White matter microstructural abnormalities in blast-exposed combat veterans: accounting for potential pre-injury factors using consanguineous controls

Purpose: Assess the prevalence of white matter microstructural changes in combat veterans, within the context of a highly matched control group comprising unexposed close relatives. Methods: This prospective study had institutional review board approval, included written informed consent, and is HIPAA-compliant. Diffusion tensor imaging was analyzed in 16 male blast-exposed combat veterans of Operation Iraqi Freedom/Operation Enduring Freedom (mean age 31.0 years) and 18 unexposed males (mean age 30.4 years) chosen on the basis of a consanguineous relationship to a member of the subject group. Whole-brain voxel-based comparison of fractional anisotropy (FA) was performed using both group and individual analyses. Areas where effects on FA were detected were subsequently characterized by extracting radial diffusivity (RD), axial diffusivity (AD), and mean diffusivity (MD) from the regions of abnormal FA. Results: Controls did not differ from veterans on any background demographic factor. In voxel-based group comparison, we identify high fractional anisotropy (FA) in veterans compared to controls (p < 0.01). Within individual veterans, we find multiple areas of both abnormally high and low FA (p < 0.01) in a heterogeneous distribution, consistent with multifocal traumatic axonal injury. In individualized analyses, low FA areas demonstrate high radial diffusivity, whereas high FA areas demonstrate low RD in both group and individual analyses. Conclusions: Combat-related blast exposure is associated with microstructural white matter abnormalities, and the nature of the control group decreases the likelihood that the findings reflect underlying background differences. Abnormalities are heterogeneously distributed across patients, consistent with TAI, and include areas of low and high FA.