This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ABSTRACT Rationale: Neurological complications including stroke and cognitive impairment cause significant morbidity and mortality in patients with sickle cell disease (SCD). Measurement of timed mean average blood flow velocity in the major cerebral arteries by transcranial Doppler (TCD) can identify children at risk for stroke. However, cognitive impairment is often only identified in older school aged children or after a clinically apparent stroke. Cerebral perfusion at the level of the arteriole and capillary may identify children at risk for or with early, potentially reversible, cognitive impairment. Proposal: We plan an ancillary study of children with SCD and no previous history of stroke concurrently enrolled in the screening portion of the Silent Infarct Transfusion (SIT) Trial and sibling controls without SCD. We hypothesize that in these children cerebral blood flow (CBF) will have an inverse correlation with performance on neuropsychological testing at baseline and predict performance on follow-up testing. In addition, we will evaluate the relationship between CBF in specific anatomical regions and test performance for specific domains of neuropsychological functioning. We will evaluate the relationship of serum levels of vascular cell adhesion molecule-1 (sVCAM-1), a soluble marker elevated in stroke and cerebrovascular disease and known risk factors for ischemic stroke in adults to silent cerebral infarct, CBF and performance on neuropsychological testing. Methods: We will enroll 113 patients ?6 and <13.5 years of age with SCD from the pediatric hematology clinics at Johns Hopkins, Sinai, Georgetown, and the University of Maryland Hospital and 35 sibling controls without SCD. All eligible consenting patients will provide a detailed family history of cardiovascular disease. They will have their blood pressure measured, neuropsychological testing, brain MRI including T1, T2, and diffusion weighted, and fluid attenuated inversion recovery (FLAIR) images, time of flight magnetic resonance angiography (MRA), measurement of CBF by continuous arterial spin labeled (CASL) MRI, and a complete blood count, reticulocyte count, fetal hemoglobin, C-reactive protein, lactate dehydrogenase, sVCAM, and apolipoprotein a and b2, at baseline and after 3 years. Implications: This study will examine the role of a promising non-invasive technique to measure CBF and predict performance on neuropsychological testing. These techniques may identify patients at risk for cognitive impairment and permit more convenient and frequent evaluation of risk in those receiving preventive treatment. Known risk factors for ischemic stroke in adults may contribute to the risk of neurological complications in children with sickle cell disease and may identify high-risk children appropriate for interventions. Hydroxyurea, chronic transfusion therapy, hematopoetic stem cell transplantation, or intensive educational support may decrease CBF and prevent further cognitive impairment in SCD.
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