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bioRxiv · 10.64898/2025.12.03.691980

Region-specific associations between cerebral arterial elasticity and grey matter volume: Evidence for lateral prefrontal vulnerability

Ware, N.·Johnson, J.·Fabiani, M.·Johnson, S.·Michie, P. T.·Low, K.·Behler, C.·Paton, B.·Barker, D.·Gratton, G.·Smith, A. E.·Karayanidis, F.
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Abstract

BackgroundAgeing is associated with increased cardiovascular health risks and disproportionate atrophy in frontotemporal brain. Regional cerebral arterial elasticity correlates with regional grey matter volume, with stronger associations frontally and in older adults. Cardiorespiratory fitness (CRF) is linked to preserved brain structure and greater arterial elasticity, while sex differences exist in the timing of vascular versus structural changes. This study examines whether regional cerebral arterial elasticity in frontotemporal cortex mediates the association between age and corresponding grey matter volume decline, and whether sex and/or CRF moderate this relationship. MethodsWe analysed data from 162 healthy adults (60-70 years) with structural MRI and diffuse optical tomography of the cerebral arterial pulse (Pulse-DOT) from the ACTIVate cohort. CRF was estimated from demographic and physiological measures. Pulse Relaxation Function (PReFx), an optical index of regional arterial elasticity, was measured across 28 frontal, temporal, and parietal regions of interest (ROI). Grey matter (GM) volume was quantified for corresponding ROIs. Mediation and moderated mediation models tested whether PReFx mediated the relationship between age and GM volume at bilateral frontal and temporal ROIs, and whether biological sex or CRF moderated this relationship. ResultsRegional bivariate correlations identified associations between age, PReFx and GM volume across multiple ROIs, which PReFx and GM volume being associated primarily in left frontal and temporal areas. PReFx partially mediated the effect of age on GM volume in a left mid-inferior frontal ROI, accounting for approximately 16% of the total age effect and this relationship was only evident in females. Although higher CRF was associated with greater PReFx, it did not moderate the relationship between age, PReFx and GM volume. ConclusionsConsistent with cascade models of neurovascular aging, cerebral arterial stiffening was found to partially explain the effect of increasing age on frontal GM volume, even in this highly age-restricted and high functioning cohort. This effect was only significant over the left prefrontal cortex, consistent with greater vulnerability of frontal brain and associated cognitive functions. It was also exclusively present in females, who had better cardiovascular health, larger grey matter volume and greater arterial elasticity than males. These findings are consistent with pulse-DOT measures of cerebral arterial elasticity being more sensitive to subclinical brain structural variability.

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Ware, N., Johnson, J., Fabiani, M., Johnson, S., Michie, P. T., Low, K., Behler, C., Paton, B., Barker, D., Gratton, G., Smith, A. E., Karayanidis, F.. 2025-12-08. Region-specific associations between cerebral arterial elasticity and grey matter volume: Evidence for lateral prefrontal vulnerability. https://doi.org/10.64898/2025.12.03.691980

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