Aquaporin-4 inhibition in the mouse brain leads to apparent cell shrinkage as measured by double diffusion encoding

Motivation: Aquaporin-4 (AQP4) inhibition has emerged as a protective therapy for cytotoxic oedema (i.e., cell swelling), but monitoring the associated effects using diffusion MRI has largely been limited to the non-specific, apparent diffusion coefficient (ADC). Goal(s): To better understand the microstructural effects of AQP4 inhibition in the healthy mouse brain - perhaps cell shrinkage - using advanced diffusion encoding. Approach: A double diffusion encoding method and analysis framework was implemented, which aims to provide specific parameters: cell size, occupancy, and exchange time. Results: AQP4 inhibition with TGN-020 yielded parameters consistent with an approximately 2 - 3% cell shrinkage, preliminarily confirming the proposed mechanism-of-action. Impact: The modulation of water permeability by aquaporins is important to normal brain function and pathology. We present a method to disentangle the apparent cell size, occupancy, and exchange time, to provide insight into the microstructural effects of aquaporin-4 inhibition.