Biological sex alters the association between cerebral pulsatility and hippocampal volume in cognitively unimpaired adults
Authors: Moir M. Erin , Fico Brandon G. , Loggie Nicole A. , Gaynor-Metzinger Sarean H.A. , Norby Alexander M. , Howery Anna J. , Rivera-Rivera Leonardo A. 
Published: May 2024

Cerebrovascular dysregulation with age contributes to cognitive decline. Age-related changes in intracranial blood flow and cerebral pulsatility are linked with adverse structural changes including white matter hyperintensities. The hippocampus represents a key area for cognition and demonstrates rapid deterioration in the early stages of Alzheimer’s disease. Yet the impact of intracranial blood flow and cerebral pulsatility on hippocampal deterioration in cognitively unimpaired adults remains unclear. Importantly, age-related changes in intracranial blood flow and cerebral pulsatility differ by sex. Therefore, this study tested the hypothesis that intracranial blood flow is positively associated with hippocampal volume, while cerebral pulsatility is negatively associated with hippocampal volume and that the associations would differ by sex. Cognitively unimpaired adults (388 total, 263 females, 64 ± 8 years of age) completed 3T magnetic resonance imaging (MRI). Hippocampal volume (mm3) was normalized to intracranial volume and evaluated from T1-weighted images. Intracranial blood flow (mL/min) and cerebral pulsatility (maximum flow − minimum flow/mean flow; a.u.) were evaluated in the internal carotid arteries (ICA), middle cerebral arteries (MCA), and basilar artery from 4D flow MRI. All data are reported for the left side of the brain. Age was negatively associated with hippocampal volume and similar relationships were observed in males (β = -16 ± 3, P < 0.01) and females (β = -17 ± 2, P < 0.01). As such, age was included as a covariate in all models. Blood flow in the ICA, MCA, and basilar artery was not associated with hippocampal volume (all P > 0.37) and there were no flow-by-sex interactions (all P > 0.19). In contrast, cerebral pulsatility was negatively associated with hippocampal volume in a sex and vessel specific manner. ICA pulsatility was associated with hippocampal volume (P = 0.03, β = -183 ± 83) and the relationship did not differ by sex (pulsatility-by-sex interaction: P = 0.19). Basilar artery pulsatility was associated with hippocampal volume in a sex-specific manner (pulsatility-by-sex interaction: P < 0.01) such that there was an association in females (β = -346 ± 63, P < 0.01) but not males (β = 60 ± 92, P = 0.51). A sex-specific relationship (pulsatility-by-sex interaction: P < 0.01) was also observed between MCA pulsatility and hippocampal volume (females: β = -180 ± 54, P < 0.01; males: β = 1 ± 136, P = 0.99). Therefore, elevated cerebral pulsatility is linked with hippocampal deterioration in a sex and vessel specific manner. These findings may provide insights into sex differences in cognitive decline with age and the development of Alzheimer’s disease. This research was funded by NIH grants (R03 AG070469-01 and R03 AG070469-S1; JNB), a Virginia Horne Henry Research Grant (JNB), and a Wisconsin Alzheimer's Disease Research Center Grant (P30-AG062715). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.