During the first hours after ischemic stroke onset, neurological deficits can be highly unstable - some patients spontaneously improve while others deteriorate. These early neurological changes are important because they have a large influence on long-term outcome. Potential mechanisms accounting for rapid improvement include fibrinolysis/ reperfusion, recruitment of collateral circulation, or endogenous neuroprotective mechanisms;while mechanisms leading to deterioration include thrombus propagation, peri-infarct spreading depression, or hemorrhagic transformation (HT). Tissue plasminogen activator (tPA), the only FDA-approved drug for the treatment of acute ischemic stroke (AIS), enhances the likelihood of fibrinolysis and reperfusion;but also increases the chances of HT. We hypothesize that genetic variant that affect pathogenic mechanism during acute ischemia may influence early neurological outcomes after AIS, and may also modulate response to IV tPA. In this grant, we propose to identify genetic variants associated with early neurological outcome in AIS patients (untreated or treated with IV tPA). These data will permit us to find novel genes/pathways and potential therapeutic targets that could improve outcome after AIS, and perhaps enhance tPA efficacy. Further, an individual's genetic profile may one day provide personalized risk stratification for treatment with IV tPA, which may guide therapeutic decisions. Currently, we have accumulated 1000 samples from phenotyped AIS patients treated with tPA from both sites (the largest such sample set in the world), which will be used for gene discovery (Discovery Series). During the grant period, we will collect an additional 3000 samples (Replication Series), which will include both tPA-treated and untreated patients so that we can determine which genetic associations are tPA-dependent or independent influences on early neurological outcomes after AIS. We propose 4 aims.
Aim 1 : To perform genome-wide association studies, examining early neurological improvement or deterioration after AIS.
Aim 2 : To determine which genetic variants that modulate levels of plasma analytes relevant to AIS pathogenesis influence early neurological outcomes.
Aim 3 : To replicate genome-wide associations, we will test candidate variants/genes in an independent cohort of AIS patients.
And Aim 4 : To determine which variants/genes associated with early outcome are tPA-dependent. At the conclusion of this grant, we will identify many variants/genes that influence early neurological outcome after AIS, and will also find variants/genes that influence outcome in a tPA-dependent manner. These findings will have both diagnostic and therapeutic implications.

Public Health Relevance

In this grant application, we propose to study genetic influences on early outcomes after acute ischemic stroke. It is likely that genes play a role in determining how a patient fares after a stroke. By identifying specific genes or mutations that play a role in early outcomes after stroke, we will be able to further understand important pathways involved in brain injury following stroke. This may lead to diagnostic tests, or the identification of potential targets for future therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS085419-01A1
Application #
8704525
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Gwinn, Katrina
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Traylor, Matthew; Malik, Rainer; Nalls, Mike A et al. (2017) Genetic variation at 16q24.2 is associated with small vessel stroke. Ann Neurol 81:383-394
Guilliams, Kristin P; Fields, Melanie E; Ragan, Dustin K et al. (2017) Large-Vessel Vasculopathy in Children With Sickle Cell Disease: A Magnetic Resonance Imaging Study of Infarct Topography and Focal Atrophy. Pediatr Neurol 69:49-57
Ong, Charlene Jennifer; Gluckstein, Jeffrey; Laurido-Soto, Osvaldo et al. (2017) Enhanced Detection of Edema in Malignant Anterior Circulation Stroke (EDEMA) Score: A Risk Prediction Tool. Stroke 48:1969-1972
Deming, Yuetiva; Li, Zeran; Kapoor, Manav et al. (2017) Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers. Acta Neuropathol 133:839-856
Shireman, Theresa I; Wang, Kaijun; Saver, Jeffrey L et al. (2017) Cost-Effectiveness of Solitaire Stent Retriever Thrombectomy for Acute Ischemic Stroke: Results From the SWIFT-PRIME Trial (Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke). Stroke 48:379-387
Cruchaga, Carlos; Del-Aguila, Jorge L; Saef, Benjamin et al. (2017) Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms. Alzheimers Dement :
(2017) 19th Workshop of the International Stroke Genetics Consortium, April 28-29, 2016, Boston, Massachusetts, USA: 2016.001 MRI-defined cerebrovascular genomics-The CHARGE consortium. Neurol Genet 3:S2-S11
Haddick, Patrick C G; Larson, Jessica L; Rathore, Nisha et al. (2017) A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer's Disease Brains. J Alzheimers Dis 56:1037-1054
Dhar, Rajat; Yuan, Kristy; Kulik, Tobias et al. (2016) CSF Volumetric Analysis for Quantification of Cerebral Edema After Hemispheric Infarction. Neurocrit Care 24:420-7
Leon Guerrero, Christopher R; Pathak, Sheel; Grange, Dorothy K et al. (2016) Neurologic and neuroimaging manifestations of CantĂș syndrome: A case series. Neurology 87:270-6

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