Small vessel disease (SVD) causes 25% of all cerebral strokes and is a major cause of cognitive decline (dementia) and functional disability (ageing) in the elderly. Two important challenges hamper the development of effective treatments. First, still little is known about the mechanism by which SVD leads to macroscopic, ischemic brain damage and, thus, to cognitive decline. Second, the current clinical markers and image-based markers of SVD do not reflect SVD itself, but macroscopic brain damage secondary to SVD. Unlike large vessels, small vessels are not visible with current imaging techniques, which leave, thus, a ‘terra incognita’ of small vessel pathology between large vessels on the one hand, and macroscopic brain damage on the other. The aim of this program is to remove the major current obstacle towards developing effective treatments for SVD, by innovative magnetic resonance imaging (MRI) techniques that yield non-invasive markers of small vessel (dys)function in the human brain. I will use two innovative sets of image-based markers to discover the ‘terra incognita’. The first set comprises pulsatile tissue motion, strain and potential pulsations in the capillary flow, recognizing the role of stress and strain in cell function (including endothelial cells and neurons). The second set uses the perivascular fluid as an endogenous marker of the blood-brain-barrier function, which is located in the endothelium of the small vessels. These innovative, image-based markers will open a window towards the mechanism by which SVD leads to brain damage. Further, these markers will enable the selection and monitoring of patients who are eligible for new treatments. I will obtain the required sensitivity and resolution, by exploiting the benefits of high field MRI (7T). I am experienced in cardiac strain imaging, high field brain imaging, and have been successful in multiple translational projects that have introduced new MRI technology into patient studies.