Neuroinflammation and neurodegeneration as mechanisms for worsened outcomes in elderly traumatic brain injury

Dissertation (Ph.D.)--University of Kansas, Molecular & Integrative Physiology, 2007.It is only recently that clinical and epidemiological data has been reported about the particularly heavy burden of traumatic brain injury (TBI) in the elderly. With the expected growth in the world population over age 65, it is likely that the burden of TBI in the elderly will worsen. While some progress has been made, we are still very far behind in understanding the molecular and cellular mechanisms of damage and repair following TBI. This is especially true in elderly TBI, in which very little pre-clinical research has been conducted. In the present study, a mouse model of sensorimotor controlled cortical impact (CCI) injury was developed, using a computer-controlled electromechanical striker. This model was first characterized with adult (4-6 month old) mice, using behavioral testing, magnetic resonance (MR) imaging and histological assessments. The model was then used for experiments with groups of adult and aged (21-24 month old) mice, in order to compare functional deficits and recovery, transient brain pathology and histology between the groups, and to identify age-related differences in outcomes and their potential mechanisms. It was found that sensorimotor deficits were greater, and recovery poorer, in the aged animals compared to the adult. Acute edema was prolonged, compromise of the blood-brain barrier was greater and prolonged, and neurodegeneration was greater in the aged animals compared to the adult. Not only was significantly increased neurodegeneration found at the site of injury in the aged brains, but subtly increased neurodegeneration was found in the aged hippocampus and thalamus - structures remote from but connected with the injured aged cortex. Overall astrocyte response in the aged hippocampus was blunted, possibly reflecting an increased vulnerability or reduced functional capacity of aged hippocampal astrocytes. Microglial response was subtly increased in aged hippocampus and thalamus, and trends over time suggested that the microglial response in these structures following cortical injury may be prolonged, as compared to the response in the adult brain. These studies demonstrate age-related differences in edema, blood-brain barrier permeability and neuroinflammation in the aged brain. All of these mechanistic elements may represent opportunities for interventions targeted specifically to elderly TBI patients