Free Water Volume Fraction: An Imaging Biomarker to Characterize Moderate-to-Severe Traumatic Brain Injury

Traumatic brain injury (TBI) is a major clinical and public health problem with few therapeutic interventions successfully translated to the clinic. Identifying imaging-based biomarkers characterizing injury severity and predicting long-term functional and cognitive outcomes in TBI patients is crucial for treatment. TBI results in white matter (WM) injuries, which can be detected using diffusion tensor imaging (DTI). Trauma-induced pathologies lead to accumulation of free water (FW) in brain tissue, and standard DTI is susceptible to the confounding effects of FW. In this study, we applied FW DTI to estimate free water volume fraction (FW-VF) in patients with moderate-to-severe TBI and demonstrated its association with injury severity and long-term outcomes. DTI scans and neuropsychological assessments were obtained longitudinally at 3, 6, and 12 months post-injury for 34 patients and once in 35 matched healthy controls. We observed significantly elevated FW-VF in 85 of 90 WM regions in patients compared to healthy controls ( < 0.05). We then presented a patient-specific summary score of WM regions derived using Mahalanobis distance. We observed that M at 3 months significantly predicted functional outcome ( = 0.008), executive function ( = 0.005), and processing speed ( = 0.01) measured at 12 months and was significantly correlated with injury severity ( < 0.001). Our findings are an important step toward implementing M as a biomarker for personalized therapy and rehabilitation planning for TBI patients.