Proteomic profiling identifies systemic drivers of blood-brain barrier injury in sickle cell disease

作者：Y Wang, Serguei V. Astafiev, Jinsheng Yu, Slim Fellah, Martin Reis, Vivan Chen, Amy Mirro, Chunwei Ying, Kristin Guilliams, Melanie E. Fields, Allison A King, Yasheng Chen, Robert A. Campbell, Jorge Di Paola, Carlos Cruchaga, Jin-Moo Lee, Hongyu An, Andria L. Ford · 发表于：Blood · 年份：2026 · DOI：10.1182/blood.2025032856 · 研究领域：Hemoglobinopathies and Related Disorders、Iron Metabolism and Disorders、Barrier Structure and Function Studies

Sickle cell disease (SCD) causes brain injury and cognitive disability. Systemic inflammation and endothelial injury are central to SCD pathophysiology, yet the relationship between systemic drivers of blood-brain barrier (BBB) disruption and brain injury remains understudied. This cross-sectional study assessed whole-brain and regional BBB permeability (Ktrans) using dynamic contrast-enhanced magnetic resonance imaging in 37 adults with SCD in steady-state and 37 non-SCD adults. Cerebral oxygen extraction fraction (OEF) and white matter mean diffusivity (MD) measured tissue hypoxia and microstructural injury, respectively. The SCD cohort showed elevated Ktrans compared with controls (3.6 x10-4min-1 vs. 2.58x10-4min-1, 95% CI median difference [0.36, 1.30]x10-4min-1, P< 0.001), indicating BBB disruption. In SCD, white matter Ktrans was associated with MD (β [95% Cl]: 6.25 [1.72, 10.77], P=0.008), independent of OEF (β [95% Cl]: 0.22 [0.09, 0.35]) and silent cerebral infarcts (β [95% Cl]: 0.01 [0.00, 0.02]). The interaction (P=0.037) between Ktrans and OEF on MD suggested a combined, deleterious effect of BBB disruption and hypoxia on microstructural injury. High-throughput plasma proteomics followed by differential expression analysis, and weighted gene correlation network analysis in a subset of 61 participants revealed 79 proteins associated with BBB permeability belonged to iron homeostasis, response to hypoxia, immune dysregulation, extracellular matrix degradation, lipop...