Impact of cerebral anatomical variations on cerebral perfusion, cerebrovascular reactivity, and biomarkers of cognitive decline

PROJECT SUMMARY
Optimal brain health requires effective cerebrovascular function, adequate perfusion, and highly responsive
blood flow regulation. If any of these, or a combination of these, are compromised, there are implications for
brain health. Previous research demonstrated that cerebral hypoperfusion and inadequate cerebrovascular
responses to vasoactive stimuli may precede the onset of cognitive impairment. Indeed, adults with cognitive
impairment, including vascular dementia and Alzheimer’s disease, exhibit inadequate cerebral perfusion. Yet,
the majority of evidence linking hypoperfusion to cognition comes from preclinical models, and there is minimal
research on how chronic cerebral hypoperfusion may impact cerebrovascular control in humans. Accordingly,
there is a critical need for more research on the pathophysiology of cognitive decline in humans. Our preliminary
data indicate that adults with cerebral anatomical variations demonstrate cerebral hypoperfusion and reduced
cerebrovascular reactivity. This finding is important as it presents our investigative team with a group of
individuals with a cerebral anatomical variant that may naturally model a state of chronic cerebral hypoperfusion.
Our overarching hypothesis is that chronic hypoperfusion, resulting from a specific variation in cerebrovascular
architecture, impacts cerebral blood flow regulation which increases the risk of cognitive impairment. Thus, the
objectives of this application are to investigate chronic models of hypoperfusion in humans, examine
compensatory mechanisms to maintain perfusion, and determine the potential impact on cognitive health. For
each aim, we will recruit participants from a unique, risk-enriched cohort of middle-aged and older adults from
the University of Wisconsin-Madison Alzheimer’s Disease Research Center. This cohort has extensive
longitudinal data on medical health, genetics, and cognitive biomarkers. We will use state-of-the-art imaging
modalities to identify differences in cerebrovascular architecture and quantify cerebral blood flow regulation in
the following specific aims: In Specific Aim 1, we will examine the compensatory responses to a model of acute
hypoperfusion and determine the impact of chronic cerebral hypoperfusion observed in adults with specific
cerebral anatomical variations. In Specific Aim 2, we will utilize aerobic exercise to characterize the
cerebrovascular responses to acute hyperperfusion and determine the impact of cerebral anatomical variations.
In Specific Aim 3 we will determine the impact of cerebral anatomical variations on cerebrovascular control and
establish whether adults with cerebral anatomical variations are at a higher risk of cognitive decline. This project
will be the first systematic investigation of cerebrovascular control mechanisms in acute and chronic cerebral
hypoperfusion in humans, and will address the potential implications of long-term hypoperfusion for cognitive
health. Upon completion, we will understand the impact of cerebral anatomical variations on cerebrovascular
health and the risk of Alzheimer’s disease and related dementias.

Grant Number: 4R01NS117746-02
NIH Institute/Center: NIH
Principal Investigator: JILL BARNES