Functional ultrasound as a quantitative approach for measuring functional hyperemia in aging models

Backgrounds and Objectives: Aging is associated with impaired cerebrovascular function, including reduced functional hyperemia (FH), which contributes to cognitive decline and dementia. Unraveling the mechanisms responsible for FH decline during aging is crucial for developing interventions to promote healthy brain aging and mitigate cognitive impairment. Currently, laser speckle contrast imaging (LSCI) serves as the standard method for assessing FH in mouse models of cognitive dysfunction and aging. However, as a terminal procedure, long-term monitoring of changes in FH using LSCI is not possible. Functional ultrasound imaging (fUS) has improved spatial and temporal resolution compared to LSCI and is a promising alternative, but surgical manipulation of the mouse model is necessary to assess FH using fUS. Research Design and Methods: Here, we validated fUS as a novel method for assessing FH and vascular density in mice using a chronological aging model and compared different surgical paradigms. Young and aged mice underwent consecutive imaging with fUS and LSCI following surgical placement of a cranial window. Mice were imaged either acutely or 14 days post window placement. Results: Our findings revealed a robust correlation between the FH measurements obtained from fUS and LSCI in mice allowed to recover for 14 days post window-implantation, underscoring the reliability of fUS as a measurement tool. Similarly, the ability of fUS ultrasound localization microscopy (ULM) to detect age-related vascular rarefaction was improved by the 14-day recovery time after window implantation. Discussion and Implications: This study not only highlights the potential of fUS in FH assessment but also suggests the importance of recovery time post-surgery for optimal cerebrovascular imaging results.