Vertebral Artery Hypoplasia Impacts Associations Between Cerebral Pulsatility and Biomarkers of Neurodegeneration in Cognitively Unimpaired Adults

Vertebral artery hypoplasia (VAH) is a common congenital anatomical variation characterized by a narrow vertebral artery (VA) and reduced VA blood flow. This may contribute to augmented age-related reductions in global cerebral blood flow (CBF) leading to hypoperfusion. Indeed, we have previously shown that older adults with VAH demonstrate reduced global CBF compared to young adults with VAH while no differences were observed between older and young controls. Also, we have shown that adults with VAH demonstrate elevated cerebral pulsatility in the basilar artery (BA) compared with controls. However, the extent to which altered hemodynamics in adults with VAH impacts biomarkers of neurodegeneration remains unknown. This research aimed to evaluate the impact of VAH on brain structural markers, and associations between cerebral hemodynamics and brain structural markers, in cognitively unimpaired older adults. We tested the hypothesis that older adults with VAH would demonstrate stronger associations between cerebral pulsatility and biomarkers of neurodegeneration. We retrospectively studied 226 cognitively unimpaired older adults (64-91 years of age, 157 females) who completed 3T magnetic resonance imaging (MRI). Intracranial volume (ICV) was evaluated from T1-weighted images. White matter hyperintensity (WMH) volume and hippocampal volume were determined from T2 fluid-attenuated inversion recovery (FLAIR) images and T1-weighted images, respectively, and normalized to ICV. Intracranial blood flow was evaluated in the left and right internal carotid artery (ICA), left and right VA, and BA using 4D flow MRI, and cerebral pulsatility index (PI) was calculated as max flow–min flow/mean flow. VAH status was determined from measures of VA diameter and blood flow (VAH+: diameter < 2.5 mm and blood flow < 47 mL/min). In cognitively unimpaired adults, WMH fraction did not differ between VAH+ (0.38 ± 0.20) and controls (0.38 ± 0.19; P = 0.94). Left hippocampal volume did not differ between VAH+ (2658 ± 363 mm 3 ) and controls (2691 ± 315 mm 3 , P = 0.32) nor did right hippocampal volume ( P = 0.43). Despite no difference in hippocampal volume, VAH+ adults demonstrated stronger inverse associations between BA PI and left hippocampal volume (β = -434 ± 135 mm 3 ) compared with controls (β = -109 ± 96 mm 3 , P = 0.04). Similar results were observed with associations between bilateral ICA PI and right VA PI and left hippocampal volume, and also with right ICA PI, right VA PI, and BA PI and right hippocampal volume (all P < 0.05). In contrast, the association between BA PI and WMH fraction did not differ between VAH+ (β = 0.10 ± 0.09) and controls (β = 0.09 ± 0.08; P = 0.93). Similar results were observed with associations between bilateral ICA and VA PI and WMH fraction (all P > 0.24). Therefore, cognitively unimpaired older adults with VAH are more sensitive to elevations in PI with advancing age, such that elevated PI is linked to greater deleterious effects on hippocampal volume compared with controls. These data suggest that VAH may increase the risk of cognitive decline and the development of Alzheimer’s disease and related dementias with advancing age. This research was supported by funding from the NIH (R03 AG070469-01 and R03 AG070469-S1 to JNB; P30-AG062715 to Wisconsin ADRC; T32HL007936 to UW-Madison CVRC-SHAGM). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.