Pathophysiological mechanisms of hypoperfusion in mouse models of Alzheimer?s disease and small vessel disease

Project summary/Abstract Hypoperfusion is broadly reported as an important symptom of Alzheimer’s disease related dementia (ADRD). Severity of cerebral blood flow (CBF) loss correlates with severity of cognitive deficit. However, hypoperfusion is only one of the signs of microvascular dysfunction in ADRD and, in fact, may not be the most sensitive or specific one. For example, in the recent NIH-funded MarkVCID Consortium study to identify the most sensitive biomarkers of vascular contributions to cognitive impairment and dementia (VCID), CBF was not selected as a candidate biomarker kit (despite proposed), whereas an index of vasodilatory function, referred to as cerebrovascular reactivity (CVR), was selected. In AD, despite the widely reported observations that there is hypoperfusion in posterior cingulate cortex and temporoparietal regions, some proposed this to be an indirect effect attributed to metabolic abnormalities via metabolism-vascular coupling. Therefore, to systematically understand the mechanism of hypoperfusion in ADRD, one needs to look beyond perfusion to examine a suite of related vascular and metabolic parameters in the brain. Therefore, the central goal of this application is to conduct a multi-parametric study to fully characterize the relationship between hypoperfusion and related vascular and metabolic underpinnings, separately in AD and small vessel disease (SVD) mice, as they represent two leading causes of dementia and most prominently linked to hypoperfusion. The proposed study in mouse models will parallel our ongoing efforts in human participants, making this work having a strong translational relevance. Using novel MRI techniques, we will measure CBF, cerebrovascular reactivity, oxygen extraction fraction, cerebral metabolic rate of oxygen, and BBB permeability concomitantly, and compare them to behavior (e.g. novel object recognition) and histology (e.g. smooth muscle cell density, tight-junction protein density) results (Aim 1). These multiple parameters will be integrated into a mechanistic model, which is fully testable based on the experimental measures proposed. The PI, an early stage investigator, is uniquely positioned to carry out this work because he has pioneered several of these MRI techniques in mice over the past few years. The non-invasive nature of these techniques (e.g. does not require skull thinning or contrast agents) also make them ideally suited for longitudinal studies (Aim 2), which will allow the characterization of the temporal relationship between hypoperfusion (and related vascular/metabolic parameters) and behavior outcomes. Two novel mouse models of Tau4RΔK-AP (replicating tauopathy and amyloidosis of AD) and CADASIL (replicating vascular pathology of SVD) will be utilized, based on the recent discovery of our collaborators. Taking together, we are in a unique position to make meaning contributions to the understanding of hypoperfusion in ADRD.