Stroke represents a major cause of death and disability in our elderly veterans. Stroke is also a major risk factor for cognitive decline, most often due to vascular cognitive impairment. Veterans with stroke or transient ischemic attack (TIA) due to large-artery disease are at highest risk for early recurrence and are, therefore, most often subjected to aggressive interventions. Furthermore, large- artery disease has been recognized as an independent risk factor for cognitive impairment. The ability to predict recurrence and prognosis following stroke is crucial for developing novel prevention and treatment strategies. Current diagnostic criteria for stroke include clinical and imaging data. However, no biomarker is currently available that can reliably predict recurrence and prognosis. Lack of such knowledge limits our ability to prevent future ischemic strokes or cognitive decline. Coated-platelets are a subset of procoagulant platelets observed after co-activation with collagen and thrombin. Coated-platelet levels are significantly higher in patients with ischemic stroke or TIA compared to unaffected controls. In addition, higher levels, measured after the initial infarct correlate with an increased risk for recurrent stroke. Among stroke patients, those with stroke due to large-artery disease and elevated coated-platelet levels have a rate of early recurrent stroke 6-7 fold higher than those with lower coated-platelet levels. Research efforts focusing on platelet biology have shown that platelet micro-RNA (miRNA) has considerable potential for deciphering mechanisms underlying differences in platelet reactivity through modulation of gene expression and protein translation. In preliminary studies, we have shown increased coated-platelet production in patients with stroke due to large-artery disease compared to patients with stroke due to cardiac causes and we have found that differences in the expression of platelet miRNA species may be linked to coated- platelet production. These findings raise the possibility that coated-platelets will serve as an additional risk stratification tool in stroke, through mechanisms that involve platelet miRNA expression. The research hypotheses for the current grant are: 1) Coated-platelet levels in patients with stroke/TIA due to large-artery disease are markers for prognosis and recurrence risk: higher levels indicate increased likelihood of recurrent ischemic stroke while lower levels indicate an increased likelihood of hemorrhagic complications, 2) Elevated coated-platelet levels predict the presence and progression of cognitive impairment in patients with stroke/TIA due to large-artery disease, and 3) Increased coated-platelet production is mediated through individual micro-RNAs in stroke patients. The objective of the current application is to determine the relationship of coated-platelets to stroke due to large-artery disease. Three specific aims will test these hypotheses: 1) Determine the relationship between coated-platelets levels and prognosis in patients with stroke/TIA due to large- artery disease, 2) Test the hypothesis that elevated coated-platelets are predictive of cognitive impairment in stroke/TIA due to large-artery disease, and 3) Identify micro-RNA (miRNA) species associated with coated-platelet production. We plan to test our hypotheses in a large group of patients with stroke/TIA due to large-artery disease (N=430). The rationale for the proposed research is that once we understand the relationship between coated-platelets and cerebrovascular disease we will be able to improve health care delivery for our veterans with stroke through individualized risk assessment strategies and to identify potential targets for novel pharmacological interventions that involve miRNA-mediated platelet reactivity.