While stroke is the third leading cause of death and the leading cause of adult disability, there is only one approved stroke therapy at present that reaches a small percentage of patients. One major factor for the lack of stroke treatments is the lack of knowledge about stroke pathophysiology. The projects of the Stroke Neuroscience Unit are focused on determining the mechanisms and modifying factors associated with ischemic brain injury and with recovery after stroke, by the in vivo analysis of human peripheral blood and tissue samples. Currently the laboratory is exploring the clinical significance of (1) inflammatory and (2) genetic markers on stroke risk and outcome, the ultimate aim being to identify biomarkers and molecular and genetic targets for novel therapies. Over the past year, a number of (1) inflammatory markers have been identified that are predictive of stroke risk, while an increase in a novel T cell subset has been found to be significantly associated with stroke recurrence and death. In the Women's Health Initiative, elevated C-reactive protein, e-selectin, total white blood cell count and interleukin-6 were predictive of stroke. Periodontal disease was found to be predictive of stroke risk in a meta-analysis performed in collaboration with investigators at the Harvard School of Public Health. In our lab, a novel marker for stroke recurrence and death has been identified: clonal expansion of a T cell subset, CD4+CD28-. Elevated levels of these cells are associated with a 2.5 times greater risk of stroke recurrence and/or death at one year, after adjustment for age, stroke severity and a history of prior stroke. These cells may serve as a biomarker and potential therapeutic target for preventing stroke recurrence and death. We have also identified a number of cytokines from peripheral blood mononuclear cells stimulated in culture that are elevated in patients relative to controls, suggesting activation of monocytes and neutrophils early after stroke onset (tumor necrosis factor and interleukin-8). In the (2) stroke genomics studies, the gene expression profile of peripheral blood mononuclear cells from 20 patients and 20 controls has been analyzed and 113 genes have been identified that are significantly different between patients and controls. Validation studies are in progress in an independent series of 10 patients and 10 controls. Initial results are showing that the training dataset shows good discrimination between patients and controls. Studies are ongoing and being extended to the genomic profile associated with stroke recovery.
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