Abstract
BACKGROUND AND OBJECTIVES: Sickle cell disease (SCD) is a hemoglobinopathy resulting in hemoglobin-S production, hemolytic anemia, and elevated stroke risk. Treatments include oral hydroxyurea, blood transfusions, and hematopoietic stem cell transplantation (HSCT). Our objective was to evaluate the neurologic relevance of these therapies by characterizing how treatment-induced changes in hemoglobin (Hb) affect brain health biomarkers. METHODS: In this interventional study, adults with and without SCD underwent a 3T-MRI at Vanderbilt University Medical Center at 2 time points before and after clinically indicated transfusion or HSCT or at 2 time points without the introduction of a new Hb-altering therapy (adult controls and patients with SCD on hydroxyurea). Cerebral blood flow (CBF; mL/100 g/min) and cerebral venous blood relaxation rate (s(-1); a marker of Hb and blood oxygen content) responses were assessed to understand how these markers of brain health vary with Hb modulation. CBF was assessed with arterial spin labeling MRI, and blood relaxation rate was assessed using T(2) relaxation under spin tagging MRI. Measures were pairwise compared within each cohort using a 2-tailed Wilcoxon signed-rank test, and regression was applied to evaluate the parameter and Hb change relationships. The significance criterion was 2-sided p < 0.05. RESULTS: Adults with (n = 43; age 28.7 ± 7.7 years; 42% male) and without (n = 13; age 33.5 ± 12.2 years; 46% male) SCD were evaluated. In adults receiving hydroxyurea (n = 10), neither Hb, CBF, nor venous relaxation rate changed between time 1 (Hb = 8.6 ± 1.2 g/dL) and time 2 (Hb = 9.0 ± 1.8 g/dL) (all p > 0.05). In transfusion patients (n = 19), Hb increased from 8.2 ± 1.4 g/dL to 9.3 ± 1.3 g/dL before vs after transfusion (p < 0.001), paralleling a CBF decrease of 14.2 mL/100 g/min (p < 0.001) toward control levels. The venous relaxation rate did not change after transfusion (p = 0.71). In HSCT patients (n = 14), Hb increased from 8.9 ± 1.9 g/dL to 12.9 ± 2.7 g/dL (p < 0.001) before vs after transplant, paralleling CBF decreases from 68.16 ± 20.24 to 47.43 ± 12.59 mL/100 g/min (p < 0.001) and increase in venous relaxation rate (p = 0.004). Across the Hb spectrum, a CBF decrease of 5.02 mL/100 g/min per g/dL increase in Hb was observed. DISCUSSION: Findings demonstrate improvement in cerebral hemodynamics after transfusion and transplant therapies compared with hydroxyurea therapy; quantitative relationships should provide a framework for using these measures as trial end points to assess how new SCD therapies affect brain health.