Understanding mechanisms of sub-acute neurodegeneration in moderate to severe traumatic brain injury

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Prevailing scientific and clinical assumptions hold that the cognitive and neurological status of people with moderate to severe TBI remains largely stable once a plateau in recovery has been achieved. Findings from our lab and a handful of others have demonstrated, however, that deleterious changes occur sub-acutely and that TBI may be a progressive, degenerative disorder. We have observed robust atrophy in our lab in the hippocampus (head, body and tail), corpus callosum (genu, body, splenium) and fornix from 5 to 24 post-injury and in a smaller sample, from 5 to 12 months post injury. These findings were revealed in volumetric MRI and diffusion tensor imaging (DTI) studies. At the same time points, we have also shown whole brain atrophy (ventricle to brain ratio) and loss of white matter integrity in a variety of regions. Critically, we have also demonstrated cognitive and functional associations with these neural changes. Based on these findings, the primary global aims of the proposed research are twofold: The first is to more fully characterize sub-acute atrophy, for example, understanding timelines of atrophy, which brain regions are most and least vulnerable, and what subject and environmental factors moderate deterioration. The second objective is to better understand mechanisms of this second wave of damage after brain injury. In particular, our prior findings suggest "transneuronal degeneration" (caused by disuse-induced delayed apoptosis) as a strong candidate mechanism. These aims will be approached through serial, longitudinal MRI analyses (structural, DTI and MR-spectroscopy) of discrete regions of the brains of patients with moderate to severe TBI, neuropsychological assessment, and mixed-effects growth curve modelling to allow individual recovery curves and impact of moderators to be assessed. We hope that the novel research questions examined in the proposed research will better elucidate the acute and chronic natural history of moderate-severe TBI, and the neuropathology that underlies it.