Pharmaceutical Research & Development (Track)


David L. Brody, Rachel E. Bennett and Christine L. Mac Donald

Washington University, School of Medicine, St. Louis MO, USA


Traumatic axonal injury may contribute greatly to neurological impairments following traumatic brain injury, but it is difficult to assess with conventional imaging. We quantitatively compared diffusion tensor imaging (DTI) signal abnormalities with histological and electron microscopic characteristics of pericontusional traumatic axonal injury in a mouse model. Two DTI parameters – relative anisotropy and axial diffusivity– were significantly reduced 6 hours to 4 days after trauma, corresponding to relatively isolated axonal injury. One to 4 weeks after trauma, relative anisotropy remained decreased while axial diffusivity “pseudo-normalized” and radial diffusivity increased. These changes corresponded to demyelination, edema and persistent axonal injury. At every time point, DTI was more sensitive to injury than conventional MRI, and relative anisotropy distinguished injured from control mice with no overlap between groups. Remarkably, DTI changes strongly predicted the approximate time since trauma (Mac Donald et al. JNeurosci 2007). These results provide an important validation of DTI for pericontusional traumatic axonal injury. With reduced injury severity, DTI changes were still detectible, and quantitatively correlated with histological injury severity (see Figure). In a model of repetitive mild repetitive closed-skull brain injury in mouse, DTI changes were apparent 7 days after injury but not 24 hours after injury. Histologically, pathological silver staining and microglial activation appeared 7 days but not 24 hours after injury (Bennett et al. Neuroscience letters 2012). This demonstrates that DTI is sensitive to delayed white matter injury. Overall, these results indicate that DTI could be useful for imaging-based pharmacodynamic strategies. A therapeutic that reduces axonal injury would be expected to reduce DTI abnormalities, and axonal integrity could be assessed serially in vivo.

Importantly, DTI performs very similarly in humans and mice. Our recent studies involving military personnel with blast-related traumatic brain injury have revealed DTI abnormalities directly comparable to those observed in mice (Mac Donald et al. New England Journal of Medicine, 2011). Our ongoing investigations involve direct radiologicalpathological correlations in human brain tissue from post-mortem traumatic brain injury samples. These studies will allow direct interpretation of DTI signals in living patients and accelerate pharmacodynamic studies using this advanced imaging method.