Blood-brain barrier integrity is linked to cognitive function, but not to cerebral arterial pulsatility, among elderly

Abstract

Blood-brain barrier (BBB) disruption may contribute to cognitive decline, but questions remain whether this association is more pronounced for certain brain regions, such as the hippocampus, or represents a whole-brain mechanism. Further, whether human BBB leakage is triggered by excessive vascular pulsatility, as suggested by animal studies, remains unknown. In a prospective cohort (N = 50; 68-84 years), we used contrast-enhanced MRI to estimate the permeability-surface area product (PS) and fractional plasma volume ( $v_p$ ), and 4D flow MRI to assess cerebral arterial pulsatility. Cognition was assessed by the Montreal Cognitive Assessment (MoCA) score. We hypothesized that high PS would be associated with high arterial pulsatility, and that links to cognition would be specific to hippocampal PS. For 15 brain regions, PS ranged from 0.38 to 0.85 (·10^-3 min^-1) and $v_p$ from 0.79 to 1.78%. Cognition was related to PS (·10^-3 min^-1) in hippocampus (β = - 2.9; p = 0.006), basal ganglia (β = - 2.3; p = 0.04), white matter (β = - 2.6; p = 0.04), whole-brain (β = - 2.7; p = 0.04) and borderline-related for cortex (β = - 2.7; p = 0.076). Pulsatility was unrelated to PS for all regions (p > 0.19). Our findings suggest PS-cognition links mainly reflect a whole-brain phenomenon with only slightly more pronounced links for the hippocampus, and provide no evidence of excessive pulsatility as a trigger of BBB disruption.

Figure 1

T1 maps (seconds) at baseline, the permeability-surface area product (PS; min⁻¹), and fractional plasma volume ($v_p$) for an example participant. The T1 maps were obtained using the variable flip angle method, and PS and $v_p$ were obtained using Patlak analysis. Note that while the images are thresholded according to the color bars to aid visualization, no thresholding or exclusion based on extreme values was used for any of the results.

Figure 2

4D flow MRI complex difference (CD) maximum intensity projections and centerlines (CLs) used to assess distal arterial (red) and internal carotid artery (ICA; blue) pulsatility. The waveforms represent group-averaged ICA and distal flows after interpolation and normalization (division by the means). The schematic shows how the CD, CLs, and velocities (${\text{V}}_x$, ${\text{V}}_y$, ${\text{V}}_{\text{z}}$) were used for automatic distal arterial waveform extraction and manual seed-point based waveform extraction in ICA and middle/posterior cerebral arteries (MCA/PCA).

Figure 3

Group-averaged gadolinium (Gd; Dotarem) concentration [mM] for cortical (Ctx), white matter (WM) and subcortical structures. The concentration curves were averaged across the entire region within each subject to obtain individual concentration estimates, and then group-averaged for visualization. The vascular input function (VIF) concentration is normalized to the region-average tissue concentration peak to facilitate visualization together with the tissue concentration curves. The swarm charts represent individual (N = 50) permeability-surface area product (PS) estimates where black lines correspond to the mean value.

Figure 4

Permeability-surface area product (PS; 10⁻³ min⁻¹) in relation to the Montreal cognitive assessment (MoCA) score for cortex and white matter (WM) lobes, average over frontal, parietal, temporal, occipital and cingulate regions, for basal ganglia (BG), averaged over caudate, putamen and pallidum, and for hippocampus and whole-brain, averaged over all 15 regions. The adj. was adjusted for age and sex by residualization. The β coefficients indicate change in MoCA score per 1.0 × 10⁻³ min⁻¹ change in PS.