Injury Severity and Free-Water Volume Fraction Predict Regional White Matter Atrophy During the First Year Following Moderate-Severe Traumatic Brain Injury

Traumatic axonal injury is a common endophenotype of traumatic brain injury (TBI) in which injury to axons is a dominant component. In previous investigations, we identified a significant reduction of white matter (WM) volume from 3 to 12 months post-injury, an increased rate of atrophy during this period associated with a longer duration of post-traumatic amnesia (PTA), widespread reductions in white-matter fractional anisotropy (FA), and elevated free-water (FW) content in a cohort of moderate-to-severe TBI patients. To provide a more comprehensive characterization of the spatiotemporal trajectory of TBI-induced WM degeneration, we have estimated the spatial distribution of WM atrophy related to the duration of PTA in the first year following moderate-to-severe TBI (msTBI) (N = 33) and examined the degree to which baseline diffusion measures of WM integrity, FW and FW-corrected fractional anisotropy (F-FA), were each associated with subsequent WM atrophy. WM atrophy was observed diffusely across the brain, with the greatest effects in the splenium of the corpus callosum, corona radiata, and brainstem. Increased atrophy in the central WM was correlated with greater duration of PTA. Finally, elevated FW volume fraction at 3 months post-injury predicted greater subsequent WM atrophy, while F-FA did not show a significant relationship. These findings suggest that early FW elevation may serve as a biomarker of progressive WM neurodegeneration following TBI, and neuroinflammatory processes may underlie this relationship. Future research should directly investigate the underlying mechanisms of FW-related neuropathology and its role in progressive neurodegeneration following msTBI.