Wardlaw, Joanna

Marshall, Ian

Blair, Gordon William

Stroke Association

Alzheimer’s Society

British Heart Foundation

EU Horizon 2020

Fondation Leduq

2023-04-24T09:23:40Z

2023-04-24T09:23:40Z

2023-04-24

INTRODUCTION: Cerebral small vessel disease (SVD) is the cause of a quarter of all ischaemic strokes and is postulated to have a role in up to half of all dementias. SVD pathophysiology remains unclear but cerebrovascular dysfunction may be important. If confirmed many licensed medications have mechanisms of action targeting vascular function, potentially enabling new treatments via drug repurposing. Knowledge is limited however, as most studies assessing cerebrovascular dysfunction are small, single centre, single imaging modality studies due to the complexities in measuring cerebrovascular dysfunctions in humans. This thesis describes the development and application of imaging techniques measuring several cerebrovascular dysfunctions to investigate SVD pathophysiology and trial medications that may improve small blood vessel function in SVD. METHODS: Participants with minor ischaemic strokes were recruited to a series of studies utilising advanced MRI techniques to measure cerebrovascular dysfunction. Specifically MRI scans measured the ability of different tissues in the brain to change blood flow in response to breathing carbon dioxide (cerebrovascular reactivity; CVR) and the flow and pulsatility through the cerebral arteries, venous sinuses and CSF spaces. A single centre observational study optimised and established feasibility of the techniques and tested associations of cerebrovascular dysfunctions with clinical and imaging phenotypes. Then a randomised pilot clinical trial tested two medications’ (cilostazol and isosorbide mononitrate) ability to improve CVR and pulsatility over a period of eight weeks. The techniques were then expanded to include imaging of blood brain barrier permeability and utilised in multi-centre studies investigating cerebrovascular dysfunction in both sporadic and monogenetic SVDs. RESULTS: Imaging protocols were feasible, consistently being completed with usable data in over 85% of participants. After correcting for the effects of age, sex and systolic blood pressure, lower CVR was associated with higher white matter hyperintensity volume, Fazekas score and perivascular space counts. Lower CVR was associated with higher pulsatility of blood flow in the superior sagittal sinus and lower CSF flow stroke volume at the foramen magnum. Cilostazol and isosorbide mononitrate increased CVR in white matter. The CVR, intra-cranial flow and pulsatility techniques, alongside blood brain barrier permeability and microstructural integrity imaging were successfully employed in a multi-centre observational study. A clinical trial assessing the effects of drugs targeting blood pressure variability is nearing completion. DISCUSSION: Cerebrovascular dysfunction in SVD has been confirmed and may play a more direct role in disease pathogenesis than previously established risk factors. Advanced imaging measures assessing cerebrovascular dysfunction are feasible in multi-centre studies and trials. Identifying drugs that improve cerebrovascular dysfunction using these techniques may be useful in selecting candidates for definitive clinical trials which require large sample sizes and long follow up periods to show improvement against outcomes of stroke and dementia incidence and cognitive function.

https://hdl.handle.net/1842/40521

http://dx.doi.org/10.7488/era/3287

en

The University of Edinburgh

Magnetic resonance imaging for assessment of cerebrovascular reactivity in cerebral small vessel disease: A systematic review. Blair GW, Doubal FN, Thrippleton MJ, Marshall I, Wardlaw JM. Journal of Cerebral Blood Flow & Metabolism. 2016;36(5):833-841. https://doi.org/10.1177/0271678X16631756

Advanced Neuroimaging of Cerebral Small Vessel Disease. Gordon W. Blair, Maria Valdez Hernandez, Michael J. Thrippleton, Fergus N. Doubal & Joanna M. Wardlaw. Current Treatment Options in Cardiovascular Medicine volume 19, Article number: 56 (2017). https://doi.org/10.1007/s11936-017-0555-1

Intracranial hemodynamic relationships in patients with cerebral small vessel disease. Gordon W. Blair, Michael J. Thrippleton, Yulu Shi, Iona Hamilton, Michael Stringer, Francesca Chappell, David Alexander Dickie, Peter Andrews, Ian Marshall, Fergus N. Doubal, Joanna M. Wardlaw. Neurology, May 2020, 94 (21) e2258-e2269; DOI: https://doi.org/10.1212/WNL.0000000000009483

Preventing cognitive decline and dementia from cerebral small vessel disease: The LACI-1 Trial. Protocol and statistical analysis plan of a phase IIa dose escalation trial testing tolerability, safety and effect on intermediary endpoints of isosorbide mononitrate and cilostazol, separately and in combination. Blair, G. W., Appleton, J. P., Law, Z. K., Doubal, F., Flaherty, K., Dooley, R., Shuler, K., Richardson, C., Hamilton, I., Shi, Y., Stringer, M., Boyd, J., Thrippleton, M. J., Sprigg, N., Bath, P. M., & Wardlaw, J. M. (2018). International Journal of Stroke, 13(5), 530–538. https://doi.org/10.1177/1747493017731947

Tolerability, safety and intermediary pharmacological effects of cilostazol and isosorbide mononitrate, alone and combined, in patients with lacunar ischaemic stroke: The LACunar Intervention-1 (LACI-1) trial, a randomised clinical trial. Gordon W. Blair, Jason P. Appleton, Katie Flaherty, Fergus Doubal, Nikola Sprigg, Richard Dooley, Carla Richardson, Iona Hamilton, Zhe Kang Law, Yulu Shi, Michael S. Stringer, Michael J. Thrippleton, Julia Boyd, Kirsten Shuler, Philip M. Bath, Joanna M. Wardlaw. EClinicalMedicine, Volume 11, 2019, Pages 34-43, ISSN 2589-5370. https://doi.org/10.1016/j.eclinm.2019.04.001

Effects of Cilostazol and Isosorbide Mononitrate on Cerebral Hemodynamics in the LACI-1 Randomized Controlled Trial. Gordon W. Blair, Esther Janssen, Michael S. Stringer, Michael J. Thrippleton, Francesca Chappell, Yulu Shi, Iona Hamilton, Katie Flaherty, Jason P. Appleton, Fergus N. Doubal, Philip M. Bath, Joanna M. Wardlaw. Stroke. 2021;0:STROKEAHA.121.034866. https://doi.org/10.1161/STROKEAHA.121.034866

Imaging NeuroVascular, Endothelial and STructural Integrity in prepAration to TrEat Small Vessel Diseases. The INVESTIGATE-SVDs study Protocol. Part of the SVDs@Target Project. Gordon W. Blair, Michael S. Stringer, Michael J. Thrippleton, Francesca M. Chappell, Kirsten Shuler, Iona Hamilton, Daniela Jaime Garcia, Fergus N. Doubal, Anna Kopczak, Marco Duering, Michael Ingrisch, Danielle Kerkhofs, Julie Staals, Hilde van den Brink, Tine Arts, Walter H Backes, Robert van Oostenbrugge, Geert Jan Biessels, Martin Dichgans, Joanna M. Wardlaw. Cerebral Circulation – Cognition and Behaviour. 2021 Vol. 2. DOI: https://doi.org/10.1016/j.cccb.2021.100020

A comparison of CVR magnitude and delay assessed at 1.5 and 3T in patients with cerebral small vessel disease. Stringer MS*, Blair GW*, Shi Y, Hamilton I, Dickie DA, Doubal FN, Marshall IM, Thrippleton MJ, Wardlaw JM. Frontiers in Physiology, 2021, Vol12 https://doi.org/10.3389/fphys.2021.644837

Effects of Isosorbide Mononitrate and/or Cilostazol on Hematological Markers, Platelet Function, and Hemodynamics in Patients With Lacunar Ischaemic Stroke: Safety Data From the Lacunar Intervention-1 (LACI-1) Trial. Appleton Jason P., Blair Gordon W., Flaherty Katie, Law Zhe Kang, May Jane, Woodhouse Lisa J., Doubal Fergus, Sprigg Nikola, Bath Philip M., 3 Wardlaw Joanna M. Frontiers in Neurology 2019, VOLUME=10, PAGE=723, ISSN=1664-2295. https://doi.org/10.3389/fneur.2019.00723

Cerebrovascular reactivity measurement in cerebral small vessel disease: Rationale and reproducibility of a protocol for MRI acquisition and image processing. Thrippleton, M. J., Shi, Y., Blair, G., Hamilton, I., Waiter, G., Schwarzbauer, C., Pernet, C., Andrews, P. J., Marshall, I., Doubal, F., & Wardlaw, J. M.. International Journal of Stroke,(2018),13(2),195–206. https://doi.org/10.1177/1747493017730740

Small vessel disease is associated with altered cerebrovascular pulsatility but not resting cerebral blood flow. Shi, Y., Thrippleton, M. J., Blair, G. W., Dickie, D. A., Marshall, I., Hamilton, I., Doubal, F. N., Chappell, F., & Wardlaw, J. M.. Journal of Cerebral Blood Flow & Metabolism, (2020) 40(1), 85–99. https://doi.org/10.1177/0271678X18803956

Cilostazol for Secondary Prevention of Stroke and Cognitive Decline: Systematic Review and Meta-Analysis. Caroline McHutchison, Gordon W. Blair, Jason P. Appleton, Francesca M. Chappell, Fergus Doubal, Philip M. Bath, Joanna M. Wardlaw. Stroke. 2020;51:2374–2385. https://doi.org/10.1161/STROKEAHA.120.029454

Cerebrovascular dysfunction

small vessel disease

cerebral small vessel disease

ischaemic strokes

dementia

cerebrovascular reactivity

cilostazol

isosorbide mononitrate

blood brain barrier permeability

monogenetic SVD

Cerebrovascular dysfunction in cerebral small vessel disease

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy