Non-invasive volumetric ultrasound localization microscopy detects vascular changes in mice with Alzheimer's disease

Alzheimer's Disease (AD) is the most common form of dementia and one of the leading causes of death. AD is known to be correlated to tortuosity in the microvasculature as well as decreases in blood flow throughout the brain. However, the mechanisms behind these changes and their causal relation to AD are poorly understood. Methods: Here, we use volumetric ultrasound localization microscopy (ULM) to non-invasively and quantitatively compare the microvascular morphology and flow dynamics of five wildtype (WT) and five APP^NL-G-F Knock-in mice, a mouse model of AD, across a 1cmx1cmx1cm brain volume and in four specific brain regions: the hippocampal formation, thalamus, hypothalamus, and cerebral cortex. Results: Comparisons between groups showed a significant increase in tortuosity, as measured by the Sum of Angles Metric (SOAM), throughout the brain (p < 0.01) and the hypothalamus (p = 0.01), in mice with AD. While differences in mean velocity (p < 0.01) and blood flow (p=0.04) were detected across the whole brain, their effect size was small and no differences were detected in the four selected regions. There was a significant decrease in the linear log relationship between vessel diameter and blood flow, with AD mice experiencing a lower slope than WT mice across the whole brain volume (p = 0.02) and in the hippocampal formation (p = 0.05), a region affected by Amyloid Beta plaques in this mouse model. The AD mice had higher blood flows in smaller vessels and smaller blood flows in larger vessels than the WT mice. Conclusions: This preliminary demonstrates that the imaging technique can be used for non-invasive, longitudinal, volumetric assessment of AD, which may allow for investigation into the poorly understood microvascular degeneration associated with AD through time as well as the development of early diagnostic techniques.