The overall goal of this research proposal is to understand mechanisms of early brain injury, identify early imaging markers of clinical progression, and introduce new diagnostic approaches as well as therapeutic targets in children with Sturge-Weber syndrome (SWS). During the first cycle of funding, our longitudinal approach to the assessment of structural and metabolic abnormalities in SWS allowed us to define the time frame of disease progression and the role of white matter changes in cognitive decline. The longitudinal design also allowed us to demonstrate imaging correlates of progressive neuro-cognitive deficit, and also showed that the metabolic abnormalities are sometimes reversible, suggesting an opportunity for early therapeutic interventions. Recent studies also suggest that leptomeningeal angiomas may not be static lesions, and remodeling of vessel abnormalities may lead to increased protein synthesis. During the previous funding period, we implemented several novel imaging modalities which now allow us to measure brain perfusion, have higher sensitivity for detecting vascular malformations and white matter changes, and can measure protein synthesis. These preliminary studies have provided new insights in the pathophysiology of SWS and have led to new hypotheses to be tested in this proposal. We will combine several advanced MRI and PET techniques, including: (1) dynamic perfusion weighted imaging (PWI);(2) diffusion tensor imaging (DTI);(3) susceptibility weighted imaging (SWI), and (4) PET scanning of cerebral glucose metabolism. In addition, we will explore the use of [11C]leucine PET to assess abnormal protein synthesis in the angioma and surrounding brain regions. We propose three aims: (1) To evaluate early cerebral hemodynamic changes and their significance for metabolic and clinical progression in young children with unilateral SWS. (2) To understand the role of cortical and white matter damage in neurocognitive outcome (including seizures, motor deficit and cognitive impairment) in children with SWS. (3) To determine whether increased protein synthesis in the region of the angioma is a predictor for severity of disease progression. The proposed studies will identify advanced imaging markers that can be used clinically to make the diagnosis early and identify damaged and ?at-risk? brain regions, and also predict clinical outcome. These imaging techniques will help select patients for novel therapeutic approaches affecting various aspects of pathology in SWS to halt or diminish the progressive course, and also monitor therapeutic effects. In addition, the proposed studies will serve the wider medical community by (i) establishing the clinical use and evaluate the functional and clinical correlates of advanced MRI and PET techniques in children, and (ii) better understanding mechanisms of progressive brain damage due to chronic ischemia. This research project will apply advanced neuroimaging techniques, including various magnetic resonance imaging (MRI) and positron emission tomography (PET) methods, in a prospective, longitudinal fashion, combined with neuro-psychology testing, to understand mechanisms of early brain injury in children with Sturge-Weber syndrome. The results are expected to introduce novel, more accurate diagnostic tests and also identify new therapeutic targets to improve the outcome of this often devastating disease.
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