Association Between Proteomic Blood Biomarkers and DTI/NODDI Metrics in Adolescent Football Players: A Pilot Study

Keisuke Kawata, Jesse A Steinfeldt, Megan E Huibregtse, Madeleine K Nowak, Jonathan T Macy, Kyle Kercher, Devin J Rettke, Andrea Shin, Zhongxue Chen, Keisuke Ejima, Sharlene D Newman, Hu Cheng, Keisuke Kawata, Jesse A Steinfeldt, Megan E Huibregtse, Madeleine K Nowak, Jonathan T Macy, Kyle Kercher, Devin J Rettke, Andrea Shin, Zhongxue Chen, Keisuke Ejima, Sharlene D Newman, Hu Cheng

Abstract

While neuroimaging and blood biomarker have been two of the most active areas of research in the neurotrauma community, these fields rarely intersect to delineate subconcussive brain injury. The aim of the study was to examine the association between diffusion MRI techniques [diffusion tensor imaging (DTI) and neurite orientation/dispersion density imaging (NODDI)] and brain-injury blood biomarker levels [tau, neurofilament-light (NfL), glial-fibrillary-acidic-protein (GFAP)] in high-school football players at their baseline, aiming to detect cumulative neuronal damage from prior seasons. Twenty-five football players were enrolled in the study. MRI measures and blood samples were obtained during preseason data collection. The whole-brain, tract-based spatial statistics was conducted for six diffusion metrics: fractional anisotropy (FA), mean diffusivity (MD), axial/radial diffusivity (AD, RD), neurite density index (NDI), and orientation dispersion index (ODI). Five players were ineligible for MRIs, and three serum samples were excluded due to hemolysis, resulting in 17 completed set of diffusion metrics and blood biomarker levels for association analysis. Our permutation-based regression model revealed that serum tau levels were significantly associated with MD and NDI in various axonal tracts; specifically, elevated serum tau levels correlated to elevated MD (p = 0.0044) and reduced NDI (p = 0.016) in the corpus callosum and surrounding white matter tracts (e.g., longitudinal fasciculus). Additionally, there was a negative association between NfL and ODI in the focal area of the longitudinal fasciculus. Our data suggest that high school football players may develop axonal microstructural abnormality in the corpus callosum and surrounding white matter tracts, such as longitudinal fasciculus. A future study is warranted to determine the longitudinal multimodal relationship in response to repetitive exposure to sports-related head impacts.

Keywords: blood biomarker; brain injury; concussion; diffusion tensor imaging; football; neurite orientation dispersion and density imaging; subconcussion; youth.

Copyright © 2020 Kawata, Steinfeldt, Huibregtse, Nowak, Macy, Kercher, Rettke, Shin, Chen, Ejima, Newman and Cheng.

Figures

Figure 1
Figure 1
The relationship between imaging and serum tau levels. (A) Example maps of DTI [axial diffusivity (AD), mean diffusivity (MD), radial diffusivity (RD), fractional anisotropy (FA)] and NODDI [neurite density index (NDI), and neurite orientation dispersion index (ODI)] from a single subject in FMRIB58_FA template. Tract-based regression analysis showed that tau was positively associated with mean diffusivity (B) and negatively associated with neurite density index (D) in several white matter tracts (red-yellow, corresponding to p-value 0.05 to 0). The regression analyses were performed on the skeletonized white matter tracts (green) derived from the mean FA maps of the study subjects, to which diffusion metrics of nearby voxels were projected. All results were corrected for multiple comparisons using threshold-free cluster enhancement (TFCE) at p ≤ 0.05. The results are overlaid on the 1-mm resolution MNI (Montreal Neurological Institute) template. Post hoc correlation analysis revealed a positive correlation between tau and mean MD of the voxels that showed a significant effect in the regression analysis (C) and a negative correlation between tau and mean NDI of the voxels that showed a significant effect in the regression analysis (E).
Figure 2
Figure 2
The relationship between imaging and serum GFAP and NfL levels. The same tract-based regression analysis as used in Figure 1 showed that GFAP was positively associated with axial diffusivity in the brain stem (A), and NfL was negatively associated with neurite orientation dispersion index (B) in a small portion of the longitudinal fasciculus. The skeletonized white matter tracts (green) are the same as that in Figure 1. The TFCE p-value was set to p ≤ 0.05. The results are overlaid on the 1-mm resolution MNI template.

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