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. 2025 Aug;56(8):2177-2189.
doi: 10.1161/STROKEAHA.125.051026. Epub 2025 May 21.

Sex Differences in the Neurovascular Health of Aging Adults

Bethany L Sussman  1 , Hannah E Wiseman  1 , Sudarshan Ranganathan  1   2 , K Austin Davis  3 , Botian Xu  2   4 , Raul Vintimilla  3 , John C Wood  2   4 , Caroline A Rickards  3 , Niema M Pahlevan  5   6 , Kevin S King  7 , Matthew T Borzage  1   4   8 ; HABS-HD Study Team
Collaborators, Affiliations

Sex Differences in the Neurovascular Health of Aging Adults

Bethany L Sussman et al. Stroke. 2025 Aug.

Abstract

Background: Poor cerebrovascular reactivity is associated with a higher risk of cerebrovascular disease. The most common method to study cerebrovascular reactivity in aging adults, transcranial Doppler ultrasound, yields measurements in large intracranial arteries, but not in regional brain parenchyma that may be more impaired in some disease processes. Measurements derived from transcranial Doppler ultrasound suggest that there are sex differences in cerebrovascular reactivity for aging adults. We investigated the association between age and sex on cerebrovascular reactivity using blood oxygen level dependent (BOLD) magnetic resonance imaging in a representative group of aging adults.

Methods: This cross-sectional study investigated BOLD cerebrovascular reactivity to CO2 in a representative group of aging adults, 51 to 83 years old. We manipulated end-tidal carbon dioxide with breathing exercises and evaluated changes in 6 brain regions: whole brain, white matter, cortical gray matter, subcortical gray matter, left hippocampus, and right hippocampus. We used 1 linear regression per region to investigate the effects of age, sex, and their interaction on BOLD cerebrovascular reactivity.

Results: We report an age-by-sex interaction for all brain regions (P≤0.050), except cortical gray matter (P=0.062). For white matter and subcortical gray matter, female participants trended toward an age-related BOLD cerebrovascular reactivity increase (P≤0.058), while male participants did not change with age (P>0.580). In the whole brain and bilateral hippocampi, the age trends for each sex were in opposite directions but not significant (P>0.211). We report a main effect of sex (female greater than male participants) for subcortical gray matter and the right hippocampus (P≤0.048) and no main effect of age in any model.

Conclusions: We present the first report of age-related BOLD cerebrovascular reactivity increases in older female participants and higher BOLD cerebrovascular reactivity in older female compared with male participants. Sex and age-by-sex-based differences seem to be driven by changes in white matter, subcortical gray matter, and bilateral hippocampi.

Keywords: aging; gray matter; magnetic resonance imaging; sex characteristics; stroke; vasodilation; white matter.

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Conflict of interest statement

Dr Davis is funded by an American Heart Association fellowship and receives compensation from the University of North Texas Health Science Campus. Dr Wood reports grants from the National Institute of Neurological Disorders and Stroke, Philips, National Heart, Lung, and Blood Institute, and National Center for Research Resources. Dr Rickards reports compensation from the Cerebrovascular Research Network for other services, travel support from the American Physiological Society, and grants from the American Heart Association. Dr Pahlevan reports grants from the National Institutes of Health—National Institute on Aging. Dr King reports grants from the National Institute on Aging and Rudi Schulte Research Institute; support from Voxel Healthcare. Dr Borzage reports grants from the National Heart, Lung, and Blood Institute, National Institute on Aging, and Rudi Schulte Research Institute; funding from the National Cancer Institute, National Institute on Aging, and National Institute of Diabetes and Digestive and Kidney Diseases; travel support from the Hydrocephalus Association. The other authors report no conflicts.

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