Optimizing High-Resolution MRI for Analyzing Perivascular Space Dynamics and Waste Clearance in Alzheimer's Disease

Efficient clearance of amyloid-β (Aβ) peptides is crucial for maintaining cognitive health and preventing Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) dynamics are vital for removing Aβ from the brain's interstitial spaces. Understanding how CSF flow and exchange influence Aβ clearance is essential for elucidating AD mechanisms and developing effective therapies. The emerging glymphatic theory suggests that the protein exchange between interstitial fluid (ISF) and cerebrospinal fluid (CSF) at the perivascular spaces (PVS) could play a critical role in Aβ clearance. However, accurately measuring CSF flow and Aβ dynamics in these small, intricate spaces, particularly in the deeper brain regions, has been a significant hurdle due to the limitations of current imaging technologies. This proposal aims to address that gap by developing advanced high-resolution MRI methods to noninvasively track CSF flow and soluble Aβ diffusion through the PVS. These tools will provide direct evidence of CSF-mediated Aβ clearance in healthy brains and reveal its disruption during AD pathogenesis. We hypothesize that Aβ plaque deposition at the PVS, a critical site for glymphatic clearance, impairs protein exchange between ISF and CSF and leads to reduced CSF Aβ42 levels. If validated, targeting CSF-mediated Aβ42 clearance via the PVS may offer a promising therapeutic strategy to enhance Aβ removal and prevent plaque formation in early-stage AD. We will test three specific aims: Aim 1. Develop and optimize novel MR mapping schemes to detect CSF flow dynamics through PVS and ventricles. This aim focuses on enhancing the resolution and accuracy of PVS mapping and developing rapid, high signal-to-noise ratio (SNR) sampling methods to measure CSF flow in the PVS and ventricles. Aim 2: Identify soluble Aβ42 dynamics in the CSF with MRI and two-photon microscopic (2PM) imaging. This aim will characterize Aβ42 distribution dynamics in the CSF of normal brains using the novel MRI method. The cortical surface distribution of Aβ42 will be validated with 2PM imaging in the same mice. Aim 3: Characterize the impaired Aβ42 diffusion through the blocked PVS by plaques in the 5xFAD AD mouse model. This aim will provide direct evidence that amyloid plaque–induced PVS blockage alters CSF Aβ42 dynamics in AD mice. Eventually, the newly developed MR methods will enable detection of CSF flow through the PVS in both normal and AD mouse brains. By integrating MRI with multiphoton deep-brain imaging, we will identify plaque accumulation near the PVS as a key driver of impaired perivascular Aβ clearance, opening a novel therapeutic avenue to restore Aβ dynamics and PVS function in AD. Project Number: 1R01AG094755-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Xiaoqing Zhou | Institution: MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MA | Award Amount: $670,530 | Activity Code: R01 | Study Section: Imaging Technology for Neuroscience Study Section[ITN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11364580