Blood-brain barrier dysfunction predicts cognitive trajectory after ischemic stroke
Ischemic stroke doubles the risk of dementia. <sup>1-4</sup> Stroke severity and location affect cognition early, <sup>5,6</sup> but late dementia risk is not related to infarct characteristics, nor is it reduced by preventing additional strokes, <sup>3,6,7</sup> and its mechanism is unknown. We identified a plasma proteomic signature of chronic stroke that was consistent with blood-brain barrier (BBB) dysfunction, including a 58% decrease in plasma levels of platelet-derived growth factor B and downregulation of its pathway compared to healthy controls. During 2 years of follow-up, the stroke-specific proteome was accentuated in stroke survivors who subsequently declined in the processing speed/executive function cognitive domain. To test BBB function, we performed dynamic contrast-enhanced MRI 6-9 months after stroke in an additional cohort and found 1.7-fold higher whole brain BBB leakage compared to controls. Finally, we compared autopsy tissue from people with infarcts and dementia at death to those with infarcts and no dementia. Those who died with dementia had dramatic loss of vascular mural cell coverage compared to those without dementia (median 0.7% vs. 27%). Thus, our proteomic, functional, and structural data implicate chronic BBB dysfunction in cognitive decline late after stroke, revealing potential proteomic and imaging biomarkers and, importantly, a novel target for intervention.
Authors
- John D. Grainger (ORCID: https://orcid.org/0000-0003-2626-0647)
- Hye‐Won Oh (ORCID: https://orcid.org/0000-0001-9819-5915)
- Lauren L. Drag (ORCID: https://orcid.org/0000-0001-9441-9205)
- Marc Ghanem (ORCID: https://orcid.org/0000-0002-7479-7994)
- Natasha Carmichael
- Alperen Aslan (ORCID: https://orcid.org/0000-0003-4315-0036)
- Jarod Rutledge (ORCID: https://orcid.org/0000-0001-7790-2801)
- Marion S. Buckwalter (ORCID: https://orcid.org/0000-0003-2807-2447)
- Tomin James (ORCID: https://orcid.org/0000-0001-9010-7423)
- O Jones (ORCID: https://orcid.org/0000-0002-1385-2048)
- Kathleen L. Poston (ORCID: https://orcid.org/0000-0003-3424-7143)
- Kacey Berry (ORCID: https://orcid.org/0000-0001-8422-9379)
- Laura M. Parkes (ORCID: https://orcid.org/0000-0001-6488-507X)
- Philip Chung (ORCID: https://orcid.org/0000-0002-1194-7510)
- Zhu Li (ORCID: https://orcid.org/0000-0002-0331-4879)
- Lei Xue (ORCID: https://orcid.org/0000-0002-7601-3989)
- Emily Huang (ORCID: https://orcid.org/0000-0002-7393-1282)
- CJ Smith
- Chi-Hung Shu (ORCID: https://orcid.org/0009-0009-3486-8856)
- Zuzanna Biesiada
- Alifiya Kapasi
- David Seong
- Patricia Moran-Losada
- Tony Wyss-Coray
- Stuart M Allan
- Kristy A Zera
- Rui Xue
- Owen M Thomas
- Michael Mlynash
- Nima Aghaeepour
- Maarten Lansberg
- Liu K Yang
- Julie A Schneider
- Elizabeth C Mormino
Institutions
- Rush University Medical Center (US)
- Allen Institute for Brain Science (US)
- Salford Royal NHS Foundation Trust (GB)
- University of Manchester (GB)
- Stanford Health Care (US)
- Salford Royal Hospital (GB)
- Stanford Medicine (US)
- Stanford University (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-03-02
- DOI
- https://doi.org/10.64898/2026.02.27.708013
- Primary Topic
- Barrier Structure and Function Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00