PROJECT SUMMARY Children with sickle cell disease are at increased risk for serious cerebrovascular complications. The most prevalent of these complications are silent cerebral infarcts, focal areas of ischemic tissue damage in the brain associated with cognitive impairment and poor school performance. Despite the significant consequences of silent cerebral infarcts, they are often detected after ischemic damage has occurred. Clinical protocols to triage sickle cell patients utilize ultrasound measurements of blood velocity in large cerebral arteries, with high blood velocity indicating increased risk for stroke. However, there is conflicting evidence whether high blood velocity is a risk factor for silent cerebral infarcts. Additionally, therapies prescribed to high-risk patients may not protect against silent cerebral infarcts. We need improved understanding of the vascular impairments associated with silent cerebral infarcts in sickle cell disease to better prevent and treat this source of neurological injury. This work proposes MRI measurements of cerebrovascular reactivity as a novel source of hemodynamic information related to silent cerebral infarct formation. Cerebrovascular reactivity is the blood flow response to a dilatory stressor and is measured in smaller vessels in the cortex, making it a more local metric of vascular health than blood velocity. Previous studies have demonstrated impaired cerebrovascular reactivity in adults and children with sickle cell disease, indicating reduced ability to increase blood flow to meet oxygen demands and increased likelihood for ischemia. The aims of this proposal are to: 1) evaluate the relationship between blood velocity in large cerebral arteries and cerebrovascular reactivity in the cortex, and 2) determine if cerebrovascular reactivity is altered in brain regions close to silent cerebral infarcts. Aim 1 is a step forward from previous work, contextualizing cerebrovascular reactivity against the clinical standard for cerebrovascular risk assessment in sickle cell disease. Aim 2 determines whether this additional information improves our understanding of the spatial distribution of silent infarcts. The proposed study will provide a comprehensive assessment of cerebral hemodynamics in children with sickle cell disease and offer preliminary evidence for cerebrovascular reactivity as a hemodynamic biomarker for silent cerebral infarct occurrence. A hemodynamic biomarker that is coupled to silent cerebral infarcts could inform the treatment of sickle cell disease and aid in the development of new preventative therapies. In the long term, the imaging techniques developed in this proposal could serve as an alternative or complementary MRI screening tool to stratify for silent cerebral infarct risk more effectively.