Sex-Related Differences in Regional Blood–Brain Barrier Integrity in Non-Demented Elderly Subjects

Abstract

The role of the blood–brain barrier (BBB) breakdown has been recognized as being important in Alzheimer’s disease pathogenesis. We aimed to evaluate whether regional BBB integrity differed according to sex and whether differences in BBB integrity changed as a consequence of aging or cognitive decline, using dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI). In total, 75 participants with normal cognition (NC) or mild cognitive impairment (MCI) underwent cognitive assessments and MRI examination including DCE-MRI. Regional Ktrans was calculated in cortical regions and the Patlak permeability model was used to calculate BBB permeability (Ktrans, min−1). Females had a lower median Ktrans in the cingulate and occipital cortices. In the “older old” group, sex differences in Ktrans were only observed in the occipital cortex. In the MCI group, sex differences in Ktrans were only observed in the occipital cortex. Age was the only predictor of cognitive assessment scores in the male MCI group; however, educational years and Ktrans in the occipital cortex could predict cognitive scores in the female MCI group. Our study revealed that females may have better BBB integrity in cingulate and occipital cortices. We also found that sex-related differences in BBB integrity are attenuated with aging or cognitive decline.

Sex-Related Differences of Matrix Metalloproteinases (MMPs): New Perspectives for These Biomarkers in Cardiovascular and Neurological Diseases

“…A difference between sexes in BBB permeability was also confirmed using dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) [ 138 ]. In that study, the authors demonstrated a better BBB integrity in cingulate and occipital cortices in females than in male non-demented elderly subjects.…”

“…In that study, the authors demonstrated a better BBB integrity in cingulate and occipital cortices in females than in male non-demented elderly subjects. They also found that this sex-related difference in BBB integrity was attenuated by aging or when cognitive decline occurred, but the difference remained in the occipital cortex independently of these two factors [ 138 ].…”

Changes in hippocampal volume during a preceding 10-year period do not correlate with cognitive performance and hippocampal blood‒brain barrier permeability in cognitively normal late-middle-aged men

“…Despite the limitations of examining a male-only cohort, we believe that the extensive information accumulated from the cohort over the years is valuable for research on ageing and should be utilized. Studies investigating sex differences in BBB permeability in humans are scarce, but some studies have indicated that there may be sex-related differences in BBB permeability [ 60 ]. This should be kept in mind when studying BBB permeability and interpreting findings.…”

The CLDN5 gene at the blood-brain barrier in health and disease

“…Likely due to the effect of estrogen receptors, it has been shown that women have a stronger resistance against age-related increases in BBB permeability than men until the late life-stage [ 42 ]. After the end of estrogen production, the BBB in the occipital cortex, where the estrogen-producing neurons are highly enriched [ 43 ], becomes more vulnerable in women [ 42 ]. CLDN5 expression is also regulated by circadian rhythms and clock transcription factor brain and muscle aryl-hydrocarbon receptor nuclear translocator like protein 1 (BMAL1); the expression of Cldn5 is higher in the morning and lower in the evening, with rhythmic expression lost in endothelial specific Bmal1 −/− mice [ 44 , 45 ].…”