Comparative analysis of regional blood–brain barrier permeability in humans and rodents: implications for functional specialization and aging

Abstract 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 Evans blue–based fluorescence analyses. Results BBB-related measurements varied across brain regions. Brainstem-relative analyses generally showed lower permeability values in several cortical regions, including the frontal cortex, than the brainstem reference, although the precise regional ordering differed before brainstem normalization. Plasma volume fraction showed higher values in the frontal and occipital cortices than in the brainstem and white matter. Complementary rat experiments also demonstrated regional BBB heterogeneity. Sex-stratified analyses revealed positive associations between age and whole-brain percent volume with a leaky BBB, normalized to plasma volume fraction, in both sexes. Formal interaction analysis demonstrated a significantly steeper whole-brain age association in males, although no lobe-specific age-by-sex interaction survived correction for multiple comparisons. Conclusions This study demonstrates regional heterogeneity in BBB-related measurements and suggests that BBB properties may reflect regional functional specialization. The association between age and whole-brain leaky BBB volume (%) was steeper in males.