Sizes and Shapes of Perivascular Spaces Surrounding Murine Pial Arteries

BACKGROUND: Flow of cerebrospinal fluid (CSF) through brain perivascular spaces (PVSs) is essential for the clearance of interstitial metabolic waste products whose accumulation and aggregation is a key mechanism of pathogenesis in many diseases. The PVS geometry has important implications for CSF flow as it affects CSF and solute transport rates. Thus, the size and shape of the perivascular spaces are essential parameters for models of CSF transport in the brain and require accurate quantification. METHODS: We segmented two-photon images of pial (surface) PVSs and the adjacent arteries and characterized their sizes and shapes of thousands of cross sections from 14 PVS segments in 9 mice. Based on the analysis, we propose an idealized model that approximates the cross-sectional size and shape of pial PVSs, closely matching their area ratios and hydraulic resistances. RESULTS: PVS size only approximately scales with vessel size, and the ratio of PVS-to-vessel area varies widely across the thousands of cross sections analyzed. The hydraulic resistance per unit length of the PVS scales with the PVS cross-sectional area, and we found a power-law fit that predicts resistance as a function of the area. Three idealized geometric models were compared to PVSs imaged in vivo, and their accuracy in reproducing hydraulic resistances and PVS-to-vessel area ratios were evaluated. The area ratio was obtained across thousands of different cross sections, and we found that the distribution peaks for the original PVS and its closest idealized fit (polynomial fit) were 1.12 and 1.21, respectively. The peak of the hydraulic resistance distribution is 1.73×10(15) Pa s/m(5) and 1.44×10(15) Pa s/m(5) for the segmentation and its closest idealized fit, respectively. CONCLUSIONS: PVS hydraulic resistance can be reasonably predicted as a function of the PVS area. The proposed polynomial-based fit most closely captures the shape of the PVS with respect to area ratio and hydraulic resistance. Idealized PVS shapes are convenient for modeling, which can be used to better understand how anatomical variations affect clearance and drug delivery transport.