Longitudinal Associations Between Blood Biomarkers and White Matter MRI in Sport-Related Concussion
Yu‐Chien Wu, Qiuting Wen, Rhea Thukral, Ho‐Ching Yang, Jessica Gill, Sujuan Gao, Kathleen A. Lane, Timothy B. Meier, Larry Riggen, Jaroslaw Harezlak, Christopher C. Giza, Joshua Goldman, Kevin M. Guskiewicz, Jason P. Mihalik, Stephen M. LaConte, Stefan M. Duma, Steven P. Broglio, Andrew J. Saykin, Thomas W. McAllister, Michael McCrea
Abstract
<h3>Objective</h3> To study longitudinal associations between blood-based neural biomarkers (including total tau, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and ubiquitin C-terminal hydrolase-L1 (UCH-L1)) and white-matter neuroimaging biomarkers in collegiate athletes with sport-related concussion (SRC) from 24-hours post-injury to 1 week after return-to-play. <h3>Methods</h3> We analyze clinical and imaging data of concussed collegiate athletes in the Concussion Assessment, Research and Education (CARE) Consortium. The CARE participants completed same-day clinical assessments, blood draws, and diffusion tensor imaging (DTI) at 3 time points: 24-48 hours post-injury, point of becoming asymptomatic, and 7 days following return-to-play. DTI probabilistic tractography was performed for each subject at each time point to render 27 subject-specific major white-matter tracts. The microstructural organization of these tracts was characterized by four DTI metrics. Mixed-effects models with random intercepts were applied to test whether white-matter microstructural abnormalities are associated with the blood-based biomarkers at the same time point. An interaction model was used to test if the association varies across time points. A lagged model was used to test if early blood-based biomarkers predict later microstructural changes. <h3>Results</h3> Data from 77 collegiate athletes were included in the following analyses. Among the 4 blood-based biomarkers, total tau had significant associations with the DTI metrics across the 3 time points. In particular, tau was positively associated with radial diffusivity (RD) in the right corticospinal tract (β=0.25, SE=0.07, <i>p</i><sub><i>FDR-adjusted</i></sub>=0.016) and superior thalamic radiation (β=0.21, SE=0.07, <i>p</i><sub><i>FDR-adjusted</i></sub>=0.042). NfL and GFAP had time-dependent associations with the DTI metrics. NfL showed significant associations only at the asymptomatic time point (|β|s>0.12, SEs<0.09, <i>ps</i><sub><i>FDR-adjusted</i></sub><0.05) and GFAP showed a significant association only at 7-days following return-to-play (βs>0.14, SEs<0.06, <i>ps</i><sub><i>FDR-adjusted</i></sub><0.05). The p-values for the associations of early tau and later RD were not significant after multiple comparison adjustment, but were less than 0.1 in seven white-matter tracts. <h3>Conclusions</h3> This prospective study using data from the CARE Consortium demonstrated that in the early phase of SRC, white-matter microstructural integrity detected by DTI neuroimaging was associated with elevated levels of blood-based biomarkers of traumatic brain injury. Total tau in the blood showed the strongest association with white-matter microstructural changes.