Sickle cell disease (SCD) is the most prevalent inherited blood disorder in the world and remains an important cause of morbidity and mortality despite the advent of modern medicine. The broad goals of this project are to determine (i) how SCD influences brain function, (ii) whether SCD causes specific neuropathological changes in brain and, if so, (iii) how these pathological changes develop, and (iv) how these changes affect the trajectory of SCD from infancy through adulthood. We will accomplish these goals by characterizing brain function with functional magnetic resonance imaging (fMRI), brain structure with diffusion tensor imaging (DTI), and neuropathology with post-mortem MRI, histology, and molecular biology, which will define the neuropathology of SCD. We will focus on a key region of the brain involved in higher cortical function: the dorsolateral prefrontal cortex (DLPFC), a region which demonstrates activation during a wide variety of cognitive tasks, including visual and spatial attention. By determining how SCD influences brain structure, function, and pathology, we will identify mechanisms by which SCD contributes to brain dysfunction and help identify appropriate targets for future interventions. PUBLIC HEALTH RELEVANCE: Sickle cell disease is the most common inherited blood disorder and is associated with significant neurological complications that can affect quality of life throughout the lifespan. The broad goals of this project are to determine how sickle cell disease influences brain function, how sickle cell disease affects the structure and integrity of white matter tracts in the brain, and how these pathological changes contribute to disease progression. We will examine these issues with functional MRI, diffusion tensor imaging (DTI), and post-mortem MRI. These studies will reveal neuropathological changes associated with the disease and identify possible causes of developmental brain abnormalities in sickle cell disease. By understanding how SCD impacts brain function, white matter integrity, and neuropathology, we will identify targets for future interventions.