Comparative Analysis of Regional Blood-Brain Barrier Permeability in Humans and Rodents: An Evolutionary Perspective

Background The blood-brain barrier (BBB) serves a critical function in regulating transport between the blood and the brain, with its dysfunction being implicated in numerous neurological diseases such as neurodegenerative disorders, epilepsy, stroke, traumatic brain injury, and brain tumors. Understanding the regional heterogeneity in BBB properties in healthy individuals remains limited. This study aims to characterize regional BBB permeability variations in the healthy brain using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and explore differences related to sex and age. Methods We retrospectively analyzed DCE-MRI scans from 102 healthy participants aged 19–85 (55.8% female), assessing BBB permeability to a Gadolinium-based contrast agent and plasma volume fraction across 124 brain regions. We examined the effects of sex and age on BBB permeability and plasma volume fraction. Additional studies were conducted on 11-week-old Sprague Dawley rats using DCE-MRI and fluorescent microscopy following peripheral injection of Evans blue dye. Results We show that BBB permeability varies across brain regions, being lower in more recently evolved cortical regions, such as the frontal cortex, compared to the phylogenetically older brainstem and subcortical areas. Plasma volume fraction showed the opposite trend with higher vascularization in cortex compared to brainstem. Age-related analysis revealed an increase in BBB permeability (normalized to plasma volume fraction) that was more pronounced in males than females. Conclusions This study underscores an evolutionary perspective in BBB properties, highlighting a gradient from higher permeability in evolutionarily older brain regions (e.g. brainstem) to lower permeability in evolutionarily younger regions (e.g. frontal cortex). These permeability differences accentuate with age, particularly in males.