Biological sex influences relationships between cerebral pulsatility and white matter hyperintensities in aging adults

Arterial stiffening with age, which is associated with elevated cerebral pulsatility in the intracranial arteries, is linked to structural alterations in the brain, including white matter hyperintensities (WMH). Biological sex differences exist in cerebral hemodynamics and Alzheimer's disease (AD) risk; yet, little is known regarding the impact of biological sex on the association between cerebral pulsatility and WMH. We studied 403 cognitively unimpaired middle-aged and older adults (45-91 yr, 272 females) who completed 3 T magnetic resonance imaging (MRI). Four-dimensional (4D) flow MRI provided measures of cerebral pulsatility index (PI) in multiple intracranial arteries. T2 fluid-attenuated inversion recovery images were analyzed for WMH volumes. In middle-aged adults, PI in the internal carotid arteries (ICA) and the right middle cerebral artery (MCA) was positively associated with WMH in females (all P < 0.01) but not in males (all P > 0.25). In older adults, PI in the left ICA and the MCAs was positively associated with WMH in males and females (all P <= 0.02). Also, in older adults, basilar artery PI was positively associated with WMH in females (P = 0.006) but not males (P = 0.31). These data suggest that, among cognitively unimpaired adults, elevated cerebral PI is linked to greater WMH; however, these relationships are influenced by sex and age such that female-specific relationships emerge in the anterior circulation in middle age, and in the posterior circulation in older adults. These findings may provide insights to vascular mechanisms contributing to sex differences in AD with advancing age.