BackgroundIn animal models, dissolved compounds in the subarachnoid space and parenchyma have been found to preferentially transport through the cortex perivascular spaces (PVS) but the transport phenomena involved are unclear.MethodsIn this study two hydraulic network models were used to predict fluid motion produced by blood vessel pulsations and estimate the contribution made to solute transport in PVS and parenchyma. The effect of varying pulse amplitude and timing, PVS dimensions, and tissue hydraulic conductivity on fluid motion was investigated.ResultsPeriodic vessel pulses resulted in oscillatory fluid motion in PVS and parenchyma but no net flow over time. For baseline parameters, PVS and parenchyma peak fluid velocity was on the order of 10 μm/s and 1 nm/s, with corresponding Peclet numbers below 103 and 10−1 respectively. Peak fluid velocity in the PVS and parenchyma tended to increase with increasing pulse amplitude and vessel size, and exhibited asymptotic relationships with hydraulic conductivity.ConclusionsSolute transport in parenchyma was predicted to be diffusion dominated, with a negligible contribution from convection. In the PVS, dispersion due to oscillating flow likely plays a significant role in PVS rapid transport observed in previous in vivo experiments. This dispersive effect could be more significant than convective solute transport from net flow that may exist in PVS and should be studied further.

Investigating the mechanisms by which metabolic wastes are cleared from nervous tissue is important for understanding natural function and the pathophysiology of several neurological disorders including Alzheimer’s disease. Recent evidence suggests clearance may be the function of annular spaces around cerebral blood vessels, called perivascular spaces (PVS), through which cerebrospinal fluid (CSF) is transported from the subarachnoid space into brain parenchyma to exchange with interstitial fluid (also known as the glymphatic system). In this work, an MRI-based methodology was developed to reconstruct the PVS network in whole rat brain to better elucidate both PVS uptake and clearance pathways. MR visible tracer (Gd-albumin) was infused in vivo into the CSF-filled lateral ventricle followed by ex vivo high-resolution MR imaging at 17.6 T with an image voxel volume two orders of magnitude smaller than previously reported. Imaged tracer distribution patterns were reconstructed to obtain a more complete brain PVS network. Several PVS connections were repeatedly highlighted across different animals, and new PVS connections between ventricles and different parts of the brain parenchyma were revealed suggesting a possible role for the ventricles as a source or sink for solutes in the brain. In the future, this methodology may be applied to understand changes in the PVS network with disease.

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The effect of a human vascular endothelial growth factor antibody on the vasculature of human tumor grown in rat brain was studied. Using dynamic contrast‐enhanced magnetic resonance imaging, the effects of intravenous bevacizumab (Avastin; 10 mg/kg) were examined before and at postadministration times of 1, 2, 4, 8, 12 and 24 h (N = 26; 4–5 per time point) in a rat model of orthotopic, U251 glioblastoma (GBM). The commonly estimated vascular parameters for an MR contrast agent were: (i) plasma distribution volume (vp), (ii) forward volumetric transfer constant (Ktrans) and (iii) reverse transfer constant (kep). In addition, extracellular distribution volume (VD) was estimated in the tumor (VD‐tumor), tumor edge (VD‐edge) and the mostly normal tumor periphery (VD‐peri), along with tumor blood flow (TBF), peri‐tumoral hydraulic conductivity (K) and interstitial flow (Flux) and tumor interstitial fluid pressure (TIFP). Studied as % changes from baseline, the 2‐h post‐treatment time point began showing significant decreases in vp, VD‐tumor, VD‐edge and VD‐peri, as well as K, with these changes persisting at 4 and 8 h in vp, K, VD‐tumor, −edge and ‐peri (t‐tests; p < 0.05–0.01). Decreases in Ktrans were observed at the 2‐ and 4‐h time points (p < 0.05), while interstitial volume fraction (ve; = Ktrans/kep) showed a significant decrease only at the 2‐h time point (p < 0.05). Sustained decreases in Flux were observed from 2 to 24 h (p < 0.01) while TBF and TIFP showed delayed responses, increases in the former at 12 and 24 h and a decrease in the latter only at 12 h. These imaging biomarkers of tumor vascular kinetics describe the short‐term temporal changes in physical spaces and fluid flows in a model of GBM after Avastin administration.