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.

[1]  A. Helmy,et al.  Microdialysis in the human brain and its potential role in the development and clinical assessment of drugs. , 2007, Current medicinal chemistry.

[2]  J. Cinatl,et al.  Neutrophils and the blood–brain barrier dysfunction after trauma , 2007, Medicinal research reviews.

[3]  Mehmet Bilgen,et al.  A mouse model of sensorimotor controlled cortical impact: Characterization using longitudinal magnetic resonance imaging, behavioral assessments and histology , 2007, Journal of Neuroscience Methods.

[4]  J. Langlois,et al.  Incidence of Traumatic Brain Injury in the United States, 2003 , 2006, The Journal of head trauma rehabilitation.

[5]  H. Thompson,et al.  Traumatic Brain Injury in Older Adults: Epidemiology, Outcomes, and Future Implications , 2006, Journal of the American Geriatrics Society.

[6]  R. Raghupathi,et al.  Differential behavioral and histopathological responses to graded cortical impact injury in mice. , 2006, Journal of neurotrauma.

[7]  P. Kochanek,et al.  Transgenic mice that overexpress the anti-apoptotic Bcl-2 protein have improved histological outcome but unchanged behavioral outcome after traumatic brain injury , 2006, Brain Research.

[8]  A. Kiss,et al.  Outcome after traumatic brain injury sustained in older adulthood: a one-year longitudinal study. , 2006, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[9]  M. Mattson,et al.  Ageing and neuronal vulnerability , 2006, Nature Reviews Neuroscience.

[10]  H. Levin,et al.  Impairment and recovery in inhibitory control after traumatic brain injury in children: effect of age at injury, injury severity and lesion location. , 2006, Brain and cognition.

[11]  N. Grigoriadis,et al.  Impairment of the ability of the injured aged brain in elevating urate and ascorbate , 2006, Experimental Gerontology.

[12]  J. O'Callaghan,et al.  Regional neuropathology following kainic acid intoxication in adult and aged C57BL/6J mice , 2006, Brain Research.

[13]  G. Manley,et al.  Recovery at one year following isolated traumatic brain injury: a Western Trauma Association prospective multicenter trial. , 2005, The Journal of trauma.

[14]  Mehmet Bilgen,et al.  A New Device for Experimental Modeling of Central Nervous System Injuries , 2005, Neurorehabilitation and neural repair.

[15]  Allen W. Brown,et al.  Outcome after traumatic brain injury: effects of aging on recovery. , 2005, Archives of physical medicine and rehabilitation.

[16]  K. Thomas,et al.  The CDC Traumatic Brain Injury Surveillance System: Characteristics of Persons Aged 65 Years and Older Hospitalized With a TBI , 2005, The Journal of head trauma rehabilitation.

[17]  E. Hall,et al.  Spatial and temporal characteristics of neurodegeneration after controlled cortical impact in mice: more than a focal brain injury. , 2005, Journal of neurotrauma.

[18]  K. Kiening,et al.  Edema and brain trauma , 2004, Neuroscience.

[19]  Ponnada A Narayana,et al.  Endogenous recovery of injured spinal cord: Longitudinal in vivo magnetic resonance imaging , 2004, Journal of neuroscience research.

[20]  G. Clifton,et al.  Post-trauma administration of caffeine plus ethanol reduces contusion volume and improves working memory in rats. , 2004, Journal of neurotrauma.

[21]  R. Keep,et al.  Intracerebral Hemorrhage: Effects of Aging on Brain Edema and Neurological Deficits , 2004, Stroke.

[22]  V. Puri,et al.  Differential expression of cytokines and chemokines during secondary neuron death following brain injury in old and young mice , 2004, Neuroscience Letters.

[23]  C. Woolf,et al.  Adult neuron survival strategies — slamming on the brakes , 2004, Nature Reviews Neuroscience.

[24]  T. Mcintosh,et al.  Motor and cognitive function evaluation following experimental traumatic brain injury , 2004, Neuroscience & Biobehavioral Reviews.

[25]  L. McCullough,et al.  Chronic behavioral testing after focal ischemia in the mouse: functional recovery and the effects of gender , 2004, Experimental Neurology.

[26]  G. Manley,et al.  The effect of age on functional outcome in mild traumatic brain injury: 6-month report of a prospective multicenter trial. , 2004, The Journal of trauma.

[27]  D. Prough,et al.  Laser capture microdissection and analysis of amplified antisense RNA from distinct cell populations of the young and aged rat brain: effect of traumatic brain injury on hippocampal gene expression. , 2004, Brain research. Molecular brain research.

[28]  B. Citron,et al.  Thrombin: a potential proinflammatory mediator in neurotrauma and neurodegenerative disorders. , 2004, Current drug targets. Inflammation and allergy.

[29]  J. Trojanowski,et al.  Age-dependent synuclein pathology following traumatic brain injury in mice , 2003, Experimental Neurology.

[30]  E. J. Green,et al.  Two effective behavioral tasks for evaluating sensorimotor dysfunction following traumatic brain injury in mice , 2003, Journal of Neuroscience Methods.

[31]  S. Dirusso,et al.  Traumatic brain injury in the elderly: increased mortality and worse functional outcome at discharge despite lower injury severity. , 2002, The Journal of trauma.

[32]  N. Berman,et al.  Ablation of the chemokine monocyte chemoattractant protein-1 delays retrograde neuronal degeneration, attenuates microglial activation, and alters expression of cell death molecules. , 2002, Brain research. Molecular brain research.

[33]  Z. Berente,et al.  In vivo water quantification in mouse brain at 9.4 Tesla in a vasogenic edema model , 2001, Magnetic resonance in medicine.

[34]  A. Faden.  Neuroprotection and traumatic brain injury: the search continues. , 2001, Archives of neurology.

[35]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[36]  L. Felzien,et al.  Increased chemokine gene expression during aging in the murine brain , 2001, Brain Research.

[37]  C. Franceschi,et al.  Inflamm‐aging: An Evolutionary Perspective on Immunosenescence , 2000 .

[38]  T. Schallert,et al.  CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury , 2000, Neuropharmacology.

[39]  R. Switzer.  Application of Silver Degeneration Stains for Neurotoxicity Testing , 2000, Toxicologic pathology.

[40]  C. Robertson,et al.  Validation of a controlled cortical impact model of head injury in mice. , 1999, Journal of neurotrauma.

[41]  M. Bullock,et al.  Current status of neuroprotection trials for traumatic brain injury: lessons from animal models and clinical studies. , 1999, Neurosurgery.

[42]  R. Raghupathi,et al.  BCL-2 Overexpression Attenuates Cortical Cell Loss after Traumatic Brain Injury in Transgenic Mice , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[43]  A. Faden,et al.  Sustained sensory/motor and cognitive deficits with neuronal apoptosis following controlled cortical impact brain injury in the mouse. , 1998, Journal of neurotrauma.

[44]  J. Morrison,et al.  Life and death of neurons in the aging brain. , 1997, Science.

[45]  B. Zink,et al.  Traumatic brain injury. , 1996, Seminars in respiratory and critical care medicine.

[46]  P. Kochanek,et al.  Severe controlled cortical impact in rats: assessment of cerebral edema, blood flow, and contusion volume. , 1995, Journal of neurotrauma.

[47]  M. Beal,et al.  Aging, energy, and oxidative stress in neurodegenerative diseases , 1995, Annals of neurology.

[48]  D F Meaney,et al.  A model of parasagittal controlled cortical impact in the mouse: cognitive and histopathologic effects. , 1995, Journal of neurotrauma.

[49]  C. Simons,et al.  Survival after severe brain injury in the aged. , 1993, Archives of surgery.

[50]  R. Hayes,et al.  The effect of age on motor and cognitive deficits after traumatic brain injury in rats. , 1992, Neurosurgery.

[51]  R. Hayes,et al.  The effect of age on outcome following traumatic brain injury in rats. , 1991, Journal of neurosurgery.

[52]  Ronald L. Hayes,et al.  A controlled cortical impact model of traumatic brain injury in the rat , 1991, Journal of Neuroscience Methods.

[53]  S. Galbraith,et al.  Head injuries in the elderly. , 1987, British medical journal.

[54]  L. Pitts,et al.  NMR imaging and spectroscopy of experimental brain edema. , 1985, The Journal of trauma.

[55]  N M Hylton,et al.  NMR in experimental cerebral edema: value of T1 and T2 calculations. , 1984, AJNR. American journal of neuroradiology.

[56]  D. Cifu,et al.  A follow-up study of older adults with traumatic brain injury: taking into account decreasing length of stay. , 2006, Archives of physical medicine and rehabilitation.

[57]  R. Keep,et al.  Aging enhances intracerebral hemorrhage-induced brain injury in rats. , 2005, Acta neurochirurgica. Supplement.

[58]  G. Schneider,et al.  Development of traumatic brain edema in old versus young rats. , 1994, Acta neurochirurgica. Supplementum.

[59]  B. Pike,et al.  The rotarod test: an evaluation of its effectiveness in assessing motor deficits following traumatic brain injury. , 1994, Journal of neurotrauma.

[60]  R. Hayes,et al.  Cognitive deficits following traumatic brain injury produced by controlled cortical impact. , 1992, Journal of neurotrauma.