Characterization and validation of cerebrovascular reactivity (CVR) as a biomarker of vascular dementia in mouse models

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Project summary/Abstract Small-vessel-related vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia in the United States. However, compared to other dementia types (e.g. amyloid and tau imaging in Alzheimer's disease), validated imaging biomarkers for VCID are limited. Recent studies in humans suggested that the brain's vasodilatory capacity, referred to as cerebrovascular reactivity (CVR), is one of the most sensitive indicators of VCID. While human studies are important in demonstrating the utility of CVR in clinical settings, animal models are invaluable for validating and characterizing this new biomarker. With appropriate animal models, one can elucidate the mechanistic link between CVR and classical measures of neuropathologic hallmarks of small vessel disease such as vessel density, vascular smooth muscle cells, and endothelial cells. Additionally, animal models can be designed to have relatively pure mechanism and therefore avoid confounding pathologies, which often occur in human patients of dementia. Therefore, the present exploratory/developmental (R21) study will address the above scientific gap by characterizing and validating CVR as a biomarker of VCID with mouse models. It should be noted that quantitative CVR techniques have not been available in mouse, because of the difficulties in both the measurement of hemodynamic parameters and quantification of vasoactive stimuli in small animals. Therefore, this application will first conduct systematic development of CVR MRI technique in mice, followed by an application of the technique in two mouse models of small vessel disease (SVD). The two models are complementary in that one is a classic genetic model of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) and the other is an environmentally based model of hyper-homocysteinemia (HHcy) mice. This study has two specific aims. Aim 1 is to develop a CVR MRI technique in mice. We will measure hemodynamic responses to vasoactive challenge, the magnitude of which will yield an index of CVR. For the choice of vasoactive challenge, we will use injection of acetazolamide as a vasodilative agent, the plasma concentration of which will be quantified and used as an input function. For imaging readouts, both global and regional CVR methods will be developed using advanced physiological MRI techniques. Dose-dependence of acetazolamide effects will also be studied. Aim 2 is to characterize CVR impairment in a longitudinal study of SVD mouse models. We will compare CVR with several histological measures, including total vessel density stained with collagen IV, vascular smooth muscle cell density stained with Acta 2, and vascular endothelial proteins stained with CD31. Regional CVR studies will focus on subcortical nuclei which are the most susceptible regions in human SVD. We will also study the longitudinal time course of CVR and compare it to that of behavioral scores, brain volume, and WM hyperintensities.