Abstract Current clinical criteria for treatment of atherosclerotic plaque, or atheromas, have focused primarily on percent stenosis of the vessel. However, measures of occlusion (percent stenosis) do not identify those plaques that are prone to rupture, which may release emboli into the blood stream feeding sensitive cerebral vasculature. A novel approach, Lagrangian carotid strain imaging, where tissue displacements are precisely measured during pulsation of blood through the artery has been developed. We propose to measure `strain indices,' that include the maximum accumulated axial, lateral, and shear strain estimated over the cardiac cycle, to probe the detailed mechanical properties of early plaque. We believe these strain indices will prove to be valuable vascular biomarkers to indicate vascular aging and possible plaque vulnerability. Our preliminary results demonstrate the ability to differentiate between soft and stiff regions in plaque under in-vivo clinical imaging conditions. Our definition of `vulnerable plaque' or `vulnerable patient' relies on the identification of lipidic depositions or softer plaques, i.e., those that undergo large axial or lateral deformations and/or large shearing strains during the cardiac cycle. Capability of strain tensor imaging and vascular biomarkers to characterize plaque severity from its early stages to a mature plaque lesion will be evaluated and quantified. A study on asymptomatic volunteers and patients also is proposed. The volunteer will provide values for vascular strain indices normalized to age-related vascular stiffening. The results will enable us to establish trends in age-related variations in vascular stiffness and to determine deviations that could establish vascular aging criteria. Interventions to reverse vascular aging might then be used, for example lifestyle modifications and common medical therapies. Strain imaging results will be validated and complimented by three- dimensional (3D) carotid magnetic resonance imaging (MRI) on a selected group of high-risk volunteers, along with 3D carotid MRI and 3D histopathological analysis of the entire excised plaque on patients to better understand plaque composition and structure. Validation of our results will foster use of real-time noninvasive ultrasound strain imaging as a screening tool for identifying human subjects susceptible to vascular aging and/or developing plaque prone to rupture or micro-embolization that could lead to `silent strokes' and possible vascular cognitive impairment. The patient study will also enable comparison of strain indices and carotid MRI to the ground truth, namely the excised plaque.