Detrimental effects of aging on outcome from traumatic brain injury: A behavioral, magnetic resonance imaging, and histological study in mice

Considerable evidence indicates that outcomes from traumatic brain injury (TBI) are worse in the elderly, but there has been little preclinical research to explore potential mechanisms. In this study, we examined the age-related effects on outcome in a mouse model of controlled cortical impact (CCI) injury. We compared the responses of adult (5-6 months old) and aged (21-24 months old) male mice following a moderate lateral CCI injury to the sensorimotor cortex. Sensorimotor function was evaluated with the rotarod, gridwalk and spontaneous forelimb behavioral tests. Acute edema was assessed from hyperintensity on T2-weighted magnetic resonance images. Blood-brain barrier opening was measured using anti-mouse immunoglobulin G (IgG) immunohistochemistry. Neurodegeneration was assessed by amino-cupric silver staining, and lesion cavity volumes were measured from histological images. Indicators of injury were generally worse in the aged than the adult mice. Acute edema, measured at 24 and 48 h post-injury, resolved more slowly in the aged mice (p < 0.01). Rotarod recovery (p < 0.05) and gridwalk deficits (p < 0.01) were significantly worse in aged mice. There was greater (P < 0.01 at 3 days) and more prolonged post-acute opening of the blood-brain barrier in the aged mice. Neurodegeneration was greater in the aged mice (p < 0.01 at 3 days). In contrast, lesion cavity volumes, measured at 3 days post-injury, were not different between injured groups. These results suggest that following moderate controlled cortical impact injury, the aged brain is more vulnerable than the adult brain to neurodegeneration, resulting in greater loss of function. Tissue loss at the impact site does not explain the increased functional deficits seen in the aged animals. Prolonged acute edema, increased opening of the blood-brain barrier and increased neurodegeneration found in the aged animals implicate secondary processes in age-related differences in outcome.