Quantitative analysis of macroscopic solute transport in the murine brain

Background: Understanding molecular transport in the brain is critical to care and prevention of neurological disease and injury. A key question is whether transport occurs primarily by diffusion, or also by convection or dispersion. Dynamic contrast-enhanced (DCE-MRI) experiments have long reported solute transport in the brain that appears to be faster than diffusion alone, but this transport rate has not been quantified to a physically relevant value that can be compared to known diffusive rates of tracers. Methods: In this work, DCE-MRI experimental data is analyzed using subject-specific finite-element models to quantify transport in different anatomical regions across the whole mouse brain. The set of regional effective diffusivities (D-eff), a transport parameter combining all mechanisms of transport, that best represent the experimental data are determined and compared to apparent diffusivity (D-app), the known rate of diffusion through brain tissue, to draw conclusions about dominant transport mechanisms in each region. Results: In the perivascular regions of major arteries, D-eff for gadoteridol (550 Da) was over 10,000 times greater than Dapp. In the brain tissue, constituting interstitial space and the perivascular space of smaller blood vessels, D-eff was 10-25 times greater than D-app. Conclusions: The analysis concludes that convection is present throughout the brain. Convection is dominant in the perivascular space of major surface and branching arteries (Pe > 1000) and significant to large molecules (> 1 kDa) in the combined interstitial space and perivascular space of smaller vessels (not resolved by DCE-MRI). Importantly, this work supports perivascular convection along penetrating blood vessels.