Detrimental Effects of Aging on Outcome from Traumatic Brain Injury: A Behavioral, Magnetic Resonance Imaging, and Histological Study in Mice

Abstract

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.

The Cerebral Extracellular Release of Glycerol, Glutamate, and FGF2 Is Increased in Older Patients following Severe Traumatic Brain Injury

“…Unfortunately, increasing age is strongly associated with a poor prognosis both in experimental trauma models and following TBI in humans (Livingston et al, 2005;Onyszchuk et al, 2008;Rothweiler et al, 1998;Sendroy-Terrill et al, 2010;Susman et al, 2002). Confirmed factors of poor prognosis for patients with GCS 3 or 4 and older than 65 years are closed basal cisterns and midline shift > 15 mm on the first CT (Brazinova et al, 2010).…”

“…From experimental studies it appears that the aged brain is more vulnerable to secondary processes, like prolonged acute edema, increased opening of the blood-brain barrier, and increased oxidative stress due to a relative shortage of freeradical scavengers, all of which would lead to increased neurodegeneration and a greater loss of function in the aged brain (Onyszchuk et al, 2008;Slemmer et al, 2008). It has been proposed that elevated basal levels of corticosterone present in aged animals may mediate the enhanced vulnerability of aged animals to TBI (White-Gbadebo and Hamm, 1993).…”

Influence of Physical Exercise on Traumatic Brain Injury Deficits: Scaffolding Effect

“…Experimental TBI reliably models the functional deficits, within cognitive, emotional, sensory, and motor domains that are observed in TBI patients (Ekmark-Lewén et al 2010;Sigurdardottir et al 2010) thereby providing analyses at all levels of TBI pathophysiology. The notion of 'age-at-injury' poses an important aspect of both clinical and experimental TBI since the immature brain may be particularly vulnerable to injury during critical periods of development (Serra-Grabulosa et al 2005), whereas considerable evidence indicates that outcomes from TBI are worse in elderly individuals (Marklund et al 2009;Onyszchuk et al 2008). Applying a diffuse TBI model in rat pups to exemplify the level of behavioral outcomes, Cernak et al (2010) showed motor deficits that persisted even after the pups had reached adulthood, as well as reduced cognitive performance 2 weeks after injury.…”

Preclinical Efficacy Testing in Middle-Aged Rats: Nicotinamide, a Novel Neuroprotectant, Demonstrates Diminished Preclinical Efficacy after Controlled Cortical Impact

“…Other studies point to an increased vulnerability to and/or decreased endogenous protection against free radical damage following injury (Barnes, 1998;Sandhu and Kaur, 2002;Shao et al, 2006). Age-related changes in glial cells, such as astrocytes and microglia, have likewise been implicated in worsened functioning following TBI (Badan et al, 2003;Onyszchuk et al, 2008Onyszchuk et al, , 2009.…”