Disruption of cerebrospinal fluid (CSF) clearance pathway (glymphatic system) might contribute to development of Alzheimer's disease (AD), which is characterized by excessive deposition of toxic soluble amyloid beta (A- beta) proteins in the brain. Recent studies of mice demonstrated that impairment of the CSF clearance pathway led to a 70% reduction in A-beta clearance, while sleep-induced enhancement of CSF flow increased A-beta clearance by 100%. It is unclear whether or not these impairment and enhancement effects exist in humans and how they change with aging. Technical limitations of noninvasive approaches hinder adequate study of CSF clearance in humans. Here we propose two new techniques to determine whether CSF clearance is enhanced during sleep, degenerated in normal aging, and disrupted in AD. Instead of studying perivascular space, this project investigates the production (at choroid plexus), bulk flow (in parenchyma), and drainage (at arachnoid villi) of CSF in the brain simultaneously. The overarching goal is to understand the changes in CSF clearance in normal aging and in AD. The proposed techniques include 1) dynamic sodium (23Na) MRI that quantifies velocity of CSF bulk flow in brain parenchyma and 2) ultrashort echo time (UTE) proton (1H) MRI that uses UTE-T2* value to quantify calcification of choroid plexus and assess deficiency of CSF production and uses high resolution (0.22 mm) to visualize trabecular structures in arachnoid villi and evaluate resistance of CSF drainage.
We aim to determine: 1) how age affects CSF production, bulk flow, and drainage in the normal brain; 2) the impact of sleep on CSF clearance in the normal aging brain; and 3) whether CSF clearance is disrupted in AD patients. This work will generate highly-desired valuable knowledge about the degeneration of CSF clearance in normal aging and disruption in AD, which will help design and determine effective interventions for and strategies to prevention of AD development.
The proposed research is relevant to public health because the proposed study of understanding CSF clearance system in aging human brain is expected to obtain highly-desired knowledge and ultimately help deign effective interventions to Alzheimer's disease. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge and/or novel technologies that will help reduce the burdens of diseases.
