Thrippleton, Michael

Wardlaw, Joanna

Valdes Hernandez, Maria

Heye, Anna Kathrin

Wellcome Trust

2017-07-19T10:36:10Z

2017-07-19T10:36:10Z

2016-11-29

Cerebral small vessel disease (SVD) is a common cause of strokes and dementia. The pathogenesis of SVD is poorly understood, but imaging and biochemical investigations suggest that subtle blood-brain barrier (BBB) leakage may contribute to tissue damage. The most widely-used imaging method for assessing BBB integrity and other microvascular properties is dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). DCE-MRI has primarily been applied in situations where contrast uptake in tissue is typically large and rapid (e.g. neuro-oncology); the optimal approach for quantifying BBB integrity in diseases where the BBB remains largely intact and the reliability of resulting measurements is unclear. The main purpose of this thesis was to assess and improve the reliability of quantitative assessment of subtle BBB disruption, in order to illuminate its potential role in cerebral SVD. Firstly, a systematic literature review was performed in order to provide an overview of DCE-MRI methods in the brain. This review found large variations in MRI procedures and data analysis methods, resulting in widely varying estimates of tracer kinetic parameters. Secondly, this thesis focused on the analysis of DCE-MRI data acquired in an on-site clinical study of mild stroke patients. After performing basic DCE-MRI processing (e.g. selection of a vascular input function), this work aimed to determine the tracer kinetic modelling approach most suitable for assessing subtle BBB disruption in this cohort. Using data-driven model selection and computer simulations, the Patlak model was found to provide accurate estimates of blood plasma volume and low-level BBB leakage. Thirdly, this thesis aimed to investigate two potential pitfalls in the quantification of subtle BBB disruption. Contrast-free measurements in healthy volunteers revealed that a signal drift of approximately 0.1 %/min occurs during the DCE-MRI acquisition; computer simulations showed that this drift introduces significant systematic errors when estimating low-level tracer kinetic parameters. Furthermore, tracer kinetic analysis was performed in an external patient cohort in order to investigate the inter-study comparability of DCE-MRI measurements. Due to the nature of the acquisition protocol it proved difficult to obtain reliable estimates of BBB leakage, highlighting the importance of study design. Lastly, this thesis examined the relationship between quantitative MRI parameters and clinical measurements in cerebral SVD, with a focus on the estimates of blood volume and BBB leakage obtained in the internal SVD patient cohort. This work did not provide evidence that BBB leakage in normal-appearing tissue increases with SVD burden or predicts disease progression; however, increased BBB leakage was found in white matter hyperintensities. Furthermore, this work raises the possibility of a role for blood plasma volume and dietary salt intake in cerebral SVD. The work described in this thesis has demonstrated that it is possible to estimate subtle BBB disruption using DCE-MRI, provided that the measurement and data analysis strategies are carefully optimised. However, absolute values of tracer kinetic parameters should be interpreted with caution, particularly when making comparisons between studies, and sources of error and their influence should be estimated where possible. The exact roles of BBB breakdown and other microvascular changes in SVD pathology remain to be defined; however, the work presented in this thesis contributes further insights and, together with technical advances, will facilitate improved study design in the future.

http://hdl.handle.net/1842/22929

en

The University of Edinburgh

Heye, A. K., Thrippleton, M. J., Armitage, P. A., Vald´es Hern´andez, M. D. C., Makin, S., Glatz, A., Sakka, E. and Wardlaw, J. M. (2016). Tracer kinetic modelling for DCE-MRI quantification of subtle blood-brain barrier permeability. NeuroImage, 125:446-455.

Heye, A. K., Thrippleton, M. J., Chappell, F., Vald´es Hern´andez, M. D. C., Armitage, P. A., Makin, S., Mu˜noz Maniega, S., Sakka, E., Flatman, P.W., Dennis, M. S. and Wardlaw, J. M. (2016). Blood pressure and sodium: association with MRI markers in cerebral small vessel disease. Journal of Cerebral Blood Flow and Metabolism, 36(1):264-274.

Heye, A. K., Culling, R. D., Vald´es Hern´andez, M. D. C., Thrippleton, M. J. and Wardlaw, J. M. (2014). Assessment of blood-brain barrier disruption using dynamic contrast-enhanced MRI. A systematic review. NeuroImage Clinical, 6:262–274.

Heye, A. K., Thrippleton, M. J., Glatz, A., Armitage, P. A. and Wardlaw, J. M. (2015). Influence of scanner drift on the accuracy of pharmacokinetic parameters in subtle leakage measured with DCE-MRI – a healthy volunteer and simulation study. ESMRMB Annual Scientific Meeting 2015, Edinburgh, UK.

Thrippleton, M. J.,Heye, A. K., Chappell, F., Vald´es Hern´andez, M. D. C., Armitage, P. A., Makin, S., Mu˜noz Maniega, S., Sakka, E., Flatman, P. W., Dennis, M. S. and Wardlaw, J. M. (2015). Added dietary salt is associated with increased white matter hyperintensity volume. European Stroke Organisation Conference 2015, Glasgow, UK.

Heye, A. K., Thrippleton, M. J., Armitage, P. A., Vald´es Hern´andez, M. D. C. andWardlaw, J. M. (2014). Model selection for DCE-MRI applied to detect subtle blood-brain barrier disruption. ISMRM British Chapter Meeting 2014, Edinburgh, UK.

eye, A. K., Thrippleton, M. J., Vald´es Hern´andez, M. D. C., Armitage, P. A. andWardlaw, J. M. (2014). Quantification of subtle blood-brain barrier permeability in white matter using DCE-MRI. ISMRM Annual Scientific Meeting 2014, Milan, Italy.

Heye, A. K., Thrippleton, M. J., Vald´es Hern´andez, M. D. C., Armitage, P. A. andWardlaw, J. M. (2013). Comparison of five quantitative analytic methods for the assessment of subtle blood-brain-barrier permeability using DCE-MRI. ESMRMB Annual Scientific Meeting 2013, Toulouse, France.

Heye, A. K., Culling, R. D., Vald´es Hern´andez, M. D. C. and Wardlaw, J. M. (2013). The use of dynamic contrast-enhanced MRI to study permeability of the blood-brain barrier – A systematic review. ESMRMB Annual Scientific Meeting 2013, Toulouse, France.

blood-brain barrier

DCE-MRI

dynamic contrast-enhanced magnetic resonance imaging

cerebral small vessel disease

Measurement of subtle blood-brain barrier disruption in cerebral small vessel disease using dynamic contrast-enhanced magnetic resonance imaging

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy