Super-resolution ultrasound imaging of cerebrovascular impairment in a mouse model of Alzheimer’s disease

Increasing evidence has suggested a link between cerebrovascular disease and the cognitive impairment of patients with Alzheimer’s disease. However, cerebrovascular disease and Alzheimer’s disease share several risk factors making it unclear whether cerebrovascular deficiency and Alzheimer’s disease pathology have additive effects on cognition or if cerebrovascular impairment merely exacerbates existing Alzheimer’s disease-associated cognitive decline. Additionally, early-stage Alzheimer’s disease typically involves hippocampal atrophy, complicating most efforts to elucidate the interplay between cerebral microvascular function and Alzheimer’s disease progression due to the necessity of probing deep-brain structures. The purpose of this study was to demonstrate the use of ultrasound localization microscopy on the 5xFAD mouse model of Alzheimer’s disease (3-month and 6-month-old cohorts) in comparison to age-matched wild-type controls, revealing microvascular scale reconstructions throughout the whole brain depth, to visualize and quantify Alzheimer’s disease-associated vascular impairments. We found that functional decreases in hippocampal and entorhinal flow velocity preceded structural derangements in regional vascular density. In addition to providing global vascular quantifications of deep brain structures with a high local resolution, this technology also permitted hierarchical analysis of individual vessels and, in some cases, potentially allowed for decoupling of arteriole and venous flow contributions. Co-registered histological sectioning confirmed the regionalized hypo-perfusion deficits seen on ultrasound imaging, which were co-localized with amyloid beta plaque deposition. Significance statement The study of the impact of cerebrovascular disease on Alzheimer’s disease pathology is complicated by the need to image deep-brain structures with high vascular fidelity. We demonstrate that ultrasound localization microscopy, a super-resolution acoustic imaging technique, is capable of imaging cerebrovasculature throughout the entire depth of the brain at a microvascular scale. This technology was applied to the 5xFAD mouse model of Alzheimer’s disease, where it was found that 5xFAD animals have significant impairments in vascular function in the entorhinal cortex and hippocampal region in comparison to age matched controls at the 3-month timepoint. Structural derangements in cerebrovasculature were only observed in the 6-month-old animal cohorts, with a maintained impairment in vascular function.