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

Matthew R Lowerison,Nathiya Vaithiyalingam Chandra Sekaran,Wei Zhang,Daniel A Llano,Xi Chen,Zhijie Dong,Pengfei Song

doi:10.1038/s41598-021-04712-8

Matthew R Lowerison, Nathiya Vaithiyalingam Chandra Sekaran + Show 5 more

Open Access

https://doi.org/10.1038/s41598-021-04712-8

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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.

Highlights

Aging-related cognitive decline is an emerging health crisis; no established unifying mechanism has been identified for the cognitive impairments seen in an aging population
Aging-related cognitive decline remains a controversial area of research, with no established unifying mechanism identified for the cognitive and memory impairments seen in an aging population
The vascular hypothesis of cognitive decline remains difficult to test within a clinical context, given the requirement of high-fidelity microvascular imaging resolution in conjunction with a broad and deep brain imaging field of view – an undertaking that is fundamentally limited by the inherent trade-off of imaging penetration depth and resolution

Summary

Introduction

Aging-related cognitive decline is an emerging health crisis; no established unifying mechanism has been identified for the cognitive impairments seen in an aging population. Two of the most commonly observed pathological findings in the aged brain, both in human and in animal models, is decreased microvascular density and increased vessel tortuosity[6,7,8,9,10,11,12] These findings imply that there is a relationship between compromised cerebral blood flow and cognitive impairment, where there are paralleled deteriorations in both small vessel function and cognitive ability. The vascular hypothesis of cognitive decline remains difficult to test within a clinical context, given the requirement of high-fidelity microvascular imaging resolution in conjunction with a broad and deep brain imaging field of view – an undertaking that is fundamentally limited by the inherent trade-off of imaging penetration depth and resolution. ULM retains the non-invasiveness and safety profile of conventional contrast-enhanced ultrasound imaging

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