NAME: Ty Shang

eRA COMMONS USER NAME: tshang

POSITION TITLE: Associate Professor, Department of Neurology, UT Southwestern Medical Center, Dallas, Texas

EDUCATION/TRAINING

A.  Personal Statement                                              

As a vascular neurologist, I possess the expertise and experience necessary to effectively manage stroke and cerebrovascular disease. Since joining the University of Texas Southwestern Medical Center (UTSWMC) in 2012, I have served as the principal investigator for several clinical trials, generating novel insights into acute stroke treatment and secondary stroke prevention. Both Clements University Hospital and Parkland Memorial Hospital, affiliated with UTSWMC, have been certified as Comprehensive Stroke Centers by the Joint Commission, with over 1000 stroke patients admitted to these institutions annually. Moreover, the Peter O’Donnell Jr. Brain Institute was established at UTSWMC in 2020, employing a multidisciplinary approach to the study of neurological disease. This state-of-the-art institute facilitates collaborative efforts across various fields of study to advance our understanding of stroke and neurovascular diseases and improve patient outcomes.

My research interests focus on the discovery of imaging or fluid biomarkers that can aid in the prevention and treatment of cerebrovascular diseases, with a particular emphasis on the roles of inflammatory and infectious processes in these conditions. I am especially interested in exploring treatment options for cerebrovascular diseases that currently lack effective therapies, such as Moyamoya Disease/Syndrome (MMD/MMS), CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy), and MELAS (Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). In my research, I apply high-resolution vessel wall imaging MRI (HR VWI) and MR spectroscopy technology to study these challenging cerebrovascular diseases.

Moyamoya Disease has captured my attention since my residency and was one of the key reasons I pursued fellowship training. I have been studying MMD/MMS using HR VWI and fluid biomarkers to explore the roles of infection, inflammation, and autoimmune processes in its pathogenesis. Several studies have been published from these work, including the first investigation into the frequency of cerebral microbleeds (cMB) and the identification of biomarkers on HR VWI for vasculopathy progression in a Western population. Over the years, increasing evidence has suggested that autoinflammatory mechanisms play a significant role in the development of Moyamoya disease. Based on my understanding, I believe that neurogenic inflammation mediated by trigeminal ganglion dysfunction in genetically susceptible individuals eventually leads to Moyamoya vasculopathy. I am deeply committed to investigating this hypothesis and exploring treatment options involving neurovascular modulation. My ultimate goal is to find an effective treatment for MMD/MMS.

1. Shang T and Yavagal D. Application of Acute Stroke Imaging: Selecting Patients for Revascularization Therapy. Neurology 2012 79(13 Suppl): S86-94. PMID: 23008419.
2. Shang T. Cerebral hemodynamics and cognitive performance in bilateral asymptomatic carotid stenosis. Neurology 2013 28;80(22):2080. PMID: 23858529. 
3. Shang T, Welch B, and Pinho M. Letter by Shang et al Regarding Article, "High-Resolution Magnetic Resonance Wall Imaging Findings of Moyamoya Disease" Stroke 2014 45(12):e299. PMID:25316280
4. Pinho MC, Hall JT, Cross JC, Shang T, Madhuranthakam AJ, and Moore WA. Intracranial Vessel Wall MRI in Clinical Practice – technical considerations, current and emerging applications, clinical pearls and pitfalls. Neurographics 8(2): 97-118, 2018.

I have published papers under the name of “Tiesong Shang”.

B.        Positions and Honors

Positions and Employment

1. 1994. Physician, Department of Internal Medicine, Qingzhou People’s Hospital, Shandong, China

1997-1999     Physician, Department of Radiology, Beijing Jishuitan Hospital, Beijing, China

2012-2020     Assistant Professor, Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas

2020-2024     Associate Professor, Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas

Other Experience and Professional Memberships

2000-                          Member, Society for Neuroscience

2008-                          Member, Society of Vascular and Interventional Neurology

2009-                          Member, American Academy of Neurology

2010-                          Member, American Heart Association

2010-                          Member, American Stroke Association

Honors and Award

2010                           Resident Travel Grant, SVIN 3^rd Annual Meeting, San Francisco, CA

2010                           Resident Travel Grant, SVIN Practicum and Interactive Laboratory, Atlanta, GA

2012                           Annual Meeting Fellow Scholarship, American Academy of Neurology, New Orleans, LA   

2020              Best Abstract Award and Oral presentation. Internal Stroke Conference Feb 19-21,    

                      2020, Los Angles, CA. (New Mutations linked to Cerebral Autosomal Recessive  

                      Arteriopathy with Subcortical Infarcts and Leukoencephalopathy in the Africa and North

                      America).

Board Certifications and Licensure

10/2011-                  Neurology, American Board of Psychiatry and Neurology

7/2011-7/2012               Florida Medical License

8/2012-                    Texas Medical License

1/2014-                    Neurosonology American Society of Neuroimaging

10/2014-                  Vascular Neurology, American Board of Psychiatry and Neurology

C.        Contribution to Science

1. The clinical presentation of MMD differs in Asian and Western populations. There is higher risk of intracerebral hemorrhage in Asian population then Western population. The etiology for this discrepancy is unclear. Cerebral microbleed is a known risk factors for intracerebral hemorrhage. The incidence of cerebral microbleed in MMD in Asian population is reported to be about 30-50%. Research from our MMD Database showed the prevalence of cerebral microbleed is about 10% in the United States, which is much lower than in Asia. This could explain the lower risk of intracerebral hemorrhage of MMD in US population. This is the first epidemiological report on cerebral microbleeds in MMD within a Western population, initially presented as an abstract at ISC 2016 and later published in Cerebrovascular Diseases Extra in 2019. As the corresponding author, I developed the idea, organized the team, and led the study to publication

Khan N, Saherwala A, Chen M, Salehian S, Salahuddin H, Welch B, Pinho M, Shang T Prevalence of and Risk Factors for Cerebral Microbleeds in Moyamoya Disease and Syndrome in the American Population. Cerebrovasc Dis Extra. 2019;9(3):139-147

2.   The role of inflammation in MMD has been a subject of debate. HR VWI demonstrated vessel wall enhancement (VWE) in MMD patients within an Asian population, suggesting inflammatory changes in the arterial walls. To explore this further, we conducted a retrospective investigation into the role of VWE in MMD among a Western population. Our findings revealed that VWE is more prevalent in Western MMD patients who experienced ischemic strokes or transient ischemic attacks (TIA) within the past two years (symptomatic MMD). Additionally, vasculopathy progression was more frequent in arteries exhibiting VWE compared to those without. This is the first study in a Western population to suggest that VWE could serve as a biomarker for selecting patients for interventional studies. The study was presented as an abstract at ISC 2022, and the manuscript is currently in preparation. As the corresponding author, I developed the concept, organized the team, and led the study toward publication.

a.   Shang T, Welch B, and Pinho M. Letter by Shang et al Regarding Article, "High-Resolution Magnetic Resonance Wall Imaging Findings of Moyamoya Disease" Stroke 2014 45(12):e299. PMID:25316280

b.   Pinho MC, Hall JT, Cross JC, Shang T, Madhuranthakam AJ, and Moore WA. Intracranial Vessel Wall MRI in Clinical Practice – technical considerations, current and emerging applications, clinical pearls and pitfalls. Neurographics 8(2): 97-118, 2018.

c.   Tran C, Rana C, Moore W, and Shang T. Vessel Wall Enhancement is Associated With Symptomatic Adult Moyamoya Disease or Syndrome in An American Population. International Stroke Conference Feb 8-10, 2023, Dallas, TX.

3.   Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL) is a rare genetic cerebrovascular disease caused by homozygous mutations in the HTRA1 gene. While it is more prevalent in Asian populations, only one case had been reported in the United States before my work. I reported the second U.S. case, involving a young Hispanic gentleman with a unique mutation that had never been documented before. Additionally, I identified and reported the second case of heterozygous HTRA1 mutations in an African American individual. These cases were patients I encountered during my practice at UTSW. I recognized the disease pattern, ordered the appropriate tests, analyzed the results, reviewed the literature, and completed the manuscript.

Ty Shang, Marco Pinho, Debarti Ray, Alka Khera. Two Unique Mutations in HTRA1-Related Cerebral Small Vessel Disease in North America and Africa and Literature Review. J Stroke Cerebrovasc Dis 2021 Nov;30(11):106029.

4. Intracranial atherosclerotic disease (ICAD) accounts for approximately 20% of ischemic strokes and is a significant cause of ischemic stroke worldwide. Despite aggressive medical therapy, patients with >70% stenosis face a high risk of recurrent stroke or death, with rates reaching up to 12.6% at one year. Currently, there is no reliable imaging biomarker to identify high-risk patients. However, we have identified a subgroup of ICAD patients who are at higher risk of recurrent stroke due to significantly altered hemodynamics. Notably, patients with a distal hyperintensity vessel sign on FLAIR imaging are at particularly high risk for early recurrent ischemic stroke. These patients may benefit from anticoagulation or endovascular therapy. As the corresponding author, I developed the concept, organized the team, and led the study toward publication. 

Salahuddin H, Saherwala A, Pinho MC, Moore W, Castonguay A, Khan NI, Jeelani F, Uppal H, He H, Campbell J, Shang T. Association of distal hyperintense vessel sign and recurrent stroke in patients with symptomatic intracranial stenosis J Stroke Cerebrovasc Dis. 31(9):106616, 2022. PMID: 35816788

5. The molecular pathogenic mechanisms in Parkinson Disease (PD) is unknown. Environmental toxin exposure and mitochondria damage are related to PD. Using a cellular model of mitochondria toxin (MPP⁺) induced neurotoxicity, complex pathways of neuronal death are delineated in my early publications. The pathways involve both free radical dependent and independent routes. Intracellular free iron induced toxicity plays major roles in free radical dependent neuronal death. For free radical independent pathway, a new neuronal death signaling pathway from mitochondria to death associated protein kinase was discovered for the first time. As a graduate student at the Medical College of Wisconsin, I published several papers under the guidance of my PhD mentor, Dr. Kalyanaraman. In addition to collaborating with my mentor, I developed my own ideas, independently designed experiments, and completed and published manuscripts, including the following: Death-associated protein kinase as a sensor of mitochondria membrane potential ― Role of lysosome in mitochondria toxin induced cell death. J. Biol. Chem. 2005 280(41):34644-53. PMID: 16085644

1. Shang T, Uihlein AV, Van Asten J, Kalyanaraman B, and Hillard CJ. 1-Methyl-4-phenylpyridinium accumulates in cerebellar granule neurons via organic cation transporter 3. J Neurochem. 2003 85:358-67. PMID: 12675912.
2. Shang T, Kotamraju S, Kalivendi SV, Hillard CJ, and Kalyanaraman B. 1-Methyl-4-phenylpyridinium-induced apoptosis in cerebellar granule neurons is mediated by transferrin receptor iron-dependent depletion of tetrahydrobiopterin and neuronal nitric-oxide synthase-derived superoxide. J. Biol. Chem. 2004 279:19099-112. PMID: 14752097.
3. Shang T, Kotamraju S, Zhao HT, Kalivendi S, Hillard CJ, and Kalyanaraman B. Sepiapterin attenuates 1-methyl-4-phenylpyridinium-induced apoptosis in neuroblastoma cells transfected with neuronal NOS: Role of tetrahydrobiopterin, nitric oxide and proteasome activation. Free Radic. Biol. Med. 2005 39(8):1059-74. PMID: 16198233.
4. Shang T, Joseph J, Hillard CJ, and Kalyanaraman B. Death-associated protein kinase as a sensor of mitochondria membrane potential ― Role of lysosome in mitochondria toxin induced cell death. J. Biol. Chem. 2005 280(41):34644-53. PMID: 16085644.

Complete List of Published Work in MyBibliography:

https://www.ncbi.nlm.nih.gov/myncbi/ty.shang.2/bibliography/public/

D.        Research Support

Ongoing Clinical Trials or Research Support

A multicenter, randomized, placebo controlled, double-blind, parallel group and event driven Phase 3 study of the oral FXIa inhibitor asundexian (BAY 2433334) for the secondary prevention of ischemic stroke in adult patients with an acute non-cardioembolic ischemic stroke or high-risk TIA (OCEANIC-Stroke)

Bayer Pharmaceutics company                                                                                        11/2023 - present

Role: Site PI  

Moyamoya Disease/Syndrome Database Registry

Department of Neurology, UTSW                      Shang (PI)                                       3/01/2013-present

This is a propective registry study aiming to investigate the pathogensis, natural history and outcome of this unique disease of intrcranial vasculopathy.

Role: PI

Completed Clinical Trials or Research Support

Optimal delay time to initiate anticoagulation after ischemic stroke in atrial fibrillation (START): a pragmatic, adaptive randomized clinical trial

Lone Start Stroke Consortium                                                                                           1/1/2018-2023

Role: Site PI

Atrial cardiopathy and antithrombotic drugs in prevention after cryptogenic stroke (ARCADIA).

Stroke net, NIH                                                                                                                  2/1/2018-2023

Role: Site PI

Phase2/3 Study of Intravenous Thrombolysis and Hypothermia for Acute Treatment of Ischemic Stroke Intravascular Cooling in the Treatment of Stroke 2/3 (ICTuS 2/3) Trial

The study is to determine whether the combination of thrombolysis and hypothermia is superior to thrombolysis alone for the treatment of acute ischemic stroke. The study will be conducted in two stages: a Phase 2 study to assess the safety of various protocol changes, to demonstrate sufficient recruitment, and to allow an interim analysis for futility; and a Phase 3 efficacy study to follow if pre-specified milestones are achieved.

NIH                                           Patrick D. Lyden, MD (PI)                                                   5/20/2014-9/31/2015

Role: Site PI

A Randomized Pilot Study Assessing Vagus Nerve Stimulation (VNS) During Rehabilitation for Improved Upper Limb Motor Function after Stroke

MicroTransponder, Deptment of Neurology, UTSW        Robert Rennaker (PI)              09/01/14-07/31/15             

This is a study designed to provide information on the clinical use of vagus nerve stimulation (VNS) during upper limb motor rehabilitation for the treatment of upper limb deficits associated with stroke. This clinical study is proposed as primary support for the design and implementation of a pivotal study for US market approval; it is expected to give safety and efficacy information.

Role: Site PI