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 variants 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.

Illustration of stroke injury and recovery, plot of NIHSS score overtime with and without Tissue plasminogen activator (TPA) treatment.


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