Dr. Nestor Gonzalez is an Assistant Professor of Neurosurgery at UCLA, where he holds a full-time Academic In-Residency position. He has a track of excellence in his studies before and during medical school, as well as during residency and fellowship training. His original work has led to the publication of 11 first-author papers in recognized scientific journals including Journal of Neurosurgery, Neurosurgery and Stroke. He has performed contributory studies in patients with intracranial aneurysms, vasospasm, ischemic stroke, and, of relevance for this application, in the use of indirect surgical revascularization (EDAS) in the management of moyamoya disease and intracranial arterial stenosis. Career Goals and Objectives: Dr. Gonzalez long-term career goal is to become a national leader in clinical translational research and clinical trials in Vascular Neurosurgery. Hi immediate goal with this application is to acquire the necessary training, knowledge and hands-on experience to become an independent leading clinical investigator in his field. His clinical expertise needs to be complemented with training in the appropriate methods of clinical research to fulfill that potential. Environment: The research project and the educational activitie planned for Dr. Gonzalez will take place at UCLA. He has support from the UCLA Stroke Center, directed by Dr. Jeff Saver - Dr. Gonzalez' mentor; the UCLA Laboratory of Neuroimaging (LONI), directed by Dr. Arthur Toga; the UCLA Division of Neuroimaging, with Dr. Noriko Salamon as co-mentor, the UCLA Clinical and Translational Science Institute (CTSI) that would provide support with the resources for clinical trial and data management, and the formal educational training for Dr. Gonzalez through the Masters in Clinical Science, directed by Dr. Elashoff - co-mentor for Dr. Gonzalez; and the Department of Neurosurgery, in which Dr. Gonzalez has obtained additional support for his research interest though the Stotter Chair Endowment for 5 years. He will be relieved of a significant portion of his teaching and clinical activities during the K23 award, to allow a dedication of at least 50%. He also has assembled a respected group of External Advisors that include Dr. Mark Chimowirz, Dr. Colin Derdeyn, Dr. Yuko Palesch, Dr. Michael Scott, and Dr. Greg Albers that would guide beyond the mentors' role the design and implementation of the trial he is proposing. Research: Stroke due to intracranial arterial atherosclerosis is a significant medical problem, carrying one of the highest rates of recurrent stroke despite medical therapy, with annual recurrence rates for ischemic stroke reported in the SAMMPRIS Trial as high as 12.2% in the intensive medical therapy arm. The incidence of recurrence stroke can be even higher in some high-risk groups, as high as 25% in African-Americans and females. The goal of the research proposed by Dr. Gonzalez is to advance a new, promising surgical treatment for symptomatic atherosclerotic intracranial stenosis - encephaloduroarteriosynangiosis (EDAS). Compared with direct revascularization operations (bypass), EDAS has the advantages of being less technically demanding, avoiding temporary occlusion of cerebral vessels, and allowing gradual development of collateral circulation where the brain demands it, deterring early hyper perfusion and hemorrhage. There has been no systematic trial exploring the use of EDAS in cases of symptomatic, non-moyamoya intracranial arterial stenosis. Based on his preliminary positive results, he has the long-term objective of demonstrating that EDAS improves the outcome in patients with symptomatic intracranial stenosis compared with aggressive medical therapy. This will require future phase III clinical trials. The present proposal has the purpose of testing in a phase II futility trial the potential of EDAS for further development before proceeding with the design of a definitive clinical trial of EDAS Revascularization in patients with Symptomatic Intracranial Arterial Stenosis (ERSIAS). The present project will be 4-year futility trial to determine if EDAS revascularization combined with aggressive medical therapy warrants further evaluation in a subsequent pivotal trial as an alternative to aggressive medical management alone for preventing the primary endpoint of stroke or death at two years in patients with symptomatic intracranial arterial stenosis (Specific Aim 1). During the investigation he also proposes to systematically evaluate the time course of collateral genesis and perfusion improvement following EDAS. This detailed knowledge on the timing of collateral development on digital subtraction angiography and of improved blood flow on perfusion MRI will provide useful physiologic information to monitor and refine the EDAS procedure and post-procedure management, and provide a better understanding of the intracranial atherosclerotic pathologic process (Specific Aim 2). Dr. Gonzalez plans year 5 of this award to the publication of the trial results, as well as the physiologic, angiographic, and MRI perfusion results on collateral formation, and to the independent planning of a subsequent phase III multicenter trial. The new knowledge generated by this study on understanding the role of collateral circulation in stroke pathophysiology, patient selection, and use of non-invasive imaging will be useful not only for EDAS evaluation but potentially next generation stents and future novel medical therapies, such as use of angiogenic growth factors and/or endothelial stem cells.

Public Health Relevance

This clinical study will advance a surgical technique to improve blood supply to the brain in patients at high risk of stroke. The improvement of blood flow could prevent strokes in a significant number of cases. The knowledge obtained in the study will allow planning and adequate selection of candidates for this novel form of treatment and provide valuable insight in the disease process of stroke of relevance for this and other forms of therapy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Mentored Patient-Oriented Research Career Development Award (K23)
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NST-1 Subcommittee (NST-1)
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Janis, Scott
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Cedars-Sinai Medical Center
Independent Hospitals
Los Angeles
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Gonzalez, Nestor R; Liou, Raymond; Kurth, Florian et al. (2018) Antiangiogenesis and medical therapy failure in intracranial atherosclerosis. Angiogenesis 21:23-35
Laiwalla, A N; Kurth, F; Leu, K et al. (2017) Evaluation of Encephaloduroarteriosynangiosis Efficacy Using Probabilistic Independent Component Analysis Applied to Dynamic Susceptibility Contrast Perfusion MRI. AJNR Am J Neuroradiol 38:507-514
Laiwalla, Azim N; Ooi, Yinn Cher; Van De Wiele, Barbara et al. (2016) Rigorous anaesthesia management protocol for patients with intracranial arterial stenosis: a prospective controlled-cohort study. BMJ Open 6:e009727
Ooi, Y C; Laiwalla, A N; Liou, R et al. (2016) Angiographic Structural Differentiation between Native Arteriogenesis and Therapeutic Synangiosis in Intracranial Arterial Steno-Occlusive Disease. AJNR Am J Neuroradiol 37:1086-91
Laiwalla, Azim N; Ooi, Yinn Cher; Liou, Raymond et al. (2016) Matched Cohort Analysis of the Effects of Limb Remote Ischemic Conditioning in Patients with Aneurysmal Subarachnoid Hemorrhage. Transl Stroke Res 7:42-8
Nikkola, Elina; Laiwalla, Azim; Ko, Arthur et al. (2015) Remote Ischemic Conditioning Alters Methylation and Expression of Cell Cycle Genes in Aneurysmal Subarachnoid Hemorrhage. Stroke 46:2445-51
Connolly, Mark; Vespa, Paul; Pouratian, Nader et al. (2015) Characterization of the relationship between intracranial pressure and electroencephalographic monitoring in burst-suppressed patients. Neurocrit Care 22:212-20
Shi, Zhong-Song; Duckwiler, Gary R; Jahan, Reza et al. (2015) New Cerebral Microbleeds After Mechanical Thrombectomy for Large-Vessel Occlusion Strokes. Medicine (Baltimore) 94:e2180
Ooi, Yinn Cher; Gonzalez, Nestor R (2015) Management of extracranial carotid artery disease. Cardiol Clin 33:1-35
Gonzalez, Nestor R; Connolly, Mark; Dusick, Joshua R et al. (2014) Phase I clinical trial for the feasibility and safety of remote ischemic conditioning for aneurysmal subarachnoid hemorrhage. Neurosurgery 75:590-8; discussion 598

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