Sturge-Weber syndrome (SWS) is a sporadic neurocutaneous disorder characterized by a facial port-wine birthmark and leptomeningeal vascular malformation (LVM). SWS most often (85%) affects one cerebral hemisphere and has a progressive but highly variable clinical course, thus providing a unique clinical model to study the neurocognitive effects of an early, postnatal, unilateral brain lesion. Most children with SWS develop seizures during the first 2 years of life and also develop neurological symptoms as well as cognitive impairment. Currently, SWS has no cure or specific treatment. With NIH support and nationwide patient recruitment, we have built a clinical imaging research program for children with SWS, in order to understand the pathophysiology of progression and find new diagnostic and treatment paradigms. We have tested novel MRI approaches for more accurate detection of SWS-related brain abnormalities and identified critical age windows when most of the progressive brain damage occurs. Recently, we have also identified two, potentially powerful compensatory mechanisms that may prevent severe neurocognitive complications of SWS-related brain injury: (i) a deep venous vascular remodeling in the ipsilateral (SWS-affected) hemisphere, and (ii) reorganization in the contralateral hemisphere affecting both verbal and non-verbal cognitive functions. We also identified a subgroup of children with SWS whose cognitive functions improved over time, presumably due to effective compensatory processes.
In Aim 1 of this renewal proposal, we will test the application of a recently developed rapid MRI protocol (called STAGE) for safe and accurate early screening and late follow-up of brain vascular and parenchymal abnormalities. This new, innovative imaging approach is widely applicable and could change clinical practice for SWS imaging, used as a screening technique in preventive trials, and be utilized in other pediatric neurological diseases.
In Aim 2, we will extend our previous studies to older children and young adults with SWS to use susceptibility-weighted imaging and diffusion tensor imaging connectivity studies to evaluate the role of vascular remodeling and structural brain reorganization, respectively, in the preservation and reorganization of motor symptoms and specific cognitive functions that can be targeted by interventions.
In Aim 3, we will use SWS epilepsy surgical tissue to harvest cells from both the LVM and various parenchymal cells and utilize a laser capture microdissection approach to identify specific cell types harboring the somatic GNAQ mutation. We will also study the imaging correlates and associated protein changes associated with dysregulated angiogenesis. The expected findings could fundamentally shape our concept as to how this mutation can lead to brain pathology and will also identify novel treatment targets.

Public Health Relevance

In this renewal application we will test a novel, rapid, non-sedate, non-contrast MRI approach to detect brain vascular and parenchymal abnormalities with a short, few-minute acquisition time in children with Sturge- Weber syndrome (SWS); this new approach can be also readily applied in other pediatric brain disorders. We will also study the effects of venous vascular remodeling and structural brain reorganization on neurocognitive outcome of school-age and adolescent children and young adults with SWS, who could benefit from targeted interventions to optimize clinical outcome. Finally, we will use brain tissue from SWS epilepsy surgeries to identify vascular and non-vascular cell types harboring the SWS-associated GNAQ somatic gene mutation and evaluate how the mutation is associated with brain abnormalities and protein changes related to abnormal cell development that could be targeted by pharmacological treatments.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Babcock, Debra J
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Wayne State University
Schools of Medicine
United States
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Luat, Aimee F; Behen, Michael E; Chugani, Harry T et al. (2018) Cognitive and motor outcomes in children with unilateral Sturge-Weber syndrome: Effect of age at seizure onset and side of brain involvement. Epilepsy Behav 80:202-207
Kumar, Ananyaa; Juhász, Csaba; Luat, Aimee et al. (2018) Evolution of Brain Glucose Metabolic Abnormalities in Children With Epilepsy and SCN1A Gene Variants. J Child Neurol 33:832-836
Kim, Jeong-A; Jeong, Jeong-Won; Behen, Michael E et al. (2018) Metabolic correlates of cognitive function in children with unilateral Sturge-Weber syndrome: Evidence for regional functional reorganization and crowding. Hum Brain Mapp 39:1596-1606
De la Torre, Alejandro J; Luat, Aimee F; Juhász, Csaba et al. (2018) A Multidisciplinary Consensus for Clinical Care and Research Needs for Sturge-Weber Syndrome. Pediatr Neurol 84:11-20
Govil-Dalela, Tuhina; Kumar, Ajay; Behen, Michael E et al. (2018) Evolution of lobar abnormalities of cerebral glucose metabolism in 41 children with drug-resistant epilepsy. Epilepsia 59:1307-1315
Sundaram, Senthil K; Michelhaugh, Sharon K; Klinger, Neil V et al. (2017) GNAQ Mutation in the Venous Vascular Malformation and Underlying Brain Tissue in Sturge-Weber Syndrome. Neuropediatrics 48:385-389
Pilli, Vinod K; Behen, Michael E; Hu, Jiani et al. (2017) Clinical and metabolic correlates of cerebral calcifications in Sturge-Weber syndrome. Dev Med Child Neurol 59:952-958
Pilli, Vinod K; Chugani, Harry T; Juhász, Csaba (2017) Enlargement of deep medullary veins during the early clinical course of Sturge-Weber syndrome. Neurology 88:103-105
Juhász, Csaba (2016) Predicting and Preventing Epilepsy in Sturge-Weber Syndrome? Pediatr Neurol Briefs 30:43
Bosnyák, Edit; Behen, Michael E; Guy, William C et al. (2016) Predictors of Cognitive Functions in Children With Sturge-Weber Syndrome: A Longitudinal Study. Pediatr Neurol 61:38-45

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