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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.

项目总结