Age-Related Decline in Blood-Brain Barrier Function is More Pronounced in Males than Females in Parietal and Temporal Regions

Abstract

The blood-brain barrier (BBB) plays a pivotal role in protecting the central nervous system (CNS), shielding it from potential harmful entities. A natural decline of BBB function with aging has been reported in both animal and human studies, which may contribute to cognitive decline and neurodegenerative disorders. Limited data also suggest that being female may be associated with protective effects on BBB function. Here we investigated age and sex-dependent trajectories of perfusion and BBB water exchange rate (kw) across the lifespan in 186 cognitively normal participants spanning the ages of 8 to 92 years old, using a non-invasive diffusion prepared pseudo-continuous arterial spin labeling (DP-pCASL) MRI technique. We found that the pattern of BBB kw decline with aging varies across brain regions. Moreover, results from our DP-pCASL technique revealed a remarkable decline in BBB kw beginning in the early 60s, which was more pronounced in males. In addition, we observed sex differences in parietal and temporal regions. Our findings provide in vivo results demonstrating sex differences in the decline of BBB function with aging, which may serve as a foundation for future investigations into perfusion and BBB function in neurodegenerative and other brain disorders.

Keywords: Ageing; Arterial spin labeling; Blood-brain barrier; Sex difference; Water exchange rate.

Figure 1.. Illustration of DP-pCASL measurements and age-related trends in kw, ATT, and CBF in gray matter.

(A) Diagram illustrating the DP-pCASL measurements. ATT represents the transit time of the labeled blood traveling from DP-pCASL labeling plane to the imaging voxel, CBF refers to the amount of labeled blood supplied to the brain per unit of time (or perfusion), and kw describe the rate of blood water exchanging from intravascular space (capillaries) into extravascular space (tissue) facilitated by multiple transport mechanisms including AQP-4 water channel assisted transport. (B-D) Scatter plots representing age-related distribution of kw (B), ATT (C) and CBF (D) values in the gray matter. In all scatter plots, individual data points for males and females are indicated by blue asterisk symbols and red circles, respectively, while the corresponding MARS fitting curves and 95% confidence interval for expected value at each age point are presented as continuous lines and dashed lines in matching colors.

Figure 2.. Sex specific age trends in kw and CBF.

(A-E) Scatter plots representing age-related distribution of kw values in the parietal lobe (A), temporal lobe (B), MTL (C), hippocampus (D) and PHG (E). F. Scatter plots representing age-related distribution of CBF values in the hippocampus. In all scatter plots, individual data points for males and females are indicated by blue asterisk symbols and red circles, respectively, while the corresponding MARS fitting curves and 95% confidence interval for expected value at each age point are presented as continuous lines and dashed lines in matching colors. Abbreviation: MTL, medial temporal lobe; PHG, parahippocampal gyrus.

Figure 3.. Age and Sex-based Variations in kw, ATT, and CBF.

(A) kw maps, (B) CBF maps, and (C) ATT maps, average across three age groups: 8–35 years (Males: n=31, average age 23.0 years; Females: n=26, average age 22.7 years), 36–63 years (Males: n=28, average age 46.8 years; Females: n=28, average age 51.3 years), and 62–92 years (Males: n=30, average age 72.7 years; Females: n=43, average age 72.8 years). These maps are superimposed on T1w anatomical images. Corresponding average kw, CBF, and ATT values are provided beneath each map. Across the spectrum, kw values remained relatively consistent between males and females, though a marked reduction in kw can be observed in males aged 62–92 years. Patterns in the maps suggest an age-related a crease in CBF and increase in ATT, while males generally had lower CBF and longer ATT values compared to females.

Figure 4:. 3D renderings of T maps depicting age-related differences.

Highlighted areas indicate significant age-related decrease in kw (A), decreased CBF (B), and increased ATT (C). The most pronounced decrease in kw was observed in the lateral and medial prefrontal cortices, ACC, PCC, temporal lobe, parietal lobe, occipital lobe and insula. A broad range of brain regions exhibits both CBF reduction and ATT increase. The color scale represents T values, and clusters consisting of over 501 voxels with an absolute T value greater than 1.97 are considered significant and displayed in the figure. The limited slice coverage of DP-pCASL (96 mm) may account for the absence of detected effects in the upper and lower regions of the brain. The effects of decrease or increase were represented by warm colors (yellow to red) and cold (gray to blue) colors, respectively.

Figure 5.. 3D renderings of T maps illustrating the interaction effects of age with sex.

Highlighted areas indicate: A. Accelerated decrease in kw with aging in males compared to females, most evident in the lateral prefrontal cortex, parietal, and lateral and medial temporal areas. B. Accelerated decrease in CBF with aging in males compared to females, prominently observed in the supramarginal gyrus, hippocampus, and frontal areas. C. Accelerated increase in ATT with aging in males compared to females, with marked changes in supramarginal gyrus, posterior temporal lobe and calcarine sulcus. The distinct interaction patterns between age and sex across kw, CBF, and ATT can be observed. The color scale denotes T values. Clusters comprising over 501 voxels and possessing an absolute T value exceeding 1.90 are deemed significant and showcased in the figure. The effects of decrease or increase were represented by warm colors (yellow to red) and cold (gray to blue) colors, respectively.