Aging-related cerebral microvascular changes visualized using ultrasound localization microscopy in the living mouse

Abstract

Aging-related cognitive decline is an emerging health crisis; however, no established unifying mechanism has been identified for the cognitive impairments seen in an aging population. A vascular hypothesis of cognitive decline has been proposed but is difficult to test given the requirement of high-fidelity microvascular imaging resolution with a broad and deep brain imaging field of view, which is restricted by the fundamental trade-off of imaging penetration depth and resolution. Super-resolution ultrasound localization microscopy (ULM) offers a potential solution by exploiting circulating microbubbles to achieve a vascular resolution approaching the capillary scale without sacrificing imaging depth. In this report, we apply ULM imaging to a mouse model of aging and quantify differences in cerebral vascularity, blood velocity, and vessel tortuosity across several brain regions. We found significant decreases in blood velocity, and significant increases in vascular tortuosity, across all brain regions in the aged cohort, and significant decreases in blood volume in the cerebral cortex. These data provide the first-ever ULM measurements of subcortical microvascular dynamics in vivo within the context of the aging brain and reveal that aging has a major impact on these measurements.

Intensity distribution segmentation in ultrafast Doppler combined with scanning laser confocal microscopy for assessing vascular changes associated with ageing in murine hippocampi

“…similar to the VVF used in this work). Since in the work of Lowerison et al 46 aged mice had lower blood velocity, without differences in blood volume and vascularity, one can hypothesize that aged mice would have lower CBV values in agreement with our Doppler results. However, this comparison should be taken carefully because experiments in Lowerison et al 46 were conducted at bregma − 3 mm, while ours were conducted at approximately bregma − 1.58 mm.…”

“…ULM has been capable of detecting vessels of 9 m in diameter and resolving between vessels up to 17 m close 27 . Recent work of Lowerison et al 46 used ULM to study microvascular changes with respect to ageing in 7-month-old vs. 27-month-old wild-type mice. In the hippocampus, they found a significant decrease in blood velocity with a significant increase in vascular tortuosity in the aged mice, while no significant differences were found in blood volume and vascularity.…”

“…In the hippocampus, they found a significant decrease in blood velocity with a significant increase in vascular tortuosity in the aged mice, while no significant differences were found in blood volume and vascularity. In Lowerison et al 46 blood volume was estimated using the mean number of microbubbles that entered a particular ROI and brain vascularity was calculated by binarizing the ULM images to determine the percentage of cross-section that was perfused (i.e. similar to the VVF used in this work).…”

Improved Ultrasound Localization Microscopy Based on Microbubble Uncoupling via Transmit Excitation

“…The primary idea of ULM is to localize microbubbles (MBs) flowing in the vascular networks to achieve super-resolution, and then track the localized MBs over time to measure blood flow velocity [ 3 ]. ULM improves the conventional ultrasound spatial resolution by approximately tenfold and it showed promising results in various tissues including brain [ 4 ], kidney [ 5 ], liver [ 6 ], and tumor [ 7 ]. However, practical implementation of ULM is currently limited by its Achilles’ heel—slow temporal resolution, which is largely attributed to the long data acquisition time that is required to capture adequate, spatially separated MB signals for localization and tracking.…”

“…These techniques showed improvement of temporal resolution while providing a spatial resolution that is similar to ULM. However, because of the absence of MB tracking, these methods fall short of providing blood flow velocity measurements, which can be an important biomarker for various applications [ 4 ], [ 10 ], [ 11 ].…”