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Background: Fractional anisotropy (FA) measured by Diffusion Tensor Imaging (DTI) is a sensitive biomarker of white matter (WM) integrity and offers a means to detect early axonal disruption and attendant cognitive impairment secondary to vascular disease.Hypothesis: We hypothesized that hypertension (HTN), of all known risk factors, is most closely linked to early WM tract injury in apparently healthy high risk relatives of patients with early-onset coronary artery disease (CAD).Methods: DTI was acquired on a Phillips 3T MRI scanner (slice thickness 2.2 mm, field of view 212X212 mm and b-value 700 mm2/s) for relatives of CAD patients. The brain was segmented into 181 regions using the Eve Atlas, Large Deformation Diffeomorphic Metric Mapping paradigm, and 48 regions representing the deep WM were selected for analysis. Mean regional FA (rFA) was assessed using t-tests in persons with and without smoking, HTN, diabetes. Continuous variable association with rFA was tested using Spearman correlations. Covariate-adjusted GEE linear regression (corrected for nonindependence of families) was performed for regions meeting the Bonferroni threshold of 0.001 (0.05/48).Results: 116 subjects had DTI data (mean age 49.5±11, 57% males, 40.5% African Americans, 23% smokers, 36% hypertensives, 12% diabetics). rFA was not significantly associated with diabetes or current smoking. Moreover, rFA was not significantly correlated with glucose level, LDL, total cholesterol or body mass index. However, patients with HTN showed a significantly lower rFA compared to normotensives in the left (L) genu of corpus callosum, L external capsule, right (R) cingulum, L fornix/ stria terminalis, L and R column and body of fornix, and R sagittal stratum. After adjusting for age, sex and race, this relation remained significant in the R sagittal stratum (P=0.012) and R cingulum (P=0.001). Systolic blood pressure (SBP) correlated with rFA after adjustment in the L superior longitudinal fasciculus as well (unadjusted rho=-0.309, p=0.00073, adjusted beta =-1.08+-0.47, P=0.02).Conclusions: Of all of the risk factors, as hypothesized, HTN and SBP were significantly associated with early WM tract injury in areas related to cognition in middle-aged persons at risk for vascular disease.