Project Summary
Although biomedical science has made remarkable progress in extending the human lifespan,
this lengthening of life has not necessarily been matched by longevity in cognition. Older
individuals are at significantly higher risk for developing Alzheimer Disease (AD). Thus, the rising
numbers of older individuals, coupled with aging-related risk for AD, is rapidly becoming a public
health crisis. It is therefore important that we understand the mechanisms underlying declining
cognitive function in AD. Although many mechanisms underlying cognitive decline in AD have
been proposed, two universal findings motivate the current work: 1) vascular risk factors are a
strong predictor of AD and 2) histopathological studies have shown profound alterations in the
microvasculature of the AD brain. Although these studies point to vascular compromise as a
potential contributory agent of AD-associated cognitive decline, there are currently no techniques
available that permit a detailed assessment of the cerebral microvasculature of deep and
superficial blood vessels in a living animal. Thus, it has not been possible to track vascular
changes over time or to determine the impact of therapeutic interventions on the
cerebral microvasculature. To this end, our team has been developing a novel form of super-
resolution vascular imaging known as ultrasound localization microscopy (ULM). ULM can image
micron-size blood vessels many millimeters deep into the brain, and can capture dynamics of
blood flow (speed, flow uniformity and direction) which are not available using histological studies.
Here, we propose to use ULM to investigate AD-related changes in blood flow dynamics and will
relate them to AD-related changes in behavior in a mouse model of AD. In addition, we will
determine if an intervention known to mitigate AD-related cognitive changes – aerobic exercise
– restores regional cerebral microvasculature dynamics in AD model animals. Successful
completion of this work will not only unveil previously poorly understood changes in microvascular
dynamics with AD, but will also advance a novel imaging technique with broad potential
applications to understand many other disorders of the brain.