Longitudinal sex differences in cerebrovascular ageing in older adults: results from the brain in motion study

Older females are at an increased risk of dementia, cardiovascular disease and stroke. However sex differences in cardiovascular and cerebrovascular ageing remain poorly understood. We examined longitudinal changes in vascular function in 82 adults (mean age: 65.4 ± 5.1 years; range: 55-75; 39 females) at two timepoints (T1 and T2) 6.1 ± 1.4 years apart. We measured middle cerebral artery velocity (MCAv) and pulsatility (PI) using transcranial Doppler ultrasound, mean arterial blood pressure (MAP) with finger photoplethysmography and cerebrovascular conductance and resistance (CVCi, CVRi) at rest, with euoxic hypercapnia, and during submaximal exercise. At T1, males had higher resting PI but lower MCAv and CVCi compared to females. By T2, these sex differences were no longer evident, except for PI. Females experienced a greater increase in resting MAP and a decline in CVCi than males between T1 and T2. No sex-time interactions were observed for MCAv or PI. In females testosterone and log-transformed oestradiol were positively associated with MCAv at T1 and with the change in MCAv reactivity from T1 to T2, respectively. In males changes in oestradiol were positively associated with changes in cerebrovascular outcomes from baseline to follow-up. The faster rate of cerebrovascular ageing in females over the follow-up period may contribute to shifting sex differences in cerebrovascular function and their increased risk for dementia, cardiovascular disease and stroke. Sex hormones and menopause may play a key role in these sex-specific ageing trajectories, highlighting the need for sex-specific research to better understand cerebrovascular ageing. KEY POINTS: At baseline, females exhibited higher middle cerebral artery velocity and cerebrovascular conductance than males. By the follow-up, these differences were no longer present. Females experienced greater increases in mean arterial blood pressure and declines in cerebrovascular conductance than males. Higher baseline oestradiol in females was linked to more favourable changes in middle cerebral artery reactivity over time. Testosterone in females was associated with a greater middle cerebral artery velocity at baseline. In males, the change in oestradiol was positively associated with the change in cerebrovascular outcomes from baseline to follow-up. Baseline data had limited ability to predict vascular function at follow-up. Sex did not modify cerebrovascular ageing at the follow-up, suggesting sex- and age-dependent cerebrovascular ageing trajectories. Accelerated cerebrovascular ageing in older females may help explain their increased risk for disease. Sex-specific research is needed to elucidate the mechanistic links between menopause, sex-hormones and vascular ageing.