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 contradictory radiologic needs of high-fidelity microvascular imaging resolution and a broad and deep brain imaging field of view. 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 cortex. These data provide the first-ever measurements of subcortical microvascular dynamics in vivo and reveal that aging has a major impact on these measurements.

Large scale in vivo acquisition, segmentation, and 3D reconstruction of cortical vasculature using open-source functional ultrasound imaging platform

“…Several strategies are now allowing for longitudinal monitoring of the brain functions of the same animal which in this context would be of high interest when considering pathologies as the brain vasculature and the associated functions have been shown affected (e.g., angiogenesis, vascular rarefaction, hypertension) in various diseases including Alzheimer’s (Meyer et al, 2008; Gutierrez et al, 2016; Zhang et al, 2019; Lowerison et al, 2021; Szu and Obenaus, 2021) and Parkinson’s diseases (Yang et al, 2015; Al-Bachari et al, 2020; Biju et al, 2020), tumors (Gambarota et al, 2008; Guyon et al, 2021), obesity (Dorrance et al, 2014; Pétrault et al, 2019; Gruber et al, 2021) currently addressed at the brain-wide scale with either technology offering reduced spatiotemporal resolution (Pathak et al, 2011; Lin et al, 2013) or post-mortem strategies (Hlushchuk et al, 2020; Todorov et al, 2020; Bumgarner and Nelson, 2022). In the stroke context, the cortex-wide skeletonization of vessels could also be used as a follow-up strategy for detecting i) progressive and long-lasting neovascularization of the infarcted tissue (Ergul et al, 2012; Liman and Endres, 2012), and ii) stroke-induced of reverse flow (Li et al, 2010; Ergul et al, 2012) both of crucial interest when considering tissue survival and functional recovery of the insulted tissue.…”

Curvelet Transform-based Sparsity Promoting Algorithm for Fast Ultrasound Localization Microscopy

“…The mouse brain dataset used to test CTSP was obtained from a previous study [45], where the details of the animal procedure were provided. All the experiments were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Illinois Urbana-Champaign.…”

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 conventional ultrasound spatial resolution by approximately 10-fold and showed promising results in various tissues including the 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].…”