Title: Quantitative and dynamic analysis of the focused-ultrasound induced blood-brain barrier opening in vivo for drug delivery
Description: The rate limiting factor for the treatment of neurodegenerative diseases is the blood-brain barrier (BBB), which protects the brain microenvironment from the efflux of large molecules, and thus it constitutes a major obstacle in therapeutic drug delivery. All state-of-the-art strategies to circumvent the BBB are invasive or non-localized, include side-effects and limited distribution of the molecule of interest to the brain. Focused Ultrasound (FUS) in conjunction with microbubbles has been shown to open the BBB non-invasively, locally and transiently to allow large molecules diffusion in rodents and non-human primates. This thesis entails a quantitative analysis of the FUS-induced BBB opening in vivo for drug delivery in neurodegenerative diseases. First, quantitative analysis and modeling of the physiologic changes of the BBB opening, such as permeability changes, volume of opening, and reversibility timeline, were studied in wild-type mice, in brain areas related to Alzheimer's and Parkinson's disease.

This study provided in vivo tools for BBB opening analysis, as well as the design of a FUS method with optimized parameters for efficient and safe drug delivery. Second, the neurotrophic factor Neurturin, which has been shown to have neuroregenerative and neuroprotective effects in dopaminergic neurons was successfully delivered in wild-type mice and MPTP-lesion parkinsonism model mice. It was shown that FUS enhanced the delivery of Neurturin to the entire regions of interest associated with the disease, downstream signaling for neuronal proliferation was also detected, and finally neuroregeneration was observed in the FUS-treated side compared to the contralateral side. In the third part of this thesis, a pre-clinical translation of the pharmacodynamic analysis was designed and analyzed in non-human primates. The permeability changes, the volume of opening separately in grey and white matter, as well as the concentration of an MR-contrast agent were measured in vivo for the first time.

The interaction of FUS with the inhomogeneous primate brain was investigated and the drug delivery efficiency of the FUS technique for BBB opening was measured non-invasively; rather critical findings for safe and optimal drug delivery using FUS in a pre-clinical setting.