Varying perivascular astroglial endfoot dimensions along the vascular tree maintain perivascular-interstitial flux through the cortical mantle.

The glymphatic system is a recently defined brain-wide network of perivascular spaces along which cerebrospinal fluid (CSF) and interstitial solutes exchange. Astrocyte endfeet encircling the perivascular space form a physical barrier in between these two compartments, and fluid and solutes that are not taken up by astrocytes move out of the perivascular space through the junctions in between astrocyte endfeet. However, little is known about the anatomical structure and the physiological roles of the astrocyte endfeet in regulating the local perivascular exchange. Here, visualizing astrocyte endfoot-endfoot junctions with immunofluorescent labeling against the protein megalencephalic leukoencephalopathy with subcortical cysts-1 (MLC1), we characterized endfoot dimensions along the mouse cerebrovascular tree. We observed marked heterogeneity in endfoot dimensions along vessels of different sizes, and of different types. Specifically, endfoot size was positively correlated with the vessel diameters, with large vessel segments surrounded by large endfeet and small vessel segments surrounded by small endfeet. This association was most pronounced along arterial, rather than venous segments. Computational modeling simulating vascular trees with uniform or varying endfeet dimensions demonstrates that varying endfoot dimensions maintain near constant perivascular-interstitial flux despite correspondingly declining perivascular pressures along the cerebrovascular tree through the cortical depth. These results describe a novel anatomical feature of perivascular astroglial endfeet and suggest that endfoot heterogeneity may be an evolutionary adaptation to maintain perivascular CSF-interstitial fluid exchange through deep brain structures.

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 ([Formula: see text]), a transport parameter combining all mechanisms of transport, that best represent the experimental data are determined and compared to apparent diffusivity ([Formula: see text]), 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, [Formula: see text] for gadoteridol (550 Da) was over 10,000 times greater than [Formula: see text]. In the brain tissue, constituting interstitial space and the perivascular space of smaller blood vessels, [Formula: see text] was 10-25 times greater than [Formula: see text]. 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.

In response to "Is solute movement within the extracellular spaces of brain gray matter brought about primarily by diffusion or flow?"

In our work, "Analysis of Convective and Diffusive Transport in the Brain Interstitium", published in this journal (2019, 16:6), we estimate the interstitial superficial velocity by comparison of transport model simulations to published experimental Real-Time Iontophoresis (RTI) data. In the Discussion section, we calculate a value for perfusion rate, or volumetric flow rate per unit mass of tissue, from these fundamental results of superficial velocity. Drs. Hladky and Barrand have proposed an alternative method for choosing the surface area per volume used to calculate perfusion rate from superficial velocity, using our model domain. Their method seems reasonable to us, as does ours. Upon reflection, a range of volumetric flow per unit mass values should have been reported in our paper, 1-40 µL/min-g. The value calculated using Drs. Hladky and Barrand surface area is a likely upper-bound on this range and the value in the paper is a low estimate at the bottom of the range. We are confident in the estimates of interstitial velocity reported in our article, using the assumptions of the model. Peclet (Pe) numbers, which compare convective and diffusive transport rates for different molecules, were calculated using the superficial velocity estimates; and we continue to believe these values are correct along with all other major results and conclusions presented in the paper.

Analysis of convective and diffusive transport in the brain interstitium.

BACKGROUND: Despite advances in in vivo imaging and experimental techniques, the nature of transport mechanisms in the brain remain elusive. Mathematical modelling verified using available experimental data offers a powerful tool for investigating hypotheses regarding extracellular transport of molecules in brain tissue. Here we describe a tool developed to aid in investigation of interstitial transport mechanisms, especially the potential for convection (or bulk flow) and its relevance to interstitial solute transport, for which there is conflicting evidence. METHODS: In this work, we compare a large body of published experimental data for transport in the brain to simulations of purely diffusive transport and simulations of combined convective and diffusive transport in the brain interstitium, incorporating current theories of perivascular influx and efflux. RESULTS: The simulations show (1) convective flow in the interstitium potentially of a similar magnitude to diffusive transport for molecules of interest and (2) exchange between the interstitium and perivascular space, whereby fluid and solutes may enter or exit the interstitium, are consistent with the experimental data. Simulations provide an upper limit for superficial convective velocity magnitude (approximately [Formula: see text] = 50 µm min-1), a useful finding for researchers developing techniques to measure interstitial bulk flow. CONCLUSIONS: For the large molecules of interest in neuropathology, bulk flow may be an important mechanism of interstitial transport. Further work is warranted to investigate the potential for bulk flow.