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

项目总结

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.