Imaging collaterals and tissue metabolism in patients with Moyamoya syndrome

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Abstract The goal of this work is to apply novel neuroimaging methods in patients with Moyamoya syndrome to test fundamental hypotheses regarding hemodynamic compensation, stroke history, and symptomatology. Moyamoya disease (MMD) has unknown etiology and is characterized by steno-occlusion of the supraclinoid internal carotid arteries and proximal branches, development of collateral vessels, and a high risk of stroke. Idiopathic MMD is relatively rare, however moyamoya syndrome (MMS), which can arise secondary to Down syndrome, sickle cell disease, atherosclerosis, and radiotherapy shares many phenotypical characteristics as idiopathic MMD, yet is observed much more frequently. Patients with MMS are at high risk for stroke, and compared with atherosclerotic disease where preferred treatment regimens are outlined by recent clinical trial results, optimal MMS therapies are less clear and may comprise medical management and/or surgical revascularization. Owing to the dynamic course of MMS, which includes a wide variation of progressive steno- occlusion, abnormal expression of endothelial growth factors and inflammatory proteins, hemo-metabolic disturbances, intimal vessel wall thickening, and neoangiogensis, there is a pressing clinical need to understand the pathophysiology of these processes, how they relate to symptomatology and stroke incidence, and ultimately may be used to stratify patients for therapy or guide development of novel pharmaceuticals. The critical barrier to achieving this rests with a lack of optimal methods that can be implemented for mapping and surveillance. Here, in adults and children with MMS, we propose to implement new MRI methods developed in our center to test focused hypotheses regarding (Aim 1) relationships between endothelial dysfunction, stroke incidence, and symptomatology; (Aim 2) changes in vessel wall morphology, disease chronicity, and neurological symptoms; and (Aim 3) oxygen extraction fraction response to surgical revascularization therapy. The short-term significance of this work is that it will improve our understanding of the physiological processes that underlie how tissue responds to proximal non-atherosclerotic steno-occlusion and revascularization, which will serve as a prerequisite for utilizing functional neuroimaging to stratify patients with MMS for appropriate therapy. The longer-term goal is to use this information to guide the development of novel pharmaceuticals or early screening procedures that may enable therapies to be titrated to patients prior to irreversible tissue damage. Finally, methods implemented are translatable to other vascular diseases, and findings should have broader relevance for discerning pathophysiological differences between atherosclerotic and non- atherosclerotic hemodynamic compensation mechanisms.