Focused Ultrasound-Induced Blood-Brain Barrier Disruption for Targeted Drug Delivery and Therapeutic Treatment of Neurodegenerative Disease

Abstract

Neurodegenerative diseases, such as Alzheimer’s Disease (AD) and Parkinson’s Disease affected an estimated 7.7 million Americans in 2020 (Alzheimer's Disease Facts and Figures, 2024) and has resulted in $392 billion in healthcare-related costs and lost wages (Understanding Parkinson's, 2024).A major obstacle for treatment of neurodegenerative disease is the blood-brain barrier (BBB), a layer of endothelial cells, astrocytes, and tight-junction proteins that prevent most therapeutic agents from crossing into the brain. Focused ultrasound (FUS + MB) with intravascular microbubbles (MB) has been introduced as a novel method of transiently opening the BBB for drug delivery and therapy in neurodegenerative disease. The gold-standard for confirmation of BBB opening after FUS + MB is T1-weighted MRI with gadolinium-based contrast agent (GBCA) enhancement. While this method provides reliable and accurate localization of BBB opening within the brain, MRI does not have the spatial resolution to resolve local distribution or kinetics of solute delivery to the brain tissue. Currently, it is not established which vessels are opened via FUS + MB or the spatiotemporal distribution of solutes relative to the targeted cells. In this dissertation, in vivo 2-photon microscopy (2PM) was used in combination with MRI FUS + MB to better understand the effect of FUS + MB on tissue microvasculature and parenchymal kinematics. Results from such multimodality experiments are presented, where FUS + MB, MRI and 2PM are carried out in the brains of mice to investigate the effects of FUS + MB on microvasculature and the movement of molecules across the blood-brain barrier in healthy and disease-model mice.