{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T23:45:55Z","timestamp":1789083955507,"version":"build-2803163510"},"reference-count":59,"publisher":"American Society of Hematology","issue":"11","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,9,10]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>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 for 37 adults with SCD in steady state and 37 adults without SCD. 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 \u00d7 10\u22124\u00b7min\u22121 vs 2.58 \u00d7 10\u22124\u00b7min\u22121; 95% confidence interval [CI] median difference, 0.36 \u00d7 10\u22124\u00b7min\u22121 to 1.30 \u00d7 10\u22124\u00b7min\u22121; P&amp;lt; .001), indicating BBB disruption. In SCD, white matter Ktrans was associated with MD (\u03b2, 6.25 [95% CI, 1.72-10.77]; P = .008), independent of OEF (\u03b2, 0.22 [95% CI, 0.09-0.35]), and silent cerebral infarcts (\u03b2, 0.01 [95% CI, 0.00-0.02]). The interaction (P = .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 that 79 proteins associated with BBB permeability belonged to iron homeostasis, response to hypoxia, immune dysregulation, extracellular matrix degradation, lipoprotein homeostasis, and arginine-proline metabolism pathways. All pathways were independently associated with microstructural injury. BBB permeability was a mediator of brain injury for all pathways except extracellular matrix degradation. Targeting specific systemic pathways to protect the BBB may represent a therapeutic approach to preserve brain health in SCD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025032856","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T17:11:43Z","timestamp":1778692303000},"page":"1481-1494","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":2,"title":["Proteomic profiling identifies systemic drivers of blood-brain barrier injury in sickle cell disease"],"prefix":"10.1182","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3750-0311","authenticated-orcid":false,"given":"Yan","family":"Wang","sequence":"first","affiliation":[{"name":"1Department of Neurology, Washington University School of Medicine, St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3736-7095","authenticated-orcid":false,"given":"Serguei","family":"Astafiev","sequence":"additional","affiliation":[{"name":"1Department of Neurology, Washington University School of Medicine, St. Louis, MO"},{"name":"2Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinsheng","family":"Yu","sequence":"additional","affiliation":[{"name":"3The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Slim","family":"Fellah","sequence":"additional","affiliation":[{"name":"1Department of Neurology, Washington University School of Medicine, St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin N.","family":"Reis","sequence":"additional","affiliation":[{"name":"2Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Chen","sequence":"additional","affiliation":[{"name":"1Department of Neurology, Washington University School of Medicine, St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy E.","family":"Mirro","sequence":"additional","affiliation":[{"name":"4Department of Pediatrics, Washington University School of Medicine, St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1060-3289","authenticated-orcid":false,"given":"Chunwei","family":"Ying","sequence":"additional","affiliation":[{"name":"2Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5518-3778","authenticated-orcid":false,"given":"Kristin P.","family":"Guilliams","sequence":"additional","affiliation":[{"name":"1Department of Neurology, Washington University School of Medicine, St. Louis, MO"},{"name":"2Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO"},{"name":"4Department of Pediatrics, Washington University School of Medicine, St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie E.","family":"Fields","sequence":"additional","affiliation":[{"name":"4Department of Pediatrics, Washington University School of Medicine, St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1951-6176","authenticated-orcid":false,"given":"Allison A.","family":"King","sequence":"additional","affiliation":[{"name":"5Division of Hematology\/Oncology, Department 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MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0276-2899","authenticated-orcid":false,"given":"Carlos","family":"Cruchaga","sequence":"additional","affiliation":[{"name":"1Department of Neurology, Washington University School of Medicine, St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Moo","family":"Lee","sequence":"additional","affiliation":[{"name":"1Department of Neurology, Washington University School of Medicine, St. Louis, MO"},{"name":"2Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6459-2269","authenticated-orcid":false,"given":"Hongyu","family":"An","sequence":"additional","affiliation":[{"name":"2Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, 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