Evaluating Permeability Surface-Area Product as a Measure of Blood-Brain Barrier Permeability in a Murine Model

Abstract

Background and Purpose Permeability surface area product has been suggested as a marker for BBB permeability with potential applications in clinical care and research. However, few studies have demonstrated its correlation with actual quantitative measurements of BBB permeability. Our aim was to demonstrate the correlation of quantitative permeability surface area product and BBB permeability in a murine model by histologic confirmation. Materials and Methods Coronal MRI was performed on mice treated with mannitol (n=6) for disruption of the BBB and controls treated with saline (n=5). Permeability surface area product was determined by ROI placement and compared between saline and mannitol treated mice. Correlation was made with contrast enhancement measurements and immunohistologic stained sections of tripeptidyl peptidase-1 distribution in mice treated with mannitol and saline followed by injection of a viral vector containing the CLN2 gene, which directs production of tripeptidyl peptidase-1. Results Significantly increased permeability surface area product was seen in mannitol compared to saline-treated mice in the whole brain (P = 0.008), MCA territory (P = 0.014) and mixed vascular territories (P = 0.008). These findings were compared to contrast enhancement measurements of BBB permeability and correlated with immunohistologic stained sections demonstrating BBB permeability to a large vector. Conclusion Permeability surface area product is increased in situations with known disruptions of the BBB, as evidenced by immunologic staining of large vector passage through the BBB and concordance with contrast enhancement measurements in a murine model. Quantitative permeability surface area product has potential as an imaging marker of BBB permeability.

Reply:

“…Our findings were consistent across subjects, as evidenced by the individual-subject DCE curves supporting our data being robust using these methods. Furthermore, our data are also concordant with other previously published animal model data, 5 and DCE-MR imaging-based human studies demonstrating increased hippocampal BBB permeability, 6 providing additional support from the literature.…”

Dynamic Contrast-Enhanced MRI Reveals Unique Blood-Brain Barrier Permeability Characteristics in the Hippocampus in the Normal Brain

“…A review of the literature revealed that increased BBBP in the hippocampus has been previously demonstrated with DCE-MR imaging in control subjects in a mouse model of BBB disruption, in which histologic assessment of BBB integrity served as the reference standard. 7 Because the hippocampal microvasculature is supplied from both the anterior and posterior circulation, 4 hypothetic explanations have related the increased susceptibility of the hippocampus to cerebrovascular autoregulatory dysfunction that has been similarly described in the sympathetic vascular innervation of the posterior circulation. 10 Most important, there is molecular evidence for elevated expression of biomarkers of BBB disruption in the hippocampus.…”

“…5 Additionally, animal studies have revealed increased protein expression of CD36, matrix metalloproteinase-13, and osteopontin correlated with increased hippocampal BBBP, 6 and dynamic contrast-enhanced (DCE)-MR imaging-derived baseline contrast enhancement curves were highest in the hippocampi in control subjects. 7 The purpose of our study was to evaluate region-specific BBBP metrics in healthy human subjects.…”

Therapeutic Remodeling of the Tumor Microenvironment Enhances Nanoparticle Delivery

“…Unlike blood vessels in other parts of the body, the permeability of central nervous system (CNS) vasculatures is also regulated by the specialized blood‐brain‐barrier. For CNS vessels, the permeability surface‐area product (PS) has been used as a marker for blood‐brain‐barrier permeability . We found that PS was highest in IgG‐treated group, indicting more plasma efflux from vessels, and dropped significantly in the DC101‐treated groups.…”