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Anna K. Heye

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4 papers

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YNIMG Journal 2021 Journal Article

A four-dimensional computational model of dynamic contrast-enhanced magnetic resonance imaging measurement of subtle blood-brain barrier leakage

Jose Bernal
Maria d.C. Valdés-Hernández
Javier Escudero
Anna K. Heye
Eleni Sakka
Paul A. Armitage
Stephen Makin
Rhian M. Touyz

Dynamic contrast-enhanced MRI (DCE-MRI) is increasingly used to quantify and map the spatial distribution of blood-brain barrier (BBB) leakage in neurodegenerative disease, including cerebral small vessel disease and dementia. However, the subtle nature of leakage and resulting small signal changes make quantification challenging. While simplified one-dimensional simulations have probed the impact of noise, scanner drift, and model assumptions, the impact of spatio-temporal effects such as gross motion, k-space sampling and motion artefacts on parametric leakage maps has been overlooked. Moreover, evidence on which to base the design of imaging protocols is lacking due to practical difficulties and the lack of a reference method. To address these problems, we present an open-source computational model of the DCE-MRI acquisition process for generating four dimensional Digital Reference Objects (DROs), using a high-resolution brain atlas and incorporating realistic patient motion, extra-cerebral signals, noise and k-space sampling. Simulations using the DROs demonstrated a dominant influence of spatio-temporal effects on both the visual appearance of parameter maps and on measured tissue leakage rates. The computational model permits greater understanding of the sensitivity and limitations of subtle BBB leakage measurement and provides a non-invasive means of testing and optimising imaging protocols for future studies.

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YNICL Journal 2021 Journal Article

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

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.

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YNIMG Journal 2016 Journal Article

Tracer kinetic modelling for DCE-MRI quantification of subtle blood–brain barrier permeability

Anna K. Heye
Michael J. Thrippleton
Paul A. Armitage
Maria del C. Valdés Hernández
Stephen D. Makin
Andreas Glatz
Eleni Sakka
Joanna M. Wardlaw

There is evidence that subtle breakdown of the blood–brain barrier (BBB) is a pathophysiological component of several diseases, including cerebral small vessel disease and some dementias. Dynamic contrast-enhanced MRI (DCE-MRI) combined with tracer kinetic modelling is widely used for assessing permeability and perfusion in brain tumours and body tissues where contrast agents readily accumulate in the extracellular space. However, in diseases where leakage is subtle, the optimal approach for measuring BBB integrity is likely to differ since the magnitude and rate of enhancement caused by leakage are extremely low; several methods have been reported in the literature, yielding a wide range of parameters even in healthy subjects. We hypothesised that the Patlak model is a suitable approach for measuring low-level BBB permeability with low temporal resolution and high spatial resolution and brain coverage, and that normal levels of scanner instability would influence permeability measurements. DCE-MRI was performed in a cohort of mild stroke patients (n =201) with a range of cerebral small vessel disease severity. We fitted these data to a set of nested tracer kinetic models, ranking their performance according to the Akaike information criterion. To assess the influence of scanner drift, we scanned 15 healthy volunteers that underwent a “sham” DCE-MRI procedure without administration of contrast agent. Numerical simulations were performed to investigate model validity and the effect of scanner drift. The Patlak model was found to be most appropriate for fitting low-permeability data, and the simulations showed v p and K Trans estimates to be reasonably robust to the model assumptions. However, signal drift (measured at approximately 0. 1% per minute and comparable to literature reports in other settings) led to systematic errors in calculated tracer kinetic parameters, particularly at low permeabilities. Our findings justify the growing use of the Patlak model in low-permeability states, which has the potential to provide valuable information regarding BBB integrity in a range of diseases. However, absolute values of the resulting tracer kinetic parameters should be interpreted with extreme caution, and the size and influence of signal drift should be measured where possible.

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YNICL Journal 2014 Journal Article

Assessment of blood–brain barrier disruption using dynamic contrast-enhanced MRI. A systematic review

Anna K. Heye
Ross D. Culling
Maria del C. Valdés Hernández
Michael J. Thrippleton
Joanna M. Wardlaw

There is increasing recognition of the importance of blood-brain barrier (BBB) disruption in aging, dementia, stroke and multiple sclerosis in addition to more commonly-studied pathologies such as tumors. Dynamic contrast-enhanced MRI (DCE-MRI) is a method for studying BBB disruption in vivo. We review pathologies studied, scanning protocols and data analysis procedures to determine the range of available methods and their suitability to different pathologies. We systematically review the existing literature up to February 2014, seeking studies that assessed BBB integrity using T1-weighted DCE-MRI techniques in animals and humans in normal or abnormal brain tissues. The literature search provided 70 studies that were eligible for inclusion, involving 417 animals and 1564 human subjects in total. The pathologies most studied are intracranial neoplasms and acute ischemic strokes. There are large variations in the type of DCE-MRI sequence, the imaging protocols and the contrast agents used. Moreover, studies use a variety of different methods for data analysis, mainly based on model-free measurements and on the Patlak and Tofts models. Consequently, estimated K (Trans) values varied widely. In conclusion, DCE-MRI is shown to provide valuable information in a large variety of applications, ranging from common applications, such as grading of primary brain tumors, to more recent applications, such as assessment of subtle BBB dysfunction in Alzheimer's disease. Further research is required in order to establish consensus-based recommendations for data acquisition and analysis and, hence, improve inter-study comparability and promote wider use of DCE-MRI.

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