Biological sex and vessel specific relationships between cerebral pulsatility and white matter hyperintensities: a 4D flow MRI study

Background Brain vascular dysfunction is a contributing factor to the increased risk of Alzheimer’s disease with advancing age. Cerebral pulsatility represents a marker of vascular function that quantifies fluctuations in blood flow within each cardiac cycle in the cerebral arteries. Increases in cerebral pulsatility may contribute to structural damage in the brain such as white matter hyperintensities (WMH). Additionally, biological sex differences are apparent in brain vascular function and Alzheimer’s disease risk. As such, this research aimed to determine associations between cerebral pulsatility and WMH and evaluate the influence of sex. This research tested the hypothesis that elevated cerebral pulsatility is associated with higher WMH, and that the associations are sex‐specific. Method 407 cognitively healthy middle‐aged and older adults (45‐87 years of age; 271 females) completed magnetic resonance imaging (MRI) performed on a 3T MRI scanner. WMH volumes were evaluated from T2 fluid‐attenuated inversion retention (FLAIR) images, while cerebral pulsatility index (PI) was evaluated in multiple intracranial arteries from 4D flow MRI. WMH fraction was calculated as the cubic root of WMH volume relative to intracranial volume. Result PI in the vertebral arteries (VA) and basilar artery was positively associated with WMH fraction in females only (all female P≤0.01, all male P≥0.20). In contrast, PI in the internal carotid arteries (ICA) and middle cerebral arteries (MCA) was positively associated with WMH fraction in both sexes (all P≤0.01). However, the relationship between WMH fraction and PI in the MCA differed by sex such that the slope of the relationship was stronger in males than females (all P≤0.03). For example, higher right MCA PI was associated with greater WMH fraction in males (β = 0.39±0.09 a.u., R2 = 0.13) compared with females (β = 0.18±0.05 a.u., R2 = 0.05). Conclusion These data suggest that, among cognitively healthy middle‐aged and older adults, elevated cerebral pulsatility is linked to greater WMH. However, the associations are sex‐ and vessel‐specific which may contribute to sex‐specific trajectories in Alzheimer’s disease with advancing age. The present results support the idea that elevated cerebral pulsatility contributes to structural alterations in the brain and thus reducing cerebral pulsatility may represent a promising target for mitigating cognitive decline.