Others have looked at more acute stress tasks in the laboratory and report changes consistent with hemoconcentration. Such findings have implications for cardiovascular disease risk in acute and chronic stress. It is also associated with aging-related brain changes including the presence of hyperintense lesions, bright areas occurring in the brain parenchyma as seen on T2-weighted magnetic resonance imaging. These changes are primarily ischemic in origin, and although are observed in normal aging, are often more severe in older depressed individuals. The relationship between these hyperintense lesions and antidepressant treatment outcomes is unclear. Several studies have concluded that greater hyperintense lesion severity is associated with poorer response to antidepressants. Greater hyperintensity severity is additionally associated with significantly more adverse drug reactions, which may result in early drug discontinuation or inability to increase doses to therapeutic levels. In contrast, other studies have not found a relationship between cross-sectional lesion severity and acute antidepressant outcomes, although relationships may exist between longitudinal change in lesion severity and longer-term course of depression. More recent work investigating late-life depression has utilized diffusion tensor imaging. DTI can MK-1775 quantify water diffusion, which in living tissue is constrained by neuronal integrity and modulated by myelin. DTI measures include the apparent diffusion coefficient, a general measure of diffusion which may serve as a surrogate marker for fiber density, and anisotropy, which measures the direction of water diffusion and has been proposed to be a surrogate marker for white matter orientation and organization. Similar to what is observed in old stroke regions, white matter hyperintense lesions increase ADC and decrease anisotropy, and greater hyperintense lesion severity is associated with more widespread alterations in DTI measures even in normal appearing white matter. Although several studies have reported that depressed elders exhibit reduced frontal and temporal anisotropy, this technique has not been used as extensively to study treatment response. One group has examined the relationship between DTI measures and antidepressant response in geriatric depression, associating failure to achieve remission with reduced fractional anisotropy in multiple regions, including the cingulate gyrus and dorsolateral prefrontal cortex. The purpose of this study was to use DTI to examine if measures of frontal white matter microstructure were associated with acute 12-week response to sertraline. We hypothesized that lower fractional anisotropy and higher diffusivity, a pattern of findings associated with both chronic stroke and hyperintense lesions, would be associated with failure to achieve remission. In turn, we hypothesized that individuals who remitted would exhibit higher frontal FA measures. Subjects were recruited from advertisements and outpatient clinical referrals at Duke University Medical Bortezomib Center.