Tracer kinetic assessment of blood–brain barrier leakage and blood volume in cerebral small vessel disease: Associations with disease burden and vascular risk factors

Michael S. Stringer, Anna K. Heye, Paul A. Armitage, Francesca Chappell, Maria del C. Valdés Hernández, Stephen D.J. Makin, Eleni Sakka, Michael J. Thrippleton*, Joanna M. Wardlaw

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Subtle blood–brain barrier (BBB) permeability increases have been shown in small vessel disease (SVD) using various analysis methods. Following recent consensus recommendations, we used Patlak tracer kinetic analysis, considered optimal in low permeability states, to quantify permeability-surface area product (PS), a BBB leakage estimate, and blood plasma volume (vP) in 201 patients with SVD who underwent dynamic contrast-enhanced MRI scans. We ran multivariable regression models with a quantitative or qualitative metric of white matter hyperintensity (WMH) severity, demographic and vascular risk factors. PS increased with WMH severity in grey (B = 0.15, Confidence Interval (CI): [0.001,0.299], p = 0.049) and normal-appearing white matter (B = 0.015, CI: [−0.008,0.308], p = 0.062). Patients with more severe WMH had lower vP in WMH (B = -0.088, CI: [−0.138,-0.039], p < 0.001), but higher vP in normal-appearing white matter (B = 0.031, CI: [−0.004,0.065], p = 0.082). PS and vP were lower at older ages in WMH, grey and white matter. We conclude higher PS in normal-appearing tissue with more severe WMH suggests impaired BBB integrity beyond visible lesions indicating that the microvasculature is compromised in normal-appearing white matter and WMH. BBB dysfunction is an important mechanism in SVD, but associations with clinical variables are complex and underlying damage affecting vascular surface area may alter interpretation of tracer kinetic results.

Original languageEnglish
Article number102883
Number of pages9
JournalNeuroImage: Clinical
Early online date17 Nov 2021
Publication statusPublished - Nov 2021

Bibliographical note

Funding Information:
The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: Wellcome Trust [grant number WT088134/Z/09/A ; SDJM, FC]; Row Fogo Charitable Trust (MCVH, FC, AKH, PAA); Scottish Funding Council Scottish Imaging Network A Platform for Scientific Excellence collaboration (JMW); NHS Lothian R + D Department (MJT); the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK MRC, Alzheimer’s Research UK and the Alzheimer’s Society (MS, FC, ES, JMW); the Fondation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease [reference number 16 CVD 05] (MS); and European Union Horizon 2020 [project number 666881, SVDs@Target] (MS, FC).

We acknowledge the participants, their relatives, and carers for their participation in this study, and the staff of NHS Lothian Stroke Services and Brain Research Imaging Centre Edinburgh for their assistance in recruiting and assessing the patients.

Data Availability Statement

Supplementary data to this article can be found online at https://doi. org/10.1016/j.nicl.2021.102883.


  • Blood brain barrier
  • Cerebrovascular disease
  • MRI
  • Stroke
  • SVD


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