Neuroimaging Core Project Summary Because of their tolerability, versatility, and spatial specificity, neuroimaging biomarkers are a prominent strategy used in AD/ADRD research to detect AD pathology, provide insights into disease mechanism and heterogeneity, track disease progression and, ultimately, monitor the efficacy of disease-modifying interventions. Neuroimaging methods can also noninvasively assess other neuropathophysiological mechanisms such as neurovascular insufficiency and neuroinflammation that are implicated as mechanisms and modulators of AD and therefore likely contribute to the heterogeneity observed in its risk, incidence, and progression. When linked to postmortem measures of proteinopathy burden, imaging measures can shed light on heterogeneity of AD/ADRD, allowing for discovery of in vivo signatures of “pure AD” and concomitant non- AD pathologies. The Penn ADRC Neuroimaging Core will consolidate expertise in advanced neuroimaging methods and applications to support the acquisition and analysis of state-of-the-art multimodal MRI of brain structure and function, molecular brain imaging using PET, retinal angiography using optical coherence tomography (OCTA). The Neuroimaging Core will oversee the acquisition and analysis of standard MRI and PET scans used in defining preclinical AD based on amyloid, tau, and neurodegeneration (“A/T/(N)”) staging and for quantifying ischemic lesions in the brain. Additional unique features of the Neuroimaging Core include the use of ultra- high-field (7T) MRI both in vivo and for post-mortem imaging of intact hemispheres, the development methods for accurate image-guided sampling of post-mortem brain tissue allowing spatial linkage between digital pathology and in vivo morphometry, the development a data infrastructure linking imaging and non-imaging databases, novel MRI and OCT methods for quantifying brain structure and vascular function in ADRC research, and infrastructure to support the translation of novel PET tracers to clinical research in AD/ADRD. The Neuroimaging Core will also share imaging data collected at the Penn ADRC with the NACC Coordinating Center at the University of Washington and SCAN U24. The Neuroimaging Core will be highly integrated with other ADRC cores, providing access to advanced imaging and derived imaging metrics for the Clinical Core, collaboration on image analysis and databasing of image-based information with the Data Management and Statistics Core, linking in vivo and postmortem neuroimaging to neuropathology in conjunction with the Neuropathology Core, leveraging imaging as a means of linking genetic factors with structural and functional brain phenotype with Genomics Core, working with the Outreach Recruitment and Engagement Core to provide research updates about neuroimaging advances and promote participation in imaging studies, and providing education and training in neuroimaging through Research Education Component.