The overall goal of this research proposal is to understand mechanisms of brain injury and clinical progression, as well as introduce new imaging biomarkers and therapeutic targets in children with unilateral Sturge-Weber syndrome (SWS). During the first cycle of funding, our longitudinal approach to the assessment of structural, metabolic and neuro-cognitive abnormalities in SWS defined the time frame of disease progression and imaging correlates of neuro-cognitive deficit. The main focus of our continuing studies is to understand the specific mechanisms leading to highly variable neurological and cognitive outcomes in SWS despite limited initial brain involvement. Our general hypothesis is that the cerebral vascular malformation, rather than the traditional view as being static, undergoes proliferative transformation in patients with a progressive course. This hypothesis is based upon our novel preliminary data that the angioma shows increased protein synthesis on [11C]leucine PET and abnormal expression of proliferation markers and angiogenic proteins in vascular endothelial cells in resected tissues. The second major finding during the first cycle of finding was evidence for a perfusion/metabolic mismatch in the cortex, due to perfusion changes measured by MR Perfusion Weighted Imaging (PWI) extending beyond the MR structural and PET glucose metabolic abnormalities. Finally, we found that white matter volume loss and abnormal water diffusion were related to cognitive deficits in our sample of children with SWS. To study these mechanisms of disease progression, we will combine advanced MRI and PET techniques, as well as immunohistochemistry studies from resected tissue to address three aims: (1) To study protein synthesis, increased proliferative activity and expression of angiogenic factors in the region of the angioma, and to determine if increased protein synthesis measured by PET is associated with progressive cognitive and neurological deficits in children with unilateral SWS. (2) To evaluate early cerebral hemodynamic changes and their significance for metabolic and neurological progression. (3) To evaluate white matter diffusion abnormalities and their contribution to cognitive outcome. The proposed studies are expected to identify novel therapeutic targets in SWS. Most importantly, proliferative leptomeningeal angiomas may be amenable to anti-angioma therapies, which would be a major breaktrough in the clinical management of SWS. The applied advanced imaging techniques can also be used to monitor future therapeutic trials aimed at preventing ischemic cortical damage and white matter injury. In addition, the proposed studies will serve the wider medical community by establishing the clinical use and evaluate the functional and clinical correlates of advanced MRI and PET techniques in children, and better understanding mechanisms of progressive brain damage due to chronic ischemia.

Public Health Relevance

The goal of this research project is to understand mechanisms of disease progression in children with Sturge-Weber syndrome. We will apply advanced neuroimaging techniques, including various magnetic resonance imaging (MRI) and positron emission tomography (PET) methods, combined with immunohistochemistry studies of resected brain and angioma tissues, to study proliferative changes and abnormal angiogenesis in the leptomeningeal angioma, as well as structural, perfusion, and metabolic changes in the underlying cortex and white matter. The results will introduce novel, more accurate diagnostic tests and also identify new therapeutic targets to improve the outcome of this often devastating disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Babcock, Debra J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wayne State University
Schools of Medicine
United States
Zip Code
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; Chugani, Harry T; Juhász, Csaba (2017) Enlargement of deep medullary veins during the early clinical course of Sturge-Weber syndrome. Neurology 88:103-105
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
Kim, Jeong-A; Jeong, Jeong-Won; Behen, Michael E et al. (2017) Metabolic correlates of cognitive function in children with unilateral Sturge-Weber syndrome: Evidence for regional functional reorganization and crowding. Hum Brain Mapp :
Juhász, Csaba (2016) Predicting and Preventing Epilepsy in Sturge-Weber Syndrome? Pediatr Neurol Briefs 30:43
Comi, Anne M; Sahin, Mustafa; Hammill, Adrienne et al. (2016) Leveraging a Sturge-Weber Gene Discovery: An Agenda for Future Research. Pediatr Neurol 58:12-24
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
Juhász, Csaba; Hu, Jiani; Xuan, Yang et al. (2016) Imaging increased glutamate in children with Sturge-Weber syndrome: Association with epilepsy severity. Epilepsy Res 122:66-72
Jeong, Jeong-won; Tiwari, Vijay N; Shin, Joseph et al. (2015) Assessment of brain damage and plasticity in the visual system due to early occipital lesion: comparison of FDG-PET with diffusion MRI tractography. J Magn Reson Imaging 41:431-8
Kamson, David O; Juhász, Csaba; Chugani, Harry T et al. (2015) Novel diffusion tensor imaging technique reveals developmental streamline volume changes in the corticospinal tract associated with leg motor control. Brain Dev 37:370-5

Showing the most recent 10 out of 45 publications