Diffuse axonal injury has a characteristic multidimensional MRI signature in the human brain

Axonal injury is a major contributor to the clinical symptomatology in patients with traumatic brain injury. Conventional neuroradiological tools, such as CT and MRI, are insensitive to diffuse axonal injury (DAI) caused by trauma. Diffusion tensor MRI parameters may change in DAI lesions; however, the nature of these changes is inconsistent. Multidimensional MRI is an emerging approach that combines T-1, T-2, and diffusion, and replaces voxel-averaged values with distributions, which allows selective isolation of specific potential abnormal components. By performing a combined post-mortem multidimensional MRI and histopathology study, we aimed to investigate T-1-T-2-diffusion changes linked to DAI and to define their histopathological correlates. Corpora callosa derived from eight subjects who had sustained traumatic brain injury, and three control brain donors underwent post-mortem ex vivo MRI at 7 T. Multidimensional, diffusion tensor, and quantitative T-1 and T-2 MRI data were acquired and processed. Following MRI acquisition, slices from the same tissue were tested for amyloid precursor protein (APP) immunoreactivity to define DAI severity. A robust image co-registration method was applied to accurately match MRI-derived parameters and histopathology, after which 12 regions of interest per tissue block were selected based on APP density, but blind to MRI. We identified abnormal multidimensional T-1-T-2, diffusion-T-2, and diffusion-T-1 components that are strongly associated with DAI and used them to generate axonal injury images. We found that compared to control white matter, mild and severe DAI lesions contained significantly larger abnormal T-1-T-2 component (P=0.005 and P<0.001, respectively), and significantly larger abnormal diffusion-T-2 component (P=0.005 and P<0.001, respectively). Furthermore, within patients with traumatic brain injury the multidimensional MRI biomarkers differentiated normal-appearing white matter from mild and severe DAI lesions, with significantly larger abnormal T-1-T-2 and diffusion-T-2 components (P=0.003 and P<0.001, respectively, for T-1-T-2; P=0.022 and P<0.001, respectively, for diffusion-T-2). Conversely, none of the conventional quantitative MRI parameters were able to differentiate lesions and normal-appearing white matter. Lastly, we found that the abnormal T-1-T-2, diffusion-T-1, and diffusion-T-2 components and their axonal damage images were strongly correlated with quantitative APP staining (r=0.876, P<0.001; r=0.727, P<0.001; and r=0.743, P<0.001, respectively), while producing negligible intensities in grey matter and in normal-appearing white matter. These results suggest that multidimensional MRI may provide non-invasive biomarkers for detection of DAI, which is the pathological substrate for neurological disorders ranging from concussion to severe traumatic brain injury.

Automated summary

The study focused on investigating the changes in different MRI parameters related to DAI in traumatic brain injury, using a combination of MRI and histopathology. The results suggest that multidimensional MRI can effectively differentiate the severity of axonal injury and may serve as non-invasive biomarkers for DAI detection.