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Biomarkers of blood vessel injury and hypercoagulability in childhood moyamoya disease
Supervisors: Dr Vijeya Ganesan, Dr Despina Eleftheriou, Dr Paul Brogan, and Professor Nigel Klein
Moyamoya disease (MMD) is a rare cerebrovascular disease radiologically characterised by occlusion of the terminal internal carotid artery and its immediate branches and the development of characteristic basal collateral vessels (1, 2). The resulting vascular blush observed on angiograms of patients with MMD gave this disease its name, which in Japanese means “puff of smoke” (1, 2). Children may present with arterial ischaemic stroke (AIS), transient ischaemic attacks (TIAs) and/or seizures (1-2). The moyamoya angiographic pattern is associated with the highest risk of recurrence in childhood AIS (3). However, patients’ clinical courses are highly variable and this is not currently predictable on the basis of any clinical or radiological parameters (3). Most studies of MMD have been in East Asian populations in whom there is an aggressive and progressive clinical course (2). However, the natural history is much more variable in other patients, making disease biomarkers of even greater potential importance (2-3). For example, surgical revascularisation is currently advocated for stroke prevention in MMD but without a prognostic indicator it is difficult to identify patients who are likely to benefit from this. A progressive disease course in MMD may, in some cases, be related to persistence of cerebral arterial injury and sub-clinical endothelial activation. Biomarkers indicative of persistence and/or propagation of cerebrovascular injury could inform the use of therapies such as surgical revascularisation to be targeted at highest risk patients, whilst avoiding unnecessary intervention in those predicted to have a non-progressive disease course. In this project we will test the hypothesis that patients with MMD and ongoing symptomatology (TIAs and/or recurrent stroke) have persistent cerebrovascular injury and impaired endothelial repair responses resulting in progressive arteriopathy and further cerebral ischaemia.
The aims of this project are therefore to:
1) Examine whether biomarkers of endothelial injury (whole circulating endothelial cells and cellular microparticles) and related hypercoagulability (microparticle mediated thrombin generation) differ between children with MMD and ongoing symptomatology (TIAs/recurrent strokes) versus those with a single stroke event.
2) Establish whether progressive MMD (ongoing symptomatology TIAs/recurrent strokes) is mediated in part by abnormalities in repair of chronic endothelial injury due to altered endothelial progenitor cells (EPC) repair responses.
Study design and plan of investigation: This will be a cross sectional study of children >28 days old with AIS (acute focal neurologic deficit attributable to cerebral infarction in a corresponding arterial distribution) and radiological evidence of MMD defined as above presenting or under follow up to Great Ormond Street Hospital NHS Foundation Trust (GOSH). Patients will be considered in 2 groups: children with MMD and ongoing symptomatology (TIAs and/or recurrent strokes) and those with MMD and a single event. Blood samples for research purposes (see below) will be taken at time of recruitment and compared between patient groups and age matched healthy controls. The following data will be collected: (i) Clinical, laboratory, and radiologic data; (ii) Biomarkers of endothelial injury and cellular activation. Circulating endotheothelial cells (CECs) will be assessed using CD 146-conjugated magnetic bead extraction from whole blood (4). Circulating microparticles will be characterised (platelet, endothelial, neutrophil and monocyte origin) using flow cytometry (4). (iii) Prothrombotic potential of circulating MPs will be evaluated using an MP mediated thrombin generation assay (4); (iv) Endothelial repair responses: EPC sub-populations will be identified with flow cytometry as PBMC expressing CD34, CD133, KDR and CD 34, CD133 and CD144. EPC function will be evaluated by the potential of these cells to form colony forming units (CFU), and by their ability to incorporate into endothelial cell vascular structures in matrigel.
We anticipated that this project will provide immediate insights into the pathogenesis of MMD and will lead to a panel of biomarkers that can be used to predict stroke recurrence and offer the possibility of risk stratification for surgical revascularisation.
1) Scott RM, Smith ER. Moyamoya disease and moyamoya syndrome. New England Journal of Medicine 2009;360:1226-1237.
2) Schoenberg BS, Mellinger JF, Schoenberg DG. Moyamoya disease in children. Southern medical journal 1978;71:237.
3) Ganesan V, Prengler M, Wade A, Kirkham FJ. Clinical and radiological recurrence after childhood arterial ischemic stroke. Circulation 2006;114:2170-2177.
4) Eleftheriou D, Ganesan V, et al. Endothelial injury in childhood stroke with cerebral arteriopathy: a cross sectional study. Neurology 2012.Epub.