Super-resolution ultrasound reveals cerebrovascular impairment in a mouse model of Alzheimer's Disease

Increasing evidence has suggested a link between cerebrovascular disease and the cognitive impairment associated with Alzheimer's Disease. However, detailed descriptions of microvascular changes across brain regions and how they relate to other more traditional pathology have been lacking. Additionally, the efforts to elucidate the interplay between cerebral microvascular function and Alzheimer's Disease progression are complicated by the necessity of probing deep-brain structures since early-stage Alzheimer's Disease typically involves hippocampal pathology. The purpose of this study was to examine changes in microvascular dynamics in a mouse model of Alzheimer's Disease using cohorts that were age-matched to wild-type controls. Data from both sexes were included in this study. Super-resolution ultrasound localization microscopy revealed microvascular functional and structural features throughout the whole brain depth to visualize and quantify. We found that functional decreases in hippocampal and entorhinal flow velocity preceded structural derangements in regional vascular density. Co-registered histological sectioning confirmed the regionalized perfusion deficits seen on ultrasound imaging, which were co-localized with amyloid beta plaque deposition. In addition to providing global vascular quantifications of deep brain structures with a high local resolution, this technology also permitted velocity-profile analysis of individual vessels and, in some cases, allowed for decoupling of arterial and venous flow contributions. These data suggest that microvascular pathology is an early and pervasive feature of Alzheimer's Disease and may represent a novel therapeutic target for this disease. Significance statement Studies of the impact of cerebrovascular pathology on Alzheimer's Disease are complicated by the difficulty of imaging deep-brain structures with high fidelity. We demonstrate that ultrasound localization microscopy, a super-resolution acoustic imaging technique, is capable of imaging cerebrovasculature throughout the entire depth of the mouse 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 hippocampus compared to age matched controls at the 3-month timepoint. Structural derangements in cerebrovasculature were only observed at the 6-month-old timepoint, with a maintained impairment in vascular function. These findings suggest that microvascular pathology occurs early in the Alzheimer's Disease cascade.