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. 2025 Apr;21(4):e70152.
doi: 10.1002/alz.70152.

Blood biomarkers of vascular dysfunction in small vessel disease progression: Insights from a longitudinal neuroimaging study

Daniela Jaime Garcia  1   2 , Una Clancy  1 , Carmen Arteaga  1 , Maria C Valdés-Hernandez  1   2 , Francesca M Chappell  1 , Angela C C Jochems  1   2 , Yajun Cheng  1   3 , Junfang Zhang  1   4 , Michael J Thrippleton  1   5 , Michael S Stringer  1   5 , Emilie Sleight  1   2 , Ellen V Backhouse  1   2 , Stewart Wiseman  1   2 , Rosalind Brown  1   2 , Fergus N Doubal  1 , Axel Montagne  1   2 , Joanna M Wardlaw  1   2 ; MSS3 Study Group
Affiliations

Blood biomarkers of vascular dysfunction in small vessel disease progression: Insights from a longitudinal neuroimaging study

Daniela Jaime Garcia et al. Alzheimers Dement. 2025 Apr.

Abstract

Introduction: This study explored the relationship between blood biomarkers of cerebrovascular function and small vessel disease (SVD) neuroimaging markers and cognitive outcomes in highly-phenotyped participants.

Methods: We conducted cross-sectional and 1-year longitudinal analyses on 181 patients with mild ischemic stroke, enriched for SVD features. We examined relationships between a panel of 13 blood biomarkers and magnetic resonance imaging (MRI) markers of SVD (structural lesions, diffusion-weighted imaging [DWI]-positive lesions, blood-brain barrier (BBB) permeability, and cerebrovascular reactivity (CVR), and cognition.

Results: In linear mixed models, vascular endothelial growth factor was significantly associated with incident DWI-positive lesions over 1 year. Intercellular adhesion molecule-1 was linked with lower CVR while platelet-derived growth factor-subunit B and Endothelin-1 were associated with higher CVR. Platelet-Selectin levels were associated with mild cognitive impairment at 1 year.

Discussion: Our results support the role of endothelial and pericyte dysfunction in SVD burden and progression and suggest that specific biomarkers relate to distinct SVD manifestations.

Highlights: Small vessel disease (SVD) lacks specific or predictive biomarker signatures. Vascular endothelial growth factor levels were linked to incident lesions detected over 1 year. Circulating intercellular adhesion molecule-1 related to lower cerebrovascular reactivity. Platelet-selectin levels were associated with mild cognitive impairment longitudinally. These findings could help stratify patients at high-risk of rapid-progression SVD.

Keywords: biomarkers; blood‐brain barrier; cerebrovascular dysfunction; cerebrovascular reactivity; cognitive impairment; endothelial dysfunction; pericyte; small vessel disease; vascular dementia.

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Conflict of interest statement

Alasdair G. Morgan, Cameron Manning, and Michael S. Stringer were part‐funded by Siemens Healthineers, administered by the University of Edinburgh. The other authors report no conflicts. Author disclosures are available in the Supporting Information.

Figures

FIGURE 1
FIGURE 1
Panel of serum biomarkers extracted and their putative involvement in pericyte and endothelial cell (dys)function in the cerebral small vessels. BBB, blood‐brain barrier; E‐Selectin, endothelial‐selectin; ICAM‐1, intercellular adhesion molecule 1; IL‐6, Interleukin 6; MMP‐9, matrix metalloproteinase 9; P‐Selectin, platelet‐selectin; PDGF‐BB, platelet derived growth factor subunit B; PDGFRβ, platelet derived growth factor receptor beta; PlGF, placental growth factor; TNF‐α, tumor necrosis factor alpha; VCAM‐1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor; vWF, von Willebrand Factor; Endo‐1, Endothelin‐1.
FIGURE 2
FIGURE 2
Flow diagram of study recruitment and data collection.
FIGURE 3
FIGURE 3
Blood biomarkers and newly appearing incident lesions (DWI‐positive) over 1 year. Logistic regression results for the association of distinct standardized blood biomarkers to the prevalence of DWI‐positive incident lesions identified throughout the 1‐year follow‐up period after adjusting for age, sex, vascular risk factors, stroke subtype, and baseline NIHSS. CI, confidence interval; DWI, diffusion‐weighted imaging; E‐Selectin, endothelial‐selectin; Endo‐1, Endothelin‐1; ICAM‐1, intercellular adhesion molecule 1; IL‐6, interleukin 6; MMP‐9, matrix metalloproteinase 9; NIHSS, The National Institutes of Health Stroke Scale; P‐Selectin, platelet‐selectin; PDGF‐BB, platelet derived growth factor subunit B; PDGFRβ, platelet derived growth factor receptor beta; PlGF, placental growth factor; TNF‐α, tumor necrosis factor alpha; VCAM‐1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor; vWF, von Willebrand Factor.
FIGURE 4
FIGURE 4
Blood biomarkers and BBB permeability (PS) from DCE‐MRI. Linear regression results for the association of distinct standardized blood biomarkers to baseline DCE‐MRI parameter PS (×104) after adjusting for age, sex, vascular risk factors, and baseline WMH volume as % ICV. BBB, blood‐brain barrier; CI, confidence interval; DCE‐MRI, dynamic contrast‐enhanced magnetic resonance imaging; E‐Selectin, endothelial‐selectin; Endo‐1, Endothelin‐1; ICAM‐1, intercellular adhesion molecule 1; ICV, intracranial volume; IL‐6, Interleukin 6; MMP‐9, matrix metalloproteinase 9; P‐Selectin, platelet‐selectin; PDGF‐BB, platelet derived growth factor subunit B; PDGFRβ, platelet derived growth factor receptor beta; PlGF, placental growth factor; PS, permeability‐surface area product; TNF‐α, tumor necrosis factor alpha; VCAM‐1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor; vWF, von Willebrand factor; WMH, white matter hyperintensity.
FIGURE 5
FIGURE 5
Blood biomarkers and CVR. Linear regression results for the association of distinct standardized blood biomarkers to baseline DCE‐CVR in NAWM, the basal ganglia and WMH after adjusting for age, sex, vascular risk factors, and baseline WMH volume as % ICV. CI, confidence interval; CVR, cerebrovascular reactivity; E‐selectin, endothelial‐selectin; Endo‐1, Endothelin‐1; ICAM‐1, intercellular adhesion molecule 1; ICV, intracranial volume; IL‐6, interleukin 6; MMP‐9, matrix metalloproteinase 9; NAWM, normal appearing white matter; P‐Selectin, platelet‐selectin; PDGF‐BB, platelet derived growth factor subunit B; PDGFRβ, platelet derived growth factor receptor beta; PlGF, placental growth factor; TNF‐α, tumor necrosis factor alpha; VCAM‐1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor; vWF, von Willebrand Factor; WMH, white matter hyperintensity.
FIGURE 6
FIGURE 6
Blood biomarkers and MoCA score. Baseline cross‐sectional linear regression and longitudinal linear mixed effects model results for the association of distinct standardized blood biomarkers and MoCA score after adjusting for age, sex, vascular risk factors, premorbid intelligence, and baseline WMH volume as % ICV. ICV, intracranial volume; CI, confidence interval; E‐Selectin, endothelial‐selectin; Endo‐1, Endothelin‐1; IL‐6, interleukin 6; MMP‐9, matrix metalloproteinase 9; MoCA, Montreal Cognitive Assessment; PDGF‐BB, platelet derived growth factor subunit B; PDGFRβ, platelet derived growth factor receptor beta; ICAM‐1, intercellular adhesion molecule 1; P‐Selectin, platelet‐selectin; PlGF, placental growth factor; TNF‐α, tumor necrosis factor alpha; VCAM‐1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor; vWF, von Willebrand Factor; WMH, white matter hyperintensity.
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References

    1. Hachinski V, Einhäupl K, Ganten D, et al. Preventing dementia by preventing stroke: the Berlin Manifesto. Alzheimers Dement. 2019;15(7):961‐984. doi:10.1016/j.jalz.2019.06.001 - DOI - PMC - PubMed
    1. Debette S, Schilling S, Duperron MG, Larsson SC, Markus HS. Clinical significance of magnetic resonance imaging markers of vascular brain injury: a systematic review and meta‐analysis. JAMA Neurol. 2019;76(1):81‐94. doi:10.1001/jamaneurol.2018.3122 - DOI - PMC - PubMed
    1. Wardlaw JM, Smith C, Dichgans M. Small vessel disease: mechanisms and clinical implications. Lancet Neurol. 2019;18(7):684‐696. doi:10.1016/S1474-4422(19)30079-1 - DOI - PubMed
    1. Clancy U, Gilmartin D, Jochems ACC, Knox L, Doubal FN, Wardlaw JM. Neuropsychiatric symptoms associated with cerebral small vessel disease: a systematic review and meta‐analysis. Lancet Psychiatry. 2021;8(3):225‐236. doi:10.1016/S2215-0366(20)30431-4 - DOI - PubMed
    1. Wardlaw JM, Doubal FN, Valdes‐Hernandez M, et al. Blood–brain barrier permeability and long‐term clinical and imaging outcomes in cerebral small vessel disease. Stroke. 2013;44(2):525‐527. doi:10.1161/STROKEAHA.112.669994 - DOI - PMC - PubMed

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