功能作为替代物或的未来研究的必要先决条件补充性化或CSF流量功能障碍。在AIM（3）中，我们将量化参与者的CHP灌注 ADRD序列，通过大量CSF流动速度通过大脑渡槽，副臂硬膜卷积，和蛋白质病。数据将用于检验有关CHP活动相关性和的基本假设在正常和增强淀粉样蛋白伯嫩和临床痴呆症的情况下，跨分子通过受损。调查结果将提供有关CHP活动如何从高中量化非侵入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外排的变化。成功的完成将提供新的收购和后处理资源，这将为基础提供用于在CSF清除功能障碍的越来越多的应用中使用这些方法。