Dramatic advances in management of congenital heart disease (CHD) have improved survival to adulthood from <10% in the 1960's to nearly 90% in the current era. With this shifting demographic, adult CHD (ACHD) patients now outnumber pediatric CHD patients.1 ACHD patients demonstrate domain-specific neurocognitive deficits such as impairment in executive function, associated with reduced quality of life that includes deficits in educational attainment and social interaction.2-7 These deficits are related to risk factors that can occur across the lifespan, including genetic abnormalities, cumulative hypoxic/ischemic injury, and, adult-onset atherosclerotic cerebrovascular disease. Our overarching hypothesis is that ACHD patients exhibit vascular brain injury and structural/physiological brain alterations that are predictive of specific neurocognitive deficits, including executive dysfunction, which are modified by behavioral and environmental enrichment proxies of CR (e.g., level of education and lifestyle/social habits). We propose an ancillary study to the NHLBI-funded Pediatric Heart Network (PHN) “Multi-Institutional Neurocognitive Discovery Study (MINDS) in Adult Congenital Heart Disease (ACHD).” We will leverage the MINDS-ACHD parent study data (i.e., NIH Toolbox neuropsychological battery/clinical data/biological samples) and our established neuroimaging harmonization, which we currently use for the PHN Single Ventricle Reconstruction (SVRIII) multi-center brain connectome study (R01-HL128818; PI-Panigrahy), to measure neuroimaging biomarkers in ACHD patients at the same PHN sites. Our specific aims are: Specific Aim #1 (brain injury): To determine if vascular-related brain injury (cortical infarcts, hemosiderin lesions, and white matter hyperintensity) is associated with specific neurocognitive deficits (e.g. NIH Toolbox total composite score) in ACHD patients. Specific Aim #2 (brain structure): To determine if reduced fronto-temporal cortical thickness and white matter connectivity are associated with specific neurocognitive deficits (e.g. NIH Toolbox frontal executive sub-score) in ACHD patients. Specific Aim #3 (brain physiology): To determine if reduced cerebrovascular reserve (regional cerebral blood flow/ resting BOLD imaging) is associated with specific neurocognitive deficits (e.g. NIH Toolbox crystallized composite score) in ACHD patients. Specific Aim #4 (cognitive reserve): To determine if the associations between neuroimaging biomarkers and neurocognitive outcomes in ACHD patients are modified by behavioral and environmental enrichment proxies of CR, using traditional statistical models and machine learning techniques. Given the paucity of multi-modal neuroimaging studies in ACHD, our proposed study addresses a major knowledge gap in the ACHD population by providing insight into the mechanism underlying impaired neurocognitive outcomes. Our study will provide structural-physiological correlates of neurocognitive outcomes, represe...