Stotesbury, Hanne; (2021) Vascular Instability and Neurological Morbidity in Sickle Cell Disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

It is well-established that patients with sickle cell disease (SCD) are at substantial risk of neurological complications, including overt stroke, silent cerebral infarction, microstructural tissue injury, and cognitive impairment. Yet the underlying mechanisms remain poorly understood, partly because findings have largely been considered in isolation. This thesis reviews mechanistic pathways for which there is accumulating evidence and proposes an integrative systems-biology framework for understanding neurological risk. The framework proposes that macro-circulatory hyper-perfusion, regions of relative micro- circulatory hypo-perfusion, and an exhaustion of cerebral reserve mechanisms, together lead to a state of cerebral vascular instability. In this state, tissue oxygen supply is fragile and easily perturbed by changes in clinical condition, with the potential for stroke, SCI, and/or microstructural tissue injury if metabolic demand exceeds tissue oxygenation; all of which may increase the risk of cognitive impairment. The thesis then describes three original cross- sectional research studies in which quantitative MRI methods are used to identify potential biomarkers that may serve to indirectly interrogate parts of the proposed framework. The first study explores silent cerebral infarction, with a comprehensive analysis of the effects of published radiological definitions on quantitative lesion metrics, and explores the value of global, regional, and lobar lesion metrics based on different definitions for prediction of cognitive outcome. The second study focuses on microstructural tissue injury, employing novel diffusion and multiparametric mapping techniques to explore tissue changes both in normal appearing white matter and silent cerebral infarction, as well as any relationships between them. The third study employs arterial spin labeling techniques to identify potential quantitative biomarkers of regional haemodynamic stress, and explores associations with exposure to hypoxia, structural tissue injury (i.e. SCI and white matter integrity reductions), and cognitive outcome. Findings are considered in the context of the proposed framework, and suggestions for future research to further refine the framework are provided.

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