OBJECTIVE We investigated the association between metabolic syndrome risk factors and brain tissue integrity, as assessed by magnetic resonance imaging. RESEARCH DESIGN AND METHODS From the Leiden Longevity Study, which is a community-based study of long-lived subjects, their offspring, and partners thereof, 130 subjects (61men; mean age 66 years)were included. A metabolic syndrome scorewas computed by summing the individual number of components according to the Adult Treatment Panel III criteria. We performed linear and logistic regression analysis and used standardized b-values to assess the association between metabolic syndrome and brainmacrostructure (brain volume andwhitematter lesion load, lacunar infarcts, and cerebral microbleeds) and microstructure (mean magnetization transfer ratio [MTR], MTR histogram peak height, fractional anisotropy, and mean diffusivity [MD]). Linear and stepwise regression analysis was performed to identify the individual contribution of one metabolic syndrome parameter adjusting for the four other parameters. Models were adjusted for age, sex, and relation to longlived family. RESULTS Brain macrostructure was not associated with metabolic syndrome. In contrast, metabolic syndrome was associated with decreased gray (b =20.3 P = 0.001) and whitematter peak height (b =20.3, P = 0.002) and increased gray matter MD (b = 0.2, P = 0.01, P = 0.01). Serum HDL cholesterol (b = 0.22, P = 0.012), triglycerides (b =20.25, P = 0.002), BMI (b =20.2, P = 0.014), and diastolic blood pressure (b = 20.17, P = 0.047, and b=20.23, P = 0.009, for gray and white matter, respectively) were independent factors in these changes in brain microstructure.CONCLUSIONS In early manifestmetabolic syndrome, brain tissue decline can be detected. Serum HDL cholesterol, triglycerides, BMI, and diastolic blood pressure were independent factors in brain tissue integrity.