Zixuan Lin1, Eboni Lance2,3, Tiffany McIntyre2, Yang Li1, Peiying Liu1, Chantelle Lim1,4, Hongli Fan1,4, Aylin Tekes1, Alicia Cannon5, James F Casella6, Hanzhang Lu1,4,7. 1. The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 2. Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, Maryland, USA. 3. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 4. Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 5. Department of Neuropsychology, Kennedy Krieger Institute, Baltimore, Maryland, USA. 6. Department of Pediatrics, Division of Hematology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 7. F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, Baltimore, Maryland, USA.
Abstract
BACKGROUND: Blood-brain barrier (BBB) disruption may lead to endothelium dysfunction and inflammation in sickle cell disease (SCD). However, abnormalities of BBB in SCD, especially in pediatric patients for whom contrast agent administration less than optimal, have not been fully characterized. PURPOSE: To examine BBB permeability to water in a group of pediatric SCD participants using a non-invasive magnetic resonance imaging technique. We hypothesized that SCD participants will have increased BBB permeability. STUDY TYPE: Prospective cross-sectional. POPULATION: Twenty-six pediatric participants (10 ± 1 years, 15F/11M) were enrolled, including 21 SCD participants and 5 sickle cell trait (SCT) participants, who were siblings of SCD patients. FIELD STRENGTH/SEQUENCE: 3 T. Water extraction with phase-contrast arterial spin tagging with echo-planer imaging, phase-contrast and T1 -weighted magnetization-prepared rapid acquisition of gradient echo. ASSESSMENT: Water extraction fraction (E), BBB permeability-surface area product (PS), cerebral blood flow, hematological measures (hemoglobin, hematocrit, hemoglobin S), neuropsychological scores (including domains of intellectual ability, attention and executive function, academic achievement and adaptive function, and a composite score). Regions of interest were drawn by Z.L. (6 years of experience). STATISTICAL TESTS: Wilcoxon rank sum test and chi-square test for group comparison of demographics. Multiple linear regression analysis of PS with diagnostic category (SCD or SCT), hematological measures, and neuropsychological scores. A two-tailed P value of 0.05 or less was considered statistically significant. RESULTS: Compared with SCT participants, SCD participants had a significantly higher BBB permeability to water (SCD: 207.0 ± 33.3 mL/100 g/minute, SCT: 171.2 ± 27.2 mL/100 g/minute). SCD participants with typically more severe phenotypes also had a significantly leakier BBB than those with typically milder phenotypes (severe: 217.3 ± 31.7 mL/100 g/minute, mild: 193.3 ± 31.8 mL/100 g/minute). Furthermore, more severe BBB disruption was associated with worse hematological symptoms, including lower hemoglobin concentrations (β = -8.84, 95% confidence interval [CI] [-14.69, -3.00]), lower hematocrits (β = -2.96, 95% CI [-4.84, -1.08]), and higher hemoglobin S fraction (β = 0.77, 95% CI [0.014, 1.53]). DATA CONCLUSION: These findings support a potential role for BBB dysfunction in SCD pathogenesis of ischemic injury. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.
BACKGROUND: Blood-brain barrier (BBB) disruption may lead to endothelium dysfunction and inflammation in sickle cell disease (SCD). However, abnormalities of BBB in SCD, especially in pediatric patients for whom contrast agent administration less than optimal, have not been fully characterized. PURPOSE: To examine BBB permeability to water in a group of pediatric SCD participants using a non-invasive magnetic resonance imaging technique. We hypothesized that SCD participants will have increased BBB permeability. STUDY TYPE: Prospective cross-sectional. POPULATION: Twenty-six pediatric participants (10 ± 1 years, 15F/11M) were enrolled, including 21 SCD participants and 5 sickle cell trait (SCT) participants, who were siblings of SCD patients. FIELD STRENGTH/SEQUENCE: 3 T. Water extraction with phase-contrast arterial spin tagging with echo-planer imaging, phase-contrast and T1 -weighted magnetization-prepared rapid acquisition of gradient echo. ASSESSMENT: Water extraction fraction (E), BBB permeability-surface area product (PS), cerebral blood flow, hematological measures (hemoglobin, hematocrit, hemoglobin S), neuropsychological scores (including domains of intellectual ability, attention and executive function, academic achievement and adaptive function, and a composite score). Regions of interest were drawn by Z.L. (6 years of experience). STATISTICAL TESTS: Wilcoxon rank sum test and chi-square test for group comparison of demographics. Multiple linear regression analysis of PS with diagnostic category (SCD or SCT), hematological measures, and neuropsychological scores. A two-tailed P value of 0.05 or less was considered statistically significant. RESULTS: Compared with SCT participants, SCD participants had a significantly higher BBB permeability to water (SCD: 207.0 ± 33.3 mL/100 g/minute, SCT: 171.2 ± 27.2 mL/100 g/minute). SCD participants with typically more severe phenotypes also had a significantly leakier BBB than those with typically milder phenotypes (severe: 217.3 ± 31.7 mL/100 g/minute, mild: 193.3 ± 31.8 mL/100 g/minute). Furthermore, more severe BBB disruption was associated with worse hematological symptoms, including lower hemoglobin concentrations (β = -8.84, 95% confidence interval [CI] [-14.69, -3.00]), lower hematocrits (β = -2.96, 95% CI [-4.84, -1.08]), and higher hemoglobin S fraction (β = 0.77, 95% CI [0.014, 1.53]). DATA CONCLUSION: These findings support a potential role for BBB dysfunction in SCD pathogenesis of ischemic injury. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.
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