Project Summary The rich multi-contrast capabilities of MRI enable the detection of a broad spectrum of tissue alterations due to cerebrovascular disease, brain injury, and other insults that significantly impact brain and cognitive health. As new noninvasive imaging technologies are developed to explore causal mechanisms of small vessel disease and blood-brain barrier integrity, there is a need for postmortem validation studies to confirm the pathological basis of early imaging biomarkers driving vascular contributions to cognitive impairment and dementia. Our current understanding of the pathophysiology of post-traumatic neurodegeneration and Alzheimer’s disease comes from 2D neuropathology and histology in which slices are cut, stained, and examined under a microscope. While these techniques yield stunning images with beautiful specificity, they lose the 3D architectural context that is critical for understanding how neuropathological changes alter connectivity and mesoscopic anatomy in the living human brain. The overall goal of this project is to build a pipeline of customized MRI acquisitions and software algorithms designed to provide a mechanistic link between neuropathology and ex vivo MRI, and from there to in vivo human brain mapping atlases. Our project will result in a well-maintained, documented, and distributed set of tools and MRI sequences that sites can download and use to map information between neuropathology and MRI. Furthermore, we will have access to precious brain donations from subjects who had high-quality in vivo multi-modal MRI, enabling us to extend the pipeline to map neuropathological findings of cerebrovascular disease and traumatic brain injury back to imaging data acquired in living subjects. By precisely mapping histopathology to ex vivo MRI and to in vivo MRI, we will develop and discover in vivo MRI biomarkers that can currently only be identified ex vivo.