Stroke is recognized as a major cause of disability and death in elderly veterans. Stroke also represents a critical, and potentially preventable, risk factor for cognitive decline mostly in the form of vascular cognitive impairment in veterans. Silent brain infarctions (SBIs) are a manifestation of covert cerebrovascular disease, without obvious clinical deficit but linked to a significant increase in risk for subsequent stroke and cognitive decline. Identifying early markers of stroke risk in all veterans is crucial for developing novel prevention and effective treatment strategies. While SBIs are strongly linked to increased rates for both stroke and cognitive decline, no biomarker is currently available that can predict the recurrence or location of these subclinical lesions. Lack of such knowledge limits our ability to prevent ischemic strokes and vascular cognitive impairment in the aging veteran population. Coated-platelets, a subset of procoagulant platelets observed after co-activation with collagen and thrombin, are significantly increased in patients with ischemic stroke or transient ischemic attack (TIA) compared to unaffected controls. Higher coated-platelet levels, measured after the initial infarct correlate with an increased risk for recurrent stroke and with lower cognitive performance post-stroke. Among medications used to prevent stroke recurrence, we identified clopidogrel as a pharmacological agent resulting in a sustained decrease in coated-platelet levels. In preliminary studies, we have shown that higher coated-platelet levels in patients with stroke and TIA are strongly associated with both the presence and number of SBIs. Additionally, we have found that differential expression of platelet micro-RNA (miRNA) species may be linked to coated-platelet production, thereby providing potential for deciphering mechanisms underlying differences in platelet reactivity through modulation of gene expression. These novel findings raise the possibility that coated-platelets will serve as a risk stratification tool for SBIs and are part of mechanisms involving platelet procoagulant potential and platelet miRNA expression that explain the occurrence of SBIs. The research questions for the current grant are: 1) Are coated-platelet levels markers for increased incidence of SBIs in patients with stroke/TIA? and 2) Does clopidogrel treatment decrease the incidence of SBIs? The objective of the current application is to determine the role of coated-platelets as a marker for SBIs and as a treatment target to decrease incident SBI. Three specific aims will test these hypotheses: 1) Determine the relationship between coated-platelets levels and incident silent brain infarction in veterans with stroke/TIA, and 2) Evaluate the efficacy of clopidogrel on the incidence of silent brain infarction in veterans with stroke/TIA using a randomized, double-blind aspirin-controlled clinical trial. We plan to test our hypotheses in a large group of patien...